A Selected Chronological Bibliography of Biology and Medicine

 

Part 7A

 

1980 — 1991

 

 

Compiled by James Southworth Steen, Ph.D.

Delta State University

 

Dedicated to my loving family

 

This document celebrates those secondary authors and laboratory technicians without whom most of this great labor of discovery would have proved impossible.

 

Please forward any editorial comments to: James S. Steen, Ph.D., Professor Emeritus, jsteen08@bellsouth.net

 

1980

“Nothing in biology is understandable except in the light of genetics.” Francisco José Ayala (63).

 

"I feel that much of the work is done because one wants to impose an answer on it. They have the answer ready, and they [know what they] want the material to tell them... [Anything else it tells them] they don't really recognize as there, or they think it's a mistake and throw it out... If you'd only just let the material tell you." Barbara McClintock (881).

 

“One of the more gratifying aspects of scientific work is the knowledge that one’s own contributions have helped and influenced other scientists and thus furthered the overall progress of science.” Pedro M. Cuatrecasas (360).

 

“I am, somehow, less interested in the weight and convolutions of Einstein’s brain than in the near certainty that people of equal talent have lived and died in cotton fields and sweatshops.” Stephen Jay Gould (626).

 

Paul Berg (US) for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA and Walter Gilbert (US) and Frederick Sanger (GB) for their contributions concerning the determination of base sequences in nucleic acids shared the Nobel Prize in Chemistry.

 

Baruj Benacerraf (VE-US), Jean Baptiste Gabriel Joachim Dausset (FR) and George Davies Snell (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions.

 

Joseph P. Pinto (US), G. Randall Gladstone (US), Yuk Ling Yung (US), Akiva Bar-Nun (IL), Sherwood Chang (US), and James F. Kasting (US) showed that photochemistry in an atmosphere containing carbon dioxide or a mixture of carbon monoxide and carbon dioxide yielded formaldehyde as a major product (83; 872; 1333).

 

Jan G.J. Bauman (NL), Joop Wiegant (NL), Piet Borst (NL), and Piet van Duijn (NL) first described the direct labeling of a nucleic acid with fluorophores using fluorescence in situ hybridization (FISH) (99; 100).

Pennina R. Langer (US), Alex A. Waldrop (US), and David C. Ward (US) developed the 'indirect' method (implemented in commonly used FISH kits) that employs immunogenic or enzymatic detection of tagged nucleic-acid probes following hybridization (971).

 

Keith Burridge (GB-US) and James R. Feramisco (US) discovered the cell adhesion protein vinculin (236).

 

Thomas N. Salzmann (US), Ronald W. Ratcliffe (US), F. Aileen Bouffard (US), and Burton G. Christensen (US) carried out the total synthesis of the antibiotic thienamycin (1448; 1449).

 

Edith Kolb (GB), Peter J. Hudson (GB), and J. Leuan Harris (GB) determined the complete amino acid sequence of phosphofructokinase from Bacillus stearothermophilus (919).

 

J. Clark Lagarias (US) and Henry Rapoport (US) determined the structure of phytochrome chromophore attached to an undecapeptide, deduced from NMR spectra (962).

 

Murray R. Badger (US), Aaron Kaplan (US), and Joe A Berry (US) developed a technique for determination of the intracellular inorganic carbon concentration. They measured it in the unicellular green alga Chlamydomonas reinhardtii and in the cyanobacterium Anabaena variabilis, and found that illuminated cells concentrate CO2 by active uptake of inorganic carbon. Elevation of the CO2 concentration at the carboxylation site raises the rate of carboxylation and decreases that of oxygenation. Consequently, algal photosynthesis is not limited by availability of inorganic carbon (70).

 

Judith Pollock Klinman (US), Hope Humphries (US), Judith G. Voet (US), and Mary J. Bossard (US) used isotope effects to isolate the chemical steps involved in the dopamine beta-monooxygenase-catalyzed conversion of dopamine and oxygen to norepinephrine and water (183; 914).

 

Ada Yonath (IL), Jutta Mussig (DE), Bernd Tesche (DE), Siegfried Lorenz (DE), Volker A. Erdmann (DE), and Heinz Guenter Wittmann (DE) crystallized the large ribosomal subunits from Bacillus stearothermophilus (1847). Note: They were the first to crystallize a ribosomal type.

 

Richard M. Wing (US), Horace R. Drew (US), Tsunehiro Takano (JP), Chris Broka (US), and Shoji Tanaka (US) gave hard evidence that the base sequence in DNA can have a pronounced effect on its structure (1803).

 

Louise Clarke (US), John Anthony Carbon (US), and Chu-Lai Hsiao (US), using Saccharomyces cerevisiae, were the first to isolate DNA specific to the centromere region of chromosomes (306-308).

Johannes Lechner (DE) and John Anthony Carbon (US) identified a 240-kDa multi-subunit complex, CBF3, which is a major component of the budding yeast centromere (983).

 

Graeme I. Bell (US), Raymond L. Pictet (US), William J. Rutter (US), Barbara Cordell (US), Edmund Tischer (US), Howard Michael Goodman (US), David Owerbach (US), and Thomas B. Shows (US) determined the nucleotide sequence of the human insulin gene and located it on chromosome 11 (108; 1272).

 

Shigekazu Nagata (JP), Hideharu Taira (JP), Alan Hall (GB), Lorraine Johnsrud (CH), Michel Streuli (US), Josef Ecsödi (CH), Werner Boll (CH), Kari Cantell (FI), and Charles Weissman (US) cloned double stranded cDNA for interferon (IF)-producing human leukocytes into Escherichia coli using the pBR322 vector. This clone produced a polypeptide with strong biological activity (1198).

 

John S. Emtage (GB), William C.A. Tacon (GB), Graham H. Catlin (GB), Brian Jenkins (GB), Alan G. Porter (GB), and Norman H. Carey (GB) demonstrated the feasibility of producing controlled amounts of influenza antigenic determinants by genetic engineering (471).

 

Fred Sherman (US), John W. Stewart (US), and Ann Marie Schweingruber (US), working with Saccharomyces cerevisiae, established that there is no absolute requirement for a particular sequence 5′ to the initiation codon, consistent with their previous suggestion that translation starts at the AUG codon closest to the 5′ end of the mRNA (1534).

 

William J. Adams, Jr. (US) and George F. Kalf (US) determined that DNA polymerase of mitochondria can act in the forward direction as a 5' to 3' polymerase and has a 3' to 5' exonuclease proofreading capacity (10).

 

Takashi Matsui (JP), Jacqueline Segall (CA), P. Anthony Weil (US), and Robert Gayle Roeder (US) developed cell-free systems, which they used in the identification of complex sets of proteins called accessory factors that are essential for each individual RNA polymerase (e.g., TFIIA, TFIIB, TFIIE, TFIIF and TFIIH for Pol II, and TFIIIB and TFIIIC for Pol III) to "read" specific target genes (1097; 1508).

 

Leslie E. Orgel (GB) and Francis Harry Compton Crick (GB) coined the phrase “selfish DNA” when referring to DNA sequences which encode a tendency to accumulate within the genome (1261). Note: This is not to be confused with “selfish genes” which is a directional increase in the proportion of individuals bearing the gene at a particular locus. “Selfish DNA” is characterized by an increase in the mean copy number of the element within the genome.

 

Leonard Guarente (US), Thomas M. Roberts (US), and Mark Steven Ptashne (US) described methods allowing for the efficient expression in Escherichia coli of cloned eukaryotic genes (664).

 

Martin G. Low (US) and Donald B. Zilversmit (US) demonstrated that alkaline phosphatase is attached to membranes of Staphylococcus aureus by a strong interaction with phosphatidylinositol (1048). Note: This discovery of anchor molecules had an impact on several areas of cell biology.

 

Ananda M. Chakrabarty (US) filed for a U.S. patent on strains of the bacteria —Pseudomona aeruginosa and Pseudomonas putidas —which had been genetically engineered to degrade crude oil. The patent was awarded to General Electric in 1980 by the U.S. Supreme Court and issued in 1981 (269).

 

David L. Rimm (US), Debra Horness (US), Jacky Kucera (US), and Frederick R. Blattner (US) reported the construction of three new lambda-phage-cloning vectors, Charons (Ch) 27, 28, and 30. Ch27 and Ch30 are suitable for cloning small and large DNA fragments, respectively, cut with BamHI, BglII, BclI, MboI, Sau3A, EcoRI, HindIII, SalI, and XhoI (1402).

 

Dagmar E. Büchel (CH), Bruno Gronenborn (FR), and Benno Müller-Hill (DE) determined the nucleotide sequence of the lacY gene coding for lactose permease (M protein) in Escherichia coli and predicted that the enzyme would consist of 417 residues with a molecular weight of 46,504 (228).

 

Leland Harrison Hartwell (US) defined seven genes that function in two cell types of Saccharomyces cerevisiae (MATa and alpha) to control the differentiation of cell type and one gene, STE2, that functions exclusively in MATa cells to mediate responsiveness to polypeptide hormone (717).

 

Arlene R. Wyman (US) and Ray White (US) discovered a locus in the human genome, not associated with any specific gene, which is a site of restriction fragment length polymorphism (RFLP). The polymorphism was found by hybridizing a 16-kilobase-pair segment of single-copy human DNA, selected from the human genome library cloned in phage lambda CH4A, to a Southern transfer of total human DNA digested with EcoRI. DNAs from a number of individuals from within Mormon pedigrees, as well as random individuals have been examined. The locus is highly variable, with at least eight alleles present, homozygotes accounting for less than 25% of the individuals examined. The polymorphism appears to be the result of DNA rearrangements rather than base-pair substitutions or modifications. Examination of the DNA from seven members of a family revealed fragment lengths that are consistent with their inheritance as Mendelian alleles through three generations (1824).

Alec John Jeffreys (GB), Polly Weller (GB), Victoria Wilson (GB), Alain Blanchetot (US), and Swee Lay Thein (GB) found two core DNA sequences common to the repeated sequences described by Arlene R. Wyman (US) and Ray White (US) in 1980. They developed complements to these core sequences to probe for the core sequences in partially digested and electrophoresed human DNA. The banding patterns, which appear upon electrophoresis and probing, are inherited in a Mendelian fashion. One half of the bands in a child’s DNA fingerprint are inherited from the mother and one half from the father (833; 1781). Note: The highly repetitious DNAs with the same core sequence are referred to as minisatellites.

Alec John Jeffreys (GB), Victoria Wilson (GB), Swee Lay Thein (GB), John F.Y. Brookfield (GB), Robert Semeonoff (GB), Peter Gill (GB), David J. Werrett (GB) Päivi Helminen (FI), Christian Ehnholm (FI), Marja-Liisa Lokki (FI), and Leena Peltonen (FI) described methodology for doing DNA fingerprinting. It was Jeffreys who coined the term DNA fingerprinting and the first to use DNA polymorphisms in paternity, immigration, and murder cases (594; 737; 831; 832). See, Colin Pitchfork, 1988. Note: DNA fingerprinting is now called DNA profiling.

Renate Schäfer (DE), Hans Zischler (DE), Uli Birsner (DE), Andrea Becker (DE), and Jörg Thomas Epplen (DE) described the classical DNA fingerprinting method using radio-labeled DNA probes containing minisatellite or oligonucleotide sequences which are hybridized to DNA that has been digested with a restriction enzyme, separated by agarose electrophoresis, and immobilized on a membrane by Southern blotting or - in the case of the oligonucleotide probes - immobilized directly in the dried gel. The radio-labeled probe hybridizes to a set of minisatellites or oligonucleotide stretches in genomic DNA contained in restriction fragments whose size differ because of variation in the numbers of repeat units. After washing away excess probe the exposure to X-ray film (autoradiography) allows these variable fragments to be visualized, and their profiles compared between individuals (1473).

Zilla Wong (GB), Victoria Wilson (GB), Ilaben Patel (GB), Sue Povey (GB), and Alec John Jeffreys (GB) devised single-locus profiling to overcome some of the limitations in the classic method. Here a single hypervariable locus is detected by a specific single-locus probe (SLP) using high stringency hybridization. Typically, four SLPs were used in a reprobing approach, yielding eight alleles of four independent loci per individual (1814). Note: This method requires only 10 ng of genomic DNA and has been validated through extensive experiments and forensic casework, and for many years provided a robust and valuable system for individual identification.

Alan L. Edwards (US), Andrew B. Civitello (US), Andrew B. Hammond (US), and C. Thomas Caskey (US) developed DNA profiling methods based on the polymerase chain reaction (PCR) exhibiting improved sensitivity, speed, and genotyping precision (464). These quickly supplanted the classic methodology. Note: Microsatellites —in the forensic community usually referred to short tandem repeats (STRs) —were found to be ideally suited for forensic applications. STR typing is more sensitive than single-locus RFLP methods, less prone to allelic dropout than VNTR (variable number of tandem repeat) systems, and more discriminating than other PCR-based typing methods, such as HLA-DQA1.

Michael D. Coble (US) and John M. Butler (US) developed validated standard protocols using miniSTRs that are used in laboratories worldwide (240; 319).

Marion Nagy (DE), Petra Otremba (DE), Carmen Krüger (DE), Sybille Bergner-Greiner (DE), Petra Anders (DE), Bärbel Henske (DE), Mechthild Prinz (DE), and Lutz Roewer (DE) produced positive results by incorporating miniSTR markers into commercial kits thus improving the application of these markers for all kinds of DNA evidence. Reproducible results could be obtained from as little as three nucleated cells and extracted even from severely compromised material (1199). Note: The probability that two individuals will have identical markers at each of 13 different STR loci (a number commonly used) within their DNA is less than one in a billion.

Kaye N. Ballantyne (AU), Victoria Keerl (DE), Andreas Wollstein (NL), Ying Choi (NL), Sofia B. Zuniga (NL), Arwin Ralf (NL), Mark Vermeulen (NL), Peter de Knijff (NL), and Manfred Kayser (NL) provided a new future for forensic Y-chromosome analysis: rapidly mutating Y-STRs for differentiating male relatives and paternal lineages. Currently forensic Y chromosome typing has gained wide acceptance with the introduction of highly sensitive panels of up to 27 STRs including rapidly mutating markers (77).

 

Mauri E. Krouse (US), Menasche N. Nass (US), Jeanne M. Nerbonne (US), Joel Nargeot (FR), Henry A. Lester (US), Nigel J.M. Birdsall (GB), Jane Stockton (US), Norbert H. Wassermann (US), and Bernard F. Erlanger (US) compared the activation of cell membrane ion channels via nicotinic and muscarinic acetylcholine receptors (AChRs). They found the muscarinic response to be about a thousand times slower than the nicotinic response (941; 1205).

 

James L. Kinsella (US) and Peter S. Aronson (US) concluded that isolated renal microvillus membranes contain a tightly coupled Na+-H+ exchanger that may play an important role in proximal tubular acidification (899).

 

John Edward Heuser (US) and Mark W. Kirschener (US) used rapid freeze drying of cellular cytoskeletons, along with coating the dried sample in platinum to make a high-contrast replica, the result was a highly detailed, three-dimensional electron micrographic (EM) view of the cytoskeletal filaments. This study also showed that the major components of the cytoskeleton — microtubules, actin filaments, and intermediate filaments — could each be identified based solely on their ultrastructural appearance (746).

The method proved useful in “seeing” all manner of cellular phenomena, including, notably, clathrin-coated pit formation (745), the budding of COPI-coated vesicles from golgi (1775), and the dynein arm power stroke (611).

Tatyana M. Svitkina (US), Alexander B. Verkhovsky (CH), and Gary G. Borisy (US) improved the quick-freeze, deep-etch EM technique by adding immunogold labeling. The study identified plectin as a cross-linking molecule between intermediate filaments and both microtubules and actin filaments in the cytoskeleton (1630).

 

W. Ford Doolittle (CA) and Carmen Spienza (CA) conjecture that natural selection operating within genomes will inevitably result in the appearance of DNAs with no phenotypic expression; whose only function is survival within genomes. Prokaryotic transposable elements and eukaryotic middle-repetitive sequences can be seen as such DNAs and thus no phenotypic or evolutionary function need be assigned to them (423). As Matt Ridley puts it, “Genes do behave as if they have selfish goals, not consciously, but retrospectively: genes that behave in this way thrive and genes that don’t don’t (1399).

 

Kristin Eiklid (NO), Sjur Olsnes (NO), and Alexander Pihl (NO) reported on the mechanism by which the plant toxins abrin from the Indian Licorice seed, ricin from the Castor Bean, and modeccin from Wild Granadilla (Adenia digitate) enter cells. Cells possess different populations of binding sites with differences in ability to facilitate the uptake of the toxins. Abrin may bind to cells specifically bearing the mannose receptor on their cell surface, since this receptor is found in a particularly high density on cells of the reticulohistiocytic system, the system that is affected in particular by the toxicity of abrin. Ricin is known to bind to the mannose receptor on specific cells i.e., macrophages or non-parenchymal liver cells. Modeccin binds to surface receptors containing terminal galactose residues (466; 1255). Note: Upon entering the cell, all three of these toxins inhibit protein synthesis by inactivating the 60S ribosomal subunits.

 

Rockford K. Draper (US), Melvin I. Simon (US), Kristen Sandvig (NO), and Sjur Olsnes (NO) discovered how the toxic portion of the diphtheria toxin enters the cell cytoplasm by translocation across the cell membrane (435; 1457).

 

Yuk-Ching Tse (US), Karla Kirkegaard (US), and James Chuo Wang (CN-US) found that the covalent bond formed between topoisomerase I and DNA in E. coli and Micrococcus luteus is most likely a phosphotyrosine linkage. They also determined the topoisomerase cleavage sites in a number of single-stranded DNA restriction fragments. They found that there was no nucleotide specificity on either the 3-prime or the 5-prime side of the site of cleavage. The protein-DNA linkage formed upon cleavage of double-stranded DNA by M. luteus DNA gyrase is accompanied by the covalent linking of subunit A, but not subunit B of gyrase, to the 5-prime side of the DNA via a phosphotyrosine bond (1695).

 

Günter Klaus-Joachim Blobel (DE-US) expanded the signal hypothesis to say that topogenic sequences within discrete segments of targeted proteins are decoded by specific receptors, either during (cotranslational) or shortly after (post-translational) their biosynthesis. The specificity of such signal sequence-receptor interactions targets the proteins to the correct intracellular membranes where they are fed into translocons that move them across the hydrophobic core of the lipid bilayer. Similarly, it has been proposed that another class of topogenic sequences — termed stop-transfer sequences — interacts with the translocon to arrest further transport and thereby achieve an asymmetric transmembrane orientation of integral membrane proteins (168).

 

Vincent F. Castellucci (US), Eric Richard Kandel (US), James H. Schwartz (US), Floyd D. Wilson (US), Angus C. Nairn (US), Paul Greengard (US), Leonard K. Kaczmarek (US), Keith R. Jennings (US), Felix Strumwasser (US), and Ulrich Walter (DE) formulated the hypothesis that a neurotransmitter in the nervous system functions in an analogous manner to that of a hormone by activating adenylyl cyclase to elevate cAMP levels. The cyclic nucleotide then activates protein kinse activity, which catalyzes the phosphorylation of a substrate protein. The phosphorylated substrate, by means of one or more additional reactions, elicits the physiological response characteristic of the neurotransmitter in question. Collaborative studies subsequently performed by Greengard’s team provided evidence for a causal relationship between protein phosphorylation and the physiological response in neurons and neurosecretory cells. The impact of this work was profound, since it provided insight into the biological processes that regulate synaptic transmission and therefore presented a more detailed understanding of neuronal function (260; 853).

Pietro De Camilli (IT-US), Richard Cameron (US), Paul Greengard (US), Susan M. Harris (US), and Wieland B. Huttner (US) demonstrated that the magnitude of neurotransmitter release was governed by the phosphorylation state of certain proteins localized to the presynaptic nerve endings. Included among these proteins were the synapsins, so named because they were detected in synaptic vesicles localized to nerve endings (391; 392). Note: Eric Richard Kandel (US), Paul Greengard (US), and colleagues showed conclusively that the magnitude of neurotransmitter release in response to a nerve impulse was regulated by phosphorylation/dephosphorylation reactions. As a consequence, a basic foundation was laid for elucidating the biological processes associated with synaptic transmission.

 

Peter J. Novick (US), Charles Field (US), and Randy Wayne Schekmann (US) found that electron microscopy of Saccharomyces cerevisiae secretory mutant cells reveals, with one exception, the temperature-dependent accumulation of membrane-enclosed secretory organelles. They suggested that these structures represent intermediates in a pathway in which secretion and plasma membrane assembly are colinear (1233).

Antii Salminen (FI) and Peter J. Novick (US) found that their analysis of SEC 4 in Saccharomyces cerevisiae predicts a protein product of 23.5 kd molecular weight that shares 32% homology with ras proteins and is essential for growth. They proposed that the SEC 4 product is a GTP-binding protein that plays an essential role in controlling a late stage of the secretory pathway (1447).

Hugh R.B. Pelham (GB), Kevin G. Hardwick (GB), and Michael J. Lewis (GB) reported that luminal endoplasmic reticulum (ER) proteins carry a signal at their C terminus that prevents their secretion; in S. cerevisiae this signal is the tetrapeptide HDEL. Indirect evidence suggests that HDEL is recognized by a receptor that retrieves ER proteins from the secretory pathway and returns them to the ER (1318; 1319).

Michael J. Lewis (GB), Deborah J. Sweet (GB), and Hugh R.B. Pelham (GB) showed that presumptive endoplasmic reticulum (ER) proteins from the budding yeast Kluyveromyces lactis can terminate either with HDEL or, in the case of BiP, with DDEL. They concluded that ERD2 encodes the receptor that sorts luminal ER proteins (1013).

Peter V. Schu (US), Kaoru Takegawa (JP), Michael J. Fry (US), Jeffrey H. Stack (US), Michael D. Waterfield (US), and Scott D. Emr (US) discovered that VPS34 of Saccharomyces cerevisiae encodes a 110-kD protein with two regions of 33% sequence identity to a comparable carboxy-terminal domain of the bovine PI-3 kinase. Functional and genetic analyses demonstrated the catalytic identity of the yeast protein and the role of this enzyme reaction in the sorting of vacuolar proteins in vivo (1500).

 

Elliott M. Ross (US) and Alfred Goodman Gilman (US) described the hormone-regulated adenylate cyclase system, which represents the origin of our understanding of the role of G proteins within the cell (1418).

 

Emile Van Schaftingen (BE), Louis Hue (BE), and Henri-Géry Hers (BE) reported the discovery of fructose 2,6-bisphosphate, a novel and potent allosteric stimulator of liver 6-phosphofructo-1-kinase. Their demonstration that the concentration of fructose 2,6-bisphosphate was greatly increased in hepatocytes incubated in the presence of glucose, and its disappearance on incubation with glucagon, provided an elegant switching mechanism between the two opposing pathways of glycolysis and gluconeogenesis (1725-1727).

Emile Van Schaftingen (BE), Louis Hue (BE), Mark H. Rider (GB), Simon J. Pilkis (US), Thomas H. Claus (US), Irwin J. Kurland (US), and Alex J. Lange (US) found that fructose 2,6-bisphosphate not only stimulates 6-phosphofructokinase-1 but also inhibits fructose 1,6-bisphosphatase-1. Fructose 2,6-bisphosphate was thus a key regulatory signaling molecule of glycolytic/gluconeogenic flux that provided a switching mechanism between the two opposing pathways of hepatic carbohydrate metabolism (795; 1331; 1724).

Louis Hue (BE) and Guy G. Rousseau (BE) were the first to show that fructose 2,6-bisphosphate concentrations were elevated in several transformed cell lines and that growth factors and oncogenes increased fructose 2,6-bisphosphate synthesis by induction of a 6-phosphofructokinase-2/fructose 1,6-bisphosphatase-2 isoenzyme that displayed no detectable bisphosphatase activity (796). Note: Diphosphate and bisphosphate are synonymous.

 

Linda D. Rhein (US) and Robert H. Cagan (US) found that fish possess olfactory cilia with binding sites for amino acids that the fish smell, providing evidence for the existence of receptors for odorants (1384).

Linda B. Buck (US), Richard Axel (US), Nina S. Levy (US), Heather A. Bakalyar (US), Randall R. Reed (US), Marc Parmentier (BE), Frédéric Libert (BE), Stéphane Schurmans (BE), Serge Schiffman (BE), Anne Lefort (BE), Dominique Eggerickx (BE), Catherine Ledent (BE), Catherine Mollereau (BE), Catherine Gérard (BE), Jason Perret (BE), Anton Grootegoed (BE), Gilbert Vassart (BE), Nissim Ben-Arie (IL), Doron Lancet (IL), Clare Taylor (GB), Miriam Khen (IL), Naoml Walker (IL), David H. Ledbetter (US), Romeo Carrozzo (US), Katen Patel (GB), Denise Sheer (GB), Hans Lehrach (GB), and Michael A. North (GB) determined that the initial step in olfactory discrimination requires the interaction of odorous ligands with a family of seven-transmembrane-domain receptors on olfactory sensory neurons. The repertoire of mammalian olfactory receptors is extremely large and consists of about 1000 different genes (110; 229; 1011; 1291).

Andrew Chess (US), Michael M. Dowling (US), Linda B. Buck (US), Richard Axel (US), John Ngai (US), Kerry J. Ressler (US), and Susan L. Sullivan (US) obtained in situ hybridization results suggesting that each olfactory neuron expresses only one or a small number of receptor genes, such that individual olfactory neurons are functionally distinct (286; 1213; 1381).

 

Anthony D. Mills (GB), Ronald A. Laskey (GB), Phillippa Black (GB), and Edward M. DeRobertis (US) presented evidence of selective entry of nucleoplasmin (a protein) through the nuclear envelope (1154).

 

Lois Jean Smith (US) showed that the mouse blastocyst, rather than being a symmetrical sphere, is slightly distorted and has recognizable axes. What's more, these axes appeared to match up with those of the fetus, suggesting that the former sets up the latter (1570; 1571).

Richard Lavenham Gardner (GB), M.R. Meredith (GB), and D.G. Altman (GB) verified Smith's conclusions (576).

 

Wolf Szmuness (PL-US), Cladd E. Stevens (US), Edward J. Harley (US), Edith A. Zang (US), William R. Oleszko (US), Daniel C. William (US), Richard Sadovsky (US), John M. Morrison (US), and Aaron Kellner (US), between 1973 and 1980, designed and executed what has been described as the finest clinical field trial in the history of medicine, one that tested a vaccine for hepatitis B. The controlled, randomized, double‐blind trial in 1,083 homosexual men from New York confirmed that a highly purified, formalin‐inactivated vaccine against hepatitis B prepared from HBsAg positive plasma, is safe immunogenic, and highly efficacious (1635).

 

Herbert Leroy Needleman (US) provided the first clear evidence that lead, even at very low levels, could adversely affect a child's IQ (1208). See, quote from Benjamin Franklin, 1786.

 

Tetsuro Fujiwara (JP), Shoichi Chida (JP), Yoshitane Watabe (JP), Haruo Maeta (JP), Tomoaki Morita (JP), and Tadaaki Abe (JP) reported that among 10 infants treated for respiratory distress syndrome with artificial surfactant in this landmark trial, significant improvements in blood pressure, acid-base status, arterial oxygenation, and radiologic findings were observed. Infants also required significantly less oxygen therapy and ventilator pressure following surfactant administration (557).

 

Dietrich W. Barth (DE), Edwin Sylvester Brokken, Jr. (US), Lyndia S. Blair (US), and William C. Campbell (US) discovered the antiparasitic nature of Ivermectin (92; 164). Note: It is derived from avermectin, a macrocylclic lactone, which is naturally produced in soil by Streptomyces avermitilis. Ivermectin proved to be remarkably effective in humans, leading to a hope that a cure for river blindness (caused by the human parasite Onchocerca volvulus) was possible.

 

Rodney A. Brooks (US), Victor J. Sank (US), Giovanni Di Chiro (IT-US), Walter S. Friauf (US), and Stephen B. Leighton (US) designed a high resolution positron emission tomograph: the Neuro-PET (212).

Christiaan Schiepers (US) and Carl K. Hoh (US) described positron emission tomography as a diagnostic tool in oncology (1481).

Eric M. Rohren (US), Timothy G. Turkington (US) and R. Edward Coleman (US) described the clinical applications of positron emission tomography (PET) in oncology (1416). Note: Positron emission tomography (PET) uses an injected dye to view tissues that are highly metabolically active. PET can identify tumors that are fast growing and active. It is more sensitive at detecting small tumors and metastatic tumors than CT or MRI and so may aid in early diagnosis.

 

Nabil N. Rizk (EG) provided a detailed anatomical and histological description of the ventral abdominal walls of 116 specimens (41 human and 75 from nine mammalian families) of various ages and both sexes (1405).

 

David E.R. Sutherland (US), Frederick C. Goetz (US), and John S. Najarian (US) performed the world's first living-donor (segmental) pancreas transplantion (1628).

 

William F. House (US) and Aziz Belal, Jr. (EG) pioneered the early diagnosis and translabyrinthine removal of schwannomas (784).

 

Manabu Kuriyama (JP), Ming C. Wang (US), Lawrence D. Papsidero (US), Carl S. Killian (US), Takashi Shimano (US), Luis Valenzuela (US), Tsuneo Nishiura (JP), Gerald P. Murphy (US), and T. Ming Chu (US) associated levels of prostate specific antigen (PSA) with risk for prostate cancer leading to the first routine protein biomarker test used in cancer screening and prevention (952).

 

Larry R. Brown (US), Robert S. Langer (US), Michael V. Sefton (US), Halimena M. Creque (US), Moses Judah Folkman (US), Kam W. Leong (US), and Brigitta C. Brott (US) pioneered the field of controlled drug release delivery systems (slow release oral systems, transdermal patches, injectable microspheres, and slow release implants). These delivery systems involve macromolecules that have been incorporated into solid polymers from which they are released at controlled rates (218; 354; 1004; 1507). Note: This development has revolutionized medical therapy, permitted new therapies for patients, and by reducing the dose administered, has avoided complications and reduced costs. Examples of current drug applications include nitroglycerin, nicotine, cancer chemotheraputics, hormones and vaccines. In subsequent work, they determined the mechanism of release of drugs from polymers and then identified the factors that could be used to control the rate of release.

 

Charles C. Shepard (GB), Richard J.W. Rees (GB), Celia Lowe (GB), Philip Draper (GB), Morton Harboe (NO), Harvindar Kaur Gill (NO-MY), Abu Salim Mustafa (NO), Juraj Ivanyi (GB), and Tore Godal (NO) played important roles in the production of a vaccine for leprosy. It was licensed to the Wellcome drug company in England (433; 434; 593; 1533).

Barry R. Bloom (US) directed clinical efficacy trials of this vaccine for leprosy under the auspices of the World Health Organization (172).

 

Victor Bruce Darlington Skerman (AU), Vicki F. McGowan (AU), and Peter Henry Andrews Sneath (GB) edited the Approved List of Bacterial Names. This publication had a major impact on bacteriology throughout the world and marked the culmination of an ambition to reform the nomenclature of the bacteria (1557).

 

In the United States of America the Commission on Uniform State Laws proposed the Uniform Determination of Death Act. It stated that an individual, who has sustained either irreversible cessation of circulatory and respiratory functions, or irreversible cessation of all the functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards. The National Conference of Commissioners on Uniform State Laws approved it in 1981, in cooperation with the American Medical Association, the American Bar Association, and the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research.

 

Bob B. Buchanan (US) discovered that thioredoxin, a small protein earlier found in bacteria by others, functions in regulating photosynthesis. In fulfilling this function, thioredoxin, in effect, acts as an "eye," allowing chloroplasts, the site of photosynthesis, to distinguish light from dark. The chloroplast thioredoxin system functions by breaking critical intrachain disulfide bonds on key enzymes thereby altering their activity in the light. In this way, the plant is able to maximize the energy obtained from the sun (227).

 

Peggy J. Farnham (US), Terry Platt (US), Howard B. Gamper (US), John E. Hearst (US), Peter H. von Hippel (US), David G. Bear (US), William D. Morgan (US), James A. McSwiggen (US), and Thomas D. Yager (US) established the bubble paradigm to describe the transcription of RNA from DNA (494; 573; 1339; 1746; 1827; 1828).

 

Christiane Jani Nüsslein-Volhard (DE), Eric F. Wieschaus (US), Gerd Jürgens (DE), and Hildegard Kluding (DE), using Drosophila as their experimental material, discovered that during embryonic development homeotic genes act hierarchically, parceling up the embryo into smaller and smaller sections to create ever more detail. They proposed that gap genes help establish large-scale body patterns, whereas the segment-polarity and pair-rule genes control segmentation. The two-segment expression pattern of pair-rule genes, they suggested, could reflect an initial segmentation into seven double segments that later divide in half — perhaps avoiding errors that could arise in dividing the relatively few cells of the blastoderm evenly into 14 segments (852; 1239; 1240).

Hans Georg Fronhöfer (DE), Christiane Jani Nüsslein-Volhard (DE), and Wolfgang Driever (DE) discovered the first classic morphogen in Drosophila melanogaster, Bicoid (Bcd). Bcd is a maternal effect gene involved in anterior development in the fruit fly, and it controls the expression of zygotic segmentation genes, such as hunchback, in the developing embryo. This 55 KDa protein is localized in a visible gradient (with the highest concentration at the anterior) within the nuclei of cleaving embryos. This was the first work to identify a protein gradient in Drosophila embryos and led the authors to conclude that the protein was indeed a morphogen which had long-range effects on neighboring cells (437-439; 549).

Thomas Berleth (DE-CA), Maya Burri (DE), Gudrun Thoma (DE), Daniel Bopp (CH), Sibyll Richstein (DE), Gabriella Frigerio (DE), Markus Noll (CH), Wolfgang Driever (DE), and Christiane Jani Nüsslein-Volhard (DE) determined that the egg of the fruit fly, Drosophila melanogaster, is already marked front and rear, top and bottom, before it is fertilized. The mother in the very process of egg formation deposits at one location strands of messenger RNA—not a gene, but the gene’s transcript—for a protein called Bicoid. The Bicoid protein is distributed in a broad anterior-posterior gradient, with peak levels present at the anterior pole (134; 437; 1236-1238). This gradient controls the differentiation of head structures and is also important for initiating the segmentation cascade.

 

Tommaso Meo (FR), Judith P. Johnson (DE), Colin V. Beechey (GB), Sandra J. Andrews (GB), Jürgen Peters (GB), and Anthony G. Searle (GB) discovered that in mice the genes coding for the production of the immunoglobulin heavy chain and serum prealbumin are located on chromosome 12 (1138).

 

Jean P. Van Wauwe (BE), Jan R. De Mey (FR), and Jan G. Goossens (BE) found that OKT3, a monoclonal anti-human T cell antibody (IgG2), induces DNA synthesis in human peripheral lymphocyte cultures. OKT3 appeared to be a T lymphocyte mitogen as only sheep red blood cell rosetting lymphocytes were responsive. As this interaction can trigger mitogenesis, the cell membrane determinant recognized by OKT3 could be described as a T cell stimulation receptor (1769).

 

Tai-Kin Wong (DE), Claude Nicolau (FR), and Peter H. Hofschneider (DE) were the first to introduce a foreign gene into a mammalian cell using electroporation. The gene was bacterial beta-lactamase (1813).

 

J. Gregor Sutcliffe (US), Thomas M. Shinnick (US), Nicola Green (US), Fu-Tang Liu (US), Henry L. Niman (US), and Richard Alan Lerner (US) discovered previously unknown viral proteins of the Moloney leukemia virus by starting with the viral nucleic acid sequence, synthesizing a protein from a particular nucleic acid segment, making rabbit antibodies to this protein, then reacting the antibodies with Moloney infected cells. The result was the precipitation of two previously unidentified viral proteins (1005; 1627).

 

Ari Helenius (FI-CH-US), Jürgen Kartenbeck (DE), Kai Simons (FI-DE), and Erik F.B. Fries (SE) discovered the pathway by which semliki forest virus (SFV) —a membrane-containing animal virus— enters BHK-21 cells. After attaching to the cell surface, the majority of viruses were rapidly trapped into coated pits, internalized by endocytosis in coated vesicles, and sequestered into intracellular vacuoles and lysosomes. Direct penetration of viruses through the plasma membrane was never observed (735).

 

Harriet Harris (GB) suggested that genes can be controlled either at the level of transcription (DNA copying into RNA) in the nucleus or at the level of translation (protein production) in the cytoplasm after the messenger RNA has been exported from the nucleus. Harris performed an experiment in which he showed that once mRNA is formed and exported to the cytoplasm, the control mechanism for translation is then in the cytoplasm. If an antibiotic blocks transcription, mammalian cells continue to synthesize specific proteins for long periods in culture (709).

 

David Botstein (US), Raymond Leslie White (US), Mark H. Skolnick (US), and Ronald W. Davis (US) suggested that a large number of DNA sequence polymorphisms must exist in the human population, and that some of these should be detectable as variants in the length of DNA fragments produced by restriction enzymes (restriction fragment-length polymorphisms or RFLPs). These RFLPs could be detected using Southern blotting experiments on human genomic DNA. Importantly, and unlike classical polymorphic antigenic and enzyme markers, these new loci could be identified in non-coding regions of the genome as well as within genes. Linkage relationships among RFLPs could be established using pedigrees, and genetic linkage to a locus of interest would allow a gene to be mapped and defined, even if the RFLPs were not in the gene. They estimated that at least 150 highly polymorphic regions at regular intervals in the human genome would make it feasible to construct a human genetic-linkage map and to localize disease genes (185).

James F. Gusella (US), Nancy S. Wexler (VZ), P. Michael Conneally (US), Susan L. Naylor (US), Mary Anne Anderson (US), Rudolph E. Tanzi (US), Paul C. Watkins (US), Kathleen Ottina (US), Margaret R. Wallace (US), Alan Y. Sakaguchi (US), Anne B. Young (VZ), Ira Shoulson (VZ), Ernesto Bonilla (VZ), and Joseph B. Martin (US) of The US–Venezuela Huntington's Disease Collaborative Research Project discovered the approximate location of a causal gene for Huntington's disease (672; 673).

 

Richard Grantham (FR) articulated the genome hypothesis as, “The genetic code is used differently by different kinds of species. Each type of genome has a particular coding strategy, that is, choices among degenerate bases are consistently similar for all genes therein. This uniformity in the selection between degenerate bases within each taxonomic group was discovered by applying new methods to the study of coding variability. It is now possible to calculate relative distances between genomes, or genome types, based on use of the codon catalog by the mRNAs therein” (632).

 

Bernard J. Poiesz (US), Francis W. Ruscetti (US), Adi F. Gazdar (US), Paul A. Bunn, Jr. (US), John D. Minna (US), Marvin S. Reitz (US), Vaniambadi S. Kalyanaraman (US), Samuel Broder (US), Elaine S. Jaffe (US), William Blattner (US), Flossie Wong-Staal (CN-US), Thomas A. Waldmann (US), Vinvent T. DeVita, Jr. (US), Robert Charles Gallo (US), Mitsuaki Yoshida (JP), Isao Miyoshi (JP), Yorio Hinuma (JP), Takashi Uchiyama (JP), Junji Yodoi (JP), Kimitaka Sagawa (JP), Kiyoshi Takatsuki (JP), and Haruto Uchino (JP) were the first to discover a virus which causes cancer in humans; a human retrovirus. The virus, named Human T Lymphocyte Virus-1 (HTLV-1), causes a rare form of adult T cell leukemia by integrating upstream of a cellular regulatory gene and causing it to over express itself leading to excess production of T cell growth factor, which stimulates proliferation of T lymphocytes (206; 1343; 1344; 1706; 1849). Note: This is the discovery of HTLV-1, the first pathogenic human retrovirus.

 

Jean-Pierre Mach (CH), Stephan Carrel (CH), Michel Forni (CH), Jürg Ritschard (CH), Alfred Donath (CH), Pierre Alberto (CH), Jean-Francois Chatal (CH), Jean-Denis Lumbroso (CH), Franz Buchegger (CH), Christian Berche (CH), Jean-Yves Douillard (CH), Meenhard Herlyn (CH), Zenon Steplewski (CH), and Hilary Koprowski (CH) used a radiolabeled monoclonal antibody (MAb) that had been shown to react specifically in vitro and ex vivo to human colorectal carcinoma and inhibit growth of human carcinomas grafted in nude mice. They treated colorectal carcinoma patients and patients with other types of cancer. Results showed the potential value and limitations of this particular MAb for tumor detection by immunoscintigraphy (1057; 1058).

 

Ruth Arnon (IL), Michael Sela (IL), Monique Parant (IL), Louis Chedid (FR), Francoise Audibert (FR), and Michel Jolivet (FR) prepared totally synthetic antigens, and these led to neutralization of a virus, MS2, as well as to protection against diphtheria and cholera (48; 58).

 

Lance A. Liotta (US), Karl Tryggvason (FI), Spiridione Garbisa (IT), Ian Hart (US), Calvin M. Foltz (US), and Samir Shafie (US) showed that tumors secrete proteases that degrade collagen and that cell lines with the highest levels of collagenase had the highest potential for metastasis (1030). Note: For tumors to metastasize they must pass through the epithelial and endothelial basement membranes and gain access to the blood stream.

Lance A. Liotta (US), Raya Mandler (US), Genesio Murano (US), David A. Katz (US), Richard K. Gordon (US), Peter K. Chiang (US), and Elliott Schiffmann (US) isolated, purified, and partially characterized a cell motility-stimulating factor from the serum-free conditioned medium of human A2058 melanoma cells. They term this activity "autocrine motility factor" (AMF) (1029).

Hideomi Watanabe (JP), Kenji Takehana (JP), Massayo Date (JP), Tetsuya Shinozaki (JP), and Avraham Raz (US) demonstrated that "autocrine motility factor" (AMF) is the previously cloned cytokine and enzyme designated as neuroleukin, and phosphohexose isomerase, which has been independently implicated in cell motility, and to be a cancer progression marker (1768).

 

Christian Brechot (FR), Christine Pourcel (FR), Anna Louise (FR), Bernadette Rain (FR), and Pierre Tiollais (FR) reported that hepatitis B virus (HBV) DNA frequently integrates into the genome of human primary liver cancer cells (194; 195).

 

Constance A. Crowley (US), John T. Curnutte (US), Richard E. Rosin (US), Janine André-Schwartz (US), John I. Gallin (US), Mark Klempner (US), Ralph Snyderman (US), Frederick S. Southwick (US), Thomas P. Stossel (US), and Bernard M. Babior (US) discovered an inherited abnormality of neutrophil adhesion. It exhibits X-linked genetic transmission and it is associated with a missing protein of 110,000 mol. wt. (358).

 

Peter M. Richardson (CA), Ursula M. McGuinness (CA), Albert Juan Aguayo (AR-CA), Sam David (CA), and Martin Benfey (CA) demonstrated that nerve fibres that are located in the central nervous system and the brain of a mammal are capable of restoring themselves after considerable damage and/or injury (115; 375; 376; 1394).

 

1981

“The reasons that have led professionals without exception to accept the hypothesis of evolution are in the main too subtle to be grasped by layman.” Peter Brian Medawar (1131).

 

“He pondered a while and said, ‘Of course, I have made mistakes—many of them. The only way to avoid making any mistakes is never to do anything at all. My biggest mistake was to get much too much involved in controversy. Never get involved in controversy. It’s a waste of time. It isn’t that controversy itself is wrong. No, it can be even stimulating. But controversy takes too much time and energy. That’s what is wrong about it. I have wasted my time and energy in controversy, when I should have been going on doing new experiments.” Birgit Vennesland quoting Otto Heinrich Warburg (1738).

 

Nicolaas Bloembergen (NL-US) and Arthur L. Schawlow (US) for their contribution to the development of laser spectroscopy and Kai M. Siegbahn (SE) for his contribution to the development of high- resolution electron spectroscopy were awarded the Nobel Prize in physics.

 

Roger Wolcott Sperry (US) for his discoveries concerning the functional specialization of the cerebral hemispheres and David Hunter Hubel (CA-US) and Torsten Niels Wiesel (SE-US) for their discoveries concerning information processing in the visual system shared the Nobel Prize in physiology and medicine.

 

Jacques Dubochet (CH) and Alasdair McDowall (DE-US) succeeded in vitrifying water, which allowed the biomolecules to retain their shape in a vacuum (443). Note: This technique is critical to cryogenic electron microscopy.

 

W. Neal Burnette (US) developed western blotting: The electrophoretic transfer of proteins from sodium dodecyl sulfate-polyacrylamide gels to unmodified nitrocellulose followed by radiographic detection with antibody and radioiodinated protein A (234).

 

James W. Jorgenson (US) and Krynn DeArman Lukacs (US) presented a simple theory of zone electrophoresis in open-tubular capillaries. According to this theory, to achieve the highest resolution of zones, tubes with as small an inside diameter as possible should be used in combination with as high an applied voltage as feasible (847).

 

John B. Corliss (US), John A. Baross (US), and Sarah E. Hoffman (US) proposed a thermophilic origin of life (342).

 

Robert Day Allen (US), Jeffrey L. Travis (US), Nina Strömgren Allen (US), and HüSeyin Yilmaz (US) perfected video-enhanced contrast polarization (AVEC-POL) microscopy (21). Robert and Nina were awarded U.S. Patent Number 4,412,246.

 

James R. Hawker, Jr. (US) and Juan Oró (US) synthesized peptides under plausible primitive Earth conditions (723).

 

Vincent R. Racaniello (US) and David Baltimore (US) produced a complete, cloned complementary DNA copy of the RNA genome of poliovirus at the Pst I site of the bacterial plasmid pBR322. Cultured mammalian cells transfected with this hybrid plasmid produced infectious poliovirus (1364).

 

John Alan Kiernan (GB-CA) reported that formaldehyde fixes tissues by reacting with water to form methylene hydrate HOCH2OH, this then reacts with various parts of proteins to form methylene cross-links (890).

 

Richard B. Sykes (GB), Christopher M. Cimaresti (US), Daniel P. Bonner (US), Karen Bush (US), David M. Floyd (US), Nafsika H. Georgopapadakou (US), William H. Koster (US), Wen-Chih Liu (US), William L. Parker (US), Pacifico A. Principe (US), Marlene L. Rathnum (US), William A. Slusarchyk (US), William H. Trejo (US), and Jerry Scott Wells, Jr. (US) described and named a novel group of monocyclic, bacterially produced beta-lactam antibiotics (1633).

 

Yong-Yeng Lin (US), Martin Risk (US), Sammy M. Ray (US), Donna Van Engen (US), Jon Clardy (US), Jerzy Golik (US), John C. James (US), Koji Nakanishi (US), Min S. Lee (US), Daniel J. Repeta (US), Koji Nakanishi (US), and Michael G. Zagorksi (US) discovered brevitoxin B, a potent lipid-soluble neurotoxin produced by dinoflagellates such as Ptycodiscus brevis Davis (Gymnodynium breve Davis) and associated with red tide. They also determined the molecular structure of this neurotoxin. It exerts its biological effect by binding to sodium channels of neurons, keeping them open, thereby causing depolarization of the cell membrane (996; 1025).

 

Hirofumi Nakano (JP), Yuzuru Matsuda (JP), Kunio Ito (JP), Shuji Ohkubo (JP), Makoto Morimoto (JP), and Fusao Tomita (JP) discovered the gilvocarcins—new antitumor antibiotics. Gilvocarcin V and gilvocarcin M, with a novel skeleton, were discovered in culture broths of Actinomycete DO-38 (1202). Note: Gilvocarcin V is a potent antitumor agent with low toxicity. It intercalates into DNA causing single-strand cleavage of duplex DNA when activated with low-energy light.

Takashi Matsumoto (JP), Takamitsu Hosoya (JP), Keisuke Suzuki (JP), and Eiji Takashiro (JP) carried out the complete synthesis of gilvocarcin M and gilvocarcin V (781; 1099).

 

Willian F. Becker (DE), Gebhard von Jagow (DE), Timm Anke (DE) and Wolfgang Steglich (DE) determined that the strobilurins and the related natural products oudemansin and myxothiazol inhibit respiratory electron transport between cytochrome b and cytochrome c1 of ubiquinol cytochrome c reductase. All of these are used to treat plants infected with fungi (103).

 

Tsuyoshi Kihara (JP), Hiroo Kusakabe (JP), Goto Nakamura (JP), Tosio Sakurai (JP), and Kiyoshi Isono (JP) isolated, determined the structure, and reported the antineoplastic activity of cytovaricin, which is produced by Streptomyces diastatochromogenes (891; 1444).

 

Wylie Vale (US), Joachim Spiess (DE), Catherine Rivier (CH-US), and Jean E.F. Rivier (CH-US) purified corticotropin-releasing factor (CRF) (1719).

 

Ronald Bach (US), Yale Nemerson (US), William H. Konigsberg (US), George J. Broze, Jr. (US), Joseph E. Leykam (US), Benjamin D. Schwartz (US), and Joseph P. Miletich (US) purified tissue factor, the substance which initiates the blood clotting cascade (68; 225).

George J. Broze, Jr. (US), Ronald Bach (US), Rodney D. Gentry (US), Yale Nemerson (US), Daryl S. Fair (US), Marsha J. MacDonald (US), Toshiyuki Sakai (US), Torben Lund-Hansen (DK), Lisa R. Paborsky (US), Anders H. Pederson (US), and Walter Kisiel (US) found that tissue factor is an integral membrane glycoprotein located in the tissue adventitia and functions as a receptor for blood clotting factor VII (or VIIa) circulating in blood (67; 224; 490; 1443).

 

Hugo E. Jasin (US) and John T. Dingle (US) discovered a factor released from monocytes, which promotes cartilage resorption (827). Note: This substance would later be known as interleukin-1

 

Aaron Ciechanover (IL), Hannah Heller (IL), Rachel Katz-Etzion (IL), Avram Hershko (IL), Louis Levinger (US), and Alexander J. Varshavsky (RU-US) helped describe how ubiquitin acts as a tagging system to mark proteins that need to be destroyed by the proteosome (298; 1009). Note: Ubiquitination controls proteins involved in many fundamental cell processes important for cancer such as cell cycle, DNA repair and apoptosis. Later work involved targeting drugs to this pathway as a mechanism to promote apoptosis.

Andreas Bachmair (DE), Daniel Finley (US), and Alexander J. Varshavsky (RU-US) encountered the N-end rule in experiments that explored the metabolic fate of a fusion between ubiquitin and a reporter protein such as E. coli beta-galactosidase (beta gal) in Saccharomyces cerevisiae (69). The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. In eukaryotes the N-end rule pathway is a part of the ubiquitin system.

Mark M. Hiller (DE), Andreas Finger (DE), Markus Schweiger (DE), and Dieter H. Wolf (DE) studied the endoplasmic reticulum (ER) degradation system with yeast mutants defective in the breakdown of a mutated soluble vacuolar protein, carboxypeptidase yscY (CPY*). The ubiquitin-conjugating enzyme Ubc7p participated in the degradation process, which was mediated by the cytosolic 26S proteasome. It is likely that CPY* entered the ER, was glycosylated, and was then transported back out of the ER lumen to the cytoplasmic side of the organelle, where it was conjugated with ubiquitin and degraded (754).

Noboru Mizushima (JP), Takeshi Noda (JP), Tamotsu Yoshimori (JP), Yae Tanaka (JP), Tomoko Ishii (JP), Michael D. George (US), Daniel J. Klionsky (US), Mariko Ohsumi (JP) and Yoshinori Ohsumi (JP) isolated 14 autophagy-defective (apg) mutants of the yeast Saccharomyces cerevisiae and examined the autophagic process at the molecular level. They found that a unique covalent-modification system is essential for autophagy to occur. The carboxy-terminal glycine residue of Apg12, a 186-amino-acid protein, is conjugated to a lysine at residue 149 of Apg5, a 294-amino-acid protein. They discovered that Apg7 is an ubiquitin-E1-like enzyme. This is the first report of a protein unrelated to ubiquitin that uses an ubiquitination-like conjugation system. Furthermore, Apg5 and Apg12 have mammalian homologues, suggesting that this new modification system is conserved from yeast to mammalian cells (1159). See, Baudhuin, 1966.

 

Sandra L. Spurgeon (US) and John W. Porter (US) described the pathway to isopentyl diphosphate (IPP) in mammals and yeasts. This pathway starts from acetyl-CoA and proceeds through the intermediate mevalonic acid (MVA) (1595). Note: IPP units condense to give rise to isoprenoids of various types.

 

Lionel V. Crawford (GB), David C. Pim (IT), Elizabeth Tucker G. Gurney (US), Peter Goodfellow (GB), Joyce Taylor-Papadimitriou (GB), Gilbert Jay (US), George Khoury (US), Albert B. DeLeo (US), Wolfgang G. Dippold (US), Lloyd J. Old (US), Samuel Benchimol (CA), Moshe Oren (IL), Nancy C. Reich (US), Arnold J. Levine (US), David Lane (GB), and Ed Harlow (GB) discovered TP53 which was thought to be an oncogene but later found to be a tumor suppressor gene producing p53 which induces apoptosis among cells whose growth is out of control (114; 353; 828; 969; 1260; 1378).

Suzanne J. Baker (US), Eric R. Fearon (US), Janice M. Nigro (US), Stanley R. Hamilton (US), Antonette C. Preisinger (US), J. Milburn Jessup (US), Peter vanTuinen (US), David H. Ledbetter (US), David F. Barker (US), Yusuke Nakamura (JP), Raymond White (US), and Bert Vogelstein (US) reported that two colon carcinoma cell lines contain deletions of chromosome 17p, causing loss of one TP53 allele, and that the remaining allele contains mutations in a highly conserved region. The authors proposed that normal p53 functions to suppress neoplastic growth, and that this suppression is relieved when TP53 is mutated or deleted (73).

Janice M. Nigro (US), Suzanne J. Baker (US), Antonette C. Preisinger (US), J. Milburn Jessup (US), Richard Hostetter (US), Karen R. Cleary (US), Sandra H. Signer (US), Nancy Davidson (US), Stephen Baylin (US), Peter Devilee (US), Thomas Glover (US), Francis S. Collins (US), Ainsley Weslon (US), Rama Modali (US), Curtis C. Harris (US), and Bert Vogelstein (US) concluded that mutations in the p53 gene play a role in the development of many common human malignancies (1224).

Michael B. Kastan (US), Onyinye Onyekwere (US), David Sidransky (US), Bert Vogelstein (US), Ruth W. Craig (US), Steven J. Kuerbitz (US), Beverly S. Plunkett (US), William V. Walsh (US), Qimin Zhan (US), Wafik S. El-Deiry (US), France Carrier (US), Tyler Jacks (US), William V. Walsh (US), Beverly S. Plunkett (US), and Albert J. Fornace, Jr. (US) described the role of p53 in the DNA damage-checkpoint response by showing that the G1-checkpoint arrest correlates with p53 protein induction. Cells with mutant or no p53 did not arrest in G1 after gamma-irradiation. GADD45 is described as one of the genes targeted by p53 (870; 871; 945). P53 has emerged as a crucial guardian of the genome.

Elisheva Yonish-Rouach (IL), Dalia Resnitzky (IL), Joseph Lotem (IL), Leo Sachs (US-IL), Adi Kimchi (IL), and Mosha Oren (IL) suggested that products of tumor suppressor genes such as p53 could be involved in restricting precursor cell populations by mediating apoptosis (1848).

Scott W. Lowe (US), H. Earl Ruley (US), Tyler E. Jacks (US), and David E. Housman (US) proposed that the cytotoxic action of many anticancer agents involves processes subsequent to the interaction between drug and cellular target and indicate that divergent stimuli can activate a common cell death program, i.e., the production of p53. Consequently, the involvement of p53 in the apoptotic response suggests a mechanism whereby tumor cells can acquire cross-resistance to anticancer agents (1049).

Holly Symonds (US), Leonard Krall (US), Lee Remington (US), Mayte Saenz-Robles (US), Scott Lowe (US), Tyler Jacks (US), and Terry Van Dyke (US) reported that p53-dependent apoptosis suppresses tumor growth and progression in vivo (1634).

Mourad Kaghad (FR), Helene Bonnet (FR), Annie Yang (FR), Laurent Creancier (FR), Jean-Christophe Biscan (FR), Alexandre Valent (FR), Adrian Minty (FR), Pascale Chalon (FR), Jean-Michel Lelias (FR), Xavier Dumont (FR), Pascual Ferrara (FR), Frank McKeon (FR), and Daniel Caput (FR) reported that a gene with significant homology to P53 had been discovered. The gene, termed P73, is found in a chromosomal region that is implicated in the molecular pathogenesis of neuroblastoma (855).

Christine A. Jost (US), Maria C. Marin (US), and William G. Kaelin, Jr. (US) noted that the similarity of P73 to P53 is not confined to sequence homology, but extends to function as well (850).

Bruce Clurman (US) and Mark Groudine (US) found that P73 is found in a minimal consensus region of chromosome 1p36 that is deleted in some neuroblastomas, and its expression is lost in many neuroblastoma cell lines (315).

Giorgio Gaglia (US), Yinghua Guan (US), Jagesh V. Shah (US), and Galit Lahav (US) used a combination of mathematical models and experiments to show that the tumor suppressor gene P53 uses pulsed signals to trigger DNA repair and cell recovery, and that the rhythm of these pulses carries crucial information (563).

 

Don Craig Wiley (US), Ian A.Wilson (GB-US), and John J. Skehel (GB) elucidated the structure of the influenza virus (Hong Kong) hemagglutinin glycoprotein (1792; 1799).

 

Patrick Charnay (FR), Elisabeth Mandart (FR), Annie Hampe (FR), Francoise Fitoussi (FR), Pierre Tiollais (FR), Francis Gailbert (FR), Pablo D.T. Valenzuela (US), Patrick Gray (US), Margarita Quiroga (US), Josephina Zaldiver (US), Howard M. Goodman (US), and William J. Rutter (US) discovered the genetic code for the B surface antigen of hepatitis B (HBsAg) (277; 1721).

Jeffrey C. Edman (US), Robert A. Hallewell (GB), Pablo D.T. Valenzuela (CL-US), Angelica Medina (US), Gustav Ammerer (AT), Howard Michael Goodman (US), William J. Rutter (US), and Benjamin D. Hall constructed plasmids capable of expressing the genes for hepatitis B surface and core antigens (HBsAg and HBcAg respectively) in hosts such as Saccharomyces cerevisiae. This promised to provide large quantities of the antigens necessary for a vaccine to this debilitating and potentially fatal disease (462; 1720). Note: This led to the production of the first genetically engineered vaccine approved by the U.S. Food and Drug Administration in 1986.

 

Joachim Messing (US), Roberto Crea (IT-US), and Peter H. Seeburg (DE) developed a method for the “shotgun” sequencing of DNA (1142).

 

Leonard E. Post (US) and Bernard Roizman (RO-US) described a generalized technique for site-specific insertion or deletions in the chromosomes of large viral genomes: applied to herpes simplex virus 1 (HSV-1) DNA (1351).

 

Ronald Berezney (US), Linda A. Buchholtz (US), Scott C. Henderson (CA), David L. Spector (US), and Ray T. O´Keefe (GB) found that rather than being distributed evenly throughout the nucleus, replication appears to be concentrated in some 50 to 250 localized sites in eukaryotic nuclei (124; 125; 1241).

 

Mark D. Matteucci (US), Marvin Harry Caruthers (US), Serge L. Beaucage (US), Christopher Becker (US), J. William Efcavitch (US), Eric F. Fisher (US), Gerald R. Galluppi (US), Ronit Goldman (IL), Pieter deHaseth (US), Lincoln McBride (US), et al., devised a way to synthesize strands of DNA of any desired base sequence (257; 258; 1104).

 

Pierre Moreau (FR), Rene Hen (FR), Bodhan Wasylyk (FR), Roger Everett (FR), Marie-Pierre Gaub (FR), and Pierre M. Chambon (FR) discovered the DNA regulatory element—called the enhancer—that amazingly has the ability to increase the volume of transcription of genes from a very great distance (1169).

Christophe Benoist (US), Pierre M. Chambon (FR), Annette M. Healy (US), Terry L. Helser (US), and Richard S. Zitomer (US) found that the TATA box region is apparently involved in fixing the initiation of transcription precisely within a narrow area. They also found that gene expression in eukaryotes could be influenced by DNA elements remote from the TATA box (122; 729).

Julian Banerji (CH), Sandro Rusconi (CH), and Walter Schaffner (CH) provided further evidence that regulation by remote elements might be a general phenomenon. They showed that the SV40 72-bp repeats, which they called 'enhancers', could drive the expression of the heterologous rabbit hemoglobin 1 gene in HeLa cells. In addition, these enhancers could exert their effect even when placed thousands of base pairs upstream or downstream of the transcription-initiation site, independent of the orientation of the enhancer (81).

Winship Herr (US-CH) and Yakov Gluzman (IL) found that damage to an enhancer region can be overcome (reverted) by simple tandem duplications in the enhancer region, which includes the 'core' element (743).

Winship Herr (US-CH) and Jennifer Clarke (US) described the modularity and redundancy (plasticity) of eukaryotic transcriptional regulatory elements (742).

Rebecca Kellum (US) and Paul Schedl (US) demonstrated in Drosophila that chromatin is organized into domains that constitute transcription units, in which regulatory elements outside the domains have no effect on the gene activity within them. They described insulator DNAs as those DNA sequences that prevent enhancers and silencers located in one gene domain from interacting with promoters in neighboring domains (883).

 

Edward L. Kuff (US), Leonard A. Smith (US), Kira K. Lueders (US), and John H. Rogers (GB) reported the existence of retrotransposons or retroposons. A retroposon is transcribed into an RNA copy that is subsequently used to produce a cDNA copy by reverse transcriptase. The cDNA copy is then inserted into the genome at a new location, leaving the original copy undisturbed and in place (946; 1415).

 

Stephen Anderson (GB-US), Agnes T. Bankier (HU-GB-AU), Barclay George Barrell (GB), Maarten H.L. de Bruijn (GB), Alan R. Coulson (GB), Jacques Drouin (GB-CA), Ian C. Eperon (GB), Donald P. Nierlich (GB-US), Bruce A. Roe (GB-US), Frederick Sanger (GB), Peter H. Schreier (GB-DE), Andrew J.H. Smith (GB), Roger Staden (GB), Ian G. Young (GB-AU), Maureen J. Bibb (US), Richard A. van Etten (US), Catharine T. Wright (US), Mark W. Walberg (US), and David A. Clayton (US) sequenced the entire human mitochondrial genome providing evidence that the mammalian mitochondrial genome possesses an extremely compact organization; comparable to that of viral genomes. The mammalian mtDNA lacks introns and is completely saturated with genes except near the origin (29; 30; 143).

 

Michael Morris Rosbash (US), Peter K.W. Harris (US), John L. Woolford, Jr. (US), and John L. Teem (US) discovered that genes for ribosomal proteins in yeast cells contain introns (1417).

 

George Klein (SE) discovered that the gene coding for the light chain of murine immunoglobulin molecules resides on chromosome number 6 (910).

 

Richard C. Mulligan (US) and Paul Berg (US) produced the first shuttle vector; simian virus 40 (SV40)-pBR322-derived deoxyribonucleic acid (DNA) vectors carrying the Escherichia coli gene (Ecogpt, or gpt) coding for the enzyme xanthine-guanine phosphoribosyltransferase (XGPRT). Cultured monkey kidney cells synthesized the bacterial enzyme after being infected (1185; 1186).

 

Sidney V. Suggs (US), R. Bruce Wallace (US), Tadaaki Horose (US), Eric H. Kawashima (US), and Keiichi Itakura (US) synthesized labeled oligodeoxyribonucleotide probes to locate a small portion of the beta₂-microglobulin. These were used to screen bacterial clones containing cDNA sequences primed with oligo (dT) and inserted into the plasmid vector pBR322 (1621).

 

Jacques Perrault (US), Robert A. Lazzarini (US), Jack D. Keene (US), and Manfred Schubert (US) found that defective interfering (DI) RNAs, which represent one of several classes of symptom-modulating RNAs identified in association with RNA plant virus infections, are derived from, and represent mutant forms of, the viral genome (976; 1323).

Bradley I. Hillman (US), David E. Schlegel (US), and Thomas J. Morris (US) were the first to definitively identify of a plant virus DI RNA when they described one associated with the small positive-sense RNA icosahedral virus, tomato bushy stunt virus (755).

 

Richard A. Collins (US), Lori L. Stohl (US), Michael D. Cole (US), and Alan M. Lambowitz (US) discovered mitochondrial plasmids with base sequences unrelated to those of mitochondrial DNA (329).

Georgiana May (US) and John W. Taylor (US) found horizontal transfer of mitochondrial plasmids, independently of mitochondrial DNA (1107).

 

Bruno Gronenborn (DE), Richard C. Gardner (US), Sabine Schaefer (DE), and Robert J. Shepherd (US) reported the successful propagation of foreign DNA in plants using cauliflower mosaic virus as vector (650).

 

Kay E. Davies (GB), Bryan D. Young (GB), Robert G. Elles (GB), Marion E. Hill (GB), and Robert Williamson (GB) constructed a library of 50,000 recombinants representative of the human X chromosome. Human X chromosomes were physically separated using a fluorescence-activated cell sorter. The DNA was purified from the chromosomes, digested to completion with the restriction enzyme EcoRI and cloned into the phage λgtWES.λB (379).

 

Eli Keshet (IL), Amit Rosner (IL), Yael Bernstein (IL), Marian Gorecki (IL), and Haim Aviv (IL) constructed a hybrid plasmid containing beta-lactamase gene of plasmid pBR322 and cloned coding sequences of bovine growth hormone (BGH). The constructed plasmid contains all DNA sequences required to encode BGH, and when used as a hybridization probe it detects one growth hormone gene in the bovine genome. The cloned DNA sequences are inserted into the beta-lactamase gene in the correct reading frame for BGH synthesis. The hybrid gene is expressed in bacteria and the product, a fused beta-lactamase-bovine growth hormone protein, is specifically immunoprecipitated with anti-serum to BGH (887). Note: Beginning in the 1930s BGH, usually in the form of pituitary gland material, had been injected into cows to increase milk yields. Biotechnology of the type mentioned above made BGH available in sufficient quantities for commercial use.

 

Marilyn Gist Farquhar (US) was the first to propose that vesicles budded off the surface of one cisterna in the Golgi too subsequently fuse with an adjacent cisterna. In this fashion material was moved via shuttle vesicles from the cis cisterna to the trans cisterna where it was released into secretory vesicles (495). The implication was that individual cisternae remain more or less fixed in position, a concept which Erik Fries (US) and James Edward Rothman (US) supported experimentally (546; 547).

Peter Novick (US), Susan Ferro-Novick (US), William Hansen (US), Irene E. Schauer (US), Randy Wayne Schekman (US), Gregory S. Payne (US), Mitchell Bernstein (US), Werner Hoffmann (US), Gustav Ammerer (AT-US), Pamela C. Esmon (US), Brent E. Esmon (US), Alice B. Taylor (US), Richard I. Feldman (US), Tilman Achstetter (FR), Alex Franzusoff (US), Charles Field (US), Akihiko Nakano (JP), Daniela Brada (US), Susie K. Lyman (US), Thomas Yeung (US), Akihiko Nakano (JP), and Charles Barlowe (US) initiated studies on the mechanism of protein secretion using the model eukaryotic cell, Saccharomyces cerevisiae. A classic genetic approach was developed to illuminate the processes of polypeptide import into the endoplasmic reticulum, protein sorting, and packaging into transport vesicles to acceptor membrane compartments. Secretory or SEC genes, which encode the proteins implicated in these processes were cloned and shown to be evolutionarily conserved. Mammalian orthologs of the yeast SEC genes are now known to define most aspects of normal and specialized secretory processes. Schekman's group developed complementary biochemical approaches to define the exact roles of SEC proteins. Novel insights included the discovery of the major subunit of the polypeptide translocation channel of the endoplasmic reticulum (sec61p), the demonstration that cytosolic hsp70 promotes the post-translational translocation of secretory and mitochondrial precursor polypeptide, and the isolation of a novel coat protein complex, COPII, responsible for secretory and membrane cargo sorting and anterograde vesicle budding from the endoplasmic reticulum (8; 138; 475; 477; 502; 513; 1056; 1201; 1232; 1314; 1477; 1844).

John E. Bergmann (US), Kiyoteru T. Tokuyasu (US), Seymour Jonathan Singer (US), Jon Green (GB), Gareth Griffiths (GB), Daniel Louvard (FR), Paul S. Quinn (DE), Graham Warren (DE), Jaakko Saraste (FI), and Esa Kuismanen (FI) using immunoelectron microscopy and viral membrane proteins as markers, demonstrated that proteins move from the endoplasmic reticulum through the Golgi cisternae (133; 637; 1462).

 

Norifumi Hirota (JP), Makito Kitada (JP), and Yasuo Imae (JP) found that in the bacterial genus Bacillus a sodium gradient substitutes for the proton gradient as the driving force behind flagellar rotation (757; 758).

Hajime Tokuda (JP), Makoto Asano (JP), Yoshiki Shimamura (JP), Tsutomu Unemoto (JP), Shigeru Sugiyama (JP), and Yasuo Imae (JP) found that in the bacterium Vibrio alginolyticus some flagella are driven by a proton gradient while others are driven by a sodium gradient (1677).

Joseph S. Tash (US) and Anthony R. Means (US) showed that flagellar motion in sperm and other flagellated cells is initiated by phosphorylation of flagellar polypeptides. Cyclic AMP-dependent protein kinase adds the phosphate groups (1649).

 

Mark C. Willingham (US), Ira Harry Pastan (US), G. Gary Sahagian (US), George W. Jourdian (US), and Elizabeth Fondal Neufeld (US) found that enzymes destined for a lysosome are marked in the Golgi by a post-insertion sorting signal that consists of a mannose sugar with a phosphate group added to its 6-carbon (1794).

 

Robert L. Margolis (FR-US) and Leslie Wilson (US) proposed microtubular treadmilling as a mechanism to explain the translocation of chromosomes during cell division and as a mechanism to move cellular organelles from one location within the cell to another (1084; 1802).

 

Sari Brenner (US), Daniel Pepper (US), Michael W. Berns (US), Eng M. Tan (US), and William R. Brinkley (US) demonstrated in eukaryotes (Eucarya) that centromeres of sister chromatids have duplicated by the G2 stage of mitosis (201).

 

Paul R. Dragsten (US), Robert Blumenthal (US), and Joseph S. Handler (US) found that tight junctions between cells block lateral movement of proteins and lipids (430; 431).

 

Peter C. Agy (US), Gary D. Shipley (US), and Richard G. Ham (US) introduced a defined, serum-free medium able to support the clonal growth of certain mammalian cells (13).

 

George A. Bartholomew (US), David Vleck (US), and Carol Masters Vleck (US) made the first valid measurements of real, moment-by-moment volume of O2 during pre-flight warm-up in two different families of large moths, but more by doing so using a clever mathematical trick, now widely used throughout the science of metabolic measurement, to reduce the data distortion caused by the time constant in flow-through respirometry (93).

 

Christopher Scot Henney (US), Kagemasa Kuribayashi (JP), Donald E. Kern (US), and Steven Gillis (US) reported that the activity of natural killer (NK) cells is stimulated by interleukin-2 (740).

 

Kirk Ziegler (US) and Emil R. Unanue (US) identified a macrophage antigen-processing event required for I-region-restricted antigen presentation to T lymphocytes (1861).

 

Avraham Ben-Nun (IL), Hartmut Wekerle (DE), and Irun R. Cohen (DE) isolated and propagated functional antigen-specific lines of T lymphoblasts. These lines were found to recognize foreign or self antigens in association with accessory cells of syngeneic major histocompatibility complex genotype. Intravenous inoculation of a T cell reactive only against myelin basic protein led to development of clinical paralysis in syngeneic rats. Thus, it is possible to study biological function as well as antigen specificity using T cell lines (111).

 

Peter J. Rizzo (US) and David C. Sigee (GB) presented evidence that the dinoflagellates have a nuclear system intermediate in structural complexity between prokaryotes and eukaryotes (Eucarya) (1406; 1548).

 

H. Ernest Schnepf (US) and Helen Riaboff Whiteley (US) cloned the Bacillus thuringiensis toxin (Bt toxin) gene in Escherichia coli (1491).

 

Ralph Lawrence Brinster (US), Howard Y. Chen (US), Myrna E. Trumbauer (US), Allen W. Senear (US), Raphael Warren (US), and Richard Deforest Palmiter (US) injected a plasmid, pMK, containing the structural gene for thymidine kinase from herpes simplex virus into the pronucleus of fertilized one-cell mouse eggs. The eggs were reimplanted into a pseudopregnant female and allowed to come to term. Of the adult mice resulting from this procedure 10 percent exhibited somatic expression of thymidine kinase (205).

 

Helmut Hahn (DE), and Stefan H.E. Kaufmann (DE) found that intracellular niches seem to be particularly useful for long-term survival of microbial pathogens in the face of an ongoing immune response because many diseases caused by intracellular microorganisms take a chronic course. Bacteria that have chosen macrophages as their preferred habitat include the following pathogens: Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium leprae, Legionella pneumophila, and Salmonella typhimurium (680).

 

Ruth L. Satter (US), Arthur W. Galton (US), Mary Jane Morse, (US), Youngsook Lee (US), Richard C. Crain (US), Gary G. Coté (US), and Nava Moran (IL) proposed that, following its interaction with light energy, phytochrome affects calcium ion release, which in turn alters other cellular processes (1463; 1464).

 

Richard Cawthon Starr (US) and Charles E. Miller (US) described the control of sexual morphogenesis in Volvox capensis (1601).

 

Tuomo Timonen (US), John R. Ortaldo (US), and Ronald Bo Herberman (US) discussed the characteristics of human large granular lymphocytes and their relationship to natural killer and K cells (1671).

 

Pat Levitt (US), M. Lee Cooper (US), and Pasko Rakic (US) found that neuronal and glial precursor cells coexisted in the cerebral ventricular zone of the fetal monkey (1010).

Sue Hockfield (US) and Ronald D.G. McKay (GB-US) generated monoclonal antibodies that distinguish among major cell types present during mammalian neurogenesis. These antibodies were used to analyze the development of cellular organization in the early nervous system (761).

Urban Lendahl (SE), Lyle B. Zimmerman (US), and Ronald D.G. McKay (GB-US) describe a gene whose expression distinguishes the stem cells from the more differentiated cells in the neural tube. This gene was named nestin because it is specifically expressed in neuroepithelial stem cells producing the intermediate filament protein, nestin (1000).

Shigeo Okabe (JP), Karin Forsberg-Nilsson (SE), A. Cyril Spiro (US), Menahem Segal (IL), and Ronald D.G. McKay (GB-US) found that neuronal precursor cells can be isolated from embryonic stem cells and that these cells can efficiently differentiate into functional post-mitotic neurons of diverse central nervous system structures (1250).

 

Diana Boraschi (IT) and Aldo Tagliabue (IT) noted that large amounts of type 1 (alpha and beta) interferon could activate macrophages to express cytotoxicity against tumor cells (179).

Judith L. Pace (US), Stephen W. Russell (US), Robert D. Schreiber (US), Amnon Altman (US), and David H. Katz (US) determined that relatively small amounts of type 2 (gamma) interferon are capable of priming macrophages for tumoricidal activity (1275).

 

Mary E. Harper (US), Axel Ullrich (DE), and Grady F. Saunders (US) demonstrated chromosomal localization of the human insulin gene to 11p15 (707).

 

Rosa Susan Penelope Beddington (GB) pioneered the use of post-implantation mouse chimeras. She was seeking to understand the patterning of the epiblast (which was then referred to as the embryonic ectoderm), the tissue that gives rise to the embryo proper. These injections showed that different regions of the epiblast gave rise to different parts of the post-gastrulation embryo: for instance, distal epiblast could contribute to somites and notochord, but anterior epiblast could not. She found no evidence for rigid cell fate in the epiblast: when transplanted to a different location, cells readily contributed structures other than those they form normally (although there were some ‘propensities’ of certain cells to contribute to one structure or another, suggesting some degree of cell fate restriction) (104; 105).

 

Martin John Evans (GB) and Matthew H. Kaufman (GB) showed that, by delaying implantation, they could obtain slightly enlarged mouse blastocysts, and that cells from these blastocysts could be used to establish embryonic stem (ES) cell cultures. These cultured cells were capable of differentiating in vitro and in vivo (481-485; 1046). Note: Evans and Kaufman were the first to culture mouse embryonic stem cells and cultivate them in vitro.

Gail R. Martin (US) established an embryonic stem (ES) cell line directly from normal pre-implantation mouse embryos and confirmed its pluripotency by showing that individual cells of this line could differentiate to form a wide variety of cell types in vitro and in vivo. She obtained the embryonic stem (ES) cell line by culturing cells isolated from blastocysts in a medium that had previously been conditioned by an established teratocarcinoma stem-cell line (1089).

James A. Thomson (US), Joseph Itskovitz-Eldor (IL), Sander S. Shapiro (US), Michelle A. Waknitz (US), Jennifer J. Swiergiel (US), Vivienne S. Marshall (US), and Jeffrey M. Jones (US) established a human pluripotent cell line, which they derived from human blastocysts. The description of the cells is that they, “have normal karyotypes, express high levels of telomerase activity, and express cell surface markers that characterize primate embryonic stem cells but do not characterize other early lineages. After undifferentiated proliferation in vitro for 4 to 5 months, these cells still maintained the developmental potential to form trophoblast and derivatives of all three embryonic germ layers, including gut epithelium (endoderm); cartilage, bone, smooth muscle, and striated muscle (mesoderm); and neural epithelium, embryonic ganglia, and stratified squamous epithelium (ectoderm). These cell lines should be useful in human developmental biology, drug discovery, and transplantation medicine” (1668).

Michael J. Shamblott (US), Joyce Axelman (US), Shunping Wang (US), Elizabeth M. Bugg (US), John W. Littlefield (US), Peter J. Donovan (US), Paul D. Blumenthal (US), George R. Huggins (US), and John D. Gearhart (US) established pleuripotent stem cell lines. Gonadal ridges and mesenteries containing primordial germ cells (PGCs, 5-9 weeks postfertilization) were cultured on mouse STO fibroblast feeder layers in the presence of human recombinant leukemia inhibitory factor, human recombinant basic fibroblast growth factor, and forskolin. The cultured cells were continuously passaged and found to be karyotypically normal and stable. Based on their origin and demonstrated properties, these human primordial germ cells-derived cultures meet the criteria for pluripotent stem cells and most closely resemble embryonic germ cells (1525).

 

Peter J. Meier (CH), Urs Giger (CH-US), Otto Brändli (CH), and Jutta Fehr (DE) found that the therapeutic efficacy of pyridoxine (vitamin B6) in treating primary sideroblastic anemia is due to its effect on defective delta-aminolevulinic acid synthetase (ALAS). More generally, the data support the view that almost all features of primary sideroblastic anemia can be ascribed to a disturbance of heme synthesis in erythroblasts (1134).

 

Jean D. Wilson (US), James E. Griffin (US), Mark Leshin (US), and Fredrick W. George (US) reported that male and female embryos develop in an identical fashion during the initial portion of gestation. If the indifferent gonad differentiates into an ovary (or if no gonad is present), a female phenotype is formed. Male phenotypic differentiation, however, requires the presence of an endocrinologically active testis. Two secretions of the fetal testis, Mullerian inhibiting substance and testosterone, are responsible for male development (1800; 1801).

 

Epidemiologists working at the Centers for Disease Control in Atlanta, GA, U.S.A. were the first to define acquired immune deficiency syndrome (AIDS). Many researchers contributed information which lead to the recognition and confirmation of this previously undescribed disease (187; 314; 336-339; 365; 489; 496; 544; 622; 623; 988; 1095; 1503; 1546). Notables include: Michael S. Gottlieb (US), Howard M. Schanker (US), Peng Thin Fan (US), Andrew Saxon (US), Joel D. Weisman (US), Robert A. Wolf (US), Irv Pozalski (US), Robert Schroff (US), Alvin E. Friedman-Kien (US), Linda J. Laubenstein (US), Pablo Rubenstein (US), Elena Buimovici-Klein (US), Michael Marmor (US), Rosalyn Stahl (US), Ilya Spigland (US), Kwang Soo Kim (US), Susan Zolla-Pazner (US), Henry Masur (US), Mary Ann Michelis (US), Jeffrey B. Greene (US), Ida M. Onorato (US), Robert A. vande Stouwe (US), Robert S. Holzman (US), Gary Wormser (US), Lee Brettman (US), Michael Lange (US), Henry W. Murry (US), Frederick P. Siegal (US), Carlos Lopez (US), Glenn S. Hammer (US), Arthur E. Brown (US), Stephen J. Kornfeld (US), Jonathan Gold (US), Joseph Hassett (US), Shalom Z. Hirschman (US), Charlotte Cunningham-Rundles (US), Bernard R. Adelsberg (US), David M. Parham (US), Marta Siegel (US), Susanna Cunningham-Rundles (US), Donald Armstrong (US), Anthony Stephen Fauci (US), Michael M. Lederman (US), Oscar D. Ratnoff (US), James Jay Scillian (US), Paul K. Jones (US), Bernice Schacter (US), James W. Curran (US), Dale N. Lawrence (US), Harold Jaffe (US), Jonathan E. Kaplan (US), Mary E. Chamberland (US), Ronald Weinstein (US), Kung-Jong Lui (US), Lawrence B. Schonberger (US), Thomas J. Spira (US), Lawrence D. Zyla (US), Joseph R. Bove (US), Gwendolyn B. Scott (US), Billy E. Buck (US), Joni G. Leterman (US), Floyd L. Bloom (US), Wade P. Parks (US), Nathan Clumeck (BE), Jean Sonnet (BE), Henri Taelman (BE), Francoise Mascart-Lemone (BE), Marc De Bruyere (BE), Philippe Vandeperre (BE), Jean Dasnoy (BE), Luc Marcelis (BE), Monique Lamy (BE), Claude Jones (BE), Luc Eyckmans (BE), Henri Noel (BE), Michel Vanhaeverbeek (BE), Jean-Paul Butzler (BE), John Leslie Fahey (US), Harry E. Prince (US), Michael Weaver (US), Jerry Groopman (US), Barbara R. Visscher (US), Kendra Schwartz (US), and Roger Detels (US).

 

Giancarlo Ghiselli (IT-US), Ernst J. Schaefer (US), Pere Gascon (ES), and H. Bryan Brewer, Jr. (US) found that patients with type 3 hyperlipoproteinemia develop premature atherosclerosis, which may be due to an absence or striking deficiency of apolipoprotein E (apoE) (587).

 

William Koopmans Summers (US), John O. Viesselman (US), Gary M. Marsh (US), and Kent Candelora (US) found that tacrine (THA; 1,2,3,4-tetrahydro-9-aminoacridine), a centrally acting anticholinesterase, gives some relief of the symptoms of Alzheimer’s disease, especially in the more advanced cases (1624). Note: This was one of the first drugs to show promise in the treatment of Alzheimer’s.

 

Adolfo J. de Bold (AR-CA), Harold Bernard Borenstein (CA), Anthony T. Veress (CA), Harald Sonnenberg (CA), and T. Geoffrey Flynn (CA) were the first to demonstrate that the heart has an endocrine function in addition to its role as a pump in the circulatory system. They discovered and isolated a hormone called atrial natriuretic factor (ANF), named thus because it is produced in the heart's atria and has very powerful diuretic and hypotensive properties. In general, de Bold explains, ANF counteracts the renin-angiotensin-aldosterone system in the body, which increases blood pressure and blood volume (388; 389). Note: The discovery of an endocrine link between the heart and the kidneys has its basis in the electron microscopic finding that the striated muscle cells of the cardiac atria in mammals are differentiated both as contractile and as endocrine cells.

T. Geoffrey Flynn (CA), Mercedes L. de Bold (CA), and Adolfo J. de Bold (AR-CA) determined the amino acid sequence of an atrial natriuretic factor (525).

Brian P. Kennedy (CA), Julian J. Marsden (CA), T. Geoffrey Flynn (CA), Adolfo J. de Bold (AR-CA) and Peter L. Davies (CA) isolated and sequenced a clone of cDNA which codes for the C-terminal 62 residues of the precursor molecule for the atrial natriuretic factor, cardionatrin (885).

 

Judy C. Chang (US) and Yuet Wai Kan (CN-US) diagnosed sickle cell anemia antenatally, directly at the gene level, by restriction enzyme analysis of the DNA. This was the first disease to be so diagnosed (274).

 

Susan Malcolm (GB), Paul Barton (GB), C. Murphy (GB), and Malcolm Andrew Ferguson-Smith (GB) localized the human beta globin genes on the short arm of chromosome 11 using in situ hybridization to fixed chromosomes (1074).

Susan Malcolm (GB), Paul Barton (GB), C. Murphy (GB), Malcolm Andrew Ferguson-Smith (GB), David L. Bentley (GB), and Terence H. Rabbitts (GB) located the human kappa light chain variable region genes on the short arm of chromosome 2 near the centromere (1075).

 

David H. Ledbetter (US), Vincent M. Riccardi (US), Susan D. Airhart (US), Richard J. Strobel (US), Bruce S. Keenan (US), and John Douglas Crawford, II (US) discovered a deletion in human chromosome 15 as the cause of Prader-Willi syndrome (985).

 

Susan Lenz (DK), Jörgen G. Lauritsen (DK), and Merete Kjellow (DK) demonstrated for the first time that eggs could be obtained from ovarian follicles directly under ultrasound control (1001; 1002).

 

William G. Hayward (US), Benjamin G. Neel (US), Harriet Robinson (US), and Susan Astrin (US) were the first to associate the c-myc gene with B cell neoplasia when they found that the avian leukosis virus (ALV), which induces lymphomas in chickens, is associated with retroviral insertion into the 5’ end of the c-myc gene (726).

 

Chiaho Shih (TW-US), Lakshmi Charan Padhy (IN), Mark Murray (US) and Robert A. Weinberg (US) found that DNAs obtained from human, rabbit and mouse bladder carcinoma lines, a lung carcinoma line, and rat neuroblastoma and mouse glioma lines, are able to induce transformation of NIH3T3 cells on transfection (1536).

 

Kenneth M. Moser (US) and John R. LeMoine (US) reported that combination of radiofibrinogen and impedance tests allows accurate detection of both the presence and location of deep venous thrombosis. The availability of sensitive and specific, noninvasive methods for detecting and localizing venous thrombosis, as well as the apparently low embolic risk of calf-only thrombosis may condition future approaches to prophylaxis and treatment of patients with or at high risk for deep venous thrombosis (1172).

 

Shiro Fujita (JP-US), William A. Conway (US), Frank J. Zorick (US), and Thomas Roth (US) introduced uvulopalatopharyngoplasty: removal of the uvula, a portion of the soft palate, and redundant tissues from the posterior wall, as treatment for obstructive sleep apnea (556).

 

Philip M.K. Leung (CA), Walter D. Rider (CA), Henry P. Webb (CA), Hélène Aget (CA), and Harold Elford Johns (CA) invented and developed the Cobalt-60 machine, which had an immediate impact on the cancer survival rate. Prior to the Cobalt-60, cancer therapy radiation could be used to treat superficial tumors but not those deep-seated (1007).

 

Philip D. Greenberg (US), Martin A. Cheever (US), and Alexander Fefer (US) accomplished eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2− lymphocytes (642).

 

Tucker W. LeBien (US), Robert W. McKenna (US), Candice S. Abramson (US), Kazimiera J. Gajl-Peczalska (US), Mark E. Nesbit (US), Peter F. Coccia (US), Clara D. Bloomfield ( US), Richard D. Brunning (US), John H. Kersey (US), Kenneth A. Foon (US), and Robert F. Todd, III (US) used monoclonal antibodies, morphology, and cytochemistry to reveal the cellular heterogeneity of acute leukemia and lymphoma (529; 982).

 

John Raymond Hobbs (GB), Kenneth Hugh-Jones (GB), Austin John Barrett (GB), N. Byrom (GB), J. David Chambers (GB), Kristin Henry (GB), David C.O. James (GB), C.F. Lucas (GB), T.R. Rogers (GB), P.F. Benson (GB), L.R. Tansley (GB), A. Desmond Patrick (GB), J. Mossman (GB), and Elisabeth P. Young (GB) used allogeneic hematopoietic stem cell transplantation (HSCT) to deliver normal lysosomal enzyme to the brain of a patient with Hurler's disease (760).

Patrick Aubourg (FR), Stéphane Blanche (FR), Isabelle Jambaqué (FR), Francis Rocchiccioli (FR), Gabriel Kalifa (FR), Catherine Naud-Saudreau (FR), Marie-Odile Rolland (FR), Mariane Debré (FR), Jean-Louis Chaussain (FR), Claude Griscelli (FR), Alain Fischer (FR), and Pierre-François Bougnères (FR) performed the first successful hematopoietic stem cell transplant. It was to treat X-adrenoleukodystrophy (57).

 

Gord McDonald (CA) and Chris Wood (CA) provided valuable insight into the mechanisms underlying acid–base disturbances in acid-exposed fish. They identified the gill as the site of acid uptake and demonstrated an important role for the kidney in excreting the acid load gained via the gill. Renal acid excretion was not, however, sufficient to compensate for branchial acid gain, resulting in a depression of blood pH. They also reported that exposure to acid water promoted a continuous loss of ions across the gill, accounting for the well-known lowering of plasma ion levels in acid-exposed fish, and they suggested that fluid shifts triggered by ion losses might ultimately cause circulatory collapse and death (1118).

 

Peter T. Boag (CA) and Peter R. Grant (GB-CA-US) found that survival of Darwin's finches through a drought on Daphne Major Island was nonrandom. Large birds, especially males with large beaks, survived best because they were able to crack the large and hard seeds that predominated in the drought. Selection intensities, calculated by O'Donald's method, are the highest yet recorded for a vertebrate population (174).

 

Joseph Felsenstein (US) created evolutionary trees using rRNA sequences and a maximum likelihood approach. He concluded that the Plantae, Animalia, and Fungi along with two new evolutionary assemblages (alveolates and stramenophiles) diverged nearly simultaneously (504). Alveolates include dinoflagellates, apicomplexans, and ciliated protozoans. The stramenophiles include brown algae, labyrinthulids, chrysophytes, xanthophytes, diatoms, and oomycetes (1310).

 

Cyril A. Walker (GB) described the Enantiornithes, a new subclass of fossil birds (1752). Note: Enantiornithes is a group of extinct avialans ("birds" in the broad sense), the most abundant and diverse group known from the Mesozoic era. Almost all retained teeth and clawed fingers on each wing, but otherwise looked much like modern birds externally.

 

1982

“These are the gentle giants

Who walk softly through our lives.

 

No shrill demand for recognition

Commands our attentive admiration.

 

No blinding glare of brilliance

Announces their presence among us.

 

They are the quietly courageous ones

Who plant for future generations.

 

They are the creators and searchers

Who teach and celebrate the truth.” Solomon Spiegelman (1592).

 

Aaron Klug (ZA-GB) was awarded the Nobel Prize in Chemistry for his development of crystallographic electron microscopy and his structural elucidation of biologically important nuclei acid-protein complexes.

 

Karl Sune Detlof Bergström (SE), Bengt Ingemar Samuelsson (SE) and John Robert Vane (GB) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning prostaglandins and related biologically active substances.

 

Gerd Karl Binnig (CH), Heinrich Rohrer (CH), Christoph Gerber (CH), and Edmund Weibel (CH) reported the discovery of the scanning tunneling microscope; an instrument for imaging surfaces at the atomic level (149; 150).

 

Kyriacos Costa Nicolaou (CY-US), Nicos A. Petasis (GR-US), Robert E. Zipkin (US), and Junìchi Uenishi (JP) carried out the complete synthesis of endiandric acids A-D. They are secondary metabolites from the Australian plant Endiandra introrsa (1219-1223).

 

Dawie P. Botes (ZA), Cornelis C. Viljoen (ZA), Helene Kruger (ZA), Philippus L. Wessels (ZA), and Dudley Howard Williams (ZA) determined the chemical structure of a hepatotoxin produced by the cyanobacterium, Microcystis aeruginosa (184).

 

Yuri A. Ovchinnikov (RU), Paul A. Hargrave (US), J. Hugh McDowell (US), Donna R. Curtis (US), Janet K. Wang (US), Elizabeth Juszczak (US), Shao-Ling Fong (US), J.K. Mohana Rao (US), and Patrick Argos (US) determined the complete amino-acid sequence of bovine rhodopsin. The molecule’s seven hydrophobic regions connected by hydrophilic loops suggested seven transmembrane alpha helices (702; 1271).

 

Sandra L. Hofmann (US) and Philip W. Majerus (US) described the isolation and preliminary characterization of two cytosolic phosphatidylinositol-specific phospholipase C enzymes from sheep seminal vesicles (766).

David B. Wilson (US), Teresa E. Bross (US), Sandra L. Hofmann (US), and Philip W. Majerus (US) compared the ability of the purified enzymes above to hydrolyze phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-diphosphate. They found that the two enzymes are able to hydrolyze all three phosphoinositides with the same affinity. From these experiments they concluded that “a single phospholipase C can account for the hydrolysis of all three phosphoinositides seen during agonist-induced stimulation of secretory cells” (1796).

David B. Wilson (US), Ellis J. Neufeld (US), and Philip W. Majerus (US) determined that there is little increase in conversion of phosphatidylinositol to phosphatidylinositol 4,5-diphosphate during thrombin stimulation. Thus, they concluded, the bulk of phosphatidylinositol breakdown that occurs in thrombin-stimulated platelets occurs via direct phospholipase C hydrolysis of phosphatidylinositol (1797).

 

Andreas Pfaltz (CH), Douglas A. Livingston (DE), Bernhard Jaun (CH), Alexander Fässler (CH), Albert Eschenmoser (CH), Rolf Jaenchen (CH), Hans-Harald Gilles (DE), Gabriele Diekert (DE), and Rudolf K. Thauer (DE) isolated the nickel-containing cofactor F430 used by methyl coenzyme M reductase to generate methane. This is the way in which swamp gas is generated. They determined the structure of the methyl ester of cofactor F430M (1325; 1326).

 

Harland Goff Wood (US), Harold L. Drake (DE), Shou-Ih Hu (US), and Lars G. Ljungdahl (US) discovered and defined a novel pathway for carbon monoxide (CO) fixation in acetogens—a group of anaerobic bacteria that synthesize acetate from carbon monoxide or carbon dioxide and hydrogen (788; 1816; 1817).

 

The cluster of differentiation (CD) nomenclature was proposed and established in the 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), which was held in Paris in 1982. This is a protocol used for the identification and investigation of cell surface molecules present on white blood cells.

 

Ursula Wilden (DE), Hermann Kühn (DE), Jeffrey L. Benovic (US), Ruth H. Strasser (US), Marc G. Caron (US), and Robert Joseph Lefkowitz (US), while exploring desensitizing or ‘shutting off’ of receptors, discovered that there exists a universal mechanism for regulation of the receptor superfamily (heptahelical G-protein-coupled receptors) (123; 1791). Subsequently two families of protein regulators were described.

Julia A. Pitcher (US), Neil J. Freedman (US), and Robert Joseph Lefkowitz (US) discovered one of these families, the G-protein-coupled receptor kinases (GRKs 1-6) which phosphorylate only the activated form of the receptors (1334).

Robert Joseph Lefkowitz (US) discovered the second family, which are called arrestins. These bind the phosphorylated receptors and interdict further signaling to the G proteins (999).

 

Nicola T. Neff (US), Christopher H. Lowrey (US), Cindi Decker (US), C. Amy Tovar (US), Caroline H. Damsky (US), Clayton Buck (US), and Alan F. Horwitz (US) made a definitive identification of the integrins as a complex linking the cytoskeleton to the extracellular matrix (ECM) (1209).

Keith Burridge (GB-US) and Laurie Connell (US) discovered talin, one of the cell adhesion proteins (235).

Alan F. Horwitz (US), Kimberly Duggan (US), Clayton Buck (US), Mary C. Beckerle (US), and Keith Burridge (US) established the transmembrane link in vitro, with integrin binding both to the extracellular matrix (ECM) fibronectin and to cytoplasmic talin (780).

 

Hartmut Michel (DE) prepared highly ordered crystals of the photosynthetic reaction center from a purple bacterium (1148).

Johann Deisenhofer (DE-US), Robert Huber (DE), Hartmut Michel (DE), Otto Epp (DE), Kunio Miki (JP), James P. Allen (US), George Feher (US), Todd O. Yeates (US), and Douglas C. Rees (US) performed x-ray analysis of three-dimensional crystals of the photosynthetic reaction center from the purple bacteria Rhodopseudomonas sphaeroides and Rhodopseudomonas viridis at 3-angstroms. The protein subunits of the complexes were identified and compared (20; 396).

Johann Deisenhorfer (DE-US), Hartmut Michel (DE), Robert Huber (DE), Otto Epp (DE), and Kunio Miki (JP) determined the details of the photosynthetically active components of protein, quinone, and iron (397; 398).

 

Tim C. Huffaker (US) and Phillips Wesley Robbins (US), using Saccharomyces cerevisiae, gave procedures for isolating temperature-sensitive mutants in asparagine-linked glycosylation as well as their characterization of one of these mutants (algl-1). They showed that algl-1 cells are able to synthesize GlcNAc2-lipid but are unable to synthesize any mannose-containing oligosaccharide-lipids. The algl-1 cells are also unable to elongate exogenous GlcNAc2-lipid but are able to convert Man1GlcNAc2-lipid to Man5GlcNAc2-lipid. These results indicated that the algl-1 mutant is blocked at the addition of the fist mannose residue to the oligosaccharide-lipid. Characterization of the Glc3Man9GlcNAc2-lipid has shown that only the mannose residue attached to GlcNAc exists in a beta-D-linkage, thus indicating that the mutant has a deficiency in the enzyme involved in this process (797).

 

R. Glenn Hammonds, Jr. (US), Pierre Nicolas (FR), and Choh Hao Li (CN-US) identified a high molecular weight beta-endorphin complex (receptor) in extracts of rat brain membrane (695).

 

Amar Gupta (IN-US), Charles DeBrosse (US), and Stephen J. Benkoic (US), working with T4 DNA polymerase, determined the stereochemical course of the enzyme’s 3'-5'-exonuclease activity. They found that the exonuclease proceeds with an inversion of configuration at the phosphorus atom, most probably via a direct displacement by water of the 3' terminus of the DNA chain to yield a 5'-nucleotide (671). This was the first example of phosphodiester hydrolysis catalyzed by an exonuclease that did not involve a covalent phosphoryl-enzyme intermediate.

Vidhya Gopalakrishnan (IN-US) and Stephen J. Benkovic (US) explored the spatial relationship between the T4 DNA polymerase and exonuclease active sites. Using a bulky biotin-streptavidin block at a specified position in an oligonucleotide sequence, they were able to monitor the closest distance of approach of the T4 enzyme before being prevented from performing either of its activities by the biotin-streptavidin complex. Their results indicated a distance of 4 –5 nucleotides between the biotin-streptavidin probe and the exonuclease site and a possible separation of 2 nucleotides between the exonuclease and polymerase active sites (616).

 

R. Wayne Davies (GB), Richard B. Waring (GB), John A. Ray (GB), Terence A. Brown (GB), and Claudio Scazzocchio (FR) proposed a model for intron removal in which the three dimensional structure of the intron brings the ends of each intron together allowing an internal guide RNA sequence to pair with exon bases adjacent to the splice junctions. By this mechanism an intron is promoting its own excision (381; 1764). They then proposed that this type of catalytic intron be called a ribozyme (1765).

Jim Haseloff (AU) and Wayne L. Gerlach (AU) produced synthetic ribozymes and deduced general rules associated with the design of such molecules (720).

 

Hiroto Okayama (JP) and Paul Berg (US) developed a high efficiency method for obtaining cDNA segments, which contain the entire nucleotide sequence of the corresponding mRNA (1251).

 

Jack William Szostak (CA-PL-GB-US) and Elizabeth H. Blackburn (AU-US) cloned yeast telomeres on linear plasmid vectors (1636).

 

Ilkka Palva (FI), Matti Sarvas (FI), Paivi Lehtovaara (FI), Mervi Sibakov (FI), and Leevi Kääriäinen (FI) constructed secretion vectors from the plasmid pUB110 and the promoter and signal sequence region of the alpha-amylase gene of Bacillus amyloliquefaciens. The Escherichia coli beta-lactamase gene was then inserted into the vector and used to transform non-secreting Bacillus subtilis cells into secretors of beta-lactamase (1284).

 

Leonard Guarente (US), R. Rogers Yocum (US), and Paula Gifford (US) demonstrated a Saccharomyces cerevisiae promoter element called an upstream activation site (UAS). This work demonstrates that the S. cerevisiae GAL UAS confers regulation in a gene fusion to the S. cerevisiae CYC1 gene thus demonstrating the autonomous function of a S. cerevisiae UAS (665).

 

Richard Hawkes (CA), Evelyn Niday (CA), and Julian Gordon (CA) developed a dot-immunobinding assay for monoclonal and other antibodies (724).

 

Michael Mackett (GB), Geoffrey L. Smith (GB), Bernard Moss (US), Dennis Panicali (US) and Enzo Paoletti (US) constructed a recombinant vaccinia virus expressing a foreign gene, the thymidine kinase (TK) gene of herpes simplex virus (HSV), which was inserted into the nonessential regions of the virus genome by homologous recombination (1061; 1287).

 

Forrest A. Spencer (US), F. Michael Hoffmann (US), and William M. Gelbart (US) described the decapentaplegic gene complex in Drosophila melanogaster as a series of allelic mutations affecting imaginal disk development with the decapentaplegic (dpp) gene complex involved in the elaboration of positional information within developing epidermal tissue (1591).

 

Rudolf Grosschedl (DE-US) and Max Luciano Birnstiel (CH) reconstructed a cell-free system from sea urchin (Psammechinus miliaris) material in which they carried out the correct initiation of transcription by RNA polymerase I (653).

 

Catherine M. Houck, (US), Carl W. Schmid (US), and Warren R. Jelinek (US) discovered the moderately repetitive nonfunctional sequence of DNA called Alu (782; 1486).

 

Joachim Messing (US) and Jeffrey Vieira (US), and Celeste Yanisch-Perron (US) pioneered in the development of single stranded cloning vectors called pUC plasmids. These were derived from a single stranded filamentous DNA virus, M13, and were particularly valuable for DNA sequencing (1143; 1743; 1841).

Joachim Messing (US) and Jeffrey Vieira (US) constructed single stranded DNA bacteriophage vectors, M13mp8 and M13mp9 containing a group of restriction sites. Because of their unique content of restriction sites DNA fragments whose ends corresponded to two of these restriction sites could be force cloned by ligation to one of these M13 cloning vehicles. M13mp8 and M13mp9 have their restriction site region arranged in opposite orientations relative to the M13 genome. Thus, a given restriction fragment can be directly orientated by forced cloning. This procedure guarantees that each strand of the cloned fragment will become the (+) strand in one or the other of the clones and thus be extruded as single stranded DNA in phage particles (1143).

 

Charles Weissmann (CH), Shigekazu Nagata (JP), Werner Boll (US), Michael Fountoulakis (CH), Atsuko Fujisawa (CH), Jun-ichi Fujisawa (CH), Joel Haynes (CA), Karsten Henco (DE), Ned Mantei (CH), Hermann Ragg (DE), Catherine H. Schein (CH), Jurg Schmid (CH), Gray D. Shaw (CH), Michael Streuli (US), Hideharu Taira (JP), Kazuo Todokoro (JP), and Ulrich Weidle (DE) fractionated poly (A)⁺ RNA by size on a sucrose gradient and cloned interferon cDNA from the active mRNA fraction assayed by injection into Xenopus laevis oocytes (1780). Note: This was the first application of expression cloning.

 

Irene Tischer (DE), Hans R. Gelderblom (DE), Wolfgang Vettermann (DE), and Meinrad A. Koch (DE) discovered and named porcine circovirus (the first circovirus) (1673).

 

E. Imre Friedmann (AT-US) discovered living microorganisms in the frigid desert of the Antarctic dry valleys where there are no visible life forms on the surface of the soil or rocks. Yet in certain rock types a narrow subsurface zone has a favorable microclimate and is colonized by microorganisms. Dominant are lichens of unusual organization (545).

 

Richard H. Scheller (US), James F. Jackson (US), Linda Beth McAllister (US), James H. Schwartz (US), Eric R. Kandel (US), and Richard Axel (US) noted that in the marine mollusc Aplysia, the bag cells, two discrete clusters of neurons, secrete a peptide of known behavioral function. This neuroactive peptide, egg-laying hormone (ELH), produces a characteristic and stereotypic behavioral repertoire, consisting first of a cessation of walking and inhibition of feeding, followed by head waving and egg laying. They cloned the genes encoding ELH and characterized their organization and expression. At least five distinct genes for ELH exist within the chromosome. Sequence analysis of one recombinant clone unambiguously identifies a contiguous stretch of nucleotides that encodes the 36 amino acids of ELH. Transcription of this small multigene family results in the expression of at least five distinct RNA transcripts encoding ELH. The pattern of transcripts differs strikingly in different tissues: bag cells express three distinct mRNA species, whereas the atrial gland, a secretory reproductive gland, expresses two distinct mRNAs. Several other neuronal and nonneuronal tissues do not express ELH RNA. In vitro these mRNAs produce a series of long polypeptide precursors that must be processed to generate the active ELH peptide. This processing event is likely to generate several additional neuroactive peptides. Thus the same peptide, ELH, may be released in association with different combinations of other neuroactive peptides. The concept of combinatorial sets of neuropeptides, each bearing one overlapping peptide ELH, and each directing a differing pattern of behavior, greatly expands the information potential of a small set of genes (1478).

 

Howard Curtis Berg (US), Michael D. Manson (US), and M. Patricia Conley (US) determined that flagellar rotation in prokaryotes is powered by a proton gradient across the cell membrane (127).

 

Peter C. Isakson (US), Ellen Puré (US), Ellen S. Vitteta (US), and Peter H. Krammer (DE) provided experimental evidence that lymphokines produced by T cells could induce B cell differentiation. In the presence of lipopolysaccharide (LPS), this B cell differentiation factor(s) (BCDF) enhances IgG secretion by surface immunoglobulin (sIgG^-) cells (811).

Maureen Howard (US), John Farrar (US), Mary Hilfiker (US), Barbara Johnson (US), Kiyoshi Takatsu (JP), Toshiyuki Hamaoka (JP), and William E. Paul (US), in the mouse, identified a T cell-derived B cell growth factor distinct from interleukin 2. It interacts with B cells to maintain proliferation (785).

 

Peter Nigel Tripp Unwin (GB) and Ronald A. Milligan (US) described some of the molecular architecture of the eukaryotic nuclear pore (1711).

 

Stamatis N. Alahiotis (GR) and George Kilias (GR) exposed Drosophila melanogaster populations to different temperature and humidity regimens for several years. They performed mating tests to check for reproductive isolation. They found some sterility in crosses among populations raised under different conditions. They also showed some positive assortative mating. These things were not observed in populations, which were separated but raised under the same conditions. They concluded that sexual isolation was produced as a byproduct of selection (15). Note: This is an example of sexual isolation as a byproduct of adaptation to environmental conditions in Drosophila melanogaster.

 

Andrew L. Mellor (GB-US), Lynn Golden (GB), Elisabeth H. Weiss (GB), Hilary M.S. Bullman (GB), Jane L. Hurst (GB), Elizabeth Simpson (GB), Roger F. James (GB), Alain R. Townsend (GB), Patricia M. Taylor (GB), Wilhelm R. Schmidt (DE), Janez Ferluga (GB), Louise Leben (GB), Manuel Santamaria (GB), Gladys Atfield (GB), Hilliard Festenstein (GB), and Richard Anthony Flavell (GB-US) observed that expression of the murine H-2Kb gene product on the L-cell surface is sufficient to make it a target for killing by allospecific anti-H-2Kb cytotoxic T cells (1136).

Alain R. Townsend (GB), Frances M. Gotch (GB), John Davey (GB), Jonathan Rothbard (GB), Gulam A. Bahadur (GB), David Wraith (GB), and Andrew J. McMichael (GB) demonstrated that viral pathogens are degraded inside antigen presenting cells, and ultimately pieces of the virus derived from its core associate with Class I products of the major histocompatibility complex (MHC) (1683; 1684).

Simon J. Powis (GB), Alain R. Townsend (GB), Edward V. Deverson (GB), Judy Bastin (GB), Geoffrey W. Butcher (GB), and Jonathan C. Howard (GB) established the essential role of these components in the assembly and surface expression of MHC Class I molecules themselves, leading to the discovery of peptide transporters in the endoplasmic reticulum (1354).

 

Eugene C. Butcher (US), Robert V. Rouse (US), Robert L. Coffman (US), Carol N. Nottenburg (US), Richard R. Hardy (US), and Irving L. Weissman (US) provided considerable support to the concept that germinal centers in Peyer's patches are the site of generation of precursors of the IgA-secreting plasma cells that characterize mucosal immune responses, and also suggest that germinal centers may play an important role in the process of heavy chain class switching (239).

 

Werner W. Franke (DE), Christine Grund (DE), Caecilia Kuhn (DE), Brian W. Jackson (CH), Karl Illmensee (CH), Roland Moll (DE), Dorothea L. Schiller (DE), Erika Schmid (DE), Jürgen Kartenbeck (DE), Helga Mueller (DE), Monika Schmelz (DE), Rainer Duden (GB), and Pamela Cowin (US) identified desmogleins, desmoplakin I, and desmoplakin II as part of animal desmosomes (538; 539; 1485).

 

Graham Warren (US), Hubert Reggio (FR), and Daniel Louvard (FR) devised a technique to make high-affinity antibodies to cellular organelles, specifically the Golgi complex (1045).

 

Terrell Hill (US) and Marc Kirschner (US) described how the free energy of hydrolysis of ATP could be converted into mechanical work if actin polymerized against a resisting force (752). Note: This has elegantly been shown to account both for the extension of the leading edge of motile cells and the intracellular motility of Listeria and other infectious organisms that capture the cell's actin-based motility apparatus.

 

Frederick Sanger (GB), Alan R. Coulson (GB), Guofan F. Hong (CN), Diane F. Hill (GB), and George B. Petersen (GB) determined the nucleotide sequence of lambda virus DNA (1459). Note: randomly selected clones were often redundant and accurately filling gaps was problematic.

Al Edwards (US) and C. Thomas Caskey (US) proposed a method to maximize efficiency by minimizing gap formation and redundancy: sequence both ends (but not the middle) of a long clone, rather than the entirety of a short clone (463).

Robert D. Fleischmann (US), Mark D. Adams (US), Owen White (US), Rebecca A. Clayton (US), Ewen F. Kirkness (US), Anthony R. Kerlavage (US), Carol J. Bult (US), Jean-Francois Tomb (US), Brian A. Dougherty (US), Joseph M. Merrick (US), Keith McKenney (US), Granger G. Sutton (US), William FitzHugh (US), Chris Fields (US), Jeannine D. Gocayne (US), John Scott (US), Robert Shirley (US), Li-Ing Liu (US), Anna Glodek (US), Jenny M. Kelley (US), Janice F. Weidman (US), Cheryl A. Phillips (US), Tracy Spriggs (US), Eva Hedblom (US), Matthew D. Cotton (US), Teresa R. Utterback (US), Michael C. Hanna (US), David T. Nguyen (US), Deborah M. Saudek (US), Rhonda C. Brandon (US), Leah D. Fine (US), Janice L. Fritchman (US), Joyce L. Fuhrman (US), Neil S.M. Geoghagen (US), Cheryl L. Gnehm (US), Lisa A. McDonald (US), Keith V. Small (US), Claire M. Fraser (US), Hamilton Othanel (US), and John Craig Venter (US) published the first complete DNA sequence of a free-living organism, Haemophilus influenzae. They solved the sequence using a technique known as whole-genome random sequencing and assembly (523).

John Craig Venter (US), Hamilton O. Smith (US), and Leroy E. Hood (US) proposed that the whole-genome shotgun approach could be used to sequence the human genome owing to two factors: its past successes in assembling genomes and the development of bacterial artificial chromosomes (BAC) libraries, which allowed large fragments of DNA to be cloned (1739).

Carol J. Bult (US), Owen White (US), Gary J. Olsen (US), Lixin Zhou (US), Robert D. Fleischmann (US), Granger G. Sutton (US), Judy A. Blake (US), Lisa M. FitzGerald (US), Rebecca A. Clayton (US), Jeannine D. Gocayne (US), Anthony R. Kerlavage (US), Brian A. Dougherty (US), Jean-Francois Tomb (US), Mark D. Adams (US), Claudia I. Reich (US), Ross Overbeek (US), Ewen F. Kirkness (US), Keith G. Weinstock (US), Joseph M. Merrick (US), Anna Glodek (US), John L. Scott (US), Neil S.M. Geoghagen (US), and John Craig Venter (US) determined the complete genome sequence of the methanogenic archaeon, Methanococcus jannaschii (232).

 

Carl R. Woese (US) originally described the progenote as the last common ancestor for archaebacteria (Archaea), eubacteria (Bacteria), and eukaryotes (Eucarya). It contained informational polymers, could synthesize polypeptides and was still evolving a link between genotype and phenotype (1806; 1807).

 

Harald Huber (DE), Michael Thomm (DE), Helmut König (DE), Gesa Thies (DE), and Karl O. Stetter (DE) isolated hydrothermophilic microorganisms (Archea) with optimal growth at 105 degrees C; first from shallow marine springs and later from deep-sea smokers (790).

 

Katherine E. Steinback (US), Salil Bose (IN), David J. Kyle (CA), John Bennett (GB), L. Andrew Staehelin (CH-US), Charles J. Arntzen (US), Peter Horton (GB), Christine H. Foyer (GB), and John F. Allen (SE) discovered that movement of electrons through the Z pathway in photosynthesis is optimized by keeping its two photosystems in balance and operating at very near the same speed. The redox state of plastoquinone and the activity of a protein kinase maintain this control (19; 120; 778; 1597; 1602).

 

Gerald Mayer Rubin (US) and Aaron C. Spalding (US) produced transgenic fruit flies. They introduced the gene for rosy eye color into a line of flies lacking a normal form of the gene. The normal rosy gene was inserted into a P element by recombinant DNA techniques, cloned in bacteria, and injected into Drosophila embryos. Adults exhibited the normal rosy eye color (1426; 1588).

Oliver Smithies (GB-US), Ronald G. Gregg (US), Sallie S. Boggs (US), Michael A. Koralewski (US), and Raju S. Kucherlapati (US) devised a method to find cells in which gene integration occurred at a chosen location. A rescuable plasmid containing globin gene sequences allowing recombination with homologous chromosomal sequences enabled them to produce, score and clone mammalian cells with the plasmid integrated into the human beta-globin locus. The planned modification was achieved in about one per thousand transformed cells whether or not the target gene was expressed. Their discovery showed that specific planned modification of native genes is possible. The DNA dart had found its corresponding sequence in the vast tangle of chromosomal DNA; they had targeted a specific gene (1572).

Thomas Doetschman (US), Ronald G. Gregg (US), Nobuyo Maeda (US), Martin L. Hooper (GB), David W. Melton (GB), Simon Thompson (GB), and Oliver Smithies (US) used gene targeting functionally to correct the mutant hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene in an embryonic stem (ES) cell line that had previously been isolated and used to produce an HPRT-deficient mouse. This modification of a chosen gene in pluripotent ES cells demonstrated the feasibility of this route to manipulating mammalian genomes in predetermined ways (420).

Kirk R. Thomas (US), Kim R. Folger (US), and Mario Renato Capecchi (IT-US) corrected a defective gene residing in the chromosome of a mammalian cell by injecting into the nucleus copies of the same gene carrying a different mutation. They determined how the number, the arrangement, and the chromosomal position of the integrated gene, as well as the number of injected molecules influence the gene-targeting frequency. This is called high frequency targeting of genes to specific sites in the mammalian genome (252; 1666).

Kirk R. Thomas (US) and Mario Renato Capecchi (IT-US) succeeded in showing that the Hprt (hypoxanthine phosphoribosyl transferase) gene could be knocked out in embryonic stem (ES) cells. This revolutionary technique had the potential to be used to introduce any type of mutation in every gene and for the mutant cells to then be stably propagated (1665). Note: Mutant ES cells could, in turn, be used to generate germ-line chimaeras, thereby allowing targeted knockouts or insertions, which could alter the expression of particular genes in the whole animal.

Kent G. Golic (US), Tian Xu (US), and Gerald Mayer Rubin (US) devised the FLP-FRT system of mosaic clone analysis. Andrea H. Brand (US) and Norbert Perrimon (US) devised the Gal4 system of mosaic clone analysis — two key techniques for disrupting gene expression in a small subset of cells, and for expressing genes ectopically in your cells of choice (193; 607; 1826).

 

Edouard M. Bevers (NL), Paul Comfurius (NL), Jan L.M.L. van Rijn (NL), H. Coenraad Hemker (NL), and Robert F.A. Zwaal (NL) reported that the activation of blood platelets triggers a change in the distribution of lipids in the plasma membrane: molecules of phosphatidylserine become exposed at the outer surface (140).

 

Richard Deforest Palmiter (US), Ralph Lawrence Brinster (US), Robert E. Hammer (US), Myrna E. Trumbauer (US), Michael Geoffrey Rosenfeld (US), Neal C. Birnberg (US), Ronald M. Evans (US), and Jean L. Marx (US) took a DNA fragment containing the promoter of the mouse metallothionein-I gene fused to the structural gene of rat growth hormone and microinjected it into the pronuclei of fertilized mouse eggs. The rat growth hormone gene was expressed giving rise to some supermice (1092; 1283).

 

Philip Goelet (GB), George P. Lomonossoff (GB), Peter J.G. Butler (GB), Michael E. Akam (GB), Michael J. Gait (GB), and Jonathan Karn (US) completed analysis of the entire nucleotide base sequence of the tobacco mosaic virus genome (600).

 

Norman D. Levine (US) completely revised the taxonomy of the coccidia, which included placing the coccidia in the phylum Apicomplexa (1008).

 

Norman Scott Jr. (US) wrote Herpetological Communities, which remains a vital reference. This book was among the first to evaluate techniques and provide guidelines for studying the community and population ecology of amphibians and reptiles (1506).

 

Monique Castagna (FR), Yoshimi Takai (JP), Kozo Kaibuchi (JP), Kimihiko Sano (JP), Ushio Kikkawa (JP), and Yasutomi Nishizuka (JP) discovered that the phorbol esters (plant substances) imitate diacylglycerol thus activating protein kinase C. This resulted in increased growth and tumor formation (259).

 

 James P. Allison (US), Bradley W. McIntyre (US), and David Bloch (US) described the presence of a glycoprotein on the cell surface of a mouse T cell lymphoma that was composed of two disulfide-bonded subunits, and they proposed that it “may be a clonally expressed epitope of a normal T cell-specific cell surface marker” (22).

 

Janet Davison Rowley (US) located the chromosomal regions involved with human chronic myeloid leukemia (long arm of 9 translocates to 22), acute myeloblastic leukemia (long arm of 21 translocates to 8), and acute promyelocytic leukemia (long arm of 17 translocates to 15) (1425).

 

Peter N. Goodfellow (GB), Peter W. Andrews (GB), Robert P. Erickson (US), Karen E. Davies (GB), Hans-Hilger Ropers (NL), Vincent R. Harley (AU), Robin H. Lovell-Badge (GB), Jamie W. Foster (GB), Paul S. Burgoyne (GB), Marina A. Dominguez-Steglich (GB), Silvana Guioli (GB), Cheni Kowk (GB), Polly A. Weller (GB), Milena Stevanovic (CS), Jean Weissenbach (FR), Sahar Mansour (GB), Ian D. Young (GB), Jennifer A. Marshall Graves (AU), J. David Brook (GB), Alan J. Schafer (GB), Andrea Pontiggia (IT), Rebecca Rimini (IT), Marco E. Bianchi (IT), Jérôme Collignon (GB), Shanthini Sockanathan (GB), Adam Hacker (GB), Michel Cohen-Tannoudji (FR), David Norris (GB), Sohaila Rastan (GB), Karin Schmitt (GB), Ricky Critcher (GB), Mark Bouzyk (GB), Nigel K. Spurr (GB), Tsutomu Ogata (JP), Joe J. Hoo (US), Leonard Pinsky (CA), Giorgio Gimelli (IT), Linda M. Pasztor (US), Nikola Arsic (CS), Tamara Rajic (CS), and Slavica Stanojcic (CS) did pioneering work on the genetic basis of sex determination in humans (50; 327; 474; 533; 612; 613; 669; 704; 705; 1347; 1471; 1472).

 

Stuart H. Orkin (US), Haig H. Kazazian, Jr. (US), Stylianos E. Antonarakis (US), Sabra C. Goff (US), Corrine D. Boehm (US), Julianne P. Sexton (US), Pamela G. Waber (US), and Patricia J.V. Giardina (US) used restriction fragment length polymorphisms (RFLPs) to “haplotype thalassemias” (1262).

 

Jennifer M. Davis (AU) and Margaret M. Peel (AU) report the clinical and bacteriological findings in two cases of osteomyelitis and one case of septic arthritis caused by Kingella kingae are presented. This appears to be the first report providing clear evidence for a pathogenic role for this species in bone and joint infections (384).

Kingella kingae is a fastidious gram-negative coccobacillus that colonizes the respiratory and oropharyngeal tract in children. K. kingae occasionally causes invasive disease, primarily osteomyelitis/septic arthritis in young children, bacteremia in infants, and endocarditis in school-aged children and adults.

 

The Centers for Disease Control, Gregory L. Armstrong (US), Jill Hollingsworth (US), and J. Glenn Morris, Jr. (US) report that E. coli O157:H7, the most commonly identified member of a group of organisms that is now referred to as the "Shiga toxin-producing E. coli" (STEC), has become one of the best- known emerging pathogens and one that is considered prototypic for the current paradigm of foodborne diseases in the United States. E. coli 0157:H7 causes hemorrhagic colitis (2; 44).

 

Douglas M. Tollefsen (US), David W. Majerus (US), Mary K. Blank (US) isolated a previously unrecognized heparin-dependent inhibitor of thrombin from human plasma. The inhibitor, was designated heparin cofactor II (HCII) (1678).

 

Naomi L. Esmon (US), Whyte G. Owen (US) and Charles Thomas Esmon (US), Philip C. Comp (US), Rene M. Jacocks (US), and Gary L. Ferrell (US) isolated thrombomodulin as a cofactor for thrombin‐catalysed protein C activation (331; 476).

 

George R. Merriam (US) and Kenneth W. Wachter (US) developed algorithms for the study of episodic hormone secretion (1140).

 

Jean Clark Dan (US), Donner F. Babcock (US), Neal L. First (US), Henry Arnold Lardy (US), and Ryuzo Yanagimachi (JP-US) found that calcium ion promotes lysis of the acrosomal membrane of the sperm head (acrosomal reaction) of both invertebrates and vertebrates (66; 371; 1835).

Gerald A. Rufo (US), Jai Pal Singh (US), Donner F. Babcock (US), and Henry Arnold Lardy (US) discovered that seminal fluid contains a calcium transport inhibitor that they termed caltrin (1429). Note: Sperm bound caltrins prevent calcium movement into the acrosome and thus prevent a premature acrosome reaction. When a sperm coated with transport inhibitor caltrins contacts the egg the inhibitor forms are converted to enhancer forms. The enhancer forms of caltrin then stimulate calcium uptake at the acrosome where it activates membrane decomposition and at the tail where it induces whiplash movement of the sperm tail.

 

Chiaho Shih (US), Robert Allan Weinberg (US), Mitchell Goldfarb (US), Kenji Shimizu (JP), Manuel Perucho (US), Michael Wigler (US), Simonetta Pulciani (US), Eugenio Santos (US), Anne V. Lauver (US), Linda K. Long (US), Keith C. Robbins (US), and Mariano Barbacid (US) all cloned the first oncogene, it came from bladder carcinoma lines. These cloned cellular genes had the same transforming properties as the oncogenes from retroviruses (603; 1360; 1537). Note: This is the discovery of oncogenes in humans.

Geoffrey M. Cooper (US), Luis F. Parada (US), Clifford J. Tabin (US), Chiaho Shih (US), Robert Allan Weinberg (US), Eugenio Santos (US), Steven R. Tronick (US), Stuart A. Aaronson (US), Simonetta Pulciani (US), Mariano Barbacid (US), Channing J. Der (US), and Theodore G. Krontiris (US) determined that the oncogenes in question are the cellular homologues of the ras genes from the Harvey and Kirsten sarcoma viruses (341; 407; 718; 902; 1288; 1460).

Clifford J. Tabin (US), Scott M. Bradley (US), Cornelia I. Bargmann (US), Robert Allan Weinberg (US), Alex G. Papageorge (US), Edward M. Scolnick (US), Ravi Dhar (US), Douglas R. Lowy (US), Esther H. Chang (US), E. Premkumar Reddy (US), Roberta K. Reynolds (US), Eugenio Santos (US), Mariano Barbacid (US), Elizabeth J. Taparowsky (US), Yolande Suard (US), Ottavio Fasano (US), Kenji Shimizu (US), Mitchell Goldfarb (US), and Michael H. Wigler (US) identified the difference between the normal cellular human c-Ha-RAS1 gene and its transforming counterpart from the carcinoma lines. They discovered the same single amino-acid change: glycine to valine at position 12 (1376; 1637; 1648). Note: Subsequent research has shown that this change alters the structure of the RAS protein to make it constitutively active.

Esther H. Chang (US), Mark E. Furth (US), Edward M. Scolnick (US), and Douglas R. Lowy (US) discovered the ras oncogene in humans (272).

James R. Feramisco (US) Michell Gross (US), Tohru Kamata (US), Martin Rosenberg (US), and Raymond W. Sweet (US) showed that microinjection of the activated human Ras protein into quiescent mammalian fibroblasts transiently stimulated cell growth in the absence of growth factors (508).

Linda S. Mulcahy (US), Mark R. Smith (US), and Dennis W. Stacey (US) found that microinjection of antibodies inhibited serum-stimulated growth of cultured fibroblasts (1182).

Dafna Bar-Sagi (US) and James R. Feramisco (US) found that the same Ras oncogene protein that stimulated cell growth is also capable of triggering cell differentiation (84).

 

The Centers for Disease Control in Atlanta, Georgia received reports on 19 cases of biopsy-confirmed Kaposi’s sarcoma (named for Moriz Kohn Kaposi, a 19th century Hungarian dermatologist) and/or Pneumocystis carinii pneumonia among previously healthy homosexual male residents of Los Angeles and Orange Counties, California. These symptoms would later be recognized as diagnostic of acquired immune deficiency syndrome (AIDS) (337).

 

Patrick C. Walsh (US) developed a nerve-sparing method of prostate removal. The procedure, in its refined form, dramatically reduces the risk of post-surgical impotence and incontinence (1757).

 

John J. Gallagher (US), Robert H. Svenson (US), Jackie H. Kasell (US), Lawrence D. German (US), Gust H. Bardy (US), Archer Broughton (AU), Giuseppe Critelli (IT), Melvin M. Scheinman (US), Fred Morady (US), David S. Hess (US), and Rolando Gonzalez (US) were the first to perform noninvasive His bundle ablation on a human (568; 1476).

Toshio Mitsui (JP), H. Jima (JP), Kenji Okamura (JP), and Motokazu Hori (JP) had reported successful transvenous electrocautery of the atrioventricular connection in dogs (1157).

Lura Harrison (US), John J. Gallagher (US), Jackie H. Kasell (US), Robert H. Anderson (US), Eileen Mikat (US), Donald B. Hackel (US), Andrew G. Wallace (US), Will C. Sealy (US), Roger Millar (US), Ronald W.F. Campbell (US), Edward L.C. Pritchett (US), and Andrew G. Wallace (US) used intraoperative mapping and cryosurgical ablation of the A-V node-His bundle to produce A-V blockage (567; 714).

 

Richard John Heald (GB), Elizabeth M. Husband (GB), and Roger D.H. Ryall (GB) in their approach to excision of rectal cancer focused their attention on the importance of performing a total mesorectal resection. The concept behind the operation is that rectal cancer spreads within the mesorectum rather than within the rectal muscle itself. They achieved low rates of local recurrance while using a reduced distal resection margin, avoiding abdomino-perineal resection and permanent colostomy in many patients with lower third tumors (727; 728).

Philip Quirke (GB), Paul Durdey (GB), Michael Frederick Dixon (GB), and Norman S. Williams (GB) found that local recurrence of rectal adenocarcinoma results from a lateral spread (1363).

The Mercury Study Group (GB) reported that high-resolution magnetic resonance imagery accurately predicts resection margin involvement. The technique was reproduced accurately in multiple research centers, allowing selection of patients for neoadjuvant treatment (655).

 

The Hypertension Detection and Follow-up Program (HDFP) previously reported a 16.9% reduction in all-cause mortality among its Stepped Care (SC) group, relative to the community-treated Referred Care (RC) group. The current report compares cerebrovascular disease (CV) morbidity and mortality in the SC and RC populations. The SC five-year stroke incidence (1.9 per 100 persons) is significantly lower than that found among the RC (2.9 per 100 persons). Reductions in stroke rates among SC were experienced for all race-sex groups, all diastolic blood pressure strata, all ages, and among those with or without evidence of long-standing hypertension. Comparisons of the CV death rates for SC (1.06 per 1,000 persons) and RC (1.91 per 1,000 persons) with those obtained for the general US population (0.83 per 1,000 persons) indicate that the CV death rate decreased in the SC hypertensive population to a level approaching that of the general US population (1359).

 

Tu You-you (CN), Ni Mu-yun (CN), Zhong Yu-rong (CN), Li Lan-na (CN), Cui Shu-lian (CN), Zhang Mu-qun (CN), Wang Xiu-zhen (CN), Ji Zheng (CN), and Liang Xiao-tian (CN) carried out a large-scale screening of animals infected with the malaria parasite and found an extract from the Artemisia annua (sweet wormwood) plant, that held promise. Called artemisinin, it and one of its metabolic derivatives dihydroartemisinin, proved highly effective against the malaria parasite in animals and humans (1853; 1854).

 

The Centers for Disease Control (CDC) added “Introduction to Table V Premature Deaths, Monthly Mortality, and Monthly Physician Contacts — United States”in 1982 (1).

 

Farooq Azam (US), Tom Fenchel (DK), John G. Field (ZA), John S. Gray (NO), Lutz-Arend Meyer-Reil (DE), and Frede Thingstad (NO) introduced the concept of the "Microbial Loop" and catalyzed a new perception of marine food webs. In this concept heterotrophic and phototrophic bacteria and small eucaryotic phytoplankton are consumed by heterotrophic nanoflagellates, which are themselves consumed by larger protozoa and then metazoa, linking the energy lost as dissolved organic matter back (loop) to copepods and other consumers of net plankton (64).

 

Charles R. Taylor (US), Norman C. Heglund (US), and Geoffrey Mole Ole Maloiy (KE) considered metabolic energy consumed during terrestrial locomotion. Their data-relating rate of oxygen consumption and speed are reported for: eight species of wild and domestic artiodactyls; seven species of carnivores; four species of primates; and one species of rodent. From ants to elephants, the mass-specific metabolic cost of transport for terrestrial legged locomotion decreases with increasing body mass in a systematic manner (primary allometric signal). Yet at each body size, one finds species with energetic costs of transport that are much greater or less than expected (secondary allometric signal) (1652).

 

Russell Lande (US) developed a dynamic theory of life history evolution by synthesizing population demography with quantitative genetics (965).

 

William Donald Hamilton (US) and Marlene Zuk (US) found that in North American passerines (sometimes known as perching birds or, less accurately, as songbirds) there exists a highly significant association over species between incidence of chronic blood infections (five genera of protozoa and one nematode) and striking display (three characters: male "brightness," female "brightness," and male song). This result conforms to a model of sexual selection in which (i) coadaptational cycles of host and parasites generate consistently positive offspring-on-parent regression of fitness, and (ii) animals choose mates for genetic disease resistance by scrutiny of characters whose full expression is dependent on health and vigor (691).

 

Stephen Jay Gould (US) and Elisabeth S. Vrba (ZA-US) explained exaptation refers to when a trait which evolved for one purpose gets used for another (such as feathers, which were originally evolved for warmth then later used for flying) (629).

 

Elaine Morgan (US) proposed that man descended from apes that adapted to an aquatic environment then returned to a terresterial lifestyle. Man is seen as retaining aquatic adaptations such as weeping, loss of body hair, bipedalism, face-to-face copulation, and the diving reflex (1170).

 

1983

“Boveri’s contributions to clear thinking on cancer ranks closely to Mendel’s contribution to clear thinking on genes.” Ruth Sager (1438).

 

Henry Taube (CA-US) was awarded the Nobel Prize in Chemistry for his work on the mechanisms of electron transfer reactions, especially in metal complexes.

 

Barbara McClintock (US) was awarded the Nobel Prize in Physiology or Medicine for her discovery of mobile genetic elements.

 

David J. Stevenson (US), Takafumi Matsui (JP), and Yutaka Abe (JP) reasoned that the Earth, a planet with a metallic core, highly convective mantle, molten surface, and massive steam atmosphere, formed as a direct result of accretion (5; 1096; 1607).

Immaunel Kant (DE) had proposed much earlier that the Earth formed by condensation (864; 865).

 

Preston Ercelle Cloud, Jr. (US) and Stanley L. Miller (US) made the argument that the Earth’s primitive atmosphere was virtually devoid of oxygen (312; 1152).

 

J. William Schopf (US), John M. Hayes (US), and Malcolm R. Walter (US), speculated that life on Earth might have arisen as early as 3.9 G (1494).

 

Stanley M. Awramik (US), J. William Schopf (US), Malcolm R. Walter (US), and Bonnie M. Packer (US) found rock bearing 3.5 G microfossils within early Archean stromatolites (Gk. archaios=ancient) (62; 1493; 1496). The microfossils were interpreted to be prokaryotes and represent the oldest fossils known (1495).

 

Choh Hao Li (CN-US), Donald Yamashiro (US), Denis Gospodarowicz (US), Selna L. Kaplan (US), and Guy Van Vliet (US) accomplished the total synthesis of insulin-like growth factor I (somatomedin C) (1015).

 

Mark D. Biggin (GB), Toby J. Gibson (DE), and Guofan F. Hong (CN) described two methods for increasing the length of DNA sequence data that can be read off a polyacrylamide gel. First they describe a way to pour a buffer concentration gradient gel that, by altering the vertical band separation on an autoradiograph, allows more sequence to be obtained from a gel and second show that the use of deoxyadenosine 5'-(alpha- [35S] (thio) triphosphate as the label incorporated in dideoxynucleotide sequence reactions increases the sharpness of the bands on an autoradiograph and so increases the resolution achieved (148).

 

William S. Dynan (US) and Robert Tjian (US) isolated the eukaryotic transcription factor Sp1 that works with RNA polymerase II (456).

 

Donald R. Senger (US), Stephen J. Galli (US), Ann M. Dvorak (US), Carole A. Perruzzi (US), V. Susan Harvey (US), Harold F. Dvorak (US), Yuen Shing (US), Moses Judah Folkman (US), Robert Sullivan (US), Catherine Butterfield (US), Joseph Murray (US), and Michael Klagsbrun (US), discovered vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF); molecules which mediate angiogenesis (1519; 1538).

Pamela J. Keck (US), Scott D. Hauser (US), Gwen Krivi (US), Kim Sanzo (US), Thomas Warren (US), Joseph Feder (US), and Daniel T. Connolly (US) demonstrated that tumor-derived vascular permeability factor (VPF) and vascular endothelial growth factor (VEGF) are one and the same (879). Note: This was an important finding in that it showed that a single vascular agent could have multiple functions.

Birgit Millauer (DE), Susanne Wizigman-Voss (DE), Harald Schnurch (DE), Ricardo Martinez (US), Niels P. Møller (DE), Werner Risau (DE), and Axel Ullrich (DE) made the first report demonstrating that VEGF is the ligand for VEGFR2 (Flk-1); this is a very important report that links VEGF to a tyrosine kinase receptor (1150).

Peter Carmeliet (BE), Valérie Ferreira (BE), Georg Breier (BE), Saskia Pollefeyt (BE), Lena Kieckens (BE), Marina Gertsenstein (BE), Michaela Fahrig (BE), Ann Vandenhoeck (BE), Kendraprasad Harpal (BE), Carmen Eberhardt (BE), Cathérine Declercq (BE), Judy Pawling (BE), Lieve Moons (BE), Désiré Collen (BE), Werner Risau (BE), Andras Nagy (BE), Napoleone Ferrara (US), Karen Carver-Moore (US), Helen Chen (US), Mary Dowd (US), Lucy Lu (US), K. Sue O'Shea (US), Lyn Powell-Braxton (US), Kenneth J. Hillan (US), Mark W. Moore (US), Guo-Hua Fong (CA), Janet Rossart (CA), Martin L. Breitman (CA), Sachie Hiratsuka (JP), Osamu Minowa (JP), Junko Kuno (JP), Tetsuo Noda (JP), Masabumi Shibuya (JP), Fouad Shalaby (CA), Terry P. Yamaguchi (CA), Xiang-Fu Wu (CA), and Andre C. Schuh (CA) found that the VEGF receptors, Flt-1 (VEGFR-1) and Flk-1 (VEGFR-2), are critical for embryonic angiogenesis (255; 511; 528; 756; 1524).

Tamar Alon (IL), Itzhak Hemo (IL), Ahuva Itin (IL), Jacob Pe'er (IL), Jonathan Stone (AU), Eli Keshet (IL), Hadassah Gnessin (IL), and Tailoi Chan-Ling (AU) described the roles of VEGF in normal vascular development (physiological hypoxia) and vessel survival, two critical issues when considering inhibition of VEGF in pathological angiogenesis. They also described the relationship between blood vessels and astrocytes (23; 1610).

Michael Jeltsch (FI), Arja Kaipainen (FI), Vladimir Joukov (FI), Xiaojuan Meng (FI), Merja Lakso (FI), Heikki Rauvala (FI), Melody Swartz (US), Dai Fukumura (US), Rakesh K. Jain (US), and Karl Alitalo (FI) established the role of VEGF-C and VEGF-R3 signaling in lymphangiogenesis (835). Note: A new field is born.

Shay Soker (US), Seiji Takashima (US), Hua Quan Miao (US), Gera Neufeld (IL), and Michael Klagsbrun (US) identified neuropilin-1 as an additional receptor for VEGF unrelated to the Flt-1 and Flk-1 tyrosine kinase receptors (1577).

 

Armando J. Parodi (AR), Daniel H. Mendelzon (AR), Gerardo Z. Lederkremer (AR), and Josefina Martin-Barrientos (AR) established the occurrence of transient glucosylation of glycoproteins in the endoplasmic reticulum (1294-1296). Note: They later showed that the glucosyltransferase involved in these reactions preferentially uses acceptor glycoproteins not displaying their native three-dimensional structure, suggesting that the enzyme might be involved in the quality control of glycoprotein folding. It was later discovered that the endoplasmic reticulum resident chaperone calnexin interacts specifically with glycoproteins bearing monoglucosylated glycans (with the structures created by the endoplasmic glucosyltransferase) thus confirming the role of transient glucosylation in quality control of glycoprotein folding.

 

Karen A. Magnus (US) and Eaton E. Lattman (US) discovered the helix-turn-helix structural motif common to many regulatory proteins (1071).

 

Robert S. Fuller (US) and Arthur J. Kornberg (US) isolated a protein from Escherichia coli that appears necessary for the initiation of DNA unwinding at the replication origin (oriC) (559).

 

Hiroto Okayama (JP) and Paul Berg (US) described the pcDV1 and pL1 plasmid vectors for cloning cDNAs in Escherichia coli; the same vector promotes expression of the cDNA segment in mammalian cells (1252).

 

Donna L. Daniels (GB), Frederick Sanger (GB), and Alan R. Coulson (GB) reported the analysis of the complete 48,502 base pair sequence of the DNA of bacteriophage lambda (372).

 

Scott D. Putney (US), Walter C. Herlihy (US), Paul Reinhard Schimmel (US), Robert J. Milner (US), and J. Gregor Sutcliffe (US) sequenced fragments of DNA by the shotgun approach discovered by Schimmel and Sutcliffe. The technique was later dubbed expressed sequence tags (ESTs) (1155; 1361).

 

Andrew W. Murray (US) and Jack William Szostak (CA-PL-GB-US) constructed artificial chromosomes in yeast (1196).

David T. Burke (US), Georges F. Carle (US), and Maynard V. Olsen (US) created yeast artificial chromosomes (YACs) which proved to be excellent cloning vectors for large pieces of DNA (233).

Hiroaki Shizuya (US), Bruce Birren (US), Ung Jin Kim (US), Valeria Mancino (US), Tatiana Slepak (US), Yoshiaki Tachiri (US), and Melvin Simon (US) modified an endogenous circular plasmid in E. coli, the fertility (F) factor present at one or two copies per cell, to create a cloning vector. In reference to its yeast cousin, they called it bacterial artificial chromosome (BAC). With a cloning capacity of ~300 kb, BACs are not as potent as YACs, but they have all the advantages of a bacterial vector: stability, and ease of manipulation and purification (1540).

 

Karen E. Davies (GB), Peter L. Pearson (BR), Pauline S. Harper (GB), Jeffrey M. Murray (GB), William T. O’Brien (US), Mansoor Sarfarazi (US) and Robert C. Williamson (GB) discovered the gene marker for Duchenne muscular dystrophy (377).

Peter N. Ray (CA), Bonnie Belfall (CA), Catherine Duff (CA), Cairine Logan (CA), Vanora Kean (CA), Margaret W. Thompson (CA), James E. Sylvester (US), Jerome L. Gorski (US), Roy D. Schmickel (US), and Ronald G. Worton (CA) located the Duchenne muscular dystrophy (DMD) X-linked recessive disorder gene within band Xp21 of the X chromosome (1375).

Susan M. Forrest (GB), Gareth S. Cross (GB), Astrid Speer (GB), David Gardner-Medwin (GB), John Burn (GB), and Karen E. Davies (GB) found that both Duchenne and Becker muscular dystrophy (DMD and BMD) genes are located in Xp21 on the short arm of the X chromosome (531).

Eric P. Hoffman (US), Robert H. Brown, Jr. (US), and Louis M. Kunkel (US) produced antibodies to the mDMD and DMD gene protein products. They used these antibodies to study the protein product of the Duchenne muscular dystrophy locus, called dystrophin, in tissues isolated from both normal and dystrophic mice and humans (763).

Karen E. Davies (GB), Terry J. Smith (GB), Sarah Bundey (GB), Andrew P. Read (GB), Tracey Flint (GB), Martyn V. Bell (GB), and Astrid Speer (GB) determined that mild and severe muscular dystrophy are associated with deletions in Xp21 of the human X chromosome (378).

Peter Sicinski (US), Yan Geng (CN), Allan S. Ryder-Cook (US), Eric A. Barnard (GB), Mark G. Darlison (DE), and Pene J. Barnard (GB) found the molecular basis of muscular dystrophy in the mdx mouse to be a point mutation (1544).

Nguyen thi Man (GB), J.M. Ellis (GB), Donald R. Love (NZ), Karen E. Davies (GB), Kevin C. Gatter (GB), George Dickson (GB), and Glenn E. Morris (GB) identified a protein they called utrophin (1664). Note: In early human life, Davies says, utrophin serves as a kind of infantile form of dystrophin, the crucial protein missing or deficient in the muscle cells of boys with Duchenne and Becker muscular dystrophies. However, as the organism reaches adulthood, the utrophin protein serves its own distinct function. "We think it's a stabilizing protein at the neuromuscular junction," Davies says.

 

Philip Leder (US), Timothy Stewart (US), and Paul Pattengale created OncoMice by using a fine glass needle to inject known cancer genes into mouse embryos just after fertilization. This genetic modification not only made the mice prone to cancer, but also ensured that they would pass the cancer genes to their offspring. This animal was patented as "Transgenic Non-Human Mammals" (986). Note: This was the first animal to be patented in the United States.

 

Gale E. Smith (US), Max D. Summers (US), and Malcolm J. Fraser (US) produced human beta interferon in insect cells (Spodoptera frugiperda, fall armyworm) infected with a baculovirus expression vector (1565).

 

Douglass J. Forbes (US), Frank D. McKeon (US), Daniel Caput (FR), Georg Krohne (DE), Elke Debus (DE), Mary Jane Osborn (US), Werner W. Franke (DE), Denny L. Tuffanelli (US), Satoru Kobayashi (JP), Kimie Fukuyama (US), John W. Newport (US), Marc Wallace Kirschner (US), and Klaus Weber (DE) used sequencing studies and antibody probes to identify nuclear envelope lamins as a form of intermediate filament closely related to cytoplasmic intermediate filaments (530; 939; 1125-1128; 1267).

 

Lawrence Greenfield (US), Michael J. Bjorn (US), Glenn Horn (US), Darlene Fong (US), Gregory A. Buck (US), R. John Collier (US), and Donald A. Kaplan (US) cloned and sequenced the structural gene for diphtheria toxin carried by corynebacteriophage beta (644).

 

Kathryn Haskins (US), Ralph Kubo (US), Janice White (US), Michelle Pigeon (US), John W. Kappler (US), and Philippa Marrack (US) used monoclonal antibody to isolate the major histocompatibility complex-restricted antigen receptor on T cells (721).

John W. Kappler (US), Ralph Kubo (US), Kathryn Haskins (US), Charles Hannum (US), Philippa Marrack (US), Michele Pigeon (US), Bradley McIntyre (US), James Allison (US), and Ian Trowbridge (US) examined the variability of the MHC restricted receptor on murine T cells by comparing tryptic peptide fingerprints of the receptor isolated from three T cell hybridomas and a T cell tumor. Both variable and constant peptides were seen. Constant peptides were most apparent when comparing receptors from the same mouse strain. Peptide fingerprints of receptors from two independent T cell hybridomas with the same idiotype and specificity were identical. They also described a molecule detected on the surface of a human T cell leukemia whose properties were identical to those reported for the MHC receptor on normal human T cells (866).

 

David A. Bass (US), J. Wallace Parce (US), Lawrence R. Dechatelet (US), Pamela Szejda (US), Michael C. Seeds (US), and Michael Thomas (US) developed a quantitative assay to monitor the oxidative burst (H2O2 production) of polymorphonuclear leukocytes (PMNL) using single cell analysis by flow cytometry, and have examined whether PMNL respond to membrane stimulation with an all-or-none oxidative burst. They found that oxidative product formation by PMNL occurs as a graded response to membrane stimulation by phorbol myristate acetate (PMA) (95).

 

Thedi Ziegler (FI), Olli H. Merurman (FI), Pertti Arstila (FI), and Pekka H. Halonen (FI) developed solid-phase enzyme-immunoassay for the detection of herpes simplex virus antigens in clinical specimens (1862).

 

Bradley W. McIntyre (US) and James P. Allison (US) characterized the mouse T cell receptor. Their data indicated that the T cell-specific receptor heteroduplex has regions of constant and regions of variable structure consistent with the properties expected for the T cell antigen receptor (1123).

 

Stefan C. Meuer (DE), Kathleen A. Fitzgerald (US), Rebecca E. Hussey (US), James C. Hodgdon (US), Stuart F. Schlossman (US), and Ellis L. Reinherz (US), working in humans, found that clonotypic T cell receptors contain two molecules of molecular weight 49,000 and 43,000 respectively. These molecules are associated with, but distinct from the T3 molecule expressed on all mature T lymphocytes (1146).

Stefan C. Meuer (DE), James C. Hodgdon (US), Rebecca E. Hussey (US), Jeffrey P. Protentis (US), Stuart F. Schlossman (US), and Ellis L. Reinherz (US) found that anticlonotypic monoclonal antibodies to the 49/43-kD heterodimer of a given clone or antibodies to the 20/25-kD membrane associated monomorphic T3 molecule selectively induce proliferation and IL-2 secretion when linked to a solid support. The antibodies behave as antigen and support the idea that the T3-Ti molecular complex represents the antigen receptor on human lymphocytes (1147).

Stephen M. Hedrick (US), David I. Cohen (US), Ellen A. Nielsen (US), and Mark M. Davis (US) used cDNA probes to locate a region in the murine T cell genome, which encodes the antigen receptor on the surface of T lymphocytes (731).

 

Robert D. Schreiber (US), Judith L. Pace (US), Stephen W. Russell (US), Amnon Altman (US), and David H. Katz (US) provided biochemical and biosynthetic evidence indicating that the macrophage activating factor (MAF) produced by the murine T cell hybridoma clone 24/G1, which primes macrophages for nonspecific tumoricidal activity, is a form of gamma-interferon (IFN gamma) (1499).

 

Aziz Sancar (TR-US), W. Dean Rupp (US), Anthony T. Yeung (US), William B. Mattes (US), Euk Y. Oh (US), and Lawrence Grossman (US) discovered that proteins which mediate the individual steps in Escherichia coli nucleotide excision repair mechanism are encoded by the uvrA, uvrB, and uvrC genes. The UvrA, UvrB, and UvrC proteins act in a series of steps to first recognize and bind to the damaged site and then hydrolyze two phosphodiester bonds, one 7 nucleotides 5’ and the other 3 or 4 nucleotides 3’ of the modified nucleotide (1454; 1842).

 

Hanspeter Streb (DE), Robin F. Irvine (GB), Michael John Berridge (GB), and Irene Schulz (DE) provided evidence that when phosphatidylinositol 4,5-biphosphate is hydrolyzed to yield inositol 1,4,5-triphosphate, the later serves as a second messenger mediator of calcium release from internal cellular reservoirs (139; 1611).

 

Ulf Skoglund (SE), Kim Andersson (SE), Birgitta Björkroth (SE), Mary M. Lamb (US), and Bertil Daneholt (SE) used electron microscopy to characterize the growth and maturation of the transcription products on the Balbiani ring (BR) genes in Chironomus tentans (1558).

 

John E. Walker (GB), Nicholas J. Gay (GB), Masamitsu Futai (JP), and Hiroshi Kanazawa (JP) successfully isolated the gene complex coding for the entire group of polypeptides forming the FoF1-ATPase in Escherichia coli (560; 1755).

 

Manfred J. Lohka (CA) and Yoshio Masui (CA) found that a cell-free preparation of the cytoplasm from activated eggs of Rana pipiens induces, in demembranated sperm nuclei of Xenopus laevis, formation of a nuclear envelope, dispersion of chromatin, initiation of DNA synthesis, and chromosome condensation (1037).

 

Hiroko Sudo (JP), Hiro-Ari Kodama (JP), Yuji Amagai (JP), Shigehisa Yamamoto (JP), and Shiro Kasai (JP) developed the MC3T3-E1 cell line. This line became confluent, exhibited properties of osteoblasts, including high alkaline phosphatase activity, and stained for calcified secretions. Calcified nodes appeared and then grew in number and size to eventually fuse with one another. Mineralization proceeded in much the same way it did in vivo, by the secretion of matrix vesicles containing crystals, which were deposited along collagen fibrils. Electron diffraction defined the crystals as hydroxyapatite, the chemical that forms bone matrix (1619).

Akira Yamaguchi (JP), Takenobu Katagiri (JP), Tohru Ikeda (JP), John M. Wozney (US), Vicki Rosen (US), Elizabeth A. Wang (US), Arnold J. Kahn (US), Tatsuo Suda (JP), and Shusaku Yoshiki (JP) discovered that bone morphogenetic protein acts as a potent inducer of osteoblast differentiation (1830).

 

Werner W. Franke (DE), Christine Grund (DE), Brian W. Jackson (CH), and Karl Illmensee (DE) discovered that during epidermal development, embryonic basal cells are the first to express detectable levels of the type 1 keratin K14 (50kD) and type 2 keratin (58kD) (537).

 

W. Michael Gallatin (US), Irving L. Weissman (US), and Eugene C. Butcher (US) described a monoclonal antibody, MEL-14, specific for a lymphocyte surface molecule that appears to mediate recognition of lymph node HEV, and to be required for lymphocyte homing into lymph nodes in vivo (569). Note: Lymphocytes migrate from the bloodstream by recognizing and binding to specialized endothelial cells lining the high endothelial venules (HEV) in lymph nodes and Peyer's patches.

 

Karl O. Stetter (DE), Helmut König (DE), and Erko Stackebrandt (DE) discovered Pyrodictium, a bacterium with an optimum growth temperature of 105° C and a maximum growth temperature of 110° C. These qualities placed it in a subgroup of the extremeophiles referred to as hyperthermophiles (1606).

 

Jean-Pierre Métraux (CH), Ilya Raskin (US), and Hans Kende (CH-US) examined the environmental and hormonal regulation of the growth response in deep-water rice and the cellular basis of rapid internodal elongation. They found that the plant hormone ethylene accumulates in submerged internodes because of enhanced synthesis under reduced partial pressures of O2 and because of its low rate of diffusion from the plant into the surrounding water (1144; 1373).

Ilya Raskin (US), Susanne Hoffmann-Benning (US) and Hans Kende (CH-US) found that the interaction of ethylene and two other plant hormones—abscisic acid (ABA), and gibberellin (GA)—determines the growth rate of deep-water rice. Ethylene renders the internode more responsive to GA, at least in part by lowering the level of endogenous ABA, a potent antagonist of GA action in rice. Growth of the internode is, ultimately, promoted by GA (765; 1374).

Margret Sauter (US) and Han Kende (CH-US) determined that the primary target tissue of GA is the intercalary meristem of the internode, where GA enhances cell division activity. Cells are displaced from the intercalary meristem into the elongation zone, where they reach their final size (1374; 1465).

 

Reinhardt Møbjerg Kristensen (DK) and Robert P. Higgins (US) discovered, described, and named the phylum Loricifera (749; 936; 937). Note: These metazoans are microscopic (meiofaunal) animals possessing spiny heads and unsegmented bodies encased in a vase-shaped anterior that can retract into the posterior trunk. Some are acoelomates and others are pseudocoelomates.

Reinhardt Møbjerg Kristensen (DK) and Peter Funch (DK) described a new meiofaunal animal representing a new group of microscopic animals, Micrognathozoa, from a cold spring at Disko Island (938).

Roberto Danovaro (IT), Antonio Dell'Anno (IT), Antonio Pusceddu (IT), Cristina Gambi (IT), Iben Heiner (DK), and Reinhardt Møbjerg Kristensen (DK) discovered that at least three species of the Loriciferans are the first known multicellular organisms, which spend their entire lives in an anoxic environment. They are able to do this because they rely on hydrogenosomes instead of mitochondria for energy (373).

 

Robert S. Hikida (US), Robert S. Staron (US), Frederick C. Hagerman (US), William Michael Sherman (US) and David L. Costill (US) demonstrated that "the stresses and strains of violent effort" could lead to microscopic injury to the muscle fiber (677; 751). Note: Archibald Vivian Hill (GB) had predicted this result.

William C. Byrnes (US), Priscilla M. Clarkson (US), John S. White (US), Sandy S. Hsieh (US), Peter N. Frykman (US), and Ronald J. Maughan (GB) found that muscle adapts to the stress of violent effort, noting that a single bout of eccentric exercise can protect against muscle soreness and damage from future bouts for up to 6 weeks (243). Note: Archibald Vivian Hill (GB) had predicted this result.

 

Mikhail S. Balayan (RU) discovered the hepatitis E virus (the only hepevirus) (74).

 

Ze’ev Trainin (IL), Dorothee Wernicke (DE), Hannah Ungar-Waron (IL), and Myron Elmer Essex (US) reported that a retrovirus responsible for feline leukemia in feral cats also produces immunodeficiency in the same animals (1687). Note: Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are sometimes mistaken for one another though the viruses differ in many ways.

Niels C. Pedersen (US), Esther W. Ho (US), Marlo L. Brown (US), and Janet K. Yamamoto (US) first isolated feline immunodeficiency virus (FIV) which was called feline T-lymphotropic virus at the time (1317).

Myron Elmer Essex (US), Mary Frances McLane (US), Tun-Hou Lee (US), Larry Falk (US), Craig W.S. Howe (US), James I. Mullins (US), Cirilo D. Cabradillo (US), Donald P. Francis (US), Edward P. Gelmann (US), Mikulas Popovic (US), Douglas Blayney (US), Henry Masur (US), Gurdip Sidhu (US), Rosalyn Stahl (US), Robert Charles Gallo (US), Prem S. Sarin (US), Marjorie Robert-Guroff (US), Ersell Richardson (US), Francoise Barré-Sinoussi (FR), Jean-Claude Chermann (FR), Francoise Rey (FR), Marie-Thérèse Nugeyre (FR), Sophie Chamaret (FR), Jacqueline Gruest (FR), Charlie Dauguet (FR), Claudine Axler-Blin (FR), Francoise Vezinet-Brun (FR), Christine Rouzioux (FR), A. Gérard Saimot (FR), Jean-Claude Gluckman (FR), David Klatzmann (FR), Etienne Vilmer (FR), Claude Griscelli (FR), C. Foyer-Gazengel (FR), Jean-Baptiste Brunet (FR), Willy Rozenbaum (FR), and Luc Montagnier (FR) produced empirical evidence for the hypothesis that AIDS is caused by one or more immunosuppressive T cell tropic retroviruses. The Americans initially referred to the viral agent as human T cell leukemia virus type 3 (HTLV-III) while the French called it lymphadenopathy-associated retrovirus (LAV) (91; 478; 571; 583; 1162; 1163). The name of the virus causing AIDS would shortly be changed to human immunodeficiency virus (HIV). It became HIV-1 after another strain, HIV-2, was isolated from West African patients (309).

Francois Clavel (FR), Denise Guetard (FR), Francoise Brun-Vezinet (FR), Sophie Chamaret (FR), Marie-Anne Rey (FR), Maria Odete Santos-Ferreira (FR), Anne G. Laurent (FR), Charles Dauguet (FR), Christine Katlama (FR), Christine Rouzioux (FR), David Klatzmann (FR), John L. Champalimaud (FR), and Luc Montagnier (FR) isolated human immunodeficiency virus type 2 from patients in West Africa. This virus causes AIDS (309).

 

Abebe Haregewoin (ET-US), Tore Godal (NO), Abu Salim Mustafa (NO), Ayele Belehu (ET), and Tebebe Yemaneberhan (ET) demonstrated that patients with severe leprosy are not producing interleukin 2 (701).

Nadia Accily Pinto Nogueira (BR), Gilla Kaplan (US), Efrat Levy (US), Euzenir Nunes Sarno (BR), Peter J. Kushner (US), Angela Granelli-Piperno (US), Luis Carlos Arango Vieira (BR), V. Colomer-Gould (US) William R. Levis (US), Ralph Marvin Steinman (US), Yum K. Yip (US), and Zanvil Alexander Cohn (US) discovered that there is a defective gamma interferon production in leprosy; reversible with antigen and interleukin 2 (1228).

 

Lee W. Riley (US), Robert S. Remis (US), Steven D. Helgerson (US), Harry B. McGee (US), Joy G. Wells (US), Betty R. Davis (US), Richard J. Hebert (US), Ellen S. Olcott (US), Linda M. Johnson (US), Nancy T. Hargrett (US), Paul A. Blake (US), and Mitchell L. Cohen (US) were able to firmly link Escherichia coli serotype O157:H7 with a clinically distinctive gastrointestinal disorder later called EHEC (enterohemorrhagic Escherichia coli) diarrhea (1401).

 

Rino Rappuoli (IT) characterized a molecule, CRM197, that today is the most widely used carrier for vaccines against H. influenzae, N. meningitidis and pneumococci (1368).

Rino Rappuoli (IT), Beatrice Aricó (IT), Gill Douce (GB), Gordon Dougan (GB), Mariagrazia Pizza (IT), Maria Rita Fontana (IT), and Vincenzo Scariato (IT) introduced the concept that bacterial toxins can be detoxified by manipulation of their genes (genetic detoxification) (43; 1336; 1337; 1371).

Rino Rappuoli (IT), Audino Podda (IT), Mariagrazia Pizza (IT), Antonello Covacci (IT), Antonella Bartoloni (IT), Maria Teresa de Magistris (IT), and Luciano Nencioni (IT) developed a vaccine against pertussis (whopping cough) by engineering B. pertussis to produce a non toxic pertussis toxin antigen (1372). Note: This was the first rationally designed molecule approved for human use as a vaccine.

Paolo Costantino (IT), Stefano Viti (IT), Audino Podda (IT), Melecia Antonio Velmonte (IT), Luciano Nencioni (IT), and Rino Rappuoli (IT) developed the first conjugate vaccine against meningococcus C. It eliminated the disease in the UK by year 2000 (345).

Rino Rappuoli (IT) introduced the use of genomes to develop new vaccines (reverse vaccinology) (1369; 1370). Note: In the process of reverse vaccinology the entire genomic sequence of a pathogen is screened using bioinformatics tools to help determine which genes code for which proteins, against which vaccines can be developed.

 

Barry James Marshall (AU) and John Robin Warren (AU) showed that the bacterium Helicobacter pylori (H. pylori) plays a major role in causing many peptic ulcers, challenging decades of medical doctrine holding that ulcers were caused primarily by stress, spicy foods, and too much acid. This discovery has allowed for a breakthrough in understanding a causative link between Helicobacter pylori infection and stomach cancer (1085-1087; 1767).

 

Denise A. Galloway (US) and James K. McDougall (US) demonstrated that after herpes simplex initiated carcinogenesis the virus did not need to remain present to maintain the carcinogenic state (572).

 

Gayle C. Bosma (US), R. Philip Custer (US), and Melvin J. Bosma (US) described a homozygous recessive mutation on chromosome 16 in mice called (scid) severe combined immunodeficiency disease which results in severely reduced populations of T cells and B cells (182). Note: These mice were found to lack mature T and B cells yet can survive up to a year in specific pathogen-free conditions and are therefore valuable for biomedical research.

 

Alexandre Fabiato (FR-US) used experiments performed in skinned cardiac cells (sarcolemma removed by microdissection) to support the hypothesis of a Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) (488). Note: According to this hypothesis, the transsarcolemmal Ca2+ influx does not activate the myofilaments directly but through the induction of a Ca2+ release from the SR.

 

A. James Hudspeth (US) determined that the hair cells of the inner ear are exquisitely sensitive transducers that in human beings mediate the senses of hearing and balance. A tiny force applied to the top of the cell produces an electrical signal at the bottom (792-794).

 

Efrain O. Aceves-Pina (MX), Ronald Booker (US), Janet S. Duerr (US), Margaret S. Livingstone (US), William G. Quinn (US), Ray F. Smith (US), Patricia P. Sziber (US), Bruce L. Tempel (US), Timothy P. Tully (US), Craig H. Bailey (US), Dusan Bartsch (DE), and Eric Richard Kandel (AT-US) determined that the brain’s storage of long-term memory is associated with a cellular program of gene expression, altered protein synthesis, and the growth of new synaptic connections (7; 71).

 

Richard G. Wyatt (US), Albert Zaven Kapikian (AM-US), Harry B. Greenberg (US), Anthony R. Kalica (US), Jorge Flores (US), Yasutaka Hoshino (US), Robert Merritt Chanock (US), and Myron M. Levine (US) were successful in developing a vaccine against rotavirus disease. The vaccine is prepared from attenuated, immunogenic rhesus rotavirus which has been characterized to be antigenically similar, if not identical, to human rotavirus serotype 3 (1823).

 

Alfred Sommer (US), Ignatius Tarwotjo (ID), Gusti Hussaini (ID), and DJoKo Susanto (ID) demonstrated that low-dose vitamin A supplementation could prevent death from infectious diseases as well as blindness in millions of third world children (1586).

 

Charles Theodore Dotter (US), Robert W. Buschmann (US), Montgomery K. McKinney (US), and Josef Rösch (US) presented a method for the percutaneous catheter placement of expandable nitinol coil stents for the nonoperative restoration and maintenance of patency in internal flow pathways, especially the lumina of blood vessels and biliary ducts (425).

Ulrich Sigwart (DE), Jacques Puel (FR), Velimir Mirkovitch (CH), Francis Joffre (FR), and Lukas Kappenberger (DE-CH) provided an intravascular mechanical support to human patients with the aim of preventing restenosis and sudden closure of diseased arteries after angioplasty. The endoprosthesis consisted of a self-expandable stainless-steel mesh (stent) that can be implanted nonsurgically in the coronary or peripheral arteries (1549).

 

Kurt Semm (DE), on 13 September 1980, performed the first laproscopic appendectomy (1515).

 

Graham R.V. Hughes (GB) described an antiphospholipid syndrome (Hughes syndrome) displaying, thrombosis, abortion and cerebral disease in the presence of lupus anticoagulant in blood (798).

 

John E. Buster (US), Maria Bustillo (US), Ian H. Thorneycroft (US), James A. Simon (US), Stephen P. Boyers (US), John R. Marshall (US), John A. Louw (ZA), Randolph W. Seed (US), and Richard G. Seed (US) had medical oversight of the first human pregnancy resulting from oocyte donation. Sperm from the male partner were introduced into the cervix of a female egg donor. When fertilization had taken place, the embryo was removed and replaced in the female partner. In the first instance, 2 pregnancies resulted from 5 embryo transfers (238).

 

Nolvadex Adjuvant Trial Organization (NATO) performed a controlled trial of tamoxifen as an adjuvant agent to manage early breast cancer. It was found to have a clear benefit (1692).

The Early Breast Trialists' Collaborative Group (international) offered strong confirmation that tamoxifen was a excellent adjuvant agent in the management of breast cancer (457).

 Michael Baum (US), Aman U. Budzar (US), Jack Cuzick (US), John Forbes (US), Joan H. Houghton (US), Jan G. Klijn (US), Tarek Sahmoud (US), and the Atac Trialists' Group, using a prospective randomized controlled trial, showed that anastrozole (aromatase inhibitor) significantly prolonged disease-free survival and time to recurrence for patients who received anastrozole alone compared with those who received tamoxifen alone or anastrozole and tamoxifen together (98).

Paul E. Goss (CA), James N. Ingle (US), Silvana Martino (US), Nicholas J. Robert (US), Hyman B. Muss (US), Martine J. Piccart (BE), Monica Castiglione (CH), Dongsheng Tu (CA), Lois E. Shepherd (CA), Kathleen I. Pritchard (CA), Robert B. Livingston (US), Nancy E. Davidson (US), Larry Norton (US), Edith A. Perez (US), Jeffrey S. Abrams (US), Patrick Therasse (BE), Michael J. Palmer (CA), Joseph L. Pater (US), and David A. Cameron (US) showed that extended adjuvant endocrine therapy with letrozole led to a significant improvement in disease-free survival, a reduction in deaths from breast cancer, improved overall survival in node-positive patients, and the breast cancers did not develop resistance (619; 620).

 

R. Rox Anderson (US) and John A. Parish (US) introduced ‘selective photothermolysis’ (SPTL): specific destruction of chromophores (light-absorbing molecules) via intense pulses of light at a preferential wavelength, allowing better localization of thermal energy and minimization of damage to surrounding tissues (28). Note: This concept was the key to modern laser dermatology and the basis for an abundance of novel therapeutic instruments, namely pulsed lasers.

 

Helmut P. Weber (DE) and Lothar Schmitz (DE) reported the first treatment of a patient with type B Wolff-Parkinson-White syndrome (WPW) using catheter ablation (1772).

 

Hartmut Land (DE-US), Luis F. Parada (CO-US), Robert Allan Weinberg (US), H. Earl Ruley (GB-US), Douglas Hanahan (US), Peter Whyte (CA), Karen J. Buchkovich (US), Jonathan M. Horowitz (US), Stephen H. Friend (US), Maragret Raybuck (GB) and Edward Harlow (US) discovered the ability of different oncogenes to cooperate in producing cellular transformation (696; 964; 1431; 1789).

 

Francis Denis (US) introduced the concept of middle column or middle osteoligamentous complex between the traditionally recognized posterior ligamentous complex and the anterior longitudinal ligament. Major spinal injuries are classified into four different categories: compression fractures, burst fractures, seat-belt-type injuries, and fracture dislocations. He presents a correlation between the three-column system, the classification, the stability, and the therapeutic indications (405).

 

William New, Jr. (US) developed the first commercially available device to measure the oxygen saturation in a patient’s bloodstream. The Nellcor pulse oximeter had the unique feature of lowering the audible pitch of the pulse tone as saturation dropped, giving anesthesiologists a warning that their patient’s heart and brain were in danger of low oxygen levels. Note: The Nellcor changed patient monitoring forever. Oxygen saturation is now monitored before, during, and after surgery (1210).

 

Stevan J. Arnold (US) reported that it is possible to measure adaptive significance directly (47).

 

Leigh M. van Valen (US) defined coevolution in the broadest sense as, “when the direct or indirect interaction between two or more evolving units produces an evolutionary response in each” (1730).

 

Carl Gans (US) and Richard Glenn Northcutt (US) noted that vertebrate body organization differs from that of other chordates in a large number of derived features that involve all organ systems. Most of these features arise embryonically from epidermal placodes, neural crest, and a muscularized hypomere (574; 1230).

 

Andrew C. Scott (GB) and William Gilbert Chaloner (GB) provided the earliest fossil record of a gymnosperm—conifers from the Upper Carboniferous (1502).

 

Raúl Patrucco (PE), Raúl Tello (PE), and Duccio Bonavia (PE) found Ascaris lumbricoides eggs in human coprolites from Peru dating from 2277 BCE (775; 1309).

 

1984

Niels Kaj Jerne (GB-DK), Georges Jean Franz Köhler (DE) and César Milstein (AR-GB) were awarded the Nobel Prize in Physiology or Medicine for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies.

 

James F. Kasting (US), James B. Pollack (US), and David Crisp (US) concluded that to keep the oceans from freezing on the primitive Earth a global greenhouse was necessary to offset the effects of a faint young Sun which was dimmer than today's by 25-30%. Climate models confirmed that 100-1,000 times the present atmospheric level of carbon dioxide would have been necessary (873).

 

James F. Kasting (US), James B. Pollack (US), David Crisp (US), and John P. Grotzinger (US) used greenhouse calculations and the sedimentary record to suggest that before 3.8 G the Earth’s surface was a warm (80-100˚C), with a bicarbonate-rich ocean at a pH perhaps as low as 6 (654; 873).

 

Michael W. Hunkapiller (US), Stephen Kent (US), Marvin Harry Caruthers (US), William J. Dreyer (US), Joseph R. Firca (US), C. Griffin (US), Suzanna J. Horvath (US), Tim Hunkapiller (US), Paul Tempst (US), and Leroy Edward Hood (US) developed a series of automated instruments that use state-of-the-art chemical methods for high-sensitivity protein sequencing, DNA synthesis, and peptide synthesis (800).

 

James E. Landegent (NL), N. Jasen in de Wal (NL), Robert A. Baan (NL), Jan Hendrik Jozef Hoeijmakers (NL), and M.P. Van der Ploeg (NL) presented a new approach for the indirect hybridocytochemical localization of specific nucleic acid sequences in microscopic preparations (966).

 

Charles N. Serhan (US), Mats Hamberg (SE), and Bengt Ingemar Samuelsson (SE) discovered a new biologically active class of compounds— lipoxins A and B —which are formed from arachidonic acid in leukocytes (1520).

Charles N. Serhan (US), Kyriacos Costa Nicolaou (CY-US), Stephen E. Webber (US), Chris A. Veale (US), Sven-Erik Dahlen (SE), Tapio J. Puustinen (SE), and Bengt Ingemar Samuelsson (SE) described the structure and formation of various lipoxins by leukocytes (1521).

 

Michel Brownlee (US), Helen Viassara (US), and Anthony Cerami (US) reported that within the body chemically reversible Schiff base and Amadori product adducts form in proportion to glucose concentration. Subsequent reactions of the Amadori product slowly give rise to nonequilibrium advanced glycosylation end products, which continue to accumulate indefinitely on longer-lived molecules. Excessive formation of both types of nonenzymatic glycosylation product appears to be the common biochemical link between chronic hyperglycemia and a number of pathophysiologic processes potentially involved in the development of long-term diabetic complications (223).

 

Shuichi Gomi (JP), Daishiro Ikeda (JP), Hikaru Nakamura (JP), Hiroshi Naganawa (JP), Fumio Yamashita (JP), Kunimoto Hotta (JP), Shinichi Kondo (JP), Yoshiro Okami (JP), Hamao Umezawa (JP), Yoichi Iitaka (JP), and Shogo Kurasawa (JP) were the first to isolate the novel antibiotic indolizomycin which is generated by a bacterium resulting from the fusion of two non antibiotic producing strains of bacteria, Streptomyces tenjimariensis NM16 and Streptomyces grisline NP1-1 (609; 1833).

 

James B. Hurley (US), Melvin I. Simon (US), David B. Teplow (US), Janet D. Robishaw (US), and Alfred Goodman Gilman (US) discovered similarities, which suggested that G proteins and ras proteins might have analogous functions (801).

 

Attila T. Lörincz (IE-US) and Steven I. Reed (US), using Saccharomyces cerevisiae, described the isolation on plasmids of one of the “start” genes, CDC28, by genetic complementation and initial characterization of its product. They then described the DNA sequence of the gene CDC28 (1043).

 

Yasutomi Nishizuka (JP) suggested that 1,2-diacylglycerol, one of the products resulting from the first messenger-induced breakdown of inositol phospholipids, initiates the activation of protein kinase C (1226; 1227).

 

Gregg Duester (US), G. Wesley Hatfield (US), Rolf Buhler (US), John Hempel (US), Hans Jornvall (SE), and Moyra Smith (ZA-US) cloned and characterized cDNA for the beta subunit of human alcohol dehydrogenase (ADH) (445).

Gregg Duester (US), G. Wesley Hatfield (US), and Moyra Smith (ZA-US) used a cDNA probe to locate the alcohol dehydrogenase 2 (ADH2) gene encoding the beta subunit of human ADH to human chromosome 4 (446).

Gregg Duester (US), Moyra Smith (ZA-US), Virginia Bilanchone (US), and G. Wesley Hatfield (US) analyzed the five distinct human alcohol dehydrogenase (ADH) subunits—each encoded by a separate gene—to determine their organization and regulation. In addition, they determined the nucleotide sequence of the gene encoding the beta subunit (447).

 

William J. Brown (US) and Marilyn Gist Farquhar (US) detected a protein in the membranes of vesicles near the Golgi, which binds mannose-6-phosphate. This modified sugar binds lysosomal proteins so that they may be transported within vesicles (220; 221).

 

Merceds L. de Bold (CA), Adolfo J. de Bold (AR-CA), and Jack Kraicer (CA) discovered stellate cells of the pars intermedia of the pituitary gland using a new silver impregnation technique (390).

 

For the starch industry, Novozymes A/S of Denmark developed the first enzyme from a genetically modified organism—maltogenic amylase—it was marketed under the name Maltogenase®. They were given the U.S. Federal trademark serial number 73782780 for Maltogenase in 1991.

 

Gregory L. Gray (US), Douglas H. Smith (US), Jane S. Baldridge (US), Richard N. Harkins (US), Michael L. Vasil (US), Ellson Y. Chen (US), and Herbert L. Heyneker (US) cloned and sequenced the exotoxin A structural gene of Pseudomonas aeruginosa (633).

 

Gerhard Heinrich (US), Henry M. Kronenberg (US), John T. Potts, Jr. (US), Joel F. Habener (US), Christine A. Weaver (US), David F. Gordon (US), Martin S. Kissil (US), David A. Mead (US), and Byron Kemper (US) sequenced the parathyroid hormone (PTH) gene (734; 1770).

 

Gian Garriga (US) and Alan M. Lambowitz (US) were the first to demonstrate self-splicing by a mitochondrial intron (577).

 

Fred K. Chu (US), Gladys F. Maley (US), Frank Maley (US), and Marlene Belfort (ZA-US) reported on the presence of an "intervening sequence" (intron) in the td gene, in the TS coding sequence, of the T4 phage (296). Note: They subsequently found the td intron to be a group 1 intron that self-splices by the guanosine-initiated pathway.

Susan M. Quirk (US), Deborah Bell-Pedersen (US), and Marlene Belfort (ZA-US) demonstrated hopping of the td and nrdD introns from intron-containing donor replicons of the T-even phages to cognate recipients lacking introns but containing the td or nrdD homing sites (1362).

 

Nobuchika Suzuki (US), Hiromi Shimomura (JP), E. William Radany (US), Chodavarapu S. Ramarao (US), Gary E. Ward (US), J. Kelley Bentley (US), and David Lorn Garbers (US) discovered a peptide (resact) associated with the eggs of the sea urchin, Arbacia punctulata, which stimulates sperm respiration rates by 5-10-fold. It was purified and its amino acid sequence was determined. The sequence was found to be Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-Leu-NH2. The peptide was subsequently synthesized. It appears that resact behaves as a sperm attractant (1629).

Dina Ralt (IL), Mordechai Goldenberg (IL), Peter Fetterolf (IL), Dana Kathryn Thompson (US), Jehoshua Dor (IL), Shlomo Mashiach (IL), David Lorn Garbers (US), and Michael Eisenbach (IL) indicate that a sperm attractant functions in humans (1366).

 

David F. Spencer (CA), Murray N. Schnare (CA), Michael W. Gray (CA), Yvon Abel (CA), David Sankoff (CA), Robert J. Cedergren (CA), Dan Yang (JP), Yaeko Oyaizu (JP), Hiroshi Oyaizu (JP), Gary J. Olsen (US), and Carl R. Woese (US) demonstrated that mitochondrial rRNA genes are of direct eubacterial (Bacteria) ancestry (268; 635; 1590; 1838).

 

Svend O. Freytag (US), Arthur L. Beaudet (US), Hans-George O. Bock (DE), and William E. O'Brien (US) presented evidence for the occurrence of alternative splicing of the argininosuccinate synthetase gene mRNA. The splicing of the argininosuccinate synthetase mRNA was found to be species specific in primates and variable among different human cell types (541).

 

Barbara Ruskin (US), Adrian R. Krainer (US), Thomas Peter Maniatis (US), Michael R. Green (US), Richard A. Padgett (US), Maria M. Konarska (US), Paula J. Grabowski (US), Stephen F. Hardy (US), and Phillip Allen Sharp (US) worked out the mechanism of pre-mRNA splicing using human cells and adenovirus 2 (1276; 1433).

 

Michael A. Blanar (US), Donald G. Kneller (US), Alexander E. Karu (US), Fred E. Cohen (US), Robert Langridge (US), Irwin D. Kuntz (US), Murty V.V.S. Madiraju (US), Ann Templin (US), and Alvin John Clark (US) identified the RecA enzyme in Escherichia coli. This enzyme can catalyze invasion of an intact DNA helix by a single nucleotide strand. The enzyme binds to the exposed single strand then catalyzes rewinding of the chain with its complement in the receiving molecule (165; 1067).

 

Jack Coleman (US), Pamela J. Green (US), and Masayori Inouye (US) constructed a plasmid that produces a complementary RNA to the E. coli lpp mRNA (mic [lpp] RNA). Induction of the mic (lpp) gene efficiently blocked lipoprotein production and reduced the amount of lpp mRNA (324).

 

Sushilkumar G. Devare (US), Allan R. Shatzman (US), Keith C. Robbins (US), Martin Rosenberg (US), Stuart A. Aaronson (US), Steven F. Josephs (US), Chan Guo (US), Lee Ratner (US), Flossie Wong-Staal (CN-US), Ing-Ming Chiu (US), E. Premkumar Reddy (US), David Givol (IL), and Steven R. Tronick (US) provided the first link between an oncoprotein and biochemical signal transduction. The amino acid sequence of platelet-derived growth factor (PDGF), a powerful mitogen, is almost identical to that of the v-sis oncogene of simian sarcoma virus. Virus transformed cells secrete a mimic PDGF protein which stimulates mitosis when it binds to a PDGF receptor. Alternatively, internal expression of the sis oncoprotein might stimulate replication in cell types lacking PDGF receptors (289; 410; 848).

 

Julian Downward (GB), Yosef Yarden (IL), Elaine L.V. Mayes (GB), Geoffrey T. Scrace (GB), Nicholas F. Totty (GB), Peter A. Stockwell (NZ), Axel Ullrich (DE), Joseph Schlessinger (US), and Michael D. Waterfield (GB) found that the amino acid sequence of the cell-surface receptor for epidermal growth factor (EGF) shares a remarkable homology with the predicted sequence of the v-erb-B oncogene protein of avian erythroblastosis virus. It appears that v-erb-B oncogene protein is an example of viral capture of an incomplete cellular gene (426).

 

David B. Rhoads (US), Phang C. Tai (US), and Bernard David Davis (US) showed that the incorporation of protein into membrane vesicles requires the setting up of a membrane potential (1386).

 

Gloria Lee (US), Richard Olding Hynes (GB-US), Eric Schulze (US) and Marc Wallace Kirschner (US), using amphibians as a model, contributed greatly to the elucidation of the pathways that underlie morphogenesis (901; 990).

 

Ann C. Chandley (GB), Paul Goetz (GB), Timothy B. Hargreave (GB), Allen M. Joseph (GB), and Robert M. Speed (GB) presented evidence that pairing between the human X and Y chromosomes could be more extensive at early pachytene than has previously been supposed and could involve even the entire euchromatic portion of the Y chromosome (271).

 

Jane Gitschier (US), William I. Wood (US), Teresa M. Goralka (US), Karen L. Wion (US), Ellson Y. Chen (US), Dennis H. Eaton (US), Gordon A. Vehar (US), Daniel J. Capon (US), and Richard M. Lawn (US) reported the complete isolation and characterization of the human blood coagulation factor VIII gene. Located on the X chromosome, it was the largest gene characterized at the time (186kb) (596).

John J. Toole (US), John L. Knopf (US), John M. Wozney (US), Lisa A. Sultzman (US), Janet L. Buecker (US), Debra D. Pittman (US), Randal J. Kaufman (US), Eugene J. Brown (US), Charles Shoemaker (US), Elizabeth C. Orr (US), Godfrey W. Amphlett (US), W. Barry Foster (US), Mary Lou Coe (US), Gaylord J. Knutson (US), David N. Fass (US), and Rodney M. Hewick (US) cloned the cDNA for human antihemophilic factor—human blood coagulation factor VIII—into COS-1 cells using the plasmid vector pCVSVL. The cells expressed the gene and produced the polypeptide (1679).

 

Grant A. Bitter (US), Kenneth K. Chen (US), Allen R. Banks (US), and Por-Hsiung Lai (TW) constructed gene fusions between the alpha-factor leader region and two chemically synthesized genes. The fusions were cloned into various yeast—E. coli shuttle vectors and reintroduced into Saccharomyces cerevisiae with the result that the synthesized genes were expressed and excreted if correctly oriented to the alpha-factor gene (158).

 

Jerszy (Jurek) Paszkowski (CH), Ray D. Shillito (US), Michael William Saul (CH), Vaclav Mandak (CH), Thomas Hohn (CH), Barbara Hohn (CH), and Ingo Potrykus (CH) constructed plasmids which they used as vectors to directly transfer foreign genes into protoplasts of Nicotiana tabacum (1303).

 

Roger D. Cone (US), and Richard C. Mulligan (US) reported the high-efficiency transfer of foreign genes into mammalian cells using a modified retrovirus with a broad mammalian host range (332).

 

Nina V. Federoff (US) Douglas B. Furtek (US), Oliver Evans Nelson, Jr. (US), Robert J. Schmidt (US), Frances A. Burr (US), and Benjamin Burr (US) cloned the bronze locus of maize (Zea mays L.) (500; 1488). Note: This was the first successful application of transposon tagging to gene cloning in plants.

 

Charles K. Paull (US), Barbara Hecker (US), A. Conrad Neumann (US), Elisabeth L. Sikes (US), James E. Hook (US), William Corso (US), Raymond P. Freeman-Lynde (US), Robert F. Commeau (US), Stjepko Golubic (US), and Joseph R. Curray (US), discovered oceanic cold seeps (cold vents) where entire communities of light independent organisms - known a extremophiles- develop in and around cold seeps, most relying on symbiotic relationship with chemoautotrophic bacteria. Both Archaea and Eubacteria in these vents use chemosynthesis to process sulfides into a variety of energy rich organic molecules. Higher organisms, namely vesicomyid clams and siboglinid tube worms use this energy to power their own life processes, and in exchange provide both safety and a reliable source of food for the bacteria (1311; 1312).

 

Kenneth Bryan Raper (US) and Ann Worley Rahn (US) wrote the important monograph, The Dictyostelids (1367).

 

William J. McAleer (US), Eugene B. Buynak (US), Robert Z. Maigetter (US), D. Eugene Wampler (US), William J. Miller (US), and Maurice Ralph Hilleman (US) developed a hepatitis B vaccine of yeast cell origin. Vaccinated chimpanzees were completely protected when challenged. This is the first example of a vaccine produced from recombinant cells, which is effective against a human viral infection (1111). Note: In May 1986 the vaccine Recombivax HB, which protects against hepatitis B infection, was approved for marketing in West Germany; approval by the United States Food and Drug Administration followed two months later. Recombivax HB marked a milestone in the development of medical biotechnology. Manufactured by Merck Sharp & Dohme, it was the first vaccine to be produced using recombinant DNA technology, and only the third recombinant product to be licensed for human use (following human insulin in 1982 and human growth hormone in 1985 and just preceding alpha interferon in June 1986).

 

Tadeusz J. Wiktor (US), Roderick I. Macfarlan (AU), Kevin J. Reagan (US), Bernhard Dietzschold (US), Peter J. Curtis (US), William H. Wunner (US), Marie-Paul Kieny (CH), Richard Lathe (GB), Jean-Pierre Lecocq (FR), Michael Mackett (GB), Bernard Moss (US), and Hilary Koprowski (PL-US) produced a vaccine for rabies by creating a vaccinia virus recombinant containing the rabies virus glycoprotein gene (1790).

 

David McKean (US), Konrad Huppi (US), Michael Bell (US), Louis Staudt (US), Walter Gerhard (US), and Martin Weigert (US) examined the amino-terminal sequence of the kappa light chains of a set of monoclonal antibodies specific for one of the major antigenic determinants (Sb) on the influenza virus PR8[A/PR/8/34(H1N1)] hemagglutinin molecule. All examples of this set belong to a subgroup of the V kappa 21 group, V kappa 21C. This sequence analysis along with the characterization of gene rearrangements at the kappa light chain loci of these hybridomas is consistent with the idea that certain members of this set are the progeny of one or two lymphocytes. Because of this potential clonal relationship, we can reach several conclusions about the diversity observed among these kappa light chains: (i) the diversity is due to somatic mutation, (ii) somatic mutations occur sequentially and accumulate in the first complementarity-determining region, and (iii) the extent of somatic variation in this sample is high, suggesting a somatic mutation rate of about 10(-3) per base pair per generation (1124).

 

Adrian Peter Bird (GB), William Robert A. Brown (GB), Susan Lindsay (GB), Richard R. Meehan (GB), Joe D. Lewis, (GB) Stewart McKay (GB), Elke L. Kleiner (AT), Francisco Antequera (ES), Donald MacLeod (GB), and Wendy A. Bickmore (GB) demonstrated that the process of DNA methylation provides a switching mechanism by which a cell can control the activity of specific genes in its nucleus. When sites within a gene are methylated the gene is inactivated; if unmethylated the gene returns to or remains active (144; 152-154; 222; 1027; 1132; 1133). Note: This process is thought to be particularly important for cell differentiation.

 

Carl M. Feldherr (US), Ernst Kallenbach (US) and Nigel Schultz (US) gave direct evidence that eukaryotic nuclear pores are the routes by which proteins are imported into the nucleus (501).

 

Frances M. Finn (US), Gail Titus (US), Diane Horstman (US), and Klaus Hofmann (CH-US) isolated the insulin receptor of the human placenta (517).

 

William A. Braell (US), William E. Balch (US), Darrell C. Dobbertin (US), James Edward Rothman (US), and William G. Dunphy (US) reconstituted and characterized protein transport between successive compartments of the Golgi apparatus in a cell-free system (75; 76; 190).

 

Michel Seigneuret (FR) and Philippe F. Devaux (FR) discovered in erythrocytes an ATP-dependent aminophospholipid-specific transporter (translocase) which transports phosphatidylserine and phosphatidylethanolamine from the outer to the inner leaflet of the plasma membrane (1509).

 

Michael N. Hall (CH), Lynna M. Hereford (US), and Ira Herskowitz (US) described an amino acid sequence, which could act as a signal for translocation of a nonnuclear protein into the cell nucleus (689).

Manfred Schleyer (DE) and Walter Neupert (DE) were the first to demonstrate that proteins traverse both mitochondrial membranes in an unfolded state (1484).

Martin Eiles (CH) and Gottfried Schatz (CH) presented data suggesting that dihydrofolate reductase must at least partly unfold in order to be transported across mitochondrial membranes (467).

Raymond J. Deshaies (US) and Randy Wayne Schekman (US) uncovered a new secretory mutant, sec61, that accumulates multiple secretory and vacuolar precursor proteins that have not acquired any detectable posttranslational modifications associated with translocation into the endoplasmic reticulum. The sec61 mutation defines a gene that is required for an early cytoplasmic or endoplasmic reticulum membrane-associated step in protein translocation (409).

 

Eckhard R. Podack (US) and Paula J. Konigsberg (US) found that dense granules of cytolytic T cells contain cytolytic proteins that polymerize to disulfide-linked tubular poly perforins in a Ca-dependent reaction and may cause cytolysis by membrane insertion and transmembrane channel. In the presence of Ca, these granules affect strong tumoricidal and hemolytic activity (1340).

 

Steven M. Block (US), Howard Curtis Berg (US), David F. Blair (US), Shahid Khan (Pakistani-US), Michaela Dapice (US), and Thomas Sargent Reese (US) proposed a model for the mechanism propelling the bacterial motor involving the M ring and the Mot proteins, found by genetic experiments to be necessary for flagellar function in prokaryotes (126; 163; 169; 889).

 

Daniel Kalderon (GB-US), William D. Richardson (GB), Alexander F. Markham (GB), Alan E. Smith (US), Bruce L. Roberts (US), William Henry Colledge (GB), Michael D. Edge (GB), Peter Gillett (GB), and Eva Paucha (GB) identified a short sequence of predominantly basic amino acids Pro-Pro-Lys-Lys-Lys-Arg-Lys-Val from SV40 Large T as responsible for the normal nuclear location of the protein (859; 860; 1560).

 

Benjamin Harrison Landing (US) discussed factors in the distribution of butterfly color and behavior patterns (967).

 

Daniel A. Portnoy (US), Hans Wolf-Watz (SE), Ingrid Bolin (SE), Ann B. Beeder (US), and Stanley Falkow (US) cloned the (inv) gene —confers invasive phenotype—from Yersinia pseudotuberculosis into the non-invasive strain HB101 of E. coli (1350). Note: This was the first demonstration of the transfer of such a virulence property by a single gene.

 

Toshio Nikaido (JP), Akira Shimizu (JP), Norio Ishida (JP), Hisataka Sabe (JP), Keisuke Teshigawara (JP), Michiyuki Maeda (JP), Takashi Uchiyama (JP), Junji Yodoi (JP), Tasuku Honjo (JP), Warren J. Leonard (US), Timothy A. Donlon (US), Roger V. Lebo (US), and Warner C. Greene (US) reported the isolation of a gene for the human interleukin-2 receptor (1003; 1225).

 

Frances J. Benham (GB), Nigel K. Spurr (GB), Sue Povey (GB), Bradford T. Brinton (GB), Peter N. Goodfellow (GB), Ellen Solomon (GB), and Tess J. Harris (AU-GB) assigned the tissue-type plasminogen activator gene to chromosome 8 in man (116).

Dingeman C. Rijken (BE) and Désiré Collen (BE) purified and characterized the plasminogen activator secreted by a cultured human melanoma cell line then compared it to urokinase and tissue plasminogen activator (t-PA) from human uterus. These findings indicate that the plasminogen activator secreted by human melanoma cells in culture is very similar to, or identical with, the plasminogen activator found in normal tissue, but different from urokinase (1400).

Timothy J.R. Harris (GB), Thakor P. Patel (GB), Fiona A.O. Marston (GB), Sheila P. Little (GB), John Spencer Emtage (GB), Ghislain Opdenakker (BE), Guido Volckaert (BE), Wilfried Rombauts (BE), Alfons Billiau (BE), and Piet DeSomer (BE) cloned cDNA coding for human tissue-type plasminogen activator into Escherichia coli and elicited its expression (713).

Katherine Gordon (US), Eric Lee (US), James A. Vitale (US), Alan E. Smith (US), Heiner Westphal (US), and Lothar Henninghausen (US) constructed a vector with which they transferred the human tissue plasminogen activator (t-PA) with its endogenous secretion signal sequence into mouse embryos. Milk obtained from lactating females was found to contain biologically active t-PA. This has medical significance since t-PA dissolves fibrin clots and thus may be used to treat myocardial infarction and other similar conditions (618).

 

Reiko Takemura (JP) and Zena Werb (DE-CA) reported that mononuclear phagocytes could produce a number of extracellular proteases including collagenolytic, elastinolytic, and gelatinolytic hydrolases. These enzymes would allow them to clear themselves a path through the macromolecular barriers of basement membranes and other extracellular matrices (1644).

 

Nicholas M. Gough (AU), Jill Gough (AU), Donald Metcalf (AU), Anne Kelso (AU), Dianne Grail (AU), Nicos A. Nicola (AU), Antony W. Burgess (AU), and Ashley R. Dunn (AU) isolated DNA clones specifying the murine granulocyte-macrophage colony stimulating factor. This haematopoietic growth factor is encoded by a unique gene specifying a messenger RNA of 1,200 nucleotides and a polypeptide of 118 amino acids. It bears no structural similarity to the functionally related factor, interleukin-3 (625).

 

Folke Lithner (SE) and Lennart Wetterberg (SE), in a retrospective study over a 20-year period in the Umeå region in Sweden, found 11 patients (7 women and 4 men, mean age 67 years) with both hepatocellular carcinoma and acute intermittent porphyria. This coincidence was highly significant. Concomitant existence of portal cirrhosis of the liver was demonstrated in those 5 patients in whom it could be examined (1032).

 

Michael J. Bastiani (US), Corey Scott Goodman (US), Chris Q. Doe (US), Sascha du Lac (US), Stephen L. Helfand (US), John Y. Kuwada (US), John B. Thomas (US), Allan L. Harrelson (US), Christian Klambt (US), J. Roger Jacobs (US), Alex L. Kolodkin (US), and David J. Matthes (US) contributed to developmental neurobiology, in particular to understanding the initial cellular and subsequent molecular and genetic mechanisms controlling the guidance of neuronal growth cones to find and recognize their correct targets (96; 614; 708; 908; 922).

 

Barry Toyonaga (US), Yusuke Yanagi (JP), Nicole Suciu-Foca (US), Mark D. Minden (CA), Tak W. Mak (CA), Carolyn A. Blanckmeister (US), Keith R. Yamamoto (US), Mark M. Davis (US), Gunter J. Hammerling (DE), Jerome Ritz (US), Thomas J. Campen (US), Reinhold E. Schmidt (DE), Hans Dieter Royer (DE), Thierry Hercend (FR), Rebecca E. Hussey (US), Ellis L. Reinherz (US), Stuart F. Schlossman (US), Andrea Biondi (IT), Paola Allavena (IT), Valentina Rossi (IT), Renato Bassan (IT), Tiziano Barbui (IT), Eric Champagne (FR), Alessandro Rambaldi (IT), and Alberto Mantovani (IT) discovered that the receptor molecule on the surface of T killer cells consists of one alpha and one beta polypeptide chain, each encoded by a separate gene (151; 166; 1404; 1487; 1685; 1745).

Tak Wah Mak (CN-CA), Yusuke Yanagi (JP), Yasunobu Yoshikai (JP), Kathleen Leggett (CA), Stephen P. Clark (CA), Ingrid Aleksander (CA), Gerald Siu (US), Marie Malissen (FR), Erich C. Strauss (US), Leroy Edward Hood (US), Karyl I. Minard (US), Shelley Mjolsness (US), Mitchell Kronenberg (US), Joan Goverman (US), Timothy Hunkapiller (US), Michael B. Prystowsky (US), Frank W. Fitch (US), and Sheryle Taylor (CA) cloned and sequenced the gene for the T cell receptor, a critical component of the body’s defense system against disease (305; 1073; 1077; 1556; 1834).

 

Kenneth L. Rock (US), Baruj Benacerraf (US), and Abul K. Abbas (US) suggested that surface Ig receptors serve to focus antigens onto specific B lymphocytes and that such cells are highly efficient at presenting linked antigenic determinants to T cells (1411).

Antonio Lanzavecchia (CH) cloned and immortalized human antigen-specific B cells with Epstein-Barr virus (EBV) and analysed their interaction with T-cell clones specific for the same antigen. He reported here that surface immunoglobulin is indeed involved in the uptake and concentration of antigen, allowing specific B cells to present antigen to T cells with very high efficiency. However, the antigen must first be internalized and processed by specific B cells and it is then presented to T cells in a major histocompatability complex (MHC) restricted manner indistinguishable from that characteristic of conventional antigen presenting cell (APC) (974).

 

Eric Westhof (FR), Daniéle Altschuh (FR), Dino Moras (FR), Anne C. Bloomer (GB), Alfonso Mondragon (US), Aaron Klug (ZA-GB), Marc H. van Regenmortel (FR), John A. Tainer (US), Elizabeth D. Getzoff (US), Yvonne Paterson (US), Arthur J. Olsen (US), and Richard Alan Lerner (US) showed that the mobility of a segment of an antigen molecule influences its antigenicity (1640; 1786).

 

Angus G. Dalgleish (GB), Peter C.L. Beverley (GB), Paul R. Clapham (GB), Dorothy H. Crawford (GB), Melvyn Francis Greaves (GB), Robin A. Weiss (GB), David Klatzmann (FR), Eric Champagne (FR), Sophie Chamaret (FR), Jacqueline Gruest (FR), Denise Guetard (FR), Thierry Hercend (FR), Jean-Claude Gluckman (FR), and Luc Montagnier (FR) concluded that the CD4 antigen is an essential and specific component of the receptor for the causative agent of AIDS (369; 909).

 

Ola Myklebost (NO), Sissel Rogne (NO), Bjørnar Olaisen (NO), Tobias Gedde-Dahl, Jr. (NO), and Hans Prydz (NO) determined that the apo CII (apolipoprotein CII) gene is situated on chromosome 19 of man, close to the apoE (apolipoprotein E) gene (1197).

 

Eugene D. Weinberg (US) stressed that the body withholds iron from microorganisms as part of its natural defense mechanism. Lactoferrin, transferrin, and leukocyte endogenous mediator (LEM) are all useful for sequestering iron thus inhibiting microbial growth (1776).

 

Robert E. Weibel (US), Beverly J. Neff (US), Barbara J. Kuter (US), Harry A. Guess (US), Carol A. Rothenberger (US), Alison J. Fitzgerald (US), Karen A. Connor (US), Arlene A. McLean (US), Maurice Ralph Hilleman (US), and Eugene B. Buynak (US) developed a live attenuated varicella (chickenpox) virus vaccine (1774).

 

Irwin R. Merkatz (US), Harold M. Nitowsky (US), James N. Macri (US) and Walter E. Johnson (US) found that compared to matched controls, women with infants affected by aneuploidy were more likely to have low levels of maternal serum a-fetoprotein (1139).

 

Davor Solter (DE), James McGrath (US), Keith E. Latham (DE), Azim Surani (GB) Sheila C. Barton (GB), Michael L. Norris (GB), Rolf Ohlsson (GB), Bernhard Horsthemke (DE), Denise Barlow(GB), and Tharapell James (GB) released studies that demonstrated the concept of genomic imprinting. All cells in the animal contain two copies of every autosomal gene, one from the mother and one from the father, and in most cases both copies are expressed. However, “imprinted” genes are expressed only from either the maternally or the paternally inherited copy (94; 364; 777; 975; 1122; 1249; 1583-1585; 1626).

Bruce Cattanach (GB) and Maggie Kirk (GB) showed that imprinted genes were not evenly distributed across the whole genome but located in particular genomic regions (261).

 Genomic imprinting has widespread roles in mammals, affecting embryonic and placental development, transmission of nutrients to the fetus, and regulating critical aspects of mammalian physiology, such as metabolism, neuronal development and adult behaviour. Extensive research based on this discovery led to the identification of numerous imprinted genes whose alleles are differentially expressed depending on the parent of origin. A number of human syndromes exhibiting parent-of-origin effects in their patterns of inheritance were known, including the fetal overgrowth disorder Beckwith-Wiedemann Syndrome (which is also associated with an increased incidence of childhood tumors), and two neurological disorders (Prader-Willi Syndrome and Angelman Syndrome). These and other syndromes were found to be caused by the inheritance of two imprinted domains from the mother and none from the father, or vice versa; by deletions at imprinted regions; or by a failure either to establish a proper imprint during gamete production or to maintain it after fertilization (440; 1575).

Déborah Bourc'his (US), Guo-Liang Xu (US), Chyuan-Sheng Lin (US), Brooke Bollman (US), Timothy H. Bestor (US), En Li (US), Caroline Beard (GB), Rudolf Jaenisch (GB), Masahiro Kaneda (JP), Masaki Okano (JP-US), Kenichiro Hata (JP), Takashi Sado (JP), Naomi Tsujimoto (JP-US), and Hiroyuki Sasaki (JP), discovered that genomic imprinting involves the transmission of epigenetic information, in the form of DNA methylation marks, from gametes to offspring, with the result that a set of around 100–200 genes (both protein coding genes and non-coding RNA genes) are expressed from only one of the two chromosomes in cells. The essential role for DNA methylation in imprinting was shown through the inheritance of mutations in DNA methyltransferases (186; 861; 1016). See, Spalding and Lorenz in 1872 for imprinting on infants. See, Schrader 1921 and Jablonka 2009 for different imprinting.

 

Yves Rouquet (FR), Agnes Choiset (FR), Sylvie Girard (FR), Francois Thepot (FR), and Livia Poenaru (FR) reported on 69 samples of chorionic villi taken from patients who were undergoing therapeutic termination of pregnancy. These samples were taken using small forceps which were guided by ultrasound. The reliability and the chances of culturing these villi in order to work out the karyotype of the fetus and to study the enzymes is discussed (1424).

 

Fred Morady (US) and Melvin M. Scheinman (US) devised a transvenous catheter to deliver high-energy direct electrical current for ablation of the aberrant pathway. They report its use on a patient with Wolff–Parkinson–White syndrome (1168).

 

Michael J. Cousins (US) and Laurence E. Mather (US) summarized animal data that elucidates the pharmacology and spinal administration of opioids. They presented the results of controlled studies in humans concerning the efficacy and safety of spinal opioids and attempted to assess the risk-benefit ratios for spinal opioids in comparison with other techniques for pain relief such as parenteral opioids and local anesthetic neural blockade (349).

 

John Baird Iain Glen (GB), Susan C. Hunter (GB), Ron D. Stark (GB), Sue M. Binks (GB), Vera N. Dutka (GB), Kathleen M. O'Connor (GB), and M.J.A. Arnstein (GB) introduced Propofol (Diprivan), now the standard intravenous anesthetic induction agent in the US and the world. It has made a vast range of operations and medical tests comfortable and acceptable for people across the globe (598; 1600).

 

Vittorio Bonomini (IT), Giovanni M. Frasca (IT), Concerttina Raimondi (IT), Giovanni Liviano D'arcangelo (IT), and Alba Vangelista (IT) reported that Defibrotide, a large single-stranded polydeoxyribonucleotide agent, is useful in the treatment of acute renal failure due to hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura (177; 178).

Orhan N. Ulutin (TR), Günay Cizmeci (TR), and Sengün Balkuv-Ulutin (TR) reported the clinical pharmacology and mode of action of a new antithrombotic drug: Defibrotide (1707).

Paul G. Richardson (US), Anthony D. Elias (US), Amrita Krishnan (US), Catherine Wheeler (US), Raj Nath (US), Debra Hoppensteadt (US), Nancy M. Kinchia (US), Donna Neuberg (US), Edmund K. Waller (US), Joseph H. Antin (US), Robert Soiffer (US), James Vredenburgh (US), Michael Lill (US), Ann E. Woolfrey (US), Scott I. Bearman (US), Massimo Iacobelli (IT), Jawad Fareed (US), and Eva C. Guinan (US) retrospectively analyzed the experiences of extremely sick patients with severe veno-occlusive disease who were treated with Defibrotide. They found the absence of significant hemorrhagic or unexpected toxicity (1393).

 

Jane Gray (US) found that the plant spore record indicates two major phases of adaptive radiation among land plants before the Devonian. The first major adaptive radiation by plants onto land occurred in the mid Ordovician. Microfossil evidence suggests a non-vascular vegetative grade of organization for plants of this interval, i.e., hepatics and mosses. The second major adaptive radiation begins with the replacement of the monotonous spore tetrad assemblage by single trilete spores in the mid-late Early Silurian (429.5-416 M). These trilete spores find morphological counterpart with spores produced by vascular cryptogams; they suggest a vegetative grade of organization at the vascular level for plants of this interval (634).

 

William H. Jopling (GB) reports there is evidence that leprosy originated in Asia and was probably transported from India to Europe in the 4th century BCE by soldiers returning from the Greek wars of conquest. From Greece it was spread slowly throughout Europe by trade and military expeditions (846).

 

John Desmond Clark (US), Berhane Asfaw (US), Getaneh Assefa (ET), Jack W.K. Harris (US), Hiro Kurashina (GU), Robert C. Walter (CA), Tim D. White (US), and Martin A.J. Williams (AU), in 1981, discovered fossil remains of Australopithecus sp., dated to c. 3.5 -4.0 M BP These remains are the earliest evidence of Australopithecus from anywhere in the world and the earliest evidence of hominid bipedalism yet discovered (303).

 

Tom D. Dillehay (US), from 1977 to 1985, excavated at Monte Verde, some 31 miles (50 km) inland from the Pacific Ocean in southern Chile. He found evidence of a known site of human habitation in the Americas at ~1.5 K B.C.E. (416; 417).

Tom D. Dillehay (US-CL), Carlos Ocampo (CL), José Saavedra (CL), Andre Oliveira Sawakuchi (BR), Rodrigo M. Vega (CL), Mario Pino (CL), Michael B. Collins (US), Linda Scott Cummings (US), Iván Arregui (CL), Ximena S. Villagran (BR), Gelvam A. Hartmann (BR), Mauricio Mella (CL), Andrea González (CL), and George Dix (CA) found that radiocarbon dating of fire-charred plants and bones suggests that people built cooking fires and made stone tools at Monte Verde 16.5K B.C.E. or earlier (418).

 

1985

“The hypothalamus is without peer in its authority over body adjustments to our external and internal environments…[It] regulates body temperature, hunger, thirst, sexual activity, goal seeking behavior, endocrine functions, affective (emotional) behavior, and the activity of the visceral nervous system.” Marian Cleeves Diamond (US), Lawrence M. Elson (US), and Arnold C. Scheibel (US) (412).

 

Michael Stuart Brown (US) and Joseph Leonard Goldstein (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning the regulation of cholesterol metabolism.

 

James C.G. Walker (US) and Peter Brimblecombe (GB) determined that in an oceanic hydrothermal system, precipitation of highly insoluble iron sulfides by abundant aqueous ferrous iron would have served as a highly effective sink for hydrogen sulfide (1753).

 

Harold W. Kroto (GB), James R. Heath (US), Sean C. O’Brien (US), Robert F. Curl, Jr. (US), and Richard E. Smalley (US) discovered the unusual stability of the carbon-60 Buckminsterfullerene molecule and deduced its structure (940).

 

George Pearson Smith (US), Stephen F. Parmley (US), Jamie K. Scott (US), Jinan Yu (CN), and Robert Davis (US) developed phage display, a technique for the production and screening of novel proteins and polypeptides by inserting a foreign gene fragment into a gene responsible for the surface protein of a bacteriophage. The new protein appears in the surface coating of the phage, in which it can be manipulated and tested for biological activity (1292; 1293; 1504; 1566-1568).

John McCafferty (GB), Andrew D. Griffiths (GB-DE), Gregory Paul Winter (GB), David J. Chiswell (GB), Robert E. Hawkins (GB), Hennie R. Hoogenboom (GB), Samuel C. Williams (GB), Oliver Hartley (GB), Ian M. Tomlinson (GB), Peter Waterhouse (GB), William L. Crosby (GB), Roland E. Kontermann (GB), Peter T. Jones (GB), Nigel M. Low (GB), Timothy J. Allison (GB), Kevin S. Johnson (GB), and Peter J. Hudson (GB) are credited with devising techniques to use phage display for creating partially humanized antibodies for therapeutic uses (1986), and later, fully humanized antibodies (647; 773; 1113; 1804). Note: Humanized monoclonal antibodies form the majority of antibody-based drugs on the market today. One of the most successful antibody drugs developed was HUMIRA (adalimumab). HUMIRA, an antibody to TNF alpha, was the world's first fully humanized antibody.

 

Jane Gray (US) reports that the first major adaptive radiation by plants onto land occurred in the mid Ordovician (466 mya). These early plants are represented by abundant obligate spore tetrads; this assemblage persisted from the mid Ordovician to about the mid-late Early Silurian (429.5-416 mya). The close similarity of the fossil tetrads with obligate spore tetrads produced by some hepatics and mosses suggests a non-vascular vegetative grade of organization for plants of this interval. During this period most land was collected into the southern supercontinent Gondwana. The interval from the mid-late Early Silurian (429.5-416 mya) to the Pridoli (423 ± 2.3 and 419.2 ± 3.2 mya) largely coincides with the appearance of vascular plant megafossils. It is hypothesized on the basis of the spore assemblages to be one of major establishment of large populations of genetically diverse plants exploiting a broad spectrum of ecological sites (634).

 

Tommie V. McCarthy (GB) and Tomas Lindahl (SE-GB) reported that the E. coli ada+ gene product that controls the adaptive response to alkylating agents has been purified to apparent homogeneity using an overproducing expression vector system. This 39 kDa protein repairs 0(6)-methylguanine and 0(4)-methylthymine residues in alkylated DNA by transfer of the methyl group from the base to a cysteine residue in the protein itself. The Ada protein also corrects one of the stereoisomers of methyl phosphotriesters in DNA by the same mechanism, while the other isomer is left unrepaired. Different cysteine residues in the Ada protein are used as acceptors in the repair of methyl groups derived from phosphotriesters and base residues (1116).

 

Robert A. Wolf (US) and Richard W. Gross (US) were the first to demonstrate a plasmalogen selective phospholipase A2 in heart tissue (1808).

 

Michael A.J. Ferguson (GB), Martin G. Low (US), and George A.M. Cross (US) determined the composition and structure of a novel phosphatidylinositol-containing glycolipid, now known as membrane anchor. It was obtained from the protozoan, Trypanosoma brucei (509).

 

Timo Hyypiä (FI), Annika Jalava (FI), Steven H. Larsen (US), Pertti Terho (FI-US), and Veijo Hukkanen (FI) used a nucleic acid spot hybridization assay to detect Chlamydia trachomatis DNA. The hybridization probes included DNA isolated from elementary bodies of lymphogranuloma venereum (LGV) strains and cloned fragments of both chromosomal and plasmid DNA. The sensitivity of the test was in the range 10 to 100 pg homologous DNA and 10 in vitro infected cells. Cross-reactivity with bacterial DNA was avoided when purified chlamydia-specific DNA fragments were used as probes. C. trachomatis was detectable in most of the clinical specimens with large amounts of infectious particles. Also some isolation-negative specimens gave a positive signal in the test (804).

 

Pascal Madaula (US) and Richard Axel (US) identified a new family of ras genes, the rho genes, which share several properties with the more classical ras gene family consisting of N-, K-, and H-ras (1066). Note: Rho/Rac proteins are involved in a wide variety of cellular functions such as cell polarity, vesicular trafficking, the cell cycle and dynamics of transcription.

Hugh F. Paterson (GB), Annette J. Self (GB), Michelle D. Garrett (GB), Ingo Just (DE), Klaus Aktories (DE), and Alan Hall (GB-US) concluded that rho somehow governed the organization of the actin cytoskeleton (1307).

Anne J. Ridley (GB), Alan Hall (GB), Hugh F. Paterson (GB), Caroline L. Johnston (GB), and Dagmar Dierkmann (DE) found that rho and kindred proteins, such as rac and Cdc42, link cell surface receptors to the cytoskeleton (1397; 1398).

Alison E.M. Adams (US), Douglas I. Johnson (US), Richard M. Longnecker (US), Barbara F. Sloat (US), John R. Pringle (US), Monica Gotta (GB), Mary C. Abraham (GB), Julie Ahringer (GB), Amanda J. Kay (US), and Craig P. Hunter (US) reported that the Rho family members help set up cell polarity (9; 621; 878).

Michael F. Olsen (GB), Alan Ashworth (GB), and Alan Hall (GB) found that Rho family members push cells to advance through the cell cycle (1254).

Anne J. Ridley (GB) found that Rho and Cdc42 control formation of the contractile ring that separates cells during cytokinesis (1396).

Tzumin Lee (US), Christopher Winter (US), Simone S. Marticke (US), Arthur Lee (US), and Liqun Luo (US) found that rho proteins fine-tune growth of dendrites in the developing nervous system (997).

P. Hande Özdinier (US) and Reha S. Erzurumiu (US) discovered that rho proteins drive differentiation of axons (1273).

John M. Russo (US), Peter Florian (US), Le Shen (US), W. Vallen Graham (US), Maria S. Tretiakova (US), Alfred H. Gitter (US), Randall J. Mrsny (US), and Jerrold R. Turner (US) showed the roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure (1434).

 

William Charles Earnshaw (US) and Naomi F. Rothfield (US) identified three of the centromere's components, which they dubbed the centromere proteins, or CENPs (458).

Carol A. Cooke (US), Margarete M.S. Heck (US), and William Charles Earnshaw (US) identified a pair of proteins that cluster on the centromere. They were named the inner centromere proteins, or INCENPs (340).

D. Mark Eckley (US), Alexandra M. Ainsztein (US), Alastair M. Mackay (US), Ilya G. Goldberg (US), and William Charles Earnshaw (US) found that during anaphase INCENPs begin to concentrate at the site of presumptive cleavage furrow formation before myosin appears there (461).

Reto Gassmann (GB), Ana Carvalho (PT-GB), Alexander J. Henzing (GB), Sandrine Ruchaud (GB), Damien F. Hudson (GB), Reiko Honda (DE), Erich A. Nigg (DE), Dietland L. Gerloff (GB), William Charles Earnshaw (US), Srinath C. Sampath (US), Ryoma Ohl (US), Oliver Leismann (US), Adrian Salic (US), Andrei Pozniakovski (US), and Hironori Funabiki (US) uncovered borealin (578), also known as Dasra (1452), and showed that it is crucial for correctly attaching microtubules to the centromeres, stabilizing the spindle, and completing cell division. They are part of the passenger complex (1452).

 

Yuh-Shyong Yang (US), James F. Hainfeld (US), Joseph S. Wall (US), and Perry Allen Frey (US) performed a quaternary structural analysis of the pyruvate dehydrogenase complex from Escherichia coli. Using scanning transmission electron microscopy and radial mass analysis, they were able to confirm a model in which six dihydrolipoyl dehydrogenase (E3) dimers are integrated into the six faces of a cubic dihydrolipoyl transacetylase (E2) core and 12 pyruvate dehydrogenase (E1) dimers are associated along the 12 edges of the core enzyme (1840).

Janima Baraniak (PL), Marcia L. Moss (US), and Perry Allen Frey (US) confirmed that the activation of lysine 2,3-aminomutase involves a transformation of S-adenosylmethionine into a form that promotes the generation of a 5'-adenosyl free radical which abstracts hydrogen from lysine to form 5'-deoxyadenosine as an intermediate (86).

 

Shripad S. Bhagwat (US), Philip R. Hamann (US), W. Clark Still (US), Stuart Bunting (US), and Frank A. Fitzpatrick (US) accomplished the synthesis and structure of the platelet aggregation factor thromboxane A2 (141).

 

David A. Hopwood (GB), Francisco Malpartida (GB), Helen M. Kieser (GB), Haruo Ikeda (JP), J. Duncan (US), Isao Fujii (US), Brian A.M. Rudd (US), Heinz G. Floss (US), and Satoshi Ömura (JP) reported the production of novel compounds by gene transfer between strains producing the isochromanequinone antibiotics actinorhodin, granaticin and medermycin. These experiments were made possible by the recent cloning of the whole set of genes for the biosynthetic pathway of actinorhodin from Streptomyces coelicolor A3(2). They believed that this represented the first report of the production of hybrid antibiotics by genetic engineering (774; 1079).

 

Ken Richardson (GB), Keith W. Brammer (GB), Michael S. Marriott (GB), and Peter F. Troke (GB) introduced the antifungal UK-49,858 (a difluorophenyl bis-triazole derivative) for the treatment of Candida albicans and Tricophyton mentagrophytes infections (1392). Note: The trade name is Diflucan.

 

Giorgio Bernardi (IT), Birgitta Olofsson (GB), Jan Filipski (FR), Marino Zerial (IT), Julio Salinas (ES), Gerard Cuny (FR), Michele Meunier-Rotival (FR), and Francis Rodier (FR) examined the proportion of guanine (G) and cytosine (C) after genome DNA was cut into large pieces. The GC content of these fragments in mammals and birds tended to fall into discrete fractions; with either higher or lower GC composition rather than lying near the overall mean of the genome. This meant that the genome is made up of large domains, some one million bases in length, which differ in GC content. Such regions they christened isochores (135; 136).

 

Michael Berger (DE) and Michael F.G. Schmidt (DE) showed that fatty acylation of membrane proteins occurs before they leave the endoplasmic reticulum (129).

 

Paul J. Pfaffinger (US), Jennifer M. Martin (US), Dale D. Hunter (US), Neil M. Nathanson (US), David J. Beech (GB), Laurent Bernheim (CH), Alistair Mathie (GB), Mark S. Shapiro (US), Lonnie P. Wollmuth (US), Humberto Cruzblanca (MX), Duk-Su Koh (US), and Bertil Hille (US) discovered the way that muscarinic acetycholine receptors in the heart, acting through G-proteins, turn on M-type Ca2+ channels and dissected the mechanism for modulation of K+ and N-type Ca2+ channels in sympathetic neurons (106; 137; 359; 753; 1324; 1526).

 

Raymond S. Brown (DE), Christian Sander (DE), Patrick Argos (DE), Jonathan Miller (GB), Andrew D. McLachlan (GB), Mair Elisa Annabelle Churchill (US), Thomas D. Tullius (US), Aaron Klug (ZA-GB), Alan D. Frankel (US), Carl O. Pabo (US), Jeremy M. Berg (US), Toby J. Gibson (DE), Pieter W. Postma (NL), Lora M. Green (US), Grace Parraga (CA), Susan Horvath (US), Leroy Edward Hood (US), Elton T. Young (US), and Rachel E. Klevit (US) were among those who worked out the zinc-finger motif as one of the features common to many regulatory proteins (128; 219; 297; 540; 589; 638; 1151; 1298).

Katherine M. Call (US), Tom Glaser (US), Caryn Y. Ito (US), Alan J. Buckler (US), Jerry Pelletier (US), Daniel A. Haber (US), Elise A. Rose (US), Astrid Kral (US), Herman Yeger (CA), William H. Lewis (CA), Carol Jones (US) and David E. Housman (US) isolated and characterized a zinc finger polypeptide gene from the human chromosome 11 Wilms' tumor locus (246).

 

Michele Sawadogo (US) and Robert Gayle Roeder (US) found that three basic transcription factors, TFIIB, TFIID, and TFIIE, are absolutely required, in addition to the RNA polymerase II, for specific transcription initiation from the adenovirus major late promoter (1467).

 

Stanley Tabor (US) and Charles Clifton Richardson (US) cloned the RNA polymerase gene of bacteriophage T7 into the plasmid pBR322 under the inducible control of the lambda P_L promoter. After induction, T7 RNA polymerase constitutes 20% of the soluble protein of Escherichia coli, a 200-fold increase over levels found in T7-infected cells. The overproduced enzyme has been purified to homogeneity (1639).

 

F. Ian Lamb (GB), Lynne M. Roberts (GB), and J. Michael Lord (GB) deduced from the nucleotide sequence of cloned DNA complementary to preproricin mRNA the primary structure of a precursor protein that contains the toxic (A) and galactose-binding (B) chains of the castor bean lectin, ricin (963).

 

Rodney K. Tweten (US), Joseph T. Barbieri (US), and R. John Collier (US) found that the glutamic acid at position148 in diphtheria toxin is essential for the ADP-ribosylation of elongation factor 2. This is consistent with other data suggesting that this residue may be at or near the catalytic center of the toxin (1703). Note: This glutamic acid residue is conserved in all ADP-ribosylating toxins like those of cholera, pseudomonas, and pertussis.

 

Roger Brent (US) and Mark Steven Ptashne (US) postulated that in S. cerevisiae the Gal4 activator protein functions by directly contacting other proteins required for initiation of transcription (202).

 

Ronald G. Schoner (US), Lee F. Ellis (US), and Brigitte E. Schoner (US) found that Escherichia coli cells transformed into high-level bovine growth hormone producers possess distinct cytoplasmic granules that are nearly homogenous bovine growth hormone (1492).

 

Bruce P. Babbitt (US), Paul M. Allen (US), Gary Matsueda (US), Edgar Haber (US), and Emil R. Unanue (CU-US) found that the small epitopic portion of hen-egg lysozyme (HEL) is physically associated with Ia (histompatibility) glycoproteins of macrophages and T cells during the antigen presentation process (65).

 

Grzegorz Grynkiewicz (PL), Martin Poenie (US), and Roger Yonchien Tsien (US) designed a new family of fluorescent Ca2+ indicators for measuring intracellular calcium. They combined an 8-coordinate tetracarboxylate-chelating site with stilbene chromophores. The new chelators offered up to 30-fold brighter fluorescence, major changes in wavelength not just intensity upon Ca2+ binding, slightly lower affinities for Ca2+, slightly longer wavelengths of excitation, and considerably improved selectivity for Ca2+ over other divalent cations (662).

 

Eckhard R. Podack (US), John Ding-E Young (US), and Zanvil A. Cohn (US) isolated then performed a biochemical and functional characterization of perforin 1 (P1) from cytolytic T cell granules (1341). Note: Pl-mediated hemolysis is Ca2+-dependent and is inhibited by Zn2 ions. Lysis is accompanied by the polymerization of P1 to membrane associated tubular complexes (poly-Pl) that form large transmembrane pores. P1 causes a rapid membrane depolarization of cells in the presence of Ca2+. Purified P1 also induces transmembrane monovalent and divalent ion flow across lipid vesicles only in the presence of Ca2+.

 

Kiyoshi Takatsu (JP), Nobuyuki Harada (JP), Yoshinobu Hara (JP), Yousuke Takahama (JP), Gen Yamada (JP), Kunio Dobashi (JP), and Toshiyuki Hamaoka (JP) purified and determined the physicochemical characteristics of murine T cell replacing factor (TRF). The TRF is an extremely hydrophobic protein with an apparent 50,000 to 60,000 m.w. (1642). Note: T cell replacing factor (TRF) has been shown to induce terminal differentiation of late-developing B cells to antibody-producing cells.

 

B. J. Fowlkes (US), Linette Edison (US), Bonnie J. Mathieson (US), and Thomas M. Chused (US) assessed the differentiation potential of dLy-1 thymocytes in the thymus in vivo. Thymic repopulation by donor-derived cells after transfer of dLy-1 thymocytes was transient, while repopulation by bone marrow was permanent. These findings suggest that the isolated dLy-1 thymocytes described herein are precursor thymocytes that represent a very early stage in intrathymic development (534).

 

Eric M. Smith (US), Deborah Harbour-McMenamin (US), and J. Edwin Blalock (US) reported that the immune and neuroendocrine systems appear able to communicate with each other by virtue of signal molecules (hormones) and receptors common to both systems. They presented data concerning the production of one type of neuroendocrine hormone, endorphins (END), by stimulated lymphocytes (1564). Note: These findings were very controversial at the time.

 

Bernhard Moss (US) reported that interest in poxviruses has been sustained primarily by the unusual biology of the infection: these are the only DNA-containing viruses, which replicate entirely in the cytoplasm of infected cells (1174).

 

Michael G. Rossmann (DE-US), Edward Arnold (US), John W. Erickson (US), Elizabeth A. Frankenberger (US), James P. Griffith (US), Hans-Jürgen Hecht (US), John E. Johnson (US), Greg Kamer (US), Ming Luo (US), Anne G. Mosser (US), Roland R. Rueckert (US), Barbara Sherry (US), and Gerrit Vriend (US) were the first to map the structure of a human common cold virus to an atomic level (1419).

 

James M. Hogle (US), Marie Chow (US), and David J. Filman (US) worked out the three dimensional structure of poliovirus using x-ray crystallography (767).

 

Isabelle Giri (FR), Olivier Danos (FR), and Moshe Yaniv (FR) determined the genomic structure of the cottontail rabbit (Shope) papillomavirus (595).

 

Pekka Saikku (FI), San-Pin Wang (CN-US), Marjaana Kleemola (FI), Eljas Brander (FI), Eeva Rusanen (FI), and J. Thomas Grayston (US) reported outbreaks of a mild respiratory infection that began with coryza and usually affected young people, such as military recruits and college students (1441).

J. Thomas Grayston (US), Cho-Chou Kuo (US), San-Pin Wang (CN-US), and Jeff Altman (US) subsequently identified a new organism, Chlamydia pneumoniae, as the cause of the infection mentioned above. They were able to show that the bacterium is distinct from its cousins Chlamydia trachomatis and Chlamydia psittaci (636).

B.R. Lang () states that this atypical bacterium commonly causes pharyngitis, bronchitis, and pneumonia mainly in elderly and debilitated patients, but also in healthy adults (970). Note: Chlamydophila pneumoniae (Chlamydia pneumoniae) is a species of Chlamydophila, which is an obligate intracellular bacterium that infects humans and is a major cause of pneumonia.

 

Richard A. Young (US), Vijay Mehta (US), Douglas Sweeter (US), Thomas Buchanan (US), Josephine Clark-Curtiss (US), Ronald W. Davis (US), and Barry R. Bloom (US) cloned genes for the major protein antigens of the leprosy parasite Mycobacterium lepta (1855).

 

Joe Cappello (US), Karl Handelsman (US), Stephen M. Cohen (US), and Harvey Franklin Lodish (US) described a retrotransposon in Dictyostelium discoideum (254). Note: The DNA of retrotransposons is transcribed, then using a gene for reverse transcriptase which they carry, make DNA copies and insert them back into the host DNA. In this way retrotransposons replicate without ever having to leave the host cell.

 

Takashi Toda (US), Isso Uno (JP), Tatsuo Ishikawa (JP), Scott Powers (US), Tohru Kataoka (US), Daniel Broek (US), Scott Cameron (US), James Broach (US), Kunihiro Matsumoto (JP), and Michael Wigler (US) found in Saccharomyces cerevisiae that RAS proteins are controlling elements of adenylate cyclase (1675).

Scott Cameron (US), Lonny Levin (US), Mark Zoller (US), and Michael Wigler (US) obtained results indicating that cAMP-independent mechanisms must exist for regulating glycogen accumulation, sporulation, and the acquisition of thermotolerance in S. cerevisiae; therefore, Ras is not alone in controlling cell growth in response to nutrients (248).

Nik C. Barbet (CH), Ulrich Schneider (CH), Stephen B. Helliwell (CH), Ian Stansfield (GB), Michael F. Tuite (GB), and Michael N. Hall (CH) found that Saccharomyces cerevisiae cells treated with the immunosuppressant rapamycin or depleted for the targets of rapamycin TOR1 and TOR2 arrest growth in the early G1 phase of the cell cycle. They proposed that the TORs, two related phosphatidylinositol kinase homologues, are part of a novel signaling pathway that activates eIF-4E-dependent protein synthesis and, thereby, G_l progression in response to nutrient availability (88).

 

Edward Brody (US) and John Norman Abelson (US) discovered and described the function of the spliceosome as an enzymatic complex used for the removal of introns during the processing of pre-messenger RNA (208).

 

Randall Keichi Saiki (US), Kary Banks Mullis (US), Fred A. Faloona (US), Stephen Joel Scharf (US), Glenn Thomas Horn (US), Henry Anthony Erlich (US), and Norman Arnheim (US) conceived that a fragment of DNA could be forced to replicate itself many times in a test tube. This was the origin of what is called the polymerase chain reaction (PCR) (1187-1189; 1440). Note: This methodology was used in the 1985 paper to diagnose sickle cell anemia.

Randall Keichi Saiki (US), David H. Gelfand (US), Susanne Stoffel (CH-US), Stephen Joel Scharf (US), Russell Higuchi (US), Glenn Thomas Horn (US), Kary Banks Mullis (US), and Henry Anthony Erlich (US) used a heat stable enzyme (DNA polymerase) from Thermus aquaticus to establish polymerase chain reaction technology (1439). See, Kjell Kleppe 1971.

 

Thomas C. Sudhof (DE-US), Joseph Leonard Goldstein (US), Michael Stuart Brown (US), David W. Russell (US), Ramila S. Patel (US), Erich Odermatt (US), Jean E. Schwarzbauer (US), and Richard Olding Hynes (GB-US) presented evidence for what would become known as exon shuffling, the exchange of exons between genes, and suggested that the process promotes evolution (1305; 1618).

 

George D. Yancopoulos (US) and Frederick W. Alt (US) reported that unrearranged V_H gene segments are indeed expressed at a high level, but only in a developmentally controlled and tissue-specific manner. Unrearranged V_H expression is limited to the very early stages of the β-lymphocyte differentiation pathway, and it is most prominent in cells undergoing V_H to DJ_H rearrangement. Germ-line V_H expression is independent of the heavy chain enhancer, may be controlled by 5′ sequence elements, and is repressible by LPS. Their results demonstrated that the lack of unrearranged V_H segment expression in mature, Ig-secreting cells is due to the inactivation of a previously active locus (1837).

 

Ronald D. Vale (US), Thomas Sargent Reese (US), Michael P. Sheetz (US), Bruce J. Schnapp (US), Timothy J. Mitchison (US), and Eric Steuer (US) identified kinesin as the "motor" that moves organelles toward the plus ends of microtubules—toward axon tips—in eukaryotes (Eucarya) (1489; 1490; 1715-1718).

Bryce M. Paschal (US), Howard S. Shpetner (US), and Richard B. Vallee (US) demonstrated that, in a kinesin-free prep, microtubule-associated protein (MAP 1C) could translocate microtubules in a unidirectional manner (1301).

Bryce M. Paschal (US) and Richard B. Vallee (US), using Chlamydomonas reinhardtii flagella that have a defined polarity, showed that microtubule-associated protein (MAP 1C) and kinesin moved the axonemes in opposite directions, and that MAP 1C is the retrograde motor (1302). Note: Retrograde refers to moving organelles from the cell periphery toward the cell body while anterograde refers to moving organelles away from the cell body.

Richard B. Vallee (US), Joseph S. Wall (US), Bryce M. Paschal (US), and Howard S. Shpetner (US) showed that microtubule-associated protein (MAP 1C) is in fact a two-headed cytoplasmic dynein (1722).

 

Paul B. Wolfe (US), Marilyn Rice (US), and William Wickner (US) determined that two membrane proteins of Escherichia coli, SecA and SecY, are very likely to promote passage of proteins through the membrane (1811).

 

Richard E. Greenblatt (US), Yoav Blatt (IL), Maurice Montal (US), H. Robert Guy (US), Peddaiahgari Seetharamulu (US), Bruce L. Tempel (US), Diane M. Papazian (US), Thomas L. Schwarz (US), Yuh Nung Jan (US), and Lily Y. Jan (US) hypothesized, based on experimental evidence, that potassium channels in cell membranes consist of proteins arranged such that they create an ion-conducting pore (643; 674; 1657).

 

Phyllis J. Kanki (US), Mary F. McLane (US), Norval W. King, Jr. (US), Norman L. Letvin (US), Ronald D. Hunt (US), Prabhat Sehgal (US), Muthiah D. Daniel (US), Ronald C. Desrosiers (US), and Myron Elmer Essex (US) isolated a simian immunodeficiency virus (SIV) from nonhuman primates (863). Note: This virus shares many characteristics with human immunodeficiency virus (HIV).

 

Joseph E. Varner (US) and Jychian Chen (TW) cloned cDNA of the carrot (Daucus carotus) cell wall protein extensin (1732).

 

Robert G. Knowlton (US), Odile Cohen-Haguenauer (FR), Nguyen van Cong (FR), Jean Frézal (FR), Valerie A. Brown (US), David Barker (US), Jeffrey C. Braman (US), James W. Schumm (US), Lap-Chee Tsui (CN), Manuel Buchwald (CA), and Helen Donis-Keller (US) located a polymorphic DNA marker linked to cystic fibrosis on chromosome 7 in humans (915).

Lap-Chee Tsui (CA), Stephanie Zengerling (DE), Huntington F. Willard (US), and Manuel Buchwald (CA) mapped the cystic fibrosis locus on chromosome 7 of humans (1698).

Lap-Chee Tsui (CN), Manuel Buchwald (CA), David Barker (US), Jeffrey C. Braman (US), Robert G. Knowlton (US), James W. Schumm (US), Hans Eiberg (US), Jan Mohr (DK), Dara Kennedy (US), Natasa Plavsic (US), Martha Zsiga (US), Danuta Markiewicz (US), Gita Akots (US), Valerie Brown (US), Cynthia Helms (US), Thomas Gravius (US), Carol Parker (US), Kenneth Rediker (US), Helen Donis-Keller (US), Stephanie Zengerling (DE), and Huntington F. Willard (US) mapped the cystic fibrosis (CF) gene to chromosome 7 in humans (1697; 1698).

David Barker (US), Philip Green (US), Robert G. Knowlton (US), James W. Schumm (US), Eric Steven Lander (US), Arnold Oliphant (US), Huntington F. Willard (US), Gita Akots (US), Valerie Brown (US), Thomas Gravius (US), Cynthia Helms (US), Christopher Nelson (US), Carol Parker (US), Kenneth Rediker (US), Marcia Rising (US), Diane Watt (US), Barbara Weiffenbach (US), and Helen Donis-Keller (US) determined the genetic linkage map of human chromosome 7 with 63 DNA markers (89).

Devra P. Rich (US), Matthew P. Anderson (US), Richard J. Gregory (US), Seng H. Cheng (US), Sucharita Paul (US), Douglas M. Jefferson (US), John D. McCann (US), Katherine W. Klinger (US), Alan E. Smith (US), Michael J. Welsh (US), Mitchell L. Drumm (US), Heidi A. Pope (US), William H. Cliff (US), Johanna M. Rommens (US), Sheila A. Marvin (US), Lap-Chee Tsui (CN), John (Jack) R. Riordan (CA), Francis Sellers Collins (US), Raymond A. Frizzell (US), and James M. Wilson (US) determined that in humans the cystic fibrosis (CF) gene regulates the passage of chlorine ions across plasma membranes. Mutations in this gene are common and lead to cystic fibrosis (328; 441; 1391).

 

Daniel A. Portnoy (US), and Rafael J. Martinez (US) determined that all three Yersinia species pathogenic for man harbor closely related virulence plasmids (1349).

 

Michael M. Mueckler (US), Celso Caruso (BR), Stephen A. Baldwin (GB), Maria Panico (GB), Ian Blench (GB), Howard R. Morris (GB), W. Jeffrey Allard (US), Gustav E. Lienhard (US), and Harvey Franklin Lodish (US) determined the amino acid sequence and the structure of the glucose transport protein from human HepG2 hepatoma cells (1179).

 

Michelle M. Le Beau (US), Carol A. Westbrook (US), Manuel O. Diaz (US), Janet Davison Rowley (US), and Moshe Oren (IL) mapped the p53 gene to human chromosome 17 (977).

 

Toru Nakano (JP), Takashi Sonoda (JP), Chieko Hayashi (JP), Atsushi Yamatodani (JP), Yoshio Kanayama (JP), Tei-Ichi Yamamura (JP), Hidekazu Asai (JP), Takeshi Yonezawa (JP), Yukihiko Kitamura (JP), and Stephen J. Galli (US) provided experimental evidence that cultured mast cells can give rise to both connective tissue type and mucosal mast cells (1203).

 

William R. Rice (US) and George W. Salt (US) presented experimental evidence in support of sympatric speciation in Drosophila melanogaster (1388-1390).

 

Hiroaki Mitsuya (JP-US), Kent J. Weinhold (US), Phillip A. Furman (US), Marty H. St. Clair (US), Sandra Nusinoff Lehrman (US), Robert Charles Gallo (US), Dani Bolognesi (US), David W. Barry (US), and Samuel Broder (US) demonstrated that 3'-azido-3'-deoxythymidine (AZT) inhibits the infectivity and cytopathic effects of the human immunodeficiency virus (HIV) in vitro (1158).

 

Ralph R. Isberg (US) and Stanley Falkow (US) noted that the precise mechanisms that permit entry of bacteria into host tissues are unclear, therefore they studied the invasion of epithelial cells by Yersinia pseudotuberculosis. As a first step towards identifying the factors required for this process, they reported here the identification of a single genetic locus from this organism that is sufficient to convert the innocuous Escherichia coli K-12 strain into an organism capable of invading cultured animal cells (812).

Ralph R. Isberg (US), Deborah L. Voorhis (US), and Stanley Falkow (US) discovered that invasin, produced by Yersinia spp., triggers its engulfment by intestinal cells on their way to colonize lymph nodes of the gut (813).

Raphael H. Valdivia (US) and Stanley Falkow (US) devised a selection methodology generally applicable to the identification of genes from pathogenic organisms that are induced upon association with host cells or tissues (1714).

 

Alessandro Guidotti (US) Paola Ferrero (AR), and Erminio Costa (US) isolated a brain neuropeptide of 105 amino acid residues, which influences the level of anxiety (668).

 

Sharon Anderson (US), Timothy W. Meyer (US), Helmut G. Rennke (US), Barry M. Brenner (US), J.L. Troy (US), R.L. DeGraphenried (US), J.L. Noddin (US), A.W. Nunn (US), and D. Sandstrom (US) suggested that control of glomerular hypertension effectively limits glomerular injury in rats with renal ablation, and further supported the view that glomerular hemodynamic changes mediate progressive renal injury when nephron number is reduced (31).

 

Colette Corpéchot (FR), Philippe Leclerc (FR), Étienne-Émile Baulieu (FR), and Paul Brazeau (FR) found that in mammals, there are certainly phermonal signals that are under the control of sex steroids (344).

 

Stewart Shipp (GB) and Semir M. Zeki (GB) found that the brain regions receiving sensory information after the primary visual cortex did are specialized for the further processing of color or movement (1539).

 

Tomaso Poggio (US), Vincent Torre (IT), and Christof Koch (US) recall that descriptions of physical properties of visible surfaces, such as their distance and the presence of edges, must be recovered from the primary image data. Computational vision aims to understand how such descriptions can be obtained from inherently ambiguous and noisy data. A recent development in this field sees early vision as a set of ill-posed problems, which can be solved by the use of regularization methods. These lead to algorithms and parallel analog circuits that can solve ‘ill-posed problems’ and which are suggestive of neural equivalents in the brain (1342).

 

Sofsite Contact Lens Laboratory (US) introduced the soft contact lens.

 

A post mortem report by Carol Richardson (GB), from the Central Veterinary Laboratory, dated Sept. 19, 1985, reveals how she had seen bovine spongiform encephalopathy in brain tissue of a Fresian from Peter Stent's farm near Midhurst, West Sussex. She said seven others had earlier been lost with "nervous" symptoms. A vet, David Bee (GB), had seen the first cases before Christmas 1984 (750). Note: This syndrome was dubbed "mad cow disease."

 

David C. Page (US), Albert de la Chapelle (FI-US), Jean Weissenbach (FR), and Mea Andersson (FI) reported that human 'XX males' are sterile males whose chromosomes seem to be those of a normal female yet contain portions of the Y chromosome. They speculated that maleness is probably due to the presence of the Y-encoded testis-determining factor (TDF) (35; 1280).

 

Richard H. Schiappacasse (US), Dariouche Mohammadi (US), and Adrian J. Christie (US) reported that praziquantel is effective in treating human fasciolasis (1480).

 

David J. Durand (US), Ronald I. Clyman (US), Michael A. Heymann (US), John Allen Clements (US), Francoise Mauray (US), Joseph A. Kitterman (US), Philip L. Ballard (US), Roderic H. Phibbs (US), Roberta A. Ballard (US), John Allen Clements (US), David C. Heilbron (US), Ciaran S. Phibbs (US), Mureen A. Schlueter (US), Susan H. Sniderman (US), William H. Tooley (US), and Ann Wakeley (US) developed a life-saving artificial surfactant now used to treat the lungs of infants suffering from respiratory distress syndrome (453; 1327).

 

Daniel Tranel (US) and Antonio R. Damasio (US) presented the neurological syndrome called prosopagnosia, where a patient has a stroke that damages the medial-inferior parts of both temporal lobes. Following the stroke, the patient may be mentally quite lucid, fluent, and attentive, but the surprising thing is that even though he can read the newspaper and score normally on the Snellen chart he is unable to recognize people by looking at their faces (370; 1690).

 

Paul D. MacLean (US) proposed that the human brain can conveniently be thought of as three separate brains, each representing a distinct evolutionary stratum that has formed upon the older layer before it, like archaeological strata: He calls it the triune brain. These three brains are the neocortex or neo-mammalian brain, the limbic or paleo-mammalian system, and the reptilian brain, the brainstem and cerebellum. Each of the three brains is connected by nerves to the other two, but each seems to operate as its own brain system with distinct capacities (1064).

 

Xavier Martin (ES), Jean-Louis Mestas (FR), Dominique Cathignol (FR), Jacqueline Margonari (FR), Albert Gelet (FR), and Jean-Michel Dubernard (FR) initiated extracorporeal shockwave lithotripsy (crushing a calculus in the urinary system with ultrasonic waves) (1091).

 

Onik Gary (US), John Gilbert (US), William Hoddick (US), Roy Filly (US), Peter Callen (US), Boris Rubinsky (US), and Linda Farrel (US) performed surgeries suggesting that sonography is an effective and accurate means of monitoring the entire freezing and thawing cycle in hepatic cryosurgery (1258).

 

David W. Kennedy (US), Simion James Zinreich (US), Arthur E. Rosenbaum (US), and Michael E. Johns (US) described functional endoscopic sinus surgery: theory and diagnostic evaluation (886).

 

Robert K. Josephson (US) developed a technique that took a monumental step towards measuring and understanding muscle function during everyday behaviors such as running, flying, swimming, breathing, sound production, eating, or even the beating of a heart. Commonly referred to as the ‘work loop technique’, this method determines mechanical function while simulating in vivo-like conditions (849).

Josephson did not develop the 'work loop technique' de novo, but rather added phasic stimulation to advance and popularize Kenneth E. Machin (GB) and John W.S. Pringle’s (GB) work on the asynchronous flight muscle of an insect (1059; 1060).

 

John W. House (US) and Derald E. Brackman (US) developed the House-Brackmann facial nerve grading system. Facial nerve dysfunction (facial paralysis) manifests in various symptom patterns. To objectively describe facial function, clinicians often use the House-Brackmann facial nerve grading system (783).

 

Brian G. Glasberg (GB) and Brian C.J. Moore (GB) described modifications to the fitting procedure of auditory filter shapes which allow more accurate derivations. These include: 1) taking into account changes in filter bandwidth with center frequency when allowing for the effects of off-frequency listening; 2) correcting for the non-flat frequency response of the earphone; 3) correcting for the transmission characteristics of the outer and middle ear; 4) limiting the amount by which the center frequency of the filter can shift in order to maximise the signal-to-masker ratio. In many cases, these modifications result in only small changes to the derived filter shape (597).

 

Scott L. Friedman (US), F. Joseph Roll (US), Janet Boyles (US), and D. Montgomery Bissell (US) identified hepatic stellate cells (HSCs), formerly known as lipocytes, Ito cells, or perisinusoidal cells, as the main collagen-producing cells in the liver (543).

Karl Wilhelm von Kupffer (DE) first described the star-shaped (sternzellen) liver cell that Tadeusz Browicz (PL) later characterized as macrophages ("Kupffer cells" ) (950).

Toshio Ito (JP) observed lipid-containing (fett speicherung zellen) perisinusoidal cells in human liver (816).

Kenjiro Wake (JP) demonstrated that the Sternzellen (star-shaped cells) of von Kupffer and the fat-storing cells described by Ito were identical. Wake also established that these cells were important sites of vitamin A storage (1750). Note: Hepatic stellate cells undergo a dramatic phenotypic activation in chronic liver diseases with the acquisition of fibrogenic properties.

 

William H. Dietz (US) and Steven L. Gortmaker (US) observed a dose-response relationship between child and adolescent television watching and obesity in children studied through the National Health Examination Survey. In multiple regression analysis, only prior history of obesity was found to be more influential than television watching on obesity prevalence (415).

 

Bernard Fisher (US), Madeline Bauer (US), Richard Margolese (CA), Roger Poisson (CA), Yosef Pilch (US), Carol Redmond (US), Edwin Fisher (US), Norman Wolmark (US), Melvin Deutsch (US), Eleanor Montague (US), Elizabeth Saffer (US), Lawrence Wickerham (US), Harvey Lerner (US), Andrew Glass (US), Henry Shibata (US), Peter Deckers (US), Alfred Ketcham (US), Robert Oishi (US), and Ian Russell (CA) provided clinical studies showing that lumpectomy plus radiation therapy resulted in improved survival compared with radical mastectomy for women with early- stage breast cancer (520).

 

C. Richter King (US), Matthias H. Kraus (US), Stuart A. Aaronson (US), Shin-Ichi Fukushige (JP), Ken-Ichi Matsubara (JP), Michihiro Yoshida (JP), Motomichi Sasaki (JP), Toshimitsu Suzuki (JP), Kentaro Semba (JP), Nobuyuki Kamata (JP), Kumao Toyoshima (JP), and Tadashi Yamamoto (JP) found amplification of the HER-2 gene that is located in region q21 of human chromosome 17 in a mammary carcinoma, a salivary gland adenocarcinoma, and the MKN-7 gastric cancer cell line in early gene discovery studies (558; 898; 1510).

Mien-Chie Hung (US), Alan L. Schechter (US), Pierre-Yves M. Chevray (US), David F. Stern (US), and Robert A. Weinberg (US) cloned the human oncogene HER-2 (also called neu and erbB2). Overexpression of the protein product of this gene, which occurs in about 20% to 25% of breast cancers (known as HER-2-positive breast cancers), is associated with more aggressive disease and a poor prognosis (799).

Dennis J. Slamon (US), Gary M. Clark (US), Steven G. Wong (US), Wendy J. Levin (US), Axel Ullrich (DE), and William L. McGuire (US) reported that the growth factor receptor gene HER-2/neu is amplified in approximately 15% of stage I breast cancers. The higher degree of amplification is associated with decreased survival (1559). Note: This biomarker would later become the target of the highly successful monoclonal antibody molecular therapy, trastuzumab (Herceptin), improving survival in HER-2/neu-positive patients. The HER-2 status is now considered essential when making adjuvant treatment decisions in all breast cancer patients.

Bernard Fisher (US), John Bryant (US), Norman Wolmark (US), Eleftherios P. Mamounas (US), Ann M. Brown (US), Edwin R. Fisher (US), D. Lawrence Wickerham (US), Mirsada Begovic (US), Arthur DeCillis (US), Andre Robidoux (US), Richard G. Margolese (US), Anatolio B. Cruz, Jr. (US), James L. Hoehn (US), Alan W. Lees (US), Nikolay V. Dimitrov (US), Harry D. Bear (US), Stewart J. Anderson (US), Roy E. Smith (US), Charles E. Geyer, Jr. (US), Morton S. Kahlenberg (US), Soonmyung Paik (US), and Atilla Soran (US) in their prospective randomized controlled trial, found that preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. The later study in which docetaxel was added to adriamycin and cyclophosphamide, either before or after breast surgery, resulted in a significant reduction in local recurrence as a first event (102; 521).

Martine J. Piccart-Gebhart (BE), Marion Procter (GB), Brian Leyland-Jones (CA), Aron Goldhirsch (IT), Michael Untch (DE), Ian Smith (GB), Luca Gianni (IT), Jose Baselga (ES), Richard Bell (AU), Christian Jackisch (DE), David Cameron (GB), Mitch Dowsett (GB), Carlos H. Barrios (BR), Günther Steger (AT), Chiun-Shen Huang (TW), Michael Andersson (DK), Moshe Inbar (IL), Mikhail Lichinitser (RU), István Láng (HU), Ulrike Nitz (DE),Hiroji Iwata (JP),Christoph Thomssen (DE),Caroline Lohrisch (CA), Thomas M. Suter (CH), Josef Rüschof (DE), Tamás Sütő (CH), Victoria Greatorex (CH), Carol Ward (CH), Carolyn Straehle (BE), Eleanor McFadden (GB), M. Stella Dolci (BE), Richard D. Gelber (US), and the Herceptin Adjuvant Trial Study Team used a prospective multi-center randomized controlled trial to show that the addition of trastuzumab to adjuvant chemotherapy significantly improves outcomes in women with HER-2-positive early breast cancer (1330).

 

Joseph Felsenstein (US) used information on the evolutionary relationships of organisms (phylogenetic trees) to compare species. The most common applications are to test for correlated evolutionary changes in two or more traits, or to determine whether a trait contains a phylogenetic signal (the tendency for related species to resemble each other). This is the paper that really started the whole emphasis on 'comparative methods' in the sense of statistically controlling for the effects of evolutionary history/phylogeny (505).

 

John Maynard-Smith (US), Richard M. Burian (US), Stuart Kauffman (US), Pere Alberch (ES-US-ES), John Campbell (), Brian Carey Goodwin (CA-GB), Russell Scott Lande (US-GB), David M. Raup (US), and Lewis Wolpert (GB) wrote this often cited work on evolutionary/developmental constraint (1110).

Stuart Kauffman (US) has argued that the complexity of biological systems and organisms might result as much from self-organization and far-from-equilibrium dynamics as from Darwinian natural selection (875).

 

Martha Allen Sherwood-Pike (US) and Jane Gray (US) reported finding fossil evidence of fungi (Ascoymcota) in material from the Silurian period (438-408 M) (1535).

 

Kamoya Kimeu (KE) discovered Turkana boy, a Homo ergaster: Homo erectus, KNMWT 15000, at Nariokotome near Lake Turkana in Kenya, in 1984. It has been dated to 1.6 M BP (215; 979; 980; 1751). Note: In the 1988 video Mysteries of Mankind, produced by National Geographic, Richard Leakey said of this skeleton, "I think [the Turkana Boy] is remarkable because it's so complete, but perhaps another aspect that is often overlooked is that many people who don't like the idea of human evolution have been able to discount much of the work that we've done on the basis that it's built on fragmentary evidence. There have just been bits and pieces, and who knows; those little bits of bone could belong to anything. To confront some of these people with a complete skeleton that is human and is so obviously related to us in a context where it's definitely one and a half million years or even more is fairly convincing evidence, and I think many of the people who are fence-sitters on this discussion about creationism vs. evolution are going to have to get off the fence in the light of this discovery."

 

1986

Ernst Ruska (DE) for his fundamental work in electron optics, and for the design of the first electron microscope and Gerd Binnig (DE) and Heinrich Rohrer (CH) for their design of the scanning tunneling microscope shared the Nobel Prize in physics.

 

Stanley Norman Cohen (US) and Rita Levi-Montalcini (IT) were awarded the Nobel Prize in Physiology or Medicine for their discoveries of growth factors.

 

Adriana Verschoor (US), Michael Radermacher (US), Joachim Frank (DE-US), Terence Wagenknecht (US), Miloslav Boublik (US), Bruce F. McEwen (US), and Conly L. Rieder (US) began work on the algorithms that would analyze fuzzy 2D electron microscopic images and reconstruct them into sharp 3D structures (1121; 1365; 1741). Note: These algorithms are critical to cryogenic electron microscopy.

 

Susan Solomon (US), Rolando R. Garcia (US), F. Sherwood Rowland (US), and Donald J. Wuebbles (US) reported on work done by a team of 16 scientists who made measurements of trace gases (1436)and physical properties of the atmosphere in Antarctica. The data showed conclusively that human-produced trace gases that contain chlorine and bromine are causing the ozone hole. Scientists from the National Aeronautics and Space Administration (NASA), National Oceanic and Atmospheric Administration (NOAA), and other organizations made the key measurements and analyses that showed the chlorofluorocarbons/ozone/polar stratospheric cloud theories of the ozone hole, and not other theories, are consistent with the observations (1582).

 

Franz Zinoni (DE), Angelika Birkmann (DE), Walfred Leinfelder (DE), and August Bock (DE) reported that the UGA codon could incorporate a new amino acid altogether: selenocysteine (1864). Selenocysteine, the 21st amino acid, has its own tRNA and is found in archaea, eubacteria, and animals.

Bing Hao (US), Weimin Gong (CH), Tsuneo K. Ferguson (US), Cary M. James (US), Joseph A. Krzycki (US), and Michael K. Chan (US) found that genes encoding methanogenic methylamine methyltransferases within the archaeon Methanosarcina barkeri all contain an in-frame amber (UAG) codon that is read through during translation. The electron density for the UAG-encoded residue is distinct from any of the 21 natural amino acids, instead it appears consistent with a lysine in amide-linkage to (4R,5R)-4-substituted-pyrroline-5-carboxylate. They suggested that this amino acid be named l-pyrrolysine (698). Note: This brings the number of amino acids with their own tRNAs to 22.

 

Peter P. Mueller (US) and Alan G. Hinnebusch (US) found that in Saccharomyces cerevisiae multiple upstream AUG codons mediate translational control of the GCN4 gene (1180).

 

Gray Shaw (US) and Robert Kamen (US) proposed that the AU sequences are the recognition signal for an mRNA processing pathway which specifically degrades the mRNAs for certain lymphokines, cytokines, and proto-oncogenes (1528).

 

Nina Saadallah (GB) and Maj Anita Hultén (GB) showed that the classical assumption that loops are invariably present at meiotic prophase to realize a homologous pairing in inversion heterozygotes is not true (1436).

 

Eric M. Phizicky (US), Richard C. Schwatz (US), and John Norman Abelson (US) purified tRNA ligase to near homogeneity. Using affinity elution chromatography, they showed that tRNA ligase is a single polypeptide of 90 kDa that also contains polynucleotide kinase and 2',3'-cyclic phosphate 3'-phosphodiesterase activities. They also determined the amino-terminal sequence of the purified protein and used this information to isolate the gene encoding tRNA ligase by hybridization of an appropriate set of mixed oligonucleotides to a library of yeast DNA (1329).

Eric M. Phizicky (US), Sandra A Counsaul (US), Keith W. Nehrke (US), and John Norman Abelson (US) demonstrated that not only is tRNA ligase critical for tRNA splicing in the yeast cell, but also it is essential for cellular survival (1328).

 

Jeremy Nathans (US), Darcy Thomas (US), and David S. Hogness (US) described the precise difference between the three opsins associated with blue, green, and red visual pigments in humans (1206).

 

Steven C. Huber (US) and Takashi Akazawa (JP) presented a new understanding of pyrophosphate cycling as a plant adaptation for sugar use under widely different metabolic conditions. This pyrophosphate cycling, when linked to sugar metabolism, facilitates previously unrecognized adaptations in plant glycolysis. Among these are distinctive, highly efficient energetics, locally minimal use of ATP, and a capacity for interface with diverse pyrophosphate-handling reactions (791).

 

Charles R. Vossbrinck (US), Carl R. Woese (US), Joseph V. Maddox (US), Stanley Friedman (US), and Bettina A. Debrunner-Vossbrinck (US) found that the eukaryotic microsporidian Varimorpha necatrix lacks 5.8S rRNA, considered ubiquitous in eukaryotes. Further, they found that the sequence of their small subunit rRNA is intermediate between those of other eukaryotes and those of prokaryotes. That microsporidia are derived from one of the earliest radiations of the eukaryotes lends credence to the notion that the early eukaryotes did not have mitochondria, rather than the view that the microsporidia are a eukaryotic group which has lost the extra-nuclear genome (1747; 1748).

 

Francesco Losinno (IT), Fiorenza Busato (IT), Pietro Pavlica (IT), and F. Garofalo (IT) introduced percutaneous nephropyelolithotomy (PCN). This is a wide passage through the kidney percutaneously with the subsequent introduction of a 26 F nephroscope to remove kidney stones (1044).

 

Wolfgang Stremmel (DE), Georg Strohmeyer (DE), and Paul D. Berk (DE) provided evidence that a specific binding protein (FABP) facilitates movement of free fatty acids through the hepatocyte plasma membrane (1613).

 

Anton J.M. Roebroek (BE), Jack A. Schalken (NL), Jack A.M. Leunissen (BE), Carla Onnekink (NL), Henri P.J. Bloemers (NL), and Wim J.M. Van de Ven (BE-NL) discovered furin, the prototype of the novel family of endoproteolytic processing enzymes called proprotein convertases (1414). Note: These enzymes are involved in the activation of a large variety of regulatory proteins like peptide hormones and their receptors, neuropeptides, growth and differentiation factors, blood coagulation factors, plasma proteins, and also exogenous proteins such as viral coat proteins (e.g. HIV-1 and Influenza virus), and bacterial toxins (e.g. diphtheria and anthrax toxin). See Steiner, 1967.

 

Lynn Y. Sakai (US), Douglas R. Keene (US), and Eva Engvall (US) discovered a new connective tissue protein, which they named fibrillin. It was isolated from the medium of human fibroblast cell cultures (1442).

Brendan Lee (US), Maurice Godfrey (US), Emilia Vitale (US), Hori Hisae (JP), Marie-Geneviéve Mattei (FR), Mansoor Sarfarazi (US), Petros Tsipouras (US), Francesco Ramirez (US), and David W. Hollister (US) linked Marfan’s syndrome and a phenotypically related disorder, congenital contractural arachnodactyly, to two different fibrillin genes (989).

Harry C. Dietz (US), Garry R. Cutting (US), Reed E. Pyeritz (US), Cheryl L. Maslen (US), Lynn Y. Sakai (US), Glen M. Corson (US), Erik G. Puffenberger (US), Ada Hamosh (US), Elizabeth J. Nanthakumar (US), Sheila M. Curristin (US), Gail Stetten (US), Deborah A. Meyers (US), and Clair A. Francomano (US) found that Marfan’s syndrome is caused by a recurrent de novo missense mutation in the fibrillin gene (414).

R. Ellen Magenis (US), Cheryl L. Maslen (US), Linda Smith (US), Leland Allen (US), and Lynn Y. Sakai (US) localized the human fibrillin (FBN) gene to chromosome 15, band q21.1 (1069).

 

Alfonso Tramontano (US), Kim D. Janda (US), Richard Alan Lerner (US), Scott J. Pollack (US), Jeffrey W. Jacobs (US), and Peter G. Schultz (US) produced antibodies specific for the transition state of substrates. These antibodies behaved as enzymes (1345; 1346; 1688; 1689). Jean L. Marx (US) named them abzymes (1093). William P. Jencks (US) had predicted that it would be possible to make such molecules (836).

Richard Alan Lerner (US), Alfonso Tramontano (US), Kevan M. Shokat (US), Christian J. Leumann (CH), Renee Joyce Sugasawara (US), and Peter George Schultz (US) produced antibodies, which could function as enzymes (1006; 1541).

 

Edward A. Clark (US) and Jeffrey A. Ledbetter (US) suggested that the Bp35 and Bp50 surface molecules function in the regulatory control of B-cell activation and progression through the cell cycle (302).

 

Maurice K. Gately (US), Darien E. Wilson (US), and Henry L. Wong (US) performed experiments suggesting that lymphokine-containing supernatant (LKS) fraction contains a late-acting factor(s), antigenically distinct from IL 2, which synergizes with IL 2 in facilitating human cytotoxic T lymphocyte (CTL) responses (580).

 

John H. Kehrl (US), Lalage M. Wakefield (US), Anita B. Roberts (US), Sonia Jakowlew (US), Melchor Alvarez-Mon (ES-US), Rik Derynck (US), Michael B. Sporn (US), and Anthony S. Fauci (US) examined the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposed that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. They found that TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta (880).

 

Timothy R. Mosmann (US), Holly Cherwinski (US), Martha W. Bond (US), Martin A. Giedlin (US), and Robert L. Coffman (US) examined a panel of antigen-specific mouse helper T cell clones. They were characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+. Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma globulin, and keyhole limpet hemocyanin (KLH) (1173).

 

Ranjan Sen (US) and David Baltimore (US) characterized proteins that bind to the immunoglobulin (Ig) heavy chain and the kappa light chain enhancers. One is NF-A, a factor found in all tested cell types that binds to the octamer sequence found upstream of all Ig variable region gene segments and to the same octamer in the heavy chain enhancer. Another was NF-kappa B, a nuclear protein found only in cells that transcribe immunoglobulin light chain genes, interacts with a defined site in the kappa immunoglobulin enhancer. This protein can be induced in pre-B cells by stimulation with bacterial lipopolysaccharlde (LPS). The induction involves a post-translational activation. They interpreted these results to indicate that factors that control transcription of specific genes in specific cells may be activated by post-translatlonal modification of precursor factors present more widely (1516; 1517).

 

Barry J. Bowman (US), Emma Jean Bowman (US), Johann Peter Gogarten (US), Henrik Kibak (US), Peter Dittrich (DE), Lincoln Taiz (US), Morris F. Manolson (CA), Ronald J. Poole (CA), Takayasu Date (JP), Tairo Oshima (JP), Jin Konishi (JP), Kimitoshi Denda (JP), and Masasuke Yoshida (JP) showed that V-type direct action proton pumps, which produce proton gradients, appeared early in cellular evolution, before the divergence of archaebacteria (Archaea) and eubacteria (Bacteria) (189; 601).

 

Rob Benne (NL), Janny Van den Burg (NL), Just P. Brakenhoff (NL), Paul Sloof (NL), Jacques H. Van Boom (NL), and Marijke C. Tromp (NL) presented evidence that in the kinetoplast (a modified mitochondrium) DNA of Trypanosoma brucei and Trypanosoma fasciculata the coding sequence in mRNAs may be altered after transcription so that they do not complement the DNA from which they were transcribed. They named this process RNA editing and considered it to be an alternative means of handling genetic information (117-119). Note: Others would later show that over 50% of the bases of the fully edited mature transcript of the COX III gene were introduced by the editing process with guide RNAs (gRNA) in some way insuring that the correct sequence appears in the mRNA.

 

Giuseppe Attardi (IT-US), Anne Chomyn (US), Paolo Mariottini (US), Michael W.J. Cleeter (GB), C. Ian Ragan (US), Marcia Riley (US), and Russell F. Doolittle (US) were the first to directly sequence genes found within mitochondria. Other researchers using different techniques indicated their presence (56; 292).

 

Mark E. Samuels (US) and Phillip Allen Sharp (US) isolated and purified a specific RNA polymerase II transcription factor (1453).

 

David M. Helfman (US), Stephen B. Cheley (US), Esa Kuismanen (FI), Linda A. Finn (US), and Yuriko Yamawaki-Kataoka (JP) proposed that by variation in the intron exon splicing pattern of the pre-mRNA of tropomyosin, fibroblasts, and skeletal muscle cells are able to produce different mRNAs thus different tropomyosins. One gene is thereby coding for more than one type of polypeptide. This discovery altered forever the one gene-one enzyme paradigm (736).

 

Maynard V. Olson (US), James E. Dutchik (US), Madge Y. Graham (US), Garrett M. Brodeur (US), Cynthia Helms (US), Mark Frank (US), Mia MacCollin (US), Robert Scheinman (US), and Thomas Frank (US) used global restriction mapping to define the physical arrangement of closely linked genes in the yeast genome (1257).

 

Peter Harris (GB), Elizabeth Boyd (GB), Bryan D. Young (GB), and Malcolm Andrew Ferguson-Smith (GB) found that the precise karyotype analysis produced by flow cytometry resolved many differences between chromosome homologs, including some that cannot be readily distinguished cytogenetically (711).

 

Cary Weinberger US), Vincent Giguere (US), Stanley M. Hollenberg US), Michael G. Rosenfeld US), Ronald M. Evans (US), Jan Sap (DE), Alberto Muñoz (DE), Klaus Damm (DE), Yves Goldberg (FR), Jacques Ghysdael (FR), Achim Leutz (DE-US), Hartmut Beug (DE), and Björn Vennström (DE), reported that c-erbA was a thyroid hormone receptor that was related to the steroid hormone receptors, thus uniting the fields of thyroid and steroid biology (1461; 1777).

Stephen Green (FR), Philippe Walter (FR), Vijay Kumar (FR), Andrée Krust (FR), Jean-Marc Bornert (FR), Patrick Argos (FR), and Pierre M. Chambon (FR) determined that human estrogen cDNA contains a sequence, whose expression and homology are that of viral erbA (v-erb-A) (639).

 

June R. Scott (US), Susan K. Hollingshead (US), Kevin F. Jones (US), Vincent A. Fischetti (US), Shabbir A. Khan (US), and Bruce W. Erickson (US) cloned an M protein gene from type 6 streptococci. Using this gene they produced pure type 6 M protein and determined its amino acid sequence. From this sequence they were able to deduce that the primary job of the M protein is thwarting the immune system. Negative charges at the N-terminus may repel phagocytic white blood cells, which also carry a negative charge. A portion of the M protein binds with factor H—a regulatory protein produced by the human host—which protects the M proteins most conserved regions from antibodies and complement enzymes. Only antibodies against the antigenically shifting hypervariable region at the N-terminus can clear an established streptococcal infection from the body (768; 769; 845; 1505).

 

Frank Emmrich (DE), Ulrike Strittmatter (DE), and Klaus Eichmann (DE) discovered that a killer T cell is activated most effectively when the same molecule binds an alpha-beta T cell receptor and a CD8 coreceptor (470).

 

Michael L. Dustin (US), Robert Rothlein (US), Atul K. Bhan (US), Charles A. Dinarello (US), and Timothy A. Springer (US), by staining of frozen sections and immunofluorescence flow cytometry, showed intercellular adhesion molecule-1 (ICAM-1) is expressed on non-hematopoietic cells such as vascular endothelial cells, thymic epithelial cells, certain other epithelial cells, and fibroblasts, and on hematopoietic cells such as tissue macrophages, mitogen-stimulated T lymphocyte blasts, and germinal center dendritic cells in tonsils, lymph nodes, and Peyer's patches (454). Note : ICAM-1 is a cell surface glycoprotein originally defined by a monoclonal antibody (MAb) that inhibits phorbol ester-stimulated leukocyte aggregation.

Robert Rothlein (US), Michael L. Dustin (US), Steven D. Marlin (US), and Timothy A. Springer (US) proposed that ICAM-1 may be a ligand in many, but not all, LFA-1-dependent adhesion reactions (1423). Note: LFA-1 is lymphocyte function-associated antigen 1

 

Mitsuru Tsudo (JP), Robert W. Kozak (US), Carolyn K. Goldman (US), Thomas A. Waldmann (US), Keisuke Teshigawara (JP), Huey-Mei Wang (JP), Koichi Kato (JP), and Kendall A. Smith (US) independently discovered that the receptor for interleukin-2 (IL-2-R) is composed of two polypeptide chains. Both of these polypeptide chains are necessary for high-affinity binding of IL-2 (1663; 1696).

Huey-Mei Wang (US) and Kendall A. Smith (US) found that the high-affinity receptor (IL-2-R) for interleukin-2 (IL-2) is formed by a unique cooperative functional interaction between the two separate and distinct binding sites expressed on the p75 alpha and p55 beta chains. The function of the p55 beta chain is as a helper-binding site with no signaling capacity of its own. The p75 alpha chain, without assistance from the p55 beta chain, is capable of promoting cell division within the T cell by triggering a second messenger system (1762).

Pawel Kisielow (PL), Hung Sia Teh (CA), Horst Blüthmann (CH), and Harald von Boehmer (DE-CH) provided evidence that positive selection of antigen-specific, class I MHC-restricted CD4-8+ T cells in the thymus requires the specific interaction of the alpha-beta T cell receptor with the restricting class I MHC molecule (906).

Pawel Kisielow (PL), Horst Blüthmann (CH), Uwe D. Staerz (US), Michael Steinmetz (US), and Harald von Boehmer (DE-CH) examined the mechanism of self-tolerance in T cell-receptor transgenic mice expressing a receptor in many of their T cells for the male (H-Y) antigen in the context of class I H-2Db MHC antigens. Autospecific T cells are deleted in male mice. The deletion affects only transgene-expressing cells with a relatively high surface-density of CD8 molecules, including nonmature CD4+ CD8+ thymocytes, and is not caused by anti-idiotype cells (905).

Hung Sia Teh (CA), Pawel Kisielow (PL), Bernadette Scott (CH), Hiroyuki Kishi (JP), Yasushi Uematsu (JP), Horst Blüthmann (CH), and Harald von Boehmer (DE-CH) found that the specific interaction of the T cell receptor on immature thymocytes with thymic major histocompatibility complex antigens determines the differentiation of CD4+8+ thymocytes into either CD4+8- or CD4-8+ mature T cells (1654).

 

Richard A.F. Dixon (US), Brian K. Kobilka (US), David J. Strader (US), Jeffrey L. Benovic (US), Henrik G. Dohlman (US), Thomas Frielle (US), Mark A. Bolanowski (US), Carl D. Bennett (US), Elaine Rands (US), Ronald E. Diehl (US), Richard A. Mumford (US), Eve E. Slater (US), Irving S. Slater (US), Marc G. Caron (US), Robert J. Lefkowitz (US), and Catherine D. Strader (US) reported that beta 2-adrenergic receptor and rhodopsin share sequence homology and a presumed ‘seven member spanning’ topography, and that they are the first two members of what is probably a large gene family. Unexpectedly the gene for the beta 2-adrenergic receptor was found to be without introns (419). Note: This superfamily of receptors has grown to include: hormonal control of virtually all physiological functions, many instances of neurotransmission, the perception of light, taste, smell and pain, the effects of numerous therapeutic agents such as analgesic effect of opiates, the attraction of motile cells by chemotaxis, the stimulation and regulation of mitosis, and even the entry of viruses such as HIV into cells.

 

Alina C. Lopo (US), Susan E. MacMillan (US), John W. B. Hershey (US), Coralie C. Lashbrook (US), Dzintra Infante (US), and Anthony A. Infante (US) found that regulation of the initiation of protein synthesis in the sea urchin egg is associated with phosphorylation of initiation factor elF4F (1040-1042).

 

Rick L. Sharp (US), David L. Costill (US), William J. Fink (US), and Douglas S. King (US) demonstrated the increased buffer capacity of muscle brought on by sprint training (1527). Note: These researchers credited Archibald Vivian Hill (GB) with putting forth the hypothesis that led to their study.

 

James W. Moulder (US) reported that the phagocytosis of microbial pathogens stimulates macrophages to acidify their phagosomes then fuse them with one or more lysosomes (1176).

 

David E. Birk (US) and Robert L. Trelstad (US) identified three kinds of pockets in the membranes of collagen-producing fibroblasts. One was a deep, narrow crevice that held a single fibril, like a hair in a follicle. The second, wider groove cradled fibril bundles, while the third, even larger indentation held clusters of bundles. The observations suggested that the cell was orchestrating collagen condensation and fibril grouping by adjusting the contours of its membrane. Trelstad and Birk hypothesized that the vesicles that carry newly synthesized collagen stack up and then merge to form the deep crevices, where collagen molecules interlink into a fibril. The cell then manipulates the membrane that separates the pockets, allowing fibrils to merge into bundles and bundles to band together (157).

 

David F. Bird (CA) and Jacob Kalff (CA) discovered that some algae phagocytize and digest bacteria. The most active alga they tested was the chrysophycean, Dinobryon sp (155; 156).

 

Angela C. Delves (AU), Anne Matthews (AU), David A. Day (AU), Andrew S. Carter (AU), Bernard J. Carroll (AU), and Peter M. Gresshoff (AU) demonstrated the existence of two critical factors involved in legume nodulation. The first is required for nodule initiation and functions in the root. The second is required for regulating nodule numbers and functions in the shoot (402).

 

George Kollias (GB), Nick Wrighton (GB), Jacky Hurst (GB), and Frank Grosveld (GB) introduced the human fetal gamma- and adult beta-globin genes into the germ line of mice. Analysis of the resulting transgenic mice shows that the human gamma-globin gene was expressed like an embryonic mouse globin gene; the human beta-globin gene was expressed like an adult mouse globin gene. These results imply that the regulatory signals for tissue- and developmental stage-specific expression of the globin genes have been conserved between man and mouse but that the timing of the signals has changed (921).

 

Michael B. Brenner (US), Joanne McLean (US), Deno P. Dialynas (US), Jack L. Strominger (US), John A. Smith (US), Frances L. Owen (US), J. G. Seidman (US), Stephen Ip (US), Fred Rosen (US), and Michael S. Krangel (US) used monoclonal antibodies to identify a population of human lymphocytes that express the T3 glycoprotein but not the T-cell receptor (TCR) alpha- and beta-subunits. Chemical crosslinking experiments revealed that these lymphocytes express novel T3-associated polypeptides, one of which appears to be the product of the T gamma gene. The other polypeptide may represent a fourth TCR subunit, designated T delta (200).

Ilan Bank (US), Ronald A. DePinho (US), Michael B. Brenner (US), Judy Cassimeris (US), Frederick W. Alt (US), and Leonard Chess (US) reported a clone of normal immature T4-T8- human thymocytes, designated CII, which does not express mature mRNA for T alpha or T beta genes, but does express high levels of T gamma mRNA. This clone also expresses high levels of surface T3 (82).

 

Klas Karre (SE), Hans Gustaf Ljunggren (SE), Gerald Piontek (SE), and Rolf Kiessling (SE) produced data suggesting that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-major histocompatability complex (868).

 

Robert E. Hammer (US), Vernon G. Pursel (US), Caird E. Rexroad, Jr. (US), Robert J. Wall (US), Douglas J. Bolt (US), Richard Deforest Palmiter (US), and Ralph Lawrence Brinster (US) produced transgenic mice by linking the coding sequences of rat growth hormone gene to the mouse metallothionein promoter. This chimeric plasmid was injected into one of the two pronuclei of fertilized mouse eggs. The resulting transgenic mice grew faster than normal mice (694; 1282).

 

Helgi Valdimarsson (IS), Barbara S. Bake (GB), Ingileif Jónsdótdr (GB), and Lionel Fry (GB) suggested that psoriasis is a skin disease in which keratocyte proliferation is initiated by T-cell infiltration and activation (1713).

Tamara Wrone-Smith (US) and Brian J. Nickoloff (US), using in vivo studies, concluded that psoriasis is caused primarily by the ability of pathogenetic blood-derived immunocytes to induce secondary activation and disordered growth of endogenous cutaneous cells including keratinocytes and vascular endothelium (1821). Note: Agents that target specific pathogenic events in the psoriatic inflammatory cascade offer a direct approach to impeding the underlying disease process, improving symptom control and reducing associated co-morbidities.

 

Syed Zaki Salahuddin (US), Dharam V. Ablashi (US), Phillip D. Markham (US), Steven F. Josephs (US), Susi Sturzenegger (US), Mark Kaplan (US), Gregory Halligan (US), Peter Biberfeld (US), Flossie Wong-Staal (US), Bernhard Kramarsky (US), and Robert Charles Gallo (US) cultivated peripheral blood mononuclear cells from patients with AIDS and lymphoproliferative illnesses. Short-lived, large, refractile cells that frequently contained intranuclear and/or intracytoplasmic inclusion bodies were documented. Electron microscopy revealed a novel virus that they named human B-lymphotrophic virus (HBLV) (1445).

Dharam V. Ablashi (US), Syed Zaki Salahuddin (US), Steven F. Josephs (US), F. Imam (US), Paolo Lusso (US), Robert Charles Gallo (US), Chia-Ling Hung (US), John F. Lemp (US), and Phillip D. Markham (US) suggested that the virus name be changed from HBLV to human herpesvirus-6 (HHV-6), in accord with the published provisional classification of herpes viruses (6).

 

 Kang-Sheng Wang (US), Qui Lim Choo (US), Amy J. Weiner (US), Jing-Hsiung Ou (US), Richard C. Najarian (US), Richard M. Thayer (US), Guy T. Mullenbach (US), Katherine J. Denniston (US), John L. Gerin (US), Michael Houghton (GB), Anastass Kos (NL), Rein Dijkema (NL), Annika C. Arnberg (NL), Peter H. van der Meide (NL), Huub Schellekens (NL), Pei-Jer Chen (TW), Ganjam Kalpana (US), Janet Goldberg (US), William Mason (US), Barbara Werner (US), and John Taylor (US) confirmed that the causative agent for delta hepatitis in mammals contains a circular, viroid-like RNA (279; 925; 1763).

 

John F. Kurtzke (US), and Kay Hyllested (DK) concluded that multiple sclerosis (MS) is a widespread, systemic, specific infectious disease only rarely causing neurologic symptoms and most transmissible between ages 13 and 26 (953).

 

Patricia Kahn (DE), Lars Frykberg (SE), Claire Brady (DE), Irene Stanley (AU), Hartmut Beug (DE), Björn Vennström (SE), and Thomas Graf (DE) reported that during the generation of avian erythroblastosis, the erbA oncogene acts to prevent irreversible erythrocyte differentiation (856). Note: ErbA oncoprotein is involved in neoplastic transformation leading to acute erythroleukemia and sarcomas.

Kenneth W. Kinzler (US) and Bert Vogelstein (US) reported that during human colon carcinogenesis, inactivation of the APC/ß-catenin pathway serves to block the egress of enterocytes in the colonic crypts into a differentiated, post mitotic state (900).

 

Karla J. Matteson (US), James Picado-Leonard (US), Bon-Chu Chung (US), Thuluvancheri K. Mohandas (US), and Walter L. Miller (US) assigned the gene for adrenal P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase) to human chromosome 10 (1103). Note: This gene is also called CYP17 and is important because its enzyme product is part of the pathway to convert cholesterol to cortisol, testosterone and estradiol.

 

Jane W. Newburger (US), Masato Takahashi (US), Jane C. Burns (US), Alexa S. Beiser (US), Kyung Ja Chung (US), C. Elise Duffy (US), Mary P. Glode (US), Wilbert H. Mason (US), Venudhar Reddy (US), Stephen P. Sanders (US), Stanford T. Shulman (US), James W. Wiggins (US), Raquel V. Hicks (US), David R. Fulton (US), Alan B. Lewis (US), Donald Y.M. Leung (US), Theodore Colton (US), Fred S. Rosen (US), and Marian E. Melish (US) reported that children with Kawasaki disease treated with a combined regimen of aspirin and intravenous gamma globulin had significantly lower rates of coronary artery aneurysms when compared to those receiving aspirin only. Children treated with the combined regimen had significantly shorter fevers and a greater decrease in inflammatory markers when compared to those treated with aspirin alone (1211).

 

Ronald H. Spiro (US) reviewed a 35-year experience with 2,807 patients treated for salivary tumors which arose in the parotid gland (1,695 patients; 70%), submandibular gland (235 patients; 8%), and seromucinous glands of the upper aerodigestive tract (607 patients; 22%). Pleomorphic adenomas comprised 45% of the total, most of which occurred in the parotid gland. The clinical findings and the distribution of patients according to the histology and the site of origin are summarized. Treatment was surgical and the resection was conservative when possible, depending upon the extent of the tumor. The impact of site, histology, grade, and tumor stage on the results is shown (1594).

 

Marilyn H. Gaston (US), Joel I. Verter (US), Gerald Woods (US), Charles Pegelow (US), John Kelleher (US), Gerald Presbury (US), Harold Zarkowsky (US), Elliott Vichinsky (US), Rathi Iyer (US), Jeffrey S. Lobel (US), Steven Diamond (US), C. Tate Holbrook (US), Frances M. Gill (US), Kim Ritchey (US), and John M. Falletta (US) reported a randomized, placebo-controlled, double-blinded trial that demonstrated an 84% reduction in the incidence of pneumococcal septicemia among patients with sickle cell taking prophylactic penicillin when compared to those taking placebo. Fifteen severe, Streptococcus pneumoniae-related infections occurred during the study with 13 occurring in patients taking placebo, 3 of which resulted in death. No patients taking prophylactic penicillin died during the study course (579).

 

Ralph Seal Paffenbarger, Jr. (US), Mary Elizabeth Laughlin (US), Alfred S. Gima (US), Rebecca A. Black (US), Robert T. Hyde (US), Alvin L. Wing (US), Dexter L. Jung (US), Chung-Cheng Hsieh (US), Susan P. Helmrich (US), David R. Ragland (US), and Rita W. Leung (US) beginning in 1960, performed the landmark College Alumni Health Study, investigating the exercise habits of over 50,000 University of Pennsylvania and Harvard University alumni and the San Francisco Longshoremen Study. The results of this study confirmed that more physically active people have a lower risk of coronary heart disease and live longer (738; 1277-1279).

 

Bruce D. Roth (US) invented trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one, patented in 1986, and developed into the on-market drug, atorvastatin, which ultimately would be sold as Lipitor (1421). Note: Atorvastatin inhibits hydroxymethlglutaryl-CoA reductase (HMG CoA reductase) a "key" enzyme in the metabolic pathway the body uses to produce cholesterol.

 

Jay N. Cohn (US), Donald G. Archibald (US), Susan Ziesche (US), Joseph A. Franciosa (US), W. Eugene Harston (US), Felix E. Tristani (US), W. Bruce Dunkman (US), William Jacobs (US), Gary S. Francis (US), Kathleen H. Flohr (US), Steven Goldman (US), Frederick R. Cobb (US), Pravin M. Shah (US), Robert Saunders (US), Ross D. Fletcher (US), Henry S. Loeb (US), Vincent C. Hughes (US), and Bonnie Baker (US) found that in patients with congestive heart failure, the combination of hydralazine and isosorbide dinitrate significantly reduced mortality when compared with placebo. This was one of the first large, randomized trials to demonstrate significant mortality benefit in the treatment of congestive heart failure (321).

 

The American Society of Anesthesiologists mandated continual end-tidal carbon dioxide analysis be performed using a quantitative method such as capnography, from the time of endotracheal tube/laryngeal mask placement until extubation/removal or initiating transfer to a postoperative care location (330).

Joseph P. Ornato (US), Edgar R. Gonzalez (US), A. Randolf Garnett (US), Ronald L. Levine (US), and Barbara K. McClung (US) reported that the first sign of the return-of-spontaneous-circulation (ROSC) during cardio-pulmonary-resusitation (CPR) is increase in end-tidal carbon dioxide (ETCO2), therefore monitoring of ETCO2 provides very useful information to guide treatment during CPR (1266).

 

Mahlon R. DeLong (US) and Alim Louis Benabid (FR) developed deep brain stimulation of the subthalamic nucleus, a surgical technique that reduces tremors and restores motor function in patients with advanced Parkinson's disease. Their work has culminated in an effective treatment for more than 100,000 individuals worldwide with severe illness who suffer from complications of levodopa therapy.

Garrett E. Alexander (US), Mahlon R. DeLong (US), Peter L. Strick (US), William C. Miller (US), Hagai G. Bergman (IL), and Thomas Wichmann (US) formulated a new model for the brain's circuitry and exposed a fresh target for this illness (17; 131; 132; 399; 400; 1153).

Alim Louis Benabid (DZ-FR), Pierre Pollak (FR), Alain Louveau (FR), Sharon Henry (FR), Jacques de Rougemont (FR), Claire-Lise Gervason (FR), Dominique Hoffmann (FR), Dongming Gao (FR), Marc Hommel (FR), Jacqueline E. Perret (FR), Patricia Limousin (FR), Abdelhamid Benazzouz (FR), Jean Francois Le Bas (FR), Emmanuel Broussole (FR), Paul Krack (FR), Claire Ardouin (FR), Alina Batir (FR), Nadège Van Biercom (FR), Stephan Chabardes (FR), Valérie Fraix (FR), Adnan Koudsie (FR), Patricia Dowsey-Limousin (FR), Mircea Polosan (FR), Nematollah Jaafari (FR), Nicolas Baup (FR), Marie-Laure Welter (FR), Denys Fontaine (FR), Sophie Tezenas du Montcel (FR), Jerome Yelnik (FR), Isabelle Chéreau (FR), Christophe Arbus (FR), Sylvie Raoul (FR), Bruno Aouizerate (FR), Philippe Damier (FR), Marie-Odile Krebs (FR), Eric Bardinet (FR), Patrick Chaynes (FR), Pierre Burbaud (FR), Philippe Cornu (FR), Philippe Derost (FR), Thierry Bougerol (FR), Benoit Bataille (FR), Vianney Mattei (FR), Didier Dormont (FR), Bertrand Devaux (FR), Marc Vérin (FR), Jean-Luc Houeto (FR), Yves Agid (FR), Bruno Millet (FR), and Antoine Pelissolo (FR) devised an effective and reversible intervention that remedies neuronal misfirings (112; 113; 929; 1022; 1023; 1078).

 

Winnifred Berg Cutler (US), George Preti (US), Abba Krieger (US), George R. Huggins (US), Celso R. Garcia (US), and Henry J. Lawley (US) discovered phermones are produced in human underarms; they were found to be odorless (367; 1357).

 

Katharine B. Payne (US), William R. Langbauer, Jr. (US), and Elizabeth M. Thomas (US) discovered that elephants frequently communicate using infrasound at frequencies below the level of human hearing. The frequency of a sound is measured in Hertz (Hz) and the infrasonic range is generally considered to be between 1 and 20 Hz (1315).

 

Jürgen Haffer (DE) combines allopatry, parapatry, refugia and superspecies in a holistic theory explaining speciation (676).

 

Zh Zhang (CN) discovered large (40-200 micrometer) spherical microfossils 1.8 to 1.9 billion years old in sedimentary rocks from China. These microfossils were interpreted to be the earliest know eukaryotes (Eucarya) (1857).

 

The Serra da Capivara National Park in northeast Brazil near the town of Sao Raimundo Nonato contains exceptional testimony to one of the oldest populations to inhabit South America. It constitutes and preserves the largest ensemble of archaeological sites, and the oldest examples of rock art in the Americas. Moreover, the iconography of the paintings provides information about the region’s early peoples. The dating of the rock art suggests continuous occupation from 6,160±130 to 32,160±100 years B.P (667).

 

1987

“Science is a search for repeated pattern.” Stephen Jay Gould (627).

 

Susumu Tonegawa (US) was awarded the Nobel Prize in Physiology or Medicine for his discovery of the genetic principle for generation of antibody diversity.

 

Rainer Grün (DE-AU) and Henry P. Schwarcz (CA) introduced electron spin resonance (ESR) dating of archaeological and palaeoanthropological materials. Fossil teeth are a ubiquitous component of prehistoric sites, and as a consequence, ESR dating of tooth enamel is very widely applicable tool for chronometric dating in the time range beyond the 40,000 yr. limit of radiocarbon and up to at least 2 Ma (660; 661).

 

Koichi Tanaka (JP), Yutaka Ido (JP), Satoshi Akita (JP), Yoshikazu Yoshida (JP), Tamio Yoshida (JP), and Hiroaki Waki (JP) developed electrospray ionization for the mass spectroscopy of large and fragile polar biomolecules important in biological systems (1645; 1646).

John B. Fenn (US), Matthias Mann (US), Chin Kai Meng (US), Shek Fu Wong (US), and Craig M. Whitehouse (US) independently developed the same technique (506).

 

Arnulfo Mar (US), Jason P. Dworkin (US) and Juan Oró (US) synthesized uridine diphosphate glucose, cytidine diphosphate choline, other phosphorylated metabolic intermediates, the coenzymes adenosine diphosphate glucose (ADPG), guanosine diphosphate glucose (GDPG), and cytidine diphosphoethanolamine (CDP-ethanolamine) under primitive Earth conditions (1082; 1083).

 

Piotr Chomczynski (US) and Nicoletta Sacchi (US) dscribed a new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples (291).

 

Kyriacos Costa Nicolaou (CY-US), Tushar K. Chakraborty (IN), Robert A. Daines (US), and Yuji Ogawa (JP) carried out the total synthesis of amphotericin B (1215).

 

Gregory Prelich (US), Matthew Kostura (US), Daniel R. Marshak (US), Michael B. Mathews (US), and Bruce Stillman (US) reported the ring-shaped eukaryotic version of the "sliding clamp" used to keep a single DNA polymerase moving progressively along the same DNA template strand. This eukaryotic version of the clamp is called proliferating cell nuclear antigen (PCVA) (1355).

Peter T. Stukenberg (US), Patricia S. Studwell-Vaughn (US), and Mike O'Donnell (US) demonstrated that the prokaryotes use a homologous enzyme, which forms around the DNA helix to keep the DNA polymerase tethered to the same molecule as it moves (1617).

Xiang-Peng (US), Rene Onrust (NL), Mike O'Donnell (US), and John Kuriyan (US) solved the three-dimensional structure of the beta subunit of one of these "sliding clamp" enzymes found in E. coli (923).

 

James C. Register, III (US), Gunna Christiansen (DK), and Jack D. Griffith (US) investigated the role of the E. coli RecA protein in homologous recombination. RecA catalyzes this process by promoting pairing and strand exchange between homologous DNA molecules. They used electron microscopy to follow reactions in three homologous DNA pairs: super twisted double-stranded (ds) DNA and linear single-stranded (ss) DNA; linear dsDNA and circular ssDNA; and linear dsDNA and colinear ssDNA. They found that all three reactions undergo a three-step pathway. First, the RecA protein-ssDNA filament makes contact with a homologous dsDNA (joining). Second, both DNA partners are at least partially enveloped within the nucleoprotein filament, and if the DNA topology is favorable, exchange of DNA strands then ensues (envelopment/exchange). Finally, upon completion of strand exchange, this complex is resolved and the products are released (1377).

Kyusung Park (US), Zeger Debyser (BE), Stanley Tabor (US), and Jack D. Griffith (US) used electron microscopy to examine the architecture of the DNA and DNA-protein intermediates involved in replication reactions employing the T7 replication proteins. This study showed the first direct evidence of the presence of a DNA loop at the replication fork and provided a long sought after proof of the "Alberts trombone model" of looping of the lagging strand during replication (1289). See, Alberts, 1975.

 

David S. Horowitz (US) and James Chuo Wang (CN-US) explored the active site of E. coli DNA gyrase to determine which residues are involved in DNA binding. They found that tyrosine 122 of the A subunit of E. coli DNA gyrase is the tyrosine that becomes covalently bound to DNA when the enzyme breaks the phosphodiester bonds of DNA (776).

 

Celia White Tabor (US) and Herbert Tabor (US) discovered that S-adenosylmethionine decarboxylase is first formed as a proenzyme. The E. coli version of this proenzyme is then cleaved posttransationally at a lysylserine bond, causing the formation of a pyruvoyl end group that is essential for the enzyme’s activity (1638).

 

Yoshizumi Ishino (JP), Hideo Shinagawa (JP), Kozo Makino (JP), Mitsuko Amemura (JP), and Atsuo Nakata (JP) discovered clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems in Escherichia coli during the course of the analysis of the gene responsible for isozyme conversion of alkaline phosphatase (814).

Francisco J. M. Mojica (ES), César Díez-Villaseñor (ES), Jesús García-Martínez (ES), Elena Soria (ES), Alexander Bolotin (FR), Benoit Quinquis (FR), Alexei Sorokin (FR), S. Dusko Ehrlich (FR), Christine Pourcel (FR), Gregory Salvignol (FR), and Gilles Vergnaud (FR) discovered sequence similarity between the spacer regions of CRISPRs and sequences of bacteriophages, archaeal viruses, and plasmids, also pointing out that the phages and plasmids do not infect host strains harboring the homologous spacer sequences in the CRISPR. From these observations, they proposed that CRISPR sequences function in the framework of a biological defense system similar to the eukaryotic RNAi system to protect the cells from the entry of these foreign mobile genetic elements (176; 1160; 1353).

Rodolphe Barrangou (FR-US), Christophe Fremaux (FR-US), Hélène Deveau (CA), Melissa Richards (US), Patrick Boyaval (FR), Sylvain Moineau (CA), Dennis A. Romero (US), and Philippe Horvath (FR) identified a new bacterial defense against phage invaders. Clustered regularly interspaced short palindromic repeats (CRISPR) are a distinctive feature of the genomes of most bacteria and archaea and are thought to be involved in resistance to bacteriophages. They found that, after viral challenge, bacteria integrated new spacers derived from phage genomic sequences. Removal or addition of particular spacers modified the phage-resistance phenotype of the cell. Thus, CRISPR, together with associated cas genes, provided resistance against phages, and resistance specificity is determined by spacer-phage sequence similarity (90).

Martin Jinek (CZ-CH), Krzysztof Chylinski (AT), Ines Fonfara (SE), Michael Hauer (CH), Emmanuelle Charpentier (SE-DE), Samuel H. Sternberg (US), Rachel E. Haurwitz (US), and Jennifer A. Doudna (US) used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems that provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. They reported here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Their study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage (841; 1605).

Le Cong (US), F. Ann Ran (US), David Cox (US), Shuailiang Lin (CN-US), Robert Barretto (US), Naomi Habib (US), Patrick D. Hsu (US), Xuebing Wu (US), Wenyan Jiang (US), Luciano A. Marraffini (US), Feng Zhang (US) developed the microbial CRISPR-Cas system as a genome editing tool for function in eukaryotic cells. They demonstrated that Cas9 can be used to make modifications at multiple sites in the genome in both human and mouse cells, and that the cuts made by Cas9 can be repaired through the incorporation of a new stretch of DNA (333).

Huber M. Vasconcelos, Jr. (BR), Brandon J. Lujan (US), Mark E. Pennesi (US), Paul Yang (US), and Andreas K. Lauer (US) were the first to use CRISPR to edit human genes within the body, which is also called in vivo gene editing. Previous gene-editing methods have involved editing genetic material after it was removed from the body. The trial’s gene editing approach was designed to be permanent, but not passed onto the offspring of those who receive it. It sought to repair mutations in the CEP290 gene that cause a rare form of inherited blindness called Leber congenital amaurosis type 10; also known as LCA10 and CEP290-related retinal dystrophy (1735).

 

Barbara Demmig (DE), Klaus Winter (DE), Almuth Krüger (DE), and Franz-Christian Czygan (DE) presented their hypothesis placing zeaxanthin in a central role for dissipative photoprotection, over short (minute to minute), medium (diurnal), and long (seasonal) time scales, in nearly every photosynthetic organism (404). Note: Plants take active measures to prevent photodamage, a process termed photoprotection. For example, evergreens can enter a photoprotected state, with strongly down-regulated photochemical efficiency, for the entire duration of a harsh winter.

 

Quentin Howieson Gibson (GB-US) and Stuart J. Edelstein (US) examined binding and subunit interaction in hemoglobin. They measured the free energy of binding of the fourth oxygen molecule and compared their result of -8.6 kcal/mol. This value was consistent with the majority of values found in the literature, and it also allowed reasonable representation of the equilibrium curve using the two-state model without invoking quaternary enhancement (588).

John S. Olson (US), Roland J. Rohlfs (US), and Quentin Howieson Gibson (GB-US) explored the rebinding of CO, O2, NO, methyl, ethyl, n-propyl, and n-butyl isocyanide to the isolated alpha- and beta-chains of hemoglobin as well as the intact molecule. From these experiments the researchers were able to determine the differences between the overall rate constants of the two hemoglobin subunits as well as the differences in binding of the various ligands (1256).

 

Carolyn Doyle (US) and Jack L. Strominger (US) discovered that interaction between CD4 and class II MHC molecules mediates cell adhesion (427).

 

Pamela J. Bjorkman (US), Mark A. Saper (US), Boudjema Samraoui (US), William S. Bennett (US), Jack Leonard Strominger (US), and Don Craig Wiley (US) determined that the class I histocompatibility antigen (HLA-A2) from human cell membranes has two structural motifs: the membrane-proximal end of the glycoprotein contains two domains with immunoglobulin-folds that are paired in a novel manner, and the region distal from the membrane is a platform of eight antiparallel beta-strands topped by alpha-helices. A large groove between the alpha helices provides a binding site for processed foreign antigens (159).

Pamela J. Bjorkman (US), Mark A. Saper (US), Boudjema Samraoui (US), William S. Bennett (US), Jack Leonard Strominger (US), and Don Craig Wiley (US) found that most of the polymorphic amino acids of the class I histocompatibility antigen, HLA-A2, are clustered on top of the molecule in a large groove identified as the recognition site for processed foreign antigens. Many residues critical for T-cell recognition of HLA are located in this site, in positions allowing them to serve as ligands to processed antigens. These findings have implications for how the products of the major histocompatibility complex (MHC) recognize foreign antigens (160).

 

Jean-Francois Brunet (FR), Francois Denizot (FR), Marie-Francoise Luciani (FR), Magali Roux-Dosseto (FR), Marie Suzan (FR), Marie-Genevieve Mattei (FR), and Pierre Golstein (FR) discovered a new member of the murine immunoglobulin superfamily; they named it CTLA-4. It consists of a V-like domain flanked by two hydrophobic regions, one of which has a structure suggestive of membrane anchoring. CTLA-4 is usually expressed in activated lymphocytes and is coinduced with T cell mediated cytotoxicity in inducible models of this process. The murine ctla-4 gene maps to the C band of chromosome 1 (226).

 

Yueh-hsiu Chien (US), Makio Iwashima (US), Kenneth B. Kaplan (US), John F. Elliott (US), and Mark M. Davis (US) discovered a new T cell receptor gene located within the alpha locus and expressed early in T cell differentiation (287).

 

Yoshihisa Kuwana (JP), Yoshihiro Asakura (JP), Naoko Utsunomiya (JP), Mamoru Nakanishi (JP), Yohji Arata (JP), Seiga Itoh (JP), Fumihiko Nagase (JP), Yoshikazu Kurosawa (JP), Gideon Gross (IL), Guy Gorochov (IL), Tova Waks (IL), and Zelig Eshhar (IL) were the first to describe chimeric antigen receptors (CARs) containing portions of an antibody and the T cell receptor. Originally termed "T-bodies", these early approaches combined an antibody's ability to specifically bind to diverse targets with the constant domains of the T cell receptor alpha (TCR-α) or T cell receptor beta ( TCR-β) proteins (651; 652; 955).

Bryan A. Irving (US) and Arthur Weiss (US) showed that chimeric receptors containing the intracellular signaling domain of CD3ζ activate T cell signaling (810).

Kristen M. Hege (US), Margo R. Roberts (US), Carl H. June (US), and Michael Sadelain (US) added CD3ζ intracellular domains to chimeric receptors with antibody-like extracellular domains, commonly single-chain fraction variable (scFV) domains, as well as proteins such as CD4, subsequently termed first generation chimeric antigen receptors (CARs) (732; 851). Note: Clinical trials in the early 2010s using second generation CARs targeting CD19, a protein expressed by normal B cells as well as B-cell leukemias and lymphomas demonstrated the clinical efficacy of CAR T cell therapies and resulted in complete remissions in many heavily pre-treated patients (191).

 

Paul D. Siebert (US) and Minoru Fukuda (JP) cloned the human glycophorin B gene and determined its genomic relationship to glycophorin A (1545). Note: It is located on the long arm of chromosome 4 (4q28-q31) and has 5 exons. The peptide sequence of 72 amino acids had been determined earlier that year. Glycophorin A and B are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups respectively.

 

Marc K. Jenkins (US) and Ronald H. Schwartz (US) found that antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo (837).

 

John W. Kappler (US), Neal Roehm (US), and Philippa Marrack (US) presented results showing that in normal animals tolerance to self-MHC is due to clonal elimination rather than suppression. In addition, they indicated that tolerance induction might occur in the thymus at the time immature thymocytes are selected to move into the mature thymocyte pool (867).

 

Elwyn Y. Loh (US), Lewis L. Lanier (US), Christoph W. Turck (US), Dan R. Littman (US), Mark M. Davis (US), Yueh-hsiu Chien (US), and Arthur Weiss (US) identified and sequenced a fourth human T cell antigen receptor chain (1036).

 

Daizo Koga (JP), Akira Isogai (JP), Shohei Sakuda (JP), Shogo Matsumoto (JP), Akinori Suzuki (JP), Shigeru Kimura (JP), and Akio Ide (JP) were the first to isolate allosamidin, an antibiotic that inhibits insect, nematode, and fungal chitinases (918).

 

Takenori Ochiai (JP), Kazuaki Nakajima (JP), Matsuo Nagata (JP), Takao Suzuki (JP), Takehide Asano (JP), Takeshi Uematsu (JP), Takesada Goto (JP), Seiji Hori (JP), Takashi Kenmochi (JP), Toshio Nakagoori (JP), and Kaichi Isono (JP) reported the effect of a new immunosuppressive agent, FK 506 (tacrolimus), on heterotopic cardiac allotransplantation in the rat. The agent was isolated from Streptomyces tsukubaensis (1242).

 

Ian M. Orme (US) infected mice with i.v. dose of the virulent Erdman strain of Mycobacterium tuberculosis. They then exhibited three distinct phases of infection within the spleen. These consisted of a primary phase, characterized by the progressive growth of the organism; a secondary phase, in which the viable organism was progressively eliminated; and a tertiary phase, characterized by a chronic or slowly recrudescing disease state. Passive transfer experiments, in which T cell-enriched spleen cells from immune donors were infused into T cell-deficient recipients and were measured for their capacity to adoptively protect these mice from challenge with M. tuberculosis, provided evidence that at least three separate populations of protective T cells were acquired in response to the infection within the time frame of the experiments. These populations of T cells could be distinguished in that they differed in their expression of the L3T4 and Lyt-2 cell surface molecules, in terms of their kinetic profiles of emergence and loss, and (c) in terms of their susceptibility to cyclophosphamide. The results may suggest that different populations of protective T cells can be generated at different times during the infection as various classes of antigens (for example, metabolic or structural antigens) become available for presentation by host macrophages. It is hypothesized, furthermore, that the kinetics of emergence and loss of these various populations may reflect switching in the mode of immunity being expressed, particularly during the chronic phase of the infection, from that of a state of active immunity to one of immunologic memory (1265).

 

Jeffrey E. DeClue (US), Ivan Sadowski (CA), G. Steven Martin (GB-US), and Anthony James Pawson (GB-CA) discovered the Src homology 2 (SH2) domain and identified its role in intracellular signaling (all cytoplasmic protein-tyrosine kinases (PTKs) share a noncatalytic domain, termed SH2, which comprises approximately 100 residues located immediately N-terminal to the kinase domain). They established that modular protein interactions control signal transduction (395). Note: It is now widely recognized that SH2 domains control a series of protein-protein interactions by which the components of the signal transduction process activate one another. It now appears that these SH2-mediated interactions are very widespread, and play a central role both in normal cell signaling, and in the abnormal stimulation of cell growth induced by many oncogene products.

 

Toshiaki Imagawa (US), Jeffrey S. Smith (US), Roberto Coronado (US), and Kevin P. Campbell (US) identified and purified a protein that regulates the passage of calcium ions in and out of muscle cells during contraction and relaxation (806).

 

Mark A. Goldberg (US), G. Allison Glass (US), James M. Cunningham (US) and H. Franklin Bunn (US) identified cells in the liver which make erythropoietin (602).

 

Palmer A. Orlandi, Jr. (US) and Sam J. Turco (US) isolated and characterized the lipid moiety of the lipophosphoglycan of Leishmania donovani as a novel lyso-alkylphosphatidylinositol (1263).

 

Michael H. Ricketts (ZA), Mikael J. Simons (BE), Jasmine Parma (BE), Luc Mercken (BE), Qihan Dong (BE), and Gilbert Vassart (BE) were the first to discover a causal mutation for a Mendelian trait in non-laboratory animals: a non-sense mutation in the thyroglobulin gene (TG), causing familial goiter in cattle (1395).

 

A human genome-sequencing plan won unanimous approval in the United States (1281).

 

The U.S. Patent Office indicated that new higher life forms, animal or plant, are proper subjects of patents if they are not naturally occurring (and are not human, in the case of animals) (762).

 

Walter Gilbert (US) proposed the Exon Theory of Genes, which is the idea that the first genes were made of small pieces. The crucial elements of the theory are that the very first genes were exons represented by small polypeptide chains ≈ 15-20 amino acids long, that the basic method used by evolution to make new genes was to shuffle the exons, and that a major trend of evolution was then to lose introns and to fuse small exons together to make complicated exons (590).

Walter Gilbert (US), Sandro J. de Souza (US), and Manyuan Long (US) supported the exon theory of genes with experimental evidence (591).

 

Ada Yonath (IL), Kevin R. Leonard (DE) and Heinz Guenter Wittmann (DE) determined that the large subunit of the ribosome houses a tunnel extending from the area of the A and P sites to the area on the ribosome where the newly assembled polypeptide exits. Therefore, the nascent polypeptide is likely to pass down this tunnel during the translation process (1846).

 

Bernd Epe (DE), Paul Woolley (DE), and Horst Hornig (DE) established that tetracycline inhibits translation of mRNA by interacting with the ribosomal A site (472).

Ditlev E. Brodersen (DK), Andrew P. Carter (GB), William M. Clemons, Jr. (GB), Robert J. Morgan-Warren (GB), Frank V. Murphy, 4th (GB), James M. Ogle (GB), Michael J. Tarry (GB), Brian T. Wimberly (US), and Venkatraman Ramakrishnan (IN-US-GB) confirmed, at the atomic level, that indeed the A site of the ribosome is where tetracycline attaches to inhibit translation (207).

 

John E. Walker (GB), Alison L. Cozens (GB), Mark R. Dyer (GB), Ian M. Fearnley (GB), Steven J. Powell (GB), Michael J. Runswick (GB), David F. McCarn (US), Richard A. Whitaker (US), Jawed Alam (US), Jacqueline M. Vrba (US), and Stephanie E. Curtis (US) isolated and sequenced the genes coding for F0F1 ATPase in Anabaena and Synechococcus (352; 366; 1114; 1754).

 

John P. Adelman (US), Chris T. Bond (US), James Douglass (US), and Edward Herbert (US) found two rat genes that occupy opposite nucleotide chains of the same DNA segment. One of the genes encodes gonadotropin-releasing hormone and the other an unidentified protein (11).

 

Ernst Hafen (CH), Konrad Basler (CH), Jan E. Edstroem (US), and Gerald M. Rubin (US) after sequencing the sevenless gene of Drosophila, discovered that it encodes a predicted transmembrane protein bearing a tyrosine kinase domain that is highly related to domains that are present in viral oncogenes and hormone receptors. Based on this homology, they correctly prophesized that the molecular mechanisms of signaling would be the same in both cases: a prediction that came to fruition a few years later (675).

Michael A. Simon (US), David D.L. Bowtell (AU), G. Steven Dodson (US), Todd R. Laverty (US), and Gerald M. Rubin (US) reported that two of the isolated enhancers of sevenless encoded known signaling molecules — the GTPase Ras, and its guanine nucleotide exchange factor, Cdc25 (1551).

 

Paul Primakoff (US), Hilary Hyatt (US), and Joanne Tredick-Kline (US) discovered a sperm protein that promotes fusion of mammalian egg and sperm membranes. It was called PH-30 (1358).

 

Leland H. Johnston (GB), Julia H.M. White (GB), Anthony L. Johnson (GB), Giovanna Lucchini (IT), and Paolo L. Plevani (IT) described the control sequences responsible for coordinated expression in the yeast cell cycle of enzymes involved in DNA synthesis (844).

 

Arthur Ashkin (US), Joseph M. Dziedzic (US), and Tetsuo Yamane (US) developed a new optical technique which made it possible to hold and move objects as small as individual microtubules and microtubule motors and measure forces generated by the motors. The technique, employing a powerful light microscope and a laser is referred to as optical tweezers (52; 53).

 

Gary J. Gorbsky (US), Douglas Edward Koshland, Jr. (US), Timothy J. Mitchison (US), Marc Wallace Kirschner (US), Paul J. Sammak (US), and Gary Guy Borisy (US) performed experiments indicating that, during anaphase A (reduction of kinetochore-to-pole distance) chromosomes move toward the cell poles by sliding over or along kinetochore microtubules (617; 927).

 

Theodore M. Klein (US), Edward D. Wolf (US), Ray Wu (US), Nelson Allen (US), and John C. Sanford (US) developed the biolistic or gene gun method for inserting foreign DNA into host plant cells. Magnesium tungsten or gold particles are coated with a DNA vector construct, which can also contain a promoter and selectable genes. The coated particles are then blasted into plant cells using gunpowder detonation in a particle gun. The method works with both monocotyledonous and dicotyledonous plants (912; 1458).

Theodore M. Klein (US), Michael E. Fromm (US), Arthur Weissinger (US), Dwight Tomes (US), Steve Schaaf (US), Margit Sletten (US), and John C. Sanford (US) successfully recovered stable transformants following transfer of foreign genes into intact maize cells with high-velocity microprojectiles (911).

 

Thomas Ganz (US), Michael E. Selsted (US), and Robert I. Lehrer (US) discovered that the phagocytosis of microbial pathogens by macrophages stimulates the macrophages to release defensins (proteins with antimicrobial potential) into the lysosomes of neutrophils and alveolar macrophages (575).

 

Roland Stocker (CH), Yorihiro Yamamoto (JP), Antony F. McDonagh (US), Alexander N. Glazer (US), and Bruce Nathan Ames (US) found that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes (1609).

 

Zlatko Dembic (CH), Werner Haas (CH), Rose Zamoyska (US), Jane Parnes (US), Michael Steinmetz (CH), and Harald von Boehmer (CH) showed that the CD8 coreceptor is actively involved in antigen recognition by killer T cells (403; 1745).

 

Prim B. Singh (GB), Richard E. Brown (GB), and Bruce C. Roser (GB) reported that classical polymorphic class I major histocompatibility complex molecules in normal rats are constitutively excreted in the urine and that untrained rats can distinguish the smell of urine samples taken from normal donors that differ only at the class I MHC locus and therefore excrete different allelomorphs of class I molecules in their urine (1555).

Jo Manning (US), Edward K. Wakeland (US), and Wayne K. Potts (US) provided evidence from seminatural populations of the house mice (Mus musculus domesticus) that females prefer communal nesting partners that share allelic forms of major histocompatibility complex genes (1080). Note: Mice detect the MHC status of an individual from the odor of broken-down MHC products (cell surface glycoproteins) in their urine. This status is used as an indicator of relatedness.

 

Ming Luo (US), Gerrit Vriend (NL), Greg Kamer (US), Iwona Minor (US), Edward Arnold (US), Michael George Rossmann (US), Ulrike Boege (CA), Douglas G. Scraba (CA), Gregory M. Duke (US), Ann C. Palmenberg (US), and Roland R. Rueckert (US) suggested that many spherical RNA viruses have evolved from a common viral ancestor. This was based on three-dimensional constructions of the viruses (1053; 1420).

 

Philippe Clerc (FR), and Philippe J. Sansonetti (FR) discovered that F-actin and myosin accumulate as aggregates subjacent to the cytoplasmic membrane in areas of the cell surface that interact with invasive shigellae. It can be concluded that S. flexneri has the capacity to induce epithelial cells to perform a phagocytic process similar to that observed in professional phagocytes (311).

 

Anthony A. Hyman (GB) and John G. White (GB) studied the early embryogenesis of Caenorhabditis elegans. From the results they inferred that microtubules running from the centrosome to the cortex have a central role in aligning the centrosome-nuclear complex (803).

 

Robert L. Davis (US), Harold M. Weintraub (US) and Andrew B. Lassar (US) discovered MyoD, a helix-loop-helix (bHLH) transcription factor characterized as a muscle regulatory factor (MRF). MoD, along with other MRFs, is essential for myoblast determination. The authors found that MyoD alone could convert 10T 1/2 fibroblasts into myoblasts (386). Note: MyoD and other bHLH MRF factors bind the E-box sequence (CANNTG) within promoters of downstream target genes.

 

Steven E. Lindow (US) produced a genetically altered bacterial strain of Pseudomonas syringae, designed to make plants resistant to frost damage (1026). Note: It was first released in California.

That same year a version of Rhizobium meliloti (Sinorhizobium meliloti) dubbed RMBPC-2, was genetically engineered to contain antibiotic resistance, as well as, genes to enhance nitrogen-fixing ability. The Environmental Protection Agency (EPA) approved its use in 1997. It was first released in Wisconsin.

 

Lauri Saxén (FI) determined that glial cell line-derived neurotrophic factor (GDNF) controls ureteric branching and thereby a fundamental step in kidney development (1468).

 

Mary D. Lee (US), Theresa S. Dunne (US), Marshall M. Siegel (US), Conway C. Chang (US), George O. Morton (US), Donald B. Borders (US), George A. Ellestad (US), and William J. McGahren (US) discovered that calicheamicin gamma, produced by Micromonospora echinospora ssp calichensis, has a phenomenally high potency against tumor cells (993-995).

 

Shinichiro Sawada (JP), Gen Suzuki (JP), Yoshiko Kawase (JP), and Fumimaro Takaku (JP) reported results indicating that the novel immunosuppressive agent, FK506, affects T cell activation with mechanisms similar to those of cyclosporin A (CsA) but at considerably lower concentrations (1466).

 

Teizo Yoshimura (JP-US), Kouji Matsushima (JP), Shuji Tanaka (US), Elizabeth A. Robinson (US), Ettore Appella (US), Joost J. Oppenheim (NL-US), and Edward J. Leonard (US) purified another proinflammatory protein that is chemotactic for human neutrophils from conditioned medium of lipopolysaccharide-stimulated monocytes (1851).

Teizo Yoshimura (JP-US), Kouji Matsushima (JP), Joost J. Oppenheim (NL-US), and Edward J. Leonard (US) supplied data suggesting that a chemotactic factor for neutrophils, different from IL 1, is produced by lipopolysaccharide-stimulated blood monocytes (1850).

 

Takushi Hasegawa (JP), Fuminori Masugi (JP), Toshio Ogihara (JP), Yuichi Humahara (JP), Tadashi Inagami (US), Masaaki Tamura (US), Stephen S. Gottlieb (US), Amy C. Rogowski (US), Michelle Weinberg (US), Cathy M. Krichten (US), Bruce P. Hamilton (US), John M. Hamlyn (US), Mordecai P. Blaustein (US), Sergio Bova (IT), Donald W. DuCharme (US), Frederic Mandel (US), W. Rodney Mathews (US), James H. Ludens (US), Zhuo Ren Lu (US), Paolo Manunta (IT), Keizo Kimura (SE), Jui R. Shah (US), James Laredo (US), Jennifer P. Hamilton (US), Matthew J. Hamilton (US), Su-Qin Li (CN), Christian Eim (DE), Ulrike Kirch (DE), Rudolf E. Lang (DE), and Wilhelm Schoner (DE) presented evidence that ouabain is a new steroid hormone of the adrenal cortex and hypothalamus with qualities like digitalis. Ouabain-like immunoreactivity has been found in almost all tissues, including plasma, but the highest concentrations have been observed in the adrenal, hypophysis, and hypothalamus (624; 692; 693; 719; 807; 1019). See, Ringer, 1885.

 

Dmitry Goldgaber (US), Michael I. Lerman (RU-US), O. Wesley McBride (US), Umberto Saffiotti (IT-US), and Daniel Carleton Gajdusek (US) reported a gene associated with Alzheimer’s disease. The gene is highly conserved in evolution and has been mapped to human chromosome 21 (604).

 

Michel Koenig (US), Eric P. Hoffman (US), Corlee J. Bertelson (US), Anthony P. Monaco (US), Chius C. Feener (US), and Louis M. Kunkel (US) completely cloned the Duchenne muscular dystrophy (DMD) cDNA, then determined the genomic organization of the DMD gene in normal and affected individuals (916).

 

David A. Cheresh (US) found that endothelial cell-surface integrin expression is critical for proliferation and survival. Targeting certain integrins has shown promise as a strategy to inhibit new blood vessel growth (284).

Yasuo Kubota (US), Hynda K. Kleinman (US), George R. Martin (US), and Thomas J. Lawley (US) provided the first demonstration that the subendothelial basement membrane can directly contribute to capillary morphogenesis within 18-24 hours. In addition, culturing on basement membrane allows endothelial cells to become quiescent in culture (944).

Peter C. Brooks (US), Richard A.F. Clark (US), David A Cheresh (US), Christopher J. Drake (US), Lynn A. Davis (US), and Charles D. Little (US) gave the first descriptions of a key role for the integrin family of adhesion receptors in angiogenesis (210; 432). Note: These findings linked the fields of cell adhesion, integrin function, and angiogenesis.

Peter C. Brooks (US), Anthony M. Montgomery (US), Mauricio Rosenfeld (US), Ralph A. Reisfeld (US), Tianhua Hu (US) (US), George Klier (US), and David A. Cheresh (US) were the first to demonstrate a plausible mechanism by which newly forming vessels can be destroyed without damaging the preformed vasculature (211). The unique sensitivity of endothelial cells in remodeling vessels to apoptosis, first documented here in response to integrin antagonists, has subsequently been observed in response to a wide variety of other antiangiogenic agents.

Martin Friedlander (US), Peter C. Brooks (US), Robert W. Shaffer (US), Christine M. Kincaid (US), Judith A. Varner (US), and David A. Cheresh (US) described two alpha V integrins involved in the bFGF and VEGF angiogenic pathways (542).

Donald R. Senger (US), Kevin P. Claffey (US), Julie E. Benes (US), Carole A. Perruzzi (US), Ageliki Sergiou (US), and Michael Detmar (US) described the importance of the alpha 1ß1 and alpha 2ß1 integrins in angiogenesis, expanding the integrin field (1518).

Menq-Jer Lee (US), Shobha Thangada (US), Kevin P. Claffey (US), Nicolas Ancellin (US), Catherine H. Liu (US), Michael Kluk (US), Mario Volpi (US), Ramadan I. Sha'afi (US), and Timothy Hla (US) pointed out the importance of platelet lipids in the regulation of endothelial morphogenesis during angiogenesis (992).

 

The Consensus Trial Study Group (US) reported that in patients with severe heart failure, treatment with enalapril significantly reduced the risk of mortality at 6-months and 1-year when compared with placebo; the reduction in mortality was due to significantly lower risk of mortality resulting from progression of heart failure; and patients on enalapril were significantly more likely to suffer from hypotension compared to those receiving placebo (657).

Jay N. Cohn (US), Gary Johnson (US), Susan Ziesche (US), Frederick Cobb (US), Gary Francis (US), Felix Tristani (US), Raphael Smith (US), W. Bruce Dunkman (US), Henry Loeb (US), Maylene Wong (US), Geetha Bhat (US), Steven Goldman (US), Ross D. Fletcher (US), James Doherty (US), C. Vincent Hughes (US), Peter Carson (US), Guillermo Cintron (US), Ralph Shabetai (US), and Clair Haakenson (US) found in patients with heart failure, that those treated with enalapril experienced significantly lower mortality at 2-years compared to patients on hydralazine and isosorbide dinitrate. Patients treated with enalapril experienced significantly higher serum creatinine levels and higher potassium levels than patients on the combination of hydralazine and isosorbide dinitrate (322).

The SOLVD Investigators (US) reported that the addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and low ejection fractions (808).

 

Thomas A. Stamey (US), Norman Yang (US), Alan R. Hay (US), John E. McNeal (US), Fuad S. Freiha (US) and Elise A. Redwine (US) concluded that prostate-specific antigen (PSA) is more sensitive than prostatic acid phosphatase (PAP) in the detection of prostatic cancer and will probably be more useful in monitoring responses and recurrence after therapy. However, since both PSA and PAP may be elevated in benign prostatic hyperplasia, neither marker is specific (1598).

 

Manuel Elkin Patarroyo (CO), Pedro Romero (CO), Martha L. Torres (CO), Pedro Clavijo (CO), Alberto Moreno (CO), Alberto Martinez (CO), Raul Rodriguez (CO), Fanny Guzman (CO), and Edelmira Cabezas (CO) developed the first synthetic vaccine against the Plasmodium falciparum parasite. Its efficacy is yet to be proved (1304).

 

Koichi Maeda (US), Norman Markowitz (US), Robert C. Hawley (US), Miodrag Ristic (US), Donald Cox (US), and Joseph E. McDade (US) first described human monocytic ehrlichiosis (HME) (1068). It is caused by intraleukocytic parasites that infect mononuclear phagocytes in blood and tissues of humans and a variety of wild and domestic animals and constitutes the genus Ehrlichia of the family Rickettsiaceae.

Burt E. Anderson (US), Jacqueline E. Dawson (US), Dana C. Jones (US), and Kenneth H. Wilson (US) isolated Ehrlichia chaffeensis and recognized it as the etiological agent of HME (27).

 

Michael S. Hershfield (US), Rebecca H. Buckley (US), Michael L. Greenberg (US), Alton L. Melton (US), Richard Schiff (US), Christine Hatem (US), Joanne Kurtzberg (US), M. Louise Markert (US), Roger H. Kobayashi (US), Ai-Lan Kobayashi (US), and Abraham Abuchowski (US) treated two children who had adenosine deaminase (ADA) deficiency and severe combined immunodeficiency disease (SCID) by injecting bovine adenosine deaminase modified by conjugation with polyethylene glycol (PEG-ADA). The therapy was considered a success (744).

 

Richard S. Schwalbe (US), Jack T. Stapleton (US), and Peter H. Gilligan (US) reported the emergence of vancomycin resistant coagulase-negative staphylococci (1501). This was an alarming development because at the time vancomycin was the antibiotic of last resort in treating methicillin-resistant-Staphylococcus aureus (MRSA).

 

Larry R. Squire (US) reported that the hippocampus region of the brain is integral to the learning of facts pertaining to people, places, and events (1596).

 

W. Ripley Ballou (US), James A. Sherwood (US), Franklin A. Neva (US), Daniel M. Gordon (US), Robert A. Wirtz (US), Gall F. Wasserman (US), Carter L. Diggs (US), Stephen L. Hoffman (US), Michael R. Hollingdale (GB), Wayne T. Hockmeyer (US), Imogene Schneider (US), James F. Young (US), Peter Reeve (US), and Jeffrey D. Chulay (US) reported on the first human trials of malaria vaccines based on recombinant or synthetic forms of the circumsporozoite protein (78).

 

John R. Fozard (FR), Paul L.R. Andrews (GB), William Garth Rapeport (GB), and Gareth J. Sanger (GB) found that antagonists of the 5-HT3 receptor for serotonin show excellent blockage of nausea and vomiting caused by cytotoxic drugs such as cisplatin (38; 535).

Luigi X. Cubeddu (VE), Irene S. Hoffmann (VE), Nery T. Fuenmayor (VE), and Andrew L. Finn (US) upon investigating the antiemetic efficacy of Ondansetron (GR 38032F; Glaxo), concluded that ondansetron is an effective and safe agent for controlling the nausea and vomiting induced by cisplatin treatment. They suggested that cisplatin treatment increases the release of serotonin from enterochromaffin cells, and that ondansetron acts by blocking S3 receptors for serotonin (361). Note: Also called Zofran

 

Nicholas R. Anthonisen (CA), Jure Manfreda (CA), C. Peter W. Warren (CA), Earl S. Hershfield (CA), Godfrey K.M. Harding (CA), and Nancy A. Nelson (CA) reported effects of broad-spectrum antibiotic and placebo therapy in patients with chronic obstructive pulmonary disease in exacerbation. They were compared in a randomized, double-blinded, crossover trial. There was a significant benefit associated with antibiotic. Exacerbations were defined in terms of increased dyspnea, sputum production, and sputum purulence (39).

 

Philippe Mouret (FR), March 1987, was scheduled to perform “laparoscopy, gynecological adhesiolysis, and cholecystectomy” for a 50-year-old woman with vague abdominal pain. According to his personal accounts, this lady requested that Mouret perform the operations at the same time, which he agreed to do if possible. After performing the pelvic phase of the procedure, Mouret reversed the Trendelenburg position and explored the gallbladder area with the laparoscope. He dissected the gallbladder antegrade with a hook dissector as he grasped the gallbladder fundus with forceps inserted directly through the abdominal wall. He cauterized the cystic artery and clipped the cystic duct with a clip applier introduced through the left rectus muscle. Video was not available at this time so Mouret was forced to lie on the patient's right thigh as he peered through the laparoscope and controlled his instruments. In the course of 2 ½ hours, Mouret performed his first laproscopic cholecystectomy. He left the case feeling both physically and mentally exhausted as he pondered the “weight of medico-legal responsibility for having innovated in a classic operation, which had reached a stage of near perfection.” The benefits of the laparoscopic approach became obvious to Mouret when he made postoperative rounds on this patient and found her fully dressed and ready to leave the hospital, angry because she did not believe Dr. Mouret had removed her gallbladder! This was the world’s first cholecystectomy by laparoscopic surgery (1178). Note: This publication was submitted as a case series by Francois Dubois, who copied Mouret's procedure after being shown a videotape of the procedure during a meeting with Mouret (444).

 

Zygmunt Henderson Krukowski (GB), Eleri L. Cusick (GB), J. Engeset (GB), and Norman A. Matheson (GB) showed that absorbable polydioxanone is the preferred suture material for closure of midline abdominal incisions because of a decreased wound infection rate (942).

Arthur Bloemen (NL), P. van Dooren (NL), Bernou F. Huizinga (NL), and Anton G. M. Hoofwijk (NL) compared suture materials for closure of the fascia after abdominal surgery. In 456 patients the abdominal fascia was closed with either non-absorbable (polypropylene; Prolene®) or absorbable (polydioxanone; PDS®) suture material. There were no significant differences between the two suture methods (171).

 

Bernadette Cummins (GB), Margaret Lucy Auckland (GB), and Peter Cummins (GB) developed a cardiac-specific troponin-I radioimmunoassay capable of diagnosing acute myocardial infarction (363).

 

James M. Robl (US), Randall Prather (US), Frank Barnes (US), Willard Eyestone (US), David L. Northey (US), B.G. Gilligan (US), and Neal L. First (US) cloned a bovine from a bovine early embryo cell (1408).

 

The Centers for Disease Control identified cigarette smoking as the chief avoidable cause of death in the United States as of 1984 (3).

Cigarette smoking has resulted in approximately 10 million deaths since the first Surgeon General’s report on smoking and health in 1964 (3; 1522; 1712).

 

Nigel Buck (GB), H. Brendan Devlin (GB), and John N. Lunn (GB) led a large-scale audit of peri-operative mortality which included both anaesthetists and surgeons. The input data was collected from Great Britain and Ireland. The conclusions were: 1) Post-operative mortality was low at 0.7% and was largely unavoidable because of the presenting pathology, comorbidity, and advanced age. 2) Participation was encouragingly high at almost 95%, although there were significant difficulties with the quality of record-keeping and availability of notes. 3) There was inadequate supervision of trainees by consultants, and trainees often failed to involve senior help before, during, or after surgery. 4) Unnecessary surgery was performed on patients with no hope of recovery. The decision to operate should be taken at consultant or senior level for all urgent or emergency cases. 5) Time to assess medical conditions and for adequate resuscitation was recommended to avoid rushing under-resuscitated patients to theatre. 6) General surgeons were found to be operating inappropriately because of a reluctance to refer to more specialist colleagues, and 7) Many units did not hold regular morbidity and mortality meetings, and combined meetings with anaesthetics and surgery were very rare (230).

 

The ancient Egyptians were using frayed, fibrous chew sticks as a form of toothbrush. Toothpaste was first used c. 2000 BCE (1285).

 

Rebecca L. Cann (US), Mark Stoneking (US), Allan C. Wilson (NZ), Linda Vigilant (US), Henry C. Harpending (US), Kristen Hawkes (US), Alan R. Templeton (US), S. Blair Hedges (US), Sudhir Kumar (IN), and Koichiro Tamura (JP) proposed that all mitochondrial DNA (mtDNA) types in contemporary humans originated in a common female ancestor present within an African population between 164,000 and 247,000 BCE, i.e., a mitochondrial eve. All the populations examined except the African population have multiple origins, implying that each area was colonized repeatedly. These results support and extend the African origin (out of Africa) hypothesis of human mtDNA evolution (250; 730; 1658; 1744).

 

Victor Almon McKusick (US) and Francis Hugh Ruddle (US) were searching for an appropriate title for a new journal which covered the newly developing discipline of mapping/sequencing (including analysis of the genetic information). Thomas H. Roderick (US) suggested the name Genomics (1129).

 

Robert Jay Charlson (US), James Ephraim Lovelock (GB), Meinrat O. Andreae (US), and Stephen G. Warren (US) produced the CLAW hypothesis (first letter in each of their surnames) which proposes a negative feedback loop that operates between ocean ecosystems and the Earth's climate. The hypothesis specifically proposes that particular phytoplankton that produce dimethyl sulfide are responsive to variations in climate forcing, and that these responses act to stabilise the temperature of the Earth's atmosphere (276). Note: The major source of cloud-condensation nuclei (CCN) over the oceans appears to be dimethylsulphide, which is produced by planktonic algae in sea water and oxidizes in the atmosphere to form a sulphate aerosol. Because the reflectance (albedo) of clouds (and thus the Earth's radiation budget) is sensitive to CCN density, biological regulation of the climate is possible through the effects of temperature and sunlight on phytoplankton population and dimethylsulphide production. To counteract the warming due to doubling of atmospheric CO2, an approximate doubling of CCN would be needed.

 

J. William Schopf (US), Bonnie M. Packer (US), Roger Buick (AU), and Stanley M. Awramik (US) presented evidence for a well-established community of oxygenic photosynthesizers c. 700 Ma (61; 231; 1496).

 

Peter R. Sheldon (GB) collected 15,000 trilobite specimens from the Ordivician stratum around Builth Wells, England. Their fossilized remains make a strong case for gradual evolutionary change (1532).

 

1988

“What gives biological research its special flavor is the long continued operation of natural selection. Every organism, every cell, and all the larger biochemical molecules are the end result of a long intricate process, often stretching back several billion years…Outside biology, we do not see the process of exact geometrical replication, which, together with the replication of mutants, leads to rare events becoming common…Another key feature of biology is the existence of many identical examples of complex structures…One type of protein molecule, on the other hand, usually exists in many absolutely identical copies. If this were produced by chance alone, without the aid of natural selection, it would be regarded as almost infinitely improbable…Biology has its laws, such as those of Mendelian genetics, but they are often only rather broad generalizations, with significant exceptions to them…Biologists must constantly keep in mind that what they see was not designed, but rather evolved…Nature can only build on what is already there.” Francis Harry Compton Crick (355).

 

“It is amateurs who have one big bright beautiful idea that they can never abandon. Professionals know that they have to produce theory after theory before they are likely to hit the jackpot.” Francis Harry Compton Crick (355).

 

“We are made of star stuff, processed through supernova, concentrated from the contracting solar nebula, spun into biochemical aggregates with a difference, and graced, during our tenure here, by the ability to imagine, to conceptualize, to hypothesize, to create science, poetry, music, and works of art and technology.” Preston Ercelle Cloud, Jr. (313).

 

Johann Deisenhofer (DE-US), Robert Huber (DE), and Hartmut Michel (DE) were awarded the Nobel Prize in Chemistry for the determination of the three-dimensional structure of a photosynthetic reaction center.

 

James Whyte Black (GB), Gertrude Belle Elion (US) and George Herbert Hitchings (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries of important principles for drug treatment.

 

Wayne A. Hendrickson (US), Janet L. Smith (US), R. Paul Phizackerley (US), and Ethan A. Merritt (US) established the anomalous dispersion effect technique as the method of choice for determining protein crystal structures in as rapid and straightforward a manner as possible and made the concept of structural genomics an experimental reality (739). Note: Hendrickson was also a pioneer in the development of computer programs that are used to build and refine atomic models for proteins on the basis of X-ray diffraction measurements.

Stevan R. Hubbard (US), Lei Wei (US), and Wayne A. Hendrickson (US) were the first to determine the structure of a tyrosine kinase domain of the human insulin receptor (789). Note: Understanding this insulin receptor may promote a treatment for diabetes.

Peter D. Kwong (US), Richard G. Wyatt (US), James Robinson (US), Raymond W. Sweet (US), Joseph Sodroski (US), and Wayne A. Hendrickson (US) determined the structure of the HIV protein, gp120, in complex with the CD4 receptor and a neutralizing human antibody (961).

 

Roger B. Ruggeri (US), Marvin M. Hansen (US), and Clayton H. Hathcock (US) carried out the complete synthesis of methyl homosecodaphniphyllate. This chemical, first discovered in a crude extract from the tree Daphniphyllum macropodum, was used to treat asthma (1430).

 

Toshikazu Oki (JP), Masakazu Konishi (JP), Kozo Tomatsu (JP), Koji Tomita (JP), Kyoichiro Saitoh (JP), Mitsuaki Tsunakawa (JP), Maki Nishio (JP), Takeo Miyaki (JP), and Hiroshi Kawaguchi (JP) discovered pradimicin, a novel class of potent antifungal antibiotics (1253).

 

Edward N. Baker (NZ), Thomas L. Blundell (GB), John F. Cutfield (NZ), Susan M. Cutfield (NZ), Eleanor J. Dodson (GB), Guy G. Dodson (GB), Dorothy Mary Crowfoot-Hodgkin (GB), Roderick E. Hubbard (GB), Neil W. Isaacs (GB), Colin D. Reynolds (GB), Kiwako Sakabe (GB), Norioshi Sakabe (GB), and Numminate M. Vijayan (GB) used computer aided x-ray diffraction analysis to determine the three dimensional structure of 2 Zn pig insulin crystals at 1.5 A resolution (72).

 

William H. Landschulz (US), Peter F. Johnson (US), and Steven Lanier McKnight (US) discovered the leucine finger, a structural motif common to many regulatory proteins (968).

 

Dwight A. Towler (US), Steven P. Adams (US), Shed R. Eubanks (US), Derek S. Towery (US), Emily Jackson-Machelski (US), Luis Glaser (US), and Jeffrey I. Gordon (US) screened over 80 synthetic peptides and discovered that a substrate hexapeptide contains much of the information necessary for recognition by N-myristoyltransferase. They also identified a number of potential N-myristoyl proteins from searches of available protein databases (1681). Note: Myristoylation is the post-translational process by which a myristoyl group is covalently attached via an amide bond to the alpha-amino group of an N-terminal glycine residue of a nascent polypeptide.

Rajiv S. Bhatnagar (US), Emily Jackson-Machelski (US), Charles A. McWherter (US), and Jeffrey I. Gordon (US) gained insights into how the N-myristoyltransferase selects its substrates and about its catalytic mechanism (142).

 

Aleksey Zaks (US) and Alexander M. Klibanov (US) demonstrated that some enzymes could function in non-aqueous environments (1856).

 

Honghua Li (US), Ulf B. Gyllensten (NL), Xiangfeng Cui (US), Randall K. Saiki (US), Henry A. Erlich (US), and Norman Arnheim (US) used the polymerase chain reaction for analysing DNA sequences in individual diploid cells and human sperm shows that two genetic loci can be co-amplified from a single sperm, which may allow the analysis of previously inaccessible genetic phenomena (1017).

 

Desmond Gerard Higgins (IE) and Paul M. Sharp (IE) devised CLUSTAL: a package for performing multiple sequence alignments on a microcomputer (748).

 

Thomas F. Donahue (US), A. Mark Cigan (US), Edward K. Pabich (US), and Beatriz Amaral de Castilho-Valavicius (BR) showed that in Saccharomyces cerevisiae the 40S ribosome recognizes the AUG initiator codon by using the anticodon tRNA_i ^Met along with contributions from elongation factors (elFs) 1, 2, and 5 (422).

A. Mark Cigan (US), Lan Feng (US), and Thomas F. Donahue (US) established that perfect base pairing between the anticodon of the initiator and the start codon in mRNA, regardless of their sequences, is a fundamental requirement for efficient initiation in yeast (299).

A. Mark Cigan (US), Edward K. Pabich (US), Lan Feng (US), Thomas F. Donahue (US), and Beatriz Amaral de Castilho-Valavicius (BR) cloned and sequenced the SU12 and SU13 genes, which they found to encode the alpha and beta subunits of elF2 (300; 422).

 

Jean Gautier (US), Chris Norbury (US), Manfred J. Lohka (US), Paul Maxime Nurse (US), and James L. Maller (US) found that a Xenopus p34cdc2 homolog is present in purified maturation-promoting factor (MPF) and suggest that p34cdc2 is a component of the control mechanism initiating mitosis generally in eukaryotic cells (581).

 

Jerry Pelletier (CA), Nahum Sonenberg (CA), Sung K. Jang (US), Hans-Georg Kräusslich (US), Martin J.H. Nicklin (US), Gregory M. Duke (US), Ann C. Palmenberg (US), and Eckard Wimmer (US) explained that poliovirus RNA is naturally uncapped, therefore its translation must proceed via a cap-independent mechanism. Translation initiation on poliovirus RNA occurs by binding of eukaryotic ribosomes to an internal sequence within the 5′ noncoding region (1321). Note: This concept is called internal ribosome entry site (IRES).

 

Kurt R. Gehlsen (US), Lena Dillner (US), Eva Engvall (US), and Erkki Ruoslahti (FI-US) reported identifying the receptor that allows a cell to attach to a specific protein called a laminin (582). Note: This discovery is important to understanding how nerves are formed and brings scientists closer to finding a way to repair them.

 

Steven I. Dworetzky (US) and Carl M. Feldherr (US) concluded that in Xenopus oocytes the nuclear translocation sites for gold particles coated with different classes of RNA are located in the centers of the nuclear pores and that particles at least 23 nm in diameter could cross the envelope. It was also determined that individual pores are bifunctional, that is, capable of transporting both proteins and RNA (455).

 

Howard M. Grey (US), Stéphane Demotz (CH), Soren Buus (DK), Alessandro Sette (US), Emil R. Unanué (CU-US), Clifford V. Harding (US), Immanuel F. Luescher (CH), Richard W. Roof (US), Pamela J. Bjorkman (US), Mark M. Davis (US), Leslie J. Berg (US), Augustin Y. Lin (US), Barbara Fazekas de St. Groth (US), Brigitte Devaux (US), Charles G. Sagerstrom (US), John F. Elliott (US), Jerry H. Brown (US), Theodore Jardetzky (US), Mark A. Saper (US), Boudjema Samraoui (US), and Don Craig Wiley (GB-US) helped reveal the mechanism by which cells transport and present peptides at their surface. They have shown that most peptides bind to major histocompatibility complex (MHC) molecules inside a cell. The molecules are of two types: class I MHC molecules, which displays peptides from proteins made inside the cell, and class II MHC molecules, which displays peptides from proteins that have entered the cell from the outside (216; 385; 646; 1708; 1745).

Jerry H. Brown (US), Theodore S. Jardetzky (US), Joan C. Gorga (US), Lawrence J. Stern (US), Robert G. Urban (US), Jack L. Strominger (US), and Don C. Wiley (US) determined the three-dimensional structure of the class II histocompatibility glycoprotein HLA-DR1 from human B-cell membranes by X-ray crystallography and is similar to that of class I HLA (217).

Theodore S. Jardetzky (US), Jerry H. Brown (US), Joan C. Gorga (US), Lawrence J. Stern (US), Robert G. Urban (US), Young-in Chi (US), Cynthia Stauffacher (US), Jack L. Strominger (US), and Don C. Wiley (US) determined the structure of a bacterial superantigen, Staphylococcus aureus enterotoxin B, bound to a human class II histocompatibility complex molecule (HLA-DR1) by X-ray crystallography. The structure of the complex helps explain how different class II molecules and superantigens associate and suggests a model for ternary complex formation with the T-cell antigen receptor (TCR), in which unconventional TCR-MHC contacts are possible (826).

 

Steven Robinow (US), Ana Regina Campos (CA), Kwok-Ming Yao (CN), and Kalpana White (US) were among the first to describe a gene that encodes an RNA-binding protein implicated in neuronal development. The gene is elav of Drosophila (1407).

 

Yona Kassir (IL), David Granot (IL), and Giora Simchen (IL) concluded that in Saccharomyces cerevisiae IME1 (inducer of meiosis) is a positive regulator of meiosis that normally is repressed by RME1. RME is repressed by a complex of MATal and MATα2 gene products. The environment also regulates IME1: no transcripts could be detected in glucose growing cells, in contrast to acetate growing cell. Starvation for nitrogen further induced (6- to 8-fold) transcription of IME1, but, as expected, the induction was found only in MATa/MATα or rmel-l/rme1-1 diploids. Furthermore, the IME1 multicopy plasmids promoted sporulation in rich media (869).

W. Mark Toone (GB), Anthony L. Johnson (GB), Geoffrey R. Banks (GB), Jeremy H. Toyn (GB-US), David Stuart (US), Curt Wittenberg (US), and Leland H. Johnston (GB) demonstrated that the RME1 (regulator of meiosis) gene could bypass the normally essential requirement for the transcription factor SBF. RME1 encodes a zinc finger protein, which is able to repress transcription of IME1 (inducer of meiosis) and thereby inhibit cells from entering meiosis. They present evidence to suggest that Rme1 may act both to promote mitosis, by activating CLN2 expression, and prevent meiosis, by repressing IME1 (inducer of meiosis) expression (1680).

 

Henny W.M. van Straaten (NL), Johan W.M. Hekking (NL), Emilie L.M.J. Wiertz-Hoessels (NL), Frans Thor (NL), and Jan Drukker (NL) showed that the notochord — a rod-like structure of mesodermal tissue that is just ventral to the neural tube — can induce the development of a specialized structure along the ventral midline of the neural tube called the floor plate. The floor plate is known to have effects on the guidance of some spinal-cord axons, and, along with the notochord, it is implicated as a signaling center (1728).

Toshiya Yamada (AU), Marysia Placzek (GB), Hideaki Tanaka (AU), Jane Dodd (US), and Thomas M. Jessell (US) through grafting experiments in the chick embryo showed that both the notochord and the floor plate can induce ectopic patterns of ventral motor neuron layers. Furthermore, removal of the notochord or floor plate results in the loss of these ventral motor neurons. So, both notochord and floor-plate cells can release signals that are required for the initial dorsal-ventral (DV) patterning of the central nervous system (CNS). Induction by notochord and floor-plate explants resulted in distinct subsets of neuron types at defined distances from the ectopic tissue source. The authors proposed a model in which a diffusible signal produced in the notochord or floor plate results in a gradient of the signal across the DV axis, and this gradient is responsible for the pattern of neurons induced (839; 1829).

Yann Echelard (US), Douglas J. Epstein (US), Benoit St. Jacques (US), Liya Shen (US), Jym Mohler (US), Jill A. McMahon (US), Andrew P. McMahon (US), Stefan Krauss (NO), Jean-Paul Concordet (FR), and Philip W. Ingham (GB) cloned mouse and zebrafish (Brachydanio rerio) homologues of the Drosophila segment polarity gene hedgehog (hh). In both cases, the expression pattern of one homologue in particular, sonic hedgehog (shh) implied that it might be involved in ventral central nervous system (CNS) patterning. Shh was expressed in both the notochord and the floor plate at the appropriate times in development that were expected for the inductive signal. Furthermore, ectopic expression of shh could induce floor-plate-specific genes. Shh was predicted to be a secreted protein, so it was an obvious candidate for the diffusible signal that was predicted by the earlier study of Jessell and colleagues (459; 934). Note: Shh has come to be known as a classic example of a morphogen — a signal that regulates the spatial pattern of cell differentiation in a concentration-dependent manner.

 

Andre-Patrick Arrigo (US), Keiji Tanaka (JP), Alfred L. Goldberg (US-CA), and William J. Welch (US) found that large cellular, multienzyme complexes are broken down by proteins they named proteasomes (49). An average body cell contains thousands of proteasomes, which chop proteins the cell has tagged for removal into bits of various sizes.

Vickie E. Baracos (CA), Cynthia DeVivo (CA), Duncan H.R. Hoyle (CA), and Alfred L. Goldberg (US-CA) found that accelerated muscle proteolysis and muscle wasting in tumor-bearing rats result primarily from activation of the ATP-dependent pathway involving ubiquitin and the proteasome with the ubiquitin serving as the tag for destruction (85).

 

Hirohisa Masuda (US), and W. Zacheus Cande (US) were the first to obtain experimental evidence that during anaphase B (lengthening of the entire spindle) the interpolar microtubules slide past one another (1094). This type of movement had first been proposed by Kent L. McDonald (US), Jeremy D. Pickett-Heaps (US), J. Richard McIntosh (US), and David H. Tippit (US) (1119).

 

Robert M. McCarroll (US) and Walton L. Fangman (US) showed that centromeres of sister chromatids are duplicated during the S phase of mitosis in Saccharomyces cerevisiae (1115).

 

Kenneth J. Kemphues (US), James R. Priess (US), Diane G.Morton (US), and Niansheng (Nick) Cheng (US) identified genes that are involved in cell-fate specification in Caenorhabditis elegans, a free-living, transparent nematode (roundworm). A study of maternal-effect lethal mutations led to the identification of the par (partitioning defective) genes par1–4. Wild-type C. elegans oocytes contain a uniform distribution of P granules — large ribonuclear particles that normally segregate into P1. Mutations in the four par genes led to abnormal positioning of the mitotic spindle and aberrant localization of the P granules, leading the authors to propose that the par genes encode products that are required for spindle placement and cytoplasmic localization (884).

Su Guo (US) and Kenneth J. Kemphues (US) cloned the C. elegans par-1 and par-3 genes. PAR-1 is a conserved serine/threonine kinase, whereas PAR-3 turned out to be a novel protein. Both of these proteins are asymmetrically distributed in the zygote: PAR-1 is enriched at the posterior periphery, whereas PAR-3 is found at the anterior periphery. In early germ-line precursor cells, PAR-1 localization correlates strikingly with P granule distribution and requires the kinase activity of PAR-1. Meanwhile, the distribution of PAR-3 controls spindle orientation. PAR-3 localization depends on the par-2 gene, and PAR-3 is required for PAR-1 localization (670).

Michelle S. Rhyu (US), Lily Yeh Jan (US), and Yuh Nung Jan (US) identified a protein in Drosophila sensory organs called Numb, which is localized within the sensory organ precursors (SOP) before cell division and segregates to only one of the daughter cells during division. These results demonstrated that the asymmetric segregation of a determinant during cell division could induce a specific fate in one of the two daughter cells (1387).

Rachel Kraut (CN), William Chia (CN), Lily Yeh Jan (US), Yuh Nung Jan (US), and Jüergen A. Knoblich (DE) showed that expression of the inscuteable gene is required for asymmetric segregation of Numb, as well as correct spindle orientation, in fly neuroblasts and epithelial cells. The Inscrutable protein localizes to the apical-cell cortex before mitosis and precedes the basal localization of Numb. These results indicated that asymmetric localization of Inscuteable establishes positional information for both spindle orientation and asymmetric localization of Numb. The Par proteins have also been shown to be involved in asymmetric Numb localization in neuroblasts (935).

 

Bernadette Connolly (GB), Charles I. White (FR), and James E. Haber (US), in describing mating type switching in the yeast Saccharomyces cerevisiae, were among the first to report a natural recombination system involving double-strand DNA breaks (335).

 

Mark J. Solomon (US), Pamela L. Larsen (US), and Alexander J. Varshavsky (RU-US) showed that formaldehyde-based in vivo mapping techniques are generally applicable, and can be used both to probe protein-DNA interactions within specific genes and to determine the genomic location of specific chromosomal proteins (1581).

Bing Ren (US), Francois Robert (US), John J. Wyrick (US), Oscar Aparicio (US), Ezra G. Jennings (US), Itamar Simon (US), Julia Zeitlinger (US), Jörg Schreiber (US), Nancy Hannett (US), Elenita Kanin (US), Thomas L. Volkert (US), Christopher J. Wilson (US), Stephen P. Bell (US), and Richard A. Young (US) developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding of gene-specific transcription activators in yeast (1380). Note: This technique acquired the moniker 'ChIP-chip'.

Vishwanath R. Iyer (US), Christine E. Horak (US), Charles S. Scafe (US), David Botstein (US), Michael Snyder (US), and Patrick O. Brown (US) used DNA microarrays to define the genomic binding sites of the SBF and MBF transcription factors in vivo. SBF and MBF are sequence-specific transcription factors that activate gene expression during the G1/S transition of the cell cycle in yeast. In addition to the previously characterized targets, they identified about 200 new putative targets. Their results support the hypothesis that SBF activated genes are predominantly involved in budding, and in membrane and cell-wall biosynthesis, whereas DNA replication and repair are the dominant functions among MBF activated genes (820).

 

Dennis E. McCabe (US), William F. Swain (US), Brian J. Martinelli (US), and Paul Christou (CY-GB) transformed soybean cells by shooting into them tiny particles of gold coated with foreign DNA (1112).

 

Suzanne L. Mansour (US), Kirk R. Thomas (US), and Mario Renato Capecchi (IT-US) developed a method of gene targeting—homologous recombination of DNA sequences residing in the chromosome with newly introduced DNA sequences—in mouse embryo-derived stem cells which promises to provide a means to generate mice of any desired genotype (1081). This technique is referred to as reverse mammalian genetics.

 

Stanley Falkow (US) introduced a set of experimental criteria (molecular Koch's postulates) that must be satisfied to show that a gene found in a pathogenic microorganism encodes a product that contributes to the disease caused by the pathogen. Genes that satisfy molecular Koch's postulates are often referred to as virulence factors (492).

 

Albertus Dominicus Marcellinus Erasmus Osterhaus (NL), Lies Vedder (NL), Jan Groen (NL), Fons G.C.M. Uytdehaag (NL), Ilona K.G. Visser (NL), Marco W.G. Van De Bildt (NL), A. Bergman (SE), and B. Klingeborn (SE) reported that an acute disease of Lake Baikal seals (Phoca sibirica) attributable to morbillivirus infection became evident in the autumn of 1987 when weakened seals crawled onto the lake's icy shores and died (1268; 1269). Note: this is currently considered to be a phocine distemper virus.

 

John B. Hibbs, Jr. (US), Read R. Taintor (US), Zdenek Vavrin (CZ), and Elliot M. Rachlin (US) discovered that the phagocytosis of microbial pathogens by macrophages stimulates the macrophages to release reactive nitrogen intermediates such as nitric oxide (747).

 

Terence P. McDonald (US) postulated that a humoral factor was present in the plasma of patients or animals with severe thrombocytopenia, and that it could increase platelet numbers when injected into animals (1120).

Frederic J. de Sauvage (US), Philip E. Hass (US), Susan D. Spencer (US), Beth E. Malloy (US), Austin L. Gurney (US), Steven A. Spencer (US), Walter C. Darbonne (US), William J. Henzel (US), Suzy C. Wong (US), Wun-Jing Kuang (US), Karl J. Oles (US), Bruce Hultgren (US), Lawrence A. Solberg Jr. (US), David V. Goeddel (US), Dan L. Eaton (US), Si Lok (US), Kenneth Kaushansky (US), Richard D. Holly (US), Joseph L. Kuijper (US), Catherine E. Lofton-Day (US), Pieter J. Oort (US), Francis J. Grant (US), Mark D. Heipel (US), Steve K. Burkhead (US), Janet M. Kramer (US), L. Anne Bell (US), Cindy A. Sprecher (US), Hal Blumberg (US), Rebecca Johnson (US), Donna Prunkard (US), Andrew F. T. Ching (US), Shannon L. Mathewes (US), Mason C. Bailey (US), John W. Forstrom (US), Michele M. Buddle (US), Sherri G. Osborn (US), Simon J. Evans (US), Paul O. Sheppard (US), Scott R. Presnell (US), Patrick J. O'Hara (US), Fredrick S. Hagen (US), Gerald J. Roth (US), Donald C. Foster (US), Virginia C. Broudy (US), Nancy Lin (US), and Thalia Papayannopoulou (US), Françoise Wendling (FR), Eugene Maraskovsky (US), Najet Debili (US), Christina Florindo (US), Mark Teepe (US), Monique Titeux (US), Nassia Methia (US), Janine Breton-Gorius (FR), David Cosman (US), and William Vainchenker (US) produced contemporaneous studies showing that the platelet-regulatory factor, thrombopoietin (c-Mpl ligand), binds to the c-Mpl receptor on cells in the megakaryocyte lineage thus stimulating both the formation of megakaryocytes and megakaryocyte maturation resulting in the release of platelets into the blood (408; 877; 1038; 1782).

S. Nomura (JP), Kinya Ogami (JP), Kazuo Kawamura (JP), I. Tsukamoto (JP), Yoko Kudo (JP), Y. Kanakura (JP), Y. Kitamura (JP), Hiroshi Miyazaki (JP), and Takashi Kato (JP) found that in mice from fetus to adults, thrombopoietin (c-Mpl ligand) is predominantly produced in hepatocytes expressing albumin but not in other liver cells, such as endothelial cells (1229). Note: The synthesis of thrombopoietin mRNA is constitutive in the liver and kidney.

 

Werner Risau (DE), Hannu Sariola (FI), Hans-Günter Zerwes (US), Joachim Sasse (US), Peter Ekblom (DE), Rolf Kemler (DE), and Thomas Doetschman (DE) were the first to show a molecular and cellular difference between angiogenesis, which occurs by sprouting from pre-existing vessels, and vasculogenesis, the development of the earliest embryonic blood vessels (1403).

Takayuki Asahara (US), Toyoaki Murohara (US), Alison Sullivan (US), Marcy Silver (US), Rien van der Zee (US), Tong Li (US), Bernhard Witzenbichler (US), Gina Schatteman (US), and Jeffrey M. Isner (US) showed that new blood vessels in adults derive not only from the remodeling of fully differentiated endothelial cells present in pre-existing blood vessels but also from circulating progenitors derived from the bone marrow (51).

David Lyden (US), Koichi Hattori (US), Sergio Dias (US), Carla Costa (US), Pamela Blaikie (US), Linda Butros (US), Amy Chadburn (US), Beate Heissig (US), Willy Marks (US), Larry Witte (US), Yan Wu (US), Daniel Hicklin (US), Zhenping Zhu (US), Neil R. Hackett (US), Ronald G. Crystal (US), Malcolm A.S. Moore (US), Katherine A. Hajjar (US), Katia Manova (US), Robert Benezra (US), and Shahin Rafii (US) reported that tumor blood-vessel growth recruits bone marrow stem cell-differentiated endothelial cells (1055).

 

Elaine Tuomanen (US) discovered in animal models of meningitis that when a bacterium shatters, body defenses mistake the shrapnel for a burst of bacterial growth and respond accordingly. The bits of the cell wall activate the body’s defenses by setting off the cytokine alarms and clotting initiators. These events prepare a platform on a vessel wall to which white blood cells stick, giving them enough purchase to squeeze themselves through the blood brain barrier. The white blood cells, now esconced in the brain, enhance the production of cytokine alarms, accelerating the disruption of the barrier. More white blood cells migrate into the brain; further exacerbating inflammation, swelling and the immune response.

In short, the animal model taught an unexpected lesson: antibiotic therapy makes meningitis worse before it makes it better.

Tuomanen discovered that she could keep white blood cells from entering the brain using an antibody (anti-CD18) known to prevent white blood cells from sticking to the vessel walls. By combining antibiotic therapy with anti-CD18 therapy in animal cases of meningitis she was able to achieve a remarkable 100 percent survival rate (1701).

Jussi Mertsola (FI), Octavio Ramilo (ES), Mahmoud M. Mustafa (US), Xavier Saez-Llorens (PA), Eric J. Hansen (US), and George H. McCracken, Jr. (US) demonstrated that antibiotic therapy for meningitis in children causes bacteria to shatter, temporarily worsening the disease by accelerating inflammation within the central nervous system (1141; 1437).

 

Anthony E. Namen (US), Ann E. Schmierer (US), Carl J. March (US), Robert W. Overell (US), Linda S. Park (US), David L. Urdal (US), and Diane Y. Mochizuki (US) purified a previously uncharacterized murine lymphopoetic growth factor designated lymphopoetin 1 (LP-1). This factor is capable of stimulating the proliferation and extended maintenance of precursor cells of the B lineage. This factor was purified to a single 25-kD species from the culture supernatant fraction of an adherent stromal cell line. This material acts on immature lymphocytes; it binds to specific receptors on cells, and is distinct from previously described hematopoietic factors (1204).

 

Thomas J. Schall (US), Jan Jongstra (US), Bradley J. Dyer (US), Jeffrey Jorgensen (US), Carol Clayberger (US), Mark M. Davis (US), and Alan M. Krensky (US) used a cDNA library enriched for T cell-specific sequences to isolate genes expressed by T cells but not by other cell types. They report here one such gene, designated RANTES, which encodes a novel T cell-specific molecule (1474).

 

Jeng-Pyng Shaw (US), Paul J. Utz (US), David B. Durand (US), J. Jay Toole (US), Elizabeth Ann Emmel (US), and Gerald R. Crabtree (US) identified a protein complex found within T cells, which they named NFAT-1. Its characteristics suggest that it transmits signals initiated at the T cell antigen receptor, which regulate early T cell activation genes (1529).

 

Kendall A. Smith (US) reminds us that IL-2 was the first of a series of lymphocytotrophic hormones to be recognized and completely characterized. It is pivotal for the generation and regulation of the immune response. A product of T lymphocytes, IL-2 also stimulates T cells to undergo cell cycle progression via a finite number of interactions with its specific membrane receptors. Because T cell clonal proliferation after antigen challenge is obligatory for immune responsiveness and immune memory, the IL-2 cell system has opened the way to a broader understanding of such fundamental cellular phenomena (1569).

 

Christopher E. Rudd (US), James M. Trevillyan (US), Jai Dev Dasgupta (US), Linda L. Wong (US), and Stuart F. Schlossman (US) provided preliminary evidence that the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (PTK) of 55-60 kDa, which is expressed specifically in T cells (1427). Note: The CD4 (T4) antigen is a cell-surface glycoprotein that is expressed predominantly on the surface of helper T cells and has been implicated in the regulation of T-cell activation and in the associative recognition of class II antigens of the major histocompatibility complex.

 

Andre Veillette (US), Michael A. Bookman (US), Eva M. Horak (US), and Joseph B. Bolen (US) produced results suggesting that p56lck is functionally and physically associated with CD4/CD8 in normal murine T lymphocytes and support the concept that an independent signal is transduced by the interaction of these surface molecules with major histocompatibility complex determinants (1737).

 

Kouji Matsushima (US), Kazuhiro Morishita (US), Teizo Yoshimura (US), Sukadev Lavu (US), Yoshiro Kobayashi (US), Wook Lew (US), Ettore Apella (US), Hsiang Kung (US), Edward J. Leonard (US), Joost J. Oppenheim (US), Stephen K. Moore (US), Michael I. Leman (US), Ian G. Colditz (US), Roland D. Zwahlen (US), Beatrice Dewald, (US), and Marco Baggiolini (US) discovered chemokines (323; 1101; 1852). Note: Chemokines are any of a class of cytokines with functions that include attracting white blood cells to sites of infection.

 

Christopher C. Goodnow (AU), Jeffrey Crosbie (AU), Stephen Adelstein (AU), Thomas B. Lavoie (US), Sandra J. Smith-Gill (US), Robert A. Brink (AU), Helen Pritchard-Briscoe (AU), John S. Wotherspoon (AU), Robert H. Loblay (AU), Kathy Raphael (AU),       Ronald J. Trent (AU),and Antony Basten (AU) produced findings indicating that self tolerance may result from mechanisms other than clonal deletion, and are consistent with the hypothesis that IgD may have a unique role in B-cell tolerance (615).

 

Günter Wächtershäuser (DE) presented a hypothesis supporting chemoautotrophy as the first form of metabolism to appear within life forms on the primitive Earth. He argued that these life forms were coatings that adhered to the positively charged surfaces of pyrite, a mineral composed of iron and sulfur. The formation of pyrite from hydrogen sulfide provides a source of electrons as an energy source (1749).

 

Ok-Ryun Choi (US) and James D. Engel (US) were the first to show that promoter competition is an important mechanism of gene regulation. They were analyzing the chicken globin locus (290).

 

H.B.J. Heiles (DE), Elke Genersch (DE), Christoph Kessler (DE), Ralf Neumann (DE), and Hans Joachim Eggers (DE) were the first to develop a protocol for correlation of the results of an in situ hybridization with the cytological appraisal in the very same smear preparation. It was an in situ hybridization with digoxigenin-labeled DNA of human papillomaviruses (HPV 16/18) in HeLa and SiHa cell (733).

 

Colin Pitchfork (GB), a bakery worker in Leicestershire, England was the first person convicted and sentenced— in this case for two murders—using DNA fingerprint information (1399). The fingerprinting evidence also exonerated Richard Buckland (GB) who had confessed to one of the murders.

 

Wolfgang Driever (DE), and Christiane Jani Nüsslein-Volhard (DE) noted that the bicoid (bcd) protein in a Drosophila embryo is derived from an anteriorly localized mRNA and comes to be distributed in an exponential concentration gradient along the anteroposterior axis. To determine whether the levels of bcd protein are directly related to certain cell fates, the authors manipulated the density and distribution of bcd mRNA by genetic means. Increases or decreases in bcd protein levels in a given region of the embryo cause a corresponding posterior or anterior shift of anterior anlagen in the embryo (436).

 

For the first time a person was convicted and given the death penalty on the strength of DNA fingerprint evidence. Randall Jones was convicted in Florida as the result of State of Florida vs. Jones and Reesh.

 

Philip Leder (US) and Timothy A. Stewart (US) patented animal life, a transgenic mouse. They devised a method of introducing specific oncogenes (genes with the potential to cause other cells to become cancerous) into mice. The transgenic non-human eukaryotic animal is bred to contract breast cancer for medial research to facilitate carcinogen testing and development of cancer therapies (987).

 

John H. Shaw (US) and Stanley Falkow (US) proposed a molecular version of Koch’s postulates, which is used to assess whether or not a gene or its products are required for virulence (1530).

 

Pratap S. Avasthi (US) and Valsala Koshy (US) analyzed the anionic macromolecules at the glomerular endothelial cell surface. They showed that an anionic matrix lines the entire capillary lumen surface, fills the fenestrae, and is interposed between the blood and the basement membrane at the fenestrae. The anionic constituents at the capillary luminal surface were identified by in vivo digestion with specific enzymes (59). Note: These findings underpin the concept that the endothelial glycocalyx of the glomerular capillary wall is a significant filtration barrier.

 

 Richard H. Scheller (US), Thomas C. Südhof (US), William S. Trimble (US), David M. Cowan (US), Mark K. Bennett (US), Nicole Calakos (US), Thomas Söllner (US), Sidney W. Whiteheart (US), James E. Rothman (US), Karen E. Peterson (US), Richard C. Lin (US), Yu A. Chen (US), Suzie J. Scales (US), Sejal M. Patel (US), Yee-Cheen Doung (US), Mark S. Perin (US), Victor A. Fried (US), Gregory A. Mignery (US), Reinhard Jahn (US), Nils Brose (US), Alexander G. Petrenko (US), Jahn Reinhard (DE), Harvey T. McMahon (US), Markus Missler (US), Cai Li (US), Rafael Fernández-Chacón (US), Andreas Königstorfer (NZ), Stefan H. Gerber (DE), Jesús Garcia (DE), Maria F. Matos (DE), Charles F. Stevens (DE), Josep Rizo (DE), Christian Rosenmund (DE), Jeong-Seop Rhee (US), Liyi Li (US), Ok-Ho Shin (US), Jong-Cheol Rah (US), Han Dai (US), Jiong Tang (US), and Anton Maximov (US) made discoveries concerning rapid neurotransmitter release, a process that underlies all of the brain's activities. They identified and isolated many of this reaction's key elements, unraveled central aspects of its fundamental mechanism, and deciphered how cells govern it with extreme precision. These advances have provided a molecular framework for understanding some of the most devastating disorders that afflict humans as well as normal functions such as learning and memory (121; 213; 245; 282; 510; 1024; 1130; 1322; 1383; 1580; 1647; 1693).

 

Raymond E. Keller (US), Elizabeth Laxon Kimberly (US), and Jeff Hardin (US) reported that apical constriction is a common early step of cell ingression during gastrulation in many organisms. For example, the bottle cells that form the sea urchin vegetal plate and the Xenopus blastopore lip all apically constrict (699; 897).

Jen-Yi Lee (US) and Bob Goldstein (US), from their studies of gastrulation in the nematode Caenorhabditis elegans, proposed that ingression of endodermal cells is driven by an actomyosin-based contraction of the apical side of the ingressing cells, which pulls neighboring cells underneath. They concluded that apical constriction can function to position blastomeres in early embryos, even before anchoring junctions form between cells (991). Note: Interestingly the morphogenetic process of gut cell internalization in C. elegans can be reduced to the study of interactions among only four cells designated MSxx, Ea,Ep, and P4.

 

Gary P. Holmes (US), Jonathan E. Kaplan (US), Nelson M. Gantz (US), Anthony L. Komaroff (US), Lawrence B. Schonberger (US), Stephen E. Straus (US), James F. Jones (US), Richard E. Dubois (US), Charlotte Cunningham-Rundles (US), Savita Pahwa (US), Giovanna Tosato (US), Leonard S. Zegans (US), David T. Purtilo (US), Nathaniel Brown (US), Robert T. Schooley (US), Irena Brus (US) applied specific criteria to, and defined, myalgic encephalitis (ME); also known as chronic fatigue syndrome and Epstein-Barr virus syndrome (770).

Pascale De Becker (BE), Neil McGregor (AU), and Kenny De Meirleir (BE) updated the criteria established by the Holmes group above (387).

 

Nubia Muñoz (CO) led a team including: John M. Kaldor (AU), Franz Xavier Bosch (ES), Silvia de Sanjosé (ES), Luis Tafur (CO), Isabel Izarzugaza (ES), Miguel Gili (ES), Pau Viladiu (ES), Carmen Navarro (ES), Carmen Martos (ES), Nieves Ascunce (ES), Maria José Alonso (ES), Fernando Gomez-Aguado (ES), Elisa Muñoz (ES), Maria del Mar Abad (ES), Manuel Roldán (ES), Isabel Curiel (CO), Jairo I. Paz (), Agustin Bullon (ES), Antonio López-Bravo (ES), Keerti V. Shah (US), André Z. Meheus (BE), Maria L. Najera (), Eloisa Guerrero (ES), Xavier Castellsague (ES), Richard W. Daniel (US), Maria Luisa Zubiri (ES), Martin Müller (DE), Raphael P. Viscidi (US), Lutz Gissmann (DE), Yeping Sun (US), Peter M. Hill (US), and Farida Shah (US) that proved human papillomavirus causes cervical cancer (24; 180; 181; 608; 666; 1184; 1190-1192).

 

Dan Tzivoni (IL), Shmuel Banai (IL), Claudio Schuger (IL), Jesaia Benhorin (IL), Andre Keren (IL), Shmuel Gottlieb (IL), and Shlomo Stern (IL) reported that intravenous magnesium sulfate was effective at acutely terminating torsade de pointes. Intravenous magnesium sulfate was not effective in terminating other ventricular tachycardias not associated with QT prolongation (1705).

 

Dvora Teitelbaum (IL), Rina Aharoni (IL), Ruth Arnon (IL), Ruth Arnon (IL), and Michael Sela (IL) obtained results suggesting that Cop 1 (glatiramer acetate) may be effective in suppression of experimental allergic encephalomyelitis, the animal equivalent of multiple sclerosis (1655).

Dvora Teitelbaum (IL), Ruth Arnon (IL), and Michael Sela (IL), in phase III clinical trials, found that Cop-1 (glatiramer acetate) can slow progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (MS) (1656).

 

Yik S. Kwoh (US), Joahin Hou (US), Edmond A. Jonckheere (US), and Samad Hayati (US) used the first surgical robot, PUMA 560, in 1985, in a stereotaxic operation, in which computed tomography was used to guide the robot as it inserted a needle into the brain for biopsy, a procedure previously subject to error from hand tremors during needle placement (959).

Simon James Harris (GB), Fernando Arambula-Cosio (GB), Q. Mei (GB), Roger D. Hibberd (GB), Brian Lawrence Davies (GB), J. E.A. Wickham (GB), M. S. Nathan (GB), and Byrum Kundu (GB), in 1988, used PROBOT, developed at Imperial College London, to perform transurethral prostate surgery, a procedure that required numerous repetitive cutting motions (712). Note: Robotic surgery was initially developed in the early 1960s when Unimation Inc. (Danbury, Conn) launched their first robot with a Programmable Universal Manipulation Arm (PUMA) to accomplish surgery remotely. Victor Scheinman developed the robot (858).

 

Mriganka Sur (IN-US), Preston E. Garraghty (US), Anna W. Roe (US), Sarah L. Pallas (US), and Jong-On Hahm (US) "rewired" the brain to explore how the environment influences the development of cortical circuits. The retina, which normally projects to the visual cortex, was induced to project to structures that normally process hearing. Visual input altered the development of neuronal connections in the auditory cortex, thus enabling animals to use their "hearing" cortex to "see" (1413; 1625).

 

Luigi Luca Cavalli-Sforza (IT-US), Alberto Piazza (IT), Paolo Menozzi (IT), and Joanna Mountain (US) used genetic, archaeological, and linguistic data to reconstruct human evolution. They concluded that the first split in the phylogenetic tree separates Africans from non-Africans, and the second separates two major clusters, one corresponding to Caucasoids, East Asians, Arctic populations, and American natives, and the other to Southeast Asians (mainland and insular), Pacific islanders, and New Guineans and Australians. Average genetic distances between the most important clusters are proportional to archaeological separation times. Linguistic families correspond to groups of populations with very few, easily understood overlaps, and their origin can be given a time frame. Linguistic superfamilies show remarkable correspondence with the two major clusters, indicating considerable parallelism between genetic and linguistic evolution. The latest step in language development may have been an important factor determining the rapid expansion that followed the appearance of modern humans and the demise of Neanderthals (267).

 

Stan Wood (GB) discovered the 20 cm long fossilized remains of a burgess Westlothiana lizziae in East Kirkton, West Lothian, Scotland; near Edinburgh.

Tim R. Smithson (GB), Robert Lynn Carroll (US-CA), Alec L. Panchen (GB), S. Mahala Andrews (GB), Roberta L. Paton (GB), and Jennifer A. Clack (GB) clarified the taxonomic status of Westlothiana lizziae concluding that it might be the oldest known reptile and thus the oldest known amniote (1286; 1308; 1573; 1574).

 

Karl F. Hirsch (US), Kenneth L. Stadtman (US), Wade E. Miller (US), and James H. Madsen, Jr. (US) discovered a fossilized dinosaur egg that contains the oldest known embryo of any kind, probably the embryo of an allosaur from about 150 Ma. The embryo of approximately 2cm was detected by X raying the egg (759).

 

Roy A. Norton (US), Patricia M. Bonamo (US), James D. Grierson (US), and William A. Shear (US) found that mites are among the oldest of all terrestrial animals, with fossils known from the early Devonian, nearly 400 Ma (1231).

 

1989

"Dear Colleagues, […] I hope that Fingerprint News will cover all aspects of hypervariable DNA and its application, including both multi-locus and single-locus systems, new methods for studying DNA polymorphisms, the population genetics of variable loci and the statistical analysis of fingerprint data, as well as providing useful technical tips for getting good DNA profiles […]. May your bands be variable." Alec John Jeffreys (830). See, Jeffreys, 1980.

 

“Wind back the tape of life to the early days of the Burgess Shale. Let it play again from an identical starting point, and the chance becomes vanishingly small that anything like human intelligence would grace the replay.” Stephen Jay Gould (628).

 

Sidney Altman (CA-US) and Thomas Robert Cech (US) were awarded the Nobel Prize in Chemistry for their discovery of catalytic properties of RNA.

 

John Michael Bishop (US) and Harold Elliot Varmus (US) were awarded the Nobel Prize in Physiology or Medicine for their discovery of the cellular origin of retroviral oncogenes.

 

Bernard J. Wood (GB) and David Virgo (US) presented evidence that the primitive atmosphere was poised at a redox state buffered close to the fayalite-quartz-magnetite system, consistent with a neutral redox atmosphere and characteristic of basalts throughout the geological record (1815).

 

Maureen D. Keller (US), Wendy K. Bellows (US), Robert R.L. Guillard (US), James Ephraim Lovelock (GB), Gordon V. Wolfe (US), and Michael Steinke (DE) reported that marine phytoplankton such as Emiliania huxleyi produce significant qualities of dimethyl sulfide (sulphide) which in the atmosphere is rapidly oxidized to non-sea salt sulfate (sulphate) NSS-SO4. Non-sea salt sulfate is one of the major sources of nuclei for cloud condensation (882; 1047; 1809).

 

Robert W. Armstrong (US), Jean-Marie Beau (US), Seung Hoon Cheon (US), William J. Christ (US), Hiromichi Fujioka (US), Won-Hun Ham (US), Lynn D. Hawkins (US), Haolun Jin (US), Sung Ho Kang (US), Yoshito Kishi (US), Michael J. Martinelli (US), William W. McWhorter, Jr. (US), Masanori Mizuno (US), Masaya Nakata (US), Arnold E. Stutz (US), Francisco X. Talamas (US), Mikio Taniguchi (US), Joseph A. Tino (US), Katsuhiro Ueda (US), Jun-ichi Uenishi (US), James B. White (US), Masahiro Yonaga (US), and Edward M. Suh (US) carried out the total synthesis of palytoxin. This substance is produced by certain soft corals of the genus Polythoa and is one of the most toxic non-peptide substances known (45; 46; 903; 904; 1622).

 

Hans van Tol (NL), Hans J. Gross (DE), and Hildburg Beier (DE) found that 5’ cleavage processing of pre-tRNAs is autocatylytic (1729).

 

Stanley Fields (US) and Ok-Kyu Song (US) provided a novel genetic system to detect protein-protein interactions by expressing them in yeasts (514).

 

Robert A. Fromtling (US) and George K. Abruzzo (US) isolated a new antifungal agent from Zalerion arboricola (550). It is referred to as a pneumocandin because of its action against Pneumocystis carinii.

 

John L. Hall (US), Zenta A. Ramanis (US), and David J. Luck (US) localized DNA in the basal bodies of Chlamydomonas reinhardtii (686; 687).

 

James O. Newell (US), David W. Markby (US), and Howard Kapnek Schachman (US) studied the binding of the bisubstrate analog N-(phosphonacetyl)-L-aspartate to aspartate transcarbamoylase (ATCase) in the absence and presence of ATP and CTP. The resulting saturation curves gave independent data for analyzing the allosteric properties of ATCase and allowed the authors to relate measured conformational changes in the enzyme directly to the fractional occupancy of the active sites (1212).

 

Robert W. Doms (US), Gustav Russ (US), Jon W. Yewdell (US), Jennifer Lippincott-Schwartz (US), Lydia C. Yuan (US), Juan S. Bonifacino (US), and Richard D. Klausner (US) demonstrated the retrograde movement of both resident Golgi proteins and those in transport back to the endoplasmic reticulum (421; 1031).

 

Franz-Ulrich Hartl (DE), Arthur L. Horwich (US), Ming Y. Cheng (US), Jörg Martin (DE), Robert A. Pollock (US), Frantisek Kalousek (US),Walter Neupert (DE), Elizabeth M. Hallberg (US), Richard L. Hallberg (US), Joachim Ostermann (DE), Thomas Langer (DE), Chi Lu (US), Harrison Echols (US), John Flanagan (US), Manajit K. Hayer (DE), Gustavo Kuhn Pfeifer (DE), Wolfgang Baumeister (DE), Judith Frydman (US), Elmar Nimmesgern (US), Kenzo Ohtsuka (JP), Andreas Bracher (DE), Manajit Hayer-Hartl (DE), Kerstin Braig (US), Zbyszek Otwinowski (US), Rashmi Hegde (US), David C. Boisvert (US), Andrze Joachimiak (US), Paul B. Sigler (US), Wayne A. Fenton (US), Yechezkel Kashi (IL), Krystynamade Furtak (US), Hays S. Rye (US), Steven G. Burston (US), Joseph M. Beechem (US), and Zhaohui Xu (US), made discoveries concerning the cell's protein-folding machinery, exemplified by cage-like structures that convert newly made proteins into their biologically active forms. They demonstrated the existence of an ATP-driven 'folding catalyst' and revealed an unimagined piece of nature: Proteins imported into the mitochondria cannot refold spontaneously (192; 283; 507; 551; 715; 779; 972; 973; 1270; 1435). Note: Certain medical conditions underscore the significance of these findings. When proteins aggregate, illnesses such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis can arise, and adjusting chaperone activity might provide therapeutic benefit. In addition, a particular Hsp60 mutation has been associated with hereditary spastic paraplegia, an illness in which the legs weaken and stiffen.

 

Shlomo Handeli (IL), Avihu Klar (US), Mark Meuth (US-GB), and Howard Cedar (IL) were the first to identify DNA regions in higher eukaryotes (Eucarya) which behave as origins of replication (697).

Daniel Kitsberg (GB-IL), Sara Selig (IL), Ilana Keshet (IL) and Howard Cedar (IL) located one origin of replication upstream of a beta globin gene in humans (907). Rather than containing a specific sequence at which replication begins, these origins appear to be zones including thousands of base pairs in which replication is more likely to begin than in other regions.

 

Hermann-Josef Lüdecke (DE), Gabriele Senger (DE), Uwe Claussen (DE), and Bernhard Horsthemke (DE) described the dissection of the Langer-Giedion syndrome region on chromosome 8 from GTG-banded metaphase chromosomes (G-banding with trypsin-Giemsa) and the universal enzymatic amplification of the dissected DNA. Eighty per cent of clones from this library (total yield 20,000) identify single-copy DNA sequences. Fifty per cent of clones detect deletions in two patients with Langer-Giedion syndrome. Although the other clones have not yet been mapped, this result demonstrates that thousands of region-specific probes can be isolated within ten days (1050).

 

Michael Altmann (CH), Nahum Sonenberg (CH), and Hans Trachsel (CH) established an essential role in Saccharomyces cerevisiae translation for elF4E and elF4A (25).

 

Malcolm Whiteway (CA), Linda Hougan (CA), Daniel Dignard (CA), David Y. Thomas (CA), Leslie Bell (US), Gena C. Saari (US), Francis J. Grant (US), Patrick J. O'Hara (US), and Vivian L. MacKay (US) proposed that in Saccharomyces cerevisiae the products of the STE4 and STE18 genes comprise the beta and gamma subunits of a G protein complex coupled to the mating pheromone receptors. The genetic data suggest pheromone-receptor binding leads to the dissociation of the alpha subunit from beta gamma (as shown for mammalian G proteins), and the free beta gamma element initiates the pheromone response (1788).

 

Giulio Draetta (US), Frank Luca (US), Joanne Westendorf (US), Leonardo Brizuela (US), Joan V. Ruderman (US), and David Beach (US) used Schizosaccharomyces pombe to offer proof that cell division can look superficially different from one organism to another, but the basic apparatus is the same (429).

 

Stefan Andersson (US), Daphne L. Davis (US), Helena Dahlbäck (SE), Hans Jörnvall (SE), and David W. Russell (US) isolated and characterized a cDNA encoding the rabbit mitochondrial sterol 26-hydroxylase. Their deduced amino acid sequence confirmed that the protein is a mitochondrial cytochrome P-450 that shares sequence similarity with the mitochondrial cholesterol side chain cleavage and steroid 11 beta-hydroxylase cytochrome P-450 enzymes. They demonstrated that the 26-hydroxylase mRNA is present in many tissues at different levels of abundance and is probably encoded by a unique copy gene in the rabbit genome (36). Note: The first step in the oxidation of the cholesterol side chain involves the introduction of a hydroxyl function at the 26-position. This reaction is catalyzed by the mixed function monooxygenase, sterol 26-hydroxylase.

Diane F. Jelinek (US), Stefan Andersson (US), Clive A. Slaughter (US), and David W. Russell (US) isolated several other enzymes in the degradative pathway of cholesterol, including the microsomal cytochrome P-450 cholesterol 7alpha-hydroxylase (7alpha-hydroxylase). This enzyme catalyzes the rate-limiting step in bile acid biosynthesis and is involved in the introduction of a hydroxyl moiety at the 7-position of cholesterol. Rat 7alpha-hydroxylase was purified and a partial amino acid sequence determined. They found that the enzyme’s mRNA is found only in the liver and that the levels of this mRNA increases when bile acids are depleted by dietary cholestyramine and decreased when bile acids are consumed. The researchers concluded that bile acids and sterols altered the transcription of the 7alpha-hydroxylase gene, explaining the previously observed feedback regulation of bile acid synthesis (834).

 

Izydor Apostol (US), Peter F. Heinstein (US), and Philip S. Low (US), using cultured plant cells, found that dye quenching was irreversible (even after pH adjustment) and was blocked by peroxidase inhibitors and antioxidant enzymes, implicating hydrogen peroxide synthesis in dye oxidation, in a manner reminiscent of the oxidative burst in human neutrophils. Second, elicitor-induced oxidative destruction of indole-3-acetic acid was also measured, implying negative cross talk between auxin and defense signaling. Finally, hydrogen peroxide was placed in a signal transduction pathway prior to and required for phytoalexin production; this was the first reported evidence of a second messenger role for reactive oxygen species in plants (40).

 

Trevor C. Dale (GB), A.M. Ali Imam (GB), Ian M. Kerr (GB), and George R. Stark (GB) suggested that interferon-stimulated gene factor 3 (ISGF3) is the ligand-dependent transcriptional activator that, in response to interferon treatment, is assembled in the cell cytoplasm, is translocated to the nucleus, and binds the consensus DNA site, the interferon-stimulated response element (368).

Xin-Yuan Fu (US), Daniel S. Kessler (US), Susan A. Veals (US), David E. Levy (US), and James Edwin Darnell, Jr. (US) purified ISGF3 and identified its constituent proteins: a DNA binding protein of 48 kD and three larger polypeptides (84, 91, and 113 kD), which themselves do not have DNA-binding activity. The multisubunit structure of ISGF3 most likely reflects its participation in receiving a ligand-dependent signal, translocating to the nucleus, and binding to DNA to activate transcription (552).

Christian W. Schindler (US), Xin-Yuan Fu (US), Teresa Improta (US), Ruedi H. Aebersold (CA), Ke Shuai (US), Vincent R. Prezioso (US), and James Edwin Darnell, Jr. (US) discovered a direct signaling pathway from the cell surface to genes in the nucleus. Darnell's group discovered that a set of dual function proteins they named STATs (signal transducers and activators of transcription) remain quiescent in the cell until circulating polypeptides bind to their specific cell surface receptors. Specific STATs are then activated, pair and travel to the nucleus to activate appropriate genes. For example, some STATs switch on a group of interferon-responsive genes when interferon contacts cells (553; 1482; 1483).

Zhong Zhong (CN-US), Zilong Wen (CN), and James Edwin Darnell, Jr. (US) discovered the first STATs to be activated by polypeptides other than interferon. Zhong says that the significance of their work is that it shows the existence of "a large gene family that is heavily used for gene regulation by a number of cytokines and growth factors." They showed that one of these (STAT3) could be activated by epidermal growth factors and interleukin-6 (1858; 1859).

Mathias Müller (DE), James Briscoe (GB), Carl Laxton (GB), Dmitry Guschin (US), Andrew Ziemiecki (GB-CH), Olli Silvennoinen (FI), Ailsa G. Harpur (GB), Giovanna Barbieri (FR), Bruce A. Witthuhn (US), Christian W. Schindler (US), Sandra Pellegrini (FR), Andrew F. Wilks (AU), James N. Ihle (US), George R. Stark (US), and Ian M. Kerr (GB) demonstrated the function of the JAK1 protein in the cellular responses to two different types of interferon signaling. The JAKs, are members of a "family of tyrosine kinases that were originally cloned by their homology to other tyrosine kinases, but without any idea as to what their function might be." Tyrosine kinases are a group of enzymes that activate various intracellular proteins by transferring phosphate groups to amino acids called tyrosines of these proteins, in response to signals from outside the cell. The initial lack of information about the JAKs is reflected in the name; JAK is an acronym for "just another kinase" (1183).

Carol Beadling (GB), Dmitry Guschin (GB), Bruce A. Witthuhn (US), Andrew Ziemiecki (CH), James N. Ihle (US), Ian M. Kerr (GB), and Doreen A. Cantrell (GB) investigated the activation of Janus protein tyrosine kinases (JAK kinases) and signal transducer and activator of transcription (STAT) proteins by interleukin-2 (IL-2). They noted an IL-2-induced increase in JAK1 and JAK3, but not JAK2 or Tyk2; tyrosine phosphorylation was observed. No induction of tyrosine phosphorylation of JAKs was detected upon stimulation of the T cell receptor (TCR). Interferon alpha (IFN alpha) induced the tyrosine phosphorylation of JAK1 and Tyk2, but not JAK2 or JAK3. IFN alpha activated STAT1, STAT2 and STAT3 in T cells, but IL-2 induced no detectable activation of these STATs. Finally, in other cell types the correlation between JAK1 activation and the induction of STAT1 has suggested that JAK1 may activate STAT1 (101).

James Edwin Darnell, Jr. (US), Ian M. Kerr (GB), and George R. Stark (US), during their investigation of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), discovered a previously unrecognized direct signal transduction pathway to the nucleus. Interferon-receptor interaction at the cell surface leads to the activation of kinases of the JAK family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and thereby direct transcription (374).

 

Stephen J. Elledge (US) and Ronald W. Davis (US) worked out a way to isolate mutant yeast strains that responded differently to DNA damage, thus identifying a set of DNA-damage response genes (468).

Stephen J. Elledge (US), Z. Hong Zhou (US), Yolanda Sanchez (US), Brian A. Desany (US), William J. Jones (US), Liu, Qinghua Liu (US), Bin Wang (US) , Calvin Wong (US), Richard S. Thoma (US), Ron Richman (US), Zhiqi Wu (US), Helen Piwnica-Worms (US), Shuhei Matsuoka (US), Mingxia Huang (US), Lee Zou (US), and J. Wade Harper (US) hypothesized that eukaryotes use a DNA repair system, very much like a burglary alarm, with a detector that senses the damage and sends signals to control posts that alert the various DNA-repair crews. They discovered that the proteins encoded by the DNA-damage response genes encode protein kinases, proteins that add phosphate groups other proteins, which is a signaling mechanism by which cells can quickly change the function of whole sets of proteins. They found that a single alarm arising from a protein kinase is sent to another protein kinase, which then amplifies it into a dramatic change in the cell’s physiology so that the DNA is repaired before the cell continues in its division cycle. They also showed how this eukaryotic system senses DNA damage, once again using the editing principle that DNA that is not in a double helix points to a corrupted text (706; 1100; 1455; 1456; 1860; 1865).

Note: Many of these DNA-damage response genes are now notorious because inherited mutations of them, as for instance in the case of BRCA1, dramatically increase the likelihood of developing cancer, while others play a role in aging or neurological disorders.

 

Franco Felici (IT), Giovanni Cesareni (IT), and John M.X. Hughes (GB) isolated and sequenced a gene for small cytoplasmic RNA (scRNA) from Saccharomyces cerevisiae (503).

 

Michael Litt (US), Jeffrey A. Luty (US), Diethard Tautz (DE), James L. Weber (US), and Paula E. May (US) discovered microsatellite DNA. These are polymorphic DNA sequences made of tandemly repeated strings of short elements, usually two, three or four nucleotides in length, and occur scattered throughout the genomes of all eukaryotes (Eucarya) (1033; 1651; 1773). Note: Microsatellite DNAs hold out great promise as markers for DNA fingerprinting.

 

Alan R. Templeton (US), Hope Hollocher (US), Susan Lawler (US-AU), and J. Spencer Johnston (US) discovered that the cellular machinery in Drosophila mercatorum has the ability to differentiate between functional and non-functional ribosomal RNA genes (1659).

 

Michael S. Davies (GB), (), Simon C. Wallis (GB), Donna M. Driscoll (GB), Judy K. Wynne (GB), Gareth W. Williams (GB), Lyn M. Powell (US), James Scott (GB), San-Hwan Chen (US), Xiaoxia Li (US), Warren S. Liao (US), June H. Wu (US), and Lawrence Chan (US) discovered an example of nuclear RNA editing in pre-mRNA encoding apolipoprotein B, a cytosine is converted to uracil in intestinal but not in liver cells (280; 380).

 

Barbara J. Trask (US), Daniel Pinkel (US), and Ger J. van den Engh (US) showed in the Chinese hamster genome that the distance between DNA sequences in interphase nuclei was correlated to molecular distance over a range of 25 to at least 250 kb. The observed relationship was such that genomic distance could be predicted to within 40 kb from interphase distance. Measured distances between sequences approximately 200 kb apart indicated that the DNA is condensed 70- to 100-fold in hybridized nuclei relative to a linear DNA helix molecule (1691).

 

Sharon Rugel Long (US) identified common and host specific nodulation (nod) genes, which determine infection and nodulation of specific leguminous hosts (1039).

 

Jürgen Grulich-Henn (DE) and Gert Müller-Berghaus (DE) reported that vascular endothelial cells play an important role in the regulation of fibrinolysis. They synthesize and secrete tissue-type plasminogen activators (t-PA), urinary-type plasminogen activators (u-PA), as well as plasminogen activator inhibitor type 1 (PAI-1). Synthesis of t-PA, u-PA, and PAI-1 are regulated by a variety of external agonists. The fibrinolytic capacity of endothelial cells derived from macrovascular and microvascular origin is regulated differently. Furthermore, endothelial cells bind plasminogen, plasminogen activators and plasminogen activator inhibitors. Depending on their state of activation endothelial cells may promote or inhibit fibrinolysis (659).

Jun Mimuro (JP) showed tissue plasminogen activator and urokinase are the activators of plasminogen and results in the breakdown of blood clots (fibrinolysis) (1156).

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (US) found that treatment of acute ischemic stroke with tissue plasminogen activator within 3 hours of symptom onset significantly improves functional outcomes three months after the incident, when compared with placebo. Tissue plasminogen activator is significantly associated with higher rates of symptomatic intracerebral hemorrhage (658).

 

Jürgen Behrens (DE), Marc M. Mareel (DE), Frans M. Van Roy (DE), and Walter Birchmeier (DE) found that nontransformed Madin-Darby canine kidney (MDCK) epithelial cells acquire invasive properties when intercellular adhesion is specifically inhibited by the addition of antibodies against the cell adhesion molecule uvomorulin (identical to E-cadherin and homologous to L-CAM); the separated cells then invade collagen gels and embryonal heart tissue (107).

Uwe H. Frixen (DE), Jürgen Behrens (DE), Martin Sachs (DE), Gertrud Eberle (DE), Beate Voss (DE), Angelika Warda (DE), Dorothea Löchner (DE), and Walter Birchmeier (DE) analyzed cell lines from many different carcinomas—epithelial tumors that are the most prevalent type of cancer in humans—and found that the invasive lines lacked E-cadherin. What's more, reinstalling the gene for E-cadherin reigned in the cells' wanderlust (548).

 

Renato Dulbecco (IT-US) realized early-on the value of obtaining the DNA sequence of all the human chromosomes as the foundation for understanding cancer (448).

P. Andrew Futreal (GB), Lachlan Coin (GB), Mhairi Marshal (GB), Timothy Hubbard (GB), Richard Wooster (GB), Nazneen Rahman (GB), and Michael R. Stratton (GB) in their inventory of the human genes associated with cancer recognized 291 cancer genes based on mutation data available in the literature: ∼1% of the coding sequence. It was noted that 90% of these genes were somatically mutated, 20% germline mutated, and 10% could be found in both categories. The most common form of variation in this 2004 inventory was translocation leading to the production of oncogenic fusion proteins (561).

Timothy J. Ley (US), Elaine R. Mardis (US), Li Ding (US), Bob Fulton (US), Michael D. McLellan (US), Ken Chen (US), David Dooling (US), Brian H. Dunford-Shore (US), Sean McGrath (US), Matthew Hickenbotham (US), Lisa Cook (US), Rachel Abbott (US), David E. Larson (US), Dan C. Koboldt (US), Craig Pohl (US), Scott Smith (US), Amy Hawkins (US), Scott Abbott (US), Devin Locke (US), Ladeana W Hillier (US), Tracie Miner (US), Lucinda Fulton (US), Vincent Magrini (US), Todd Wylie (US), Jarret Glasscock (US), Joshua Conyers (US), Nathan Sander (US), Xiaoqi Shi (US), John R. Osborne (US), Patrick Minx (US), David Gordon (US), Asif Chinwalla (US), Yu Zhao (US), Rhonda E. Ries (US), Jacqueline E. Payton (US), Peter Westervelt (US), Michael H. Tomasson (US), Mark Watson (US), Jack Baty (US), Jennifer Ivanovich (US), Sharon Heath (US), William D. Shannon (US), Rakesh Nagarajan (US), Matthew J. Walter (US), Daniel C. Link (US), Timothy A. Graube (US), John F. DiPersio (US), Richard K. Wilson (US), David A. Wheeler (US), Maithreyan Srinivasan (US), Michael Egholm (US), Yufeng Shen (US), Lei Chen (US), Amy McGuire (US), Wen He (US), Yi-Ju Chen (US), Vinod Makhijani (US), G. Thomas Roth (US), Xavier Gomes (US), Karrie Tartaro (US), Faheem Niazi (US), Cynthia L. Turcotte (US), Gerard P. Irzyk (US), James R. Lupski (US), Craig Chinault (US), Xing-zhi Song (US), Yue Liu (US), Ye Yuan (US), Lynne Nazareth (US), Xiang Qin (US), Donna M. Muzny (US), Marcel Margulies (US), George M. Weinstock (US), Richard A. Gibbs (US), and Jonathan M. Rothberg (US) used massively parallel sequencing introduced by the Roche 454 and Illumina in 2004–2006 and soon demonstrated the feasibility of sequencing complete normal and tumor genomes of exemplar human subjects on both platforms (1014; 1787).

Laura D. Wood (US), D. Williams Parsons (US), Siân Jones (US), Jimmy Lin (US), Tobias Sjöblom (US), Rebecca J. Leary (US), Dong Shen (US), Simina M. Boca (US), Thomas Barber (US), Janine Ptak (US), Natalie Silliman (US), Steve Szabo (US), Zoltan Dezso (US), Vadim Ustyanksky (US), Tatiana Nikolskaya (US), Yuri Nikolsky (US), Rachel Karchin (US), Paul A. Wilson (US), Joshua S. Kaminker (US), Zemin Zhang (US), Randal Croshaw (US), Joseph Willis (US), Dawn Dawson (US), Michail Shipitsin (US), James K. V. Willson (US), Saraswati Sukumar (US), Kornelia Polyak (US), Ben Ho Park (US), Charit L. Pethiyagoda (US), P. V. Krishna Pant (US), Dennis G. Ballinger (US), Andrew B. Sparks (US), James Hartigan (US), Douglas R. Smith (US), Erick Suh (US), Nickolas Papadopoulos (US), Phillip Buckhaults (US), Sanford D. Markowitz (US), Giovanni Parmigiani (US), Kenneth W. Kinzler (US), Victor E. Velculescu (US), and Bert Vogelstein (US) amplified and sequenced each coding exon of 18,000 genes, defined by the human genome sequence, in 11 each of breast and colorectal tumors (1818). Note: This brute force whole-exome sequencing (WES) approach afforded for the first time a comprehensive view of the mutation profile of each patient, which, when summed across patients, revealed the “cancer genes” for the patients in the given cohort. In one stroke, the mutation profile, composed of recurrently mutated genes, plus a collection of one-off mutations belonging to pathways and processes known to be involved in tumorigenesis, were revealed for a cancer. The fact that the most frequently mutated genes they observed, APC, TP53, and KRAS for colon cancer and TP53 for breast cancer, recapitulated what was already known, validated the approach and paved the way for expanded application of genome-scale sequencing.

Thomas J. Albert (US), Michael N. Molla (US), Donna M. Muzny (US), Lynne Nazareth (US), David A. Wheeler (US), Xingzhi Song (US), Todd A. Richmond (US), Chris M. Middle (US), Matthew J. Rodesch (US), Charles J. Packard (US), George M. Weinstock (US), Richard A. Gibbs (US), Andreas Gnirke (US), Alexandre Melnikov (US), Jared Maguire (US), Peter Rogov (US), Emily M. LeProust (US), William Brockman (US), Timothy Fennell (US), Georgia Giannoukos (US), Sheila Fisher (US), Carsten Russ (US), Stacey Gabriel (US), David B. Jaffe (US), Eric S. Lander (US), and Chad Nusbaum (US) introduced DNA sequence enrichment technologies from NimbleGen and Agilent that enabled whole-exome sequencing on a large scale (16; 599).

Lynda Chin (US), William C. Hahn (US), Gad Getz (US), and Matthew Meyerson (US) noted that using whole-genome sequence (WGS), genetic alterations observed in the DNA of the cancer cell span six orders of magnitude, from single-base point mutations to chromosome-scale amplification, using different modes of sequence analysis available today (288). Note: With these tools in hand, The Cancer Genome Atlas, the Cancer Genome Project, the International Cancer Genome Consortium, Therapeutically Applicable Research to Generate Effective Treatments, and other privately funded large-scale projects began in earnest to systematically catalog all the mutations in a wide variety of adult and pediatric cancers.

Philip J. Stephens (GB), Chris D. Greenman (GB), Beiyuan Fu (GB), Fengtang Yang (GB), Graham R. Bignell (GB), Laura J. Mudie (GB), Erin D. Pleasance (GB), King Wai Lau (GB), David Beare (GB), Lucy A. Stebbings (GB), Stuart McLaren (GB), Meng-Lay Lin (GB), David J. McBride (GB), Ignacio Varela (GB), Serena Nik-Zainal (GB), Catherine Leroy (GB), Mingming Jia (GB), Andrew Menzies (GB), Adam P. Butler (GB), Jon W. Teague (GB), Michael A. Quail (GB), John Burton (GB), Harold Swerdlow (GB), Nigel P. Carter (GB), Laura A. Morsberger (GB), Christine Iacobuzio-Donahue (GB), George A. Follows (GB), Anthony R. Green (GB), Adrienne M. Flanagan (GB), Michael R. Stratton (GB), P. Andrew Futreal (GB), and Peter J. Campbell (GB) using next-generation sequencing (NGS), characterized a phenomenon, which they termed chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. They found that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer (1604).

Next-generation sequencing (NGS) is defining and expanding the spectrum of genetic neurologic disorders. Clinically, NGS encompasses the use of large gene panels, whole-exome sequencing (WES), or whole-genome sequencing (WGS) to discover novel genes as the cause of neurologic disorders. An example is research by Mika H. Martikainen (FI), Markku Päivärinta (FI), Marja Hietala (FI), and Valtteri Kaasinento (FI) to further define the phenotype of a previously reported SNCA mutation that is associated with autosomal dominant Parkinson disease (1088).

NGS is permitting the connection of novel phenotypes with previously described genes as in the work by Gudrun Schottmann (DE), Dominik Seelow (DE), Franziska Seifert (DE), Susanne Morales-Gonzalez (DE), Esther Gill (DE), Katja von Au (DE), Arpad von Moers (DE), Werner Stenzel (DE), and Markus Schuelke (DE) in identifying REEP1 mutations as the cause of a severe axonal neuropathy with a spinal muscular atrophy with respiratory distress (SMARD) phenotype. This gene was previously associated with a hereditary spastic paraplegia phenotype (1498).

 

William D. Huse (US), Lakshmi Sastry (US), Sheila A. Iverson (US), Angray S. Kang (GB), Michelle Alting-Mees (CA), Dennis R. Burton (US), Stephen J. Benkovic (US), and Richard Alan Lerner (US) produced a bacteriophage lambda vector system, which expressed in Escherichia coli a combinatorial library of fragment antigen binding (Fab) fragments of the mouse antibody repertoire. The system allows rapid and easy identification of monoclonal Fab fragments in a form suitable for genetic manipulation (802).

 

Lewis G. Tilney (US) and Daniel A. Portnoy (US) demonstrated that Listeria monocytogenes, once inside a cell, acquires a “comet tail” of actin. It moves with the comet to the cell surface and into a cell extension that is eventually engulfed by a neighboring cell. Gaining entry to a host cell, the infecting Listeria and their progeny can spread from cell to cell by remaining intracellular and thus bypass the humoral immune system of the organism (1670).

 

Rosaria Orlandi (IT), Detlef H. Gussow (GB), Peter T. Jones (GB), and Gregory Winter (GB) designed oligonucleotide primers used to amplify the cDNA of mouse immunoglobulin heavy and light chain variable domains by the polymerase chain reaction (1264). Note: these synthetic human antibodies against human targets (such as cancer and inflammatory disease) can be used in such a way that they will not be rejected by the immune system.

 

Great Britain launched its human genome program (413).

 

David W. Deamer (US) and Richard M. Pashley (AU) found membrane-forming nonpolar molecules within the Murchison carbonaceous chondritic meteorite (394).

 

Keith A. Kvenvolden (US), James G. Lawless (US), Katherine Pering (US), Etta Peterson (US), Jose Flores (US), Cyril Ponnamperuma (LK-US), Isaac R. Kaplan (US), Carleton Moore (US) and John R. Cronin (US) examined the Murchison carbonaceous chondritic meteorite and found racemic mixtures of 74 different amino acids: 8 that are present in proteins, 11 with other biological roles (including, quite surprisingly, some neurotransmitters), and 55 that have been found almost exclusively in extraterresterial samples (357; 956; 957).

 

Napoleone Ferrara (US) and William J. Henzel (US) were the first to isolate and clone vascular endothelial growth factor (VEGF) (512).

 Shmuel Banai (US), Michael T. Jaklitsch (US), Ward Casscells (US), Matic Shou (US), Shashi Shrivastav (US), Rosaly Correa (US), Stephen E. Epstein (US), and Ellis F. Unger (US) demonstrated that administration of acidic fibroblast growth factor (aFGF or FGF-1) induced angiogenesis in a dog ischemic heart model (79).

Atsuko Yanagisawa-Miwa (JP), Yasumi Uchida (JP), Fumitaka Nakamura (JP), Takanobu Tomaru (JP), Hideaki Kido (JP), Takeshi Kamijo (JP), Tsuneaki Sugimoto (JP), Kazuhiko Kaji (JP), Masanori Utsuyama (JP), Chieri Kurashima (JP), and Ito Hideki (JP) demonstrated that an angiogenic growth factor, administered after myocardial infarction, could augment neovascularization, preserve left ventricular function and thereby improve outcome, thus introducing the concept that angiogenesis could be used therapeutically (1836).

K. Jin Kim (US), Bing Li (US), Jane Winer (US), Mark Armanini (US), Nancy Gillett (US), Heidi S. Phillips (US), and Napoleone Ferrara (US) presented the first preclinical example of targeted antiangiogenic therapy, the target in this case being paracrine (tumor-cell derived) vascular endothelial growth factor (VEGF) and the drug being a monoclonal antibody directed to human VEGF, which was found to inhibit the growth of human tumor xenografts in nude mouse, but not of the same tumor cells, in vitro (894).

Yukio Tsurumi (US), Satoshi Takeshita (US), Dongfen Chen (US), Marianne Kearney (US), Susan T. Rossow (US), Jonathan Passeri (US), Jeffrey R. Horowitz (US), James F. Symes (US), and Jeffrey M. Isner (US) showed that a gene therapy approach, using naked plasmid DNA encoding for a secreted protein, can exert a therapeutic effect, improving tissue perfusion and alleviating ischemia (1700).

Wadih Arap (US), Renata Pasqualini (US), and Erkki Ruoslahti (US) showed that differences exist between the endothelial cells in different organs or between tumor and normal blood vessels. They provide a molecular understanding of those differences. Their paper allowed investigators to consider the possibility of selectively targeting drugs to the tumor vasculature (41).

Karen S. Moulton (US), Eric Heller (US), Moritz A. Konerding (US), Evelyn Flynn (US), Wulf Pulinski (US), and Moses Judah Folkman (US) demonstrated that growth of atherosclerotic plaques is angiogenesis dependent, and that plaque growth in the mouse aorta can be inhibited 85% by antiangiogenic therapy with endostatin. This experiment argued against the conventional assumption that antiangiogenic therapy would close off collateral blood vessels in the heart. Instead, these results indicate that coronary artery flow may be improved because of inhibition of plaque growth, thus lessening dependence on collateral blood supply (1177).

Tomono Takahashi (US), Christoph Kalka (US), Haruchika Masuda (US), Donghui Chen (US), Marcy Silver (US), Marianne Kearney (US), Meredith Magner (US), Jeffrey M. Isner (US), and Takayuki Asahara (US) documented mobilization of bone marrow-derived endothelial progenitors by ischemia or cytokine administration, suggesting that the participation of these cells is modulated by remote stimuli and could therefore be manipulated therapeutically (1641).

Timothy Browder (US), Catherine E. Butterfield (US), Brigit M. Kräling (US), Bin Shi (US), Blair Marshall (US), Michael S. O' Reilly (US), and Moses Judah Folkman (US) showed that the antiangiogenic effects of a standard chemotherapeutic agent-in this case, cyclophosphamide-could be significantly enhanced by a more frequent schedule of administration with no breaks, using doses of drug significantly lower than the maximum tolerated dose (MTD), so that even cyclophosphamide resistant tumors could be successfully treated with the drug. This type of antiangiogenic scheduling or dosing of chemotherapy has become known as 'metronomic' therapy (214).

Rakesh K. Jain (US) provided a rationale for sequencing angiogenic therapy and chemotherapy to maximize the efficiency of both (824).

Eriko Tateishi-Yuyama (JP), Hiroaki Matsubara (JP), Toyoaki Murohara (JP), Uichi Ikeda (JP), Satoshi Shintani (JP), Hiroya Masaki (JP), Katsuya Amano (JP), Yuji Kishimoto (JP), Kohji Yoshimoto (JP), Hidetoshi Akashi (JP), Kazuyuki Shimada (JP), Toshiji Iwasaka (JP), and Tsutomu Imaizumi (JP) administered bone marrow and circulating mononuclear cells to patients with critical limb ischemia. The patients experienced physiologic improvement. Apparent superiority of bone marrow cells, with higher content of CD34+ cells, provides further evidence of the unique role of this population of monocytes (1650).

Lloyd Paul Aiello (US), Daniel J. George (US), Mark T. Cahill (US), Jun S. Wong (US), Jerry Cavallerano (US), Allison L. Hannah (US), and William G. Kaelin (US) successfully treated angiolastoma of the eye of a von Hippel-Lindau patient with an angiogenesis inhibitor (which blocks the receptor for vascular endothelial growth factor VEGF) (14).

 

Øivind Bergh (NO), Knut Yngve Y Børsheim (NO), Gunnar Bratbak (NO), and Mikal Heldal (NO), using a new method for quantitative enumeration, found up to 2.5 x 10⁸ virus particles per millilitre in natural waters. These concentrations indicate that virus infection may be an important factor in the ecological control of planktonic micro-organisms, and that viruses might mediate genetic exchange among bacteria in natural aquatic environments (130).

 

Qui Lim Choo (US), George Ching-Hung Kuo (US), Amy J. Weiner (US), Lacy R. Overby (US), Daniel W. Bradley (US), Michael Houghton (GB), Harvey J. Alter (US), Gary L. Gitnick (US), Allan G. Redeker (US), Robert Harry Purcell (US), Tatsuo Miyamura (US), Jules L. Dienstag (US), Miriam J. Alter (US), Cladd E. Stevens (US), Gary E. Tegtmeier (US), Ferruccio Bonino (IT), Massimo Colombo (IT), W.-S. Lee (), C. Kuo (), Kim M. Berger (US), and Jeffrey R. Shuster (US) identified the hepatitis C virus (HCV) as the main causative agent of post-transfusion non-A, non-B hepatitis. This was the first infectious agent discovered entirely by cloning nucleic acid. A blood test to detect antibodies to hepatitis C soon followed (293; 947).

Leslie H. Tobler (US) and Michael P. Busch (US) established hepatitis C virus (HCV) as the causative agent of over 90% of non-A, non-B post-transfusion hepatitis (1674).

 

Shyh-Cheng Lo (US), James Wai-Kuo Shih (US), Perry B. Newton III (US), Dennis M. Wong (US), Michael M. Hayes (US), Janet R. Benish (US), Douglas J. Wear (US), and Richard Yuan-Hu Wang (US) identified a pathogenic virus-like infectious agent (VLIA), originally reported in patients with AIDS, but also known to be pathogenic in previously healthy non-AIDS patients and in non-human primates. They classified it as a member of the order Mycoplasmatales, class Mollicutes and named it Mycoplasma incognitus (1035).

 

Stuart K. Kim (US), Armin Dale Kaiser (US) and Adam Kuspa (US) found that independent cells of Myxococcus xanthus (a type of bacterium) congregate when facing starvation and or drought. Factor A secreted by the cells themselves causes cellular aggregation when its concentration reaches a threshold. Factor C on the surface of the cells allows them to signal one another that they are packed together in such a way that spore formation can take place (895; 896; 954).

 

Mitchell Lloyd Sogin (US), John H. Gunderson (US), Hillie J. Elwood (US), Rogelio A. Alonso (US), and Debra A. Peattie (US) determined that in the diplomonad Giardia lamblia 16S-like rRNA has retained many of the features that may have been present in the common ancestor of eukaryotes (Eucarya) and prokaryotes (Archaea or Bacteria). They concluded that it represents the earliest-branching eukaryotic lineage (1576).

 

Kam-Ha Anna Yeung (US), Mark A. Schell (US), and Peter G. Hartel (US) developed an ingenious three-nested-cup set-up for studying the rhizosphere (1843).

 

Joseph Frank Sambrook (US), Edward F. Fritsch (US), and Thomas Peter Maniatis (US) authored the manual Molecular Cloning, which became a mainstay of molecular-biology laboratories (1451).

 

Gerald J. Spangrude (US), John Klein (US), Shelly Heimfeld (US), Ykoh Aihara (US), and Irving Lerner Weissman (US) used monoclonal antibodies to identify totipotent cells in mouse bone marrow. They found that these totipotent cells account for only about 0.1 percent of all bone marrow cells (1589). Note: These totipotent cells came to be called stem cells.

 

David Haig (AU-US), Mark Westoby (AU), Tom Moore (GB), and Chris Graham (GB) predicted that in placental animals and in plants whose seed gain sustenance from the parent plant the paternal genes have been selected to be aggressive in their bid to obtain nourishment (681-685; 1167). Note: This is called paternal imprinting

 

Kevin S. Johnson (AU), Gavin L.B. Harrison (AU), Marshall W. Lightowlers (AU), Kim L. O'Hoy (AU), Wendy G. Cougle (AU), Robert P. Dempster (AU), Stephen B. Lawrence (AU), Jennifer G. Vinton (AU), David D. Heath (AU), and Michael D. Rickard (AU) used the first recombinant vaccine against a helminth worm to vaccinate sheep against Taenica ovis (843).

 

David G. Wilkinson (GB), Sangita Bhatt (GB), Martyn Cook (GB), Edorado Boncinelli (IT), Robb Krumlauf (GB), Jarema Malicki (US), Klaus Schughart (DE), and William McGinnis (US) provided genetic evidence that the serial repetition of body parts is an ancient feature of animal design (1076; 1793).

 

Isidore Tepler (US), Cynthia C. Morton (US), Akira Shimizu (JP), Randall F. Holcombe (US), Roger L. Eddy (US), Thomas B. Shows (US), and Philip Leder (US) determined that the gene for human IgE receptor alpha chain is located on chromosome number one (1660).

 

David K. Grandy (US), Michael Litt (US), Lee Allen (US), James R. Bunzow (US), Mark A. Marchionni (US), Haripriya Makam (US), Leslie Reed (US), R. Ellen Magenis (US), and Olivier Civelli (US) identified and localized the dopamine D2 receptor to human chromosome 11 (630). Note: Human dopaminergic neurons are involved in the control of hormone secretion, voluntary movement, and emotional behavior. Mediating these effects are the dopamine D1 and D2 receptors. These macromolecules belong to a large family of related sequences known as the G protein-coupled receptors.

 

Siegfried Roth (DE), David Stein (DE), Christiane Jani Nüsslein-Volhard (DE), Christine A. Rushlow (US), Kyuhyung Han (US), James L. Manley (US), Michael Levine (US), and Ruth Steward (US) determined that in the early Drosophila embryo the Dorsal protein is uniformly distributed along the anterior-posterior axis of the body yet it is distributed in a broad ventral-to-dorsal gradient, with peak levels present along the ventral surface (1422; 1432; 1608). Note: The Dorsal gradient is responsible for initiating the differentiation of several embryonic tissues, including the mesoderm, neurogenic ectoderm, and the dorsal ectoderm.

 

Harold M. Weintraub (US), Stephen J. Tapscott (US), Robert L. Davis (US), Mathew J. Thayer (US), Mohammed A. Adam (US), Andrew B. Lassar (US), and A. Dusty Miller (US) discovered that MyoD is a master regulatory gene for myogenesis. Expression of muscle-specific proteins was observed in chicken, human, and rat primary fibroblasts and in differentiated melanoma, neuroblastoma, liver, and adipocyte lines. The ability of MyoD to activate muscle genes in a variety of differentiated cell lines suggests that no additional tissue-specific factors other than MyoD are needed to activate the downstream program for terminal muscle differentiation or that, if such factors exist, they are themselves activated by MyoD expression (1778).

 

Tomoyuki Yokota (JP), Kenji Konno (JP), Shuichi Mori (JP), Shiro Shigeta (JP), Masao Kumagai (JP), Yohko Watanabe (JP), and Haruhiko Machida (JP) described sorivudine (E-5-(bromovinyl) arabinofuranosyluracil), also called BVaraU, as the most potent inhibitor of Varicella zoster (1845).

 

George Streisinger (HU-US), Frank Coale (US), Cori Taggart (US), Charline Walker (US), and David Jonah Grunwald (US) demonstrated the clonal origins of cells in the pigmented retina of the zebrafish eye (1612).

 

Mariella Chaput (BE), Victor Claes (BE), Daniel Portetelle (BE), Isabelle Cludts (BE), Alfredo Cravador (BE), Arsène Burny (BE), Hélène Gras (BE), and André Tartar (BE) cloned the gene for pig muscle phosphohexose isomerase (glucose-6-phosphate isomerase) which catalyses the conversion of glucose-6-phosphate to fructose-6-phosphate, an obligatory step in glycolysis, and determined its amino-acid sequence. Surprisingly, it is 90% homologous to the sequence of mouse neuroleukin (275). Neuroleukin is a neurotrophic factor for spinal and sensory neurons and a lymphokine product of lectin-stimulated T-cells.

 

David G. Schatz (US), Marjorie A. Oettinger (US), and David Baltimore (US) isolated the RAG-1 (recombination activating gene-1) genomic locus, which activates V(D)J recombination when introduced into NIH 3T3 fibroblasts, by serial genomic transfections of oligonucleotide-tagged DNA. Nucleotide sequencing of human and mouse RAG-1 cDNA clones predicts 119 kd proteins of 1043 and 1040 amino acids, respectively, with 90% sequence identity. RAG-1 has been conserved between species that carry out V(D)J recombination, and its pattern of expression correlates exactly with the pattern of expression of V(D)J recombinase activity. RAG-1 may activate V(D)J recombination indirectly, or it may encode the V(D)J recombinase itself (1475).

 

Alain Townsend (GB), Claes Ohlén (SE), Judy Bastin (GB), Hans-Gustaf Ljunggren (SE), Linda Foster (GB), and Klas Kärre (SE) speculated that association of antigenic peptides with the binding site of class I molecules may be required for correct folding of the heavy chain, association with beta 2-microglobulin and transport of the antigen-MHC complex to the cell surface (1682).

 

Stephan C. Meuer (DE), Hubert Dumann (DE), Karl-Hermann Meyer zum Buschenfelde (DE), and Hans Köhler (DE) demonstrated the safety and efficacy of treating humans with interleukin-2. This was determined during immunization trials with hepatitis B vaccine (1145).

 

Masanori Hatakeyama (JP), Mitsuru Tsudo (JP), Seijiro Minamoto (JP), Takeshi Kono (JP), Takeshi Doi (JP), Tomoko Miyata (JP), Masayuki Miyasaka (JP), and Tadatsugu Taniguchi (JP) were able to isolate the gene encoding for a second polypeptide making up the receptor for interleukin-2 (722).

 

Ralph T. Kubo (US), Willi Born (US), John W. Kappler (US), Philippa Marrack (US), and Michele Pigeon (US) produced monoclonal antibody that reacts with surface receptors on all alpha beta TCR-bearing cells and does not react with receptors on gamma delta+ T cells. In an immobilized form, this antibody can directly activate T cells bearing alpha beta TCR. In combination with anti-CD3, the antibody can be used in cytofluorographic analyses to measure numbers of CD3+, alpha beta+, and CD3+, gamma delta+ cells in the thymus and periphery (943).

 

Robert L. Coffman US), Deborah A. Lebman (US), and Barbara Shrader (US) discovered that the addition of transforming growth factor-beta (TGF-beta) to cultures of lipopolysaccharide-stimulated murine B cells causes an approximately 10-fold enhancement of IgA production, yet causes a 10-fold decrease in total Ig production. IL-2 and, to a lesser extent, IL-5 synergize with TGF-beta to further enhance IgA production and partially reverse the inhibition of total Ig production. These findings suggests that TGF-beta acts as an isotype-specific switch factor for IgA (320).

Eiichiro Sonoda (JP), Ryoji Matsumoto (JP), Yasumichi Hitoshi (JP), Takehisa Ishii (JP), Mineharu Sugimoto (JP), Shukuro Araki (JP), Akira Tominaga (JP), Naoto Yamaguchi (JP), and Kiyoshi Takatsu (JP) also discovered that transforming growth factor-beta induces IgA production and acts additively with interleukin 5 for IgA production (1587).

 

Lewis C. Cantley (US), Lyuba Varticovski (RU-US), Brian J. Druker (US), Deborah Morrison (US), Thomas M. Roberts (US), George Q. Daley (US), Peter D. Jackson (US), David Baltimore (US), Hwai Wen Chang (US), Masahiro Aoki (US), David Fruman (US), Kurt R. Auger (US), Alfonso Bellacosa (US), Philip N. Tsichlis (US), Peter K. Vogt (US) and Benjamin G. Neel (US) discovered a growth signaling molecule called phosphoinositide 3-kinase (PI3K), a key factor in tumor growth. Their discovery showcased a new language of how cells control themselves internally (251; 273; 1733; 1734).

 

Zena Werb (US), Patrice M. Tremble (US), Ole Behrendtsen (US), Eileen Crowley (US), and Caroline H. Damsky (US) found that degradation products of fibronectin in the extracellular matrix and bound to integrins could turn on protease expression within the cell. Cells were recognizing different states of the matrix molecule. An extracellular matrix molecule was endowed with both the mechanism for homeostasis as well as for cell migration and changes that might occur, for example, in wound healing (1783).

Richard A. Clark (US), Norman E. Wikner (US), Dennis E. Doherty (US), and David A. Norris (US) found that human monocytes had chemotactic activity to the cell-binding domain of fibronectin, but not to the intact molecule (304).

Christopher E. Turner (US), John R. Glenney (US), and Keith Burridge (US) discovered paxillin, one of the cell adhesion proteins (1702).

Keith Burridge (US), Christopher E. Turner (US), and Lewis H. Romer (US) obtained results suggesting a role for integrin-mediated tyrosine phosphorylation in the organization of the cytoskeleton as cells adhere to the extracellular matrix. Focal adhesion kinase (FAK) was implicated as a key relay for extracellular matrix signals (237). ECM proteins pass their messages to the cell by tweaking integrins.

Magdalena Chrzanowska-Wodnicka (US) and Keith Burridge (US) went on to show that the molecular switch called Rho spurs formation of focal adhesions by increasing the contractility of actin fibers (295).

 

Masaaki Eto (JP), Kiyoshi Watanabe (JP), and Isao Makino (JP) concluded that both epsilon 2 and epsilon 4 alleles of the apolipoprotein gene E (epsilon) are more associated with ischemic heart disease (IHD) than the epsilon 3 allele (479).

 

Étienne Émile Baulieu (FR) developed RU 486, the first safe, effective contraceptive medication. This drug, also known as Mifepristone, works by acting on the woman's body to block progesterone, a hormone needed to maintain pregnancy (97).

 

Hugo A. Katus (DE), Andrew Remppis (DE), Siegfried Looser (DE), Klaus Hallermeier (DE), Thomas Scheffold (DE), and Wolfgang Kübler (DE) designed the enzyme linked immune assay of cardiac troponin T for the diagnosis of acute myocardial infarction (AMI) in patients where circulating constituents of the contractile apparatus may be measured instead of cytosolic cardiac enzymes. The potential advantages of the use of myofibrillar cardiac proteins as marker proteins for AMI results from their expression as cardio-specific isoforms, their high intracellular concentration, and their continuous release from infarcting myocardium (874). Note: Elecsys Tropinin T is the proprietary name of the test while “troponin test” is its common name.

 

William L. Gerald (US) and Juan Rosai (IT-AR-US) were the first to describe desmoplastic small-round-cell tumor, an aggressive rare soft tissue sarcoma that primarily occurs as masses in the abdomen of children (585).

Amanda J. Murphy (CA), Karen Bishop (CA), Carlos Pereira (CA), Susan Chilton-MacNeill (CA), Michael Ho (CA), Maria Zielenska (CA), and Paul S. Thorner (CA) found that DSRCT is associated with a unique chromosomal translocation (t11;22)(p13:q12) (1194).

William L. Gerald (US) and Daniel A. Haber (US) found that this translocation results in an EWS/WT1 transcript (584).

Yi-Shuan Lee (CN) and Cheng-Hsiang Hsiao (CN) found that this transcript codes for a protein that acts as a transcriptional activator that fails to suppress tumor growth and is diagnostic of this tumor (998).

 

Suzanne Fortney (US), Elizabeth Miescher (US), and Barbara Rolls (US) determined that body fluid homeostasis might be impaired with aging, such that older individuals compensate more slowly to changes in body water. Older subjects seem less able to sense changes in hydration and at a given body water deficit, they have greater difficulty maintaining plasma volume and osmolality (532).

 

Carol Bower (AU) and Fiona J. Stanley (AU) showed that dietary intake of folate in early pregnancy protects against the occurrence of isolated neural-tube defects in infants (188).

 

Victor Candas (FR) and Gabrielle Brandenberger (FR) found that progressive rehydration during exercise was more efficient than initial hyperhydration in reducing the homeostatic disturbances associated with exercise in the heat (249).

 

Vijay K. Chaudhary (IN), Gary Queen (DE), Richard P. Junghans (US), Thomas A. Waldmann (US), David J. FitzGerald (US), and Ira Harry Pastan (US) produced a recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin A. The new chimeric protein was produced in E. coli and shown to selectively kill CD25-expressing cells (278). Note: This paper clearly shows that one can design and produce a powerful and specific cell-killing agent using a combination of protein design and genetic engineering.

 

Jorge E. Galán (US) and Roy Curtis III (US), using an in vitro system, isolated a genetic locus, inv that confers to a noninvasive strain of Salmonella typhimurium the ability to penetrate tissue culture cells (565).

Jorge E. Galán (US), Christine Ginocchio (US), and Paul Costeas (US) predicted the sequence of InvA and found it to be homologous to Caulobacter crescentus FlbF, Yersinia LcrD, Shigella flexneri VirH, and E. coli FlhA proteins. They suggested that these proteins might form part of a family of proteins with a common function, quite possibly the translocation of specific proteins across the bacterial cell membrane (566).

Koné Kaniga (US), David Trollinger (US), and Jorge E. Galán (US) found that inv encodes a type 3 secretion system (TTSS) (862).

Robert M. Mcnab (US), Gregory V. Plano (US), James B. Day (US), and Franco Ferracci (US) reported that the TTSS is a complex protein export pathway that is used by numerous gram-negative pathogens to export flagella or to secrete effector proteins into the extracellular milieu or into the membrane or cytosol of an infected host eukaryotic cell (1065; 1338).

Guy R. Cornelis (CH) found that pathogenic Yersinia species carry a plasmid-encoded TTSS required for counteracting immune defenses after the pathogen has penetrated host tissues (343).

 

Jack P. Dumbacher (US) encountered a poisonous bird, the hooded pitohui (Pitohui dichrous) in 1989.

Jack P. Dumbacher (US), Bruce M. Beehler (US), Thomas F. Spande (US), H. Martin Garraffo (US), and John W. Daly (US) determined that the birds have cardio- and neurotoxins called batrachotoxins in their feathers and skin that make them smell and taste terrible (450).

John P. Dumbacher (US), Avit Wako (PG), Scott R. Derrickson (US), Allan Samuelson (US), Thomas F. Spande (US), and John W. Daly (US) likely discovered the source of the toxins: tiny Melyrid beetles (e.g., Choresine pulchra), which the birds eat. If tasted, both birds and the beetles cause people to have burning, tingling sensations in their mouths (451). Note: Avit Wako (PG), of Papua New Guinea, seems to have led the way on this discovery.

Jack P. Dumbacher (US) reported a taxonomic revision of the genus Pitohui, with historical notes on names (449).

 

Benjamin P. Bidstrup (GB), David Royston (GB), Ralph N. Sapsford (GB), and Kenneth M. Taylor (GB) reported that the effect of high dose aprotinin (Trasylol) was evaluated in three groups of patients undergoing cardiopulmonary bypass. In a prospective, placebo-controlled, double blind study, 80 patients having primary aorta-coronary bypass grafting received aprotinin (700 mg approximately) or saline placebo from the beginning of the procedure until skin closure. Standardized anesthetic, perfusion, and surgical techniques were used. The total loss from the thoracic drains was significantly reduced in the aprotinin group as compared with the loss in the placebo group (145).

 

Fionula M. Brennan (GB), David Chantry (GB), Andrew Jackson (GB), Ravinder Nath Maini (GB), and Marc Feldman (GB) found that tumor necrosis factor alpha (TNF-alpha) is the dominant inducer of IL-1 production in rheumatoid but not in osteoarthritic joints (198).

 

Craig B. Thompson (US), Tullia Lindsten (US), Jeffrey A. Ledbetter (US), Steven L. Kunkel (US), Howard A. Young (US), Stephen G. Emerson (US), Jeffrey M. Leiden (US), and Carl H. June (US) showed that CD28 stimulation augments T cell immune responses by specifically inducing a 5- to 50-fold enhancement in the expression and secretion of interleukin 2 (IL-2), tumor necrosis factor type alpha, lymphotoxin, interferon gamma, and granulocyte-macrophage colony-stimulating factor in normal human T cells stimulated to proliferate by crosslinking of the T cell receptor/CD3 complex (1667). CD28 is a 44-kD glycoprotein expressed as a homodimer on the surface of a major subset of human T cells. Previous studies have demonstrated that the binding of monoclonal antibodies to the CD28 surface antigen can augment the proliferation of purified human T cells stimulated with suboptimal doses of mitogens or anti-T cell receptor/CD3 complex antibodies.

Cornelis L. Verweij (NL), Marlieke Geerts (NL), and Lucien A. Aarden (NL) demonstrated that costimulation of T cells via CD28 provides a signal which activates transcription of the IL-2 gene. A CD28-responsive element (CD28RE) in the IL-2 enhancer at position -162 to -152 was identified. Besides an effect on lymphokine mRNA stabilization, stimulation via CD28 acts at the level of transcription via coinduction of an NF-kB-like activity (1742).

 

Noemia P. Goldraich (BR), Osvaldo Luiz Ramos (BR), and Isidoro Henrique Goldraich (BR) concluded that abnormalities detected by the technetium-dimercaptosuccinic acid (DMSA) renal scan may precede the radiological findings, especially in young children. Even severe reflux neuropathy (RN) can be established in kidneys that appear normal on the intravenous urography IVU (605).

 

David H. Ledbetter (US), Susan A. Ledbetter (US), Peter vanTuinen (US), Kim M. Summers (US), Terence J. Robinson (US), Yusuke Nakamura (US), Roger Wolff (US), Ray White (US), David F. Barker (US), Margaret R. Wallace (US), Francis S. Collins (US), and William B. Dobyns (US) discovered frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated "island" in the Miller-Dieker chromosome region as the cause of the Miller-Dieker syndrome (984).

 

Irving L. Lichtenstein (US), Alex G. Shulman (US), Parviz K. Amid (US), and Michele M. Montllor (US) described a totally new approach to groin hernia repair. The technique used a polyproplene mesh to repair the hernia defect and avoided suture-line tension. It was ssimple, highly effective, caused less pain, and rapidly gained acceptance throughout the world (1020). See, Bassini, 1889

 

Ronald Jaffe (US), Jonathan D.K. Trager (US), Adriana Zeevi (US), Enigul Sonmez-Alpan (US), Rene J. Duquesnoy (US), Satoru Todo (US), Marc Rowe (US), and Thomas Earl Starzl (US) reported the diagnostic surgical pathology of two children who underwent multivisceral abdominal transplantation; one survived for 1 month, the other for 6 months (823).

 

Trevor J. Crofts (GB), Kenneth G.M. Park (GB), Robert J.C. Steele (GB), Sydney S.C. Chung (CN), and Arthur K.C. Li (CN) reported that non-operative treatment of perforated duodenal ulcer is safe in selected patients and with close observation (356).

 

Duke Edward Cameron (US), Bruce A. Reitz (US), Benjamin Solomon Carson, Sr. (US), Donlin M. Long (US), Craig R. Dufresne (US), Craig A. Vander Kolk (NL), Lynne Gerson Maxwell (US), Donald M. Tilghman (US), David G. Nichols (US), Randall C. Wetzel (US), et al. successfully separated 7-month-old occipitally joined craniopagus Siamese twins using cardiopulmonary bypass and hypothermic circulatory arrest during surgery. The infants shared a large sagittal venous sinus that precluded a conventional neurosurgical approach because of risk of exsanguination and air embolism. Both infants survived. This case demonstrates the valuable supportive role of cardiopulmonary bypass and hypothermic circulatory arrest in the management of complex surgical problems of otherwise inoperable patients (247).

 

Jerry A. Coyne (US) and H. Allen Orr (US) found that postzygotic isolation evolves at about the same rate as prezygotic isolation between allopatric species of Drosophila (350; 351). Note: many other studies ask whether any patterns characterize the evolution of reproductive isolation in a large group of species. One of the clearest lessons to emerge from this question is that biology matters: although postzygotic isolation, for instance, evolves at about the same rate as prezygotic between allopatric species of Drosophila, the same is not true in birds, where prezygotic isolation typically evolves long before postzygotic.

Joachim Wittbrodt (DE), Dieter Adam (DE), Barbara Malitschek (DE), Winfried Maueler (DE), Friedrich Raulf (DE), Agnes Telling (DE), Scott M. Robertson (DE), and Manfred Schartl (DE) found several genes that cause reproductive isolation have been identified and characterized. These genes are Xmrk-2, which causes inviability in backcross hybrids between the platyfish Xiphophorus maculatus and the swordtail Xiphophorus helleri (1805).

Chau-Ti Ting (US), Shun-Chern Tsaur (US), Mao-Lien Wu (US), and Chung-I Wu (US) discovered that OdsH causes male sterility in backcross hybrids between the flies Drosophila simulans and Drosophila mauritiana (1672; 1822).

Daniel A. Barbash (GB), Dominic F. Siino (US), Aaron M. Tarone (US), and John Roote (GB) found Hmr, which causes inviability in F1 hybrids between the flies Drosophila melanogaster and D. simulans (87).

Daven C. Presgraves (US), Lakshmi Balagopalan (US), Susan M. Abmayr (US), and H. Allen Orr (US) discovered Nup96, which causes inviability in F2-like hybrids between D. melanogaster and D. simulans (1356).

Nicholas J. Brideau (US), Heather A. Flores (US), Jun Wang (US), Shamoni Maheshwari (US), Xu Wang (US), and Daniel A. Barbash (US) identified Lhr, which causes inviability in F1 hybrids between the flies D. melanogaster and D. simulans (204).

Jerry A. Coyne (US) and H. Allen Orr (US) suggested that the genetics of speciation thus provides strong support for the traditional view that reproductive isolation evolves as an epiphenomenon of Darwinian adaptation, a result that has rightly received much attention (351).

 

John A. Jarcho (US), William McKenna (US), J.A. Peter Pare (US), Scott D. Solomon (US), Randall F. Holcombe (US), Tatjana Levi (US), Helen Donis-Keller (US), J.G. Seidman (US), and Christine E. Siedman (US) identified the chromosomal location of a gene responsible for familial hypertrophic cardiomyopathy. Their data indicated that in this kindred, the odds were greater than 2,000,000,000:1 that the gene responsible for familial hypertrophic cardiomyopathy was located on chromosome 14 (band q1) (825).

 

William Martin (DE), Alfons Gierl (DE), and Heinz Saedler (DE) report molecular evidence suggesting that angiosperm ancestors underwent diversification more than 300 Myr ago (1090).

Kenneth H. Wolfe (US), Manolo Gouy (US), Yau-Wen Yang (US), Paul M. Sharp (US), and Wen-Hsiung Li (US) estimated the date of the divergence between monocots and dicots by reconstructing phylogenetic trees from chloroplast DNA sequences, using two independent approaches: the rate of synonymous nucleotide substitution was calibrated from the divergence of maize, wheat, and rice, whereas the rate of nonsynonymous substitution was calibrated from the divergence of angiosperms and bryophytes. Both methods lead to an estimate of the monocot-dicot divergence at 200 million years (Myr) ago (with an uncertainty of about 40 Myr). This estimate is also supported by analyses of the nuclear genes encoding large and small subunit ribosomal RNAs. These results imply that the angiosperm lineage emerged in Jurassic-Triassic time, which considerably predates its appearance in the fossil record (approximately 120 Myr ago). They estimated the divergence between cycads and angiosperms to be approximately 340 Myr ago, which can be taken as an upper boundary for the age of angiosperms (1810). Note: The two papers above suggest that the genomes of maize, rice, and wheat have been isolated for more than 60 million years.

 

Baruch Arensburg (IL), Anne-Marie Tillier (FR), Bernard Vandermeersch (FR), Henri Duday (FR), Lynne A. Schepartz (US), and Yoel Rak (IL) reported the discovery of a well-preserved human (Neanderthal) hyoid bone from Middle Paleolithic layers of Kebara Cave, Mount Carmel, Israel, dating from about 60,000 years BP The bone is almost identical in size and shape to the hyoid of present-day Homo sapiens populations, suggesting that there has been little or no change in the visceral skeleton (including the hyoid, middle ear ossicles, and inferentially the larynx) during the past 60,000 years of human evolution. They concluded that the morphological basis for human speech capability appears to have been fully developed during the Middle Paleolithic (42).

 

1990

“Often I am asked if I prefer chimpanzees to humans. The answer to that is easy—I prefer some chimpanzees to some humans, some humans to some chimpanzees!” Valerie Jane Goodall (610).

 

Joseph Edward Murray (US) and E. Donnall Thomas (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning organ and cell transplantation in the treatment of human disease.

 

Wolfgang Krätschmer (DE), Lowell D. Lamb (US), Konstantinos Fostiropoulos (DE), and Donald Huffman (US) synthesized the soccer-ball-shaped C60 buckminsterfullerene, a.k.a. "buckyball, in honor of Buckminster Fuller who designed the geodesic dome (933).

 

Seiji Ogawa (JP-US), Ravi S. Menon (US), David W. Tank (US), Seong-Gi Kim (US), Hellmut Merkle (US), Jutta M. Ellermann (US), Kamil Ugurbil (US), Winfried Denk (US), Robert M. Keolian (US), Lynn W. Jelinski (US), Asha R. Kay (US), Tso-Ming Lee (US), and Paul Glynn (US) discovered that Magnetic Resonance Imaging (MRI) could be used to visualize active regions in the living human brain. They showed that this functional brain mapping depended on the oxygenation status of the blood feeding the active neurons. Functional MRI (fMRI) has been used to map the visual, auditory and sensory regions. It is used in surgical planning to identify the motor cortex. fMRI is a revolutionary tool for neuroscience and has become essential for investigating higher order cognitive function and brain interconnectivity and plasticity (406; 1244-1247).

 

Jason D. Morrow (US), Kristina E. Hill (US), Raymond F. Burke (US), Tarek M. Nammour (US), Kamal F. Badr (LB), and L. Jackson Roberts, II (US) discovered new prostaglandin-like molecules, which they named isoprostanes (1171).

 

David A. Evans (US), Stephen W. Kaldor (US), Todd K. Jones (US), Jon Clardy (US), and Thomas J. Stout (US) carried out the total synthesis of the antineoplastic macrolide antibiotic cytovaricin (480).

 

Kyriacos Costa Nicolaou (CY-US), Robert D. Groneberg (US), Tohru Miyazaki (JP), Nicolas A. Stylianides (CY), Thomas J. Schulze (US), Wilhem Stahl (DE), Adrian L. Smith (GB), Chan-Kou Hwang (US), Emmanuel N. Pitsinos (GR), Gerard R. Scarlato (US), Conrad W. Hummel (US), Masahisa Nakada (JP), Katsuhiro Shibayama (JP), Hiroyuki Saimoto (JP), Erwin P. Schreiner (AT), Toshio Suzuki (JP), Yoshiharu Iwabuchi (JP), Yukio Mizuno (JP), and Kai-Uwe Baldenius (DE) carried out a total synthesis of calicheamicin gamma (649; 1214; 1216-1218; 1561; 1562). Note: Calicheamicin gamma 1I is a recently discovered diyne-ene-containing antitumor antibiotic with considerable potency against murine tumors.

 

Timothy W. Short (US) and Winslow R. Briggs (US) presented the first in vitro evidence that blue-light irradiation can activate the phosphorylation of a plasma membrane protein isolated from etiolated pea stem tissue as well as the recovery of the protein to its dark state over a matter of minutes (1542).

 

Guncheol Kim (US), Margaret Y. Chu-Moyer (US), Samuel J. Danishefsky (US), and Gayle K. Schulte (US) carried out the total synthesis of indolizomycin (892; 893).

 

Stephen F. Altschul (US), Warren R. Gish (US), Webb C. Miller (US), Eugene W. Myers (US), and David J. Lipman (US) presented a new approach to rapid sequence comparison in nucleotides, basic local alignment search tool (BLAST), which directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score. BLAST is an order of magnitude faster than existing sequence comparison tools of comparable sensitivity and has proved to be a favorite method for comparing nucleotide sequences (26).

 

Edward E. Farmer (US) and Clarence A. Ryan (US) found that methyl jasmonate, a common plant secondary compound, when applied to surfaces of tomato plants, induces the synthesis of defensive proteinase inhibitor proteins in the treated plants and in nearby plants as well. The presence of methyl jasmonate in the atmosphere of chambers containing plants from three species of two families, Solanaceae and Fabaceae, results in the accumulation of proteinase inhibitors in leaves of all three species demonstrating that interplant communication can occur from leaves of one species of plant to leaves of another species to activate the expression of defensive genes (493).

 

William A. Catterall (US), Ruth E. Westenbroek (US), Michael K. Ahlijanian (US), Todd Scheuer (US), William Thomsen (US), Sandra Rossie (US), Randal E. Numann (US), James W. West (US), Brian J. Murphy (US), Lori L. Isom (GB), Karen S. De Jongh (US), D. Earl Patton (US), Bernhard F. Reber (US), Janice R. Offord(US), Harry Charbonneau (US), Kenneth B. Walsh (US), Alan L. Goldin (US), Ming Li (US), Yvonne Lai (US), Joerg Striessnig (AT), Max Willow (US), Stephen M. Taylor (US), Richard H. Finnell (US), David M. Rock (US), Michael J. McLean (US), Robert L. Macdonald (US), Charles P. Taylor (US), and Stanislav Sokolov (GB) that discovered the voltage-gated sodium and calcium channel proteins, which are responsible for generation of electrical signals in the brain, heart, skeletal muscles, and other excitable cells. Their subsequent work contributed much to understanding the structure, function, regulation, and molecular pharmacology of these key cell-signaling molecules. Recent work has turned toward understanding diseases caused by impaired function and regulation of voltage-gated ion channels, including epilepsy and periodic paralysis (262-266; 815; 1018; 1234; 1410; 1578; 1579; 1784; 1785; 1795).

 

Chiu-Yin Kwan (CA), Haruo Takemura (JP), Johnny F. Obie (US), Ole Thastrup (US), and James W. Putney, Jr. (US) investigated the Ca2(+)-mobilizing actions of the muscarinic receptor agonist, methacholine (MeCh), and the microsomal Ca2+ pump inhibitor, thapsigargin, in lacrimal acinar cells. Thapsigargin was found to activate both internal Ca2+ release and Ca2+ entry from the extracellular space without increasing cellular inositol phosphates (958).

 

Petra M. Nederlof (NL), Silvia van der Flier (NL), Joop Wiegant (NL), Anton K. Raap (NL), Hans J. Tanke (NL), Johan S. Ploem (NL), and Mels van der Ploeg (NL) described a method for multiple fluorescence in situ hybridization allowing the simultaneous detection of more than three target DNA sequences with only three fluorescent dyes (FITC, TRITC, AMCA), respectively emitting in the green, red, and blue. The possibility to detect multiple targets simultaneously is important for prenatal diagnosis and the detection of numerical and/or structural chromosome aberrations in tumor diagnosis (1207).

 

John M. Wozney (US), Vicki Rosen (US), Michael H. Byrne (US), Anthony J. Celeste (US), Ioannis K. Moutsatsos (US), and Elizabeth A. Wang (US) approached the study of growth factors affecting cartilage and bone development by investigating those factors present in bone which are able to initiate new cartilage and bone formation in vivo. They identified and cloned seven novel human factors, which they named BMP-1 through BMP-7. Six of these molecules are related to each other, and are also distantly related to TGF-beta. The presence of one of these molecules, recombinant human BMP-2 (rhBMP-2) is sufficient to produce the complex developmental system of cartilage and bone formation when implanted subcutaneously in a rat assay system (1820). Note: This factor, rhBMP-2, is now in clinical trials and showing remarkable promise as an agent to promote bone growth following surgery.

 

Manfred S. Weiss (DE), Thomas Wacker (DE), Jürgen Weckesser (DE), Wolfram Welte (DE), and Georg E. Schulz (DE) reported the structure of porin from Rhodobacter capsulatus at 3-angstroms resolution (1779).

 

Beat Blum (CH), Norbert Bakalara (FR), and Larry Simpson (US) discovered what they called guide RNAs (gRNAs). These molecules serve as controls for RNA editing to determine the extent and positioning of editing (173).

 

Peter M. Flanagan (US), Raymond J. Kelleher (US), William J. Feaver (CA), Neal F. Lue (US), Janice W. LaPointe (US), and Roger David Kornberg (US) were able to fractionate a yeast nuclear extract and resolve five yeast RNA polymerase II initiation factors that they designated a, b, c, d, and e (522).

William J. Feaver (CA), Opher Gileadi (US), Yang Li (US), and Roger David Kornberg (US) identified factor d as yeast TFIID, and factor b was found to be a multisubunit protein kinase that phosphorylates the repetitive carboxyl-terminal domain in the largest subunit of RNA polymerase II (499).

Michael H. Sayre (US), Herbert Tschochner (US), and Roger David Kornberg (US) presented a fractionation scheme to isolate initiation factors a, b, and e, as well as a fifth essential factor, designated g, which co-purifies with factor b through several chromatographic steps. These factors were found to be sufficient, when combined with bacterially expressed yeast transcription factor TFIID, to enable RNA polymerase II to initiate transcription. They described factor a and discussed its possible relationship to mammalian initiation factors (1469; 1470).

N. Lynn Henry (US), Michael H. Sayre (US), and Roger David Kornberg (US) described the purification and polymerase-binding activity of factor g (741).

 

Barbara E. Bierer (US), Patricia K. Somers (US), Thomas J. Wandless (US), Steven J. Burakoff (US), and Stuart Lee Schreiber (US) appear to be the researchers who coined the term immunophilin to mean a soluble, intracellular molecule, which binds a powerful and specific immunosuppressant (147).

 

Peter Lichter (DE), Chieh-Ju Chang Tang (US), Katherine Call (US), Gary Hermanson (US), Glen A. Evans (US), David Housman (US), and David C. Ward (US) performed a high resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones (1021).

 

Nigel P. Carter (GB), Maria E. Ferguson-Smith (GB), Nabeel A. Affara (GB), Henry Briggs (GB), and Malcolm Andrew Ferguson-Smith (GB), in preliminary studies of 5 male and 6 female controls, noted that a consistent difference between the two X homologues in females was found which could not be totally explained by errors of the fitting procedure. They suggested that this difference could be due to X inactivation and that the two X homologues in females might be distinguishable (256).

 

Alexander Hoffmann (US), Masami Horikoshi (JP), C. Kathy Wang (US), Stephanie C. Schroeder (US), P. Anthony Weil (US), and Robert Gayle Roeder (US) cloned the gene encoding transcription factor IID (TFIID) (764). Note: TFIID is considered to be the most important of the transcription factors.

 

Steven M. Block (US), Lawrence S. Goldstein (US), Bruce J. Schnapp (US), Scot C. Kuo (US), Jeff Gelles (US), Eric Steuer (US), Michael P. Sheetz (US), Karel Svoboda (US), and Christoph F. Schmidt (US) measured the force generated by a single kinesin motor using the optical tweezer technique (170; 948; 949; 1531; 1631; 1632).

 

William Donald Hamilton (GB) developed mathematical models to explain the evolution of sexual reproduction, models that relied upon a genetic arms race between parasites and their hosts, and resulted in what Hamilton called “the permanent unrest of many [genes]” (690).

Hamilton’s line of thinking went back to John Burdon Sanderson Haldane (GB-IN) who, in 1949, wrote of genetic variation as a way of dealing with parasitic pressure. Others who continued this line included Suresh Jayakar (IN), 1970s, and Robert McCredie May (AU-GB) who demonstrated that there might be no equilibrium between parasite and host, only eternal chaotic motion (829; 1108; 1109).

 

Thomas J. Jentsch (DE), Klaus Steinmeyer (DE), and Gisela Schwarz (DE) discovered the first voltage-gated chlorine channel in cell membranes. It was found in the ray Torpedo (838).

 

Susanna Cotecchia (IT-CH), Sabrina T. Exum (US), Marc G. Caron (US), and Robert Joseph Lefkowitz (US) were the first to report the results of mutations in G-protein-coupled receptors, which make them constitutively active, specifically a mutagenized third cytoplasmic loop of the alpha_1B-adrenergic receptor (346).

Philippe Samama (US), Susanna Cotecchia (IT-CH), Tommaso Costa (IT), and Robert Joseph Lefkowitz (US) produced a mutation-induced activated state of the beta 2-adrenergic receptor. In this article they concluded that the ternary model needed to be extended to include an explicit isomerization of the receptor (R) to an active state (R*) (1450). Note: A number of pathological conditions are now known to be the result of such constitutively active mutant G-protein-coupled receptors.

Andre de Léan (CA), Jeffrey M. Stadel (US), and Robert Joseph Lefkowitz (US) proposed the ternary model, which postulates that receptor activation requires the agonist-promoted formation of an active, ternary complex consisting of agonist, receptor, and G protein (393).

 

Michael J. Klemsz (US), Scott R. McKercher (US), Antonio Celada (US), Charles Van Beveren (US), and Richard A. Maki (US) isolated a cDNA clone, PU.1, that codes for a new tissue-specific DNA binding protein. The PU.1 protein was shown to be a transcriptional activator that is expressed in macrophages and B cells. The amino acid sequence in the binding domain of PU.1 has considerable identity with proteins belonging to the ets oncogene family (913).

 

Peter E. Thorsness (US) and Thomas D. Fox (US) detected the movement of DNA between mitochondria and the nucleus in yeast (1669).

 

Pierre A. Coulombe (US), Yiu-Mo Chan (US), Kathryn M. Albers (US), Elaine V. Fuchs (US), Robert Vassar (US), Linda Degenstein (US), M. Elizabeth Hutton (US), Anthony G. Letai (US), Adelaide A. Hebert (US), and Amy S. Paller (US) demonstrated that as basal epidermal cells differentiate they reduce K5 and K14 keratin production and step-up K1 and K10 keratin production. In fully differentiated squamous cells these keratins constitute approximately 85% of total cellular protein. They isolated and characterized human K5 and K14 genes, went on to modify their DNA, used it to transfect culture cells, and produce transgenic mice. The results indicate that mutated keratin genes can induce tissue conditions very similar to diseases such as epidermolysis bullosa simplex (EBS) and therefore, may serve as good animal models to study human skin disease (347; 348; 555; 1736).

 

Jon A. Wolff (US), Robert W. Malone (US), Phillip Williams (US), Wong Chong (US), Gyula Acsadi (US), Agnes Juni (US), and Philip L. Felgner (US) injected RNA and DNA expression vectors containing genes for chloramphenicol acetyltransferase, luciferase, and β-galactosidase into mouse skeletal muscle in vivo. Protein expression was readily detected in all cases (1812). Note: This strongly suggested that vaccines consisting of nucleic acids alone, yet carried within a fatty particle, could initiate an immune response that builds the body’s ability to fend off actual virus particles.

 

Toshiki Tsurimoto (JP), Thomas Melendy (US), and Bruce Stillman (US) prepared the first completely defined eukaryotic cell-free system for replicating DNA (1699).

 

Donald Nuss (US) and Yigal Keltin (US) showed that infection of different host fungi by different mycoviruses might result in different effects on the host fungi (beneficial, neutral, and harmful) (1235).

 

Jacek Bielecki (US), Philip Youngman (US), Patricia Connelly (US), and Daniel A. Portnoy (US) cloned the structural gene for the Listeria monocytogenes hemolysin, hlyA, into an asporogenic mutant of Bacillus subtilis under the control of an IPTG-inducible promoter. After being internalized by the macrophage-like cell line J774, hemolytic B. subtilis disrupted the phagosomal membrane and grew rapidly within the macrophage cytoplasm. These results show that a single gene product is sufficient to convert a common soil bacterium into a parasite that can grow in the cytoplasm of a mammalian cell (146).

 

Peter C. Sijmons (NL), Ben M.M. Dekker (NL), Barbara Schrammeijer (NL), Theo C. Verwoerd (NL), Peter J.M. van den Elzen (NL), and André Hoekma (NL) succeeded in creating transgenic potato plants which could produce human serum albumin useful as a blood extender (1550).

 

Andrew H. Paterson (US), Joseph W. DeVerna (US), Brenda Lanini (US), and Steven D. Tanksley (US) devised the technique of quantitative trait loci mapping (QTL) using the tomato as their test organism (1306). Note: QTL is a type of linkage analysis involving a determination of the probability that specific DNA marker loci are situated near genes that control expression of the phenotype in question.

 

Marc Hubert Victor Van Regenmortel (BE-FR) is convenced that the species concept is applicable in virology because viruses have genomes, replicate, evolve, and occupy particular ecological niches. He notes the following definition of virus species was accepted in 1991 by the International Committee on Taxonomy of Viruses: ‘A virus species is a polythetic class of viruses that constitutes a replicating lineage and occupies a particular ecological niche’ (1723).

 

Bruce A. Sullenger (US), Humilidad F. Gallardo (US), Grace E. Ungers (US), and Eli Gilboa (US) isolated a gene from the HIV virus called tar that binds and blocks a protein the virus needs in order to replicate (1623).

 

David A. Relman (US), Jeffrey S. Loutit (US), Thomas M. Schmidt (US), Stanley Falkow (US), and Lucy S. Tompkins (US) used 16S rRNA analysis and polymerase chain reaction (PCR) to identify pathogens, which had resisted culturing. They identified the causative agents of bacillary angiomatosis and cat-scratch disease as Bartonella henselae and Bartonella quintana respectively (1379).

 

Haroun N. Shah (GB) and Matthew D. Collins (GB) created Prevotella; a new genus of bacteria to include Bacteroides melaninogenicus and related species formerly classified in the genus Bacteroides. The genus name comes from Andre R. Prévot (FR), a pioneer in anaerobic microbiology (1523).

Sydney M. Finegold (US) states that Prevotella strains are gram-negative, non-motile, singular cells that thrive in anaerobic growth conditions. They are generally host associated and most species exist as obligate anaerobes (516).

Gorazd Avguštin (SI), Andreja Ramšak (SI), and Matjaz Peterka (SI) reported that species of Prevotella were present in humans, often existing in the oral cavity, gastrointestinal tract, and vagina (60). In humans, they can act as an opportunistic pathogen, causing periodontal and tooth problems such as gingivitis and periodontitis (516).

 

Erhard Kranz (DE), Brigitte Krautwig (DE), Jaqueline Bautor (DE), and Horst Lörz (DE) accomplished in vitro fertilization with isolated single gametes resulting in zygotic embryogenesis and recovery of fertile maize plants (930-932).

 

Jean-Yves Exposito (FR) and Robert Garrone (FR) determined that sponges have collagen genes that are homologous to those of echinoderms and vertebrates. Since collagen is confined to animals this suggests that all metazoans belong to the same monophyletic clade (487).

 

Edward Osborne Wilson (US) and Berthold Karl Holldobler (US) authored The Ants, possibly the most authoritative book to date on this important group of insects (1798).

 

Theodore G. Andreadis (US) and Ronald M. Weseloh (US) discovered a biological control of the gypsy moth, Lymantria dispar (37).

 

Shawn J. Green (US), Sylvie Mellouk (US), Stephen L. Hoffman (US), Monte S. Meltzer (US), Carol A. Nacy (US), and John B. Hibbs, Jr. (US) determined that nitric oxide (NO) produced by cytokine-treated macrophages and hepatocytes plays a vital role in protective host responses to infectious pathogens (640; 641).

Dennis J. Stuehr (US), Hearn J. Cho (US), Nyoun Soo Kwon (US), Mary F. Weise (US), and Carl F. Nathan (US) purified soluble nitric oxide synthase from a mouse macrophage cell line activated with interferon gamma and bacterial lipopolysaccharide (1616).

 

Graham Le Gros (US), Shlomo Z. Ben-Sasson (IL), Robert Seder (US), Fred D. Finkelman (US), and William E. Paul (US) found that injection of anti-IgD into mice, a stimulus that leads to striking increases in serum levels of IgG1 and IgE, causes a striking increase in the IL-4 producing capacity of T cells. This increase is first observed 4 d after injection of anti-IgD. IL-4 production by T cells from anti-IgD-injected donors is mainly found among large- and intermediate-sized T cells. The capacity of T cells from anti-IgD-injected donors to produce IL-4 is enhanced by addition of IL-2 (978).

 

Marjorie A. Oettinger (US), David G. Schatz (US), Carolyn Gorka (US), and David Baltimore (US) found that recombination activating gene 1 (RAG-1), which is exclusively expressed in maturing lymphocytes, inefficiently induces V(D)J recombinase activity when transfected into fibroblasts. Co-transfection with an adjacent gene, RAG-2 results in at least a 1000-fold increase in the frequency of recombination (1243).

 

Haruhiko Koseki (JP), Kenji Imai (JP), Fumiaki Nakayama (JP), Toshihiko Sado (JP), Kazuro Moriwaki (JP), and Masaru Taniguchi (JP) experiments suggested that there are some selection mechanisms for V14J281-positive T cells in a C57BL/6 environment other than those for conventional alpha beta T cells and also that the homogenous VJ junction of the V14J281 alpha chain plays a pivotal role in the selection of the T cell and its ligand reactivity (926).

Steven Porcelli (US), Courtland E. Yockey (US), Michael B. Brenner (US), and Steven P. Balk (US) analyzed T cell antigen receptor (TCR) expression by human peripheral blood CD4−8− α/β T cells and found it demonstrates preferential use of several Vβ genes and an invariant TCR α chain (1348).

 

Peter S. Linsley (US), Edward A. Clark (US), and Jeffrey A. Ledbetter (US) discovered that T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1 (1028).

 

Maarten Zijlstra (US), Mark Bix (US), Neil E. Simister (US), Janet M. Loring (US), David H. Raulet (US), and Rudolf Jaenisch (US) produced results strongly supporting earlier evidence that MHC class I molecules are crucial for positive selection of T cell antigen receptor alpha beta+ CD4-8+ T cells in the thymus and call into question the non-immune functions that have been ascribed to MHC class I molecules (1863).

 

John J. Monaco (US), Sungae Cho (US), and Michelle Attaya (US) cloned the HAM1 and HAM2, which have sequence similarities to a superfamily of genes involved in the ATP-dependent transport of a variety of substrates across cell membranes. These MHC-linked transport protein genes may be involved in transporting antigen, or peptide fragments thereof, from the cytoplasm into a membrane-bounded compartment containing newly synthesized MHC molecules (1161).

Edward V. Deverson (GB), Irene R. Gow (GB), W. John Coadwell (GB), John J. Monaco (US), Geoffrey W. Butcher (GB), and Jonathan C. Howard (GB) found that the rat cim gene, maps to a highly polymorphic part of the MHC class II region encoding two novel members of the family of transmembrane transporters related to multidrug resistance. Other members of this family of transporter proteins are known to be capable of transporting proteins and peptides across membranes independently of the classical secretory pathway. Such molecules are credible candidates for peptide pumps that move fragments of antigenic proteins from the cytosol into the endoplasmic reticulum (411).

John Trowsdale (GB), Isabel Hanson (GB), Ian Mockridge (GB), Stephan Beck (GB), Alain Townsend (GB), and Adrian Kelly (GB) report the finding of a new gene in the MHC that might have a role in antigen presentation and which is related to the ABC (ATP-binding cassette) superfamily of transporters. This superfamily includes the human multidrug-resistance protein, and a series of transporters from bacteria and eukaryotic cells capable of transporting a range of substrates, including peptides (1694).

Thomas Spies (US), Maureen Bresnahan (US), Seiamak Bahram (US), Daniele Arnold (US), George Blanck (US), Elizabeth Mellins (US), Donald Pious (US), and Robert DeMars (US) identified peptide supply factor gene (PSF) in the MHC class II region. PSF is homologous to mammalian and bacterial ATP-dependent transport proteins, suggesting that it operates in the intracellular transport of peptides (1593).

 

Joachim Hombach (DE), Takeshi Tsubata (DE), Lise Leclercq (DE), Heike Stappert (DE), and Michael Reth (DE) showed that the IgM molecule is non-covalently associated in the membrane of B cells with two proteins of relative molecular mass 34,000 (Mr 34 K; IgM-alpha) and 39 K (Ig-beta) which form a disulphide-linked heterodimer. Surface expression of IgM seems to require the formation of an appropriate complex between IgM and the heterodimer. A transfection experiment indicates that IgM-alpha is the product of mb-1, a B-cell specific gene encoding a transmembrane protein with sequence homology to proteins of the T-cell antigen receptor-CD3 complex (772).

 

Beverly H. Koller (US), Philippa Marrack (US), John W. Kappler (US), and Oliver Smithies (US) produced mouse chimeras derived from embryonic stem cells with a disrupted beta 2M gene transmitted the inactivated gene to their progeny. Animals homozygous for the mutated beta 2M gene were obtained at expected frequencies after further breeding. The homozygotes appeared normal, although no class I antigens could be detected on their cells and the animals are grossly deficient in CD4- CD8+ T cells, which normally mediate cytotoxic T cell function (920). Note: Major histocompatibility class I proteins display viral and self antigens to potentially responsive cells and are important for the maturation of T cells; beta 2-microglobulin (beta 2M) is required for their normal expression.

 

Kevin W. Moore (US), Paulo Vieira (US), David F. Fiorentino (US), Mary L. Trounstine (US), Tariq A. Khan (US), and Timothy R. Mosmann (ZA-CA-US) isolated and expressed complementary DNA clones encoding mouse cytokine synthesis inhibitory factor (CSIF; interleukin-10), which inhibits cytokine synthesis by TH1 helper T cells. The predicted protein sequence shows extensive homology with an uncharacterized open reading frame, BCRFI, in the Epstein-Barr virus genome, suggesting the possibility that this herpes virus exploits the biological activity of a captured cytokine gene to enhance its survival in the host (1166).

 

The Recombinant Advisory Committee of the National Institutes of Health (U.S.A.) approved the first clinical trials of gene therapy. The proposed work would insert a normal gene for adenosine deaminase (ADA) into infants with severe combined immune deficiency (SCID) (32; 586). See Kenneth W. Culver, 1991.

 

Qianjin Hu (US), Nicholas Dyson (US), and Edward Everett Harlow, Jr. (US) showed that the adenovirus E1A protein binds to the Rb protein. Sense Rb protein is the product of the anti-oncogene Rb. This suggested that dominant-acting oncogenes might bring about malignancy by interfering with anti-oncogene proteins required to suppress cell proliferation (787).

 

Fumi-ichiro Yamamoto (US), Henrik Clausen (US), Thayer White (US), John Marken (US), and Sen-itiroh Hakomori (US) cloned and sequenced the gene controlling the ABO blood antigens. They found that the A and B genes differ in a few single-base substitutions, changing four amino-acid residues that may cause differences in A and B transferase specificity. A critical single-base deletion in the O gene resulted in the production of a faulty glycosyl transferase incapable of transferring a sugar unit to the correct site (1831).

 

Henry Harris (AU-GB) discovered tumor-suppressor genes whose job was to detect excessive growth and shut it down (710).

 

Eric R. Fearon (US) and Bert Vogelstein (US) amalgamated the findings that oncogenes and tumor-suppressor genes are altered in human cancer together with the idea of clonal evolution to produce a coherent molecular model of multistep tumorigenesis (498).

 

Baya Cherif-Zahar (FR), Christian Bloy (FR), Caroline Le Van Kim (FR), Dominique Blanchard (FR), Pascal Bailly (FR), Patricia Hermand (FR), Charles Salmon (FR), Jean-Pierre Cartron (FR), and Yves Colin (FR) isolated cDNA clones encoding a human blood group Rh polypeptide from a human bone marrow cDNA library by using a polymerase chain reaction-amplified DNA fragment encoding the known common N-terminal region of the Rh proteins. The entire primary structure of the Rh polypeptide has been deduced from the nucleotide sequence of a 1384-base-pair-long cDNA clone (285).

 

Andrew H. Sinclair (GB), Philippe Berta (FR), Mark S. Palmer (GB), J. Ross Hawkins (GB), Beatrice L. Griffiths (GB), Matthijs J. Smith (GB), Jamie W. Foster (GB-AU), Anna-Maria Frischauf (GB), Robin H. Lovell-Badge (GB), and Peter N. Goodfellow (GB) searched for a 35-kilobase region of the human Y chromosome necessary for male sex determination and in the process identified a new gene. This gene is conserved and Y-specific among a wide range of mammals, and encodes a testis-specific transcript. The gene has been termed SRY (for sex-determining region Y) and proposed to be a candidate for the elusive testis-determining gene, TDF (1554).

 

Eric R. Fearon (US), Kathleen R. Cho (US), Janice M. Nigro (US), Scott E. Kern (US), Jonathan W. Simons (US), J. Michael Ruppert (US), Stanley R. Hamilton (US), Antonette C. Preisinger (US), Giles Thomas (US), Kenneth W. Kinzler (US) and Bert Vogelstein (US) found that the Deleted in Colorectal Cancer (DCC) gene, located on chromosome 18, may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth (497).

 

Craig A. Smith (US), Terri Davis (US), Dirk Anderson (US), Lisabeth Solam (US), M. Patricia Beckmann (US), Rita Jerzy (US), Steven K. Dower (US), David Cosman (US), and Raymond G. Goodwin (US) found that a receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins (1563).

Anthony F. Suffredini (US), Debra G. Reda (US), Steven M. Banks (US), Margaret M. Tropea (US), Jan M. Agosti (US), and Renee Miller (US) led the way to discovering that tumor necrosis factor receptor is useful as a drug in the treatment of rheumatoid arthritis (1620). Enbrel is the trade name for the drug.

Walter Charles Cornelius Fiers (BE), Rudi Beyaert (BE), Elke Boone (BE), Wim Declercq (BE), Els Decoster (BE), Dirk Devalck (BE), Vera Goossens (BE), Johan Grooten (BE), Guy Haegemann (BE), Karen Heyninck (BE), Louis C. Penning (BE), Stéphane Plaisance (BE), Mark Van de Craen (BE), Peter Vandenabeele (BE), Eva A. van den Berg (BE), André Van de Voorde (BE), and Dominique Vercammen (BE) described the intracellular mechanism of action of tumor necrosis factor (515).

 

Thaddeus P. Dryja (US), Terri L. McGee (US), Elias Reichel (US), Lauri B. Hahn (US), Glenn S. Cowley (US), David W. Yandell (US), Michael A. Sandberg(US), and Eliot L. Berson (US) examined the gene coding for rhodopsin in patients with autosomal dominant retinitis pigmentosa. They found a C----A transversion in codon 23 (corresponding to a proline----histidine substitution) in 17 of 148 unrelated patients and not in any of 102 unaffected individuals. This mutation could be the cause of one form of autosomal dominant retinitis pigmentosa (442).

 

Antonio Rafael Cabral (MX), Javier Cabiedes (MX), and Donato Alarcón-Segovia (MX) reported a patient with hemolytic anemia who was producing antiphosphatidylcholine antibodies (244).

 

Isabel Zuazu-Jausoro (ES), Arturo Oliver (ES), Montserrat Borrell (ES), Mercé Gari (ES), Isabel Pich (ES), Enric Grau (ES), and Jordi Fontcuberta (ES) reported on 30 cases of patients with lupus anticoagulant who possessed specific antibodies to phosphatidylserine (1866).

 

Sheng-Min Chen (US), J. Stephen Dumler (US), Johan S. Bakken (US), and David H. Walker (US), in 1990, determined that human granulocytic anaplasmosis (HGA), previously known as human granulocytic ehrlichiosis (HGE) is caused by Anaplasma phagocytophilum. This pathogen, which attacks granulocytes, was known to cause veterinary disease since 1932. Anaplasma phagocytophilum is a small, obligate, intracellular bacterium with a gram-negative cell wall. It is 0.2–1.0 μm and lacks a lipopolysaccharide biosynthetic machinery (281).

 

Peter J. Fleming (GB), Ruth E. Gilbert (GB), Yehu Azaz (GB), P. Jeremy Berry (GB), Peter T. Rudd (GB), Alison Stewart (GB), and Elizabeth Hall (GB) showed in a study of sudden death in infants (sudden infant death syndrome or SIDS) that it occurred more commonly among infants who slept prone as opposed to sleeping on their side or supine. A significant increase in SIDS risk was seen among infants who were wrapped in more blankets, wore heavier clothing to bed, or were in a home that was heated overnight when compared to control infants (524).

 

Eberhard Deltz (DE), Wolfgang Mengel (DE), and Horst Hamelmann (DE) reported one of the first cases of small bowel transplantation in humans (401).

 

David R. Grant (CA), William J. Wall (CA), Richard Mimeault (CA), Robert A. Zhong (CA), Cameron N. Ghent (CA), Bertha M. Garcia (CA), Calvin R. Stiller (CA), and John H. Duff (CA) reported a successful small-bowel/liver transplantation (631).

 

Andreas G. Tzakis (US), Camillo Ricordi (US), Rodolfo Alejandro (US), Yijun Zeng (US), John J. Fung (US), Satoru Todo (US), Anthony J. Demetris (US), Daniel H. Mintz (US), and Thomas Earl Starzl (US) performed the first unequivocal example of successful clinical islet cell transplantation (1704).

 

Gary Onik (US), Barbara Porterfield (US), Boris Rubinsky (US), and Jeffrey Cohen (US) successfully performed percutaneous transperineal prostate cryosurgery using transrectal ultrasound guidance in a dog (1259).

 

Henry Brem (US) surgically implanted a quarter-size biodegradable polymer containing a chemotherapeutic drug directly into the site of a patient's brain tumor (196). Note: He first did this in 1987.

Henry Brem (US), M. Stephen Mahaley, Jr. (US), Nicholas A. Vick (US), Keith L. Black (US), Stanley C. Schold, Jr. (US), Peter C. Burger (US), Allan H. Friedman (US), Ivan S. Ciric (US), Theodore W. Eller (US), Jeffrey W. Cozzens (US), and James N. Kenealy (US) directed a Phase I-II study trial in which 21 patients with recurrent malignant glioma were treated with BCNU (carmustine) released interstitially by means of a polyanhydride biodegradable polymer implant. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure (197). Note: This is referred to as a polymer wafer implant.

 

Robert G.C. Teepe (NL), Robert W. Kreis (NL), Eline J. Koebrugge (NL), Johanna A. Kempenaar (NL), Adrianus F.P.M. Vloemans (NL), Rudy P. Hermans (NL), Han Boxma (NL), Jan Dokter (NL), Jo Hermans (NL), Maja Ponec (NL), and Bert J. Vermeer (NL) grafted seventeen patients with deep second- and third-degree burn wounds with cultured autologous epidermis. These epidermal cell sheets were cultivated according to the feeder layer technique as described by James G. Rheinwald (US) and Howard Green (US). Wound infection was the main cause of graft failure. Up to 4 years after grafting, the grafted areas showed continued stability and the regenerated skin became supple, smooth, and pliable (1385; 1653).

 

Barbara P. Lukert (US) and Lawrence G. Raisz (US) found that osteoporosis is common in patients requiring long-term treatment with glucocorticoids. Careful attention to preventive management may minimize the severity of this serious complication. Reasonable recommendations include the use of a glucocorticoid with a short half-life in the lowest dose possible, maintenance of physical activity, adequate calcium and vitamin D intake, sodium restriction and use of thiazide diuretics, and gonadal hormone replacement. In refractory cases, the use of calcitonin, bisphosphonates, sodium fluoride, or anabolic steroids should be considered (1052).

 

Scott D. Boden (US), David O. Davis (US), and Thomas S. Dina (US) performed magnetic resonance imaging on sixty-seven individuals who had never had low-back pain, sciatica, or neurogenic claudication. In view of the findings in asymptomatic subjects, they concluded that abnormalities on magnetic resonance images must be strictly correlated with age and any clinical signs and symptoms before operative treatment is contemplated (175).

 

Olaf B. Paulson (DK), Svend Strandgaard (DK), and Lars Edvinsson (DK) reported that autoregulation of cerebral blood flow (CBF) is most likely accomplished by autoregulatory vessel caliber changes mediated by an interplay between myogenic and metabolic mechanisms. Perivascular nerves and the vascular endothelium are also suspected of playing a role in the control (1313).

 

Jeff M. Hall (US), Ming K. Lee (US), Beth Newman (US), Jan E. Morrow (US), Lee A. Anderson (US), Bing Huey (US), and Mary-Claire King (US) found that chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease. The identification of gene variants associated with a family history of breast cancer allowed screening of high-risk women and the choice for those with known increased risk to take preventive measures such as tamoxifen therapy or mastectomy (688).

 

Philip B. Clement (S) and Robert E. Scully (US) described the Müllerian adenosarcoma of the uterus (310).

 

Margaret R. Wallace (US), Douglas A. Marchuk (US), Lone B. Andersen (US), Roxanne Letcher (US), Hana M. Odeh (US), Ann M. Saulino (US), Jane W. Fountain (US), Anne Brereton (US), Jane Nicholson (US), Anna L. Mitchell (US), Bernard H. Brownstein (US), and Francis S. Collins (US) described a patient with Von Recklinghausen neurofibromatosis (NF1) which they identified with a de novo 0.5-kilobase insertion in the NF1LT gene. These observations, together with the high spontaneous mutation rate of NF1 (which is consistent with a large locus), suggest that NF1LT represents the elusive NF1 gene (1756). Note: Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder characterized by abnormalities in multiple tissues derived from the neural crest.

 

Juan Carlos Parodi (AR), Julio C. Palmaz (AR), and Hector D. Barone (AR) introduced the minimally invasive endovascular aneurysm repair (EVAR) to the world and performed the first successful endovascular repair of an abdominal aortic aneurysm in 1990 (1297).

Roger M. Greenhalgh (GB), Louise C. Brown (GB), Grace P.S. Kwong (GB), Janet T. Powell (GB), Simon G. Thompson (GB), David Epstein (GB), Mark J. Sculpher (GB), Evar Trial Participants, and United Kingdom, Evar Trial Investigators determined that endovascular aneurysm repair (EVAR) in the first trial had one-third of the operative mortality of open abdominal aortic aneurysm (AAA) repair. With increasing follow-up EVAR offers no significant advantage with respect to all-cause mortality or aneurysm-related mortality when compared with open repair. Long-term follow-up and surveillance of EVAR patients is essential because of more complications and a greater need for re-intervention (645; 1300; 1710).

The United Kingdom EVAR Trial Investigators, and The EVAR Trial Participants (Roger M. Greenhalgh (GB), Louise C. Brown (GB), Janet T. Powell (GB), Simon G. Thompson (GB), David Epstein )—in the EVAR 2 trial— used randomized controlled trial (RCT) to compare (EVAR) with best medical therapy for patients unfit for open repair. They demonstrated that EVAR is associated with a significantly lower rate of aneurysm-related mortality compared with best medical therapy. There was no difference in all-cause mortality, and EVAR was associated with increased complications and re-interventions at a higher cost (1299; 1709).

 

Malcolm R. Walter (US), Du Rulin (US), and Robert Joseph Horodyski (US) discovered the oldest known multicellular fossils. They were removed from 1400Ma Old Greyson Shale, Lower Belt Supergroup, in Montana, US, and from the similarly aged Gaoyuzhuang Formation, Upper Changcheng Group, in the Jixian Section, Northern China. The organism was identified as Grypania spiralis, a coiled ribbon-like creature. It was judged to most likely have been a multicellular eukaryotic alga (1758). Note: Shale is rock formed by condensation of layers of clay or mud sediment, along with phytoplankton and other debris, at the bottoms of lakes or ocean basins.

 

Edward M. Golenberg (US), David E. Giannasi (US), Michael Tran Clegg (US), Charles J. Smiley (US), Mary Durbin (US), David Henderson (US), and Gerard Zurawski (US) isolated DNA from a 17 to 20 Ma (Miocene) Magnolia leaf; indicative of the resistance of DNA to degradation (606).

 

Jennifer A. Clack (GB) and Michael I. Coates (GB) reported on fossil specimens of the Devonian fish-like Acanthostega gunneri they collected during 1987 in Greenland. Their work strongly suggested that legs appeared in tetrapods well before they abandoned water and not vice-versa as had been suggested by the popular dry pond theory first articulated by Alfred Sherwood Romer (US) (301; 316-318).

 

1991

“The distinctive features of microbes are that they can make use of unusual and ingenious methods of obtaining energy in order to drive a fairly conventional metabolism, and that they can adjust themselves to run such a metabolism in circumstances that would be lethal to higher organisms. They can be found all over the planet, can grow and perform chemical transformations in what seem, from an anthropomorphic point of view, the most unlikely places. For this reason they have a profound, and often unrealized, effect, not only on the balance of nature but on the existence of mankind and on our economy.” John R. Postgate (1352).

 

Richard R. Ernst (CH) was awarded the Nobel Prize in Chemistry for his contributions to the development of the methodology of high-resolution nuclear magnetic resonance (NMR) spectroscopy.

 

Erwin Neher (DE) and Bert Sakmann (DE) were awarded the Nobel Prize in Physiology or Medicine for their work on electrical signals in single ion channels in membranes and development of the patch–clamp method to isolate small sections of membrane.

 

John W. Belliveau (US), David N. Kennedy, Jr. (US), Robert C. McKinstry (US), Bradley R. Buchbinder (US), Robert M. Weisskoff (US), Mark S. Cohen (US), James M. Vevea (US), Thomas J. Brady (US), and Bruce R. Rosen (US), using dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) with a gadolinium-based Gd-DPTA contrast agent, mapped the changes in cerebral blood volume (CBV) following neural activation in a subject responding to a simple visual stimulus. Their results represented the first unambiguous images of human brain activity changes observed with magnetic resonance, i.e., functional magnetic resonance imaging (fMRI) (109).

Kenneth K. Kwong (US), John William Belliveau (US), David A. Chesler (US), Inna E. Goldberg (US), Robert M. Weisskoff (US), Brigitte P. Poncelet (US), David N. Kennedy (US), Bernice E. Hoppel (US), Mark S. Cohen (US), and Robert Turner (US) demonstrated magnetic resonance imaging (MRI) detection of brain activation based on changes in deoxyhemoglobin concentration, and thus anticipated the importance of blood oxygen level-dependent (BOLD) contrast for functional imaging (960).

 

Stephen P. Fodor (US), J. Leighton Read (US), Michael C. Pirrung (US), Lubert Stryer (US), Amy Tsai Lu (US), and Dennis Solas (US) provided a method to measure the expression level of every gene in the genome all at once. They showed that DNA could be made into microarrays, a diverse set of oligonucleotides could be chemically synthesized on a glass slide through photolithography, a process using precisely aimed beams of light to direct chemical reactions to specific spots (526).

Mark Schena (US), Dari Shalon (US), Ronald W. Davis (US), and Patrick O. Brown (US) used a microarray of 45 Arabidopsis complementary DNAs to which they hybridized fluorescently labeled total cellular messenger RNA (mRNA). The intensity of fluorescence at a spot reflected the amount of mRNA hybridized, which in turn reflected the level of that particular mRNA in the initial sample. This paper showed for the first time that the expression of many genes in a small sample could be quantitatively monitored in parallel (1479). This technique has now become very important in many areas of genomic research.

 

Gregory R. Reyes (US) and Jungsuh P. Kim (US) devised the Sequence-Independent, Single-Primer Amplification (SISPA) methodology that is especially useful when the nucleotide sequence of the desired molecule is both unknown and present in limited amounts making its recovery by standard cloning procedures technically difficult. These conditions are present in the initial isolation and cloning of previously uncharacterized viral genomes. The application and quantitation of SISPA is described, together with its utility in the cloning and recovery of low abundance genetic sequences, as illustrated here with the hepatitis C virus (1382).

 

Hitoshi Matsushime (JP), Martine F. Roussel (US), Richard A. Ashmun (US), Charles J. Sherr (US), Yue Xiong (US), Tim Connolly (US), Bruce Futcher (US), David Beach (US), Daniel Julio Lew (US), Vjekoslav Dulic (FR), Steven I. Reed (US), Andrew Koff (US), Fred Cross (US), Alfred Fisher (US), Jill Schumacher (US), Katherine LeGuellec (US), Michel Philippe (US), James M. Roberts (US), Toru Motokura (JP), Theodora Bloom (US), Hyung Goo Kim (KR), Harald Jüppner (US), Joan V. Ruderman (US), Henry M. Kronenberg (US), and Andrew Arnold (US) identified, using a variety of techniques, a new class of cyclins—which consists of cyclins C, D and E—in mammals (917; 1012; 1102; 1175; 1825).

 

Domenico Maglione (IT), Valente Guerriero (IT), Giuseppe Viglietto (IT), Pasquale Delli-Bovi (IT), and Maria Graziella Persico (IT) cloned, purified, and determined the structure, by crystallography resolution, of the placental growth factor (PlGF). It is an angiogenic protein belonging to the vascular endothelial growth factor (VEGF) family (1070). Note: The VEGF family are signal proteins, produced by many cells, that stimulate the formation of blood vessels. VEGF-A was the first to be discovered.

 

Elaine O. Davis (GB), Steven G. Sedgwick (GB), M. Joseph Colston (GB), Peter J. Jenner (GB), and Patricia C. Brooks (GB) described a novel mechanism of protein biosynthesis in mycobacteria (382; 383).

 

Birgitta Agerberth (SE), Jong-Youn Lee (SE), Thomas Bergman (SE), Mats Carlquist (SE), Hans G. Boman (SE), Viktor Mutt (SE), and Hans Jörnvall (SE) isolated from the pig intesine a new member of the family of proline-arginine-rich antibacterial peptides. The peptide was named PR‐39 (proline‐arginine‐rich with a size of 39 residues). The lethal concentration of the peptide was determined against six Gram‐negative and four Gram‐positive strains of bacteria (12). Note: The abundance, activity, and evolutionary history of several epithelial peptides suggest that antimicrobial peptides play a key role in host defence at mucosal surfaces.

 

Michael Meisterernst (DE), Ananda L. Roy (US), Hsiao Mei Lieu (US), and Robert Gayle Roeder (US) discovered coactivators, large protein complexes that provide a bridge between the activators and repressors and the RNA polymerases and other components of the general transcription machinery (1135).

 

Sanford M. Simon (US) and Günter Klaus-Joachim Blobel (DE-US) presented direct evidence for the existence of protein-conducting channels in the endoplasmic reticulum (1552; 1553).

 

Hali A. Hartmann (US), Glenn E. Kirsch (US), John A. Drewe (US), Maurizio Taglialatela (IT), Rolf H. Joho (US), and Arthur M. Brown (US) performed experiments which gave one of the first clues about the location of the channel pore in a potassium channel (716).

 

Masatoshi Takeichi (JP) named calcium-dependent cell adhesion molecules (CAMS) cadherins (1643).

 

James B. Bliska (US), Kun-Liang Guan (CN-US), Jack E. Dixon (US), and Stanley Falkow (US) discovered that YopH is a type of enzyme, which causes the removal of a phosphate group (phosphatase). (167). Note: YopH, produced by cells of Yersinia pestis, inhibits their being phagocytized by macrophages.

 

Catharinus Terpstra (NL), Gert Wensvoort (NL), and Maria Anthonis Joannes Pol (NL) experimentaly reproduced porcine epidemic abortion and respiratory syndrome (mystery swine disease) by infection with Lelystad virus - Koch's postulates fulfilled (1661).

 

William J. Rodriguez (US), Linda S. Wyatt (US), Narayanaswamy Balachandran (US), and Niza Frenkel (US) reported that human herpesvirus-7 (HHV-7) is a ubiquitous virus which is immunologically distinct from the highly prevalent T-lymphotropic human herpesvirus-6 (HHV-6). On the basis of the analyses of sera from children and adults it was concluded that HHV-7 is a prevalent human herpesvirus which, like other human herpesviruses, infects during childhood (1412).

 

Kun-Liang Guan (CN-US) and Jack E. Dixon (US) used purified recombinant protein-tyrosine phosphatase to explore the catalytic mechanism employed by the enzyme. They found that Cys215 was essential for enzyme activity finding that the cysteine residue forms a covalent thiol phosphate bond (663). Note: It was later shown that the entire family of phosphatases uses this same catalytic mechanism.

 

Bernadette Connolly (GB), Hazel J. Dunderdale (GB), Fiona E. Benson (GB), Carol A. Parsons (GB), Gary J. Sharples (GB), Robert G. Lloyd (GB), and Stephen C. West (GB) identified the RuvC gene of Escherichia coli which codes for a nuclease capable of resolving Holliday intermediates (334; 452). Note: The Holliday junction, a key intermediate in both homologous and site-specific recombination, is generated by the reciprocal exchange of single strands between two DNA duplexes.

 

Norman Henry Giles, Jr. (US), Robert F. Geever (US), David K. Asch (US), Javier Avalos (ES), and Mary E. Case (US) expressed the results of a decades-long study of gene organization and regulation in the quinic acid gene cluster of Neurospora crassa (and other fungi), showing that the quinic acid cluster represents a group of adjacent coding sequences whose expression is regulated at the level of transcription and is under the combined control of quinic acid and the qa-1 protein. This group found that a single enzyme, a product of one gene, catalysed two distinct reactions in the same pathway (592).

 

Gary G. Shutler (CA-US), Alex E. MacKenzie (CA), Han G. Brunner (NL), Berend Wieringa (NL), Pieter J. de Jong (US), Frans P. Lohman (NL), Suzanne Leblond (CA), Jane Bailly (CA), and Robert G. Korneluk (CA) mapped the myotonic dystrophy gene locus to the region of 19q13.2-13.3 lying distal to the gene for creatine kinase subunit M (CKM) (1543).

Charalampos Aslanidis (US), Gert Jansen (NL), Chris T. Amemiya (US), Gary G. Shutler (CA-US), Mani S. Mahadevan (CA), Catherine Tsilfidis (CA), Chira Chen (US), Jennifer Alleman (US), Nicole G.M. Wormskamp (NL), Marc Vooijs (US), Jessica Buxton (GB), Keith Johnson (GB), Hubertus J.M. Smeets (NL), Gregory G. Lennon (US), Anthony V. Carrano (US), Robert G. Korneluk (CA), Bé Wieringa (NL), Pieter J. de Jong (US), J. David Brook (US), Mila E. McCurrach (US), Helen G. Harley (GB), Alan J. Buckler (US), Deanna Church (US), Hiroyuki Aburatani (JP), Kent Hunter (US), Vincent P. Stanton (US), Jean-Paul Thirion (CA), Thomas Hudson (CA), Robert Sohn (US), Boris V. Zemelman (US), Russell G. Snell (US), Shelley A. Rundle (GB), Stephen Crow (GB), June Davies (GB), Peggy Shelbourne (GB), Clare Jones (GB), Vesa Juvonen (FI), Peter S. Harper (US), Duncan J. Shaw (GB), David E. Housman (US), Tracey Van Tongeren (GB), Maria Anvret (GB), Brien Riley (GB), Robert Williamson (GB), Ying-Hui Fu (US), Antonio Pizzuti (IT), Raymond G. Fenwick, Jr. (US), J. King (), S. Rajnarayan (), Patrick W. Dunne (US), Jacqueline R. Dubel (US), G.A. Nasser (), Tetsuo Ashizawa (JP-US), M. Benjamin Perryman (US), Henry F. Epstein (US), Charles Thomas Caskey (US), William Reardon (GB), Luc Sabourin (CA), Catherine E. Neville (CA), Monica A. Narang (CA), Juana M. Barceló (CA-US), Kim L. O'Hoy (AU), Suzanne Leblond (CA), and J. Earle-Macdonald (CA) discovered the myotonin-protein kinase (Mt-PK) gene, which contains a track of CTG trinucleotide repeats in the 3’-untranslated region. While normal individuals have 5-30 repeats of this trinucleotide, affected individuals exhibit repeats in the hundreds to thousands resulting in myotonic dystrophy (55; 209; 241; 554; 703; 1072).

 

Jonathan Pines (GB) and Tony Hunter; Anthony Rex Hunter (US) reported that movements of cyclin A and cyclin B suggested that position dictates their function and helped foster the general realization that the cell cycle is controlled by the spatial separation of regulators from their targets (1332).

Jonathan D. Moore (GB), Jane A. Kirk (GB), and Richard Timothy Hunt (GB) confirmed that location determines cyclin function, i.e., subcellular localization of vertebrate cyclin-dependent kinases (CDKs) and the control of their activity are thus critical factors for determining their specificity (1165).

Anja Hagting (GB), C. Karlsson (GB), Paul Clute (GB), Mark Jackman (GB), and Jonathan Pines (GB) discovered that a nuclear export sequence in cyclin B1 provokes its ejection through the nuclear membrane (679).

Jing Yang (US), Elaine S.G. Bardes (US), Jonathan D. Moore (US), Jennifer Brennan (US), Maureen A. Powers (US), Sally Kornbluth (US) Anja Hagting (GB), Mark Jackman (GB), K. Simpson (GB), and Jonathan Pines (GB) discovered that phosphorylation is the cyclin's "ticket" into the nucleus (678; 1839).

Fumiko Toyoshima-Morimoto (JP), Eri Tangiguchi (JP), Nobuko Shinya (JP), Iwamatsu Akihiro (JP), and Eisuke Nishida (JP) found that the protein called polo-like kinase 1 phosphorylates cyclin B1 (1686).

Mark Jackman (GB), Catherine Lindon (GB), Erich A. Nigg (GB), Jonathan Pines (GB) concluded that cyclin B1-cyclin dependent kinase1 is first activated in the cytoplasm and that centrosomes may function as sites of integration for the proteins that trigger mitosis (822).

 

Michael J. Kuranda (US) and Phillips W. Robbins (US) cloned and sequenced the gene responsible for producing chitinase in Saccharomyces cerevisiae. By disrupting this gene they demonstrated that chitinase is necessary for cell separation (951).

 

Alexander Yu Rudensky (US), Paula Preston-Hurlburt (US), Soon-Cheol Hong (US), Avlin Barlow (US), and Charles A. Janeway Jr. (US) performed sequence analysis of peptides bound to major histocompatability complex (MHC) class II molecules. The finding of predominant self peptides has interesting implications for antigen processing and self-non-self discrimination (1428).

Kirsten Falk (DE), Olaf Rotzschke (DE), Stefan Stevanovic (DE), Gunther Jung (DE), and Hans-Georg Rammensee (DE) provided exact information about the contents of MHC grooves. Moreover, each MHC class I allele has its individual rules to which peptides presented in the groove adhere (491).

 

Paul A. Roche (US) and Peter Cresswell (US) reported that treatment of purified alpha beta I with the cysteine proteinase cathepsin B results in the specific proteolysis of the HLA-DR-associated I chain in vitro suggesting that the I chain inhibits immunogenic peptide binding to alpha beta I early during intracellular transport and demonstrate that proteolysis is likely to be the in vivo mechanism of I chain removal (1409). Note: HLA-DR molecules are heterodimeric transmembrane glycoproteins that associate intracellularly with a polypeptide known as the invariant (I) chain. Shortly before expression of the HLA-DR alpha beta dimer on the cell surface, however, the I chain is removed from the intracellular alpha beta I complex by a mechanism thought to involve proteolysis.

 

Graham Moore (GB), Hélène Lucas (FR), Nigel P. Batty (GB), and Richard Anthony Flavell (GB-US) investigated the segregation of different phenotypes within identical genotypes using wheat (1164).

 

Charlotte E. Alford (US), Talmadge E. King, Jr. (US), Priscilla A. Campbell (US), Thomas F. Byrd (US), and Marcus A. Horowitz (US) reported that phagocytosis of microbial pathogens by macrophages includes the microbes being deprived of intracellular iron (18; 242).

 

Jacques Banchereau (FR), Paolo de Paoli (FR), Alain Valle (FR), Eric Garcia (FR), and Francoise Rousset (FR) found that resting B lymphocytes enter a state of sustained proliferation when incubated with both the mouse fibroblastic Ltk- cell line, that had been transfected with the human Fc receptor (Fc gamma RII/CDw32) and monoclonal antibodies to CD40 (80). Note: CD40 is a 45-50 kD transmembrane glycoprotein expressed on B lymphocytes, epithelial cells, and carcinoma cell lines.

 

Richard R. Hardy (US), Condie E. Carmack (US), Susan A. Shinton (US), John D. Kemp (US), and Kyoko Hayakawa (US) resolved B220+ IgM- B-lineage cells in mouse bone marrow into four fractions based on differential cell surface expression of determinants recognized by S7 (leukosialin, CD43), BP-1, and 30F1 (heat stable antigen). Functional analysis demonstrates that the proliferative response to IL-7, an early B lineage growth factor, is restricted to S7+ stages and, furthermore, that an additional, cell contact-mediated signal is essential for survival of fraction A (700).

 

David F. Fiorentino (US), Albert Zlotnik (US), Paulo Vieira (US), Timothy R. Mosmann (US), Maureen Howard (US), Kevin W. Moore (US), and Anne O'Garra (US) presented data suggesting that IL-10 (cytokine synthesis inhibitory factor) may inhibit macrophage accessory cell function which is independent of T cell receptor (TCR)-class II major histocompabability complex (MHC) interactions.

They examined the direct effects of IL-10 on both macrophage cell lines and normal peritoneal macrophages. LPS (or LPS and IFN-gamma)-induced production of IL-1, IL-6, and TNF-alpha proteins was significantly inhibited by IL-10 in two macrophage cell lines. Furthermore, IL-10 appears to be a more potent inhibitor of monokine synthesis than IL-4. LPS or LPS- and IFN-gamma-induced expression of IL-1 alpha, IL-6, or TNF-alpha mRNA was also inhibited by IL-10. The potent action of IL-10 on the macrophage, particularly at the level of monokine production, supports an important role for this cytokine not only in the regulation of T cell responses but also in acute inflammatory responses (518; 519).

Kerstin Steinbrink (DE), Matthias Wölfl (DE), Helmut Jonuleit (DE), Jürgen Knop (DE) and Alexander H. Enk (DE) generated data suggesting that IL-10 converts immature dendritic cells (DC) into tolerogenic antigen-presenting cells (APC), which might be a useful tool in the therapy of patients with autoimmune or allergic diseases (1603).

 

Susan H. Chan (US), Bice Perussia (US), Jean W. Gupta (US), Michiko Kobayashi (US), Miloslav Pospisil (CZ), Howard A. Young (US), Stanley F. Wolf (US), Deborah Young (US), Steven C. Clark (US), and Giorgio Trinchieri (US) showed that human natural killer cell stimulatory factor (NKSF) induces IFN-gamma production from both resting and activated human peripheral blood lymphocytes (PBL) and from freshly isolated murine splenocytes. Human T and NK cells produce IFN-gamma in response to NKSF, but resting PBL require the presence of nonadherent human histocompatibility leukocyte antigens DR+ (HLADR+) accessory cells to respond to NKSF. The ability of NKSF to directly induce IFN-gamma production and to synergize with other physiological IFN-gamma inducers, joined with the previously described ability to enhance lymphocyte cytotoxicity and proliferation, indicates that this lymphokine is a powerful immunopotentiating agent (270). Note: NKSF, a heterodimeric lymphokine purified from the conditioned medium of human B lymphoblastoid cell lines, induces interferon gamma (IFN-gamma) production from resting peripheral blood lymphocytes (PBL) and synergizes with interleukin-2 (IL-2) in this activity.

 

Hubert Schorle (DE), Thomas Holtschke (DE), Thomas Hünig (DE), Anneliese Schimpl (DE), and Ivan Horak (DE) found that mice homozygous for a IL-2 gene mutation are normal with regard to thymocyte and peripheral T cell subset composition, but that dysregulation of the immune system is manifested by reduced polyclonal in vitro T cell responses and by dramatic changes in the isotype levels of serum immunoglobulins (1497).

 

Brunella Franco (US), Silvana Guioli (US), Antonella Pragliola (US), Barbara Incerti (US), Barbara Bardoni (US), Rossana Tonlorenzi (US), Romeo Carrozzo (US), Elena Maestrini (US), Maura Pieretti (US), Patricia Taillon-Miller (US), Carolyn J. Brown (US), Huntington F. Willard (US), Charles Lawrence (US), M. Graziella Persico (US), Giovanna Camerino (US), and Andrea Ballabio (US) found that Kallmann's syndrome (clinically characterized by hypogonadotropic hypogonadism and inability to smell) is caused by a defect in the migration of olfactory neurons, and neurons producing hypothalamic gonadotropin-releasing hormone. A gene has now been isolated from the critical region on Xp22.3 to which the syndrome locus has been assigned: this gene escapes X inactivation, has a homologue on the Y chromosome, and shows an unusual pattern of conservation across species (536).

 

Joanna Groden (US), Andrew Thliveris (US), Wade Samowitz (US), Mary Carlson (US), Lawrence Gelbert (US), Hans Albertsen (US), Geoff Joslyn (US), Jeff Stevens (US), Lisa Spirio (US), Margaret Robertson (US), Leslie Sargeant (US), Karen Krapcho (US), Erika Wolff (US), Randall Burt (US), J.P. Hughes (US), Janet Warrington (US), John McPherson (US), John Wasmuth (US), Denis Le Paslier (US), Hadi Abderrahim (US), Daniel Cohen (US), Mark Leppert (US), and Ray White (US) examined DNA from 61 unrelated patients with adenomatous polyposis coli (APC) for mutations in three genes (DP1, SRP19, and DP2.5) located within a 100 kb region deleted in two of the patients. These data have established that DP2.5 is the APC gene (648).

 

Judith P. Johnson (DE) reported that a change in expression of cell-cell adhesion molecules (CAMs) in the immunoglobulin superfamily appears to play a critical role in the processes of invasion and metastasis (842).

Ulrich Kaiser (DE), Bernhard Auerbach (DE), Marcus Oldenberg (DE) and Judith P. Johnson (DE) presented the case where neural cell adhesion molecule (N-CAM) undergoes a switch in expression from a highly adhesive isoform to poorly adhesive forms in Wilm's tumor, neuroblastoma, and small cell lung cancer (842; 857).

Paola Fogar (IT), Daniela Basso (IT), Claudio Pasquali (IT), Massimo De Paoli (IT), Cosimo Sperti (IT), Giovanni Roveroni (IT), Sergio Pedrazzoli (IT), and Mario Plebani (IT) showed that in invasive pancreatic and colorectal cancers there is a reduction in overall expression level of neural cell adhesion molecule (N-CAM) (527).

Judith A. Varner (US), David A. Cheresh (US), Matvey E. Lukashev (US), and Zena Werb (DE-CA-US) reported that carcinoma cells facilitate invasion by shifting their expression of integrins from those that favor the extracellular matrix (ECM) present in normal epithelium to other integrins (e.g., alpha3ß1 and alphaVß3) that preferentially bind the degraded stromal components produced by extracellular proteases (1051; 1731).

Gerhard Christofori (DE) and Henrik Semb (DK) report on coupling between adjacent cells by E-cadherin bridges resulting in the transmission of antigrowth and other signals via cytoplasmic contacts with ß-catenin to intracellular signaling circuits that include the Lef/Tcf transcription factor. E-cadherin function is apparently lost in a majority of epithelial cancers, by mechanisms that include mutational inactivation of the E-cadherin or ß-catenin genes, transcriptional repression, or proteolysis of the extracellular cadherin domain. Forced expression of E-cadherin in cultured cancer cells and in a transgenic mouse model of carcinogenesis impairs invasive and metastatic phenotypes, whereas interference with E-cadherin function enhances both capabilities (294). Note: Therefore, E-cadherin serves as a widely acting suppressor of invasion and metastasis by epithelial cancers, and its functional elimination represents a key step in the acquisition of this capability.

 

Roderick MacKinnon (US) found that the K+ channels in membranes have a tetrameric structure. This is consistent with the sequence relationship between a K+ channel and each of the four internally homologous repeats of Na+ and Ca2+ channels (1062).

Roderick MacKinnon (US), Steven L. Cohen (US), Anling Kuo (US), Alice Lee (US), Brian T. Chait (ZA-US), Declan A. Doyle (GB), João Morais Cabral (PR-US), Richard A. Pfuetzner (CA), and Jacqueline M. Gulbis (AU) found that membrane K+ channels have “four identical subunits creating an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12-angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K+ channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K+ ions but not smaller Na+ ions. The selectivity filter contains two K+ ions about 7.5-angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K+ ions and the selectivity filter.” They also showed that a prokaryotic K+ channel has the same pore structure as eukaryotic K+ channels (428; 1063).

Youxing Jiang (CN-US), Alice Lee (US), Jiayun Chen (US), Martine Cadene (FR), Brian T. Chait (ZA-US), and Roderick MacKinnon (US) determined the crystal structure of a K+ channel (MthK) from Methanobacterium thermoautotrophicum in the Ca(2+)-bound, opened state. Eight RCK domains (regulators of K+ conductance) form a gating ring at the intracellular membrane surface. The gating ring uses the free energy of Ca(2+) binding in a simple manner to perform mechanical work to open the pore (840).

Roderick MacKinnon (US) would be awarded the 2003 Nobel Prize in Chemistry for structural and mechanistic studies of ion channels.

 

Jun Liu (US), J. Dean Farmer, Jr. (US), William S. Lane (US), Jeffrey M. Friedman (US), Irving Lerner Weissman (US), and Stuart Lee Schreiber (US) found that both cyclophilin-cyclosporin and FKBP12-FK506 bind and inactivate calcineurin, a ubiquitous protein phosphatase. This leads to immunosuppression (1034). Note: Cyclophilin and FKBP12 are immunophilins (a soluble, intracellular molecule which binds a powerful and specific immunosuppressant).

 

Sherine E. Gabriel (US), Liisa Jaakkimainen (CA), and Claire Bombardier (CA) found that users of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) are at approximately three times greater relative risk for developing serious adverse gastrointestinal events than are nonusers (562).

 

Hayata Yamasaki (JP), Chitoshi Itakura (JP), and Makoto Mizutani (JP) presented the first evidence that neurofilaments are the primary determinant of axonal caliber. This came from the identification of a mutant Japanese quail (quiver or Quv) that accumulates no neurofilaments in its axons (1832).

 

Edward J. Pearce (US), Patricia Caspar (US), Jean-Marie Grzych (US), Fred A. Lewis (US), and Alan Sher (US) suggested that coincident with the induction of Th2 responses, murine schistosome infection results in an inhibition of potentially protective Th1 function. This previously unrecognized downregulation of Th1 cytokine production may be an important immunological consequence of helminth infection related to host adaptation (1316).

 

Brian D. Evavold (US) and Paul M. Allen (US) suggests that the T helper cell receptor has the capacity of differential signaling depending on how it is stimulated (486).

 

William E. Holmes (US), James Lee (US), Wun-Jing Kuang (US), Glenn C. Rice (US), and William I. Wood (US) showed that mammalian cells transfected with the IL-8 receptor cDNA clone bind IL-8 with high affinity and respond specifically to IL-8 by transiently mobilizing calcium. The IL-8 receptor may be part of a subfamily of related G protein-coupled receptors that transduce signals for the IL-8 family of pro-inflammatory cytokines (771).

 

Phillip M. Murphy (US) and H. Lee Tiffany (US) isolated a cDNA clone from HL-60 neutrophils, designated p2, that encodes a human IL-8 receptor. When p2 is expressed in oocytes from Xenopus laevis, the oocytes bind 125I-labeled IL-8 specifically and respond to IL-8 by mobilizing calcium stores with an EC50 of 20 nM. This IL-8 receptor has 77% amino acid identity with a second human neutrophil receptor isotype that binds IL-8 with higher affinity. It also exhibits 69% amino acid identity with a protein reported to be an N-formyl peptide receptor from rabbit neutrophils, but less than 30% identity with all other known G protein-coupled receptors, including the human N-formyl peptide receptor (1195).

 

William G. Kaelin, Jr. (US), Peter J. Ratcliffe (GB), Gregg L. Semenza (US), Guang L. Wang (US), Mary K. Nejfelt (US), Suzie M. Chi (US), Stylianos E. Antonarakis (CH), Othon Iliopoulos (US), Andrew P. Levy (US), Chian Jiang (US), Mark A. Goldberg (US), Michael Ohh (KR-US), Cheol Won Park (US), Mircea Ivan (US), Michael A. Hoffman (US), Tae You Kim (US), L. Eric Huang (US), Vincent Chau (US), Nikola Pavletich (US), Keiichi Kondo (US), HaifengYang (US), Jennifer Valiando (US), John M. Asara (US), Thomas Haberberger (US), David C. Gervasi (US), Kristen S. Michelson (US), Volkmar Gunzler (US), Irina Sorokina (US), Ronald C. Conaway (US), Joan W. Conaway (US), Patrick H. Maxwell (GB), Christopher W. Pugh (GB), Michael Sean Wiesener (GB), Gin-Win Chang (GB), Steven C. Clifford (GB), Emma C.Vaux (GB), Matthew E. Cockman (GB), Charles C. Wykoff (GB), Eamonn R. Maher (GB), Panu Jaakkola (GB), David R. Mole (GB), Ya-Min Tian (GB), Michael I. Wilson (GB), Janine Gielbert (GB), Simon J. Gaskell (GB), Alexander von Kriegsheim (GB), Holger F. Hebestreit (GB), Mridul Mukherji (GB), Christopher J. Schofield (GB), Andrew C.R. Epstein (GB), Jonathan M. Gleadle (GB), Luke A. McNeill (GB), Kirsty S. Hewitson (GB), John F. O’Rourke (GB), Eric Metzen (GB), Anu Dhanda (GB), Norma Masson (GB), Donald L. Hamilton (GB), Robert Barstead (GB), Jonathan Hodgkin (GB), Bing-Hua Jiang (US), and Elizabeth A. Rue (US) discovered the pathway by which cells from human and most animals sense and adapt to changes in oxygen availability, a process that is essential for survival. They illuminated the core molecular events that explain how almost all multicellular animals tune their physiology to cope with varying quantities of the life-sustaining element—oxygen—thus exposing a unique signaling scheme (473; 805; 817; 818; 821; 854; 1105; 1106; 1248; 1512; 1514; 1759-1761). Note: Hypoxia is a pathophysiologic component of many disorders, including heart attack, stroke, and cancer.

 

Gregg L. Semenza (US), Peter H. Roth (US), Hon-Ming Fang (US), and Guang L. Wang (US) demonstrated the effect of erythropoietin (EPO) on erythroid cell lines in humans (1511; 1513).

Shinga Matsumoto (JP), Koji Ikura (JP), Makoto Ueda (JP), and Ryuzo Sasaki (JP) created transgenic tobacco cells capable of producing human erythropoietin; a mitogen for blood cells (1098).

Narayan V. Iyer (US), Lori E. Kotch (US), Faton Agani (US), Sandra W. Leung (US), Erik Laughner (US), Roland H. Wenger (CH), Max Gassmann (CH), John D. Gearhart (US), Ann M. Lawler (US), Aimee Y. Yu (US), and Gregg L. Semenza (US) demonstrated that hypoxia-inducible factor 1 alpha (HIF-1α) is a master regulator of cellular and developmental oxygen homeostasis. defective (819). Note: HIF-1α deficiency, in addition to interfering with the development of a circulatory system required for adequate tissue oxygenation, may also render many cell populations within the embryo unable to adapt to oxygen deprivation.

 

Charles H. Streuli (US), Nina Bailey (US) and Mina J. Bissell (US) provided evidence for a central role of basement membrane in the induction of tissue-specific gene expression (1614).

Charles H. Streuli (US), Christian Schmidhauser (US), Nina Bailey (US), Peter Yurchenco (US), Amy P. Skubitz (US), Calvin Roskelley (US), and Mina J. Bissell (US) showed that laminin is the basement membrane protein that prods the mammary epithelial cells to activate the β-casein gene (1615).

Valerie M. Weaver (US), Ole William Peterson (DK), Fei Wang (US), Carolyn A. Larabell (US), Per Briand (DK), Caroline Damsky (US), and Mina J. Bissell (US) showed that blocking integrin function is sufficient to revert the malignant phenotype of human breast cancer cells both in culture and in vivo (1771).

 

Peter Koopman (GB), John Gubbay (GB), Nigel Vivian (GB), Peter N. Goodfellow (GB), and Robin H. Lovell-Badge (GB) discovered the sex-determining gene in mice (924).

 

John A. Todd (GB), Timothy J. Aitman (GB), Richard J. Cornall (GB), Soumitra Ghosh (GB), Jennifer R. S. Hall (GB), Catherine M. Hearne (GB), Andrew M. Knight (GB), Jennifer M. Love (GB), Marcia A. McAleer (GB), Jan-Bas Prins (GB), Nanda Rodrigues (GB), Mark Lathrop (FR), Alison Pressey (FR), Nicole H. DeLarato (US), Laurence B. Peterson (US), and Linda S. Wicker (US) reported two genes, ldd-3 and ldd-4, that influence the onset of autoimmune type 1 diabetes in the nonobese diabetic mouse have been located on chromosomes 3 and 11, outside the chromosome 17 major histocompatibility complex. A genetic map of the mouse genome, analyzed using the polymerase chain reaction, has been assembled specifically for the study. On the basis of comparative maps of the mouse and human genomes, the homologue of ldd-3 may reside on human chromosomes 1 or 4 and ldd-4 on chromosome 17 (1676).

 

Annemiske J.M.H. Verkerk (NL), Maura Pieretti (NL), James S. Sutcliff (NL), Ying-Hui Fu (NL), Derek P.A. Kuhl (NL), Antonio Pizzuti (NL), Orly Reiner (NL), Stephen Richards (NL), Maureen F. Victoria (NL), Fuping Zhang (NL), Bert E. Eussen (NL),Gert-Jan B. van Ommen (NL), Lau A.J. Blonden (NL), Gregory J. Riggins (NL), Jane L. Chastain (NL), Catherine B. Kunst (NL), Hans Galjaard (NL), C. Thomas Caskey (NL), David L. Nelson (NL), Ben A. Oostra (NL), and Stephen T. Warren (NL) showed that localization of the brain-expressed FMR-1 gene to a particular EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome (1740). Note: fragile X syndrome is the most frequent form of inherited mental retardation.

 

Alan Ashworth (GB), Sohaila Rastan (GB), Robin H. Lovell-Badge (GB), and Graham Kay (GB) devised a system to analyze whether specific genes on the mouse X chromosome are inactivated. They demonstrated that both genes Zfx and Rps4X undergo normal X-inactivation in mice. Thus the relative viability of XO mice compared to XO humans may be explained by differences between the two species in the way that dosage compensation of specific genes is achieved (54). Note: Only about 1% of human XO conceptuses survive to birth and these usually have the characteristics of Turner's syndrome.

 

Sam J. McCullough (GB), Francis McNeilly (GB), Gordon M. Allan (GB), Seamus Kennedy (GB), Joan A. Smyth (US), S. Louise Cosby (GB), Stephen McQuaid (GB), and Bert K. Rima (GB) isolated and characterized porpoise morbillivirus (PMV) from harbor porpoises (Phocoena phocoena) that died along the Irish coast in 1988 (1117).

 

Kenneth W. Culver (US), R. Michael Blaese (US), Lauren Chang (US), Yawen Chang (US), William French Anderson (US), Craig A. Mullen (US), Arthur W. Nienhuis (US), Charles S. Carter (US), Cynthia E. Dunbar (US), Susan F. Leitman (US), Melvin Berger (US), A. Dusty Miller (US), Richard A. Morgan (US), Thomas Fleisher (US), Roger Kobyashi (US), Ai Lan Kobyashi (US), Harvey Klein (US), Gene Shearer (US), Mario Clerici (US), Paul Toltoshev (US), Jay J. Greenblatt (US), Steven A. Rosenberg (US), Linda Muul (US), Harvet Klein (US), Gerald McGarrity (US), and Aliza Cassell (US) treated severe combined immune deficiency (SCID) patients with CD34+ selected autologous peripheral blood cells transduced with a human adenosine deaminase (ADA) gene. The white-cell count of patients trebled, and they made about one-quarter of the ADA that a normal person makes (33; 34; 161; 162; 362). Note: This represents the first case of gene therapy to clinically treat a disease in humans.

 

Laryssa N. Kaufman (US), Mary M. Peterson (US), and Stephen M. Smith (US) demonstrated that, “Male Sprague-Dawley rats fed either a high-fat or a glucose enriched diet developed higher blood pressure than rats fed a control diet… Rats fed the high-fat diet developed hypertension only when they were allowed to overeat and become obese and hyperinsulinemic. But when their feeding was restricted to prevent obesity… they remained normotensive” (876).

 

Meir J. Stampfer (US), Graham A. Colditz (US), Walter C. Willett (US), JoAnn E. Manson (US), Bernard Rosner (US), Frank E. Speizer (US), and Charles H. Hennekens (US) found that healthy postmenopausal nurses aged 30-53 years on estrogen therapy had a 44% reduced risk of major coronary disease compared to women not on estrogen. Age-adjusted relative risk of cardiovascular mortality for postmenopausal women on estrogen was 0.72 (CI: 0.55-0.95, p=0.02) (1599).

 

Arnold I. Caplan (US), Stephen E. Haynesworth (US), Jun Goshima (US), Victor M. Goldberg (US), Mark F. Pittenger (US), Alastair M. Mackay (US), Stephen C. Beck (US), Rama K. Jaiswal (US), Robin Douglas (US), Joseph D. Mosca (US), Mark A. Moorman (US), Donald W. Simonetti (US), Stewart Craig (US) and Daniel R. Marshak (US) characterized the mesenchymal stem cells (MSC) of the bone marrow as having the potential to differentiate to all mesenchymal cell types, including osteocytic, chondrocytic, adiocytic, myocytic, tenocytic, and also dermal and stromal lineages (253; 725; 1335).

 

David Gailani (US), George J. Broze, Jr. (US), Koji Naito (JP), and Kazuo Fujikawa (US) found that thrombin activates factor XI in the presence of high molecular weight kininogen (HMWK) and a negatively charged surface. The activation of factor XI by thrombin triggers the intrinsic pathway of coagulation that also takes place on the surface of the activated platelets (564; 1200).

 

Rosalba Salas (VE), Maria E. Pacheco (VE), Bricio Ramos (VE), Maria E. Taibo (VE), Edgar Jaimes (VE), Clovis Vasquez (VE), Jesus Querales (VE), Nuris De Manzione (VE), Oswaldo Godoy (VE), Adelfa Betancourt (VE), Francisco Araoz (VE), Rafael Bruzual (VE), Garcia Jorge Tomayo (VE), Robert B. Tesh (US), Rebecca Rico-Hesse (US), and Robert Ellis Shope (US) were the first to identify Venezuelan hemorrhagic fever (VHF) as a zoonotic human illness. The disease is most prevalent in several rural areas of central Venezuela (1446).

Robert B. Tesh (US), Peter B. Jahrling (US), Rosalba Salas (VE), and Robert Ellis Shope (US) identified the etiological agent of VHF as the Guanarito virus (GTOV) which belongs to the Arenaviridae family. The short-tailed cane mouse (Zygodontonys brevicauda) is the main host for GTOV (1662).

Mary L. Milazzo (US), Narua N.B. Caimat (US), Gloria Duno (VE), Freddy Duno (VE), Antonio Utera (VE), and Charles F. Fulhorst (US) found that VHF is spread mostly by inhalation of aerosolized droplets of saliva, respiratory secretions, urine, or blood from infected rodents (1149).

 

Jamie A. Koufman (US) studied the otolaryngologic manifestation of gastroesophageal reflux disease (GERD) in a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and experimental investigation of the role of acid and pepsin in the development of laryngeal injury. By traditional symptomatology, GER was occult or silent in the majority of the study population (928). Note: Dr. Koufman coined the terms “laryngopharyngeal reflux” and “silent reflux."

 

In 1991, 100 years after cholera was vanquished from South America, there was an outbreak in Peru that spread across the continent, killing 10,000 people. It was a similar strain to the pandemic that petered out more than a decade earlier in Japan and the South Pacific. The scope of the epidemic was enormous: As a CDC report stated, “Because of underreporting, the more than 1,000,000 cholera cases and 10,000 deaths reported from Latin America through 1994 represent only a small fraction of the actual number of infections.” (1137)

 

Clifford J. Woolf (GB) and Stephen W.N. Thompson (GB) found that N-methyl-D-aspartic acid (NMDA) receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs. Because central sensitization is likely to contribute to the post-injury pain hypersensitivity states in man, these data have a bearing both on the potential role of NMDA antagonists for pre-emptive analgesia and for treating established pain states (1819).

 

Wesley W. Parke (US) has shown that when spinal nerve compression occurs that it is the impairment of the less resilient venous return system that produces the clinical symptoms. This means that surgeons cannot merely "unroof" nerves in treating lateral spinal stenosis but must also relieve tension and stretch on the structure to allow return to a normal state (1290).

 

James R. Lupski (US), Robert Montes de Oca-Luna (US), Susan Slaugenhaupt (US), Liu Pentao (US), Vito Guzzetta (US), Barbara J. Trask (US), Odila Saucedo-Cardenas (US), David F. Barker (US), James M. Killian (US), Carlos A. Garcia (US), Aravinda Chakravarti (US), and Pragna I. Patel (US) localized Charcot-Marie-tooth disease type 1A (CMT1A) by genetic mapping to a 3 cM interval on human chromosome 17p. DNA markers within this interval revealed a duplication that is completely linked and associated with CMT1A (1054).

 

Erich Mühe (DE) performed the first laproscopic cholecystectomy in 1985 but it was not reported until 1991 (1181).

Frederik Keus (NL), Hein G. Gooszen (NL), Cornelis Jhn van Laarhoven (NL) carried out a meta-analyisis which showed no difference in mortality or complications between open, laproscopic, and small-incision cholecystectomy. However, laproscopic and small-incision cholecystectomy are associated with a shorter hospital stay and faster recovery (888).

 

Jerry Pelletier (US), Wendy Bruening (US), Clifford E. Kashtan (US), S. Michael Mauer (US), J. Carlos Manivel (US), Jane E. Striegel (US), Donald C. Houghton (US), Claudine Junien (US), Renée Habib (US), Laurie Fouser (US), Richard N. Fine (US), Bernard L. Silverman (US), Daniel A. Haber (US), and David Housman (US) provided evidence of a direct role for Wilm's tumor suppressor gene (WT1) in Denys-Drash syndrome and thus urogenital system development (1320). Note: This study along with others suggests a multifaceted role for WT1 functioning at multiple levels in the kidney; it is essential first for normal renal development, then acts as a tumor supressor gene, and finally is required to maintain the healthy biology of the glomerulus.

 

Jerome M. Siegel (US), Robert Nienhuis (US), Heidi M. Fahringer (US), Richard Paul (US), Priyattam Shiromani (US), William C. Dement (US), Emmanuel Mignot (US), and Charles Chiu (US) discovered that unusual activity in the medial medulla region of the brain can bring a cataplectic episode such as those commonly experienced by narcoleptics (1547). Note: Horace W. Magoun (US), in the 1940s, discovered that when he electrically stimulated the medial medulla (a part of the brain stem), muscle tone vanished. He did not connect this with narcolepsy.

 

Debra S. Echt (US), Philip R. Liebson (US), L. Brent Mitchell (US), Robert W. Peters (US), Dulce Obias-Manno (US), Allan H. Barker (US), Daniel Arensberg (US), Andrea Baker (US), Lawrence Friedman (US), H. Leon Greene (US), Melissa L. Huther (US), and David W. Richardson (US) reported that the use of class IC anti-arrhythmic agents flecainide and encainide in patients following myocardial infarction with left ventricular dysfunction increases the risk of death due to arrhythmia and shock (460).

 

North American Symptomatic Carotid Endarterectomy Trial Collaborators (CA) found that carotid endarterectomy, in addition to medical therapy, significantly reduces risk of major and fatal stroke in patients with symptomatic, high-grade (70-99%) carotid stenosis (325).

 

Nicholas C. Gallegos (GB), Joseph Dawson (GB), Mark Jarvis (GB), and Michael Hobsley (GB) reported that the cumulative probability of hernia strangulation was greatest in the first 3 months for both inguinal and femoral hernias. Therefore, the authors concluded that patients with a short history of herniation should be referred urgently to hospital and given priority on the waiting list (570).

 

The Medical Research Council (MRC) Vitamin Study Research Group (GB) demonstrated that folic acid supplementation can now be recommended for all women who have had a previously affected pregnancy, and public health measures should be taken to ensure that all women of childbearing age receive adequate dietary folic acid. This study has established the specific role of folic acid in the prevention of neural tube defects (656).

 

Patients with atrial fibrillation are at higher risk of ischemic stroke and systemic embolism. Compared to placebo, warfarin and aspirin significantly reduced the risk of ischemic stroke and systemic embolism in patients with atrial fibrillation. Today, antithrombotic therapy remains a vital consideration in managing patients with atrial fibrillation, though many more agents are available (4).

 

North American Symptomatic Carotid Endarterectomy Trial Collaborators (CA), Henry J.M. Barnett (CA), D. Wayne Taylor (CA), R. Brian Haynes (CA), David L. Sackett (CA), Sydney J. Peerless (CA), Gary G. Ferguson (CA), Allan J. Fox (CA), Richard N. Rankin (CA), Vladimir C. Hachinski (CA), David O. Wiebers (CA), Michael Eliasziw (CA), MRC European Carotid Surgery Trial, and Charles Warlow (CA) concluded from their data that carotid endarterectomy is useful for stenosis of 70% or more and that surgery is harmful in patients with stenoses less than 50% and also those near occlusion. In the group with moderate stenosis, carotid endarterectomy is beneficial in men but not women (326; 1766).

 

George L. Irvin, 3rd (US), Victor D. Dembrow (US), and David L. Prudhomme (US) introduced a 'quick' intra-operative parathyroid gland hyperfunction assay that could be used to determine that all hyperfunctioning parathyroid tissue had been removed at the time of surgery and identify those patients who do not have a solitary parathyroid adenoma (809).

 

Brigitte Bressac (US), Michael Kew (ZN), Jack Wands (US), Mehmet Ozturk (US), Ih Chang Hsu (US), Robert A. Metcalf (US), Tsung-tang Sun (CN), Judith A. Welsh (US), N.J. Wang (CN), and Curtis C. Harris (US) found that mutations in codon 249 of p53 in hepatocellular carcinoma, a cancer endemic in locations in southern Africa and Asia, are associated with aflatoxin exposure (203; 786; 1274).

 

Christopher W. Elston (GB) and Ian O. Ellis (GB) found a significant correlation bettween histological grade and prognosis in breast cancer This was the first study to objectively modify the grading of invasive breast cancer and correlate this grading system with prognosis in a large group of patients (469).

 

Troyen A. Brennan (US), Lucian L. Leape (US), Nan M. Laird (US), Liesi Hebert (US), A. Russell Localio (US), Ann G. Lawthers (US), Joseph P. Newhouse (US), Paul C. Weiler (US), and Howard H. Hiatt (US) found that adverse events occurred in 3.7% of hospitalizations. Approximately 27.6% of adverse events occurring in hospital were attributed to negligence (199).

Lucian L. Leape (US), Troyen A. Brennan (US), Nan Laird (US), Ann G. Lawthers (US), A. Russell Localio (US), Benjamin A. Barnes (US), Liesi Hebert (US), Joseph P. Newhouse (US), Paul C. Weiler (US), and Howard Hiatt (US) found that drug-related complications were the most common type of adverse event in hospitalized patients. Adverse events due to negligence in hospitalized patients were more likely to cause serious disability or death than adverse events not attributed to negligence (981).

 

Mark A. Munson (US), Paul Baumann (US), and Marvin G. Kinsey (US) found that because of their high carbohydrate diet Aphidoidea have established mutualistic relationships with the obligate intracellular endosymbiont Buchnera aphidicola to supply amino acids (1193).

 

South America experienced an outbreak of cholera in 1991 lasting on into 1994.

 

Felix Eijgenraam (NL) and Alun Anderson (NL) described a 4 K-year-old Bronze Age man found frozen since his death in the Italian Alps. It is hoped that this body—found by Helmut and Erika Simon— will shed light on the racial structure and culture of early Europe (465). Note: A subsequent radiocarbon analysis performed on Ötzi's (a nickname given the man) tissues found that he was even older than 4,000 years. Radiocarbon dating determined that the iceman was about 5,300 years old, dating to 3300 B.C.E. This meant that Ötzi lived during the era of history known as the Copper Age, the transition period between the Neolithic, or the "New Stone Age," and the late Bronze Age.

The Copper Age (3500 B.C.E. to 1700 B.C.E.), also known as the Chalcolithic period, represents the time when the populations of what is now Europe began to make widespread use of metals while still using stone tools but had not yet smelted copper and tin to make bronze. It was also a time when the first complex social hierarchies developed and populations began to erect large, monumental structures made of stone — the famous megalithic tombs, standing stones and dolmens of Europe.

Leopold Dorfer (AT), Maximilian Moser (AT), Frank Bahr (DE), Konrad Spindler (AT), Eduard Egarter-Vigl (IT), Sonia Guillen (PE), Gottfried Dohr (AT), and Thomas Kenner (AT) reported that the Bronze Age “Ice Man,” (see above) found in the Italian Alps near the Austrian border, possesses many "tattoos" corresponding very near or on acupuncture points and meridians, including the 'master point for back pain'. If these are acupuncture sites then this is the oldest known example of such treatment (424). See, Shen Nung c. 2.7 K B.C.E.

 

English country names and code elements taken from the International Organization for Standardization:

DZ = Algerian; US = American; AR = Argentinian; AU = Australian; AT = Austrian; AT/HU = Austro/Hungarian; BA = Bosnian-Herzegovinian; BE = Belgian; BR = Brazilian; GB = British; BG = Bulgarian; CM = Cameroonian; CA = Canadian; TD = Chadian; CL = Chilean; CN = Chinese; CO = Colombian; CR = Costa Rican; HR = Croatian; CU = Cuban; CY = Cypriot; CZ = Czechoslovakian; DK = Danish; NL = Dutch; EC = Ecuadorian; EG = Egyptian; EE = Estonian; ET = Ethiopian; FI = Finnish; FR = French; DE = German; GR = Greek; GT = Guatemalan; GU = Guamanian; HU = Hungarian; IS = Icelander; IN = Indian; ID = Indonesian; IR = Iranian; IQ = Iraqi; IL = Israeli; IE = Irish; IT = Italian; JP = Japanese; KE = Kenyan; KR = South Korean; KW = Kuwaiti ; LV = Latvian; LB = Lebanese; LT = Lithuanian; LU = Luxembourgian; MK= Macedonian; MG = Malagasy; MT = Maltese; MY = Malaysian; MX = Mexican; NA = Namibian; NZ = New Zealander; NG = Nigerian; NO = Norwegian; PK = Pakistani; PA = Panamanian; PE = Peruvian; PG = Papua New Guinea; PH = Filipino; PL = Polish; PT = Portuguese; PR = Puerto Rican; RO = Romanian; RU = Russian; SA = Saudi Arabian; SN = Senegalese; CS = Serbian-Montenegrin; SK = Slovakian; SI = Slovenian; ZA = South African; KR= South Korea; ES = Spanish; LK = Sri Lankan; SE = Swedish; CH = Swiss; SY = Syrian; TW = Taiwan; TH = Thai; TN = Tunisian; TR = Turkish; UG = Ugandan; UA = Ukrainian; UY = Uruguayan; VE = Venezuelan; ZW = Zimbeze

 

 

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