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, DSU Box 3262, Cleveland, MS 38733. jsteen08@bellsouth.net



“Nothing in biology is understandable except in the light of genetics.” Francisco José Ayala (59).


"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 (838).


“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 (342).


“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 (597).


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 (79; 829; 1274).


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) (93; 94).

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 (925).


Keith Burridge (GB-US) and James R. Feramisco (US) discovered the cell adhesion protein vinculin (223).


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 (1386; 1387).


Edith Kolb (GB), Peter J. Hudson (GB), and J. Leuan Harris (GB) determined the complete amino acid sequence of phosphofructokinase from Bacillus stearothermophilus (875).


J. Clark Lagarias (US) and Henry Rapoport (US) determined the structure of phytochrome chromophore attached to an undecapeptide, deduced from NMR spectra (916).


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 (66).


Akira Endo (JP) discovered monacolin K (lovastatin), a drug which inhibits the synthesis of cholesterol and lowers cholesterol levels in the blood (449).

Karl August Folkers (US), J. Lan Tucker (US), Richard Willis (US), Li-Jun Xia (CN), Chun-Qu Ye (CN), and Hiroo Tamagawa (JP) found that lovastatin decreases coenzyme Q levels in rats and humans (1726).


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 (172; 870).


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 (1777). 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 (1735).


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 (292-294).

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 (937).


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 (101; 1217).


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 (1144).


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 (448).


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 (1472).


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 (1045; 1446).


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 (1206). 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 (629).


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 (999). 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 (256).


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 (1341).


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 (216).


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 (683).


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 (1754).

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 (792; 1712). 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 (568; 700; 790; 791). 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 (1411).

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 (1745). 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 (442). 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 (227; 304).

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 (1145). 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 (73)


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 (897; 1151).


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 (855).


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 (709).

The method proved useful in “seeing” all manner of cellular phenomena, including, notably, clathrin-coated pit formation (708), the budding of COPI-coated vesicles from golgi (1706), and the dynein arm power stroke (584).

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 (1566).


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 (404). 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 (1338).


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 (444; 1200). 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 (416; 1395).


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 (1630).


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 (159).


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 (247; 810).

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 (373; 374). 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 (1178).

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 (1385).

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 (1260; 1261).

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 (966).

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 (1437).


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 (1357).


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 (1658-1660).

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 (757; 1272; 1657).

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 (758). 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 (1323).

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 (102; 217; 964; 1236).

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 (273; 1158; 1320).


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 (1102).


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 (1508; 1509).

Richard Lavenham Gardner (GB), M.R. Meredith (GB), and D.G. Altman (GB) verified Smith's conclusions (550). 


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, doubleblind trial in 1,083 homosexual men from New York confirmed that a highly purified, formalininactivated vaccine against hepatitis B prepared from HBsAg positive plasma, is safe immunogenic, and highly efficacious (1571).


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 (533).


Dietrich W. Barth (DE), Edwin Sylvester Brokken, Jr. (US), Lyndia S. Blair (US), and William C. Campbell (US) discovered the antiparasitic nature of Ivermectin (87; 155). 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 (200).

Christiaan Schiepers (US) and Carl K. Hoh (US) described positron emission tomography as a diagnostic tool in oncology (1419).

Eric M. Rohren (US), Timothy G. Turkington (US) and R. Edward Coleman (US) described the clinical applications of positron emission tomography (PET) in oncology (1355). 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 (1344)


David E.R. Sutherland (US), Frederick C. Goetz (US), and John S. Najarian (US) performed the world's first living-donor (segmental) pancreas transplantion (1564).


William F. House (US) and Aziz Belal, Jr. (EG) pioneered the early diagnosis and translabyrinthine removal of schwannomas (746).


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 (908).


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 (206; 337; 957; 1445). 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 (414; 415; 567; 1471).

Barry R. Bloom (US) directed clinical efficacy trials of this vaccine for leprosy under the auspices of the World Health Organization (162).


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 (1495).


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 (215).


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 (472; 547; 1280; 1678; 1757; 1758).


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 (809; 1184; 1185).

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 (418-420; 525).

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 (126; 418; 1181-1183). 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 (1086).


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 (1700).


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 (1744).


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 (958; 1563).


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 (698).


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 (674).


Elizabeth S. Williams (US) and Stephanie Ming Young (US) discovered that chronic wasting disease of deer is a transmissible spongiform encephalopathy caused by a prion (1724).


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 (174).

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 (637; 638).


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” (603).


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 (194; 1284; 1285; 1641; 1779). Note: This is the discovery of HTLV-1, the first pathogenic human retrovirus.


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 (45; 54).


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 (981). 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) (980).

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 (1699).


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 (182; 183).


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. (340).


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 (107; 357; 358; 1333).



“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 (1079).


“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 (1670).


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 (424). 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 (221).


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 (805).


John B. Corliss (US), John A. Baross (US), and Sarah E. Hoffman (US) proposed a thermophilic origin of life (325).


Robert Day Allen (US), Jeffrey L. Travis (US), Nina Strömgren Allen (US), and HüSeyin Yilmaz (US) perfected video-enhanced contrast polarization (AVEC-POL) microscopy (20). 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 (689).


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 (1303)


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 (846).


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 (1569).


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 (949; 976).


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 (1148). 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 (743; 1047).


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 (96).


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 (847; 1382).


Wylie Vale (US), Joachim Spiess (DE), Catherine Rivier (CH-US), and Jean E.F. Rivier (CH-US) purified corticotropin-releasing factor (CRF) (1652).


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 (64; 213).

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 (63; 212; 468; 1381).


Hugo E. Jasin (US) and John T. Dingle (US) discovered a factor released from monocytes, which promotes cartilage resorption (786). 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 (284; 962). 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 (65). 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 (717).

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 (1106). 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) (1533). 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 (106; 336; 787; 923; 1205; 1317).

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 (69).

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 (1169).

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 (827; 828; 901). 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 (1778).

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  (1000).

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 (1570).

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 (812).

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 (808).

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 (300).

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 (538).


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 (1722; 1731).


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) (264; 1654).

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 (440; 1653). 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 (1090).


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 (1292).


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 (116; 117; 1186).


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 (244; 245; 1052).


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 (1115).

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 (114; 693).

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 (77).

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 (706).

Winship Herr (US-CH) and Jennifer Clarke (US) described the modularity and redundancy (plasticity) of eukaryotic transcriptional regulatory elements (705).

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 (840).


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 (902; 1354).


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 (28; 29; 135).


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 (1356).


George Klein (SE) discovered that the gene coding for the light chain of murine immunoglobulin molecules resides on chromosome number 6 (866).


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 (1131; 1132).


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 (1557).


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 (930; 1265).

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 (718).


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 (313).

Georgiana May (US) and John W. Taylor (US) found horizontal transfer of mitochondrial plasmids, independently of mitochondrial DNA (1055).


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 (620).


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 (361).


   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 (844). 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 (473). 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 (522; 523).

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