A Selected Chronological Bibliography of Biology and Medicine

 

Part 6B

 

1971 — 1979

 

 

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

 

1971

“Well, the only thing I’d like to say at the end is that it has all been wonderful fun. I wouldn’t change a single thing; it has been a tremendous privilege, and I hope that in the next generation, where things are going to be more complicated, that it will still be possible for people to have as much fun and reward as I had.” William Barry Wood, Jr. (1764).

 

Earl Wilbur Sutherland, Jr. (US) was awarded the Nobel Prize in Physiology or Medicine for his discoveries concerning the mechanisms of the action of hormones.

 

James Ephraim Lovelock (GB) invented the electron capture detector (ECD), which ultimately allowed him along with Robert J. Maggs (GB), and Roger J. Wade () to discover the persistence of chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons (HCFCs) and their role in stratospheric ozone depletion (1228; 1233). Note: An electron capture detector (ECD) is a device for detecting atoms and molecules in a gas through the attachment of electrons via electron capture ionization. The device was invented in 1957 by James Ephraim Lovelock (GB) and is used in gas chromatography to detect trace amounts of chemical compounds in a sample (1227; 1229).

 

Byungkook Lee (US) and Frederic Middlebrook Richards (US) introduced the concept and a quantitative measure for the solvent-accessible surface (SAS) of amino acid residues in folded protein structures. The surface is constructed by tracing the center of an imaginary ball, its radius that of a water molecule (taken as 1.4 Å), as it rolls over the van der Waals surfaces of the proteins. Thus defined, the surface is continuous and each point on it is unambiguously associated with a specific protein atom (the nearest) (1152). The Lee & Richards definition has been widely adopted as the standard measure for solvent accessibility, for instance to evaluate exposure per residue as a percentage of accessible vs. total surface area.

 

Kyoyu Sasaki (JP), Yoshimasa Hirata (JP), Masaaki Toda (JP), and Shosuke Yamamura (JP) determined the structure of methyl homosecodaphniphyllate by x-ray crystallographic analysis (1658; 1892). This chemical is a member of a family of alkaloids originally extracted from the bark of the Yuzuriha tree, Daphniphyllum macropodum, and used to treat asthma.

 

Sung Hou Kim (US), Gary J. Quigley (US), Fred Leroy Suddath (US), and Alexander R. Rich (US) produced crystals of yeast tRNA^PHE that diffracted to 2-3 Ångstrom resolutions by using spermine, a naturally occuring polyamine, which bound to and stabilized the tRNA (1049).

Sung-Hou Kim (US), Gray J. Quigley (US), Fred Leroy Suddath (US), Alexander McPherson (US), Daryll Sneden (US), Jung-Ja Park Kim (US), Jon Weinzierl (US), and Alexander Rich (US) determined the molecular structure of yeast tRNA^PHE to a 4-Ångstrom resolution (1048). By 1974, together with Joel L. Sussman (US), Andrew H.J. Wang (US), and Nadrian C. Seeman (US) they had interpreted the three-dimensional tertiary structure of yeast tRNA^PHE to a resolution of three angstroms (1050). Note: This work represents the first solution of a long-chain nucleic acid structure of any kind - RNA or DNA.

 

Anatol G. Morell (US), Gregory Gregoriadis (US), I. Herbert Scheinberg (US), Jean Hickman (US), and G. Gilbert Ashwell (US) found that plasma membranes of the liver are the primary site of binding for circulating glycoproteins (1362).

Roger L. Hudgin (US), William E. Pricer, Jr. (US), G. Gilbert Ashwell (US), Richard J. Stockert (US), and Anatol G. Morell (US) hypothesized that the exposure of terminal, nonreducing galactosyl residues by the removal of sialic acid provides a means by which the liver recognizes and removes the defective molecules from circulation as part of their normal catabolic pathway. They isolated the asialoglycoprotein binding protein from rabbit liver (923).

Toshisuke Kawasaki (JP) and G. Gilbert Ashwell (US) isolated an avian hepatic binding protein that was specific for terminal N-acetylglucosamine residues on glycoproteins (1027).

 

Henry Arnold Lardy (US), David L. Garbers (US), Wesley David Lust (US), and Neal L. First (US) found that caffeine increases respiration and dramatically induces whiplash-type motility in sperm by increasing cyclic AMP (1135).

Andrew L. Milkowski (US), Donner F. Babcock (US), and Henry Arnold Lardy (US) noted that the respiratory response is dependent on the utilization of acetylcarnitine (1340).

 

Stanislav Fakan (DE) and Wilhelm Bernhard (CH) found that nascent RNA is predominantly found in the interchromatin region. High-resolution autoradiography associates nascent RNA with perichromatin fibrils (586).

 

Leonard S. Lerman (US), Thomas Peter Maniatis (US), and John H. Venable, Jr. (US) studied transitions in individual DNA molecules from an extended structure to a highly compact structure as seen in the heads of bacteriophage or condensed chromatin. They concluded that the higher-order structural transition occurs without a dramatic alteration of the secondary DNA structure, presaging the same conclusion for the structure of compact DNA in chromatin (1166; 1280).

 

Douglas Brutlag (US), Randy Wayne Schekman (US), Arthur J. Kornberg (US), and William Wickner (US) discovered that short RNA chains are synthesized onto DNA to act as primers during DNA replication (272; 2021).

 

Thomas Kornberg (US) and Malcolm L. Gefter (US) discovered DNA polymerase III (third polymerase recognized) of Escherichia coli (1098).

 

W. Dean Rupp (US), Charles E. Wilde III (US), Donna L. Reno (US), and Paul Howard-Flanders (US) showed that replication is used to repair or bypass DNA damage (1624).

Anne Marie Skalka (US) was the first to suggest that recombination can be used to complete DNA replication (1748).

Bénédicte Michel (FR), S. Dusko Ehrlich (FR), and Marilyne Uzest (FR) demonstrated fork breakage by replication arrest in E. coli (1338).

Andreas Luder (US) and Gisela Mosig (US) detailed the first clear elucidation that phage T4 initiates most of its DNA replication by a recombinational mechanism (1236).

Timothy Formosa (US) and Bruce M. Alberts (US) developed an in vitro DNA synthesis system that requires seven highly purified proteins encoded by the T4 bacteriophage: the DNA polymerase "holoenzyme" (four proteins), gene 32 protein, dda DNA helicase, and uvsX protein—an enzyme that catalyzes homologous DNA pairing and is functionally homologous to the recA protein. In the reaction observed, the 3'OH end of one single-stranded DNA molecule primes DNA synthesis using a double-stranded DNA molecule of homologous sequence as the template. They incorrectly surmised that DNA is synthesized by a conservative mechanism (633).

Joing Liu (US), Liewei Xu (US), Steven J. Sandler (US), and Kenneth J. Marians (US) provided key evidence that recombination provides an important pathway for completing DNA replication in E. coli (1208).

Sophie Maisnier-Patin (SE), Kurt Nordström (SE), and Santanu Dasgupta (SE) directly measured how often (DnaC-dependent) replication restart is invoked during E. coli growth (1263).

Martin R. Singleton (GB), Sarah Scaife (GB), and Dale B. Wigley (GB) determined the structure of RecG helicase bound to a replication fork-like DNA molecule (1746).

 

Kjell Kleppe (NO-US-GB-NO), Eiji Ohtsuka (JP), Ruth Kleppe (NO), Ian Molineux (US), and Har Gobind Khorana (IN-US) described a process called repair replication for synthesizing short DNA duplexes and single-stranded DNA by polymerases. This report outlined several features that are hallmarks of PCR but fell short of an experimental test. It predicted, for example, that the DNA duplex would have to be denatured to single strands, that an excess of primer to template would be required to overcome secondary structures generated by single-stranded template and that, following completion of the reaction by DNA polymerase, the cycle would have to be reinitiated if the template duplex had renatured (1065).

 

Hisayuki Matsuo (JP), Akira Arimura (US), R.M.G. Nair (US), Andrew Victor Schally (PL-US) synthesized active porcine luteinizing hormone-releasing factor (LRF) with the following amino acid sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (1302).

 

Orville L. Chapman (US), Michael Roy Engel (US), James P. Springer (US), and Jon C. Clardy (US) synthesized carpanone, a lignin from the carpano tree (353).

 

William S. Johnson (US), Michael B. Gravestock (US), Brian E. McCarry (US), Ronald J. Parry (US), and Bruce E. Ratcliffe (US) synthesized progesterone, a hormone that prepares the lining of the uterus for implantation of the fertilized egg (754; 983).

 

Stephen Fahnestock (US) and Alexander Rich (US) were the first to use the cell’s protein synthesizing machinery to produce a polypeptide containing a non-natural residue (582; 583).

 

Ramakrishnan Nagarajan (US), LaVerne D. Boeck (US), Marvin Gorman (US), Robert L. Hamill (US), Calvin E. Higgens (US), Marvin M. Hoehn (US), William M. Stark (US), and Joel G. Whitney (US) discovered the cephamycin antibiotics (1385). Note: These antibiotics are produced by species of Streptomyces.

 

Harvey J. Cohen (US), Irwin Fridovich (US), and Krishnakumar V. Rajagopalan (IN-US) documented the presence and function of molybdenum in sulfite oxidase and described some aspects of its electron paramagnetic resonance (EPR) signal (387). Note: In subsequent papers they discussed the purification and properties of sulfite oxidase from bovine liver and the nature of its heme prosthetic group.

Jean L. Johnson (US), Bryan E. Hainline (US), and Kasturi V. Rajagopalan (IN-US) developed a method to isolate the oxidized, inactive form of the molybdenum cofactor from sulfite oxidase, xanthine oxidase, and nitrate reductase and provided evidence that a pteridine moiety acts as a structural component of the cofactor (980). The molybdenum cofactor consists of a complex between molybdenum and a unique pterin, which they named molybdopterin.

Steven Philip Kramer (US), Jean Luc Johnson (US), Anthony A. Ribeiro (US), David S. Millington (US), and Kasturi V. Rajagopalan (IN-US) isolated a stable alkylated derivative of molybdopterin, camMPT, from sulfite oxidase and xanthine oxidase. Structural studies on the product confirmed that molybdopterin is a 6-alkylpterin with a 4-carbon side chain, which has an enedithiol at carbons 1' and 2', a hydroxyl at carbon 3', and a terminal phosphate group (1101).

 

Richard E. Moore (US) and Paul J. Scheuer (US) were the first to isolate palytoxin (1361). This substance is produced by certain soft corals of the genus Polythoa and is one of the most toxic non-peptide substances known.

Daisuke Uemura (JP), Katsuhiro Ueda (JP), Yoshimasa Hirata (JP), Hideo Naoki (JP), Takashi Iwashita (JP), Richard E. Moore (US), Giovanni Bartolini (US), Joseph J. Barchi, Jr. (US), Aksel A. Bothner-By (US), Josef Dadok (CZ-US), and Joseph Ford (US) worked out the structure of palytoxin (1359; 1360; 1918).

Ernst Richard Habermann (DE) found that palytoxin binds to Na/K pumps to generate nonselective cation channels (792).

 

Susan N. Meloan (US), Linda S. Valentine (US), and Holde Puchtler (US) established the structure of carmine and its Ca⁺⁺ and Al⁺⁺⁺ lakes (1328).

 

Bayer Chemical Company introduced the herbicide metribuzin, a symmetrical triazine, useful in soybeans (Glycine max), sugar cane (Saccharum officinarum), and potatoes (Solanum tuberosum). ref

 

Basil T. Doumas (US), W. Ard Watson (US), and Homer G. Biggs (US) developed a bromocresol green assay for serum albumin (508).

Tsuyoshi Ueno (JP), Satoshi Hirayama (JP), Masayuki Ito (JP), Emiko Nishioka (JP), Yoshifumi Fukushima (JP), Tomoaki Satoh (JP), Mayumi Idei (JP), Yuki Horiuchi (JP), Hiromichi Shoji (JP), Hirotoshi Ohmura (JP), Toshiaki Shimizu (JP), and Takashi Miida (JP) offered a modified bromocresol purple method as superior to the bromocresol green method for assessing nutritional status in malnourished patients with inflammation (1919).

 

Paul Barnett Green (US), Ralph O. Erickson (US), and James Buggy (US) examined the dynamic relationship of plant cell expansion to turgor pressure in the alga Nitella. Their findings supported the concept of a minimum “yield threshold turgor” for cell wall extension that is subject to rapid compensatory metabolic adjustments following changes in turgor pressure, allowing relative constancy of elongation rate despite changes in cell water status (757).

 

Jack D. Griffith (US), Joel A. Huberman (US), and Arthur J. Kornberg ((US) produced an electron photomicrographic image of Escherichia coli DNA polymerase I bound to DNA. This was not only the first EM image of DNA bound to a known protein, but it also showed that electron microscopy had the potential to provide quantitative information about macromolecular assemblies involving DNA (769).

 

Stratis Avrameas (FR), Brigitte Guilbert (FR), Eva Engvall (SE-US), Peter Perlmann (SE), Bauke K. van Weeman (NL), and Anton H. W. M. Schuurs (NL) developed the enzyme immunoassay procedure to quantify antigen and subsequently antibody (73; 74; 566; 567; 1937).

 

Marina Seabright (GB) developed a rapid banding technique for human chromosomes (1700). Note: The immediate application was to determine the location of break points in naturally occurring chromosome rearrangement in patients with congenital defects, and to study the lesions and patterns of exchange induced by X-irradiation.

 

Giuseppe Attardi (IT-US), Barbara Attardi (IT-US), Yosef Aloni (US), Donald L. Robberson (US), Livia Pica-Mattoccia (IT), and Norman Davidson (US) made significant progress toward understanding the structure of the human mitochondrial genome and its role in human disease (35; 36; 70; 1500; 1573; 1574).

 

John W. Kebabian (US), Paul Greengard (US) and James A. Nathanson (US) discovered how dopamine (prolactin-inhibiting hormone) and several other transmitters exert their action in the nervous system. The transmitter first acts on a receptor on the cell surface. This will trigger a cascade of reactions that will affect certain "key proteins" that in turn regulate a variety of functions in the nerve cell. The proteins become modified as phosphate groups are added (phosphorylation) or removed (dephosphorylation), which causes a change in the shape and function of the protein. Through this mechanism the transmitters can carry their message from one nerve cell to another (760; 1029; 1400).

John W. Kebabian (US), Gary L. Petzoid (US), and Paul Greengard (US) produced results suggesting that dopamine-sensitive adenylate cyclase may be the receptor for dopamine (prolactin-inhibiting hormone) in mammalian brain (1030).

 

Günter Klaus-Joachim Blobel (DE-US), David D. Sabatini (US), and Bernhard Dobberstein (DE) used data from experiments with in vivo and in vitro systems to predict that eukaryotic cells use signals to route proteins across membranes of the rough endoplasmic reticulum. This concept became part of the signal hypothesis (also referred to as topogenesis) (184-186).

César Milstein (AR-GB), George G. Brownlee (GB), Timothy M. Harrison (GB), Michael B. Mathews (GB), David Swan (US), Haim Aviv (IL), and Philip Leder (US) were the first to experimentally support the signal hypothesis. This was based on their studies of the manufacture and secretion of antibodies. The signal is a group of amino acid residues at the end of a nascent polypeptide with affinity for the membrane of the endoplasmic reticulum (262; 1345; 1839). Note: Günter Klaus-Joachim Blobel (DE-US) and his colleagues extended this concept to other proteins destined to be secreted by the cell (see Blobel references).

 

Grant Fairbanks (US), Theodore L. Steck (US), and Donald F.H. Wallach (US) were the first to describe the proteins of erythrocyte ghosts (585).

 

Lawrence Spatz (US) and Philipp Strittmatter (US) used detergents to isolate the complete cytochrome b5 molecule. This molecule contains an additional sequence of 40 amino acids more than the version isolated using hydrolytic agents. The additional sequence contains a predominance of hydrophobic side chains. They concluded that cytochrome b5 in its native form is anchored to the hydrophobic interior of a membrane (1774).

 

Clay M. Armstrong (US) provided the first general description of the K+ channel pore, including the fundamental ideas of a selectivity filter, a wider inner vestibule and a gate on the inside (62; 63).

 

Lars U. Lamm (DK), Arne Svejgaard (DK), and Flemming Kissmeyer-Nielsen (DK) assigned the human leukocyte antigen (HLA) region to chromosome 6 (1129).

 

Jacques M. Chiller (US), Gail S. Habicht (US), and William O. Weigle (US) found that apparently, immune unresponsiveness in only one cell type (either thymus or bone marrow cells) is sufficient for the tolerant state to be exhibited by the intact animal (361).

 

Tetsuo Hiyama (US) and Bacon Ke (US) examined spinach and several cyanobacteria where they identified pigment 430 as possibly the primary electron acceptor of photosystem 1 (891).

 

Joel H. Weiner (US) and Leon A. Heppel (US) showed that E. coli contains a specific binding protein for glutamine uptake, which they isolated, purified, and characterized. Their data suggested that this protein plays a role in the active transport of the amino acid across the bacterial membrane (2005).

 

J. Murdoch Mitchison (GB) reported that the gap 1 (G1) and gap 2 (G2) phases of the eukaryotic cell cycle may vary considerably between organisms and cell types but the synthesis (S) phase is typically restricted to a small fraction of the cell cycle (1346).

 

Martin Rodbell (US), Lutz Birnbaumer (US), Stephen L. Pohl (US), and Hendrik Michiel Jan Krans (US) were the first to determine that G protein is involved in transmembrane signaling. They noted that hormonal activation of adenylyl cyclase requires GTP (1583). They also noted that GTP interfers with detection of hormone (glucagon) binding to receptors which regulate adenylyl cyclase activity (1584).

Michael E. Maguire (US), Pamela M. Van Arsdale (US), and Alfred Goodman Gilman (US) found that guanine nucleotides effected receptor binding for specific agonists by reducing their affinity for the receptor (1261).

Dan Cassel (DE), Zvi Selinger (DE), and Thomas Pfeuffer (DE) discovered that GTP protein-linked systems are activated upon binding GTP; hydrolysis of GTP initiates or is responsible for deactivation; dissociation of GDP is linked with the rate-limiting step and is controlled by receptor (327-329).

Joseph Orly (IL) and Michael Schramm (DE) demonstrated that components of the adenylyl cyclase system could be mixed and exchanged by cell fusion (1453).

Elliott M. Ross (US), Alfred Goodman Gilman (US), Allyn C. Howelett (US), Kenneth M. Ferguson (US), and Thomas Pfeuffer (DE) reconstituted the adenylyl cyclase system in vitro (1498; 1600-1602).

John K. Northup (US), Paul C. Sternweis (US), Murray D. Smigel (US), Leonard S. Schleifer (US), Elliott M. Ross (US), and Alfred Goodman Gilman (US) purified G proteins associated with adenylyl cyclase (1425).

D. Michael Gill (US), Roberta Meren (US), Dan Cassel (DE), Thomas Pfeuffer (DE), Joel Moss (US), Martha Vaughn (US), Toshiaki Katada (JP), and Michio Ui (JP) discovered that cholera toxin and pertussis toxin possess ADP-ribosylate specific G proteins (327; 697; 1020; 1021; 1370).

Robert G.L. Shorr (US), Robert Joseph Lefkowitz (US), and Marc G. Caron (US) purified the beta-adrenergic receptor (1734).

Thomas Pfeuffer (DE), Bernhard Gaugler (DE), and Heinz Metzger (DE) purified adenylyl cyclase (1499).

Bernard Kwok-Keung Fung (US), James B. Hurley (US), and Lubert Stryer (US) discovered that G proteins are necessary for flow of information in the light-triggered cyclic nucleotide cascade of vision in the retina (656).

 

Robert D. Bremel (US), Annemarie Weber (DE-US), and John M. Murray (US) found that ATP hydrolysis in solutions containing actin filaments and heavy meromyosin subfragment (HMMS-1) units will proceed quite well even at low calcium ion levels, provided that the ATP level is also sufficiently low for rigor complexes to form. They found that the formation of rigor complexes could increase the affinity of troponin for calcium ions and that at high calcium ion levels, when actin filaments should be in the on state, the rate of ATP hydrolysis increased, provided the ATP level was low, to give what was called the potentiated state. This was found to be due to an increase in the rate of binding of subfragment-1 to actin. They found that potentiation by active complexes (i.e., force-producing) at high ATP levels was also observed provided the concentration of subfragment-1 in solution was abnormally high (229-232; 1516; 1996).

 

Werner Kundig (US) and Saul Roseman (US) isolated a phosphotransferase system from Escherichia coli. It catalyzed the transfer of phosphate from phosphoenolpyruvate to sugars of the D-gluco, and D-manno configurations, yielding pyruvate and the corresponding sugar 6-phosphate esters. This mechanism provides a way of concentrating sugars as their phosphates, against a gradient. Some of the components of this system are membrane associated while others are cytoplasmic (1113; 1114).

 

Kim D. Collins (US) and George R. Stark (US) synthesized a transition state analogue for the reaction catalyzed by aspartate transcarbamylase. The resulting analogue, N-phosphonacetyl-L-aspartate (PALA), combined most of the structural features of the two natural substrates, carbamyl phosphate and L-aspartate. They found that PALA was a very specific inhibitor of aspartate transcarbamylase at nanomolar concentrations and that it put the enzyme into a conformation closely resembling that associated with binding the transition state (399).

Patrick F. Coleman (US), D. Parker Suttle (US), and George R. Stark (US) purified mammalian aspartate transcarbamylase and discovered that it is one of three enzymes covalently linked in a single giant polypeptide, CAD, that also includes carbamyl phosphate synthetase and dihydro-orotase, two enzymes in the de novo pyrimidine pathway (399).

Geoffrey M. Wahl (US), Richard A. Padgett (US), and George R. Stark (US) investigated the cause of CAD overproduction in PALA-resistant cells. They found that all the mutant cell lines had increased levels of CAD mRNA. The increase in mRNA was found to be due to an increase in the number of CAD genes in the mutants. This was some of the earliest evidence for gene amplification in mammalian cells (1957).

 

Thomas Ferenci (AU) and Hans Leo Kornberg (GB-US) were able to elucidate the main routes whereby E. coli utilizes fructose as a sole carbon source for growth (600-602).

 

Michael Abercrombie (GB), Joan E.M. Heaysman (GB), and Sue M. Pegram (GB) were the first to identify focal adhesions. They observed them in electron microscopic studies of cultured fibroblasts. Many cells grown in cell culture adhere tightly to the underlying substrate through discrete regions of the plasma membrane, referred to as adhesion plaques, focal contacts, or focal adhesions (13).

 

Keith E. Summers (US) and Ian R. Gibbons (US) present evidence supporting the hypothesis that the propagated bending waves of live-sperm tails are the result of ATP-induced shearing forces between outer tubules which, when resisted by the native structure, lead to localized sliding and generate an active bending moment (1825).

 

Richard William Dutton (US), Reuben J.M. Falkoff (US), John A. Hirst (US), Michael Hoffmann (US), John W. Kappler (US), Jack R. Kettman (US), Jayne F. Lesley (US), and Douglas C. Vann (US) were the first to propose that soluble products released from T cells might mediate helper functions of T cells (520). Anneliese Schimpl (DE) and Eberhard Wecker (DE) confirmed this (1674).

 

Otto Götze (DE) and Hans Joachim Müller-Eberhard (DE-US-DE) described the C3-activator system: an alternate pathway of complement activation (741).

 

Anthony C. Allison (GB), A. Michael Denman (GB) and Roxann D. Barnes (GB) suggested that thymus-derived lymphocytes play two roles in preventing autoimmunity. T-lymphocytes, but not B- lymphocytes, are unresponsive to autoantigens. Ways in which the requirement for autoreactive T- lymphocytes can be bypassed are discussed. These result in stimulation of B- lymphocytes to secrete autoantibodies. Suppressor T-lymphocytes can also inhibit autoimmune reactions (31).

 

Michael Hoffmann (US) and Richard W. Dutton (US) found that depression of the in vitro immune response of mouse spleen cell suspensions to sheep erythrocytes by removal of macrophages could be reversed by the addition of supernatant fractions from peritoneal macrophage cultures. The red cell antigen can absorb supernatant fraction activity, and supernatant fraction-treated red cells are stimulatory in the absence of macrophages or supernatant fraction (899).

 

Ivan J. Ryrie (US) and André Tridon Jagendorf (US) observed changes in the conformation of the CF₁ unit of chloroplasts when the chloroplasts were illuminated or when the pH of the medium was changed from acidic to basic, creating a momentary pH gradient (1632).

 

Richard Kelly (US) reported the first successful in vitro cultivation of a spirochete. He grew Borrelia hermsi in a complex organic medium under microaerophilic conditions (1034).

 

Mark S. Bretscher (GB) pioneered work that established the overall organization and asymmetry of the erythrocyte polypeptides. He showed that most of the membrane proteins, including the most prevalent protein, spectrin, are associated with the cytoplasmic surface of the membrane. It was also recognized that spectrin is involved in maintenance of erythrocyte shape. Bretscher developed an important way of labeling cell membranes with nonpenetrating molecules such that the inside of the membrane could be distinguished from the outside (236-243).

Stanley E. Gordesky (US) and Guido V. Marinetti (US) demonstrated that nearly all phosphatidylserine and a minimum of seventy percent of phosphatidylethanolamine is on the inside surface of the human erythrocyte membrane, thus suggesting an asymmetric arrangement of membrane phospholipids (732).

Knute A. Fisher (US) demonstrated that cholesterol in human erythrocytes is asymmetrically distributed across the plane of the cell membrane, being more prominent on the exterior side than on the interior side (623).

Garth Lamb Nicolson (US), Serafeim P. Masouredis (US), Robert Hyman (US), Vincent T. Marchesi (US), and Seymour Jonathan Singer (US) demonstrated that the distribution of membrane proteins is asymmetric. They were the first to suggest that there is likely to be an interrelation between protein array and membrane function in cells with a variable distribution of proteins (1415-1418).

 Harden Marsden McConnell (US), Roger David Kornberg (US), Phillipe F. Devaux (FR), Mark G. McNamee (US), Kenneth L. Wright (US), and Betty Gaffney McFarland (US) used electron spin-resonance spectroscopy to show that lipid molecules move laterally and flip-flop within cell membranes (489; 1096; 1310-1312; 1322).

Robert F.A. Zwaal (NL), Ben Roelofsen (NL), Paul Comfurius (NL), and Laurens L.M. van Deenen (NL) demonstrated an asymmetric phospholipid distribution in red cell membranes from humans (2113).

 

David Baltimore (US) defined all viral mRNAs as plus strand RNAs. In this same publication Baltimore presented what is now called the Baltimore classification, a classification scheme that groups viruses into families, depending on their type of genome (DNA, RNA, single-stranded (ss), double-stranded (ds), etc.) and their method of replication (91).

 

George M. Baer (US), Melvin K. Abelseth (US), John G. Debbie (US), William G. Winkler (US), Robert G. McLean (US), and James C. Cowart (US) developed the concept, strategy, and programs for oral vaccination of wildlife against rabies (83; 474; 2039-2041).

 

Peter I. Payne (GB) and Tristan A. Dyer (GB) isolated 5.8S ribosomal RNA (5.8S rRNA) from plant tissue (1479).

 

Pierre Tiollais (FR), Francis Galibert (FR), and Michel Boiron (FR) discovered 45S ribosomal RNA (45SrRNA), also called hnRNA (1889).

Asen A. Hadjiolov (BG), Georgui I. Milchev (BG) and others found that the 45S rRNA is cleaved into 18S, 28S, and 5.8S rRNAs (793).

 

Jonathan Sprent (AU), Jacques F. A. P. Miller (AU), and Graham F. Mitchell (AU) described a methodology for selectively collecting thoracic duct lymphocytes induced by a specific antigen (1777).

 

Susan W. Craig (US) and John J. Cebra (US) found that Peyer's patches are a highly enriched source of cells which have the potential to proliferate and differentiate into IgA-producing immunocytes and that the Peyer's patch cells are far more efficient in seeding the gut of irradiated recipient rabbits with donor cells that give rise to immunoglobulin-producing cells than cells from peripheral blood or popliteal lymph nodes (425).

 

Billie L. Padgett (US), Gabriele M. Zurhein (US), Duard L. Walker (US), Robert J. Eckroade (US), and Bert H. Dessel (US) cultivated a papova-like virus from the brain of a case of progressive multifocal leucoencephalopathy (P.M.L.) complicating Hodgkin's disease. The virus was isolated by inoculation of primary cultures of human fetal glial (P.H.F.G.) cells with extracts made from brain obtained at necropsy. Electron-microscopic examination of sections of brain and of infected P.H.F.G. cultures revealed cells with nuclei containing virions, often in crystalline array, which are similar in size to members of the polyoma-SV40 subgroup of papovaviruses (1462). Note: This virus is also called PC virus

 

Donald E. Carey (US), Rachel Reuben (US), K.N. Panicker (), Robert Ellis Shope (US), and Richard M. Myers (US) discovered Thottopalayam thottimvirus, formerly Thottapalayam virus (TMPV), in India where it is part of a group of hantaviruses which are hosted by shrews instead of rodents (314). Note: Thottimviruses are not known to cause any disease in humans.

 

 Max Luciano Birnstiel (CH), Margaret I.H. Chipchase (US), Jim Speirs (US), Donald D. Brown (US), John Bertrand Gurdon (GB), and Kazunori Sugimoto (US) were the first to isolate and purify the genes coding for ribosomal RNAs (18S, 28S, and 5S) (169; 255; 256).

 

Kathleen J. Danna (US), Daniel Nathans (US), Ching-Juh Lai (US), George H. Sack, Jr. (US), Stuart P. Adler (US), George Khoury (US), Malcolm A. Martin (US), Theresa N.H. Lee (US), and Hamilton Othanel (US) used restriction endonucleases in the analysis and restructuring of DNA molecules. They used HindII to cut the purified DNA of simian virus 40 and separated the resulting restriction fragments by size using agarose gel electrophoresis. The order of the fragments was deduced (and corresponding restriction sites) in the 5000-nucleotide circular chromosome, creating a restriction map. In the 1972 paper they established that replication of SV40 DNA is bidirectional and proceeds symmetrically (21; 449-451; 1041; 1125; 1399). Note: These papers ushered in a new era in genetics.

 

Yasuji Oshima (JP) and Isamu Takano (JP), from genetic mapping data, predicted the physical arrangement of the yeast mating-type genes on a chromosome in Saccharomyces cerevisiae (1458).

 James B. Hicks (US), Ira Herskowitz (US), Amar J.S. Klar (US), Seymour Fogel (US), and David N. Radin (US) found that the two mating types of the yeast Saccharomyces cerevisiae could be interconverted in both homothallic and heterothallic strains. A defective alpha mating type locus can be converted to a functional a locus and subsequently to a functional alpha locus (868; 1062). Note: This has been called the "Cassette Model."

Jeffrey N. Strathern (US), James B. Hicks (US), and Ira Herskowitz (US) discovered that mating type switching during the haploid phase of the yeast, Saccharomyces cerevisiae is controlled by three adjacent gene loci on chromosome 3. These loci determine whether the cell is one of two mating types, a or alpha. A gene designated MAT is flanked on one side by a silent copy of a, and on the other side by a silent copy of alpha. If the a gene is duplicated, then inserted at the MAT locus the resulting cell is mating type a. If the alpha gene is duplicated then inserted at the MAT locus the resulting cell is mating type alpha (1815).

Jeffrey N. Strathern (US), Amar J.S. Klar (), James B. Hicks (US), Judith A. Abraham (US), John M. Ivy (US), Kim A. Nasmyth (GB), and Carolyn McGill (US) worked out many of the details of homothallic switching of yeast mating types in Saccharomyces cerevisiae (1816).

Alan Bender (US) and George F. Sprague, Jr. (US) determined that the alpha 1 product of the yeast alpha mating-type locus binds to homologous sequences within the control regions of the three-known alpha-specific genes and there acts a transcription activator (126).

Cynthia A. Keleher (US), Michael J. Redd (US), Janet Schultz (US), Marlan Carlson (US), and Alexander D. Johnson (US) found that Ssn6-Tup 1 proteins are a general repressor of transcription, which influences many genes thereby resulting in a pleiotropic effect. Part of this effect involves alpha 2-mediated repression resulting in the a-specific STE phenotype (1032).

 

Ronald J. Konopka (US) discovered the Period gene, which he found to be involved in the circadian clock of Drosophila (1088). See, de Marian1729

Pranhitha Reddy (US), William A. Zehring (US), David A. Wheeler (US), Ronald J. Konopka (US), Charalambos P. Kyriacou (GB), Vincent Pirrotta (US), Christopher Hadfield (US), Thaddeus A. Bargiello (US), F. Rob Jackson (US), Michael Warren Young (US) Jeffrey Connor Hall (US), and Michael Morris Rosbash (US) cloned Period, the first Drosophila clock gene and investigated the relationship of genes in the restoration of circidian rhythms (94; 95; 1551; 2098).

Paul E. Hardin (US), Jeffrey Connor Hall (US), and Michael Morris Rosbash (US) discovered that period mRNA and its associated protein (PER) had fluctuating levels during the circadian cycle. They proposed a Transcription Translation Negative Feedback Loop (TTFL) model as the basis of the circadian clock. Rosbash, Hall, and Hardin hypothesized that PER protein is involved in a negative feedback loop that controls per mRNA levels, and that this transcription-translation feedback loop is a central feature of the Drosophila circadian clock (811; 812).

Amita Sehgal (US), Adrian Rothenfluh-Hilfiker (US), Melissa Hunter-Ensor (US), Yifeng Chen (US), Michael Myers (US), and Michael Warren Young (US) found strong functional connections between the timeless gene (tim) and the period gene (per). Tim mutants interfered with per mRNA cycling. After finding strong functional connections between TIM and PER they concluded that per and tim worked together (1705).

Lino Saez (US) and Michael Warren Young (US) saw that PER and TIM associate with each other to stabilize each other and to allow their nuclear accumulation (1638).

Michael P. Myers (US), Karen Wager-Smith (US), Adrian Rothenfluh-Hilfiker (US), Michael Warren Young (US), Choogon Lee (US), Vaishali Parikh (US), Tomoko Itsukaichi (US), Kiho Bae (US), and Isaac Edery (US) revealed that light causes the rapid degradation of TIM and resets of the phase of the circadian rhythm (1153; 1380).

Jeffrey Price (US) Justin Blau (US), Adrian Rothenfluh (US), Marla Abodeely (US), Brian Kloss (US), and Michael Warren Young (US) discovered a kinase called "doubletime" (casein kinase 1) that phosphorylates PER on certain serine residues. This signal marks it for degradation. When PER and TIM are bound, "doubletime" does not seem to be able to phosphorylate PER, allowing it to accumulate (1526).

Kong L. Toh (US), Christopher R. Jones (US), Yan He (US), Erik J. Eide (US), William A. Hinz (US), David M. Virshup (US), Louis J. Ptacek (US), and Ying-Hui Fu (US) discovered a form of Familial Advanced Sleep Phase Syndrome (FASPS) in humans, which is linked to an hPer2 polymorphism that removes a serine normally phosphorylated by casein kinase 1 (1895).

 

John O´Keefe (US-GB) and Jonathan O. Dostrovsky (CA) discovered neurons called "place cells," which fire only when a rat moves to a specific spot in an enclosure (1437; 1438).

Vegard H. Brun (NO), Mona K. Otnæss (NO), Sturla Molden (NO), Hill-Aina Steffenach (NO), Menno P. Witter (NL), May-Britt Moser (NO), Edvard Ingjald Moser (NO), Marianne Fyhn (NO), Stefan Leutgeb (NO), Jill K. Leutgeb (NO), Alessandro Treves (IT), Carol A. Barnes (US), Bruce L. McNaughton (US), Torkel Hafting (NO), and Francesca Sargolini (NO) discovered "grid cells" that fire at regularly spaced intervals as animals roam, forming a navigational grid in the brain (267; 663; 794; 1170; 1171; 1657).

 

Julian Tudor Hart (GB) proposed the inverse care law which states: The availability of good medical care tends to vary inversely with the need for it in the population served. This inverse care law operates more completely where medical care is most exposed to market forces, and less so where such exposure is reduced. The market distribution of medical care is a primitive and historically outdated social form, and any return to it would further exaggerate the maldistribution of medical resources (822). Note: Its conclusions are valid today.

 

G. Barry Pierce, Jr. (US) and Carol Wallace (US) demonstrated with squamous cell carcinomas that some cells within a tumor can differentiate into benign cells incapable of forming a tumor when transplanted. This finding supported the idea of a cancer stem cell (1501).

 

Henry Harris (AU-GB) observed that normal mouse cells are dominant to malignant cells when the two types are fused in the laboratory. This work cast doubt on the theory that (dominant) oncogenes are the general rule (819).

David Comings (US) articulated a general framework for a role of tumor suppressor genes in all types of cancer: inherited tumors, he argued, are the result of a germ line mutation in regulatory genes that suppresses tumor genesis, followed by the somatic loss of the homologous allele. In non-heritable cancers, both alleles are affected in somatic cells (403).

Uta Francke (US) showed that cells of retinoblastomas typically contained abnormalities involving chromosome 13 (636). Later Jorge J. Yunis (US), and Nora Ramsay (US) refined the location as a deletion in the long arm of chromosome 13 (2095).

Christine Coulondre (FR), Jeffrey H. Miller (US), Philip J. Farabaugh (US), and Walter Gilbert (US) identified 5-methylcytosine as a mutational hotspot in Escherichia coli (422).

Arthur D. Riggs (US) and Peter A. Jones (US) reported that in mammalian DNA most if not all 5-methylcytosine bases are found in the dinucleotide sequence CpG (1569).

Webster K. Cavenee (US), Thaddeus P. Dryja (US), Robert Allan Phillips (CA), William F. Benedict (US), Roseline Godbout (US), Brenda L. Gallie (CA), A. Linn Murphree (US), Louis C. Strong (US), Raymond L. White (US), Marc F. Hansen (US), Magnus Nordenskjold (SE), Erik Kock (SE), Irene H. Maumenee (US), and Jeremy A. Squire (CA) localized the retinoblastoma gene (RB; also known as RB1) to a small region on chromosome 13 in man; they found that tumor genesis may result from the development of homozygosity for the mutant allele at the Rb-1 locus (333; 334).

Alan Y. Sakaguchi (US), Peter A. Lalley (US), and Susan L. Naylor (US) found that a rearrangement of human c-myc (cellular myelocytomatosis) gene was observed in Burkitt's lymphoma cells possessing the t (8;14) translocation suggesting that human c-myc is located close to the breakpoint on chromosome 8 (q24) involved in the t (8;14) translocation. The mouse c-myc gene segregated concordantly with chromosome 15 in mouse-Chinese hamster cell hybrids. These gene assignments are noteworthy, as structural and numerical abnormalities of human chromosome 8 and mouse chromosome 15 are frequently associated with B-cell neoplasms (1641).

Andrew P. Feinberg (US) and Bert Vogelstein (US) compared gene methylation in DNA from primary human tumor tissues with DNA from adjacent normal cells. They found lowered DNA methylation in the tumor tissue DNA (593).

Stephen H. Friend (US), Rene Bernards (US), Snezna Rogelj (US), Robert Allan Weinberg (US), Joyce M. Rapaport (US), Daniel M. Albert (US), and Thaddeus P. Dryja (US) isolated a human cDNA that mapped to the RB region and, importantly, was deleted at least partly in tumors. They were thus the first to discover a human tumor suppressor gene—retinoblastoma (649).

Wen-Hwa Lee (US), Robert Bookstein (US), Frank Hong (US), Lih-Jiuan Young (US), Jin-Yuh Shew (TW-US), and Eva Y. Lee (US) found a fundamentally different type of oncogene associated with a rare childhood tumor, retinoblastoma. In this cancer, malignancy results from the absence of a functional copy of the retinoblastoma (Rb) gene, which is therefore said to be recessive acting. Rb is an anti-oncogene, because its presence (even in a single copy) inhibits formation of this cancer (1159).

Wen-Hwa Lee (US), Robert Bookstein (US), Frank Hong (US), Lih-Jiuan Young (US), Jin-Yuh Shew (TW), Eva Y. H. P. Lee (US), Yuen-Kai T. Fung (US), A. Linn Murphree (US), Anne T'Ang (US), Jin Qian (US), Steven H. Hinrichs (US), and William F. Benedict (US) cloned RB by chromosome walking their way to a cDNA fragment that hybridized to transcripts in normal tissue, but was aberrantly expressed or deleted in retinoblastomas. This pointed to the inactivation of RB as being causative for cancer (657; 1160).

Huei-Jen Su Huang (US), Jing-Kuan Yee (US), Jin-Yuh Shew (US), Phang-Lang Chen (US), Robert Bookstein (US), Theodore Friedmann (US), Eva Y.H.P. Lee (US), and Wen-Hwa Lee (US) confirmed this by rescuing the neoplastic phenotype of RB-mutant retinoblastoma cells with wild-type RB (918).

James A. DeCaprio (US), John W. Ludlow (US), James Figge (US), Jin-Yuh Shew (TW), Chun-Ming Huang (US), Wen-Hwa Lee (US), Erika Marsilio (US), Eva Paucha (US), David M. Livingston (US), Peter Whyte (US), Karen J. Buchkovich (US), Jonathan M. Horowitz (US), Stephen H. Friend (US), Margaret Raybuck (US), Robert Allan Weinberg (US), Edward Harlow (US), Nicholas John Dyson (US), Peter M. Howley (US), and Karl Munger (US) found that the viral oncoproteins: E1A of adenovirus, large tumor (T) antigen of SV40, and E7 of papillomavirus bind to retinoblastoma protein (a tumor suppressor). This provided the first evidence of a physical link between oncoproteins and tumor suppressors (476; 524; 2020).

Valerie Greger (DE), Eberhard Passarge (DE), Wolfgang Höpping (DE), Elmar Messmer (DE), and Bernhard Horsthemke (DE) showed that an unmethylated CpG island at the 5' end of the retinoblastoma gene becomes hypermethylated in tumors from retinoblastoma patients, leading the authors to speculate that methylation could contribute directly to the silencing of tumor suppressors (761).

James A. DeCaprio (US), John W. Ludlow (US), Dennis Lynch (US), Yusuke Furukawa (US), James Griffin (US), Helen Piwnica-Worms (US), Chun-Ming Huang (US), David M. Livingston (US), Karen Buchkovich (US), Linda A. Duffy (US), and Ed Harlow (US) found that the product of the retinoblastoma susceptibility gene, retinoblastoma protein (RB), has properties of a cell cycle regulatory element (276; 477).

They reported, separately, that SV40 T antigen, which can drive G1-arrested cells into the cell cycle, only binds unphosphorylated RB — the first indication that this is the growth-suppressive form of RB. Therefore, they surmised that unphosphorylated RB acts to block exit from G1.

Note: Disruption of the pRb pathway liberates E2Fs and thus allows cell proliferation, rendering cells insensitive to antigrowth factors that normally operate along this pathway to block advance through the G1 phase of the cell cycle. The effects of the soluble signaling molecule TGFß (transforming growth factor beta) are the best documented. TGFß prevents the phosphorylation that inactivates pRb; in this fashion, TGFß blocks advance through G1.

Jennifer A. Pietenpol (US), Roland W. Stein (US) (US), Elizabeth Moran (US), Peter Yaciuk (US), Richard Schlegel (US), Russette M. Lyons (US), Mark R. Pittelkow (US), Karl Münger (US), Peter M. Howley (US), and Harold L. Moses (US) reported that in some cell types, transforming growth factor beta (TGFß) suppresses expression of the c-myc (cellular myelocytomatosis) gene, which regulates the G1 cell cycle machinery (1505). Note: Malfunctions in the c-Myc gene have also been found in carcinoma of the cervix, colon, breast, lung and stomach.

Peter A. Jones (US), William M. Rideout, III (US), Jiang-Cheng Shen (US), Charles H. Spruck, III (US), and Yvonne C. Tsai (US) found 5-methylcytosine to be a source of genetic mutation in tumors (989). These findings implied that altered DNA methylation could underlie oncogene activation.

Thomas M. Fynan (US) and Michael Reiss (US) discovered that the pRb signaling circuit, as governed by TGFß and other extrinsic factors, can be disrupted in a variety of ways in different types of human tumors (664).

Gregory J. Hannon (US), David Beach (US), Michael B. Datto (US), Patrick Pei-Chih Hu (US), Timothy F. Kowalik (US), Jonathan Yingling (US), and Xiao-Fan Wang (US) reported that TGFß causes synthesis of p15INK4B and p21 proteins, which block the cyclin: CDK complexes responsible for pRb phosphorylation (453; 809).

Peter W. Laird (US), Laurie Jackson-Grusby (US), Amin Fazeli (US), Stephanie L. Dickinson (US), W. Edward Jung (US), En Li (US), Robert Allan Weinberg (US), and Rudolf Jaenisch (US) provided evidence linking DNA hypermethylation with cancer formation. Mice with the 'Min' mutation in the adenomatous polyposis coli (Apc) gene develop intestinal polyps early in life. They reduced DNA methylation in Min mice, which led to a decreased number of polyps in the animals, lending support to the idea that tumor-suppressor genes are hypermethylated and silenced in cancer and can be reactivated by inhibiting DNA methylation (1126).

Masanori Hatakeyama (JP) and Robert Allan Weinberg (US) related that the retinoblastoma protein (pRb) is an inhibitor of cell cycle progression from the G1 to the S phase of the cell cycle. It acts through its ability to interact with cellular target molecules such as the E2F transcription factors. Recent evidence indicates that pRB inactivation is a key molecular event leading to the S-phase commitment at the G1 restriction point in the cell cycle. Deregulated inactivation of pRB in G1 phase may be a universal mechanism underlying cellular transformation (824).

 

Carl R. Merril (US), Mark R. Geier (US), and John C. Petricciani (US) were the first to stably incorporate genes from bacterial viruses into mammalian cells and have them expressed (1333).

 

Sylvia D. Gardner (US), Anne M. Field (US), Dulcie V. Coleman (US), and Bill Hulme (US) isolated the BK virus from the urine of a renal transplant patient (672). It is thought that up to 80% of the population contains a latent form of this virus, which remains latent until the body undergoes some form of immunosuppression. Note: later this virus would be classified as a polyoma virus.

Billie L. Padgett (US), Gabriel M. ZuRhein (US), Duard L. Walker (US), Robert J. Eckroade (US), and Bert H. Dessel (US) isolated the polyomavirus JC responsible for progressive multifocal leukoencephalopathy (PML) (1462).

 

Bert Geoffrey Achong (TT-GB), Peter W. Mansell (US), and Michael Anthony Epstein (GB) discovered a new human virus in cultures from a nasopharyngeal carcinoma (16). Note: This virus was later named simian foamy virus.

 

Peter C. Hinkle (US) and Lawrence L. Horstman (US) took isolated mitochondrial inner membranes and created some vesicles with the F₀F₁ ATPase facing inward and some with F₀F₁ ATPase facing outward. Protons were pumped in only one direction, depending on the direction in which the F₀F₁ ATPase faced (884).

 

William B. Amos (GB) discovered two types of Ca++ binding contractile fibers in the stalks of Vorticella; these proteins are collectively called spasmin (49).

Jean Febvre (FR) found these nanofilaments in the contractile organelles of the myonemes in acantharia (592). Note: Since then, these nanofilaments have been found to be the major constituents of the paraflagellar rod (PFR) in euglena, trypanosomes and dinoflagellates. They are also found in the rootlets of flagella and cilia in all eucaryotes studied so far and in mammalian cells. In the latter, they are associated with the centrosomes, which may suggest a crucial role in mitosis.

 

Lung T. Yam (US), Chin Yang Li (US), and William H. Crosby (US) developed several cytochemical methods to identify the monocytes and the granulocytes. These methods are simple, sensitive, easily reproducible, and can be used either singly or in combination. They may be used as objective means for accurate identification of the human blood cells (2073).

 

Judith L. Vaitukaitis (US), John B. Robbins (US), Eberhard Nieschlag (DE), and Griff T. Ross (US) developed a method for generating antisera with small doses of immunogen. With this technique, 100 ug or less of immunogen induced specific antibody production in rabbits injected intradermally. Moreover, animals injected with a single dose of the immunogen continued to produce antisera for several months in response to the single immunizing dose (1926).

 

Theodore Thomas Puck (US), Paul Wuthier (US), Carol Jones (US) and Fa-ten Kao (US) introduced the technique of selectively killing cells by using antisera directed against specific cellular surface markers. This simultaneously selected against the chromosome, which likely coded for the marker (1531).

 

Tom J. Carew (US), Eric Richard Kandel (US), Vincent F. Castellucci (CA), Harold M. Pinsker (US), and Wayne A. Hening (US), using the sea slug Aplysia as their subject, determined that learning seemed to change the nature of synapses between sensory and motor neurons. When the slug is sensitized to a stimulus the synapse is strengthened; when the slug habituates to a false alarm the synapse weakens (313; 1506).

Eric Richard Kandel (US), Marcello Brunelli (IT), Jack Byrne (US), and Vincent F. Castellucci (CA) found that cyclic AMP plays an important role in strengthening or weakening the synapse (1006).

Samuel M. Schacher (US), Vincent F. Castellucci (CA), and Eric Richard Kandel (US) determined that the actions of cyclic AMP included the activation of cyclic-AMP response elements (CREBs) (1667). Note: Animals, which lack this activated form of CREB, can still remember things, but cannot remember them for more than an hour or so.

 

Frank Hugh Ruddle (US), Verne M. Chapman (US), Florence C. Ricciuti (US), Mary J. Murnane (US), Robert J. Klebe (US), and P. Meera Kahn (NL) established the genetic linkage relationships of seventeen enzymes of humans (1619).

 

Ronald Duff (US) and Fred Rapp (US) showed that Herpes simplex virus types 1 and 2 are capable of inducing host cell transformation in vitro (514; 515).

 

Paul W. Webb (US) estimated metabolic power input, mechanical power output, and overall efficiency of swimming rainbow trout (Oncorhynchus mykiss). Webb’s efficiency data were significant as they represented the first realistic values obtained using estimates of mechanical power output derived from a swimming fish. Overall efficiency approached 15% at the upper end of the sustainable speed range (1995).

 

Janice Harumi Yen (US) and A. Ralph Barr (US), Jeffrey L. Dean (US), and Stephen L. Dobson (US) found substantial numbers of rickettsia-like microbes (Wolbachia type) in adults, eggs and embryos of mosquitoes. Mating compatibility of mosquito strains seems to be correlated with the strain of the microbe present. Mosquitoes that carry different strains of the microbe exhibit cytoplasmic incompatibility; those that carry the same strain of microbe are interfertile (473; 2081).

 

Roger Yate Stanier (CA) commenting on the blue-green algae said, “these organisms are not algae; their taxonomic association with eukaryotic groups is an anachronism…Blue-green algae can now be recognized as a major group of bacteria” (321).

 

George Henry Hepting (US) wrote, Diseases of Forest and Shade Trees in the United States, the most comprehensive text on these topics (856).

 

Roger S. Payne (US) found: 1) that barn owls (Tyto alba) can locate prey in total darkness using only the sense of hearing, with an error of less than 1° in both the vertical and horizontal planes, 2) that differences between the behavior of barn owls flying at prey in complete darkness (analyzed from films taken under infrared illumination) and their behavior in the light are correlated with the problems they must face in acoustic orientation, 3) that experiments with owls trained to strike a concealed loudspeaker show that they depend on frequencies of sound above 5 kHz, 4) that measurements of sound pressure in the region of the owl's eardrum, made with a probe-tube microphone while moving a loudspeaker around the owl's head, reveal that for frequencies above 8-5 kHz the ear is highly directional. At such frequencies, regions of high sensitivity (tightly isolated by peripheral regions of low sensitivity) are directed along different neuronal paths for the two ears, 5) that these regions of good sensitivity are correlated with the asymmetry of the barn owl's external ears, and 6) that movements of a flap of skin in front of the ear opening changes the overall directional sensitivity patterns by redirecting the regions of maximum sensitivity.

Payne posited a theory to explain how a barn owl might locate the position of a sound source by moving its head until the intensity of all frequencies comprising a complex sound is brought to a maximum in both ears (aided perhaps by differences in inter-aural time delay that are enhanced by intensity disparities) (1480).

 

Robert Lee Metcalf (US), Gurcharan K. Sangha (US), and Inder P. Kapoor (US) developed a model ecosystem for the evaluation of pesticide biodegradability and ecological magnification (1336).

 

Francesco G. Giannelli (GB) showed that the defect in DNA repair exhibited by Xeroderma pigmentosum cells could be corrected when they were fused with normal fibroblasts (685).

 

Gerald Medoff (US), Megan Comfort (US), and Genki S. Kobayashi (US) observed for the first time a synergistic effect of flucytosine (5FC) with amphotericin B (Amph B) in vitro. At the same time the monotherapy with 5FC caused in clinical trials a significant increase of resistant mutants (1325). Note: From these finding of additive effects in vitro, over sophisticated animal models to clinical trials. Combination therapy of 5FC plus Amph B became the gold standard for the acute phase of cryptococcal meningitis and was also used for other opportunistic fungal diseases in severely immunosuppressed patients.

 

Eleanor E. Storrs (US), Waldemar F. Kirchheimer (US) and Chapman H. Binford (US) attempted to establish the nine-banded armadillo (Dasypus novemcinctus Linn.) as a model for the study of leprosy. They reported that 18-24 hours following inoculation the animals developed a systemic infection like lepromatous leprosy in humans (1057; 1058; 1811).

 

Carolyn M. Giles (GB), John D. Crossland (GB), W.K. Haggas (GB), George H. Longster (GB) discovered the Rh 33 blood group antigen (695).

 

Barry M. Brenner (US), Julia L. Troy (US), and Terrance M. Daugharty (US) calculated the net driving force for renal ultrafiltration in rats. The average value of 14 cm H₂O is lower by some two-thirds than the majority of estimates reported previously based on indirect techniques. Single nephron GFR (glomerular filtration rate) was also measured, thereby permitting calculation of the glomerular capillary ultrafiltration coefficient. The average value of 0.044 nl sec⁻¹ cm H₂O⁻¹ glomerulus⁻¹ is at least fourfold greater than previous estimates derived from indirect observations (233).

 

Saul Krugman (US), Joan P. Giles (US), and Jack Hammond (US) produced the first vaccine to hepatitis B virus by extracting proteins from the virus, diluting them in water, and inactivating them by heat (1107).

 

Hans Olaf Bang (DK), Jörn Dyerberg (DK), and Aase Brøndum Nielsen (DK) examined the plasma-lipid pattern in 130 Eskimos (69 females, 61 males)—hunters and/or fishermen, and their wives—in the northern part of the west coast of Greenland and consuming a predominantly meat diet rich in polyunsaturated fatty acids. Most types of lipid were decreased, compared with Danish controls and Eskimos living in Denmark. The most remarkable finding was much lower levels of pre-β-lipoprotein and consequently of plasma-triglycerides in Greenlandic Eskimos than in Danish controls. These findings may explain the very low incidence of ischemic heart disease and the complete absence of diabetes mellitus in Greenlandic Eskimos (93).

 

Patrick Montrose Smythe (ZA), G.G. Brereton-Stiles (ZA), H.J. Grace (ZA), A. Mafoyane (ZA), Mary Schonland (ZA), Hoosen Mahomed Coovadia (ZA), Walter E.K. Loening (ZA), M.A. Parent (ZA), and G.H. Vos (ZA) performed investigations of the thymolymphatic system and cell mediated immunity in children with protein-calorie-malnutrition (PCM) that showed a decrease in: tonsil size, chemical sensitization of the skin, rate of lymphocyte transformation, the hemolytic serum complement, and thymic and peripheral lymphoid tissue. Lymphopenia below 2,500 prognosed death. In measles less than half had a rash and a giant-celled pneumonia was common (1761).

 

Herbert L. Bonkowsky (US), Donald P. Tschudy (US), Annie Collins (US), Joyce M. Doherty (US), Irene C. Bossenmaier (US), Ruth Cardinal (US), Cecil James Watson (US), G. Jeelani Dhar (US), Zbyslaw J. Petryka (US), and Claus A. Pierach (US) discovered that acute porphyric attacks can be successfully treated by the infusion of hematin. They recognized that these attacks are associated with severe heme depletion in the liver (198; 1989; 1990).

 

Louis Gluck (US), Maria V. Kulovich (US), Robert C. Borer, Jr. (US), Paul H. Brenner (US), Gerald G. Anderson (US), and William N. Spellancy (US) in studies on 302 amniocenteses showed that changes in phospholipids in amniotic fluid (PLAF) reflect those in the lung of the developing fetus. A sudden increase in lecithin concentration after 35 weeks heralds maturity of the pulmonary alveolar lining when respiratory distress syndrome will not occur should the fetus then be born. Clinical interpretation is made on a thin-layer chromatogram by inspection; a lecithin spot clearly larger than that of sphingomyelin marked pulmonary maturity in the fetus (712).

 

Gary John Douglas (CA) and James Stanley Simpson (CA) reported the conservative, symptomatic management of 16 patients following assumed splenic injury from blunt abdominal trauma resulted in normalization of hemodynamic stability within 2 days of hospital admission, complete normalization of clinical examination by 2 weeks post-discharge, and no hospital readmissions (507).

This approach to splenic injury management was later supported by future investigations, eventually leading to the acceptance of conservative management as standard of care.

 

Thomas Earl Starzl (US), Geoffrey R. Giles (US), John R. Lilly (US), Hiroshi Takagi (US), Gerard L. Martineau (US), Gerhard P.J. Schroter (US), Charles G. Halgrimson (US), Israel Penn (US), and Charles W. Putnam (US) corrected the metabolic abnormality of Wilson’s disease, first of more than two dozen liver-based inborn errors cured or ameliorated with liver replacement. These liver recipients and patients cured of mesoderm-based inborn errors by bone marrow transplantation were the first examples of effective genetic engineering (1787).

 

Fritz Derom (BE), Fabrice Barbier (BE), Severin Ringoir (BE), Jacques Versieck (BE), Georges Rolly (BE), Guyla Berszenyi (BE), Paul A. Vermeire (BE), and L. Vrints (BE) performed the first successful lung homotransplantation in man (486).

 

Paul Ichiro Terasaki (US), Miguel Kreisler (ES), and Max Ray Mickey (US) developed the Panel Reactive Antibody (PRA) Test to identify presensitized patients at high immunologic risk for an allograft (1872).

 

Marianne N. O’Donoghue (US) and Harvey A. Zarem (US) described the stimulation of neovascularization by skin grafts (862; 1433).

 

Gustavo Cudkowicz (US) and Michael Bennett (US) presented evidence from mouse experiments favoring the concept that allograft reactivity to hemopoietic cells is elicited by recessive tissue-specific antigens (434; 435).

 

Neil S. Painter (GB) and Denis Parsons Burkitt (GB) used geographical, historical, and physiological evidence to argue that diverticulosis coli is a preventable disease caused by the consumption of refined carbohydrates (1466).

 

Denis Parsons Burkitt (GB) deduced that a refined diet, low in fiber, might be a major contributing factor in bowl cancer and other non-infective diseases of the bowl, such as benign tumor, diverticular disease, and appendicitis (284).

 

David L. Page (US), James B. Caulfield (US), John A. Kastor (US), Roman W. DeSanctis (US), and Charles A. Sanders (US) found that cardiogenic shock is associated with extensive loss of left ventricular myocardium due to new and frequently old infarcts. They concluded that loss of more than approximately 40 percent of the left ventricular myocardium produced irreversible pump failure (1464).

 

Henry J. Mankin (US), Howard Dorfman (US), Louis Lippiello (US), and Antra Zarins (US) presented data indicating that human osteoarthritis is a highly focal disorder, that the proteoglycan concentration declines with advancing disease, and that a significant inverse relationship exists between synthetic activities and the severity of the process (strongly implying a “reparative” response) (1281).

 

Tavia Gordon (US) and William B. Kannel (US) reported that since 1948, a cohort of 5,209 residents of Framingham, Mass, have been examined biennially. In the first 14 years, 120 died of coronary heart disease (CHD) before reaching 65 years of age. Two thirds of these deaths occurred outside the hospital—the majority suddenly— within one hour of onset of the terminal event. Nearly one half of the deaths from the initial coronary attack were sudden and unexpected. One half of all persons with sudden deaths had no prior clinical heart disease. While nonsudden coronary deaths were ordinarily preceded by clinical CHD, the disease was frequently first manifest close to the final episode. Only a small percentage of persons were seriously disabled six months before their death. Even among persons with known CHD, nearly one half of the deaths occurred outside the hospital. It is concluded that the only road to a substantial reduction in premature CHD mortality is prevention of CHD (735).

 

Alfred G. Knudson, Jr. (US) proposed the "two-hit" theory of cancer causation, which explained the relationship between the hereditary and non-hereditary forms of a cancer and predicted the existence of anti-oncogenes (tumor suppressor genes) that can suppress cancer cell growth (1074-1077). Note: This now-confirmed theory has advanced understanding of errors in the genetic program that turns normal cells into cancer cells. The “two hit” theory later merged with the concept of allelic loss of tumor-suppressor genes.

 

Jan Koch-Weser (US) and Stuart W. Klein (US) reported procainamide dosage schedules, plasma concentrations, and clinical effects (1079).

 

Harris Miller Benedict (US), and Clarence J. Miller (US), and Ralph Eugene Olson (US) made the first systematic attempt to estimate the effects of air pollutants on plant productivity (129).

 

The Centers for Disease Control (CDC) report that between October 1970 and March 1, 1971, eight United States Hospitals in seven states experienced 150 bacteremias caused by Enterobacter cloacae or Gram-negative organisms of the Erwinia group. There were nine deaths; all associated with intravenous (IV) fluid therapy. This large nationwide outbreak of nosocomial bloodstream infections (BSIs) traced to intrinsic contamination of IV solutions led to widespread changes at industry, hospital, state, and federal levels (1).

 

Thomas W. Schoener (US) summarized the extant theory and created new theory for the field of feeding strategies. The theory is in four parts to explain why organisms select certain types of food from those encountered, where organisms feed, when organisms feed, and why organisms feed solitarily rather than in groups (1680).

 

Paul K. Dayton (US) utilized field experimentation to demonstrate that different types of physical and biological disturbance as well as competitive relationships have predictable funtional roles in the intertidal community. An important conclusion is that relatively few species have disproportionately important selective influences on most of the other species (463).

 

Robert L. Trivers (US), regarding human reciprocal altruism, shows that a model can explain the details of the psychological system that regulates altruism. Specifically, friendship, dislike, moralistic aggression, gratitude, sympathy, trust, suspicion, trustworthiness, aspects of guilt, and some forms of dishonesty and hypocrisy can be explained as important adaptations to regulate the altruistic system. Each individual human is seen as possessing altruistic and cheating tendencies, the expression of which is sensitive to developmental variables that were selected to set the tendencies at a balance appropriate to the local social and ecological environment (1906).

 

Mandred Eigen (DE) deduced that biological self-organization is based on natural selection. A prerequisite of natural selection is self- or complementary-reproduction. Such a process generates information, which is the physical basis of life (548).

 

Henry de Lumley (FR) discovered the earliest human remains of Homo erectus (upright man) from Europe, dated at c. 450 K BCE They were unearthed from the Caune de l'Arago cave (Tautavel, Pyrenees-Orientales, France) in 1971 (1532; 2042).

 

Jean-Jacques Jaeger (FR) and M. Abdeslem Dakka (MA), in 1971, discovered fossil remains of Homo erectus near Rabat, Morocco (963; 964). It was dated to 400 K BP

 

Michael H. Day (GB) reported the fossil remains of a Homo erectus found on the west side of Lake Turkana, Northern Kenya. It was dated to 1.6 M BP (461).

 

The United States Congress passed, and the President signed into law The National Cancer Act of 1971. This was the first mobilization of government and public support of basic biological research in the United States during the gene splicing age (2).

 

1972

"In our view, gene therapy may ameliorate some human genetic diseases in the future. For this reason, we believe that research directed at the development of techniques for gene therapy should continue. For the foreseeable future, however, we oppose any further attempts at gene therapy in human patients because (i) our understanding of such basic processes as gene regulation and genetic recombination in human cells is inadequate; (ii) our understanding of the details of the relation between the molecular defect and the disease state is rudimentary for essentially all genetic diseases; and (iii) we have no information on the short-range and long-term side effects of gene therapy. We therefore propose that a sustained effort be made to formulate a complete set of ethicoscientific criteria to guide the development and clinical application of gene therapy techniques." Theodore Friedmann (US) and Richard Roblin (US) (648).

 

Christian Boehmer Anfinsen (US) for his work on ribonuclease, especially concerning the connection between the amino acid sequence and the biologically active confirmation and Stanford Moore (US) and William Howard Stein (US) for their contribution to the understanding of the connection between chemical structure and catalytic activity of the active center of the ribonuclease molecule shared the Nobel Prize in Chemistry.

 

Gerald Maurice Edelman (US) and Rodney Robert Porter (GB) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning the chemical structure of antibodies.

 

Preston Ercelle Cloud, Jr. (US) proposed a working model of the primitive Earth in which he related atmospheric-geologic-biologic history of the Precambrian (384).

 

Gail Dodge (US), Charles Balitsky (US), Charles I. Sukenik (US), and John Adam (US) used thermoluminescence (TL) as a method for dating objects. This technique later proved useful for dating archaeological and paleoanthropological sites. The method is typically applied to dating samples of burned flint, which is between 5 K and 1M years old (498).

 

David Edmund Kuhl (US), Martin Reivich (US), Abass Alavi (US), Istvan Nyary (HU), and Muni M. Staum (US) performed the first quantitative measurement of cerebral blood volume in living patients (1112).

Louis Sokoloff (US), Martin Reivich (US), David Edmund Kuhl (US), Alfred P. Wolf (US), Tibor Farkas (US), Joel H. Greenberg (US), Michael E. Phelps (US), Tatsuo Ido (JP), Vito Casella (US), Joanna S. Fowler (US), Edward J. Hoffman (US), Gerald D. Robinson, Jr. (US), Norman S. MacDonald (US), Abass Alavi (US), Prantika Som (US), Harold L. Atkins (US), Debashis E. Bandoypadhyay (), Robert R. MacGregor (US), David R. Christman (US), K. Matsui (), Zvi H. Oster (US), Donald F. Sacker (US), Chyng-Yann Shiue (US), H. Turner (US), Chung-Nan Wan (), and Susan V. Zabinski (US) developed a method to visualize the simultaneous biochemical activity of an entire network of neural pathways in the brain and central nervous system. This new method maps and measures their functioning, both as a whole and in localized areas, under both normal and abnormal conditions. The technique involves measuring the brain's utilization of glucose, since glucose is the primary fuel for the central nervous system. But since glucose itself metabolizes too quickly for adequate study, analogues of glucose, 2-deoxy-D-glucose and 2-deoxy-2- [¹⁸F]-fluoro-D-glucose, (¹⁸FDG), a radiotracer, are used. These analogues differ infinitesimally from glucose itself but can be trapped in brain tissue long enough for chemical analysis and tomography, thus serving as a marker for central nervous system metabolism. ¹⁸FDG remains the most sensitive tracer to image tumors and tumor metastases, and it has provided the means of directly studying the effects of drugs on the human brain (590; 938; 1111; 1557; 1765-1767; 1770; 2051). These methods led the way to the development of Positron Emission Transverse Tomography (PETT); often shortened to (PET).

 

Kenneth E. Rubenstein (US), Richard S. Schneider (US), and Edwin F. Ullman (US) discovered that addition of morphine antibodies to a conjugate of morphine and lysozyme resulted in inhibition of lysozyme activity. Addition of free morphine to a mixture of the conjugate and morphine antibodies reduced the inhibition of enzyme activity in proportion to the quantity of free morphine added. As little as 1 × 10−9 M morphine could be detected in this manner. The method constitutes a powerful new immunochemical technique for the quantitative determination of haptens (1617).

 

Edith M. Carlisle (US) determined that silicon is required for normal growth and development in the chick when a low silicon diet is fed in a trace element-controlled environment. Silicon meets the criteria for an essential trace element (318).

 

Eli Lilly & Co., in 1972, synthesized fluoxetine hydrochloride and now sells this prescription product under the trade name Prozac.

Ray W. Fuller (US), Harold D. Snoddy (US), Andrew M. Snoddy (US), Susan K. Hemrick (US), David T. Wong (US), and Byran B. Molloy (US) discovered that p-iodoamphetamine (fluoxetine hydrochloride) blocks the reuptake of serotonin but not of other neurotransmitters (acts as a depletor) in rats (655). Note: This led directly to the introduction, in 1987, of the anti-depressant (Prozac), the first selective-serotonin re-uptake inhibitor (SSRI).

 

Hidekazu Suginaka (JP), Peter M. Blumberg (US) and Jack Leonard Strominger (US) reported that Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, and Escherichia coli have many penicillin-binding components (1821).

Peter M. Blumberg (US) and Jack Leonard Strominger (US) identified the major penicillin-binding component, V, as the D-alanine carboxypeptidase, the activity of which was not vital for the cell. Three of the other components, in contrast, bound penicillins and cephalosporins at rates comparable to that of the penicillin-killing site in B. subtilis (189).

 

Gertrude Belle Elion (US) developed azathioprine (Imuran); an agent to prevent the rejection of kidney transplants (553-555).

 

James Whyte Black (GB), William A.M. Duncan (GB), Graham J. Durant (GB), C. Robin Ganellin (GB), and Michael E. Parsons (GB), while trying to discover a useful H2 antagonist, performed work leading to the production of cimetidine (Tagamet) (176). Note: The hormone histamine influences the secretion of gastric acid. Histamine causes the release of chemicals when it interacts with points along cell membranes known as H-receptors. Black theorized that there are two types of H-receptors. H1-receptors cause allergic reactions and cold symptoms. Antihistamines suppress these symptoms, but fail to suppress the release of gastric acid, which occurs when histamine binds with the second type of H-receptor, called the H2-receptor.

 

Frederic Middlebrook Richards (US), Harold W. Wyckoff (US), William D. Carlson (US), Norma M. Allewell (US), Byungkook Lee (US), and Yukio Mitsui (US) solved the three-dimensional structure of ribonuclease-S (1564).

 

Howard K. Schachman (US) and John C. Gerhart (US) proved that the active site and inhibitor site on aspartate transcarbamylase are separate entities (1668).

 

Haim Aviv (IL) and Philip Leder (US) purified biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose (72).

 

Ann S. Henderson (US), Dorothy Warburton (US), and Kimball C. Atwood (US) hybridized ³H-labeled ribosomal RNA to human chromosomes on slides resulting in specific labeling of the satellite regions of chromosomes 13, 14, 15, 21, and 22, with an over-all efficiency of about 5% (845).

 

Democleia Panagou (US), Malcolm D. Orr (US), John R. Dunstone (US), and Raymond L. Blakley (US) were the first to give experimental evidence for a single-chain protein— ribonucleotide reductase of Lactobacillus leichmannii —that has both a catalytic site and a regulatory site, i.e., allosteric (1470).

 

Earl Wilbur Sutherland, Jr. (US) and his colleagues demonstrated that when the enzyme phosphorylase is itself phosphorylated by ATP its sensitivity to regulatory compounds is altered. They further demonstrated that this covalent change is controlled by the hormone adrenaline (epinephrine) through its messenger, cyclic AMP (1833).

 

Joan E. Mertz (US) and Ronald W. Davis (US) discovered that one of the restriction enzymes of Escherichia coli cuts DNA asymmetrically to produce fragments with single-stranded termini in which the nucleotide sequences are complementary. Such termini, being cohesive, permit the annealing of any fragments of DNA that are cut by this enzyme. This observation can be regarded as the starting point of recombinant DNA technology (1335).

 

David Jackson (US), Robert H. Symons (US), and Paul Berg (US) ligated genes from the lambda bacteriophage and galactose operon of Escherichia coli into the circular DNA of simian virus 40. This complex was taken up by Escherichia coli and replicated (958). Note: This was the first man-made recombinant DNA.

 

Joe Hedgpeth (US), Howard Michael Goodman (US), and Herbert Wayne Boyer (US) determined the DNA nucleotide sequence restricted by the EcoRI endonuclease (834).

 

Douglas Brutlag (US) and Arthur J. Kornberg (US) were the first to propose that some DNA polymerases may run in the 3' to 5' direction on DNA and carry out a proofreading function (271).

 

Vittorio Sgaramella (IT) and Har Gobind Khorana (IN-US) found that T4 ligase brings about the joining of duplexes at their base-paired ends by a bimolecular type of reaction and that an intramolecular mechanism can be ruled out (1718).

 

Randolph Wall (US), Lennart Philipson (SE), Jeffrey L. Weber (US), Zooey Gage (US), and James Edwin Darnell, Jr. (US) showed that cells copy viral genes into very large nuclear RNA molecules, too large to be mRNA, suggesting that some of the copied RNA ends up on the cutting room floor (1970; 1971).

 

Milton Adesnik (US), Marianne Salditt (US), W. Thomas (US), and James Edwin Darnell, Jr. (US) obtained the first direct evidence for RNA processing in messenger RNA formation, i.e., the addition of poly A to the 3' end of large nuclear RNA transcripts (20).

 

James Dewey Watson (US) realized that because of the requirement for an RNA primer, DNA polymerases are unable to replicate the extreme 3' end of a parental DNA strand of the linear T4 phage molecule. He accordingly proposed the presence of the end-replication problem (1991).

Alexy M. Olovnikov (RU) recognized that the end-replication problem would result in telomere shortening with each round of replication, he proposed that chromosome shortening might be a mechanism to limit the number of divisions of human diploid fibroblasts in culture and thus might make telomere shortening the basis for the Hayflick limit (1451). See, Hayflick, 1961.

Elizabeth H. Blackburn (US) and Joseph G. Gall (US) established that telomeres of Tetrahymena contain simple tandemly repeated sequences (178).

Janis Shampay (US), Carol W. Greider (US), Elizabeth H. Blackburn (AU-US), Eric R. Henderson (US), Marina S. Lee (US), Dorothy Shippen-Lentz (US), and Jack William Szostak (CA-US) showed that replacement of the primer of the leading chain on a DNA molecule during replication depends on a group of repeated sequences that cap the ends, or telomeres, of all eukaryotic chromosomes. They revealed that a specialized ribonucleoprotein enzyme, telomerase, maintains the telomere sequences and, thereby, the length of the leading chain (179; 763-765; 1720).

Robert K. Moyzis (US), Judy M. Buckingham (US), L. Scott Cram (US), Maria Dani (US), Larry L. Deaven (US), Myrna D. Jones (US), Julianne Meyne (US), Robert L. Ratliff (US), and Jung-Rung Wu (US) identified TTAGGG as the human telomere sequence (1372).

Victoria Lundblad (US) and Jack William Szostak (CA-US) described a general assay designed to detect mutants of yeast that are defective for any of several aspects of telomere function. Using this assay, we have isolated a mutant that displays a progressive decrease in telomere length as well as an increased frequency of chromosome loss. This mutation defines a new gene, designated EST1 (for ever-shorter-telomeres). Null alleles of EST1 are not immediately inviable; instead, they have a senescence phenotype, due to the gradual loss of sequences essential for telomere function, leading to a progressive decrease in chromosomal stability and subsequent cell death (1239).

Titia de Lange (US), Lily Shiue (US), Richard M. Myers (US), David R. Cox (US), Susan L. Naylor (US), Ann M. Killary (US), Harold Elliot Varmus (US), Carol W. Greider (US), Calvin B. Harley (US), and A. Bruce Futcher (GB-US) proposed that telomere shortening serves as a mitotic clock that counts cell divisions and ultimately results in cellular senescence (469; 762; 814; 815).

Christopher M. Counter (CA), Ariel A. Avilion (CA), Chatering E. LeFeuvre (CA), Nancy G. Stewart (CA), Carol W. Greider (CA), Carol B. Harley (CA), Silvia Bacchetti (CA) and Jerry W. Shay (US) showed that telomere maintenance is evident in virtually all types of malignant cells (423; 1724).

Junli Feng (US), Walter D. Funk (US), Sy-Shi Wang (US), Scott L. Weinrich (US), Ariel A. Avilion (GB), Choy-Pik Chiu (US), Robert R. Adams (US), Edwin Chang (US), Richard C. Allsopp (GB), Jinghua Yu (US), Siyuan Le (US), Michael D. West (US), Calvin B. Harley (US), William H. Andrews (US), Carol W. Greider (US), and Bryant Villeponteau (US) determined that telomerases have a region composed of RNA. They also noted that human telomerase is a critical enzyme for the long-term proliferation of immortal tumor cells (598).

Woodring E. Wright (US), Mieczyslaw A. Piatyszek (US), William E. Rainey (US), William Byrd (US), and Jerry W. Shay (US) found that telomerase activity is repressed in most human tissues during development (2065).

Joachim Lingner (CH), Timothy R. Hughes (US-CA), Andrej Shevchenko (RU), Matthias Mann (DK), Victoria Lundblad (US), and Thomas Robert Cech (US) found that the reverse transcriptase protein fold, previously known to be involved in retroviral replication and retrotransposition, is essential for normal chromosome telomere replication in diverse eukaryotes (Eucarya) (1205). Note: Could telomerase be the ancestor of retroviruses and transposons?

Andrea G. Bodnar (US), Michel Ouellette (US), Maria Frolkis (US), Shawn E. Holt (US), Choy-Pik Chiu (US), Gregg B. Morin (US), Calvin B. Harley (US), Jerry W. Shay (US), Serge Lichtsteiner (US), and Woodring E. Wright (US) showed that overexpression of telomerase in primary fibroblasts causes telomeres to elongate and the cells with the elongated telomeres do not enter senescence (191).

Tracy M. Bryan (AU) and Thomas Robert Cech (US) reported that telomere maintenance is evident in virtually all types of malignant cell; 85%-90% of them succeed in doing so by up regulating expression of the telomerase enzyme, which adds hexanucleotide repeats onto the ends of telomeric DNA (274).

Tom Vulliamy (GB), Anna Marrone (GB), Frederick Goldman (US), Andrew Dearlove (GB), Monica Bessler (US), Philip J. Mason (GB), and Inderjeet Dokal (GB) found that autosomal dominant dyskeratosis congenita results from a mutation in the RNA region of telomerase (1954).

Titia de Lange (US), Eros Lazzerini Denchi (US), Wilhelm Palm (DE), Agnel Sfeir (US), Fabian Erdel (US), Katja Kratz (US), Smaranda Willcox (US), Jack D. Griffith (US), Eric C. Greene (US), Yi Gong (US), Naofumi Handa (US), Stephen C. Kowalczykowski (US), and others, discovered that the ends of chromosomes are bound by a complex of proteins Titia de Lange (US) named shelterin. Their work addressed the mechanism by which telomeres protect chromosome ends, an issue referred to as the “telomere end-protection problem.” It was revealed that telomeres need to repress six distinct DNA damage response (DDR) pathways that threaten genome integrity. They identified the shelterin protein complex that protects telomeres and established how distinct shelterin subunits repress different DDR pathways (466-468; 482; 569; 725; 1468; 1717).

 

Peter M. Price (US), James H. Conover (US), and Kurt Hirschhorn (US) hybridized radioactive RNA specific for the production of haemoglobin with human metaphase chromosomes. The regions on the chromosomes which may contain the corresponding structural genes were identified by autoradiography (1529).

 

Norton B. Gilula (US), O. Raymond Reeves (GB), and Alan Steinbach (US) observed using electron microscopy and freeze-etching techniques that both metabolic coupling and ionic coupling in fibroblasts are associated with the appearance of “gap” junctions (703).

 

Alfred L. Goldberg (US) showed that cells lacking lysosomes, such as bacteria and immature erythrocytes, could nonetheless destroy abnormal proteins (715). Note:This led the way to the eventual discovery of cellular structures called proteasomes.

 

Richard Cawthon Starr (US) was the first to discover a sexual pheromone in green plants (Volvox carteri f. nagariensis) (1784).

Richard Cawthon Starr (US) and Lothar Jaenicke (DE) purified and fully characterized the sexual pheromone produced by Volvox carteri f. nagariensis Iyengar (1785). Note: Having Starria zimbabweensis, Chlorococcum starrii, and Cystomonas starrii named for him honored Starr.

Richard Cawthon Starr (US), Franz Joseph Marner (DE), and Lothar Jaenicke (DE) reported that the male gametes of Chlamydomonas are attracted by a pheromone produced by female gametes (1786).

Lothar Jaenicke (DE) and Richard Cawthon Starr (US) described the lurlenes, a new class of plastoquinone-related mating pheromones from Chlamydomonas allensworthii (Chlorophyceae). Female cells temporarily or constantly excrete these alluring signals into the medium to attract the male cells for mating (965).

 

Norman R. Klinman (US) produced results interpreted as indicating that (a) primary stimulation, like secondary stimulation, results from the selective stimulation by antigen of a population of cells differing from one another in their potential antibody product but each having only a single such product; (b) the antigen receptors of primary cells interact with antigen as if they are monovalent while receptors of secondary cells evidence multivalence; (c) antigenic stimulation appears to require both a relatively high affinity of receptors for bound antigen and an interlinking of receptors through such antigen; stimulation is thus seen as resulting from a stabilization of receptors within antigen-receptor aggregates to the cell surface; (d) T-cells appear to serve both in cross-linking antigens and in amplifying the size of stimulated clones (1067).

 

Antony Basten (AU), Jacques Francis Albert Pierre Miller (AU), Jonathan Sprent (AU), and Stephanie J. Pye (AU) proved the existence of Fc receptors on the surface of B cells but not on T cells (106).

 

Baruj Benacerraf (US) and Hugh O. Devitt (US) identified a new class of histocompatibility-linked genes that controls the formation of specific immune responses (125).

 

Stuart F. Schlossman (DE-US) reported that T cell epitopes on protein antigens or polypeptides involve at least seven amino acids (1675).

 

Hermann Wagner (AU) and Marc Feldmann (AU) introduced a new in vitro system for the generation of cell-mediated cytotoxic activity (1956).

 

Margaret Oakley Dayhoff (US) observed that most amino-acid sequences could be classified into relatively few families (462). Note: this work grew out of research agendas from the previous decade, including the biochemical investigation of the relations between the structures and function of proteins and the theoretical attempt to decipher the genetic code.

Walter Gilbert (US) later confirmed her observation (692).

 

Bo F. Oberg (US), Aaron Jeffrey Shatkin (US), George Jen (US), Claire H. Birge (US), Robert E. Thach (US), John L. Fakunding (US), William A. Held (US), Masayasu Nomura (JP-US), John W.B. Hershey (US), Michael J. Clemens (US), Brian Safer (US), Irving Myer London (US), William C. Merrick (US), William F. Anderson (US) Norton A. Elson (US), and Sherrill L. Adams (US) worked out the steps which occur during the initiation of protein synthesis in eukaryotes (Eucarya) (382; 561; 587; 840; 972; 1332; 1441; 1639).

Cha Mer Wei (US), Bernard Moss (US), Yasuhiro Furuichi (JP), Maureen A. Morgan (US), Subbaratnam Muthukrishnan (US), and Aaron Jeffrey Shatkin (US) discovered that the messenger RNAs (mRNAs) of a DNA virus (vaccinia) and of a double stranded RNA virus (reovirus) possess at their 5' termini the structure m⁷GpppG^mpCp- (661; 1997). This capping was subsequently found to be common in cells and to promote mRNA activity.

 

Joseph A. Gally (US) and Gerald Maurice Edelman (US) hypothesized that immunoglobulin genes have arisen in evolution from those specifying the histocompatibility system (670).

 

Diana F. Amsbaugh (US), Carl T. Hansen (US), Benjamin Prescott (US), Philip W. Stashak (US), David R. Barthold (US), and Philip J. Baker (US) described an X-linked recessive mutant in mice (xcid) which prevented them from developing a normal humoral response to certain antigens (50).

 

Chung-Mei Ling (US) and Lacy R. Overby (US) were the first to apply radioimmunoassay technology to the detection of a viral antigen in serum. It was the hepatitis B surface antigen (1203).

Robert H. Purcell (US), Doris C. Wong (US), Harvey J. Alter (US), and Paul V. Holland (US) developed a micro-solid-phase radioimmunoassay (micro-SPRIA) for hepatitis B antigen (HB Ag) for use with microtiter serological equipment (1534).

 

Bernice Kindred (AU), Donald Cecil Shreffler (US), David H. Katz (US), Toshiyuki Hamaoka (JP), Baruj Benacerraf (VE-US), Alan S. Rosenthal (US), Ethan Menahem Shevach (US), Rolf Martin Zinkernagel (CH-US), and Peter Charles Doherty (AU-US) discovered that T cells recognize only antigens that are present on the surfaces of other cells in the context of polymorphic cell-surface molecules encoded by the major histocompatibility complex (MHC), e.g. virus-specific CD8⁺ cytotoxic T lymphocytes (CTLs) recognize viral antigens presented by other cells only in the context of MHC molecules (1025; 1052; 1595; 1596; 2108; 2109). Note: The altered self hypothesis was born.

 

Howard B. Dickler (US) and Henry George Kunkel (US) described a method for the detection of Fc-gamma receptors on the surface of human mononuclear cells (493).

 

Mikael Jondal (SE), Göran Holm (SE), and Hans Wigzell (SE) concluded that sheep erythrocyte rosetting might be the first human T-lymphocyte marker and that it possibly could be used for T lymphocyte enumeration, classification of lymphoid malignancies, and fractionation of cells for experimental use (985).

 

Torkel Weis-Fogh (DK-GB) and William B. Amos (GB) while studying vorticellids discovered that their stalk employed a new mechanism of cell motility, which occurs without microtubules or microfilaments. It is based on calcium ion sensitive contractile proteins (2008).

 

Rochelle E. Esposito (US), Norman Frink (US), Paul Bernstein (US), and Michael S. Esposito (US) defined the first eleven sporulation-defective (spo) genes affecting various stages of meiosis in budding yeast (573).

 

Manfred Martin Mayer (DE-US) proposed that the C5-C9 complement membrane attack complex (MAC) exists as a transmembrane doughnut shaped unit which allows free flow across the membrane and typically leads to explosive rupture of the cell (1306). Note: This bold suggestion turned out to be essentially correct.

Eckhard R. Podack (US), Jürg Tschopp (CH), and Hans J. Müller-Eberhard (US) and others would later show that the MAC consists of polymerized C9 (1515; 1909).

 

Elio Raviola (US) and Morris John Karnovsky (ZA-US) provided evidence for a blood-thymus barrier using electron-opaque tracers (1545).

 

J. Victor Small (AT), John M. Squire (GB), Catherine F. Shoenberg (GB), and John C. Haselgrove (GB) proved the existence of myosin filaments in smooth muscle cells (1733; 1752).

 

Mark S. Bretscher (GB) determined that phospholipids of the plasma membrane assume an asymmetrical distribution (240).

 

 

Vladimir J. Balcar (AU) and Graham A.R. Johnston (AU) determined the structural specificity of the high affinity uptake of L-glutamate and L-aspartate by rat brain slices (88).

 

Rajko Igi (CS-US), Ervin G. Erdös (HU-US), Howard S.J. Yeh (US), K. Sorrells (?), and Tadashi Nakajima (JP) discovered that angiotensin I converting enzyme (ACE) and kininase II are identical and that this enzyme exerts a dual effect on blood pressure by controlling two oppositely acting peptides. It activates the vasoconstrictor angiotensin, which raises blood pressure, while also inactivating bradykinin, which is a vasodilator (939).

 

Jacques Benveniste (FR), Peter M. Henson (US), and Charles G. Cochrane (US) discovered platelet-activating factor (130; 131). Note: PAF was the first phospholipid known to have messenger functions. Benveniste and his colleagues made significant contributions in the role and characteristics of PAF and its importance in inflammatory response and mediation. These developments led to the finding that macrophages produce PAF and that macrophages play an important function in aggregation of platelets and liberation of their inflammatory and vasoactive substances.

 

 Eugene B. Rosenberg (US), Ronald Bo Herberman (US), Paul H. Levine (US), Roger H. Halterman (US), James L. McCoy (US), John R. Wunderlich (US), Frances C. Donnelly (US), Chris Alford (US), Rolf Kiessling (SE), George Klein (SE), Hans L.R. Wigzell (SE), Gyösö G. Petranyi (SE), Myrthel E. Nunn (US), Howard T. Holden (US), David H. Lavrin (US), and John C. Roder (SE) discovered and described natural killer cells (NK), which were later defined as effector cells with spontaneous cytotoxicity against various target cells; these effector cells lack the properties of classical macrophages, granulocytes, or cytotoxic T lymphocytes (CTL); and the observed cytotoxicity does not show restriction related to the major histocompatibility complex (MHC) (857; 858 18541; 859; 1044-1046; 1314; 1585; 1593).

Inessa Yu Chernyakhovskaya (RU), Elena G. Slavina (RU), George J. Svet-Moldavsky (RU), Sylvia B. Pollack (US), Gloria Heppner (US), R. James Brawn (US), Karen Nelson (US), Robert K. Oldham (US), David R. Siwarski (US), James L. McCoy (US), Ernest J. Plata (US), Ronald Bo Herberman (US), and John R. Ortaldo (US) produced results indicating that natural killer cells (NK) may play important roles in natural host resistance against cancer and infectious diseases (359; 860; 1447; 1518).

Gunther Dennert (US) cloned lines of natural killer cells (484).

 

Derek C. Ellwood (GB) and David W. Tempest (NL) documented the capacity of bacterial cells to alter their wall chemistry in response to growth rate and nutritional conditions (560).

 

Seymour Jonathan Singer (US), and Garth Lamb Nicholson (US) were the first to propose the fluid mosaic model to explain membrane structure (1745).

 

Cheryl A. Janson (US) and William Wallace Cleland (US) reported their analysis of the kinetic mechanism of glycerokinase (adenosine triphosphate: glycerol 3-phosphotransferase), which catalyzes the following reaction:

MgATP + glycerol ↔️MgADP + L-glycerol 3-phosphate (970).

 

David C. Hinkle (US), Michael John Chamberlin (US), Janet Ring (US), and Walter F. Mangel (US) determined that the sequence of steps leading to the initiation of transcription in Escherichia coli and T7 bacteriophage involves the binding of RNA polymerase to DNA, location of a specific promoter, and finally, RNA chain initiation. A model for RNA chain initiation by RNA polymerase was presented (341; 880-883; 1270-1272).

 

George Manolov (SE) and Yanka Manolova (SE) discovered that in most cells of freshly isolated Burkitt’s lymphoma there is an extra band at the end of the long arm of chromosome 14 (1284).

Lore Zech (SE), Ulla Haglund (SE), Kenneth Nilsson (SE), and George Klein (SE) later suggested that this band is a translocation from chromosome 8 (2097). Note: Growing evidence indicated that the chromosomal translocation (8;14) was a consistent feature in both sporatic and endemic Burkitt lymphomas.

 

Charlotte Boone (US), Tchaw-Ren Chen (US), and Francis Hugh Ruddle (US) located the human gene for thymidine kinase on the long arm of chromosome number 17 (200).

 

Eberhard Neumann (IL-DE), Kurt Rosenheck (IL), Ullrich Zimmerman (DE), J. Schulz (DE), and Gunther Pilwat (DE) discovered that when cells are exposed to high electric fields their membrane permeability increases and they are induced to fuse with one another (cell fusion and electroporation) (1411; 2105).

 

Peter S. Carlson (US), Harold H. Smith (US) and Rosemarie D. Dearing (US) obtained the first interspecific somatic hybrid by fusion of protoplasts between various species of tobacco (Nicotiana) (319).

 

Elizabeth Anna de Weerd-Kastelein (NL), Wilma Keijzer (NL), and Dick Bootsma (NL) used somatic cell hybridization to show that there is a multi-step pathway for the repair of ultraviolet light damage inflicted on DNA and that Xeroderma pigmentosum could result from a fault at any one of these steps. Normal cells in the hybridization are complementing, thus compensating for, the abnormal cells (472).

 

Efraim Racker (PL-AT-US) purified the calcium-pump from natural membrane, added it to artificial membrane, supplied it with ATP, and found that it would accumulate calcium against a concentration gradient (1537).

 

Robert R. Friis (US) concluded that tissue invasion by the elementary bodies of Chlamydia involves a phagocytic process (650).

 

Harvey J. Alter (US), Paul V. Holland (US), Robert Harry Purcell (US), Jerrold J. Lander (US), Stephen M. Feinstone (US), Andrew G. Morrow (US), Paul J. Schmidt (US), Yasuo Moritsugu (US), Hans Popper (US), Albert Zaven Kapikian (US), Qui Lim Choo (GB), George Kuo (GB), Amy J. Weiner (GB), Lacy R. Overby (GB), Daniel W. Bradley (GB), Michael Houghton (GB), George Ching-Hung Kuo (GB), Gary L. Gitnick (GB), Allan G. Redeker (GB), Tatsuo Miyamura (GB), Jules L. Dienstag (GB), Miriam J. Alter (GB), Cladd E. Stevens (GB), Gary E. Tegtmeier (GB), Ferruccio Bonino (GB), Massimo Colombo (GB), W.S. Lee (GB), C. Kuo (GB), Kim M. Berger (US), Jeffrey R. Shuster (US), Alexander A. Kolykhalov (US), Eugene V. Agapov (US), Keril J. Blight (US), Kathleen Mihalik (US), and Charles M. Rice (US) identified Hepatitis C virus. Prior to their work, the discovery of the Hepatitis A and B viruses had been critical steps forward, but the majority of blood-borne hepatitis cases remained unexplained. The discovery of Hepatitis C virus revealed the cause of the remaining cases of chronic hepatitis and made possible blood tests and new medicines that have saved millions of lives (39-41; 364; 595; 1087; 1118).

 

Albert Zaven Kapikian (US), Richard G. Wyatt (US), Raphael Dolin (US), Thomas S. Thornhill (US), Anthony R. Kalica (US), and Robert Merritt Chanock (US) associated a 27-nm particle in the stools of patients with acute infectious nonbacterial gastroenteritis. They suggested that the particle was the etiological agent of Norwalk gastroenteritis (Norwalk, Ohio) (1009). Note: Norwalk agent was the first virus that was identified as causing gastroenteritis in humans.

 

Marianne Weiss (CH), Franz Steck (CH), and Marian C. Horzinek (CH), in 1972, isolated a virus from a horse in Berne, Switzerland. The virus did not react with antisera against known equine viruses and was shown to have a unique morphology and substructure (2011).

Gerald N. Woode (US), Dan E. Reed (US), Paul L. Runnels (US), Marion A. Herrig (US), and Howard T. Hill (US), in 1982, isolated an unclassified virus from calves in Breda, Iowa (2062).

Graham Malcolm Beards (GB), Cheryl Hall (GB), Jon Green (GB), Thomas H. Flewett (GB), F. Lamouliatte (FR), and P. Du Pasquier (FR), in 1984, discovered particles resembling these viruses (immediately above) in the feces of humans (111). Note: By agreement at conference these became known as toroviruses

 

Stephania Ginsburg-Jabłońska (PL), Jan Dabrowski (PL), and Kazimierz Jakubowicz (PL) proposed the association of the human papilloma viruses with skin cancer in epidermodysplasia verruciformis (706).

Harald zur Hausen (DE) hypothesized that human papilloma virus plays an important role in the cause of cervical cancer (2112).

Stephania Ginsburg-Jabłońska (PL), Gérard Charles Jacques Orth (FR), Maria Jarzabek-Chorzelska (PL), Genowefa Rzesa (PL), Slavomir Obalek (PL), Wieslaw Glinski (PL), Michel Favre (FR), and Odile Croissant (FR) discovered human papilloma virus 5 (HPV-5) in skin cancer (707; 1457).

Matthias Dürst (DE), Lutz Gissmann (DE), Hans Ikenberg (DE), Harald zur Hausen (DE), Michael Boshart (DE), Andreas Kleinheinz (DE), and Wolfram Scheurien (DE) linked human papillomavirus type 16 and type 18 to cervical cancer in humans (204; 519). Note: Human papillomavirus (HPV) is the most common sexually transmitted virus in the United States. Almost every sexually active person will acquire HPV at some point in their life.

Luisa L. Villa (BR), Ronaldo L.R. Costa (BR), Carlos A. Petta (BR), Rosires P. Andrade( BR), Kevin A. Ault (BR), Anna R. Giuliano (BR), Cosette M. Wheeler (BR), Laura A. Koutsky (BR), Christian Malm (BR), Matti Lehtinen (BR), Finn Egil Skjeldestad (BR), Sven-Eric Olsson (BR), Margareta Steinwall (BR), Darron R. Brown (BR), Robert J. Kurman (BR), Brigitte M. Ronnett (BR), Mark H. Stoler (BR), Alex Ferenczy( BR), Diane M. Harper (BR), Gretchen M. Tamms (BR), Jimmy Yu (BR), Lisa Lupinacci (BR), Radha Railkar (BR), Frank J. Taddeo (BR), Kathrin U. Jansen (BR), Mark T. Esser (BR), Heather L. Sings (BR), Alfred J. Saah (BR), and Eliav Barr (BR) developed a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine (1944).

 

Allan Jacobs (GB), F.M. Miller (GB), Mark Worwood (GB), Michael R. Beamish (US), and Charles A.J. Wardrop (GB) introduced a method for measuring the quantity of ferritin in serum (960). Note: This is especially important for patients suspected of having iron imbalance.

 

Robert H. Allen (US) and Philip Warren Majerus (US) developed a method of affinity chromatography that is a potent tool for isolation of the trace vitamin B₁₂ binding proteins (30).

 

Jack Hirsh (AU-CA), John F. Cade (AU), Alexander S. Gallus (AU), and Dilip Basu (US) noted the relationship between the in vitro anticoagulant activity of heparin and its efficacy in patients with venous thrombosis (107; 889). Note: The superior clinical efficacy of low-molecular-weight heparin revolutionized anti-thrombotic treatment, allowing management on an outpatient basis.

 

Eloise R. Giblett (US), Jeanne E. Anderson (US), Fossie Cohen (US), Bernard Pollara (US), Hilaire J. Meuwissen (US), Hans D. Ochs (DE-US), John E. Yount (US), Shi-Han Chen (US), Clifford Ronald Scott (US), Ralph J. Wedgewood (US), Peter Nicholas (US), and Sam P. Hammar (US) were the first to discover a human immunodeficiency disease: adenosine deaminase deficiency (356; 689; 1442; 1698; 2088).

 

John F. R. Kerr (AU), Alastair R. Currie (GB), and Andrew H. Wyllie (GB) coined the term apoptosis, outlined the cardinal characteristics of this program of cell death and articulated the significance of apoptosis in human disease. They coined the term to rhyme with necrosis, and to mean literally a "falling off," as the petals fall off a flower or the leaves fall from a tree. The cell death machinery is a set of genes, which stand ever ready to self-destruct. In the 1972 article the authors described massive apoptosis in the cells populating rapidly growing, hormone-dependent tumors following hormone removal and offered the suggestion that apoptosis serves as a barrier to cancer (1036; 2068-2071).

John Edward Sulston (GB), H. Robert Horvitz (US), Einhard Schierenberg (DE), John G. White (GB-US), and J. Nicoll Thomson (GB) traced the embryonic cell lineage of the nematode Caenorhabditis elegans “from zygote to newly hatched larva, with the result that the entire cell lineage of this organism is now known. In every worm, out of 1,090 newborn cells, the same 131 cells die during development, resulting in a nematode of 959 cells exactly. The embryonic lineage is highly invariant, as are the fates of the cells to which it gives rise. Despite the fixed relationship between cell ancestry and cell fate, the correlation between them lacks much obvious pattern. Thus, although most neurons arise from the embryonic ectoderm, some are produced by the mesoderm and a few are sisters to muscles; again, lineal boundaries do not necessarily coincide with functional boundaries. Nevertheless, cell ablation experiments (as well as previous cell isolation experiments) demonstrate substantial cell autonomy in at least some sections of embryogenesis. They concluded that the cell lineage itself, complex as it is, plays an important role in determining cell fate” (1822-1824).

H. Robert Horvitz (US) and John Edward Sulston (GB) described the isolation and genetic characterization of 24 mutants defining 14 genes that affect the normally invariant post-embryonic cell lineages of C. elegans. The existence of these mutants demonstrates that it is possible to isolate strains defective in post-embryonic cell divisions. The spectrum of phenotypes suggests that different genes are involved in different cell lineages (910).

Hilary M. Ellis (US), H. Robert Horvitz (US), Michael O. Hengartner (US), Ding Xue (US), and Shai Shaham (US) described the genetic basis of programmed cell death, apoptosis, in the development of Caenorhabditis elegans (a nematode). They found many of the regulatory genes controlling apoptosis and showed that similar genes exist in humans. They identified genes that control the fate of doomed cells by screening for worms that — after mutagenesis of their genome — contained 'un-dead' cells (that is, cells that should have died, but survived instead). Tracing the mutations in these worms led them to two genes, ced-3 and ced-4 (called ced for cell death abnormal), which were both essential for cell death, and one, ced-9, which prevented death in cells that needed to survive. These experiments established a genetic basis for programmed cell death. Moreover, they showed that most developmental deaths are cell-autonomous — thereby establishing suicide rather than murder as the cause of death (558; 853; 854; 2072).

David Vaux (AU), Suzanne Cory (AU) and Jerry Adams (AU) showed that expression of the B cell lymphoma 2 (BCL2) gene could promote the survival of hematopoietic cells after the removal of growth factors. They also showed that the oncogene Myc cooperated with BCL2 to produce tumors in immunocompromised mice. They suggested that BCL2 provided a distinct survival signal that might contribute to neoplasia by allowing a clone to persist until other oncogenes, such as Myc, became activated. This provided evidence that cell survival is regulated independently of cell proliferation, and that impaired cell death, similar to enhanced proliferation, is indeed a key step in tumor development (1940).

Valerie A. Fadok (US), Dennis R. Voelker (US), Priscilla A. Campbell (US), J. John Cohen (US), Donna L. Bratton (US), and Peter M. Henson (US) discovered the exposure of phosphatidylserine at the lymphocyte’s outer surface during apoptosis triggering their recognition and removal by macrophages (581).

Masayuki Miura (JP), Hong Zhu (US), Rocco J. Rotello (US), Erika A. Hartwieg (US), and Junying Yuan (CN-US) found that the activities of mammalian interleukin-1 beta-converting enzyme (ICE) suggest that it may function during mammalian development to cause programmed cell death (apoptosis). Interleukin-1 beta-converting enzyme (ICE) is a member of a group of cysteine-dependent, aspartate-specific proteases (caspases) (1348).

Steve Frisch (US) and Hunter Francis (US) reported that epithelial cells, which lose touch with the extracellular matrix (ECM), kill themselves, a phenomenon the scientists dubbed anoikis (651). This type of apoptosis turned out to be an important mechanism for managing cell numbers, preventing abnormal growth, and squelching cancer.

Yuri A. Lazebnik (US), Scott H. Kaufmann (US), Serge Desnoyers (CA), Guy G. Poirier (CA), and William Charles Earnshaw (US) identified the specific amino acid sequence where caspases clip the DNA repair protein poly [ADP-ribose] polymerase (PARP) (1145).

Curtis C. Harris (US) found that the functional inactivation of p53 protein (product of the p53 gene) is seen in greater than 50% of human cancers and results in the removal of a key component of the DNA damage sensor that can induce the apoptotic effector cascade (818).

Arnold J. Levine (US) states that the functioning of the p53 DNA damage-signaling pathway is lost in most, if not all, human cancers (1174).

Joseph Lotem (IL), Leo Sachs (IL), Alison J. Butt (AU), Sue M. Firth (AU), and Robert C. Baxter (AU) suggested ligand/receptor molecules, which serve to bind either survival or death factors. Examples of these ligand/receptor pairs include survival signals conveyed by IGF-1/IGF-2 through their receptor, IL-3R (295; 1226). Note: IGF = insulin-like growth factor. IL-3R = interleukin 3 receptor.

Robert M. Pitti (US), Scot A. Marsters (US), David A. Lawrence (US), Margaret Roy (US), Frank C. Kischkel (US), Patrick Dowd (US), Arthur Huang (US), Christopher J. Donahue (US), Steven W. Sherwood (US), Daryl T. Baldwin (US), Paul J. Godowski (US), William I. Wood (US), Austin L. Gurney (US), Kenneth J. Hillan (US), Robert L. Cohen (US), Audrey D. Goddard (US), David Botstein (US), and Avi Ashkenasi (US) discovered a decoy receptor for Fas ligand which entices the death-inducing signal away from the Fas death receptor. The result is the abrogation of the Fas death signal. This decoy signal has been revealed in a high fraction of lung and colon carcinoma cell lines (1511). The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis).

Avi Ashkenazi (IL-US) and Vishva M. Dixit (KE-US) determined that death signals are conveyed by the Fas ligand binding the Fas receptor and by TNF alpha binding TNF-R1 (69). Note: The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis). TNF = tumor necrosis factor.

Gerard Evan (GB) and Trevor Littlewood (GB) noted that intracellular sensors monitor the cell's well-being and activate the death pathway in response to detecting abnormalities, including DNA damage, signaling imbalance provoked by oncogene action, survival factor insufficiency, or hypoxia (576).

Douglas R. Green (US) and John C. Reed (US) reported that many of the signals that elicit apoptosis converge on the mitochondria, which respond to proapoptotic signals by releasing cytochrome C, a potent catalyst of apoptosis (755).

Nancy A. Thornberry (US) and Yuri Lazebnik (US) determined the ultimate effectors of apoptosis to include an array of intracellular proteases termed caspases (1883).

Douglas Hanahan (US) and Robert Allan Weinberg (US) state that "collectively, the data indicate that a cell's apoptotic program can be triggered by an overexpressed oncogene. Indeed, elimination of cells bearing activated oncogenes by apoptosis may represent the primary means by which such mutant cells are continually culled from the body's tissues. Other examples strengthen the consensus that apoptosis is a major barrier to cancer that must be circumvented" (806).               

H. Robert Horvitz (US) and John Edward Sulston (GB) would be awarded the 2002 Nobel Prize in Physiology or Medicine for their discoveries concerning genetic regulation of organ development and programmed cell death.

 

Geoff Alan Parker (GB), R. Robin Baker (GB), and Veon G.F. Smith (NG) proposed a theory that attempts to explain the evolution of anisogamy (a difference in size on gametes), based upon gamete competition (1473).

 

Francisco J. Ayala (US), Jeffrey R. Powell (US), Martin L. Tracey (US), Celso A. Mourao (US), and Santiago Perez-Salas (US) reported allelic variation at 28 gene loci coding for enzymes in 70 natural populations of Drosophila willistoni. There was a great deal of variation —on the average, 58% of the loci were polymorphic and an individual fly was heterozygous at 18.4% of the loci. Although significant differences occurred between populations, the configuration of allelic frequencies was remarkably similar throughout the several million square miles covered by the distribution of the species (75).

 

John J. Bullen (GB), Henry J. Rogers (GB), and L.C. Leigh (GB) reported that human milk contains large quantities of iron-binding protein, of which the greater proportion is lactoferrin, though small amounts of transferrin are also present. Three samples of human milk with unsaturated iron-binding capacities of between 56 and 89% had a powerful bacteriostatic effect on Escherichia coli O111/B4. The bacteriostatic properties of milk were abolished if the iron-binding proteins were saturated with iron. It seems that iron-binding proteins in milk may play an important part in resistance to infantile enteritis caused by E. coli (278).

 

Porter W.Anderson (US), Georges Peter (US), Richard B. Johnston, Jr. (US), Leslie H. Wetterlow (US), David H. Smith (US), Richard A. Insel (US), Thomas R. Cate (US), Robert B. Couch (US), and William P. Glezen (US) produced and tested the first vaccine against Haemophilus influenzae type b (Hib) disease. It was licensed in the United States, in 1985, and first used in the US in 1988 (51; 52).

John B. Robbins (US), Rachel Schneerson (US), Shousun Chen Szu (US), Ali Fattom (US), Yonghong Yang (US), Teresa Lagergard (PL), Chiayung Chu (US) and Uffe B. Sørensen (DK) produced the first conjugate vaccine against Haemophilus influenzae (Hib) disease licensed in the United States. Conjugate vaccines are better able to induce an immune response than polysaccharide vaccines in infants and young children, the age group most at risk from Hib. This vaccine replaced a previous polysaccharide Hib disease vaccine (1575).

 

Rudy G. Danzinger (CA), Alan F. Hofman (US), Leslie J. Schoenfield (US), and Johnson L. Thistle (US) demonstrated that the ingestion of a pure, naturally occurring human bile acid, chenodeoxycholic acid (CDC), produced gradual dissolution of radiolucent (cholesterol) gallstones in four of seven women. Dissolution took from six to 22 months with the only notable side effect of dose-related diarrhea (452). Note: Perhaps 20 percent of all patients with gallstones could benefit from this form of therapy.

 

Edith Louise Potter (US) undertook microdissection and histology studies on human fetuses. She showed how the mechanisms of kidney development and maldevelopment can begin to be deduced from descriptive data. Potter for the first time clearly distinguished four varieties of cystic kidney (1524).

 

Hans R. Brunner (CH), John H. Laragh (US), Leslie Baer (US), Michael A. Newton (US), Frank T. Goodwin (US), Lawrence R. Krakoff (US), Richard H. Bard (US), and Fritz R. Bühler (US) in a retrospective analysis of 219 patients with essential hypertension, found that heart attacks and strokes were observed when plasma renin activity was normal or high, but in no instance when it was low. It was concluded that renin might be a risk factor in these patients (270).

 

Graham Collingwood Liggins (NZ-GB) and Ross N. Howie (NZ) found that respiratory distress syndrome (RDS) and perinatal mortality were significantly less common among preterm infants whose mothers received betamethasone prior to delivery (1193).

 

William F. Bernhard (US), S. Bert Litwin (US), Willis W. Williams (US), Jimmy E. Jones (US), and Robert Edward Gross (US) pioneered operations on inborn cardiovascular defects found in infants during the first year of life (147).

 

Charles Theodore Dotter (US), Josef Rösch (US), Arthur J. Seaman (US), Daniel Dennis (US), and William H. Massey (US) pioneered the techniques of low-dose fibrinolysis with injection of streptokinase directly into an occluding thrombus (505; 506).

 

David J. H. Brock (GB) and Roger G. Sutcliffe (GB) found that amniotic alphafetoprotein in fetuses is common to cases of anencephaly and spina bifida (248).

Stewart S. Sell (US), Alfredo A. Jalowayski (US), Clifford J. Bellone (US), and Harold T. Wepsic (US) developed a radioimmunoassay for alphafetoprotein (1715).

Malcolm Andrew Ferguson-Smith (GB) found that testing maternal serum for alphafetoprotein could reduce births with anencephalia and or spina bifida (603).

Irwin R. Merkatz (US), Harold M. Nitowsky (US), James N. Macri (US), and Walter E. Johnson (US) noted that maternal serum levels of alphafetoprotein are lower in Down's syndrome pregnancies than in unaffected pregnancies (1331).

 

Gustavo Reynoso (US), Tsann Ming Chu (US), Douglas Holyoke (US), Elias Cohen (US), Takuma Nemoto (US), J-J Wang (US), J. Chuang (US), Patrick Guinan (US), and Gerald P. Murphy (US) found carcinoembryonic antigen in patients with different cancers (1560). Note: Carcinoembryonic antigen (CEA) is a cancer-specific antigen described by Gold in 1965. It is a glycoprotein present in malignant entodermal tissues, in fetal colonic mucosa, and in the plasma of patients with gastrointestinal tract cancers.

 

Endel Tulving (EE-CA) first made the distinction between episodic and semantic memory. Episodic memory is the ability to consciously recollect previous experiences from memory (e.g., recalling a recent family trip to Disney World), whereas semantic memory is the ability to store more general knowledge in memory (e.g., the fact that Disney World is in Florida) (1914).

 

Niles Eldredge (US) and Stephen Jay Gould (US) proposed punctuated equilibrium effects in evolution; stating that evolution often occurs in short bursts, followed by long periods of stability. In his 1977b book, Gould critically revisits Haeckel's idea that ontogeny recapitulates phylogeny. He presents heterochrony as a concept that allows us to describe most of developmental processes in evolution (552; 747; 748).

 

Henry S. Horn (US) and Robert H. MacArthur (US) examined the qualitative behavior of differential equations in describing the potential for stable coexistence or competitive exclusion based on rates of migration and local extinction (906). Note: Their technique has subsequently been applied to questions about plant competition, landscape change, biodiversity maintenance, and parasite management.

 

Zofia Kielan-Jaworowska (PL) and Rinchen Barsbold (PL), during 1971, with their team and Mongolian paleontologists discovered the entwined skeletons of a Protoceratops and a juvenile Velociraptor in the Gobi Desert, most likely locked in mortal combat (1043). Note: These are late Cretaceous animals.

 

Dietrich Mania (DE), in 1972, discovered the first fossil skull fragment of Homo erectus bilzingslebenensis; Homo erectus; Homo sapiens near Bilzingsleben in Central Germany (1273). This fragment and those subsequently discovered has been dated to the Middle Pleistocene, c. 1.29 M BP

 

Maurice Taieb (FR), Yves Coppens (FR), Donald C. Johanson (US), Jon Kalb (US), and Raymonde Bonnefille (FR) discovered and described fossil remains of Australopithecus afarensis from the Hadar site in the Afar depression in the west central sedimentary basin, north-east of Addis Ababa, Ethiopia (976; 1849-1851). These specimens were dated to c. 2.9-3.0 M BP

Donald C. Johanson (US), Maurice Taieb (FR), Tim D. White (US), and Yves Coppens (FR) discovered a female fossil hominid at Hadar, Ethiopia (Australopithecus afarensis) and named her Lucy. Lucy's discovery established that hominids walked upright before developing large brains, overturning many long-held beliefs about hominid evolution. Australopithecus afarensis is considered to be the first human, but this is now being challenged by Meave G. Leakey’s discovery of Kenyanthropus in 2001 (975; 978). Note: Lucy was named for the girl in Elton John’s musical hit of the time, “Lucy in the Sky with Diamonds.”

Donald C. Johanson (US) and Tim D. White (US) discovered more specimens of Australopithecus afarensis (977). Australopithecus afarensis had an apelike face with a low forehead, a bony ridge over the eyes, a flat nose, and no chin. They had protruding jaws with large back teeth. Cranial capacity varied from about 375 to 550 cc. The skull is like that of a chimpanzee, except for the more humanlike teeth. The canine teeth are much smaller than those of modern apes, but larger and more pointed than those of humans, and shape of the jaw is between the rectangular shape of apes and the parabolic shape of humans. However, their pelvis and leg bones far more closely resemble those of modern man and leave no doubt that they were bipedal (although adapted to walking rather than running (386).

Mary Douglas Nicol Leakey (GB-KE) and Richard L. Hay (US) reported hominid footprints preserved in Pliocene ash deposits in the Laetolil Beds at Laetoli, Northern Tanzania. These footprints, discovered by the geochemist Paul I. Abell (US) in 1978, constitute the earliest evidence of bipedalism in the hominid fossil record. This hominid was very likely Australopithecus afarensis (1147).

Carol V. Ward (US), William H. Kimbel (US) and Donald Carl Johanson (US) found fossil feet confirming that the A. afarensis foot was functionally like that of modern humans and support the hypothesis that this species was a committed terrestrial biped (1982).

 

1973

“Nothing in biology makes sense except in the light of evolution.” Theodosius Grigorievich Dobzhansky (497).

 

“It is evolution which is the real creator of originality and novelty in the universe.” Jacob Bronowski (250).

 

"One cannot necessarily assign a function to an enzyme merely based on its in vitro properties or its abundance. A genetic approach using mutants makes meaningful in vivo correlates possible." Geoffrey L. Zubay and Marmur Julius.

 

Karl von Frisch (AT-DE), Konrad Zacharias Lorenz (AT) and Nikolaas Tinbergen (NL) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning organization and elicitation of individual and social behavior patterns.

 

BASF Chemical Company introduced the herbicide bentazon, a benzothiadiazine, for the control of broadleaf weeds in soybeans (Glycine max), rice (Oryza sativa), corn (Zea mays), and peanuts (Arachis hypogaea). Ref

 

Clive A. Hendrick (US), Gerardus B. Staal (US), and John B. Siddall (US) described a new class of insect growth regulators with very potent juvenile hormone activity (juvenoids), including isopropyl (2E,4E)-1 1-methoxy-3,7,11-triniethyl-2,4-dodecadienoate (methoprene) and ethyl (2E,4E)-3,7,11-trimethyl-2,4-dodecadienoate (hydroprene). This was the first practically useful class of juvenoids, and three commercial products for insect control (methoprene, hydroprene, and kinoprene) (855).

 

Valery I. Ivanov (RU), Lyudmila E. Minchenkova (RU), Anya K. Schyolkina (RU), and Andrei I. Poletayev (RU) presented a general classification of forms of the nucleic acid double helix according to families. The physical mechanisms for the gradual change within the B and A families of forms and for interfamily B-A transitions were suggested (955).

 

Sambhorao T. Rao (US) and Michael T. Rossmann (DE-US) described the "Rossmann fold", a nucleotide binding motif found in enzymes such as dehydrogenases or kinases that bind molecules such as adenosine triphosphate or nicotinamide adenine dinucleotide (1541).

 

Ari Helenius (FI) and Kai Simons (FI) described the mechanisms of detergent action on biological and artificial membranes. The interactions between proteins and detergents are described in detail, and a conceptual framework is presented for the use of mild detergents in membrane isolation and characterization (841; 842).

 

Giovanni Bucolo (US) and Harold David (US) introduced a simplified, highly specific enzyme-based method for serum triacylglycerol (TG) determination (277).

 

Phillip Allen Sharp (US), Bill Sugden (US), and Joseph Sambrook (GB-US-AU) were the first to use agarose gel electrophoresis for rapid analysis of DNA restriction patterns and the first to use the fluorescent dye, ethidium bromide, to stain DNA bands in agarose (1722).

 

Marshall Elzinga (US), John H. Collins (US), W. Michael Kuehl (US), and Robert S. Adelstein (US) determined the amino acid sequence of G-actin (19; 563). This study represents the first complete determination of the amino-acid sequence of a myofibrillar protein. This protein polymerizes to form F-actin the main component of actin filaments.

 

Alexander N. Glazer (PL-AU-US) and Suen Fang (US) described a method for the quantitative separation of the alpha and beta subunits of phycocyanin and reported the phycocyanobilin chromophore content of the alpha and beta subunits of phycocyanin and allophycocyanin from Synechococcus sp., a unicellular cyanobacterium. By spectroscopic analysis, they showed that the alpha subunit of phycocyanin carries a single chromophore, the beta subunit carries two chromophores, and the subunits of allophycocyanin carry a single chromophore per polypeptide chain. Experiments with cyanobacteria belonging to other taxonomic groups established the generality of the findings (711).

Daniel J. Lundell (US), Robley Cook Williams (US), and Alexander N. Glazer (PL-AU-US) elucidated the mode of assembly of the phycobilisome rod substructures. They purified four uncolored polypeptides from the phycobilisomes of this unicellular cyanobacterium and showed that three of these, 33-, 30-, and 27-kDa polypeptides, were involved in the assembly of phycocyanin into the rod substructures. They showed for the 30-kDa and 33-kDa polypeptides that each facilitated the assembly of phycocyanin into (alpha beta) 6 discs and linked them into rods. Phycocyanin and the 27-kDa polypeptide formed an (alpha beta) 6-27-kDa complex that did not itself stack into rods, but its addition to a rod terminated further growth (1240).

 

Hans Leo Kornberg (GB-US) recognized that there exists a "pecking order" in the sequence in which E. coli takes up different hexoses. For example, as little as micromolar amounts of glucose will powerfully inhibit the continued uptake of fructose, even though the cells are fully induced for fructose utilization and that ketose is present in great excess (1091).

 

Cyril Jeremy Craven (GB) and Desmond J. Dawson (GB) showed that tetanus toxin prepared from cells consists of a single polypeptide chain of an approximate M.W. of 160,000 daltons (426).

 

Frederick Sanger (GB), Alan R. Coulson (GB), Steve Nicklen (GB), Gillian M. Air (GB), Nigel L. Brown (GB), John C. Fiddes (GB), Clyde A. Hutchison III (US), Patrick M. Slocombe (GB), Michael Smith (GB-CA), Barclay George Barrell (GB), Allan M. Maxam (US), and Walter Gilbert (US) developed rapid methods for sequencing the bases of DNA (691; 1304; 1305; 1647; 1648; 1651). The 1977 article by Sanger et al. established the sites for initiation and termination of transcription and revealed that in some cases two genes are transcribed from the same DNA region using different reading frames. See, Berget, 1977 and Chow, 1977

Eugene D. Sverdlov (RU), Galina S. Monastyrskaya (RU), Arsenii V. Chestukhin (RU), and Edward I. Budowsky (RU-US) originated the methodology found in the Maxam-Gilbert method (1837). Their laboratory chief, Yuri A. Ovchinnikov (RU), thought the scheme would not work, so it was not tested.

Lloyd M. Smith (US), Jane Z. Sanders (US), Robert J. Kaiser (US), Peter Hughes (US), Chris Dodd (US), Charles R. Connell (US), Cheryl Heiner (US), Stephen B.H. Kent (US), and Leroy E. Hood (US) developed a method for the partial automation of DNA sequence analysis. Fluorescence detection of the DNA fragments is accomplished by means of a fluorophore covalently attached to the oligonucleotide primer used in enzymatic DNA sequence analysis. A different colored fluorophore is used for each of the reactions specific for the bases A, C, G and T. The reaction mixtures are combined and co-electrophoresed down a single polyacrylamide gel tube, the separated fluorescent bands of DNA are detected near the bottom of the tube, and the sequence information is acquired directly by computer (1757).

 

Paul Brazeau (US), Wylie W. Vale (US), Roger Cecil Burgus (US), Nicholas Ling (US), Madalyn Butcher (US), Jean Rivier (US), and Roger Louis Guillemin (FR-CA-US) discovered a hypothalamic polypeptide (somatostatin) that inhibits the secretion of immunoreactive pituitary growth hormone (227).

Roger Cecil Burgus (US), Nicholas Ling (NZ), Madalyn Butcher (US), and Roger Charles Louis Guillemin (FR-CA-US) determined that H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH is the primary structure of somatostatin (somatotropin-release inhibiting factor), a hypothalamic peptide that inhibits the secretion of pituitary growth hormone (282).

Steven W.J. Lamberts (NL), Aart-Jan van der Lely (NL), Wouter W. de Herder (NL), and Leo J. Hofland (NL) found that somatastatin could inhibit a variety of gastrointestinal processes (1128).

 

John Truman Rotruck (US), Arthur L. Pope (US), Howard E. Ganther (US), Alfred B. Swanson (US), Dean G. Hafeman (US), and William G. Hoekstra (US) discovered that selenium is a dietary essential because it is a component of glutathione peroxidase (1613).

 

Donald Yamashiro (US) and Choh Hao Li (CN-US) synthesized the entire human adrenocorticotropin hormone (ACTH) containing 39 residues. During the process they learned that as residues 19 through 26 were added the ACTH potency increased until at 26 it became as potent as the natural hormone (2074).

 

Shunji Natori (JP), Kazuyuki Takeuchi (JP), and Den’ichi Mizuno (JP) identified elongation factor SII (TFIIS) by its ability to stimulate transcription in vitro and to enable RNA polymerase II (pol II) to synthesize long transcripts (1401).

John Logan (US), Erik Falck-Pedersen (US), James Edwin Darnell, Jr. (US), Thomas Shenk (US), Sheila Connelly (US), and James L. Manley (US) established that polyadenylation and transcription termination are dependent on the same DNA sequences at the 3' ends of genes (409; 1222).

Daniel Reines (US), Michael G. Izban (US) and Donal S. Luse (US) provided insights into the mechanism of SII activity. They noticed that the addition of elongation factor SII caused a shortening of transcripts associated with stalled RNA pol II. They found that, in the presence of SII, the RNA pol II complex could serve as a nuclease, cleaving its nascent transcript from the 3' end (957; 1555).

Daguang Wang (US) and Diane K. Hawley (US) also presented evidence to support these observations and proposed a possible proofreading role for the activity described. Surprisingly, it was noted that this process leaves the pol II complex intact and the remaining transcript can subsequently be elongated. The nuclease activity that is stimulated by SII helps pol II bypass specific blocks to elongation and therefore increases elongation efficiency (1976).

 

Richard E. McCarty (US), John Fagan (US), and Ronald P. Magnusson (US) showed that the reactivity of a chemical group in one subunit of chloroplast CF₁ is enhanced when chloroplasts are illuminated (1260; 1309).

 

Walter Gilbert (US) and Allan M. Maxam (US) showed that the operator of the lac gene contains a highly symmetrical base sequence recognized by the lac repressor molecule (693; 694).

 

Stanley Norman Cohen (US), Paul Berg (US), John Anthony Carbon (US), John F. Morrow (US), Thomas E. Shenk (US), Herbert Wayne Boyer (US), Achilles Dugaiczyk (US), Howard Michael Goodman (US), Annie C.Y. Chang (US), Robert B. Helling (US), and Stephen Payne Goff (US) developed techniques for recombining DNA from two different sources using restriction endonucleases. Berg’s experiments showed that a restriction endonuclease can be used to cut DNA in a predictable manner and that DNA fragments from different organisms can be joined together. Foreign DNA could be recombined with plasmid DNA then maintained and replicated within Escherichia coli (312; 389; 391; 392; 516; 714; 1366).

Stanley Norman Cohen (US) and Herbert Wayne Boyer (US) applied to patent this process (390).

 

Eric H. Davidson (US) and Roy J. Britten (US) pioneered nucleic acid hybridization kinetics to study eukaryotic gene expression (455).

 

Paul Delos Boyer (US), Richard L. Cross (US), William Momsen (US), B.O. Stokes (US), Richard G. Wolcott (US), and Chemda Degani (IL) presented the binding change hypothesis which suggests that at one time (a) ADP and Pi (inorganic phosphate) bind weakly at one site of the alpha-beta pair of the F1 part of the ATP synthase enzyme; (b) bound ATP is formed from bound ADP and Pi, without the use of energy at a second alpha-beta pair; and (c) the pH gradient energy is converted into rotational energy, mainly of the gamma subunit that extends up to the third alpha-beta pair, that is used to flip off the ATP free from the third alpha-beta binding site. These three sites alternate in time (213-218).

R. Lee Hutton (US) and Paul Delos Boyer (US) were able to characterize the three catalytic sites of ATP synthase as displaying identical behavior, ruling out the possible participation of two types of catalytic sites (934).

According to Boyer’s "binding change mechanism" for ATP synthesis, the three catalytic sites on the enzyme bind ADP and phosphate in sequence and then undergo a conformational change to make a tightly bound ATP. The sites then change conformation again to release the ATP. These changes are accomplished by rotational catalysis driven by the rotating inner core of the enzyme, which is in turn driven by the protons crossing the mitochondrial membrane.

Roderick A. Capaldi (GB) demonstrated the rotation feature of the Boyer model directly by fluorescence microscopy and by photoselection and other experiments (311).

Jan Pieter Abrahams (NL), Andrew G.W. Leslie (GB), René Lutter (NL), and John E. Walker (GB) deduced the atomic resolution structure of beef-heart mitochondrial F₁-ATPase at the 2.8-angstrom level. They found that the structure supports a catalytic mechanism in intact ATP synthase in which the three catalytic subunits are in different states of the catalytic cycle at any instant. Interconversion of the states may be achieved by rotation of the α₃β₃ subassembly relative to an α-helical domain of the γ-subunit (14).

Daniel J. Smith (US), Barry O. Stokes (US), Michael Gresser (US), Jeffrey W. Cardon (US), Gary Rosen (US), Paul Delos Boyer (US), Ian M. Fearnley (GB), René Lutter (NL), Nicholas J. Gay (GB), Bradford W. Gibson (US), Frederick D. Northrop (GB), Steven J. Powell (GB), Michael J. Runswick (GB), Matti Saraste (DE), Roberta J. Todd (GB) and Victor L.J. Tybulewicz (GB) also contributed significantly to the elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP) (767; 1754; 1964-1968).

 

Malcolm Andrew Ferguson-Smith (GB) and Brenda M. Page (GB) offered the first study in which two pachytene bivalents have been identified in terms of the mitotic karyotype through their involvement in a translocation. The chromosome patterns of the two bivalents involved in the pachytene quadrivalent are characteristic enough to allow the identification of the same two bivalents in individuals who do not carry the translocation. The chromomere pattern of bivalents 10 and 11 corresponded with the patterns produced in mitotic chromosomes by Giemsa banding (605).

 

Miklós Müller (HU-US), and Donald G. Lindmark (US) characterized, within the trichomonads, a completely new type of cytoplasmic particle, with the capacity of converting pyruvate to acetate, carbon dioxide, and molecular hydrogen, the hydrogenosome (1199-1201; 1374).

 

Wolfgang D. Bauer (US), Kenneth W. Talmadge (US), Kenneth Keegstra (US), and Peter Albersheim (US) established that xyloglucan binds noncovalently to cellulose microfibrils then concluded that there are covalent crosslinks between the hemicellulose xyloglucan, the pectins, and the glycoprotein network in sycamore cell walls. From these findings the first model of the molecular structure of a plant cell wall emerged (109; 1031).

 

Clanton C. Black, Jr. (US) used specific biochemical, structural, and physiological features of green plants to divide them into three photosynthetic groups C3, C4, and CAM (173).

 

Bertil Hille (US) explained the functional and structural architecture of ion channel proteins, which govern the electrical potential of membranes. These channels are critical to generating nerve impulses, controlling muscle contraction, cardiac rhythm, and hormone secretion (873-879).

 

Ronald J. Hill (AU), Kinsey G. Maundrell (CH), and Harold Garnet Callan (GB) found that the length of the S phase of cell division in the amphibian Triturus varies, depending on the stage of embryonic development. They observed that the variations are correlated with differences in the distances that separate replicating segments in the DNA (303; 871).

 

K. Nakamuro (), Nobuyuki Tanigaki (US), and David P. Pressman (US) observed that the beta microglobulin protein is the light polypeptide chain of histocompatibility antigen (HLA) (1395).

 

David H. Sachs (US) and James L. Cone (US), in view of their data and the recent report by others of a T-cell alloantigen determined by gene(s) in the major histocompatibility complex, hypothesized that there may be a variety of H-2-linked alloantigens expressed preferentially on subclasses of lymphocytes (1635).

 

Nooshin Foroozanfar (GB), John Raymond Hobbs (GB), Kenneth Hugh-Jones (GB), Joseph G. Humble (GB), David C.O. James (GB), S. Selwyn (GB), J.G. Watson (GB), and Masaichi Yamamura (GB), in 1973, performed the world's first bone marrow transplant using a matched but unrelated volunteer donor (634).

 

Hugo A. Armelin (US) was the first to isolate fibroblast growth factor (FGF). Pituitary extract was the source material (61).

Denis J. Gospodarowicz (US) described a more defined isolation of proteins from cow brain extract which, when tested in a bioassay caused fibroblasts to proliferate, this led him to apply the name "fibroblast growth factor" (FGF) (737).

 

Dilruba Yasmeen (AU), James R. Ellerson (), Keith J. Dorrington (US), and Robert H. Painter (CA) found that the constant heavy chain 3 (CH3) domain of the antibody molecule can bind macrophage membranes (2080).

 

Lewis G. Tilney (US), Sadashi Hatano (JP), Harunori Ishikawa (US), and Mark S. Mooseker (US) confirmed that that the force for the generation of the acrosomal process is brought about by the polymerization of the sperm actin (1886).

 

James M. O’Donnell (GB) and Micah Warren Smith (GB) were the first to report of the vitamin D-like action of a shrub (Solanum malacoxylon) that causes a severe illness with metabolic calcification in cattle (1432).

Robert H. Wasserman (US), John D. Henion (US), Mark R. Haussler (US), and Toni A. McCain (US) identified the active ingredient as 1,25-dihydroxyvitamin D3-glycoside, the active form of vitamin D. Thus, this active metabolite of vitamin D exists in the plant world, and its presence probably accounts for pathologic calcification in grazing animals ingesting Solanum malacoxylon (1986).

 

Sydney Brenner (ZA-GB) pioneered the use of the nematode Caenorhabditis elegans as a tool for genetics. It is especially useful because it is highly tractable genetically, simple, and virtually invariant in its cellular anatomy (234; 235).

Sydney Brenner (ZA-GB) would be awarded the 2002 Nobel Prize in Physiology or Medicine for his discoveries concerning genetic regulation of organ development and programmed cell death (apoptosis).

 

Malcolm Andrew Ferguson-Smith (GB), Briony F. Newman (GB), Patricia M. Ellis (GB), Diane M.G. Thomsom (GB), and Ian D. Riley (GB) described deletion mapping and used it to assign the human red cell acid phosphatase gene locus to the short arm of chromosome 2 (604).d

 

Paul L. Modrich (US), Yasuhiro Anraku (JP), and I. Robert Lehman (LT-US) discovered the enzyme, which catalyzes the joining of DNA molecules. They purified DNA ligase from E. coli, and noted some of its physical properties (1349).

Paul L. Modrich (US) and I. Robert Lehman (LT-US) reported on the kinetic analysis of the DNA ligase reaction catalyzed by the pure enzyme as well as several of its partial reactions. These studies, coupled with previous findings of others in the Lehman lab including Baldomero Olivera (PH-US), Zach W. Hall (US), and Richard Gumport (US), showed that the formation of the phosphodiester bond proceeds through a pathway involving the generation of two intermediates. First, ATP reacts with DNA ligase to form a ligase-AMP intermediate in which the adenylyl group is bound by a phosphoamide bond to a lysine in the active site of the enzyme. Then, the activated adenylyl group is transferred to the phosphate group at the 5'terminus of a DNA chain, forming a DNA-adenylate complex. In the final step there is an attack of the 3'-hydroxyl of the DNA on the activated 5'-phosphoryl group to form a phosphodiester bond. It was later discovered that this mechanism also held for the T4 DNA ligase and for the mammalian ligases (1350).

 

Howard Curtis Berg (US) and Robert A. Anderson (US) determined that bacteria swim by rotating their flagellar filaments (136).

Michael R. Silverman (US) and Melvin I. Simon (US) dramatically demonstrated this by tethering flagellated bacteria to a glass slide coated with antiflagellar antibodies. When this was done the cells rotated both clockwise and counterclockwise (1736).

 

Klaus Hantke (DE) and Volkmar Braun (DE) found that proteins with covalently bound fatty acids occur in the prokaryotes (810).

 

Mark S. Bretscher (GB) proposed that cell membranes contain protein flippases, which facilitate the flip-flopping of some lipids from the interior of the membrane to the exterior (243).

Harvey Franklin Lodish (US), James Edward Rothman (US), Flora N. Katz (US), David M. Knipe (US), Jonathan M. Backer (US), and Eliezar A. Dawidowicz (US) performed experiments which supported Mark S. Bretscher’s hypothesis (81; 1218; 1219; 1607; 1611).

Michel Bitbol (FR) and Philippe F. Devaux (FR) described an ATP-dependent flippase in erythrocytes. It transports aminophospholipids and cholinephospholipids from the inner to outer leaflet (171).

 

Urs-Peter Roos (CH) determined that kinetochores represent the points of attachment of chromosomes to the spindle and are vital to the correct segregation of chromosomes during anaphase (1591).

 

Edwin Morton Bradbury (GB), Robert J. Inglis (GB), Harry R. Matthews (GB), and Nitza Sarner (GB) presented evidence that the rise in phosphorylation of histone H1 coincides with the beginning of chromosome condensation and represents a major controlling event that shifts cells from G2 to mitosis (221; 222).

 

Jim Patrick (US) and Jon Lindstrom (US) induced experimental autoimmune myasthenia gravis (EAMG) by injecting rabbits with nicotinic acetylcholine receptors from fish electric organs (1476).

 

Dharam P. Singal (CA) and Morris A. Blajchman (CA) made the first known association of the major histocompatibility complex (MHC) markers with insulin-dependent diabetes mellitus. They associated HLA-B with increased incidence of insulin-dependent diabetes mellitus (1744). Insulin-dependent diabetes mellitus is also known as type-1 diabetes.

Arne Svejgaard (DK), Per Platz (DK), and Lars Peter Ryder (DK) demonstrated that HLA-B markers are not as strongly associated with insulin-dependent diabetes mellitus as are HLA-DR markers (1836).

 

Kenneth J. Judy (US), David A. Schooley (US), M. Sharon Hall (US), B. John Bergot (US), and John B. Siddall (US) discovered and isolated insect juvenile hormone III from an organ culture of tobacco hornworm (Manduca sexta) (997).

 

Hans Leo Kornberg (GB-US), Anne K. Soutar (GB), Pelin Faik (GB), Jacques M. Pouyssegur (FR), and Brigitte Bächi (CH) were able to elucidate the main routes whereby E. coli utilizes gluconate as a sole carbon sources for growth (79; 80; 584; 1092; 1525).

 

Bernadette Bouges-Bocquet (FR), Bruno R. Velthuys (NL-US), and Jan Amesz (NL) showed that there is a two-electron gate on the acceptor side of photosystem 2 (208; 1941).

André Vermeglio (FR), Roderick K. Clayton (US), and Colin A. Wraight (GB) discovered a similar gate in anoxygenic photosynthetic bacteria (1942; 2064).

 

Dieter Oesterhelt (DE) and Walther Stoeckenius (DE-US) discovered a new photosynthetic mechanism powered by a different pigment (bacteriorhodopsin), one that is closely related to rhodopsin. They discovered this system in the archaebacterium, Halobacterium halobium and found that it functions as a light driven proton pump in the bacterial plasma membrane (1443).

Efraim Racker (PL-AT-US) and Walther Stoeckenius (DE-US) incorporated bacteriorhodopsin into a liposome membrane along with the F₁Fo-ATPase from bovine heart. They found that upon illumination bacteriorhodopsin pumped protons out. These protons subsequently flowed back through the F₁Fo-ATPase generating ATP from ADP and inorganic phosphate. This experiment confirmed Peter Mitchell’s chemiosmotic hypothesis and tied together the mechanism of ATP formation in mitochondria, chloroplasts, and the bacterial plasma membrane (1538).

Peter Hegemann (DE) led a team of colleagues including: Sabine Ehlenbeck (DE), Dietrich Gradmann (DE), Franz-Josef Braun (DE), Georg Nagel (DE), Doris Ollig (DE), Markus Fuhrmann (DE), Suneel Kateriya (IN), Anna Maria Musti (DE), Ernst Bamberg (DE), Tanjef Szellas (DE), Wolfram Huhn (DE), Nona Adeishvili (DE), Peter Berthold (DE), Oliver P. Ernst (DE), Pedro A. Sánchez Murcia (DE), Peter Daldrop (DE), Satoshi P. Tsunoda (DE), Andreas Möglich (DE), Jonas Wietek (DE), J. Simon Wiegert (DE), Franziska Schneider (DE), Hiroshi Watanabe (DE), Arend Vogt (DE), Marcus Elstner (DE), and Thomas G. Oertner (DE) that characterized natural sensory photoreceptors, mainly from microalgae. They described behavioral and photoelectric responses of the unicellular alga, Chlamydomonas, which culminated in the claim that the photoreceptors for these responses was a rhodopsin that unified the sensor and ion channel in one protein. They proved this hypothesis by identifying the light-gated channel, channelrhodopsin, and by demonstrating its functionality in animal cells.

The team, in close collaboration with Karl Deisseroth (US), discovered the fundamental principles of the unique channelrhodopsin proteins in molecular detail by a wide range of genomic, biophysical, electrophysiological and structural techniques. This led to their deciphering of the unprecedented light-gated ion channel mechanism, including its pore gating by photons and its ion selectivity. This basic work fundamentally enabled optogenetics, defined as the technology wherein light-activated proteins—first and foremost channelrhodopsin—control selected cells within systems as complex as the mammalian brain, with unprecedented precision in space and time (479; 547; 571; 837; 1387; 1388; 2025).

Edward S. Boyden (US), Karl Deisseroth (US), Li-Ping Wang (US), Feng Zhang (US), Ernest Bamberg (DE) and Georg Nagel (DE) collaborated to demonstrate the first optical control of neural activity using microbial opsins (212; 2099).

Seung-Hee Lee (US), Alex C. Kwan (US), Siyu Zhang (US), Victoria Phoumthipphavong (US), John G. Flannery (US), Sotiris C. Masmanidis (US), Hiroki Taniguchi (US), Z. Josh Huang (US), Feng Zhang (US), Edward S. Boyden (US), Karl Deisseroth (US), and Yang Dan (US) developed the first effective optogenetic silencing in live mammals (1157).

Jeffery N. Stirman (US), Matthew M. Crane (US), Steven J. Husson (US), Alexander Gottschalk (US), and Hang Lu (US) developed noninvasive optogenetic silencing (1805).

John L. Spudich (US) developed multicolor optogenetic control (1778).

Or A. Shemesh (US), Dimitrii Tanese (FR), Valeria Zampini (FR), Changyang Linghu (US), Kiryl Piatkevich (US), Emiliano Ronzitti (FR), Eirini Papagiakoumou (FR), Edward S. Boyden (US), and Valentina Emiliani (FR) developed temporally precise single-cell optogenetic control (1725).

 

Dean R. Hewish (AU) and Leigh A. Burgoyne (AU), Ada L. Olins (US), Donald E. Olins (US) and Jennifer Mobbs (AU) took electron photomicrographs and used DNA endonucleases to cut chromatin and found that the pieces which resulted were roughly 200 base pairs long or a multiple of this length. This was strong evidence suggesting that eukaryotic DNA is organized into nucleosome units, which occur along the DNA molecule like beads on a string (281; 867; 1448).

Roger David Kornberg (US) and Jean O. Thomas (US) discovered the histone tetramer, (H3)₂ (H4)₂, then proposed a model for the basic unit of chromatin (the nucleosome) as a bead of about 100 A diameter, containing a stretch of DNA 200 base pairs long condensed around a protein core made from 8 histone molecules, namely the (H3)₂ (H4)₂ tetramer and 2 each of H2A and H2B. The fifth histone, H1, was somehow associated with the outside of each nucleosome. They conceived that eukaryotic DNA is tightly packaged around a core of structural proteins — histones — to generate a nucleosome array that is fundamental for controlling gene expression, i.e., the nucleosome hypothesis (1093; 1097).

John T. Finch (GB), Leonard C. Lutter (GB), Daniela Rhodes (GB), Raymond S. Brown (GB), Barbara Rushton (GB), Michael Levitt (GB), Aaron Klug (GB), Karolin Luger (CH), Armin W. Maeder (CH), Robin K. Richmond (CH), Davd F. Sargent (CH), Timothy J. Richmond (CH), Curt A. Davey (CH), and Armin W. Maeder (CH) reported the x-ray crystal structure of the nucleosome complex (454; 616; 1237).

 

Oliver H. Lowry (US) developed the methodology to isolate, prepare, weigh and chemically study single nerve cells and subcellular particles (1235).

 

Howard R. Six (US) and Sidney Harshman (US) isolated two stable forms of Staphylococcus aureus alpha-toxin from broth cultures of the Wood 46 strain. Alpha-toxin was later found to be a potent hemolysin and leucocidin (1747).

 

Charles E. Lankford (US) states that microorganisms combat biological shortages of iron in aerobic environments—at neutral pH iron exists almost exclusively in the form of insoluble ferric hydroxide—by producing low molecular weight iron-chelating compounds known as siderophores (1134).

 

Peter Lobban (US) and Armin Dale Kaiser (US) developed a technique for adding cohesive ends to DNAs, which had been cut with an endonuclease which cleaves straight across (1216).

 

Armin Dale Kaiser (US), Michael Syvanen (US), and Terrie Masuda (US), found that the DNA molecule extracted from the Escherichia coli phage lambda can combine with the phage-precursor proteins present in a cell extract of lambda-infected bacteria to form infectious particles (1000).

 

Paul Wuthier (US), Carol Jones (US), and Theodore Thomas Puck (US) established a linkage between human cell surface antigen A_L and the lactic dehydrogenase A gene (2067).

 

Eric A. Jaffe (US), Ralph L. Nachman (US), Carl G. Becker (US), C. Richard Minick (US), Michael A. Gimbrone, Jr. (US), Ramzi S. Cotran (US), and Moses Judah Folkman (US) presented the methodology for culturing endothelial cells from human blood vessels. This allowed the study of angiogenic processes in vitro (704; 966).

Michael A. Gimbrone, Jr. (US), Ramzi S. Cotran (US), Stephen B. Leapman (US), and Moses Judah Folkman (US) developed the in vivo assay, which became the gold standard for detection of angiogenic activity and its inhibition (705).

Moses Judah Folkman (US), Christian C. Haudenschild (US), Bruce R. Zetter (US) showed that there are significant biological differences between capillary endothelial cells and endothelial cells from large vessels that are maintained in long-term culture (632).

Moses Judah Folkman (US) and Christian C. Haudenschild (US) showed that endothelial cells in culture could be induced to express the necessary genetic information to undergo morphogenesis into a capillary phenotype (631).

 

Paul R. Dendy (GB) and Henry Harris (AU-GB) showed that diphtheria toxin, which is about 100,000 times more lethal to human than to mouse cells, can be used as a selective system for man-mouse hybrid cells (483).

 

Arthur Karlin (US), David A. Cowburn (US), Cheryl L. Weill (US), and Mark G. McNamee (US) purified acetylcholine receptor (AChR) from Electrophorus electricus and Torpedo californica. They determined that it contains four different types of polypeptide subunits (1013; 2004). Note: It turned out that these subunits are common to all vertebrate striated muscle-type AChRs.

 

Leslie D. Gottlieb (US) documented the speciation of Stephanomeira malheurensis. He found a single small population (< 250 plants) among a much larger population (> 25,000 plants) of S. exigua in Harney Co., Oregon. Both species are diploid and have the same number of chromosomes (N = 8). S. exigua is an obligate outcrosser exhibiting sporophytic self-incompatibility. S. malheurensis exhibits no self-incompatibility and self-pollinates. Though the two species look very similar, Gottlieb was able to document morphological differences in five characters plus chromosomal differences. F1 hybrids between the species produce only 50% of the seeds and 24% of the pollen that conspecific crosses produce. F2 hybrids show various developmental abnormalities (739).

 

Frank L. Graham (CA) and Alex J. van der Eb (NL) showed that human adenovirus 5 could be transferred to cells in culture, with retention of function, if the viral DNA is precipitated onto the cells by means of calcium phosphate. The particulate complex of viral DNA and calcium phosphate is apparently taken into the cells by endocytosis, and the DNA is then released in a functional state (751).

 

Joseph Stokes, Jr. (US), Robert E. Weibel (US), Victor M. Villarejos (US), Jorge A. Arguedas (CR), Eugene B. Buynak (US), and Maurice Ralph Hilleman (US) administered four lots of combined trivalent Moraten measles, Jeryl Lynn mumps, and HPV-77 duck rubella vaccine to a total of 715 children, 7 months to 7 years of age, who were initially without antibody against any of the three viruses. The combined measles-mumps-rubella vaccine (MMR) provides a simple means for immunizing against all three of these diseases without impairment of antibody response and without significant increase in clinical reaction (1806).

Robert E. Weibel (US), Victor M. Villarejos (US), Gloria Hernandez (ES), Joseph Stokes, Jr. (US), Eugene B. Buynak (US), and Maurice Ralph Hilleman (US) developed a combined live measles-mumps virus vaccine (MMR) (1999).

William J. McAleer (US), Eugene B. Buynak (US), Robert E. Weibel (US), Victor M. Villarejos (US), Edgar M. Scattergood (US), Hermann E. Wasmuth (US), Arlene A. McLean (US), and Maurice Ralph Hilleman (US) developed measles, mumps and rubella virus vaccines (MMR) prepared from virus produced by the unit process (1307).

Andrew Wakefield (UK), in 1998, was paid by lawyers to find a way to discredit the MMR. He did this effectively, by publishing a paper claiming that there was a link between the MMR vaccine and autism (1962). Wakefield’s research has since been entirely discredited, but the effects on vaccination rates was devastating (478).

 

Bernard M. Babior (US), Ruby S. Kipnes (US), and John T. Curnutte (US) found that superoxide is made by leukocytes under circumstances which suggest that it may be involved in bacterial killing (77; 78).

 

Elaine G. Diacumakos (US) developed microinjection techniques accurate enough to deliver foreign molecules into mammalian cells (491).

 

Andrew G. Szent-Gyorgyi (US), Eva M. Szentkiralyi (US), Robert M. Simmons (GB) and others worked out the mechanism which controls the ability of myosin to bind actin and proceed through the cross-bridging cycle (1741; 1845-1847).

 

Antonio S. Roche (US) and Juha P. Kokko (US) demonstrated that the medullary thick ascending limb of the loop of Henle is water impermeable while having the capacity for active outward solute transport as a consequence of an electrogenic chloride pump. The combination of these characteristics allows this segment to generate a dilute tubular fluid and participate as the principal energy source for the overall operation of the countercurrent multiplication system (1581).

 

Thomas Dean Pollard (US) and Edward David Korn (US) working with Acanthamoeba castellanii discovered an unconventional myosin called myosin-1 (1519).

Edward David Korn (US) and Thomas Dean Pollard (US) described the binding of the purified myosin-1 to actin and the partial purification and characterization of the cofactor protein required for the activation of the Mg2-ATPase by actin (1520).

Edward David Korn (US) and Hiroshi Maruta (JP) showed that this cofactor is a kinase that phosphorylates the myosin heavy chain. This was the first example of regulation of myosin activity by heavy chain phosphorylation (1295).

 

Vincent Gaston Dethier (US), while studying the swallowtail butterfly, became the first to prove that caterpillars select their food by the plant’s taste and smell, not its nutritional value (488).

 

James S. Clegg (US) and Frank P. Conte (US) report that the brine shrimp, Artemia salina, produce encysted embryos that are capable of surviving complete dehydration – or at least as complete as is technically feasible; according to the best measurements available, they can be reduced to <0.007 g water g–1 dry mass, at which water containing metabolism as we understand it ceases. The dry cysts persist in this state (anhydrobiosis) for decades, but when they are rehydrated they rapidly imbibe water and resume active metabolism and development. Following further development, they then emerge from the cysts as free-swimming nauplii (379-381).

Jim Clegg (US) studied the metabolic events occurring during the resumption of development, implicating trehalose as a key molecule involved in the survival of desiccation thus sparking a revolution in the preservation of biological systems (378).

 

George Laver (US) and Robert G. Webster (US) demonstrated that the genomes of influenza virus strains responsible for pandemics possess genome fragments acquired by genome segment reassortment from influenza strains circulating in animals (1140).

 

E. Alan Bevan (GB), Alan J. Herring (GB), and Diane J. Mitchell (GB) noted that the non-Mendelian phenotype, "killer," is controlled by cytoplasmic nucleic acids, which constitute the family of L-A double-stranded RNA viruses (156).

 

Joël Bockaert (FR), Christian Roy (FR), Rabary Rajerison (FR), and Serge Jard (FR) demonstrated, in cell membrane fractions from kidney medulla, the presence of molecular receptors which stereospecifically bind vasopressin molecules and are coupled to adenylate cyclase (190).

 

Sally H. Zigmond (US) and James Gerald Hirsch (US), in their study of leukocyte locomotion and chemotaxis, described new methods for evaluation, and demonstration of a cell-derived chemotactic factor (2103).

 

Torkel Weis-Fogh (DK-GB) found that the majority of hovering animals, including large lamellicorn beetles and sphingid moths, depend mainly on normal aerofoil action. However, in some groups with wing loading less than 10 N m-2 (1 kgf m-2), non-steady aerodynamics must play a major role, namely in very small insects at low Reynolds number, in true hover-flies (Syrphinae), in large dragonflies (Odonata), and in many butterflies (Lepidoptera Rhopalocera).

The specific aerodynamic power ranges between 1.3 and 4.7 WN-1 (11-40 cal h-1 gf-1) but power output does not vary systematically with size, inter alia because the lift/drag ratio deteriorates at low Reynolds number.

Comparisons between metabolic rate, aerodynamic power and dynamic efficiency show that most insects require and depend upon an effective elastic system in the thorax which counteracts the bending moments caused by wing inertia.

The free flight of a very small chalcid wasp Encarsia formosa has been analyzed by means of slow-motion films. At this low Reynolds number (10-20), the high lift co-efficient of 2 or 3 is not possible with steady-state aerodynamics and the wasp must depend almost entirely on non-steady flow patterns.

The wings of Encarsia are moved almost horizontally during hovering, the body being vertical, and there are three unusual phases in the wing stroke: the clap, the fling and the flip. In the clap the wings are brought together at the top of the morphological upstroke. In the fling, which is a pronation at the beginning of the morphological down stroke, the opposed wings are flung open like a book, hinging about their posterior margins. In the flip, which is a supination at the beginning of the morphological upstroke, the wings are rapidly twisted through about 180°.

The fling is a hitherto undescribed mechanism for creating lift and for setting up the appropriate circulation over the wing in anticipation of the down stroke. In the case of Encarsia the calculated and observed wing velocities at which lift equals body weight agree, and lift is produced almost instantaneously from the beginning of the down stroke and without any Wagner effect. The fling mechanism seems to be involved in the normal flight of butterflies and possibly of Drosophila and other small insects. Dimensional and other considerations show that it could be a useful mechanism in birds and bats during takeoff and in emergencies.

The flip is also believed to be a means of setting up an appropriate circulation around the wing, which has hitherto escaped attention; but its operation is less well understood. It is not confined to Encarsia but operates in other insects, not only at the beginning of the upstroke (supination) but also at the beginning of the down stroke where a flip (pronation) replaces the clap and fling of Encarsia. A study of freely flying hover-flies strongly indicates that the Syrphinae (and Odonata) depend almost entirely upon the flip mechanism when hovering. In the case of these insects a transient circulation is presumed to be set up before the translation of the wing through the air, by the rapid pronation (or supination), which affects the stiff anterior margin before the soft posterior portions of the wing. In the flip mechanism vortices of opposite sense must be shed, and a Wagner effect must be present.

In some hovering insects wing twisting occurs so rapidly that the speed of propagation of the elastic torsional wave from base to tip plays a significant role and appears to introduce beneficial effects.

Non-steady periods, particularly flip effects, are present in all flapping animals and they will modify and become superimposed upon the steady-state pattern as described by the mathematical model presented here. However, the accumulated evidence indicates that most hovering animals conform reasonably well to that model (2007).

 

William P. Kolb (US), James A. Haxby (US), Carlos M. Arroyave (US), and Hans Joachim Müller-Eberhard (DE-US-DE) described the membrane attack mechanism of complement and reversible interactions among the five native components in free solution (1084).

 

Andrew G. Engel (US) and Corrado I. Angelini (IT) discovered carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: a new syndrome (564).

 

Jean-Paul Butzler (BE), Paul J. Dekeyser (BE), M. Detrain (BE), F. Dehaen (BE), Victor D. Bokkenheuser (US), Neville J. Richardson (US), John H. Bryner (US) Daniel J. Roux (US), Awie B. Schutte (US), Martin B. Skirrow (GB), Trevor W. Steele (AU), Suzanne McDermott (US), Chik H. Pai (CA), Simon Sorger (CA), Lynn Lackman (CA), Roberto E. Sinai (FR-CA-US), Melvin I. Marks (CA), Signe Ringertz (NO), Robert C. Rockhill (US), Olof Ringertz (NO), Arini Sutomo (ID), Martin J. Blaser (US), Joy G. Wells (US), Roger A. Feldman (US), Robert A. Pollard (US), and James R. Allen (US) found that Campylobacter jejuni is the leading cause of acute gastroenteritis in humans throughout the world (181; 193; 299; 1465; 1570; 1749; 1789).

 

Alice S. Huang (US) defined defective interfering viral particles as follows: (1) they are deletion mutants and therefore lack large amounts of the genetic material present in the standard virus; (2) they contain the same viral structural proteins as standard virus; (3) they are unable to replicate alone; however, they are replicated in cells co-infected with standard virions; and (4) at the same time as they require standard virus to replicate, they inhibit the replication of standard virus and hence are interfering (917).

 

John Edward Heuser (US) and Thomas Sargent Reese (US) found in their studies of the frog neuromuscular junction that during stimulation the intracellular compartments of this synapse change shape and take up extracellular protein in a manner which indicates that synaptic vesicle membrane added to the surface during exocytosis is retrieved by coated vesicles and recycled into new synaptic vesicles by way of intermediate cisternae. This evidence argued strongly for a rapid recycling of synaptic vesicle membrane via endocytosis (865).

Bruno Ceccarelli (IT), William Paul Hurlbut (US), and Alexander Mauro (US) traced the depletion and reformation of synaptic vesicles from the frog neuromuscular junction but reached an altogether different conclusion: that vesicles reformed directly from the plasma membrane at the site of their release (335).

Ralph Marvin Steinman (US), Scott E. Brodie (US), and Zanvil Alexander Cohn (US) found that in nonneuronal cells so much membrane was coming into the cell (cells pinocytosed their entire cell surface area in ∼30 min) that there must be a general recycling flow back to the plasma membrane (1795).

John Edward Heuser (US), Thomas Sargent Reese (US), Michael J. Dennis (US), Yuh Nung Jan (US), Lily Yeh Jan (US), and Louise Evans (US) found a correlation between synaptic vesicle exocytosis and quantal transmitter release, thus confirming the one vesicle–one quantum theory (866).

Riccardo Fesce (IT), Fabio Grohavaz (IT), Flavia Valtorta (IT), and Jacopo Meldolesi (IT) proposed the “kiss-and-run” hypothesis: that synaptic vesicles could deliver their cargo by fusing slightly with the membrane and then reform by pinching back off (609).

 

Douglas L. Coleman (CA-US) postulated that the obese mouse is unable to produce sufficient satiety factor to regulate its food consumption, whereas the diabetes mouse produces satiety factor, but cannot respond to it because of a defective satiety center (393).

Yiying Zhang (CN-US), Ricardo Proenca (US), Margherita Maffei (US), Marisa Barone (US), Lori Leopold (US), and Jeffrey M. Friedman (US) cloned and characterized the ob gene from mice. They confirmed that it encodes a novel adipocyte-derived hormone, which they named leptin (Gr. leptos, thin) (2100). The wild-type obese allele is necessary to produce leptin. The wild-type allele at another locus diabetes is necessary to produce a receptor for leptin.

Margherita Maffei (US), Hon Fei (US), Gwo-Hwa Lee (US), Christian Dani (US), Pascale Leroy (US), Yiying Zhang (CN-US), Ricardo Proenca (US), Raymond Negrel (US), Gérard Ailhaud (FR), and Jeffrey M. Friedman (US) studied the action of leptin and found that body fat content is regulated by a negative feedback loop centered in the hypothalamus and elsewhere. They suggested that weight is regulated by a set point mechanism and that weight is set at different levels among different individuals. When at the set point, a state of energy balance in which food intake equals energy expenditure is maintained. Increasing adipose tissue mass leads to an increase in the production of leptin (1255).

Margherita Maffei (US), Jeffrey L. Halaas (US), Eric Ravussin (US), Richard E. Pratley (US), Gwo-Hwa Lee (US), Yiying Zhang (CN-US), Hon Fei (US), Sharon Kim (US), Roger L. Lallone (US), Subramanian Ranganathan (CA), Philip A. Kern (US), and Jeffrey M. Friedman (US) found that the plasma level of leptin is highly correlated with adipose mass and falls in both humans and mice after weight loss (1256).

Christian Vaisse (US), Jeffrey L. Halaas (US), Curt M. Horvath (US), James Darnell, Jr. (US), Markus Stoffel (US), and Jeffrey M. Friedman (US) proposed that the activation of the Stat3 gene suggests that leptin (a hormone secreted by adipocytes) modulates gene transcription in the hypothalamus (1925).

Carl T. Montague (GB), I. Sadaf Farooqi (GB), Jonathan P. Whitehead (GB), Maria A. Soos (GB), Harald Rau (GB), Nicholas J. Wareham (GB), Ciaran P. Sewter (GB), Janet E. Digby (GB), Shehla N. Mohammed (GB), Jane A. Hurst (GB), Christopher H. Cheetham (GB), Alison R. Earley (GB), Anthony H. Barnett (GB), Johannes B. Prins (GB), and Stephen O'Rahilly (GB) found severe obesity in congenitally leptin-deficient subjects thus providing the first genetic evidence that leptin is an important regulator of energy balance in humans (1356).

Jeffrey M. Friedman (US) established that there is a powerful biological basis for obesity. The cloning of the ob gene and its gene product, leptin, has led to the elucidation of a robust physiologic system that maintains fat stores at a relatively constant level. Leptin is a peptide hormone secreted by adipose tissue in proportion to its mass. Recessive mutations in the leptin gene are associated with massive obesity in mice and humans, establishing a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall, stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. The discovery of leptin has advanced our understanding of metabolic disease in a number of respects. Its identification has revealed a new endocrine system regulating body weight. This system provides a means by which changes in nutritional state regulate other physiologic systems. A number of leptin deficiency syndromes that are treatable with leptin replacement have been identified. The majority of obese subjects are leptin resistant, which establishes that obesity is the result of hormone resistance. Leptin treatment results in weight loss in a subset of obese patients and can also synergize with other anti-obesity agents to reduce weight in the general population (644; 645).

 

Timothy Vivian Pelham Bliss (GB) and Terje Lømo (NO) published the first evidence of a Hebb-like synaptic plasticity event induced by brief tetanic stimulation, known as long-term potentiation (LTP). They used extracellular microelectrodes in urethane-anesthetized rabbits to examine the after-effects of repetitive stimulation of the perforant path fibers to the dentate area of the hippocampal formation.

The results suggest that two independent mechanisms are responsible for long-lasting potentiation: (a) an increase in the efficiency of synaptic transmission at the perforant path synapses; (b) an increase in the excitability of the granule cell population (183).

 

Russell W. Schaedler (US) states that after birth, an important microbial ecosystem develops in the digestive tract. The major source of this microflora is normally the mother (1669).

 

Ralph Marvin Steinman (US) and Zanvil Alexander Cohn (US) reported a new cell type from mouse peripheral lymphoid organs (spleen, lymph node, and Peyer’s patch). Present in small numbers (0.1-1.6 % of the total nucleated cells) the cells have distinct morphological features. The nucleus is large, refractile, contorted in shape, and contains small nucleoli (usually two). The abundant cytoplasm is arranged in processes of varying length and width and contains many large spherical mitochondria. In the living state, the cells undergo characteristic movements, and unlike macrophages, do not appear to engage in active endocytosis. The term, dendritic cell, was proposed for this novel cell type (1796).

Ralph Marvin Steinman (US) and Margaret D. Witmer (US) identified lymphoid dendritic cells as potent stimulators of the primary mixed leukocyte reaction (1797). Note: This identification of the dendritic cell, a phagocytic cell, as the principal antigen-presenting cell of the immune system constituted a major revision to the role of the phagocyte assigned by Metchnikoff in the 19th century.

Gerold Schuler (DE) and Ralph Marvin Steinman (US) found that Langerhans cells seem to be immunologically immature but acquire many of the features of spleen dendritic cells during culture. They suggested that functioning lymphoid dendritic cells may, in general, be derived from less mature precursors located in nonlymphoid tissues (1689).

Christophe Caux (FR), Colette Dezutter-Dambuyant (FR), Daniel Schmitt (FR), and Jacques Banchereau (FR) found that in man, cooperation between granulocyte-macrophage-colony-stimulating factor (CM-CSF) and tumor necrosis factor-alpha (TNF-alpha) is crucial for the generation of human dendritic Langerhans cells from hematopoietic progenitors (332). Dendritic cells are highly efficient antigen presenting cells which initiate immune responses such as the sensitization of T cells restricted by major histocompatibility complex molecules, the rejection of organ transplants and the formation of T cell-dependent antibodies. Dendritic cells are found in non-lymphoid tissues, such as skin (Langerhans cells) and mucosa, and they migrate after antigen capture through the afferent lymph or the bloodstream to lymphoid organs, where they efficiently present antigen to T cells.

Kayo Inaba (JP), Ralph Marvin Steinman (US), Margit Witmer Pack (US), Hikeki Aya (JP), Muneo Inaba (JP), Tesuo Sudoo (JP), Stephen Wolpe (US), and Gerold Schuler (AT) found that murine blood contains GM-CSF-dependent, proliferating progenitors that give rise to large numbers of dendritic cells with characteristic morphology, mobility, phenotype, and strong T cell stimulatory function (942).

Nikolaus Romani (AT), Stefan Gruner (DE), Daniela Brang (AT), Eckhart Kampgen (DE), Angela Lenz (AT), Bettina Trockenbacher (AT), Günther Konwalinka (AT), Peter O. Fritsch (AT), Ralph Marvin Steinman (US), and Gerold Schuler (AT) found that large numbers of dendritic cells can be mobilized by specific cytokines from progenitors in the blood stream (1590).

Frank O. Nestle (CH), Selma Alijagic (CH), Michel Gilliet (CH), Yuansheng Sun (CH), Stephan Grabbe (CH), Reinhard Dummer (CH), Günter Burg (CH) and Dirk Schadendorf (CH) found that vaccination with autologous dendritic cells generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma (1410).

Manfred B. Lutz (DE), Nicole Kukutsch (DE), Alexandra L.J. Ogilvie (DE), Susanne Rössner (DE), Franz Koch (DE), Nikolaus Romani (AT), and Gerold Schuler (DE) developed an advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow (1241).

Beatrice Thurner (DE), Ina Haendle (DE), Claudia Röder (DE), Detlef Dieckmann (DE), Petra Keikavoussi (DE), Helmut Jonuleit (DE), Armin Bender (DE), Christian Maczek (DE), Doris Schreiner (DE), Peter von den Driesch (DE), Eva B. Bröcker (DE), Ralph Marvin Steinman (US), Alexander H. Enk (DE), Eckhart Kämpgen (DE), and Gerold Schuler (DE) proved the principle that dendritic cell "vaccines" can frequently expand tumor-specific cytotoxic T lymphocytes (CTLs) and elicit regressions even in advanced cancer and, in addition, provides evidence for an active CD8(+) CTL-tumor cell interaction in situ as well as escape by lack of tumor antigen expression (1885).

Helmut Jonuleit (DE), Edgar Schmitt (DE), Gerold Schuler (DE), Jürgen Knop (DE), and Alexander H. Enk (DE) showed that immature and mature dendritic cells induce different types of T cell responses: inflammatory Th1 cells are induced by mature dendritic cells, and IL-10 producing T cell regulatory 1-like cells by immature dendritic cells (992).

 

Armond S. Goldman (US), C. Wayne Smith (US), Larry W. Thorpe (US), Randall M. Goldblum (US), and Lars Å. Hanson (US) found that human milk contains a complex immune system consisting of direct-acting antimicrobial agents, anti-inflammatory factors, immunomodulating agents, and living cells (719-721).

 

Lee Schlosstein (US), Paul I. Terasaki (US), Rodney Bluestone (US), and Carl M. Pearson (US) obtained evidence through genetic studies that rheumatoid arthritis and ankylosing spondylitis are different clinical entities (1676).

 

James Whyte Black (GB) and Brian N.C. Prichard (GB) explored the activation and blockade of beta adrenoceptors in common cardiac disorders, i.e., role of beta-blockers (177).

 

John C. Liebeskind (US), Gisèle Guilbaud (FR), Jean-Marie Besson (FR), and Jean-Louis Oliveras (FR) discovered that stimulation of the midbrain area called the PAG (periaqueductal gray) produces pain in animals, but reducing the stimulation produces analgesia (1192).

Huda Akil (US), David J. Mayer (US), and John C. Liebeskind (US) went on to show the effect was blocked by the opioid antagonist naloxone (22).

Hanan Frenk (IL), Brad C. McCarty (US), and John C. Liebeskind (US) suggested that the effect was like the analgesia produced by opiates (642).

Eric J. Simon (US), Lars Terenius (SE), Candace Beebe Pert (US), and Solomon Halbert Snyder (US) proposed then demonstrated opioid receptors in the brain (1491; 1492; 1742; 1874; 1875). Note: This would lead to the discovery of encephalins by other workers.

Eric J. Simon (DE-US), Jacob M. Hiller (US), and Irit Edelman (US) discovered potent narcotic analgesic opiate receptors in the rat-brain (1743).

Eric J. Simon (US), in 1975, proposed the name endorphin (synthesized from endogenous and morphine) for endogenous substances which bind with opiate receptors in the brains of mammals (405).

John Hughes (GB), Hans W. Kosterlitz (GB), Terry W. Smith (GB), Barry A. Morgan (GB), and Linda A. Fothergill (GB), from pig brain, discovered and named enkephalin, a natural ligand for opiate receptors (924; 926).

John Hughes (GB), Terry W. Smith (GB), Hans W. Kosterlitz (GB), Linda A. Fothergill (GB), Barry A. Morgan (GB), and Howard R. Morris (GB) determined the amino acid sequences of two morphinomimetic pentapeptides, the enkephalines, to be H-Tyr-Gly-Gly-Phe-Met-OH and H-Tyr-Gly-Gly-Phe-Leu-OH (925). The term enkephalin (meaning literally "in the head") is also applied to endorphins, but usually refers to smaller molecules that have pain-relieving properties. This work strongly supported a long-standing theory that there are normally opiate-like substances in the brain, which are neurotransmitters of messages relating to pain and emotional behavior.

Rabi Simantov US) and Solomon Halbert Snyder (US) isolated morphine-like peptides from calf brain (1739; 1740).

Roger Charles Louis Guillemin (FR-CA-US), Nicholas Ling (US), and Roger Cecil Burgus (US), from a crude extract of porcine neurohypophysis-hypothalamus, isolated several peptides called endorphins, which mimic opiads in a classical bioassay for morphine. The primary structure of alpha-endorphin is H-Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-OH (786; 787).

Choh Hao Li (US), David Chung (US), and Derek George Smyth (GB) recorded the sequences of α-, β-, and γ-endorphin isolated from camel pituitary glands for their opioid activity. β-endorphin was fround to produce strong analgesic effects (1185; 1186; 1760).

Brian M. Cox (US), Avram Goldstein (US), and Choh Hao Li (CN-US) reported the opioid activity of the peptide, beta-lipotropin-(61-91), derived from beta-lipotropin (424).

Choh Hao Li (CN-US), Simon Lemaire (US), Donald Yamashiro (US), and Byron A. Doneen (US) synthesized and reported the opiate quality of beta-endorphin (1187).

Nabil G. Seidah (CA), N. Dragon (CA), Suzanne Benjannet (CA), Richard Routhier (CA), and Michel Chretien (CA) determined the complete sequence of sheep beta-endorphin (1707).

Wilhelm Siegmund Feldberg (DE-GB) and Derek George Smyth (GB) found β-endorphin to be a much stronger analgesic than morphine. In addition, they found that it is completely removed from opiate receptors by naloxone, an identified morphine antagonist (596).

 

Philip R. Loe (US), David L. Tomko (US) Georges H. Werner (US), Cesar Fernandez (US) and Jay M. Goldberg (US) provided the first complete characterization of the physiology of the mammalian peripheral otolith system, which senses linear accelerations, including gravity and the inertial motion of the head in space (606-608; 1220).

 

Kenneth L. Jones (US), David W. Smith (US), Christy N. Ulleland (US), and Ann Pytkowicz Streissguth (US) described fetal alcohol syndrome in the following manner: “Eight unrelated children and three different ethnic groups, all born to mothers who were chronic alcoholics, have a similar pattern of craniofacial, limb, and cardiovascular defects associated with prenatal-onset growth deficiency and developmental delay” (988).

 

Roscoe O. Brady (US) John F. Tallman (US) William G. Johnson (US), Andrew E. Gal (US), William R. Leahy (US), Jane M. Quirk (US), and Anatole S. Dekaban (US) pioneered in the use of enzyme replacement therapy to treat genetic diseases (223).

 

Herbert L. Needleman (US), Philip Graham (US), Charles Gunnoe (US), Alan Leviton (US), Robert Reed (US), Henry Peresie (US), Cornelius Maher (US), and Peter Barrett (US) conducted studies that yielded strong evidence that lead, even at very low levels, can affect a child's IQ. By measuring levels of lead in children’s teeth, Needleman provided the first evidence that low-level lead exposure not only reduces IQs, but also shortens attention spans and delays acquisition of language proficiency. In studies that followed, he determined that lead poisoning had long term implications for a child's attentiveness, behavior, and academic success (1402-1405).

After extensive scientific review, Needleman's findings were instrumental in convincing the Centers for Disease Control (CDC) to issue guidelines for the diagnosis and management of lead poisoning in children, in goading the Environmental Protection Agency (EPA) to mandate the removal of lead from gasoline and inducing the Consumer Product Safety Commission to ban lead from interior paints. Needleman's research also helped cause the Department of Housing and Urban Development (HUD) to remove lead from thousands of housing units across the US.

 

Gottfried Kellermann (DE-US), Charles R. Shaw (US), and Mieke Luyten-Kellermann (US) reported that genetic variation in aryl hydrocarbon hydrolase (AHH) levels in normal subjects can be linked to susceptibility to bronchogenic carcinoma, thus demonstrating a close association between high levels of AHH and an increased risk of lung cancer (1033). Aryl hydrocarbon hydrolase (AHH) is involved in the metabolism of chemical carcinogens, and present in many tissues including lung and mitogen stimulated lymphocytes.

 

Anthony Martin Halliday (GB), William I. McDonald (GB), and Joan Mushin (GB) introduced a visual evoked response in diagnosis of multiple sclerosis (799).

 

Derrick Arthur Brewerton (GB), Frank Dudley Hart (GB), Anne Nicholls (GB), Maeve Caffrey (GB), David C.O. James (GB), and Roger D. Sturrock (GB) showed that the histocompatibility antigen HLA-B27 predisposes an individual to ankylosing spondylitis, an autoimmune disease (245).

Derrick Arthur Brewerton (GB), Anne Nicholls (GB), Maeve Caffrey (GB), David Walters (AU-GB), and David C.O. James (GB) found that the histocompatibility antigen HLA-B27 (W 27) was identified in 26 out of 50 patients with acute anterior uveitis, compared with 2 out of 50 controls. Twenty-one patients had significant, associated diseases, and 18 of these had HLA-B27. HLA-B27 was present in 8 of the 29 patients with no associated diseases (246).

Riitta Saario (FI), Rauli Leino (FI), Riitta Lahesmaa (FI), Kaisa Granfors (FI), Auli Toivanen (FI), Timo Yli-Kerttula (FI), Reijo Luukkainen (FI), Riitta Merilahti-Palo (FI), and Jouko Seppälä (FI) found that mild or unapparent infections of Yersinia enterocolitica may trigger autoimmune disorders such as thyroiditis and reactive arthritis, especially in individuals harboring the HLAB27 histocompatibility allele (1633; 1896).

 

Adrian R.M. Upton (GB) and Alan J. McComas (AU-GB-CA) found in 81/115 cases of carpal tunnel syndrome that there was an associated cervical radiculopathic finding as well. They proposed that if a nerve is impaired at one location it makes that patient more susceptible to other entrapments along the same neuraxis. They felt that either nerve compression alone or by itself would not be enough to cause clinical dysfunction. The two or more sites of nerve compression may slow axonal transport, thus creating conduction abnormalities. They concluded it is of vital importance to identify each area of nerve compression or entrapment and treat each one individually. They referred to this as the double crush syndrome (1924).

 

Renate Huch (DE), Albert Huch (DE), and Dietrich Lübbers (DE) demonstrated that when skin is heated to 42-45° C, it is possible to measure transcutaneously a reasonable value for arterial PO2, especially in newborn babies (922). Note: Shortly afterward, transcutaneous electrodes were developed for measuring PCO2.

 

H.J. Marsteller (DE), Werner K. Lelbach (DE), Regina Müller (DE), S. Jühe (DE), Carlos Ernesto Lange (DE), Heiner G. Rohner (DE), and Getine Veltman (DE) suggested a link between hepatic damage and occupational exposure to vinyl chloride (1289).

John L. Creech, Jr. (US) and Maurice N. Johnson (US) evaluated three men with angiosarcoma of the liver during a 2-year period. They realized, through careful history-taking, that all the men with this rare malignancy were employed in the same department of the plant where vinyl chloride monomer (VCM) was manufactured. Publication of this report and a related journal article stimulated a series of clinical investigations, epidemiologic studies, and toxicologic analyses (429).

Henry Falk (US), John L. Creech, Jr. (US), Clark W. Heath, Jr. (US), Maurice N. Johnson (US), and Marcus M. Key (US) confirmed the existence of the outbreak and discovered a premalignant lesion—idiopathic hepatic fibrosis—in additional members of the population heavily exposed to VCM (588).

A major international conference on the toxicity of VCM confirmed the carcinogenicity of VCM. VCM is now universally considered to be a highly potent chemical carcinogen (1714).

 

Neil Kaplowitz (US), Engeline Kok (US), and Norman B. Javitt (US) showed that a two-hour postprandial serum bile acid determination is a sensitive screening test for hepatobiliary disorders (1011).

 

Richard N.H. Pugh (GB), Iain M. Murray-Lyon (GB), Jeffrey L. Dawson (GB), M.C. Pietroni (GB), and Rachel Williams (GB) found that emergency ligation of bleeding esophageal varices (extremely dilated sub-mucosal veins in the lower third of the esophagus) using the Milnes Walker technique resulted in an overall 6-month survival of 32 per cent. In patients with good preoperative liver function this rose to 71 per cent, and the simple scoring system for grading the severity of disturbance of liver function was found to be of value in predicting the outcome of surgery. They developed the Child-Pugh score that consists of five clinical features and is used to assess the prognosis of chronic liver disease and cirrhosis; the score is used with the Model for End-Stage Liver Disease (MELD) to determine priority for liver transplantation; the Child-Pugh score was originally developed to predict surgical outcomes in patients presenting with bleeding esophageal varices (1533).

 

Andrew F. Brooker (US), Jack W. Bowerman (US), Robert A. Robinson (US), and Lee H. Riley, Jr. (US) presented the incidence and a method of classification of ectopic ossification following total hip replacement (251).

 

John Terborgh (US) proposed the geographical area hypothesis. It asserts that the tropics are the largest biome and that large tropical areas can support more species. More area in the tropics allows species to have larger ranges, and consequently larger population sizes. Thus, species with larger ranges are likely to have lower extinction rates (1873).

 

Frederick Hamerstrom (US) and Frances Hamerstrom (US) focused on the habitat needs of the greater prairie chicken. They developed and initiated a successful management plan based on their observation that the prairie chicken required a "checkerboard" pattern of habitat (803).

 

Leigh M. van Valen (US) formulated what he termed a new evolutionary law. He hypothesized that because of antagonistic interactions such as predation and parasitism, evolution would continue in the absence of environmental change (1936). This concept has been dubbed the Red Queen effect because in Lewis Carroll’s Alice Through the Looking Glass the Red Queen states of her country that: “… Now here, you see, it takes all the running you can do to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that” (323).

 

The United States Congress passed the Endangered Species Act, a much-strengthened version of a 1966 omnibus bill. This is the first U.S. law concerned exclusively with wildlife. It specifically prohibits federally funded projects from jeopardizing endangered species or their habitats (406).

 

1974

“Looking back... the facts have been far better than the dreams. In the long course of cell life on this earth it remained for our age, for our generation, to receive the full ownership of our inheritance. We have entered the cell, the mansion of our birth, and started the inventory of our acquired wealth.” Albert Claude (1257).

 

Albert Claude (BE-US), Christian Rene de Duve (GB-BE-US) and George Emil Palade (RO-US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning the structural and functional organization of the cell.

 

William M. Bonner (GB) and Ronald A. Laskey (GB) showed that tritium can be detected in polyacrylamide gels using a solution of the scintillator PPO in dimethyl sulphoxidethem (199).

 

Raymond F. Greene, Jr. (US) and Carlos Nick Pace (US) described a new method for estimating protein stability called the linear extrapolation method. They used optical rotation measurements to follow the unfolding of ribonuclease, lysozyme, alpha-chymotrypsin, and goat beta-lactoglobulin in urea and guanidine hydrochloride. By analyzing the proteins’ denaturation curves, they were able to make linear plots of the free energy of unfolding (delta G) versus denaturant concentration. The plot’s intercept gave a measure of the protein’s stability whereas the slope gave an “m value” that measured how strongly �G depended on urea concentration (759).

 

Yoram Salomon (IL), Constantine Londos (IL), and Martin Rodbell (US) developed a highly sensitive assay for adenylate cyclase (1643).

 

Knud H. Nierhaus (DE) and Ferdinand Dohme (DE) carried out the total reconstitution of functionally active 50S ribosomal subunits from Escherichia coli (1419).

 

Richard Anthony Flavell (GB-US), Donna L. Sabo (US), Eric F. Bandle (CH-US), and Charles Weissmann (CH-US) performed the first site-directed mutagenesis experiment that marked the beginning of reverse genetics (630). Note: Reverse genetics attempts to connect a given genetic sequence with specific effects on the organism.

 

Hubert Guilley (AT), Gerard Jonard (AT), and Léon Hirth (AT) were among the first to determine some of the base sequences in the RNA of tobacco mosaic virus (788).

 

Pieter C. Wensink (US), David J. Finnegan (US), John E. Donelson (US), and David S. Hogness (US) cloned fragments of Drosophila genomic DNA and developed a system for mapping DNA sequences in the chromosomes of Drosophila melanogaster (2013).

 

Takashi Kasai (US-IT) analyzed the effects of deletions that ended in the leader region of the his operon of Salmonella. Kasai concluded that the his operon leader region may contain a regulated site of transcription termination. He introduced the term transcription attenuation to describe the mechanism of transcription regulation that presumably occurs at this site (1018).

Charles Yanofsky (US) and Robert Kolter (US) while studying the tryptophane operon of Escherichia coli discovered a type of operon control mechanism called attenuation (1086; 2078).

Frank Lee (US), Catherine L. Squires (US), Craig Squires (US), and Charles Yanofsky (US) found that the trp leader transcript of the tryptophan operon can fold to form alternative hairpin structures, each of which plays an essential role in determining whether transcription will be completed (1154).

Charles Yanofsky (US) reported that one mRNA hairpin serves as a transcription terminator; it directs RNA polymerase to terminate transcription. The second, alternative mRNA hairpin functions as an antiterminator. Which of the alternative hairpin structures would form would depend on the cell's ability to translate the two Trp codons in the 14-residue leader peptide-coding region. When these two tryptophan codons are translated, the antiterminator would not form; this would allow the terminator to form and terminate transcription (2078; 2079). Gerard Zurawski (US), George Stauffer (US), Dirk Elseviers (US), Keith Brown (US), and Dale Oxender (US) all contributed to this knowledge.

Bob Landick (US), Robert F. Fisher (US), Malcolm E. Winkler, (US), Robert Kolter (US), Anathbandhu Das (US), and Charles Yanofsky (US) established the role of a third hairpin structure that can form in the trp leader transcript, a structure that precedes and is an alternative to the antiterminator. This structure, which also serves as an anti-antiterminator, causes the transcribing RNA polymerase to pause during transcription of the leader region. This pause allows sufficient time for a ribosome to bind to and initiate translation of the leader peptide-coding region (624; 625; 1130; 2038).

 

Roger E. Fenna (US), Brian W. Matthews (AU-US), John M. Olson (US), and Elizabeth K. Shaw (US) determined the structure of a bacteriochlorophyll-protein from the green photosynthetic bacterium Chlorobium limicola: crystallographic evidence for a trimer (599).

 

Brian W. Matthews (AU-US), Larry H. Weaver (US), and William R. Kester (US) were able to generate an improved electron density map for thermolysin by further refining three heavy atom derivatives that he had used previously and by including data for two additional isomorphs. They concluded that the enhanced stability of thermostable proteins relative to thermolabile ones could not be attributed to a common determinant such as metal ion binding, but in a given instance could be due to rather subtle differences in a combination of factors including hydrophobic interactions, metal binding, hydrogen bonding, and ionic interactions (1303).

 

Elias Lazarides (US) and Klaus Weber (PL-DE-US) developed a technique whereby they could visualize actin filaments in non-muscle cells (1144).

 

Koichi Kawai (JP), Michiya Fujita (JP), and Makoto Nakao (JP) found that the apical and basolateral membranes of epithelial cells have different lipid compositions, and specifically that glycolipids are enriched apically (1026).

Enrique Rodriguez Boulan (US) and David D. Sabatini (US) discovered that infection of two different lines of polarized epithelial cells grown as monolayers with several types of enveloped viruses results, for each virus type, in a characteristic asymmetric budding of virions. Influenza virus (WSN strain), simian virus 5, and Sendai virus bud exclusively from the free (apical) surface of the cells, while vesicular stomatitis virus acquires its envelope only from the basolateral plasma membrane (209).

Gerrit van Meer (NL) and Kai Simons (NL) showed that the different phospholipid compositions of the viruses from polarized cells reflect differences in the phospholipid composition of the plasma membrane domains (1930).

Morris J. Karnovsky (US), Alan M. Kleinfeld (US), Richard L. Hoover (US), Richard D. Klausner (US), Thomas E. Thompson (US), and Thomas W. Tillack (US) reported that heterogeneous lipid domains exist (1014) and that glycosphingolipids cluster in both model membrane systems and biological membranes (1882).

Gerrit van Meer (NL-DE), Ernst H. Steizer (DE), Roel W. Wijnaendts-van-Resandt (DE), and Kai Simons (NL-DE) provided data that lipids are potentially sorted in the Golgi complex. The lipids wound up on the exoplasmic leaflet of the plasma membrane where they could not diffuse past tight junctions, so it seemed logical that they might be synthesized on the lumenal leaflet of the Golgi and transported to the plasma membrane via vesicles. Lipid “sorting,” they stated, “must involve the lateral segregation in this leaflet of lipids into those areas of the membrane that will bud to form transport vesicles destined for either the apical or basolateral plasma membrane domain (1931).

Deborah A. Brown (US) and James A. Rose (US) discovered that cold detergent extraction allows the isolation of membranes enriched in glycosphingolipids and glycosyl-phosphatidylinositol anchored proteins (254). These detergent-resistant membranes (DRMs) literally float like rafts to the top of the preparations.

Richard G.W. Anderson (US) and Ken Jacobson (US) reviewed many later studies on DRMs showing that raft-associated proteins are important for cell signaling and that movement of those proteins into the DRM fraction is associated with signal activation (56).

 

Russell Ross (US), John A. Glomset (US), Beverly Kariya (US), Laurence Harker (US), Nancy Kohler (US), and Allan Lipton (US) demonstrated that platelets contain a potent mitogen for cells such as fibroblasts. It is called platelet-derived growth factor (PDGF) (1082; 1605).

 

Alan T. Nurden (FR) and Jacques P. Caen (FR) made observations on platelet membrane glycoproteins, which provided the basis for important advances in understanding hemostasis and prevention of thrombosis (1429).

 

Robert Peter Aaronson (US) and Günter Klaus-Joachim Blobel (DE-US) studied rat liver nuclei where they found that the nuclear pore complex does not require the nuclear membranes either for attachment to the nucleus or for maintenance of its own structural integrity (10).

Robert Peter Aaronson (US) and Günter Klaus-Joachim Blobel (DE-US), in rat liver nuclei, showed that the nuclear pore complexes possess a 150-angstrom thick lamina. The pore complexes exhibit characteristic morphology and appear to be attached in a highly specific orientation to the lamina, which extends over relatively large areas. The pore complex-lamina fraction is composed of three major and several minor polypeptides with little or no DNA, RNA, or phospholipid. They suggested that the association of the pore complexes and the lamina reflects the structural arrangement of the nuclear periphery in vivo (11).

Nancy Dwyer (US) and Günter Klaus-Joachim Blobel (DE-US) presented evidence from rat liver nuclei that the isolated lamina, a 150-angstrom thick, proteinaceous structure, apposes the inner nuclear envelope membrane, connecting nuclear pore complexes and surrounding the entire nucleus (521).

Larry Gerace (US), Andrea Blum (US), and Günter Klaus-Joachim Blobel (DE-US) characterized three lamina proteins. These proteins turned out to be lamins A, B₁, and C, three of the four major components that interweave to form the lamina. Rather than a mesh that permeates the nucleus, the lamina is a protein polymer that hugs the nuclear membrane, the researchers concluded—and subsequent work has backed them up (679).

Larry Gerace (US), Claudette Comeau (US), Margaret Benson (GB), and Brian Burke (US) determined that the nuclear envelope is a distinct organelle in that it contains membrane proteins not found in other cellular membranes, e.g. proteins which interact with nuclear lamins and signal proteins allowing it to reassemble following mitosis (283; 680).

 

Charles D. Taylor (US) and Ralph Stoner Wolfe (US) were the first to describe coenzyme M. It was isolated from a methanogenic bacterium (1864).

 

Robert Nyfeler (CH) and Walter Keller-Schierlein (CH) reported the isolation of an antifungal agent, echinocandin B, from Aspergillus nidulans var. echinulatus. It inhibits beta glucan synthase activity (1430).

 

Richard D. Thompson (US), Herbert T. Nagasawa (US) and John W. Jenne (US) developed a methodology for determination of Theophylline (a methylxanthine drug used in therapy for respiratory diseases) and its metabolites in human urine and serum. There was a significant direct correlation between serum theophylline levels and the urine theophylline fraction, and a significant inverse correlation between serum theophylline and the urine 3-methylxanthine fraction (1881).

 

John M. Taylor (US), William M. Mitchell (US), and Stanley Cohen (US) discovered epidermal growth factor (1865).

 

Charles J. Arntzen (US), Claudie Vernotte (FR), Jean-Marie Briantais (FR), Paul A. Armond (US), Kenneth R. Miller (US), Gayle J. Miller (US), and Katherine R. McIntyre (US) produced experimental evidence that photosystem 2 is found within a large chlorophyll-protein complex (CP II) which spans the thylakoid membrane (67; 1343).

 

Thomas Peter Maniatis (US), Mark Steven Ptashne (US), Bart Barrell (GB), and John Donelson (US) determined the base sequence of the binding site in the left operator of the lambda virus DNA that had the highest affinity for the repressor protein (1279).

 

Henri Beaufay (BE), Alain Amar-Costesec (BE), Denise Thines-Sempoux (BE), Maurice Wibo (BE), Mariette Robbi (BE), and Jacques Berthet (BE) determined that many proteins are common to both the smooth and rough endoplasmic reticulum (47; 115).

 

Stephen Coplan Harrison (US), Anthony Jack (GB), Daniel A. Goodenough (US), and Bartholomew M. Sefton (US) determined the structure of two small spherical viruses (820).

 

Loretta Leive (US) has drawn attention to the fact that many bacterial envelope mutants have been shown to possess dramatically altered permeability characteristics, which influence their antibiotic susceptibility (1163).

 

Robert W. Hedges (GB) and Alan E. Jacob (GB), Naomi Datta (GB), and Jack N. Coetzee (ZA) postulated that resistance to ampicillin in bacteria is carried by a DNA element that can be transposed or moved from one DNA molecule to another. They called this element a transposon. This was the first direct evidence that such a transfer is by a procedure analogous to the insertion of IS (insertion sequence) elements (832; 833).

 

Steven H. Larsen (US), Julius Adler (US), J. Jay Gargus (US), and Robert W. Hogg (US) showed that a proton gradient is the driving force behind flagellar movement in bacteria (1136).

Steven H. Larsen (US), Robert W. Reader (US), Edward N. Kort (US), Wung-Wai Tso (US), and Julius Adler (US) found that change in direction of flagellar rotation is the basis of the chemotactic response in Escherichia coli (1137).

Steven J. Kleene (US), Myron L. Toews (US), and Julius Adler (DE-US) discovered that E. coli contains several MCPs (methyl-accepting chemotaxis proteins), all of which play a central role in the chemotaxis sensory transduction system. Strains of bacteria lacking these proteins or the ability to methylate or demethylate them are unable to respond to stimuli. Adler and colleagues also noted that an increase in the concentration of attractants led to an increase in the methylation level of MCPs, whereas a decrease in the concentration of attractants or an increase in the concentration of repellents led to a decrease in methylation level (1063).

Myron L. Toews (US) and Julius Adler (DE-US) identified the product formed during MCP demethylation as methanol (1894).

Michael Eisenbach (US) and Julius Adler (DE-US) isolated cell envelopes with intact flagella from E. coli and Salmonella typhimurium. They found that by adding artificial electron donors and an energy source, they could restore counterclockwise flagellar rotation resulting in smooth swimming toward the attractant. This suggested that the proton electrochemical potential was the driving force behind counterclockwise flagellar rotation, whereas clockwise rotation required a cytoplasmic component (550).

 

John Shine (AU) and Larry Dalgarno (AU) while studying mRNA translation in Escherichia coli discovered a ribosome-binding site upstream from the AUG initiation codon. This binding site consisted of a group of six to eight purine-rich nucleotides (1730).

 

Jim Speirs (US) and Max Luciano Birnstiel (CH) demonstrated that in Xenopus laevis the 5.8 S RNA is cleaved from the same precursor as 18 and 28 S RNA (1776).

 

Rolf Martin Zinkernagel (CH-US) and Peter Charles Doherty (AU-US) discovered that killer T cells are not stimulated unless they simultaneously recognize the antigen and the antigen-presenting MHC molecule (1950).

 

D. Scott Linthicum (US) and Stewart S. Sell (US) described the role of endocytosis in activation of B lymphocytes (1206).

 

Hiroshi Shiku (US) and Pawel Kisielow (US) discovered that the CD8 receptor protein is unique to killer T cells and can be used to distinguish them from other lymphocytes (1950).

 

Harry van Someren (NL), Andries Westerveld (NL), Anna Hagemeijer (NL), Jules R. Mees (NL), P.M. Meera Kahn (IN-NL), and Otto B. Zaalberg (NL) assigned the HLA histocompatibility gene to human chromosome 6 (1935).

 

Howard O. Nornes (US) and Gopal D. Das (US) determined the precise timing of neuron formation in the rat spinal cord (1424).

 

William A. Frazier (US), Linda F. Boyd (US), and Ralph A. Bradshaw (US) studied the interaction of nerve growth factor (NGF) with its receptors on the surface membranes of responsive chick embryo sympathetic and sensory neurons. They reported that the binding is a complex process with properties like the binding of insulin to fat and liver cell membranes and human lymphocytes (638).

William A. Frazier (US), Linda F. Boyd (US), Morris W. Pulliam (US), Andrzej Szutowicz (PL), and Ralph A. Bradshaw (US) reported on the binding of nerve growth factor (NFG) in embryonic heart and brain tissues from chickens. They found that binding in these tissues is very similar to that in the sympathetic and sensory nervous systems (639). This latter study presaged the much wider range of responsive tissues for NGF, particularly the central nervous system that was eventually established several years later.

 

Dorothy A. Miller (US), Orlando J. Miller (US), Vaithllingam G. Dev (US), Shahnaz Hashmi (US), Ramana V. Tantravahi (US), Leandro Medrano (US), and Howard Green (US) found a gene coding for a poliovirus virus receptor in humans located on chromosome 19 (1341).

 

Jon Robertus (US), Jane E. Ladner (GB), John T. Finch (GB), Daniela Rhodes (GB), Ray S. Brown (GB), Brian F.C. Clark (GB-DK), and Aaron Klug (ZA-GB) described the detailed three-dimensional structure of yeast phenylalanine tRNA. It was determined by x-ray diffraction at a resolution of three angstroms (1577).

 

Timothy C. Hall (US), Ronald K. Wepprich (US), Jeffrey W. Davies (US), Lewis G. Weathers (US), and Joseph S. Semancik (US) showed that the etiological agent of exocortis, an infectious disease of citrus trees, previously assumed to be caused by a virus, is in fact a viroid (798).

 

Francis J. Tedesco (US), Robert W. Barton (US), and David H. Alpers (US) found a significant association between patients receiving clindamycin and the development of pseudomembraneous colitis (PMC) (1868).

John G. Bartlett (US), Te-Wen Chang (US), Marc Gurwith (US), Sherwood Leslie Gorbach (US), and Andrew B. Onderdonk (US) provided evidence that the etiological agent of pseudomembraneous colitis (PMC) is Clostridium difficile (101).

 

Ronald Berezney (US) and Donald S. Coffey (US) developed a technique for treating cells in such a way as to reveal what was called the nuclear matrix. Detergent, RNAases, DNAases, and concentrated salts were used (134; 135).

 

Monsanto Chemical Company introduced the herbicide glyphosate, a substituted glycine, for the control of perennial broadleaved weeds and grasses. ref

 

Friedrich G. Constabel (CA), Kuo Nan Kao (CA), Morris R. Michayluk (CA), Kutty K. Kartha (CA), and Oluf L. Gamborg (CA) discovered that polyethylene glycol is extremely efficient at promoting the fusion of cellular protoplasts (410; 1008; 1016).

 

Peter G. Shepherd (GB), B. Fraissignes (GB), W.A. Peet (GB) discussed a fermentation process designed to produce single cell protein from hydrocarbons (1726).

 

Rolf Martin Zinkernagel (CH-US) and Peter Charles Doherty (AU-US) discovered how the immune system recognizes cells that must be eliminated because they have been infected by a virus (2110).

 

Jean David Rochaix (CH), Adrian Peter Bird (GB), Aimee Bakken (US), Debra J. Wolgemuth-Jarashow (US), Georgiana M. Jagiello (US), Ann S. Henderson (US), Robert W. Old (GB), Harold Garnet Callan (GB), Kenneth W. Gross (US), Lynn Golden (), Ulrich Schaefer (DE), Michael Rosbash (US), Manuel O. Diaz (UY-US), and Joseph Grafton Gall (US) performed experiments establishing that the appearance of the unusual lampbrush chromosomes probably represents a specialization for the intensive transcription of mRNAs, 5S rRNA, and tRNAs required for growth of the oocyte cytoplasm during diplotene (305; 492; 717; 1445; 1582; 2054).

Harold Garnet Callan (GB), Joseph Grafton Gall (US), and Celeste A. Berg (US) published the first physical maps of the Xenopus laevis lampbrush chromosomes (304).

 

John J. Strange (GB), R. J. Kenworthy (GB), Adam J. Webb (GB), and Carolyn M. Giles (GB) discovered Wka (Weeks), a new antigen in the Kell blood group system (also known as Kell-Cellano system) (1814).

 

Terje Torsvik (NO) and Ian D. Dundas (NO) discovered the first archaeal virus. It was associated with Halobacterium salinarium (1901).

Giuseppe Bertani (US) and Larry Baresi (US) discovered the first virus isolated from a methanogen. It was found associated with a culture of Methanobrevibacter smithii (150).

Davorin Janekovic (DE), Simon Wunderl (DE), Ingelore Holz (DE), Wolfram Zillig (DE), Andrea Martin (DE), Siobhán Yeats (DE), Wolf-Dieter Reiter (DE), and Wilhelm Aicher (DE) discovered the first thermophilic viruses. They were isolated from the sulfur-dependent Thermoproteales and Sulfolobales (968; 1292).

 

Denis Parsons Burkitt (GB), Alec R. Walker (ZA), and Neil S. Painter (GB) became convinced that a diet high in roughage prevents many ailments. Their efforts encouraged scientists and the public to think differently about nutrition (285).

 

Hans-Udo Schweikert (DE) and Jean D. Wilson (US) reported on the necessity of steroid hormones for normal hair development (1696; 1697).

 

H. Frederik Nijhout (US) and Carroll M. Williams (US) used the tobacco hornworm, Manduca sexta, to develop the concept of a critical weight necessary for metamorphosis. Critical weight is an important but cryptic milestone for an insect larva in determining its final size. Crossing the critical weight threshold initiates a suite of physiological mechanisms that determine the duration of feeding thereafter and thus dictate the size of the adult (1420). Note: Details of these processes, however, vary among insects.

 

Pernilla Lindahl (FR), Patricia Leary (FR), and Ion Gresser (FR) found that interferon preparations in the mouse enhanced the expression of histocompatibility antigens on thymocytes from mice of different ages, but of splenic lymphocytes only from young mice. Interferon did not alter the expression of the theta antigen of thymocytes or splenic lymphocytes (1196).

Pernilla Lindahl (FR), Ion Gresser (FR), Patricia Leary (FR), and Michael Tovey (FR) found that treatment of young and mature mice with potent preparations of interferon results in a marked enhancement of the expression of histocompatibility antigens on the surface of thymocytes and splenic lymphocytes (1195).

 

Saimon Gordon (US), Jean A. Todd (US), Zanvil Alexander Cohn (US), and Jay C. Unkeless (US) contributed to the characterization of the synthesis and secretion of lysozyme and plasminogen activator by activated macrophages (733; 734).

 

H. Robson MacDonald (CH), Howard D. Engers (CA), Jean-Charles Cerottini (CH), and K. Theodor Brunner (CH) generated mouse cytotoxic T lymphocytes (CTL) in unidirectional mixed leukocyte cultures (MLC) using normal C57BL/6 spleen cells as responding cells and irradiated DBA/2 spleen cells as stimulating cells (1246).

 

Per Brandtzaeg (NO) found that secretory epithelial cells contain membrane-associated IgA and secretory component (SC). Free secretory component was detected in the Golgi region whereas both free and IgA-complexed SC were detected in the cell membranes and in the apical portion of the cytoplasm. He proposed that SC acts as a specific surface receptor for dimeric IgA, and that the formed complexes become mobilized and at least partially stabilized in the cell membrane. They subsequently enter the gland lumen via the epithelial cell cytoplasm outside the Golgi apparatus, and perhaps, to some extent, directly from the cell membrane (226).

 

Michael J. Brownstein (US), Juan M. Saavedra (US), Julius Axelrod (US), Gary H. Zeman (US), and David O. Carpenter (US) were able to show the coexistence of several neurotransmitters in single identified neurons of Aplysia californica, the California sea slug (263).

Tomas Hökfelt (SE), Olle Johanssen (SE), Ake Ljungdahl (SE), Jan M. Lundberg (SE), and Marianne Schultzberg (SE) demonstrated the coexistence of more than one neurotransmitter in single neurons within the mammalian brain (903).

 

 Michiaki Takahashi (JP), Terumasa Otsuka (JP), Yoshiomi Okuno (JP), Yoshizo Asano (JP), Takehiko Yazaki (JP), and Shin Isomura (JP) successfully developed the first live attenuated varicella (chickenpox) vaccine in the world. The virus used for this vaccine was varicella-zoster virus isolated from the vesicular fluid of a child with typical varicella and it was named the Oka strain (1852).

 

Stephen J.W. Busby (GB), John R. Griffiths (GB), George Karoly Radda (HU-GB), Jan A. Berden (NL), Pieter R. Cullis (CA), David I. Hoult (GB), Alan C. McLaughlin (US), Rex Edward Richards (GB), David G. Gadian (GB), and P. John Seeley (GB) were the first to introduce the use of nuclear magnetic resonance (NMR) to study tissue metabolites (132; 290; 912).

Brian D. Ross (GB), George Karoly Radda (GB), David G. Gadian (GB), Graeme Rocker (GB), Margaret Esiri (GB), and James Falconer-Smith (GB) published the first scientific report on the clinical application of nuclear magnetic resonance (NMR) when they showed that the method of 31P NMR is suited to rapid non-invasive diagnosis in various muscle disorders (1599).

 

Donald W. Mercer (US) evaluated sera from 71 patients with myocardial infarction and other diseases associated with elevated creatine kinase (CK) activity. This evaluation revealed isoenzyme patterns that resembled those of either cardiac muscle or skeletal muscle. The cardiac pattern (presence of MB isoenzyme) and clinical documentation of myocardial infarction were 100% correlated in the 35 patients so studied (1330). Note: CK-MB is found in the heart and rises in the blood when heart muscle is damaged. This test, also called the creatine phosphokinase test, is used as strong evidence of myocardial infarction.

 

Kuzuo Fujikawa (US), Michael H. Coan (US), Mark E. Legaz (US), and Earl Warren Davie (US) linked the intrinsic pathway with the extrinsic pathway of blood coagulation at the level of Stuart factor (652).

 

Richard Rodewald (US) and Morris J. Karnovsky (US) revealed the highly ordered, isoporous substructure of the glomerular slit diaphragm in rat and mouse kidneys. Physiological data indicate that the glomerular filter functions as if it were an isoporous membrane which excludes proteins larger than serum albumin. The similarity between the dimensions of the pores in the slit diaphragm and estimates for the size and shape of serum albumin supports the conclusion from tracer experiments that the slit diaphragm may serve as the principal filtration barrier to plasma proteins in the kidney (1586).

 

Peter C. Elwood (GB), Archie L. Cochrane (GB), Michael L. Burr (GB), Peter M. Sweetnam (GB), G. Williams (GB), E. Welsby (GB), S. Janie Hughes (GB), and Ross Renton (GB) discovered that aspirin may be useful in the secondary prevention of mortality from myocardial infarction (562).

The Steering Committee of the Physician’s Health Study Research Group (US) concluded that aspirin reduces the risk of myocardial infarction but stated that the effect on cardiovascular morbidity remains inconclusive (774; 775).

 

Gian Franco Bottazzo (IT), Alejo Florin-Christensen (AR), Jim I. Mann (GB), Margaret Thorogood (GB), J. David Baum (GB), Deborah Doniach (CH-GB) suggested that an autoimmune factor may contribute to juvenile diabetes and that such autoimmune diabetes tends to run in families and may be more likely to cause complications (206; 207).

Agus C. MacCuish (GB), W. J. Irvine (GB), E. W. Barnes (GB), and Leslie J. P. Duncan (GB) provided further direct evidence to support the hypothesis of an autoimmune form of diabetes mellitus (1245).

 

E. Müller (CH), H.R. Marti (CH), J. Bach (CH), J.L. Michell (CH), C. Gasser (CH), John J. Hutton (US), and Robert R. Chilcote (US) reported cases of non-spherocytic hemolytic anemia caused by glucose-6-phosphate isomerase deficiency (933; 1373).

 

William H. Sweet (US) and James G. Wepic (US) developed radiofrequency lesioning of the trigeminal ganglion, the most frequently used procedure for the treatment of trigeminal neuralgia (1842).

 

Lawrence A. Loeb (US), Clark F. Springgate (US), and Narayana Battula (US) proposed that as DNA was synthesized the polymerase might make errors in which bases were incorporated either during replication or repair. These mutations might be the consequence of an error-prone polymerase or the presence of carcinogens (1221).

 

Takuo Aoyagi (JP), Micho Kishi (JP), Kazuo Yamaguchi (JP), and Shinichi Watanabe (JP) invented the pulse oximeter to measure blood oxygen saturation. It is based on the equation they derived that makes it possible to compute arterial oxygen saturation without precalibration, independent of ear thickness, skin pigment, hemoglobin concentration, and light intensity (58; 59).

 

Eugene J. van Scott (US) and Ruey J. Yu (US) introduced the use of alpha hydroxy acids to control keratinization (1932-1934). Note: Dermatologists administer these substances routinely as an ingredient in countless anti-aging products marketed by the cosmetics industry.

 

Susan P. Baker (US), Brian O'Neill (US), William Haddon, Jr. (US), and William B. Long (US) indicated that the Injury Severity Score represents an important step in solving the problem of summarizing injury severity, especially in patients with multiple traumas. The score is easily derived and is based on a widely used injury classification system, the Abbreviated Injury Scale. Use of the Injury Severity Score facilitates comparison of the mortality experience of varied groups of trauma patients, thereby improving ability to evaluate care of the injured (87).

 

Graham Teasdale (GB) and Bryan Jennett (GB) presented a way to assess coma and impaired consciousness on a practical scale (1867). Note: This is referred to as The Glasgow Coma Scale.

 

William F. House (US) pioneered the development of cochlear implants (913; 914).

 

Robert L. Trivers (US) published on parent–offspring conflict and the genetics of offspring solicitation and parental response, i.e., genetic interests of parents and offspring (1907).

 

Julien Mendlewicz (BE) and Joseph L. Fleiss (BE) demonstrated that a dominant X-linked gene is involved in the biological transmission of bi- polar manic-depressive illness. This was done through the application of linkage methods using chromosome markers in a large sample of families. The paper also emphasizes the notion that depression is heterogeneous from the genetic point of view since X-linked inheritance could not be found in unipolar depressive illness (1329).

 

Bruce R. Bistrian (US), George L. Blackburn (US), Edward Hallowell (US), and Robert Heddle (US) in their survey of the protein nutritional status of all patients on the surgical wards of an urban municipal hospital, found protein-calorie malnutrition (PCM) in one half of these patients as judged by triceps skin fold and arm muscle circumference measurements (170).

Bruce R. Bistrian (US), George L. Blackburn (US), Joseph Vitale (US), David Cochran (US), and Judy Naylor (US) found that significant protein-calorie malnutrition occurs commonly in municipal hospitals in both medical and surgical services .

 

Richard Charles Lewontin (US) in his book, The Genetic Basis of Evolutionary Change, promotes the study of protein polymorphisms to measure the amount of genetic variation present in natural populations. The methods described here make possible studies of population genetics in natural populations of animals on a large scale (1183).

 

Christopher C. Smith (US) and Steve D. Fretwell (US) designed a graphical model supported by standard analytical procedures to demonstrate that for any given environmental situation there is one optimal amount of resource for a parent to expend on each of its offspring (1753).

 

Wolfgang Ernst Wendt (DE) discovered seven limestone slabs of rock with traces of animal figures in the Apollo 11 Cave in the Huns Mountains of southwestern Namibia. They have been dated with unusual precision for ancient rock art. Their age is between 28,000 and 32,000 BP (2012).

 

Marvin J. Allison (US), Alejandro Pezzia (PE), Ichiro Hasegawa (US), Enrique Gerszten (AR), Ronald F. Giffler (US), Dandl Mendoza (US), Harry P. Dalton (US) and Vincent A. Sawicki (US) presented evidence that an individual from the Huari culture in pre-columbian Peru exhibited an array of ailments at the time of his death (890-950 A.D.). Radiological diagnosis revealed aspiration pneumonia, which was possibly initiated during a systemic salmonellosis such as typhoid fever. His health was further jeopardized by the presence of two helminthic infestations, hookworm and trichinosis (33; 34; 1663).

 

1975

“For him [the scientist], truth is so seldom the sudden light that shows new order and beauty; more often, truth is the uncharted rock that sinks the ship in the dark.” John Warcup Cornforth (418). Speech given in 1975.

 

John Warcup Cornforth (AU-GB) for his work on the stereochemistry of enzyme-catalyzed reactions and Vladimir Prelog (BA-CH) for his research into the stereochemistry of organic molecules and reactions shared the Nobel Prize in Chemistry.

 

David Baltimore (US), Renato Dulbecco (IT-US) and Howard Martin Temin (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning the interaction between tumor viruses and the genetic material of the cell.

 

Benoit B. Mandelbrot (PL-FR-US) originated and named fractal geometry. He emphasized the use of this geometry to model many "rough" phenomena in the real world. Natural fractals include the shapes of mountains, coastlines, and river basins; the structures of plants, blood vessels, and lungs; the clustering of galaxies; and Brownian motion. Fractals are found in human pursuits, such a music, painting, architecture, and stock market prices. Mandelbrot believed that fractals, far from being unnatural, were in many ways more intuitive and natural than the artificially smooth objects of traditional Euclidean geometry (1267-1269).

 

Patrick H. O’Farrell (US) devised a two-dimensional gel system for analyzing protein mixtures in which SDS polyacrylamide-gel electrophoresis is combined with separation according to isoelectric point (1434).

 

Dick F. Swaab (NL), Chris W. Pool (NL), and F. Nijveldt (NL) reported the development and application of a method for the specific localization of vasopressin and oxytocin in the rat brain by immunofluorescence. The topographic distribution of these neuropeptides is given not only in the classical neuroendocrine cells of the supraoptic and paraventricular nucleus, but vasopressin was also found in the suprachiasmatic nucleus (1838).

 

Peter Nigel Tripp Unwin (GB), Richard Henderson (GB), Andrew D. McLachlan (GB), Gebhard F.X. Schertler (AT), Joyce M. Baldwin (GB), Thomas A. Ceska (GB), Friedrich Zemlin (DE), Erich Beckmann (DE), and Kenneth H. Downing (US) used computer-based reconstruction from electron micrographs of unstained samples to determine the structure of bacteriorhodopsin. They established that this protein contains seven alpha-helical rods spanning the membrane. They were the first to use an electron microscope to generate a 3D image of a protein at atomic resolution (847-852; 1320; 1922).

 

Howard G. Gratzner (US), Robert C. Leif (US), Diane J. Ingram (US) and Albert Castro (US) developed immunochemical techniques to detect incorporation of bromodeoxyuridine (BrdUrd) labeled nucleotides. This was enabled by development of an antibody against (BrdUrd) labeled DNA (753).

Frank A. Dolbeare (US), Howard G. Gratzner (US), Maria G. Pallavicini (US), and Joel W. Gray (US) developed a flow cytometric technique that simultaneously measured DNA content and incorporated (BrdUrd) (500).

 

Reuben Lotan (US), Ehud Skutelsky (US), David Danon (US), and Nathan Sharon (US) described the first purification and characterization of an anti-T lectin from peanut. The use of affinity chromatography on an immobilized galactopyranosylamine derivative to obtain a homogeneous protein by a single-step procedure is described along with some physicochemical properties, hemagglutinaing activity, and carbohydrate- and glycoprotein binding specificity of the pure lectin (1225).

 

Paul G. Richman (US) and Alton Meister (US) discovered that glutathione regulates its own synthesis. Glutathione is synthesized from L-glutamate and L-cysteine via a gamma-glutamyl-cysteine intermediate. By examining the effect of glutathione and several related compounds on the activity of kidney gamma-glutamyl-cysteine synthetase, Meister was able to conclude that, "gamma-glutamyl-cysteine synthetase is inhibited by glutathione under conditions similar to those which prevail in vivo, thus strongly suggesting a physiologically significant feedback mechanism" (1326; 1565).

 

Mats Hamburg (SE), Jan Svensson (SE), and Bengt Ingemar Samuelsson (SE) discovered thromboxanes as a new class of prostaglandins. They showed 1) that the structure of metabolites formed from arachidonate-derived endoperoxides could be more variable than had been imagined, and 2) that these eicosanoids are powerful regulators of platelet aggregation, and thus important in blood clotting and possibly atherogenesis (802).

James S. Goodwin (US) and David R. Webb (US) reviewed the evidence for a role for prostaglandin E (PGE) as an endogenous regulator of immune function. They concluded that PGE acted as a feedback inhibitor of T-cell proliferation and function, but that the available data on PGE in B-cell function was too conflicting to draw general conclusions (731).

 

A major component of the homeostatic response is the hypothalamic-pituitary-adrenal (HPA) axis, an intricate, yet robust, neuroendocrine mechanism that mediates the effects of stressors by regulating numerous physiological processes, such as metabolism, immune responses, and the autonomic nervous system.

The paraventricular nucleus houses three functional neuronal types that act as central regulators of the stress response, 1) parvocellular, 2) neurosecretory magnocellular, and 3) long-projecting neurons.

Federic Vandesande (BE), Kamiel Dierickx (BE), C.H. Rhodes (US), Joan L. Morrell (US), Donald W. Pfaff (US), Larry W. Swanson (US), and Paul E. Sawchenko (US) discovered that neurosecretory magnocellular neurons project to the neurohypophysis to regulate the secretion of oxytocin and arginine vasopressin directly into the general circulation (1563; 1840; 1939).

Jacques L. Michaud (US), Thomas Rosenquist (US), Noah R. May (US), and Chen-Ming Fan (US) found that the Sim1 transcription factor acts as a key regulatory gene of the paraventricular nucleus, encoding a protein that also regulates arginine vasopressin, thyrotropin releasing hormone, and oxytocin expression, as well as corticotropin releasing hormone and somatostatin (1337).

K. Abe (US) and Vaughn Critchlow (US) reported that normal hypothalamic-pituitary-adrenal axis function is highly influenced by the dose and duration of glucocorticoid exposure (12). Note: The hypothalamic-pituitary-adrenal axis is governed by a closed-loop glucocorticoid-dependent negative feedback system that is essential for the termination of the stress response.

Robert M. Sapolsky (US), Lewis C. Krey (US), Bruce S. McEwen (US), Joseph Weidenfeld (IL), Shaul Feldman (IL), Anna Itzik (IL), Louis D. Van de Kar (IL), and Michael E. Newman (IL) found that initiation of hypothalamic-pituitary-adrenal axis negative feedback occurs via glucocorticoid-receptor-expressing-neurons in the hippocampus and the hypothalamus following stress-induced elevations in corticosterone (1654; 2001). Krisztina J. Kovács (HU), Anna Földes (HU), and Paul E. Sawchenko (US) observed that at the paraventricular nucleus, this first acts upon arginine vasopressin neurons (1100).

Robert M. Sapolsky (US), L. Michael Romero (US), Allan U. Munck (US), Julia K. Gjerstad (GB), Stafford L. Lightman (GB), and Francesca Spiga (GB) showed that glucocorticoid-dependent negative feedback relies on the rhythmic release of glucocorticoid in diurnal and ultradian patterns that are fundamental to the termination of the stress response (708; 1655).

Stafford L. Lightman (GB), and Becky L. Conway-Campbell (GB) showed that in all vertebrates, a peak of circulating corticosterone occurs just before the onset of daily activity. The diurnal rhythm of hypothalamic-pituitary-adrenal axis activity is driven by the central circadian pacemaker, the suprachiasmatic nucleus, which has major inputs to the paraventricular nucleus to regulate daily rhythms of glucocorticoid output (1194).

 

 Willy F. Piessens (US), Winthrop Hallowell Churchill, Jr. (US), John R. David (US), Alexandra Dimitriu (FR), Michel Dy (FR), Napier Thomas (FR), and Jean Hamburger (FR) found that normal macrophages could be rendered cytotoxic by incubation with acellular supernatants of mixed lymphocyte cultures (MLC) between an allograft recipient and a donor. Supernatants alone were not cytotoxic. They characterized this as resulting from a macrophage-arming factor (496; 1504).

Elizabeth A. Carswell (US), Lloyd John Old (US), Robert L. Kassel (US), Saul Green (US), Nancy C. Fiore (US), and Barbara D. Williamson (US) coined the phrase tumor- necrosis factor (TNF) and defined it as “an activity produced by activated macrophages that led to hemorrhagic necrosis of transplanted tumors in mice and killed certain transformed cell lines in culture” (325).

Saul Green (US), Areta Dobrjansky (US), Elizabeth A. Carswell (US), Robert L. Kassel (US), Lloyd John Old (US), Nancy Fiore (US), and Morton K. Schwartz (US) achieved partial purification of a serum factor that causes necrosis of tumors (TNF) (758).

Daniela N. Männel (US), Robert N. Moore (US), and Stephan E. Mergenhagen (US) found evidence suggesting that the macrophage-derived cytotoxins are identical with serum-derived cytotoxic factor, which further implies that the macrophage is the cellular source of tumor-necrosis factor (1283).

Carl F. Nathan (US), Henry W. Murray (US), Murray E. Wiebe (US), and Berish Y. Rubin (US) identified interferon-γ as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity (1398).

Diane Pennica (US), Glenn E. Nedwin (US), Joel S. Hayflick (US), Peter H. Seeburg (US), Rik M. Derynck (US), Michael A. Palladino (US), William Jack Kohr (US), Bharat B. Aggarwal (US), and David VanNorman Goeddel (US) purified tumor-necrosis factor (TNF) to homogeneity, and identified cDNA clones for human TNF (1486).

Diane Pennica (US), Joel S. Hayflick (US), Timothy S. Bringman (US), Michael A. Palladino (US), and David VanNorman Goeddel (US) cloned cDNA for murine tumor- necrosis factor and expressed it in Escherichia coli (1485).

Bruce Alan Beutler (US), David A. Greenwald (US), Jeffrey D. Hulmes (US), May Chang (US), Yu-Ching E. Pan (US), John C. Mathison (US), Richard Joel Ulevitch (US), and Anthony Cerami (US) reported a high degree of homology between the N-terminal sequence of mouse cachectin and the N-terminal sequence of human tumor-necrosis factor (TNF). Purified cachectin also possesses potent TNF activity in vitro. Evidence strongly suggests that cachectin and tumor-necrosis factor (TNF) activities in mice are attributable to a single protein, which modulates the metabolic activities of normal as well as neoplastic cells through interaction with specific high-affinity receptors (151).

Bruce Alan Beutler (US), John R. Mahoney, Jr. (US), Nguyen Le Trang (US), Phillip H. Pekala (US), and Anthony Cerami (US) purified cachectin. The isolated protein has an isoelectric point of 4.7 and a subunit molecular weight of 17,000 (152).

Bruce Alan Beutler (US), Ian W. Milsark (US), and Anthony C. Cerami (US) prepared a highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF). When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli. The data suggested that cachectin/TNF is one of the principal mediators of the lethal effect of endotoxin (153).

Kevin J. Tracey (US), Bruce Alan Beutler (US), Stephen F. Lowry (US), James P. Merryweather (US), Stephen D. Wolpe (US), Ian W. Milsark (US), Robert J. Hariri (US), Thomas J. Fahey, 3rd (US), Alessandro Zentella (US), James D. Albert (US), G. Tom Shires (US), and Anthony Cerami (US) infused recombinant human cachectin (tumor- necrosis factor) into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities like those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, because of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin (1903).

 

Robert H. Waldmann (US), John W. Rebuck (US), Hidehiko Saito (US), Joseph P. Abraham (US), June Caldwell (US), and Oscar D. Ratnoff (US) discovered the previously unrecognized human blood coagulation factor they named Fitzgerald factor (1640; 1963). Note: Fitzgerald factor, Williams trait, Fleaujeac trait, and Reid trait were all later determined to be high-molecular-weight kininogen.

 

Sin Fu Tzing (US), Ralph S. Wolfe (US), and Marvin P. Bryant (US) found that hydrogen and formate, the only known energy sources for Methanobacterium ruminantium and many other methanogenic bacteria, should be essentially equivalent as sources of electrons in the metabolism of this organism (1916).

 

Claude Vézina (CA), Alicia Kudelski (CA), Surenda Nath Sehgal (IN-CA), and Harold Baker (CA) found that Streptomyces hygroscopicus, a bacterial species indigenous to the soil of Rapa Nui (Easter Island), produces rapamycin (sirolimus, Rapamune), a potent immunosuppressive antibiotic, with cytotoxic properties (1706; 1943).

Rene R. Martel (CA), J. Klicius (CA), S. Galet (CA) reported that rapamycin, a new antifungal antibiotic, was found to inhibit the immune response in rats (1290).

D.C. Neil Swindells (CA), Peter S. White (CA), John A. Findlay (CA), and Lajos Radics (CA) used spectroscopic and x-ray crystallographic analysis to determine the structure of the antibiotic rapamycin (617; 1843).

Kyriacos Costa Nicolaou (CY-US), Tushar K. Chakraborty (IN), Anthony D. Piscopio (US), Nobuto Minowa (JP), Peter Bertinato (US), and Kazunori Koide (US) carried out the total synthesis of the antibiotic rapamycin (1412; 1413; 1510).

Eric J. Brown (US), Mark W. Albers (US), Tae Bun Shin (US), Kazuo Ichikawa (US), Curtis T. Keith (US), William S. Lane (US), Stuart Lee Schreiber (US), David Domingo Sabatini (US), Hediye Erdjument-Bromage (US), Mary Lui (US), Paul Tempst (US), and Solomon Halbert Snyder (US) found that the FKBP12-rapamycin complex binds to FRAP, a protein kinase in mammalian cells. This leads to immunosuppression (258; 1634). Rapamycin is an immunophilin (a soluble, intracellular molecule which binds a powerful and specific immunosuppressant).

Laura Beretta (FR), Ann-Claude Gingras (CA), Yuri V. Svitkin (CA), Michael N. Hall (CH), and Nahum Sonenberg (CA) found that the immunosuppressant drug rapamycin blocks progression of the cell cycle at the G1 phase in mammalian cells and yeast by inhibiting cap-dependent, but not cap-independent, translation in NIH 3T3 cells. This inhibition is causally related to the dephosphorylation and consequent activation of 4E-BP1, a protein recently identified as a repressor of the cap-binding protein, eIF-4E, function (133).

 

M. Jerome Moses (US), Sheila J. Counce (US), and Debra E. Paulson (US) used the electron microscope to characterize human pachytene chromosome pairs in spread preparations on the basis of synaptonemal complex length, kinetochore position and attached nucleoli when present. The X and Y chromosomes could be followed by their filamentous axial cores from partial synapsis, through precocious disjuction and end-to-end attachment, to differentiation of a network in the sex chromosome pair (1369).

 

Breck Byers (US) and Loretta Goetsch (US) provided a largely accurate description of the structure of the spindle-pole body (SPB) and its changes during the life cycle, considerable detail about the organization and behavior of the spindle microtubules (sMTs), the first descriptions of the cytoplasmic microtubules (cMTs) and their behavior during the life cycle, and the first views of the septin-associated "neck filaments" (300).

Barbara F. Sloat (US), Alison E.M. Adams (US), and John R. Pringle (US) found that chitin is randomly distributed over the entire cell surface of Saccharomyces cerevisiae in growing unbedded cells. They suggested that the CDC24 gene product seems to be involved in selection of the budding site, formation of the chitin ring at that site, the subsequent localization of new cell wall growth to the budding site and the growing bud, and the balance between tip growth and uniform growth of the bud that leads to the normal cell shape (1750).

John V. Kilmartin (GB), Alison E.M. Adams (US), and John R. Pringle (US) used immunofluorescence to locate actin in cytoplasmic cables and cortical patches, both of which were strikingly associated with regions of localized cell surface growth, both during the normal cell cycle and in various morphogenetic mutants (17; 1047). This suggested that actin was involved in the polarized delivery of secretory vesicles during both bud growth and cytokinesis.

Charles W. Jacobs (US), Alison E.M. Adams (US), Paul J. Szaniszlo (US), and John R. Pringle (US) presented evidence that microtubules (cytoplasmic, intranuclear, or both) appear to be necessary for the migration and proper orientation of the nucleus, as well as for spindle-pole body (SPB) separation, spindle function, and nuclear division. Cytoplasmic microtubules are apparently not essential for the establishment of cell polarity and the localization of cell-surface growth (961).

Michael P. Rout (GB) and John V. Kilmartin (GB) defined at least three components of the spindle-pole body (SPB) and spindle in Saccharomyces cerevisiae. Two of the components were localized exclusively to the SPB region, and the other (a 90 k-D component) was localized both to the SPB region and to particulate dots in short spindles. The 90-kD component was also found in an inner nuclear layer close to where spindle microtubules emerge. This work provided a preliminary molecular map of the spindle-pole body (SPB), which pointed the way to the corresponding genes to be isolated (1616).

John Chant (US) and Ira Herskowitz (US), using Saccharomyces cerevisiae, identified four genes, BUD1-BUD4, necessary for the axial pattern of bud formation by isolating mutants of alpha cells that do not exhibit this pattern. These observations indicate the existence of a basal budding pattern, requiring no BUD products, that is random; BUD1 and BUD2 act on this basal pattern to create the bipolar pattern; the further action of BUD3 and BUD4 leads to the axial pattern. These studies thus identify a set of gene products that directs cell morphogenesis to a genetically programmed site (352).

Daniel Julio Lew (US) and Steven I. Reed (US), in Saccharomyces cerevisiae, found that in the case of pre-bud site assembly following START (see below), the actin rearrangement could be triggered by Cln/Cdc28 activation in the absence of de novo protein synthesis, suggesting that the kinase may directly phosphorylate substrates (such as actin-binding proteins) that regulate actin distribution in cells (1177). Analysis of cell cycle regulation in the budding yeast Saccharomyces cerevisiae had shown that a central regulatory protein kinase, Cdc28, undergoes changes in activity through the cell cycle by associating with distinct groups of cyclins that accumulate at different times. The various cyclin/Cdc28 complexes control different aspects of cell cycle progression, including the commitment step known as START and mitosis.

 

Harvey I. Cantor (US) and Edward Arthur Boyse (US) described the cooperation between subclasses of Ly⁺ cells in the generation of killer cell activity (309; 310).

 

At the Asilomar Conference Center near Monterey, California more than 100 internationally respected molecular biologists met and voluntarily agreed to restrict cloning of DNA to organisms that had been specifically genetically disabled so that they would not grow well outside of the test tube. Government guidelines followed in 1976 but were relaxed in 1979 when cloning of cancer genes began (138; 139; 1955).

The National Institutes of Health issued guidelines for the conduct of NIH supported research using recombinant DNA technology. The guidelines define physical and biological containment levels for research (828).

 

Hiroaki Sawai (JP) and Leslie Eleazer Orgel (GB-US) showed that RNA can replicate without RNA-replicase and that zinc aids this replication (1662).

 

Bruce Michael Alberts (US), Charles F. Morris (US), Navin K. Sinha (US), Michael Bittner (US), and Larry Moran (US) proposed the "trombone" model of DNA replication to explain how coordination of replication of leading and lagging strands might take place (26).

 

Argiris Efstratiadis (GR-US), Thomas Peter Maniatis (US), Fotis Constantine Kafatos (DE), Andrea Jeffrey (US), and John N. Vournakis (US) optimized conditions for synthesis and characterization of full-length single-stranded cDNA molecules from globin mRNAs using reverse transcriptase (545).

 

Theresa N.H. Lee (US) and Daniel Nathans (US) identified early and late genes of SV40 and demonstrated that they are transcribed in divergent directions (1158).

 

Melanie I. Oakes (US), Michael W. Clark (US), Eric Henderson (US), Andrew Scheinman (US), Tom Atha (US), Anna Marie A. Aguinaldo (US), Lawrence Kahan (US), Gary Shankweiler (US), James A. Lake (US), Georg Stöffler (AT), Gilbert W. Tischendorf (DE), Heinz Zeichhardt (DE), Reinhard Luhrmann (DE), Marina Stöffler-Meilicke (DE), Harry F. Noller, Jr. (US), Seth Stern (US), Gloria M. Culver (US), Gabriele M. Heilek (US), Simpson Joseph (US), Bryn Weiser (US), Walter E. Hill (US), Anchalee Tassanakajohn (US), Dimitri M. Graifer (RU), Alexander A. Malygin (RU), Natalia B. Matasova (RU), Dmitri A. Mundus (RU), Marina A. Zenkova (RU), Galina G. Karpova (RU), Peter B. Moore (US), Albert E. Dahlberg (US), James E. Dahlberg (US), Michael J.R. Stark (GB), Richard J. Gregory (US), Richard L. Gourse (US), David L. Thurlow (US), Robert A. Zimmerman (DE), Christian W. Zwieb (DE), Carola Glotz (DE), Piotr Gornicki (US), Barbara Greuer (DE), Philip Mitchell (DE), Monika Osswald (DE), Jutta Rinke-Appel (DE), Dierk Schuler (DE), Katrin Stade (DE), and Richard L.C. Brimacombe (DE) were some of the pioneers in discovering where various proteins and rRNA molecules are located within the ribosome (247; 437; 444; 752; 872; 995; 1127; 1238; 1358; 1439; 1440; 1671; 1783; 1800; 1890; 2114).

 

Marcia J. Ensinger (US), Scott A. Martin (US), Enzo Paoletti (US), and Bernard Moss (US) elucidated the three-enzyme pathway by which eukaryotic and viral mRNA receives a 5’ cap. Their experimental subject was vaccinia virus (568). The cap structure consists of 7-methyl guanosine linked via an inverted 5’-5’ triphosphate bridge to the initiating nucleoside of the transcript.

 

Richard D. Kolodner (US) and Krishna K. Tewari (US) demonstrated that the mechanism of DNA replication in chloroplasts is somewhat different from DNA replication in both the mitochondrium and in the eukaryotic nucleus. Here the replication begins at two points of origin, runs in opposite directions around the circle (each going 5’ to 3’) until completion (1085).

 

Frederick Sanger (GB), Alan R. Coulson (GB), Steve Nicklen (GB), Gillian M. Air (GB), Barclay George Barrel (GB), Nigel L. Brown (GB), John C. Fiddes (GB), Clyde A. Hutchison III (US), Patrick M. Slocombe (GB), and Michael Smith (GB-CA) developed the first method for sequencing long sections of DNA nucleotides (1646-1649; 1651).

 

Arthur D. Riggs (US), Robin Holliday (GB), and John E. Pugh (GB) suggested that DNA methylation might control gene expression during cellular differentiation or cancer progression by changing the affinity of sequence-specific DNA-binding proteins for their target sites (904; 1568).

Peter A. Jones (US) and Shirley M. Taylor (US) introduced the use of cytidine analogues to prevent the methylation of cytosine residues in DNA, and directly linked changes in the patterns of methylation with changes in the differentiated state of the treated cells. The analogue 5-azacytidine was shown to be a potent inhibitor of DNA methylation (990). It is now used routinely to reactivate genes that are silenced by methylation. It has also entered the clinic as a treatment for myelodysplastic syndrome.

Andrew P. Feinberg (US) and Bert Vogelstein (US) compared gene methylation in DNA from primary human tumor tissues with DNA from adjacent normal cells. They found lowered DNA methylation in the tumor tissue DNA (593).

Stephen B. Baylin (US), Jo W.M. Höppener (NL), André de Bustros (US), Paul H. Steenbergh (NL), Cornelis J.M. Lips (NL), and Barry D. Nelkin (US) demonstrated that the methylation patterns of some genes were different in tumors compared with cells in the same tissue that were not part of the tumor (110).

Adrian Bird (GB), Mary Taggart (GB), Marianne Frommer (AU), Orlando J. Miller (US), and Donald Macleod (GB) characterized the small fraction of the mouse genome that is frequently cleaved by a methylation-sensitive restriction enzyme. These sequences, which would come to be known as CpG islands, are CpG-rich fragments with low or undetectable levels of methylation. The available literature indicated that CpG islands were typically located near the 5' ends of genes, and the authors predicted correctly that genes might be associated with “methylation-free zones near sequences of regulatory significance” (162).

Xinsheng Nan (GB), Huck-Hui Ng (GB), Colin A. Johnson (GB), Carol D. Laherty (US), Bryan M. Turner (GB), Robert N. Eisenman (GB), Adrian Bird (GB), Peter L. Jones (US), Gert C. Jan Veenstra (US), Paul A. Wade (US), Danielle Vermaak (US), Stefan U. Kass (BE), Nicoletta Landsberger (IT), John Strouboulis (US), and Alan P. Wolffe (US) showed that the methyl-CpG-binding protein 2 (MeCP2) which had been shown to bind to methylated DNA and repress transcription, does so by recruiting a histone deacetylase complex that alters chromatin structure (991; 1396).

 

David Baltimore (US) coined the term retrovirus (92).

 

 

Alfred Walz (CH) and Vincenzo Pirrotta (US), using lambda virus, demonstrated that in the absence of repressor the enzyme RNA polymerase binds tightly to, and protects from DNAase digestion, a 45-base-pair sequence that includes most of the repressor binding sites (1974).

 

Vladimir M. Zhdanov (RU) was the first to report the presence of cDNA from a nonretroviral virus (measles) within its host cells (2101).

 

Michael Gottlieb (US), Bernard David Davis (US), and Robert C. Thompson (US) discovered that ribosome initiation factor 3 (IF-3) acts as a dissociation factor for maintaining 30S and 50S subunits (740).

 

Thomas Peter Maniatis (US), Andrea Jeffrey (US), and J. Hans van deSande (DE-CA) showed that small DNA fragments can be separated according to size on denaturing polyacrylamide gels with the electrophoretic mobilities of the single-stranded DNA fragments exhibiting a linear function of the logarithm of their chain lengths. They found it possible to separate DNA fragments that differ by only a single nucleotide (1276).

 

Thomas Peter Maniatis (US), Andrea Jeffrey (US), and Dennis G. Kleid (US) established the base sequence of most of the right operator in lambda virus (1275).

Thomas Peter Maniatis (US), Mark Steven Ptashne (US), Keith C. Backman (US), Dennis G. Kleid (US), Stuart M. Flashman (US), Andrea Jeffrey (US), and Russell Maurer (US) noted that both operators in lambda virus contain sequences of bases, which are strikingly similar. Presumably they are the sites recognized by the repressor molecules (1278).

 

Errol C. Friedberg (US), Ann K. Ganesan (US), and Kenneth Minton (US) detected in crude extracts of Bacillus subtilis an N-glycosidase activity that catalyzes the release of free uracil from DNA of the subtilis phage PBS2. Phage DNA contains deoxyuridine instead of thymidine (643).

Tomas Lindahl (SE) determined the precise mechanism of action of the uracil-specific enzyme. This discovery led to the recognition of a new class of repair enzymes, now called DNA glycolylases, and his discovery of base excision repair (1197; 1198).

Zhigang Wang (US) and Dale W. Mosbaugh (US) found that the uracil-DNA glycosylase inhibitor gene of bacteriophage PBS2 encodes a binding protein specific for uracil-DNA glycosylase (1981).

 

Robert W. Old (GB), Kenneth Murray (GB), and Gerard Roizes (GB) determined the recognition sequence of restriction endonuclease III from Haemophilus influenzae (1446).

 

Edwin M. Southern (GB) developed a technique for identifying specific DNA fragments following their separation by agarose gel electrophoresis. The technique is called the Southern blot method (1772).

 

Roger D. Sloboda (US), Stephen A. Rudolph (US), Joel L. Rosenbaum (US), and Paul Greengard (US) discovered microtubule-associated proteins (MAPs). These are proteins, which stabilize microtubules and reduce their tendency to separate into individual heterodimers (1751).

 

Murray D. Weingarten (US), Arthur H. Lockwood (US), Shu-Ying Hwo (US), and Marc Wallace Kirschner (US) isolated a protein, tau, which appears to act on the 6S tubulin dimer, activating it for polymerization. The unique ability of tau to restore the normal features of in vitro microtubule assembly makes it likely that tau is a major regulator of microtubule formation in cells (2006).

 

Thomas P. Stossel (US) and John H. Hartwig (US) found that two other proteins influence actin and myosin of rabbit pulmonary macrophages. A protein cofactor is required for the actin activation of macrophage myosin Mg₂ ATPase activity, and a high molecular weight actin-binding protein aggregates actin filaments (1812).

Thomas P. Stossel (US) and John H. Hartwig (US) provided findings suggesting that the actin-binding protein initiates a cooperative interaction of contractile proteins to generate cytoplasmic gelation, and that phagocytosis influences the behavior of the actin-binding protein (1813).

 

Daniel Israel Arnon (PL-US) and Richard K. Chain (US) found that under aerobic conditions, in the presence of ferredoxin and NADP, cyclic photophosphorylation operated concurrently with noncyclic photophosphorylation, producing an ATP: NADPH ratio of about 1.5. An unexpected discovery was that the operation of cyclic photophosphorylation by itself was also regulated by a back reaction of NADPH and ferredoxin with two components of chloroplast membranes, component C550 and cytochrome b559 (66).

 

Henry H. Hagedorn (US), John D. O'Connor (US), Morton S. Fuchs (US), Becky A. Sage (US), Dorothy A. Schlaeger (US), and Marguerite K. Bohm (US) were the first to report that ecdysone (a molting hormone) stimulates vitellogenin synthesis in the fat body of an insect. Their subject was the mosquito (795). Vitellogenins are proteins synthesized outside the ovaries that become the major egg yolk proteins.

 

Richard P. Creagan (US), Suzie Chen (US), and Francis Hugh Ruddle (US) located the gene for diphtheria toxin receptor on human chromosome 5 in human cells in mouse-human somatic cell hybrids. This work also indicated that entry of toxin into cells seems to be a two-step process involving: (1) binding of toxin to the cell surface, and (2) endocytotic uptake of toxin (427).

 

Carl R. Woese (US), George E. Fox (US), Kenneth R. Pechman (US), Lawrence Zablen (US), Tsuneko Uchida (JP), Linda Bonen (US), Bobby J. Lewis (US), David Stahl (US), Linda J. Magrum (US), William E. Balch(US), and Ralph S. Wolfe (US) pioneered the analysis of ribosomal RNAs as a means of identifying organisms and inferring their natural relationships. This is possible because these molecules are universally distributed, constant in function, slow to change in sequence and easily manipulated. Their examination of many bacteria suggested that the methanogens are older than any other bacterial group. Methanogenic metabolism (the reduction of carbon dioxide) is ideally suited to the kind of atmosphere thought to have existed on the primitive earth. These methanogens were named Archaebacteria (Archaea) to emphasize that they were the dominant ones in the primeval biosphere. This work showed that the prokaryotes are composed of two distinct groups, the Bacteria and the Archaea. In the 1977 articles there are 6 kingdoms: Eubacteria, Archaebacteria, Protista, Plantae, Fungi, and Animalia (89; 635; 2047-2050).

Carl R. Woese (US) proposed that the halophilic archaebacteria (Archaea) are a group of aerobic or microaerophilic organisms that evolved from a strictly anaerobic and nonhalophilic methanogen ancestor. Woese also constructed a trifurcated, unrooted, universal evolutionary tree in which all known organisms can be grouped in one of three major lineages: Eubacteria (Bacteria), the Archaebacteria (Archaea), and the Eukaryotic (Eucarya) nucleocytoplasm. This is often referred to simply as the three-kingdom scheme (2046).

Carl R. Woese (US), Otto Kandler (US), and Mark L. Wheelis (US), based primarily on ribosomal RNA (rRNA) comparisons, proposed that all biological diversity falls into three primary groupings, or domains: Archaea (formerly Archaebacteria), Bacteria (formerly Eubacteria), and Eucarya (all eukaryotes) (2049).

James G. Elkins (DE), Mircea Podar (US), David E. Graham (US), Kira S. Makarova (US), Yuri Wolf (US), Lennart Randau (US), Brian P. Hedlund (US), Céline Brochier-Armanet (FR), Victor Kunin (US), Iain Anderson (US), Alla Lapidus (US), Eugene Goltsman (US), Kerrie Barry (US), Eugene V. Koonin (US), Phil Hugenholtz (US), Nikos Kyrpides (US), Gerhard Wanner (DE), Paul Richardson (US), Martin Keller (US), and Karl O. Stetter (DE-US) presented the candidate division Korarchaeota as comprising a group of uncultivated microorganisms that, by their small subunit rRNA phylogeny, may have diverged early from the major archaeal phyla Crenarchaeota and Euryarchaeota. They report the initial characterization of a member of the Korarchaeota with the proposed name, “Candidatus Korarchaeum cryptofilum,” which exhibits an ultrathin filamentous morphology (557).

Michael A. Ruggiero (US), Dennis P. Gordon (NZ), Thomas M. Orrell (US), Nicolas Bailly (PH), Thierry Bourgoin (FR), Richard C. Brusca (US), Thomas Cavalier-Smith (GB), Michael D. Guiry (IE), and Paul M. Kirk (GB) presented a consensus classification of life to embrace the more than 1.6 million species already provided by more than 3,000 taxonomists expert opinions in a unified and coherent, hierarchically ranked system known as the Catalogue of Life (CoL). This scheme contains 7 kingdoms: Bacteria, Archaea, Protozoa, Chromista, Plantae, Fungi, and Animalia (1622).

Note: The chloroplast of the chromists is located in the lumen of the endoplasmic reticulum instead of in the cytosol. Moreover, only chromists contain chlorophyll c. Many non-photosynthetic phyla of protists, thought to have secondarily lost their chloroplasts, have been integrated into the kingdom Chromista.

There is ongoing debate as to whether viruses can be included in the tree of life.

 

Georges Jean Franz Köhler (DE), César Milstein (AR-GB) introduced the methodology for generating monoclonal antibodies (1080; 1081). Note: This discovery led to major biological insights and clinical successes in treating autoimmunity and cancer.

 

Lars O. Magnius (SE), Annika Lindholm (SE), Per Lundin (SE), and Sten Iwarson (SE) produced evidence further linking e antigen to hepatitis B (1259).

 

vsKnud E. Mogensen (FI), Liisa Pyhälä (FI), Kari Cantell (FI) produced antibodies to human leukocyte interferon (1351).

 

Shlomo Z. Ben-Sasson (US), William E. Paul (US), Ethan M. Shevach (US), and Ira Green (US) obtained specific selection of antigen-responsive guinea pig peritoneal exudate lymphocytes (PELs) using a selective culture procedure. These selected cells were largely T lymphocytes and could be maintained in culture (124).

 

Pawel Kisielow (PL), John A. Hirst (US), Hiroshi Shiku (US), Peter C.L. Beverly (GB), Michael K. Hoffmann (US), Edward A. Boyse (US), and Herbert F. Oettgen (US) reported experiments with mice showing that antisera to different Ly alloantigens can identify functionally distinct subpopulations of thymus-derived lymphocytes (T cells) (1059).

 

Erik Svedmyr (SE) found that in vitro he could induce up to 4 months of long-term maintenance of human T cells by repeated exposure to the same stimulator cells (1835).

Gunther Dennert (US) and Margaret De Rose (US) found that BALB/c (H-2d) thymus derived lymphocytes sensitized to C57BL/6 (H-2b) alloantigens could be propagated in vitro for over 9 months. These T lymphocytes are specifically cytotoxic to H-2b target cells but are stimulated to proliferate by both H-2b and H-2k spleen cells. This indicates that for these selected cells the antigen requirements for cell proliferation are different from those for cell-mediated cytotoxicity (485).

 

Gustav Joseph Victor Nossal (US) and Beverley L. Pike (US) found that the capacity of bone marrow cells to mount an adoptive immune response rose by a factor of about fivefold over 3 days in tissue culture. This rise was completely abolished by the presence in the culture of hapten-HGG conjugates with about one mole of hapten per carrier molecule. The prevention of the emergence of immune competence amongst maturing B cells was termed clonal abortion tolerogenesis. They speculated that clonal abortion may be a tolerance mechanism of great physiological significance for self- recognition (1426).

 

Michael John Bevan (GB-US) suggested that cytotoxic cells are restricted in specificity to preferentially recognizing alterations in structures that are coded in the major histocompatibility complex (157).

 

Jan Rosing (NL), Edward Charles Slater (AU-GB), David A. Harris (NL), and Albertus Kemp, Jr. (NL) found that the CF₁ unit of chloroplasts and the F₁ unit of mitochondria have ADP and ATP firmly bound to them (1598).

 

George Emil Palade (RO-US), Alan M. Tartakoff (US), James D. Jamieson (US), and George A. Scheele (US) used pulses of radioactive amino acids to demonstrate that proteins synthesized on the endoplasmin reticulum typically move from there to the Golgi apparatus and, depending on the protein, to the cell surface or into the cytoplasm (1467; 1861).

 

Pierre Oudet (FR), R. Douglas Carlson (US), Christopher L.F. Woodcock (US), Ling-Ling Y. Frado (US), Christopher L. Hatch (US), Luigi Ricciardiello (US), Donald E. Olins (US), Maria Gross-Bellard (FR), Pierre M. Chambon (FR), and Jack D. Griffith (US) showed that chromatin fibers occur as linear arrays of spherical particles, about 100 A° in diameter, connecting apparently naked strands of DNA (320; 768; 1459; 2059).

 

Alexander Tzagoloff (US), Anna Akai (US), Richard B. Needleman (US), and George Zulch (US) isolated cytoplasmic mutants of Saccharomyces cerevisiae with lesions in enzymes of the respiratory chain and in the mitochondrial ATPase (1915).

 

Kyung June Kwon-Chung (US) described sexual reproduction in the fungus Cryptococcus neoformans (1122).

 

Roy R. Gould (US) and Gary Guy Borisy (US) found that isolated pericentriolar material of eukaryotes (Eucarya), and not the centriole, acts as a center for microtubule assembly if supplied with tubulin under polymerizing conditions. It now appears that centrioles are merely passengers during astral spindle formation. Their distribution ensures that daughter cells receive centrioles and can generate the 9+2 system of microtubules of flagella, which seems to be the primary or exclusive function of centrioles (744-746).

 

Taiji Nakae (US) and Hiroshi Nikaido (US) introduced the concept of pore-forming proteins (porins) in the outer membrane of gram-negative bacteria. These porins go a long way toward explaining the ability of low molecular weight hydrophilic nutrients to penetrate the outer membrane (1394).

 

Carol Jones (US), Paul Wuthier (US), and Theodore Thomas Puck (US) placed the human lactic dehydrogenase gene and the A_L gene on the same chromosome 11 (987).

Carol Jones (US), Fa-Ten Kao (US), Beverly Moore (US), David Patterson (US), and Theodore Thomas Puck (US) identified the A_L gene’s product as a glycophorin (986).

 

Andrew G. Cudworth (GB) and Jenna C. Woodrow (GB) found by HLA typing of 150 patients with early onset diabetes mellitus a significant association with B8 and Bw15. Determination of the HLA haplotypes inherited by siblings affected with this type of diabetes showed an increase in identity of haplotypes above random expectation, strongly supporting the existence of HLA-linked disease susceptibility genes (436).

 

Peter F. Brumbaugh (US) and Mark R. Haussler (US) confirmed the discovery of a protein receptor that binds the active vitamin D metabolite (1,25-dihydroxyvitamin D3) to the nucleus of cells in the intestine (265; 266).

 

Walter Jakob Gehring (CH), Gerold Schubiger (US), Welcome W. Bender (US), Pierre Spierer (CH), David Swenson Hogness (US), Pierre M. Chambon (FR), Sean B. Carroll (US), Robert A. Laymon (US), Mark A. McCutcheon (US), Peter D. Riley (US), Matthew P. Scott (US), Amy J. Weiner (US), Valerie K.L. Merrill (US), F. Rudolf Turner (US), and Thomas C. Kaufman (US) analyzed three homeotic mutants of Drosophila melanogaster with respect to their time of expression, aristapedia (ssa and ssa-UCl) and Nasobemia (Ns) which involve antenna-leg transformations.

The DNA associated with homeotic genes of the bithorax complex was localized.

Sequence homology between the antennapedia, ultrabithorax, and fushi tarazu loci of Drosophila was noted and it was concluded that Dfd is a homeotic gene necessary for proper specification of both the embryonic and the adult head (127; 324; 677; 1334; 1699).

 

Peter N. Goodfellow (GB), Elizabeth A. Jones (GB), Veronica van Heyningen (GB), France Ellen Solomon (GB), Roger H. Kennet (GB), Martin Bobrow (GB), and Walter Fred Bodmer (GB) located the gene for human ß₂-microglobulin on chromosome 15 (729).

 

Richard P. Creagan (US), and Francis Hugh Ruddle (US) introduced the technique of screening panels of hybrid cell clones selected to provide a maximally informative representation of human chromosomes. This became the standard technique for determining synteny, the correlation of gene activity with the presence or absence of a specific chromosome in hybrid cells (428).

 

Stephen J. Goss (GB) and Henry Harris (AU-GB) used hybrids of rodent cells and lethally irradiated human cells to devise the first systematic method for determining the order of human genes along the chromosome and the distances between them (738).

 

Michael Grunstein (US) and David Swenson Hogness (US) developed colony hybridization, a technique to transfer bacterial colonies to filters, lyse, and fix the DNA. Labeled probes of single stranded DNA, complementary to the fixed DNA, can be applied to determine the identity of the unknown bacterium (784).

 

Philip John (GB) and Frederick Robert Whatley (GB) found evidence that the non-sulfur purple bacteria (Proteobacteria) are the closest contemporary bacterial relatives of mitochondria (979).

 

Francois Rougeon (FR), Philippe Kourilsky (FR), and Bernard Mach (FR) were the first to insert an identifiable mammalian gene, rabbit ß-globin, into a plasmid (1615).

 

Dorothy E. Schumm (US) and Thomas E. Webb (US) found that export of ribonucleoprotein materials through nuclear pores requires energy expenditure in the form of ATP or GTP (1692).

 

D. Michael Gill (US) and Carolyn A. King (GB) established that choleragen, the exotoxin of Vibrio cholerae, mimics the effects of hormones, which activate the release of adenylate cyclase leading to the production of intracellular cyclic AMP (cAMP) (696).

Dan Cassel (DE) and Thomas Pfeuffer (DE) presented evidence that choleragen stimulates G proteins to cause the ultimate release of cAMP (327).

 

Guido Pontecorvo (IT-GB) was the first to fuse animal cells using polyethylene glycol (1521).

 

Joseph William Sanger (US) found actin present in the nucleoli, kinetochore and centriolar regions, and in the mitotic spindle of kangaroo rat (Dipodomys) cells. The specific localization of actin in chromosomal spindle fibers suggests an actin-myosin interaction as the force-producing mechanism for chromosomal movement (1652).

 

 Kenneth R. Robinson (US) and Lionel F. Jaffe (US), while working with Pelvetia (brown alga) eggs noted that electrical currents are caused by stabilized accumulations of cation pumps on one side of the cell, and of permeability channels on the opposite side.The currents were strong enough to suggest that the accompanying gradient in electrical potential could have an electrophoretic effect on the distribution of cytoplasmic constituents, including those that serve as morphogenetic determinants (1579).

Clarence D. Cone, Jr. (US) and Charlotte M. Cone (US) reported that DNA synthesis and mitosis were induced in vitro in fully differentiated neurons from the central nervous system by depolarization with a variety of agents that produce a sustained rise in the intracellular sodium ion concentration and a decrease in the potassium ion concentration. Apparently normal nuclear mitosis ensued, but cytokinesis was not completed in most cells (404).

Richard I. Woodruff (US) and William H. Telfer (US) gave evidence that an endogenously generated gradient in electrical potential in the oocyte–nurse cell syncytium of Hyalophora cecropia (cecropia moth) can, in fact, influence the distribution of soluble proteins in a cytoplasmic continuum (2063).

Kevin B. Hotary (US) and Kenneth R. Robinson (US) gathered evidence of a role for endogenous electrical fields in normal chick embryo development (911).

Riyi Shi (US) and Richard B. Borgens (US) presented direct experimental tests supporting the hypothesis that extracellular electric fields both polarize the early vertebrate embryo and serve as cues for morphogenesis and pattern (201; 1727).

Lisa S. Jenkins (US), Bradley S. Duerstock (US), and Richard B. Borgens (US) found that immediately following amputation of the limb in salamanders, a strong, steady, and polarized flow of ionic current is produced by the injury. Current flows in a proximodistal direction within the limb stump and is associated with a fall in electrical potential of about 50 mV/mm near the stump's end. This current is electrogenically driven by the sodium ion-dependent, internally positive transcutaneous voltage of the intact skin of the limb stump. Reduction of this electromotive force (EMF), the skin's battery, by topical application of sodium ion blocking agents leads to inhibition or disruption of normal limb regeneration. This suggests electrical factors are a critical control of limb regeneration. Additional experiments confirmed that electrical (physiological) factors are indeed a critical control of limb regeneration in urodeles (973).

Laura N. Vandenberg (US), Ryan D. Morrie (US), and Dany Spencer Adams (US) concluded that bioelectric signal has a role in development of the face. Thus, it exemplifies an important, under-studied mechanism of developmental regulation (1938).

 

Malcolm Burrows (GB) performed anatomical and physiological studies of the connections between stretch receptors of the wings and motoneurons innervating flight muscles of the locust, Schistocerca gregaria. He observed: 1. That the single neuron of a forewing stretch receptor has a complex pattern of branches within the mesothoracic ganglion and branches, which extend into the pro- and meta-thoracic ganglia. 2. The single neuron of a hind-wing stretch receptor has extensive branches in the metathoracic ganglion and branches in the mesothoracic ganglion. The branches of both receptors are confined to the ipsilateral halves of the ganglia. 3. A stretch receptor gives information about the velocity and extent of elevation of a wing. 4. Each spike of a forewing stretch receptor causes an EPSP in ipsilateral mesothoracic depressor motoneurons and an IPSP in elevators. The connections are thought to be monosynaptic. 5. The connections therefore comprise a monosynaptic negative feedback loop; elevation of the wing excites the stretch receptor, which then inhibits the elevator motoneurons and excites the depressors. 6. A hind wing stretch receptor synapses upon met thoracic flight motoneurons in the same way, causing EPSPs in depressor and IPSPs in elevator motoneurons. 7. No connections of either fore- or hind wing stretch receptors were found with contralateral flight motoneurons. 8. Interganglionic connections are made by both receptors. For example, both fore- and hind wing stretch receptors cause EPSPs upon the meso- and metathoracic first basalar motoneurons. 9. Stimulation of the axon of a stretch receptor with groups of three stimuli repeated every 50-100 msec thus simulating the pattern, which it shows during flight, causes subthreshold waves of depolarization in depressor motoneurons. When summed with an unpatterned input, the stretch receptor can influence the production of spikes in motoneurons on each cycle. During flight, it was predicted that the stretch receptor would influence the time at which a motoneuron would spike and hence effect the amplitude of the upstroke and upon the phase relationship between spikes of motoneurons (286).

 

Joseph Kuc (US), Gary Shockley (US), and Karen Kearney (US) demonstrated that plants could be immunized against microbial diseases by using a restricted infection with fungi, bacteria, or viruses. Pathogens stopped by this method included fungi, local lesions and systemic viruses, fungal and bacterial wilts. Immunization was systemic and required a lag period. Immunization can be enhanced with booster inoculations (1108-1110).

 

Charles Richard Madeley (GB) and Bonnie P. Cosgrove (GB), using electron microscopes, discovered astrovirus following an outbreak of diarrhea in humans (1253).

David W. Brown (US), Kerry B. Gunning (US), Dorothy M. Henry (US), Zuheir L. Awdeh (US), James P. Brinker (US), Saul Tzipori (US), and John E. Hermann (US) reported that human astroviruses have been shown in numerous studies to be an important cause of gastroenteritis in young children worldwide (257).

 

Charles P. Romaine (US) and Ralph K. Horst (US) identified the etiologic agent of chrysanthemum chlorotic mottle as a viroid (1589).

 

Yvonne E. Cossart (AU-GB), Anne M. Field (GB), B. Cant (GB), and D. Widdows (GB) demonstrated Parvovirus-like particles in human sera (421).

Albrecht K. Eugster (US), Raymond A. Bendele, Jr. (US), Larry P. Jones (US), Max J.G. Appel (US), Fredric W. Scott (US), and Leland E. Carmichael (US) detected canine parvovirus (CPV2) as the cause of new diseases in dogs throughout the world, when it rapidly spread throughout domestic populations, as well as becoming widespread in wild dogs (60; 575). Note: CPV2 was soon shown to be a variant of the long recognized feline panleukopenia virus (FPV).

Yvonne E. Cossart (AU) identified Parvovirus B19 as the etiological agent of slapped cheek, erythema infectiosum or fifth disease (there were six childhood rashes recognized at the turn of the century and this was number five) (420).

Rajesh Rajput (IN), Ashish Sehgal (IN), Deepak Jain (IN), Rajeev Sen (IN), and Abhishek Gupta (IN) reported a case of severe aplastic anemia in a previously healthy adult female due to acute parvovirus B19 infection (1540).

 

Douglas M. Watts (US), Somsak Pantuwatana (TH), Thomas M. Yuill (US), Gene R. DeFoliart (US), Wayne H. Thompson (US), and Robert Paul Hanson (US), working with mosquito larvae, discovered the transovarial transmission of La Crosse virus (a bunyavirus) (1992).

Barry J. Beaty (US) and Wayne H. Thompson (US) grew the La Crosse virus in suckling mice (112).

 

Richard P. Blakemore (US) discovered that some bacteria are sensitive to the geomagnetic field of the earth (180). Later analysis revealed that these bacteria contain particles of magnetic iron oxide, which behave as a compass.

 

Alexander Tomasz (US) and Susan Waks (US) found that most bacteria, including the pneumococcus, disintegrate as they die in a fascinating process that involves the dissolution of the cell wall. Penicillin takes advantage of this suicidal tendency by triggering lysis, a process that involves a bacterium’s own enzymes, which normally nip and tuck the wall into a perfect fit. Penicillin destroys the controls that restrain the enzymes, so the enzymes tear the cell wall to pieces (1898).

 

Ronald John Gibbons (US) and Johannes van Houte (US) state that the evolution of specific adhesion mechanisms by a wide spectrum of bacterial species furnishes evidence of the general importance of such interactions and may account, at least in part, for the specific distribution of organisms in different habitats (688).

Kenneth Gould (US), Carlos H. Ramirez-Ronda (PR), Randall K. Holmes (US), and Jay P. Sanford (US) documented the significance of bacterial adhesion in the pathogenesis of streptococcal endocarditis (743).

 

George A.M. Cross (US) characterized the glycoprotein surface coat of Trypanosoma brucei (432).

 

Kamla K. Pandey (NZ) used irradiated pollen of tobacco (Nicotiana tabacum) to realize interspecific crossings. One theory to explain this is that a high dose of ionizing irradiation "pulverizes" the generative nucleus to produce a mass of chromatin fragments. The generative nucleus then fails to divide, and the fragmented nuclear material is discharged into the egg, with some of these fragments possibly being incorporated into the DNA of the stimulated egg nucleus (1471).

 

Anthony E. Butterworth (KE), Robert F. Sturrock (KE), Vaclav Houba (KE), Adel A.F. Mahmoud (US), Alan Sher (US), Philip Howell Rees (KE), John Rouben David (US), David Franks (US), Peter H. David (US), and Heinz G. Remold (US) demonstrated that schistosomules coated with IgG antibody attract and bind eosinophils that attack the parasites (296-298).

 

Elsa Bello-Reuss (US), Romulo E. Colindres (US), Enrique Pastoriza-Munoz (US), Robert A. Mueller (US), Daniel L. Trevino (US), and Carl W. Gottschalk (US) found by direct measurements that denervation of the kidney decreases sodium reabsorption by the proximal tubules and that stimulation of renal sympathetic nerves increases the rate of sodium reabsorption (122; 123).

 

Lyndall Molthan (US) and Carolyn M. Giles (US) discovered Yk-a (York), a new blood group antigen (1352).

 

Kenneth C. Carey (US), Richard E. Carey (US), and Susan Y. Schmidt (US) showed that degeneration of the retinal photoreceptor cells develops in cats when casein is the source of dietary protein. Amino acid profiles indicate that the degeneration is associated with a selective decrease in plasma and retinal taurine concentrations. A sulfur amino acid deficit in the casein diet combined with specific amino acid requirements of the cat appear related to this unique expression of taurine deficiency (827).

 

Chulee Mitrakul (TH), Vinai Suvatte (TH), Chularatana Mahasandana (TH), Vichai Tamphaichitr (TH), and Soodsarkorn Tuchinda (TH) were the first to describe acquired platelet dysfunction with eosinophilia or nonthrombocytopenic purpura with eosinophilia. This acquired disorder presents with bleeding of unknown etiology associated with platelet dysfunction and eosinophilia (1347; 1834).

 

Harry K. Ziel (US) and William D. Finkle (US) presented data suggesting increased risk of endometrial carcinoma among users of conjugated estrogens (2102).

 

Joseph Leonard Goldstein (US) and Jean D. Wilson (US) reported that phenotypic sexual differentiation during embryogenesis is a complex process involving the action of at least 18 genes. These genes regulate gonadal differentiation, gonadal hormone formation, and in the male the cellular action of three necessary hormones, namely mullerian regression factor, testosterone, and dihydrotestosterone. Two androgens testosterone and dihydrotestosterone have separate and specific roles in virilization of the male urogenital tract, testosterone stimulating Wolffian duct development and dihydrotestosterone mediating development of the urogenital sinus and external genitalia. In the disorder familial incomplete male pseudohermphroditism, type 2, deficient dihydrotestosterone formation is associated with a selective failure of virilization of the urogenital sinus and external genitalia, whereas the Wolffian duct derivatives develop normally. On the other hand, in the testicular feminization syndrome there is a complete failure in the development of the male phenotype, indicating that the primary defect involves an abnormality in some biochemical step that is common to the action of both androgens (723).

 

A. Malcolm R. Taylor (GB), David G. Harnden (GB), Colin F. Arlett (GB), Susan A. Harcourt (GB), Alan R. Lehmann (GB), S. Stevens (GB), and Bryn A. Bridges (GB) discovered that ataxia-telangiectasia cells are abnormally sensitive to being killed by X rays, an observation suggesting a relationship between the disease and DNA repair (1863).

Carmel M. McConville (GB), Caroline J. Formstone (GB), Dianna Hernandez (GB), J.A. Thick (GB), and Alexander Malcolm R. Taylor (GB) used fine mapping of the human chromosome 11q22-23 region to localize the gene for ataxia telangiectasia to a 5cM region flanked by NCAM/DRD2 and STMY/CJ52.75, phi 2.22 (1313).

 

James Edward Cleaver (US), Dirk Bootsma (DK), and Errol C. Friedberg (US) were the first to provide molecular evidence that DNA damage is a direct cause of cancer (377).

 

Werner Schmid (CH) noted that for large-scale genotoxicity screening in mammals, metaphase analysis of bone marrow cells is impractical. Searching for other end points of chromosome damage in hematological preparations from rodents he demonstrated that scoring micronuclei in young polychromatic erythrocytes in bone marrow smears of mice is a sensitive, simple, and reliable method (1678).

 

Robert H. Fitts (US), Frank W. Booth (US), William W. Winder (US), and John O. Hollaszy (US) were the first to titrate multiple doses of exercise to fully characterize training-mediated changes in skeletal muscle mitochondrial function as well as physical performance capacity in a dose-dependent manner. In this project involving controlled treadmill running in rats for 13 wk, intensity (1.2 mph, 15% grade) and frequency (5 days/wk) were held constant while daily running duration varied across four groups of animals (10, 30, 60, or 120 min per session). Overall, the authors found that a minimum of 30 min/day was required to induce favorable changes in gastrocnemius muscle oxidative capacity. While no gains were noted in the 10 min/day training group, the authors found incremental improvements in several markers of muscle oxidative capacity across the 30, 60, and 120 min/day training protocols. Compared with sedentary control, muscle respiratory capacity (malate pyruvate oxidation) was elevated more than twofold in the 120 min/day training group, which was significantly higher than all other training groups. Additionally, the elevation after training 60 min/day was 28% higher than the gain found in the 30-min/day group (626).

 

John M. Leventhal (US), Walter U. Brown (US), J.B. Weiss (US), and Milton H. Alper (US) devised a new method of continuous fetal heart rate monitoring, employing for cardiotachometry the fetal electrocardiogram obtained from electrodes placed on the maternal abdomen (1172).

 

Henry Jay Heimlich (US), Karol A. Hoffman (US), and Felix R. Canestri (US) noted that applying subdiaphragmatic compression has been used successful in saving victims of food choking and drowning by expelling the asphyxiating bolus or aspirated water. Sudden elevation of the diaphragm compresses the lungs, which explosively forces air out through the trachea, ejecting the obstructing object (838; 839). This became known as the Heimlich maneuver.

 

Ronald Levy (IL), Esther Hurwitz (IL), Ruth Maron (IL), Ruth Arnon (IL), Michael Sela (IL), Meir Wilchek (IL), Yutaka Tsukada (JP), Rina Kashi (IL), Nozomu Hibi (JP), Akihiko Hara (JP), and Hidematsu Hirai (JP) found that immunotargeting could focus the supply of a drug exclusively to a cancer area. They bound daunomycin and adriamycin via a dextran bridge to antibodies against antigens of leukemia, lymphoma, and plasmacytoma cells. They showed that these are effective as "guided missiles" both in vitro and in vivo. Daunomycin linked to anti-tumor antibodies penetrated the cell membrane at a higher rate than daunomycin linked to dextran or to normal immunoglobulin. They could show a chemotherapeutic effect against hepatoma in the rat (930; 1176; 1911).

 

Norman C. Staub (US), Richard D. Bland (US), Kenneth L. Brigham (US), Robert Demling (US), A. John Erdmann III (US), and William C. Woolverton (US) noted that the majority of lung lymph in the sheep drains through a large caudal mediastinal lymph node. At a preliminary operation, they removed the systemic lymph contamination. They obtained lung lymph by cannulating the efferent duct of the node. They used a physiologic test in which they elevated systemic and pulmonary venous pressures separately to show that the origin of the lymph is from the lung. The overall success rate in obtaining lung lymph flow for periods longer than 1 week is less than 50%. Successful animals are excellent models in which to study net lung fluid and protein flow (1788).

 

James G. Rheinwald (US) and Howard Green (US) succeeded in developing a procedure by which large amounts of human skin could be cultured (1561; 1562).

Nicholas E. O’Connor (US), John B. Mulliken (US), Susan Banks-Schlegel (US), Olanyi Kehinde (US), and Howard Green (US) reported the successful use of cultured epithelial autografts (CEA) (1431).

Nathan Sternberg (IL), Yechiel Becker (IL), Jacob Golan (IL), and Nahum Ben-Hur (IL) developed tissue culture of human skin for grafting (1801).

G. Gregory Gallico, III (US), Nicholas E. O'Connor (US), Carolyn C. Compton (US), Olaniyi Kehinde (US), and Howard Green (US) developed the methodology for culturing epithelium as a skin substitute and applying it to patients with severely burned skin (668; 669).

 

Mladen Vranic (HR-CA), Sumer Pek (CA), Ryuzo Kawamori (CA), Natasa Kovacevic (CA), Gary A. Wrenshall (CA), Walter A. Muller (CA), Lucien Girardier (CA), Josianne Seydoux (CA), Michael Berger (CA), Albert E. Renold (CA), Kunihiro Doi (CA), Marc Prentki (CA), Cecil C. Yip (CA), and Bernard Jeanrenaud (CA) discovered extrapancreatic glucagon in dogs, which changed the prevailing dogma and permitted precise exploration of the roles of insulin and glucagon in physiology and diabetes, and provided conclusive evidence about the role of glucagon in diabetes. They were the first to indicate that glucagon only acts on the liver and the first to quantify the physiological secretion of insulin (499; 1375; 1951; 1953).

Mladen Vranić (HR-CA), Soichiro Morita (JP), George Steiner (CA), Alexandre Wajngot (SE), Arved Roovete (SE), Rolf Luft (CA), Suad Efendić (SE), Friedrich W. Kemmer (DE), Anna Sirek (HR-CA), Otakar V. Sirek (HR-CA), Gerardo Javier Perez (CA), Adria Glacca (SE), Valdemar Grill (SE), Simon J. Fisher (CA), Rajiv Gupta (CA), Z. Qing Shi (CA), and Hazel Lavina Agnes Lickley (CA) were first to establish the critical role of glucagon-insulin interaction and the control of glucose metabolism during moderate exercise and of catecholamines during strenuous exercise. They quantified the deficiencies in the release and effects of these hormones in diabetes. They also revealed how acute and chronic hyperglycemia affects the expression of GLUT2 gene and protein in diabetes (683; 1035; 1952; 1959; 1960).

MladenVranic (HR-CA), Bela Issekutz (HR), David H. Wassarman (CA), Hazel Lavina Agnes Lickley (CA), Ola Bjorkman (CA), Philip D.G. Miles (CA), R.A. John Challis (GB), George K. Radda (GB), Keiichi Yamatani (CA), Errol B. Marliss (CA), Natalia A. Kaniuk (CA), Michael A. Kiraly (CA), Holly E. Bates (CA), Allen Volchuck (CA), John H. Brumell (CA), Jessica T.Y. Yue (CA), Stephen G. Matthews (CA), Michael C. Riddell (CA), Anna Sirek (CA), and Danitza Goche Montes (CA) pioneered new concepts of the role of exercise in diabetes, leading to precise methods of controlling insulin, allowing type 1 diabetics to participate in the Olympics and clinicians to recommend exercise and healthy eating habits to prevent type 2 diabetes. He outlined molecular and physiological mechanisms whereby exercise training and adaptation to repetitive neurogenic stress can prevent diabetes in Zucker Diabetic Fatty (ZDF) rats (108; 172; 340; 952; 1007; 1056; 1288; 1339; 1985).

Mladen Vranic (HR-CA), Adria Giacca (CA), Simon J. Fisher (CA), Rajiv Gupta (CA), Z. Qing Shi (CA), Hazel Lavina Agnes Lickley (CA), Richard H. McCall (CA), Gary F. Lewis (CA), Patricia Harley (CA), George Steiner (CA), and Andre C. Carpentier (CA) established that the indirect effect of insulin plays an important role in the regulation of glucose production in dogs. They confirmed this effect in humans and its role in type 2 diabetes (683; 684; 1178-1180).

Mladen Vranic (HR-CA), Suad Efendic (SE), Alexandre Wajngot (CA), Keiichi Yamatani (CA), Z. Qing Shi (CA), Adria Giacca (CA), Rajiv Gupta (CA), Simon J. Fisher (CA), Hazel Lavina Agnes Lickley (CA), Andre Marette (CA), Julia M. Richardson (CA), Toolsie Ramlal (CA), Thomas William Balon (CA), Jeffrey E. Pressin (CA), Amira Klip (CA), Hubert Vidal (CA), Gerald van de Werve (CA), Theodoros Tsakiridis (CA), and Julian M.R. Mathoo (CA) showed that because the muscle and the liver are protected against changes in glucose levels, these organs do not have diabetic complications (542; 1287; 1299; 1728; 1908; 2075).

Mladen Vranic (HR-CA), Hazel Lavina Agnes Lickley (CA), Friedrich W. Kemmer (DE), Kamil M.A. El-Tayeb (CA), Saud Efendic (SE), Sven Karlander (SE), K. Sudha Rastogi (CA), Martin Jokay (CA), Z. Qing Shi (CA), Michael C. Lekas (CA), Daniel J. Drucker (CA), Owen Chan (CA), Stephen Chan (CA), Karen E. Inouye (CA), Stephen G. Matthews (CA), Kathy Shum (CA), Julian M.R. Mathoo (CA), Jessica T.Y. Yue (CA), Tony Kim (CA), Eitan M. Akirav (CA), Edward Park (CA), Michael C. Riddel (CA), Elena Burdett (CA), David H. Coy (US), Adria Giacca (CA), Danitza Goche Montes (CA), Holly E. Bates (CA), and Michael A. Kiraly (CA) described the molecular mechanisms responsible for increased hypothalamic-pituitary-adrenal axis in diabetes and for the diminished responses of hypothalamic-pituitary-adrenal axis, catecholamines and glucagon to hypoglycemia. They proposed a new approach to decrease the threat of hypoglycemia by blocking the effect of somatostatin (344; 345; 541; 946; 947; 1191; 1544; 1729; 2091-2093).

 

Edward Donnall Thomas (US), Rainer Storb (US), Reginald A. Clift (US), Alexander Fefer (US), F. Leonard Johnson (US), Paul E. Neiman (US), Kenneth G. Lerner (US), Harold Glucksberg (US), and C. Dean Buckner (US) reviewed studies of marrow transplantation in rodents, dogs, and primates. The experiences in man regarding histocompatibility typing, preparation of the recipient, the technique of marrow transplantation, and supportive care of the patient without marrow function were described. Clinical data were presented, and problems associated with marrow engraftment, graft-versus-host disease, opportunistic infections, and recurrence of malignancy were summarized (1878).

 

Vijay V. Kakkar (GB), T.P. Corrigan (GB), David Paul Fossard (GB), I. Suther-Land (GB) J., Michael G. Shelton (GB), and J.Thirlwall (GB), concluded that low-dose subcutaneous heparin prevents fatal post-operative pulmonary embolism, is well tolerated by the patient, requires no laboratory control, and does not produce serious bleeding during surgery (1001).

 

Marian Weiss (PL) developed a spring-loading device for skeletal fixation of the injured spinal cord (2010).

 

Allan C. Wilson (NZ-US) and Mary-Claire King (US) surveyed protein and nucleic acid studies and found that the average human protein was more than 99% identical to its chimpanzee counterpart; the coarse DNA hybridization methods of the time showed that the average nucleic acid sequence was almost as similar. They concluded that humans and chimpanzees were genetically as similar as sibling species of other organisms, such as fruit flies or mice (1053; 1054).

Jorge J. Yunis (US) and Om Prakash (US) performed a comparative analysis of high-resolution chromosomes from orangutan, gorilla, chimpanzee, and man. The results suggested that 18 of 23 pairs of chromosomes of modern man are virtually identical to those of our "common hominoid ancestor", with the remaining pairs slightly different. From this lineage, gorilla separated first, and three major chromosomal rearrangements presumably occurred in a progenitor of chimpanzee and man before the final divergence of these two species. A precursor of the hominoid ancestor and orangutan is also assumed (2094).

 

Edward Osborne Wilson (US) wrote Sociobiology: The New Synthesis, in which he analyzes social behaviors at all phylogenetic levels (2036).

 

Colin Groves (AU) and Vratislav Mazák (CZ) proposed the name Homo ergaster (man the workman). The type specimen for ergaster is KNM-ER 992 (777).

 

1976

"Je cherche à comprendre" [I try to understand] Jacques Lucien Monod (268). Agnes Ullmann (letter of Nov. 21, 1994 to Benno Müller-Hill) reports that Monod spoke this to his doctor, Gerard Mantoux, near the time of Monod's death in 1976.

 

“In all human affairs … there is a single dominant factor—time. To make sense of the present state of science, we need to know how it got like that: we cannot avoid an historical account …. To extrapolate into the future, we must look backwards a little into the past.” John M. Ziman (2104).

 

“We are survival machines—robot vehicles blindly programmed to preserve the selfish molecules known as genes. This is a truth that still fills me with astonishment.” Clinton Richard Dawkins (460).

 

“Be warned that if you wish, as I do, to build a society in which individuals cooperate generously and unselfishly towards a common good, you can expect little help from biological nature. Let us try to teach generosity and altruism, because we are born selfish. Let us understand what our selfish genes are up to, we may then at least have the chance to upset their designs, something that no other species has ever aspired to.” Clinton Richard Dawkins (460).

 

Baruch Samuel Blumberg (US) and Daniel Carleton Gajdusek (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases.

 

Robert S. Langer (US) and Moses Judah Folkman (US) were the first to demonstrate sustained release of large molecules (peptides and proteins) from implanted polymers. This was an essential step for the establishment of gradients of angiogenic activity in vivo (1133).

 

Gilbert Stork (US), Stanley Raucher (US), Takashi Takahashi (US), Isao Kawamoto (US), and Toshio Suzuki (US) synthesized the hormones prostaglandin A₂ (PGA₂) and prostaglandin F2a (PGF2a) (1807; 1808).

 

Ursula Dähn (DE), Hanspaul Hagenmaier (DE), Hildegard Hohne (DE), Wilfried A. Konig (DE), G. Wolf (DE), and Hans Zahner (DE) were the first to isolate the antifungal antibiotic nikkomycin. It is produced by Streptomyces tendae (446).

 

The azoles were introduced as systemic plant fungicides. They included ketoconazole, triadimefon, propiconazole, prochloraz, epoxiconazole, fluquinconazole, and triticonazole. These fungicides act by inhibiting the synthesis of ergosterol, the major sterol component of fungal cell membranes. Ketoconazole was discovered in 1976 by Jan Heeres (BE), Leo J. Backx (BE), Joseph H. Mostmans (BE), and J. Van Cutsem (BE). It was initially introduced in 1977, followed by introduction in the United States in 1981. It was introduced as the prototypical drug of the imidazole antifungals. Oral ketoconazole has been replaced with oral itraconazole for many.

 

Paul A. Price (US), James W. Poser (US), Nerja Raman (US), Allen S. Otsuka (US), and Joanne Kristaponis (US) were the first to isolate and characterize the hormone osteocalcin, also referred to as bone γ-carboxyglutamic acid (Gla) protein or BGP. It is a 46–50 amino acid, 5.6 kDa secreted protein that is produced primarily by osteoblasts with smaller amounts produced by odontoblasts of the teeth and hypertrophic chondrocytes (1527; 1528). Note: Beginning in 1996, Gerard Karsenty (US) and his colleagues led the way to the understanding that osteocalcin can now be viewed as a bone-derived factor that influences glucose metabolism, reproduction and cognition through endocrine loops between bone and the pancreas, brain and testes, as well as, osteoblastic developmental pathways that regulate the ability of bone cells to generate the energy necessary to sustain bone formation.

 

Michael Botchan (US), William C. Topp (US), and Joseph Frank Sambrook (GB-US-AU) provided detailed descriptions of the organization of viral DNA sequences integrated into the genomes of an isogenic set of 11 rat cell lines transformed by simian virus 40. The junctions between viral and cellular sequences map at different places on the viral genome (205). They speculated that integration was a cellular process that might operate on any foreign DNA. It is now known that integration of SV40 DNA is the result of cellular mechanisms that evolved to repair damaged chromosomal DNA and that randomly broken viral DNA is joined together and linked to the chromosome to eliminate free ends.

 

Richard Olding Hynes (GB-US), Antonia T. Destree (US), Vivien Mautner (US), Kenneth D. Noonan (US), David S. Lindberg (US), Julie A. McClure (US), Jorma Keski-Oja (FI), Antti Vaheri (FI), Pentti Kuusela (FI), Erkki Ruoslahti (FI-US), and Eva Engvall (SE-US), identified the extracellular glycoprotein fibronectin (LETS protein or fibroblast surface antigen) (936; 1038; 1120; 1423).

Jorma Keski-Oja (FI), Antti Vaheri (FI), and Erkki Ruoslahti (FI) showed that cross-linking of a major fibroblast surface-associated glycoprotein (fibronectin) is catalyzed by blood coagulation factor XIII (1038).

Richard Olding Hynes (GB-US), Antonia T. Destree (US), Margaret E. Perkins (US), and Denisa D. Wagner (US) found that cell surface fibronectin is reduced in amount or absent on transformed cells and in many cases its loss correlates with acquisition of tumorigenicity and metastatic ability (937).

Erkki Ruoslahti (FI-US) found that cell-matrix interactions are important in development and neoplasia (1623).

Michael D. Pierschbacher (US), Edward G. Hayman (US), and Erkki Ruoslahti (FI-US) showed that the interaction of fibronectin with cells is restricted to a defined portion of the fibronectin molecule and is independent of the direct involvement of the known affinities toward other macromolecules (1502). Fibronectin is the best-characterized extracellular adhesive protein.

Michael D. Pierschbacher (US) and Erkki Ruoslahti (FI-US) reported that the ability of fibronectin to bind cells could be accounted for by the tetrapeptide L-arginyl-glycyl-L-aspartyl-L-serine, a sequence that is part of the cell attachment domain of fibronectin and present in at least five other proteins. This tetrapeptide may constitute a cellular recognition determinant common to several proteins (1503).

Jean E. Schwarzbauer (US), John W. Tamkun (US), Ihor R. Lemischka (US), and Richard Olding Hynes (US) found that three different fibronectin mRNAs arise by alternative splicing within the same coding region and are probably all encoded by a single gene (1695). In humans about 20 different messenger RNAs are produced, each encoding a somewhat different fibronectin subunit. This form of splicing allows a cell to produce the type of fibronectin most suitable for its needs at a time and place.

John W. Tamkun (US), Jean E. Schwarzbauer (US), and Richard Olding Hynes (GB-US) found that a single rat fibronectin gene generates three different mRNAs by alternative splicing of a complex exon (1858).

John W. Tamkun (US), Douglas W. DeSimone (US), Deborah Fonda (US), Ramila S. Patel (US), Clayton Buck (US), Alan F. Horwitz (US), and Richard Olding Hynes (GB-US) reported the structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin (1857).

Charles French-Constant (GB), Livingston Van de Water (US), Harold F. Dvorak (US), and Richard Olding Hynes (GB-US) found that an embryonic pattern of fibronectin splicing reappears during wound healing in the adult rat (641).

 

Kenneth B.M. Reid (GB) and Rodney Robert Porter (GB) discovered that the subunit composition and structure of subcomponent C1q of the first component of human complement is rich in repeats of the sequence —Gly—Gly—Pro— ordinarily seen in collagen. The authors proposed that these are the basis for a triple helix (such as exists in collagen itself), which binds three C1q subcomponents together into an overall trimeric structure (1554).

 

Rudolph L. Juliano (US), Victor Ling (CA), Paul G. Debenham (GB), Norbert Kartner (CA), Louis Siminovitch (CA), and John (Jack) R. Riordan (CA) discovered P-glycoprotein, which is encoded by the multidrug resistant gene (MDR) (475; 998; 1017).

John (Jack) R. Riordan (CA), Johanna M. Rommens (CA), Bat-Sheva Karem (US), Noa Alon (US), Richard Rozmahel (US), Zbyszko Grzelczak (CA), Julian Zielenski, Si Lok, Natasa Plavsic (CA), Jia-Ling Chou (CA), Mitchell L. Drumm (CA), Michael C. Iannuzzi (CA), Francis S. Collins (CA), and Lap-Chee Tsui (CA) succeeded in the cloning and characterization of complementary DNA of the cystic fibrosis gene (1571).

Stephen C. Hyde (GB), Paul Emsley (GB), Michael J. Hartshorn (GB), Michael M. Mimmack (GB), Uzi Gileadi (GB), Stephen R. Pearce (GB), Maurice P. Gallagher (GB), Deborah R. Gill (GB), Roderick E. Hubbard (GB), and Christopher F. Higgins (GB) found that P-glycoprotein is not only important clinically, as it confers multidrug resistance in many cancers, it also can protect the brain from poisonous substances. P-glycoprotein is the first protein discovered in humans that belongs to a group of membrane transport proteins called the ATP Binding Cassette (ABC) proteins. ABC is very important in maintaining normal cell functions. Mutations in this group of proteins cause many well-known diseases. One example is the cystic fibrosis transmembrane regulator (CFTR), which is responsible for cystic fibrosis (935).

 

Barbara M. F. Pearse (GB) identified and named clathrin (clathratus = lattice) as a unique protein associated with intracellular transfer of membrane by coated vesicles (1481).

 

Robert Palese Perry (US), James P. Calvet (US), and Thoru Pederson (US) determined that the genes for 5S rRNA lie outside the nucleolus in higher plant and animal cells, but 5.8S rRNA arises from processing of the pre-rRNA primary transcript and ends up base-paired with 28S rRNA in the nucleolus (306; 1490).

 

Alice Chien (US), David B. Edgar (US), and John M. Trela (US) discovered that the extreme thermophile, Thermus aquaticus, contains a DNA polymerase with a temperature optimum of 72°C. This enzyme is routinely used in biotechnology where it goes by the name Taq DNA polymerase (360).

 

John J. Byrnes (US), Kathleen M. Downey (US), Vicky L. Black (US), and Antero G. So (US) discovered eukaryotic DNA polymerase delta. This enzyme has a 5’ to 3’ polymerizing ability and a 3’ to 5’exonuclease activity for proofreading (301).

 

Francis Harry Compton Crick (GB), Sydney Brenner (ZA-GB), Aaron Klug (ZA-GB), and George Pieczenik (US) proposed that the assignment of codons to amino acids was simply an historical accident, there being no special reasons why a particular codon stands for a given amino acid (430).

 

Bart G. Barrell (GB), Gillian M. Air (US), and Clyde A. Hutchison III (US) discovered overlapping genes in bacteriophage phiX174 (100).

 

Argiris Efstratiadis (GR-US), Fotis Constantine Kafatos (DE), Allan M. Maxam (US), and Thomas Peter Maniatis (US) performed the in vitro synthesis of globin genes (544).

Thomas Peter Maniatis (US), Sim Gek Kee (US), Argiris Efstratiadis (GR-US), Fotis Constantine Kafatos (DE), Richard M. Lawn (US), Edward F. Fritsch (US), Richard C. Parker (US), Geoffrey Blake (US), and Chris O’Connell (US) isolated and determined the nucleotide sequence of the gene which produces the human beta globin protein (1142; 1143; 1277).

 

Terence H. Rabbitts (GB), Thomas Peter Maniatis (US), Sim Gek Kee (US), Argiris Efstratiadis (GR-US), and Fotis Constantine Kafatos (DE) made in vitro cDNA from the messenger RNA for beta-globin then cloned a full copy of the gene into bacteria (1277; 1536).

 

César Milstein (AR-GB), Leroy Edward Hood (US), William R. Gray (US), and Bob G. Sanders (US), and William J. Dreyer (US) concluded that each immunoglobulin chain is specified by two genes, a V gene and a C gene (905; 1344). Although not quite correct they were very close.

Nobumichi Hozumi (CH), Susumu Tonegawa (US), Christine Brack (US), Minoru Hirama (US), Rita Lenhard-Schuller (US), Jonathan G. Seidman (US), Edward E. Max (US), Philip Leder (US), Hitoshi Sakano (US), Konrad Hüppi (US), Günther Heinrich (US), Philip W. Early (US), Henry V. Huang (US), Mark M. Davis (US), Kathryn Calame (US), Leroy Edward Hood (US), Nicholas M. Gough (US), Ora Bernard (US), Patricia J. Gearhart (US), Nelson D. Johnson (US), Richard Douglas (US), Erik Selsing (US), Ursula Beate Storb (US), Frederick Wayne Alt (US), David Baltimore (US), Wendy D. Cook (US), Stuart Rudikoff (US), Angela M. Giusti (US), Matthew Daniel Scharff (US), Daniel F. Bogenhagen (US), Charles Wood (US), Tim Manser (US), Shu Y. Huang (US), Malcolm L. Gefter (US), Claudine Schiff (FR), Michèle Milili (FR), and Michel Fougereau (FR) discovered how the diversity of antibodies produced by B cells of vertebrates could be explained by the recombination of a relatively small number of alleles. The intact linear code for the heavy chains of antibody molecules does not pre-exist in the fertilized egg, rather four sets of mini-genes located in widely separated parts of the nucleus combine in many different ways (37; 219; 411; 525; 675; 676; 742; 915; 1285; 1642; 1673; 1709; 1716; 1899; 2055).

 

Michael John Bevan (GB-US) presented the first evidence of immune cross-presentation after he injected cells carrying alloantigens into experimental animals. This resulted in CD8 T cell responses that were induced by antigen-presenting cells of the recipient, implying that these must have taken up and processed the injected cells. This observation was termed “cross-priming” (159). Note: Cross-presentation has been shown to play a role in the immune defense against many viruses (Herpesvirus, Influenza virus, Cytomegalovirus, Epstein-Barr virus, Simian immunodeficiency virus, Papillomavirus, and others), bacteria (Listeria, Salmonella, E. coli, M. tuberculosis, and others) and tumors (brain, pancreas, melanoma, leukemia, and others).

Cross-priming avoids viral immune evasion strategies, such as suppression of antigen processing. Consequently, immune responses against viruses that can do so, such as herpes viruses, are largely dependent on cross-presentation.

 

Michael John Bevan (GB-US) investigated the cellular basis of the cross-priming observed with minor histocompatibility antigens on H-2 different cells. Cytotoxic T cells induced against minor alloantigens show absolute H-2 restriction at the effector level ([51Cr]-release). Cross-priming may be explained by foreign minor H antigens being presented to F1 host T cells on the surface of host macrophages. Therefore priming is not restricted to the H-2 type of the injected cells but to both H-2 types of the F1 host (158).

 

 Nils Kaj Jerne (GB-DK) proposed the concept of the control of antibody synthesis by means of a network of idiotypes and anti-idiotypes (974).

 

John H. Robinson (GB) and John J. T. Owen (GB) offer an in vitro model for the study of T-cell ontogeny is presented. The generation of mitogen responsive thymocytes in embryonic mouse thymus using an organ culture system is described. The pattern of development of mitogen responsiveness in vitro is similar to that seen in vivo except that responses were greater and appeared later in culture than in thymus of a temporally equivalent age in vivo. This suggests that organ culture selectively enriches T-cell activity and thus offers a novel approach to the analysis of T-cell reactivity as well as to the understanding of defects in T-cell development (1578).

 

Thomas E. Carey (US), Toshitada Takahashi (JP), Lois A. Resnick (US), Herbert F. Oettgen (US), Lloyd John Old (US), Thomas J. Garrett (US), Bayard D. Clarkson (US), Philip O. Livingston (US), Hiroshi Shiku (JP), Michael A. Bean (US), Carl M. Pinsky (US), Ryuzo Ueda (JP), Hiroshi Shiku (JP), Michael Pfreundschuh (DE), L.T.C. Li (JP), Willet F. Whitmore, Jr. (US), Tadashi Watanabe (JP), Alan N. Houghton (US), Anthony P. Albino (US), Richard W. Michitsch (US), Alexander Knuth (US), Barbara Danowski (US), Francisco X. Real (ES), M. Jules Mattes (US), Kenneth O. Lloyd (US), Tae June C. Chung (KR), Yao-Tseng Chen (US), Matthew J. Scanlan (US), Ugur Sahin (US), Özlem Türeci (US), Ali O. Gure (US), Solam Tsang (US), Barbara Williamson (US), Elisabeth Stockert (US), Nasser K. Altorki (US), Dirk Jäger (DE), Elke Jäger (DE), John D. Gordan (US), Neil H. Bander (US), Victor C. Jongeneel (CH), Maha Ayyoub (US), Charles S. Hesdorffer (US), Genevieve Metthez (US), Stefan Stevanovic (US), Gerd Ritter (US), Daniel Speiser (US), Jean-Charles Cerottini (US), Danila Valmori (US), Yu Wang (CN), Xiao-Jiang Wu (CN), Ai-Lian Zhao (CN), Yan-Hua Yuan (CN), Achim A. Jungbluth (CN), Sacha Gnjatic (CN), Darren Santiago (CN), Wei-Feng Chen (CN), Jia-Fu Ji (CN), Toshiaki Ishida (JP), Yuichi Obata (JP), Nobuya Ohara (JP), Hirokazu Matsushita (JP), Shuichiro Sato (JP), Akiko Uenaka (JP), Takashi Saika (JP), Takako Miyamura (JP), Kosuke Chayama (JP), Yurika Nakamura (JP), Hisashi Wada (JP), Toshiharu Yamashita (JP), Tsuneo Morishima (JP), and Eiichi Nakayama (JP) used serology to define antigens and establish the autologous typing system. These approaches led to the identification of the first known specific human tumor antigens recognized by antibodies and T cells and the most comprehensive analysis of the humoral immune response to human cancer, which defined the cancer 'immunome' and identified an array of new targets for human cancer vaccines (76; 316; 358; 673; 790; 951; 1078; 1209-1211; 1444; 1550; 1664; 1665; 1917; 1980). Note: Immunome refers to the set of genes and proteins that constitute the immune system.

 

Kunio Yamazaki (JP), Edward A. Boyse (GB-US), V. Mike (US), Howard T. Thaler (US), Bonnie J. Mathieson (US), Joan N. Abbott (US), Jeanette Boyse (US), Zoilo A. Zayas (US), Lewis Thomas (US), Gary K. Beauchamp (US), Charles J. Wysocki (US), and Burton M. Slotnick (US) noted that male mice, given the opportunity to mate with a female of major histocompatibility type either identical to or different from the male, reliably selected the female of different haplotype. Controlled mating trials established that the H-2 major histocompatibility complex was responsible for preferential mating in mice. It was also appreciated that this chemosensory recognition extended across species (113; 114; 2076).

 

Klaus Radsak (DE), Karl-Werner Knopf (DE), Arthur Weissbach (US), Arthur Bolden (US), Guido Pedrali Noy (IT), Michiyuki Yamada (JP), William J. Adams, Jr. (US), and George F. Kalf (US) demonstrated that the DNA polymerase alpha of mitochondria is different from that in the nucleus because it can act as a polymerase in the 5’ to 3’ direction and as an exonuclease in the 3’ to 5’ direction (18; 194; 1072; 1539).

 

Nancy B. Kinderman (US) and Arthur LaVelle (US) named and described coiled bodies as structures frequently attached to nucleoli in facial motor neurons of the golden hamster. These round-to-oval structures were seen at 15, 19, and 24 days post-natal and in the adult, both in normal neurons and in chromatolytic neurons, which had been axotomized 4 days previously. With one exception, the coiled bodies attached via fibrillar material to the nucleolar periphery (1051).

 

Kevin Struhl (US), John R. Cameron (US), and Ronald W. Davis (US) integrated genetic material from Saccharomyces cerevisiae into the lambda virus, which was used as a vector to transfer the yeast material to Escherichia coli where it was expressed (1817).

 

Louise Clarke (US) and John Anthony Carbon (US) sheared the total Escherichia coli genome into fragments of 8.5 X 10⁶ dalton average size. These fragments were inserted into hybrid Col El plasmids constructed in vitro by the poly (dA•dT) connector method then used to transform a F⁺ recA E. coli strain (JA200) with transformants selected by resistance to colicin. Over 80 hybrid Col El-DNA (E. coli) plasmid-bearing clones were identified (375).

 

Nguyen van Cong (FR), Dominique Weil (FR), Catherine C. Finaz (FR), Chantal Cochet (FR), Regis Rebourcet (FR), Jan De Grouchy (FR), and Jean Frézal (FR) assigned the ABO-nail patella-adenylate kinase (ABO-Np-AK1) linkage group to chromosome 9 in man-hamster hybrids (1928). The ABO locus produces galactosyl transferase.

 

John T. Finch (GB) and Aaron Klug (ZA-GB), using X ray diffraction analysis, proposed that nucleosomes coil into a structure of higher complexity, which they called a solenoid. A string of solenoids forms the chromatin fiber (615).

Brad W. Baer (US) and Roger David Kornberg (US) described and defined the nucleosome (82).

Ada L. Olins (US), Donald E. Olins (US), Hans Zentgraf (DE), Werner W. Franke (DE), Henri A. Levy (US), Richard C. Durfee (US), Stephen M. Margle (US), Ed P. Tinnel (US), Christopher L.F. Woodcock (US), Ling-Ling Y. Frado (US), Jerome B. Rattner (US-CA), and Joachim Frank (US) prepared electron photomicrographs of eukaryotic chromatin which suggested that it is organized into a string of spherical units called nucleosomes (1449; 1450; 2058; 2060; 2061).

Aaron Klug (ZA-GB), P. Jo G. Butler (GB), Roger David Kornberg (US), John T. Finch (GB), Daniela Rhodes (GB), John Smith (GB), Dame Jean O. Thomas (GB), Ray S. Brown (US), Tim Richmond (US), Barbara Rushton (US), and Leonard C. Lutter (US) determined the location of the individual histone proteins within the core octomer of nucleosomes (614; 1070; 1071; 1095).

 

George Poste (US), Demetrios P. Papahadjopoulos (US), and William J. Vail (CA) discovered that macromolecules can be artificially delivered into cells by placing the macromolecules into unilamellar liposomes and then encapsulating the cells with these (1523).

 

Rudolph L. Juliano (KR-US) and Victor Ling (CA) described a P-glycoprotein or multidrug resistance ATP binding cassette transporter MDR1/ABCB1 (998).

Yossef Raviv (US), Harvey Pollard (US), Edward P. Bruggermann (US), Ira Pastan (US), Michael M. Gottesman (US), and Victor Ling (CA) proposed that this type transporter acts as a ‘hydrophobic vacuum cleaner’ because of its ability to remove both lipids and drugs as they intercalate and diffuse through the cell membrane (1204; 1546).

Christopher F. Higgins (GB) and Michael M. Gottesman (US) noted that the human MDR1 and other MDR-ABC transporters contained an internal chamber resembling the chamber within the bilayer of a ‘flippase’ transporter (869).

Mark F. Rosenberg (GB), Richard Callaghan (GB), Robert C. Ford (GB), and Christopher F. Higgins (GB) promoted our understanding of drug transporter structure with their observations of a single particle of human MDR1 using 2D cryo-EM (1594). Note: Clinical multidrug resistance is caused by a group of integral membrane proteins that transport hydrophobic drugs and lipids across the cell membrane. One class of these permeases, known as multidrug resistance ATP binding cassette (ABC) transporters, translocate these molecules by coupling drug/lipid efflux with energy derived from the hydrolysis of ATP. In humans, 46 ABC transporters have been identified and play important roles in human diseases, which include cystic fibrosis, macular dystrophy, and several neurological disorders.

 

Archie R. Portis, Jr. (US) and Richard E. McCarty (US) found that the rate of phosphorylation in chloroplasts is critically dependent on magnitude of the pH gradient across the chloroplast’s membrane (1522).

 

Yadin Dudai (US), Yuh Nung Jan (US), Duncan Byers (US), William G. Quinn (US), and Seymour Benzer (US) discovered the dunce mutation in Drosophila. This mutation rendered its bearers incapable of learning simple tasks such as a certain smell is always followed by an electrical shock (512). Other learning mutations were soon discovered in Drosophila.

James P. Hoeffler (US), Terry E. Meyer (US), Gerard Waeber (CH), and Joel F. Habener (US) localized the human CREB-327/341 gene to chromosome 2 (898).

Tim Tully (US), Thomas Preat (US), Susan C. Boynton (US), Maria Del Vecchio (US), and Josh Dubnau (US) removed the cyclic AMP response binding protein gene (CREB) from Drosophila resulting in a fly with an extremely short-term memory. They also produced flies, which learned very rapidly, i.e., with a photographic memory (510; 1913).

Xiao-Ning Chen (US) and Julie R. Korenberg (US) used a cDNA probe for the mouse CREB binding protein gene to localize the gene CREBBP to human chromosome 16p13.3 (357). The protein product of this gene facilitates the functioning of the CREB-327/341 protein. The protein products of CREB-327/341 and CREBBP promote learning in humans.

Craig H. Bailey (US), Dusan Bartsch (US), and Eric Richard Kandel (US) reported that these learning mutations resulted from molecular damage to a mechanism for making or responding to cyclic AMP (85).

Michael S. Grotewiel (US), Christine D.O. Beck (US), Kwak Hang Wu (US), Xin-Ran Zhu (US), and Ronald L. Davis (US) discovered volado, a new memory mutant of Drosophila. The locus encodes two isoforms of a new alpha-integrin, a molecule that dynamically mediates cell adhesion and signal transduction. The volado gene is expressed preferentially in mushroom body cells, which are neurons known to mediate olfactory learning in insects. Volado proteins are concentrated in the mushroom body neuropil, brain areas that contain mushroom body processes in synaptic contact with other neurons. Volado mutants display impaired olfactory memories within 3 min of training, indicating that the integrin is required for short-term memory processes. Conditional expression of a volado transgene during adulthood rescues the memory impairment. This rescue of memory is reversible, fading over time along with expression of the transgene. Thus, the volado integrin is essential for the physiological processes underlying memory. They proposed a model in which integrins act as dynamic regulators of synapse structure or the signaling events underlying short-term memory formation (773).

 

Dominique Stehelin (FR), Ramareddy V. Guntaka (US), Harold Elliot Varmus (US), John Michael Bishop (US), and Peter Klaus Vogt (US) found that DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA (1792; 1793).

Peter H. Duesberg (DE-US), Lu-Hai Wang (US), Karen Beemon (US), Sadaaki Kawai (JP), and Hidesaburo Hanafusa (JP) identified a cluster of three sarcoma gene (src)-specific oligonucleotides within the sarcoma virus RNA (513). The src genes represent the first known oncogenes.

G. Steven Martin (US) was the first to identify src (sarcoma) genes (1293).

Deborah Spector (US), Harold E. Varmus (US), and John Michael Bishop (US) detected nucleotide sequences related to the transforming gene of avian sarcoma virus (ASV) in the DNA of uninfected vertebrates (1775).

 

Gerald Maurice Edelman (US), Cheng-Ming Chuong (US), Warren J. Gallin (CA), Annie Delouvée (FR), Bruce A. Cunningham (US), and Jean-Paul Thiery (FR) developed the concept of what they called cell adhesion molecules (CAMs). These molecules were important in adhesion and morphogenesis. It was realized that CAMs appear in a definite sequence of expression during embryogenesis and histogenesis. Their appearance reflecting the formation of cell collectives and boundaries having morphological and functional significance (527-539).

 

Samuel J. Leibovich (US) and Russell Ross (US) discovered macrophage derived growth factor (MDGF), a potent mitogen (1161).

 

Janet M.D. Plate (US) found that following antigenic stimulation soluble factors are produced by T-helper cells which promote differentiation of committed cytotoxic T-killer cells into T-effector (T-killer) cells (1512).

 

Garth Lamb Nicolson (US) provided evidence that some transmembrane proteins and glycoproteins are held in a cluster by a protein, which is joined to all of them on the inside of the membrane (1414).

 

William S. Bowers (US), Tomihisa Ohta (US), Jeanne S. Cleere (US), and Patricia A. Marsella (US) discovered precocene, an anti-juvenile hormone, in plants. It induces irreversible precocious metamorphosis and sterilization in some insects (such as grasshoppers and locusts) by suppressing the function of the corpora allata gland, which plays a major role in vitellogenin synthesis (210).

 

Erwin Neher (DE) and Bert Sakmann (DE) recorded single-channel currents from membranes of denervated frog muscle fibers (1406).

 

Jorma Keski-Oja (FI), Deane F. Mosher (FI), and Antti Vaheri (FI) found that the cross-linking of fibroblast cell surface fibronectin by blood coagulation factor XIIIa (plasma protransglutaminase) requires highly specific enzyme-substrate and protein-protein interactions and may be an important physiological reaction (1037).

 

Edward Donnall Thomas (US), David W. Golde (US), Robert E. Ramberg (US), George E. Sale (US), and Robert S. Sparkes (US) demonstrated that lung macrophages are derived from bone marrow stem cells (716; 1877).

 

Clifford B. Saper (US), Arthur D. Loewy (US), Larry W. Swanson (US), and W. Maxwell Cowan (US) demonstrated that the neurons in the paraventricular nucleus and lateral hypothalamus contact autonomic control areas in the brain stem and the spinal cord, including the preganglionic neurons of both the sympathetic and parasympathetic nervous system (1653).

Michael B. Hancock (US) also established the paraventricular nucleus as a source of spinal projections (807).

 

Richard G.W. Anderson (US), Michael S. Brown (US), Joseph L. Goldstein (US) and Ulrike Beisiegel (DE) indicated that the coated regions of plasma membrane are specialized structures of rapid turnover that function to carry receptor-bound low-density lipoprotein (LDL), and perhaps other receptor-bound molecules, into the cell. The receptors are recycled back to the surface (53-55). These findings supported the notion that the hormone receptors are “swallowed” and replaced by fresh proteins—an inference later studies confirmed.

Graham Carpenter (US) and Stanley Cohen (US) found that the epidermal growth factor (EGF) hormone once internalized ends up in lysosomes for demolition (322).

 

Max Ferdinand Perutz (AT-GB) and Joyce M. Baldwin (GB) presented the details of how hemoglobin performs its physiological functions (90; 1493; 1494).

 

Richard Mathies (US), Allan R. Oseroff (US), Lubert Stryer (US), Alfred Goodman Gilman (US), Michael A. Lochrie (US), Melvin I. Simon (US), Michael Freissmuth (AT), and Patrick J. Casey (US) worked out many of the steps in the visual cascade including the finding that metarhodopsin II interacts with a G-protein, transducin, which activates phosphodiesterase molecules which regulate cyclic GMP levels in photoreceptor cells. Cyclic GMP somehow opens the sodium channels in the outer membrane of retinal cone cells and hydrolysis of cyclic GMP leads to their closing. Their closing leads to hyperpolarization. Membrane voltage of the photoreceptor cell is therefore related to cyclic GMP levels and modulates neurotransmitter release (640; 702; 1217; 1298; 1819; 1820).

Evgeniy E. Fesenko (RU), Stanislav S. Kolesnikov (RU), and Arkadly L. Lyubarsky (RU) determined that the sodium channels are directly opened by cyclic GMP (610).

 

Eveline Schneeberger (US) and Morris John Karnovsky (ZA-US) determined the substructure of intercellular junctions in freeze-fractured alveolar-capillary membranes of the mouse lung, i.e., the blood-air barrier of the lungs (1679).

 

Walter Charles Cornelius Fiers (BE), Roland R. Contreras (BE), Fred Duerinck (BE), Guy Haegemann (BE), Dirk Iserentant (BE), Joseph Merregaert (BE), Willy Min Jou (BE), Francis Molemans (BE), Alex Raeymaekers (BE), Antoon Vandenberghe (BE), Guido Volckaert (BE), and Maarten Ysebaert (BE) worked out the entire nucleotide sequence for bacteriophage MS2. This was the first single-stranded RNA genome to be sequenced completely (612).

Frederick Sanger (GB), Gillian M. Air (GB), Barclay George Barrel (GB), Nigel L. Brown (GB), Alan R. Coulson (GB), John C. Fiddes (GB), Clyde A. Hutchison III (US), Patrick M. Slocombe (GB), Michael Smith (GB-CA), and Theodore Friedmann (GB) determined the nucleotide base sequence of the bacteriophage phi chi 174. This was the first single-stranded DNA genome to be sequenced completely (1648; 1650).

 

Tony R. Hunter; Anthony Rex Hunter (GB-US), Tim Hunt; Richard Timothy Hunt (GB), John Knowland (GB), and David Zimmern (GB) found that tobacco mosaic virus (TMV) RNA is not an efficient template for translation of the viral coat protein, despite containing nucleotide sequences coding for the protein. Efficient translation requires the prior synthesis within infected cells of a smaller RNA (messenger) carrying only a portion of the information encoded in the whole genome (929).

 

John N. Champness (GB), Anne C. Bloomer (GB), Gerard Bricogne (GB), P. Jo G. Butler (GB), and Aaron Klug (ZA-GB) elucidated the three-dimensional structure of tobacco mosaic virus using crystallographic electron microscopy. Their work showed that the assembly of TMV starts with one disk of protein surrounding the nucleation or initiation region of a strand of RNA, the initial disk serves as a center for the assembly of a stack of 100 such disks composed of a total of 2,200 identical protein molecules that make up the complete virus (342; 1069).

David Zimmern (GB) isolated the nucleation region and determined that it represents approximately 60 nucleotides near the middle of the viral RNA molecule (2106; 2107).

 

Christoph Scholtissek (DE), Rudolf Rott (DE) Michaela Orlich (DE), Etti Harms (US), Wolfgang Rhode (DE), Angelika Vallbracht (DE), and Bertram Flehmig (DE) made gene reassortments between highly virulent and avirulent strains of avian influenza virus, exchanging separately each of the eight genome segments of each strain. The virulence of the progeny viruses they obtained varied in complex patterns. They showed that some genes worked better together than others, that there was an optimum combination of genes, an optimum gene constellation, that favored viral survival in nature and determined virulence (1614; 1681; 1682).

 

Richard B. Sykes (US) and Margaret J. Matthew (US) discovered that some bacteria are resistant to penicillins and cephalosporins because they produce beta-lactamases, which can split the lactam ring, found in these types of molecules (1844).

 

Hiroshi Nikaido (US) reported that gram-negative bacteria are usually insensitive to antibiotics that are effective against gram-positive bacteria because the antibiotics have difficulty penetrating the gram-negative outer membrane (1421).

 

Lean-Han San-Noeum (FR) made the first successful in vitro culture of non-fertilized ovaries of barley (1645).

 

Harry A. Bernheim (US) and Matthew J. Kluger (US) showed that a cytokine-mediated rise in body temperature is a survival mechanism in poikilothermic lizards (148).

 

William Trager (US) and James B. Jensen (US) discovered a simple method to grow the pathogenic human malaria, Plasmodium falciparum, in continuous culture inside erythrocytes (1904).

 

Paul D. Shirk (US), Karl H. Dahm (US), and Herbert Röller (US) discovered that the accessory sex glands of the male Cecropia moths (Hyalophora cecropia, giant silk moth) can sequester insect juvenile hormone (JH) (1732).

 

Ji-Won Yoon (US), Abner L. Notkins (US), Rainer Gladisch (DE), Werner Hofmann (DE), and Rüdiger Waldherr (DE) presented evidence that viruses play a role in the pathogenesis of insulin-dependent diabetes mellitus (710; 2085).

 

Yuet Wai Kan (US), Mitchell S. Golbus (US), and Andree-Marie Dozy (US) diagnosed alpha-thalassemia in a prenatal human using DNA-DNA hybridization on cells cultured from amniotic fluid. This approach is based on the finding that the molecular defect in these syndromes is due to deletion of the gene that determines the structure of the alpha globin (alpha globin structural gene). A non-thalassemic person has four alpha globin structural genes per diploid cell; in alpha-thalassemia-1 and hemoglobin-H disease, two and one alpha globin genes are left intact respectively, and in homozygous alpha-thalassemia associated with hydrops fetalis, no alpha globin genes remain intact. The Hybridization Test can detect the number of intact globin structural genes (1004).

 

Roger Harold Unger (US) gave clear experimental evidence that the control of glucose levels within the body involves a homeostatic system, which is capable of augmenting glucose outflow from the extracellular space to compensate for increases in inflow of glucose (1921). Any extra glucose is stored as glycogen or fat.

 

Karin B. Nelson (US) and Jonas H. Ellenberg (US) report that through the inclusion of infants from the Collaborative Perinatal Project, this large, multicenter, prospective study found that children with febrile seizures, complex febrile seizures (seizures that were longer than 15 minutes in duration, occurred more than once in 24 hours, or had focal neurologic findings), and febrile seizures of earlier onset (before 6 months of age) were at increased risk of developing epilepsy when compared to individuals who had febrile seizures without these features. Abnormal performance on neurologic testing was linked to increased epilepsy risk (1409).

 

The Centers for Disease Control (CDC) reported that a total of 152 persons associated with a state American Legion convention in Philadelphia July 21–24 had been hospitalized with respiratory infections. Onsets of illness were in the period July 22–August 3. Twenty-two of these patients died. The deaths were primarily due to pneumonia (3).

David W. Fraser (US), Theodore R. Tsai (US), Walter A. Orenstein (US), William E. Parkin (US), H. James Beecham (US), Robert G. Sharrar (US), John M. Harris (US), George F. Mallison (US), Stanley M. Martin (US), Joseph E. McDade (US), Charles C. Shepard (US), Philip S. Brachman (US), Martha A. Redus (US), and Walter R. Dowdle (US) isolated and named Legionella pneumophila as the causative agent of legionellosis; Legionnaires disease. The bodies of dead legionnaires were the source (637; 1315).

 

Nemat O. Borhani (US), Manning Feinleib (US), Robert J. Garrison (US), Joe C. Christian (US), and Ray H. Rosenman (US) presented evidence that the variability of both systolic and diastolic blood pressure within the total human population can be attributed to genetic differences. They calculated that the "heritability" indexes were 0.82 and 0.64 respectively for systolic and diastolic blood pressures (202).

 

Peter C. Nowell (US) gave strong support to the hypothesis of tumor stemlines that describe neoplastic progression in terms of sequential selection of mutant subpopulations derived from a common progenitor (1428).

 

Robert E. Weibel (US), Victor M. Villarejos (US), Philip P. Vella (US), Allen A. Woodhour (US), Arlene A. McLean (US), and Maurice Ralph Hilleman (US) created a vaccine against meningococcal disease, caused by bacteria (Neisseria meningitidis) that infect the bloodstream and linings of the brain and spinal cord, resulting in fever, vomiting, or trouble waking from sleep. This was the first vaccine to be based on polysaccharides (groups A and C), rather than on a whole pathogen or its protein subunits (2000).

 

George Sachs (AT-US), Hsuan Hung Chang (US), Edd Rabon (US), Robert Schackmann (US), Gaetano Saccomani (US), and Marcus Goodall (US) discovered the proton or acid pump in the stomach (350; 728; 1637)

Erik Fellenius (SE), Thomas Berglindh (SE), George Sachs (AT-US), Lars Olbe (SE), Berit Elander (SE), Sven-Erik Sjöstrand (SE), Björn Wallmark (SE), and Sven Mardh (SE) led the development of H+K+ dependent ATPase inhibitors or PPI's. These agents have truly revolutionized the therapy for gastric acid disorders such as ulcers and gastroesophageal reflux (597; 1636; 1972).

 

Philip K. Hench (US) coined the phrase fibromyalgia syndrome (FMS) (844).

 

John C. Hobbins (US), Clarence D. Davis (US) and John Webster (US) described a new technique which utilizes ultrasound to diminish fetal exposure to x-ray during intrauterine transfusion. In replacing x-ray imagery, ultrasound better localizes the exact position of the intrauterine contents, including the vital fetal intraabdominal structures. Using an A mode needle aspiration transducer, it is possible to guide the tip of the transfusing needle into the center of the fetal intraperitoneal cavity (893).

 

Peter Davies (US) and Anthony J.F. Maloney (GB) reported that there is selective loss of central cholinergic neurons in Alzheimer's disease (457).

 

Allen C. Alfrey (US), Gary R. LeGendre (US), and William D. Kaehny (US) documented that brain aluminum levels were higher in dialyzed uremic patients dying of dialysis encephalopathy than in dialysis patients dying of other causes. It was the first hint that aluminum intoxication was responsible for this disease (29). Aluminum-contaminated dialysate was confirmed to be the culprit.

 

Russell Ross (US) and John A. Glomset (US) discussed the structure of the normal artery wall and data on our understanding of the cell biology of endothelium and smooth muscle in vitro and in vivo. Three hypotheses of atherogenesis are discussed including the ‘response to injury hypothesis, ’l the ‘monoclonal hypothesis, ’2 and the ‘clonal senescence hypothesis,’ 3. These are each evaluated, compared, and contrasted, and the potential role of lipids and connective tissues in atherogenesis is discussed (1603; 1604).

 

Gianni Bonadonna (IT), Ercole Brusamolino (IT), Pinuccia Valagussa (IT), Anna Rossi (IT), Luisa Brugnatelli (IT), Cristina Brambilla (IT), Mario De Lena (IT), Gabriele Tancini (IT), Emilio Bajetta (IT), Renato Musumeci (IT), and Umberto Veronesi (IT), from their prospective single-center randomized controlled trial, concluded that adjuvant systemic chemotherapy could improve relapse-free survival in women with node-positive breast cancer. With longer follow-up the improvements in disease-free survival were shown to translate into improved overall survival (197).

 

A Conference of the Medical Royal Colleges and Their Faculties in the United Kingdom established brain death as: “All of the following [conditions] should coexist [for considering a diagnosis of brain death]. The patient is deeply comatose…. The patient is being maintained on a ventilator because spontaneous respiration had previously become inadequate or had ceased altogether…. There should be no doubt that the patient's condition is due to irremediable structure brain damage. The diagnosis of a disorder, which can lead to brain death, should have been fully established…. All brainstem reflexes should be absent” (1055).

 

Paul Webb (US) investigated the effect of size on fast-start performance in the rainbow trout, Salmo gairdneri, and used the results to make some theoretical considerations on predator–prey interactions. He found that the time required to complete the first muscle contraction (i.e. one tail beat) of a fast-start increases with fish size and that both distance covered and velocity at the end of the first two half tail beats (stage 1 and 2) increased with size. Webb introduced evaluation of swimming performance within a fixed time and found that, in this case, distance and speed were size independent, in line with the size independence of acceleration. This is a major finding because it implies, as Webb suggested, that predators may be unable, based on swimming performance alone, to catch a geometrically similar, smaller prey. Webb's work is particularly relevant for predator–prey interactions of relatively short duration, such as those often encountered in structurally complex environments (1994).

 

Meyer Friedman (US) and Ray H. Rosenman (US) developed the theory that Type A behavior (chronically angry and impatient people) increases the likelihood of heart disease (646; 647).

 

Clinton Richard Dawkins (GB), in his book The Selfish Gene, suggested that organisms are designed by evolution as vessels by which genes project themselves through the generations, i.e., to have the greatest chance of perpetuation genes exhibit a selfish quality (460).

 

John L. Spudich (US) and Daniel Edward Koshland, Jr. (US) described the individuality of bacterial cells grown in homogeneous conditions was demonstrated by showing characteristic behavioural differences, which persist over their lifespans. Poissonian fluctuation of small numbers of generator molecules can explain this individuality and may apply to such processes as differentiation and asynchrony of cultures (1779).

 

Charles B. Beck (US) reported that the original arborescent plant bore a planated lateral branch systems with helically arranged simple leaves very similar to those of some modern conifers (116).

 

J. William Schopf (US) found rock bearing 3.5-billion-year-old microfossils in the Onverwacht formation in South Africa (1683). The microfossils were interpreted to be prokaryotes (1684; 1685).

 

Leif Størmer (NO) reported that arthropods likely invaded the land during late Silurian and early Devonian times (1809; 1810).

 

James M. Bowler (AU) and Alan G. Thorne (AU) reported Lake Mungo 3 (Mungo Man), discovered in 1974, as an early human inhabitant of the continent of Australia, who is believed to have lived between 40,000 and 68,000 years ago, during the Pleistocene epoch (211). Note: Lake Mungo is in New South Wales, Australia.

 

Richard Erskine Frere Leakey (KE) reported on Bernard Ngeneo’s (KE) discovery of Homo ergaster (Homo erectus), KNMER 3733, at Koobi Fora in Kenya (1148). Its estimated age is 1.7 Ma.

 

On July 20, 1976 the Viking 1 space-lander from earth came to rest in the Chryse Planitia region of Mars. Its test results strongly suggested that life did not exist on Mars (1064).

 

1977

“Species differ in their nutrition: if species are delimited by their genes, then genes must control the biosynthetic steps which are reflected in nutritional patterns.” Joshua Lederberg (1151).

 

“An organism is a molecular society, and biological order is a kind of social order.” André Michel Lwoff (1242).

 

"Lymphocytes circulate and recirculate, so that the cells present in the blood at any one time are like the chorus of soldiers in a provincial production of the Opera Faust—they make a brief public appearance and then disappear behind the scenes only to re-enter by the same route." Peter Medawar and Jean Medawar (GB) (1324).

 

"So far from being 'alive' a virus is simply a piece of bad news wrapped up in protein." Peter Medawar and Jean Medawar (GB) (1324).

 

“The way to capture a student's attention is with a demonstration where there is a possibility the teacher may die." Attributed to: Jearl Walker, Cleveland State University, c. 1977 (1719).

 

Roger Charles Louis Guillemin (FR-CA-US), and Andrew Victor Schally (PL-US) for their discoveries concerning the peptide hormone production of the brain and Rosalyn Sussman Yalow (US) for the development of radioimmunoassays of peptide hormones shared the Nobel Prize in physiology and medicine.

 

J. Andrew McCammon (US), Bruce R. Gelin (US), and Martin Karplus (US) studied the dynamics of a folded globular protein (bovine pancreatic trypsin inhibitor) by solving the equations of motion for the atoms with an empirical potential energy function. The results provide the magnitude, correlations and decay of fluctuations about the average structure. These suggest that the protein interior is fluid-like in that the local atomic motions have a diffusional character (1308).

 

Koscak Maruyama (JP), Saburo Matsubara (JP), Reiji Natori (JP), Yoshiaki Nonomura (JP), Sumiko Kimura (JP), Kazuyo Ohashi (JP), Fumiko Murakami (JP), Shizuo Handa (JP), Goro Eguchi (JP) Kuan Wang (US), Janela McClure (US), and Ann Tu (US) independently discovered titin (connectin), a giant protein molecule in muscle cells (1296; 1979).

John Trinick (GB) determined that titin functions as a molecular scaffold for myosin, keeping it properly aligned. It is also an elastic protein, which can exist in both an extended and a compact form. In the extended form it determines the maximum allowable movement of the myofibril (1905).

 

Richard E. Reeves (US), Harland Goff Wood (US), Nancy A. Robinson (US), and Neil H. Goss (US) found that there are some cellular reactions in which inorganic pyrophosphate and polyphosphate replace ATP as a source of energy (1553; 1580; 2056; 2057).

Catherine A. Pepin (US) and Harland Goff Wood (US) showed that a bacterial glucokinase utilizes polyphosphate much more effectively than ATP in the reaction with glucose (1487).

 

Kuniaki Nagayama (JP), Kurt Wüthrich (CH), Peter Bachmann (DE), and Richard R. Ernst (CH) were the first to use two-dimensional nuclear magnetic resonance to solve the structure of biological macromolecules, amino acids and a protein, the basic pancreatic trypsin inhibitor (1386).

 

Don W. Cleveland (US), Stuart G. Fischer (US), Marc W. Kirschner (US), and Ulrich K. Laemmli (CH) used common proteases such as chymotrypsin and papain to partially digest several proteins. They found that the pattern of peptide fragments produced was characteristic of the protein substrate and the proteolytic enzyme and was highly reproducible. They also showed that a protein band in a gel slice could be analyzed without prior elution by its direct application to a resolving gel, which was then overlaid with a proteolytic enzyme. Thus, a very useful, rapid analytic technique requiring small amounts of protein was born (383).

 

John Warcup Cornforth (AU-GB) Scott A. Reichard (US), Paul Talalay (US), Horace L. Carrell (US), and Jenny P. Glusker (US) determined the absolute configuration at the sulfonium center of S-adenosyl-methionine (419).

 

William R. Kester (US) and Brian W. Matthews (AU-US) compared thermolysin and carboxypeptidase A by superimposing one active site upon the other and identifying corresponding structural and functional elements. They observed that although the overall folding of the respective enzymes is quite different, their active sites have several features in common, their modes of binding of dipeptide inhibitors are very similar, and they potentially had similar mechanisms for peptide hydrolysis. However, they concluded that the similarities between carboxypeptidase A and thermolysin are due to convergent rather than divergent evolution (1039).

 

Choh Hao Li (CN-US), Donald Yamashiro (US), Liang-Fu Tseng (US), and Horace H. Loh (US) synthesized human beta-endorphin and found that when it is applied centrally, beta h-endorphin is 17-48 times more potent than morphine (1188).

 

Toshiro Itoh (JP) and Hiroshi Kaneko (JP) isolated pyrophosphatidic acid from the yeast Cryptococcus neoformans and found that it, through phosphatidic acid, plays a role in phospholipid metabolism (954).

 

John M. Essigmann (US), Robert G. Croy (US), Alex M. Nadzan (US), William F. Busby, Jr. (US), Vernon N. Reinhold (US), George Hermann Büchi (CH-US), and Gerald N. Wogan (US) obtained chemical data which indicates that the major product of the interaction of metabolically activated aflatoxin B1 (a potent carcinogen) and DNA is 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 with the guanine and hydroxyl functions possessing a trans configuration. The structural data support the hypothesis that the putative 2,3-oxide of aflatoxin B1 is quantitatively important as an intermediate in the binding of aflatoxin B1 to the guanine of nucleic acids (574).

 

William R. Hargreaves (US), Sean J. Mulvihill (US), and David W. Deamer (US) found that fatty acids and glycerol combine spontaneously to produce phospholipids when heated to dryness at 65°C, as they might have been in an evaporating tide pool along a primitive sea (813).

 

James R. Paulson (US) and Ulrich K. Laemmli (CH) found that histone-depleted chromosomes consist of a scaffold or core, which has the shape characteristic of a metaphase chromosome, surrounded by a halo of DNA; the halo consists of many loops of DNA, each anchored in the scaffold at its base; most of the DNA exists in loops at least 10–30 μm long (30–90 kilobases). These results suggest a scaffolding model for metaphase chromosome structure in which a backbone of nonhistone proteins is responsible for the basic shape of metaphase chromosomes, and the scaffold organizes the DNA into loops along its length (1477).

 

James J. Champoux (US) discovered the topoisomerases, which introduce negative supercoils to prokaryotic DNA (343).

 

Howard Cedar (IL), Aharon Razin (IL), and Adrian Bird (GB), along with their respective team members, Yosef Gruenbaum (IL), Tally Naveh-Many (IL), Reuven Stein (IL), Nira Sciaky-Gallili (IL), Craig Webb (US), Moshe Szyf (IL-CA), Joel K. Yisraeli (IL), Arnon Rosenthal (IL_US), Shlomo Handeli (IL), Avihu Klar (IL), Mark Meuth (IL), Daniel Kitsberg (IL), Sara Selig (IL), Ilana Keshet (IL), Edwin M. Southern (GB), Mary Taggart (GB), and Donald Macleod (GB), demonstrated how adding a simple chemical group (a methyl group) to DNA affects how and when genetic information is used. They showed that there is an inverse relationship between DNA methylation and gene expression. Thus, almost all tissue-specific genes are found fully methylated in cell types which do not express the genes, while they are unmodified in cells which show active transcription (163-167; 336; 337; 779; 808; 1060; 1547-1549; 1794). Note: Understanding how to turn methylation on and off could lead to treatments for cancer and other diseases.

 

E. Stephen-Sherwood (US), Aditya Joshi (US), and John Oró (ES-US) produced polynucleotide polymers under primitive Earth conditions (1798).

 

John P. Devlin (CA), Oliver E. Edwards (CA), Paul R. Gorham (CA), Norman R. Hunter (CA), R.K. Pike (CA), and Bozidar Stavric (CA) identified a toxin they derived from Anabaena flos-aquae, and named it anatoxin-a. It turned out to be an alkaloid neurotoxin (321; 490). These poisons, which periodically and fatally contaminate the water supplies of wild and domestic animals, can also harm humans.

Carol Saunderson Huber (CA) had previously determined the chemical structure of the cyanobacterial toxin (anatoxin-a) for the first time (920).

 

K. Peter C. Vollhardt (US) synthesized estrone (1947; 1948).

 

James C. Alwine (US), David J. Kemp (US), and George R. Stark (US) developed a technique for identifying specific RNA fragments following their separation by agarose gel electrophoresis. The technique is called the northern blotting method (45).

Patricia S. Thomas (US) improved this method considerably by electrophoresing the RNA in a denaturing agent to prevent the RNAs from spontaneously folding back and interacting with themselves or bonding to other RNAs (1880).

Peter W.J. Rigby (GB), Marianne Dieckman (US), Carl Rhodes (US), and Paul Berg (US) originated the nick translation reaction as a rapid and efficient method for uniformly labeling double stranded DNA suitable for hybridization studies such as Northern and Southern blots and in situ hybridizations (1567).

 

Salvador Moncada (GB), E. Annie Higgs (GB), and John Robert Vane (GB) discovered that prostacyclin is generated in human arteries and venous tissue. It is postulated that prostacyclin is important for prevention of deposition of platelets on the vessel wall and that the inhibition or prevention of the generation of prostacyclin is important in the genesis of diseases, especially those in which increased lipid peroxidation occurs, such as atherosclerosis (1354).

 

William P. Arnold (US), Chandra K. Mital (US), Shoji Katsuki (US), and Ferid Murad (US) showed that nitrovasodilators and nitric oxide activate guanylyl cyclase to effect smooth muscle relaxation and vasodilation (65).

Robert F. Furchgott (US) and John V. Zawadzki (US) demonstrated that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by acetylcholine requires the presence of endothelial cells, and that acetylcholine, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle (660).

Louis J. Ignarro (US) Russell E. Byrns (US), Georgette M. Buga (US), Keith S. Wood (US) and Gautam Chaudhuri (US) realized that the properties of nitric oxide were the same as those seen in the endothelium derived relaxing factor (940; 941).

Richard M.J. Palmer (GB), Anthony G. Ferrige (GB), and Salvador Moncada (GB) reported that nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor (1469).

 

Gertrude Belle Elion (US), Phillip A. Furman (US), James A. Fyfe (US), Paulo de Miranda (US), Lilia Beauchamp (US), and Howard J. Schaeffer (US) synthesized 9-(2-hydroxyethoxymethyl) guanine, a.k.a. acyclo-Guo or acyclovir or Zovirax (556).

James A. Fyfe (US), Paul M. Keller (US), Phillip A. Furman (US), Richard L. Miller (US), and Gertrude Belle Elion (US) report that acyclo-Guo is phosphorylated at a 30- to 120-fold faster rate in cells infected with Herpes simplex virus than in uninfected cells. They determined that the virus-encoded enzyme thymidine kinase is responsible for this phosphorylation and that phosphorylation is necessary for acyclo-Guo to effectively inhibit virus replication. These results explained why the purine nucleoside analogue is such a potent and specific inhibitor of Herpes simplex virus (662).

David Derse (US), Yung-Chi Cheng (US), Phillip A. Furman (US), Marty H. St. Clair (US), and Gertrude Belle Elion (US) examined the inhibition of highly purified Herpes simplex virus by acyclo-GTP and discovered that it competitively inhibits the incorporation of dGMP into DNA, catalyzed by Herpes simplex virus DNA polymerase. Additionally, l4C-labeled acyclo-GMP residues incorporated into activated DNA by herpes simplex virus-1 DNA polymerase cannot be excised by the polymerase-associated 3',5'-exonuclease activity, thus leading to the prevention of further polymerization (487). Acyclovir became one of the most commonly used antiviral drugs and is primarily used for the treatment of Herpes simplex virus infections, as well as in the treatment of Herpes zoster (shingles).

 

Carl S. Parker (US) and Robert Gayle Roeder (US) reconstructed in a cell-free Xenopus laevis system the correct initiation of transcription by RNA polymerase III (1472).

 

Keiichi Itakura (US), Tadaaki Hirose (US), Roberto Crea (US), Arthur D. Riggs (US), Herbert L. Heynker (NL), Francisco Bolivar (MX), and Herbert Wayne Boyer (US) synthesized the mammalian gene for somatostatin then fused it to the beta-galactosidase gene of Escherichia coli on the plasmid pBR322. Cells of Escherichia coli were then transformed using this chimeric plasmid, which led to the in vivo synthesis of a large polypeptide that included somatostatin. Active somatostatin was then cleaved from the large chimeric protein using cyanogen bromide (953). This represents the first synthesis of a functional polypeptide product from a gene of chemically synthesized origin.

 

John E. Hobbie (US), Ralph J. Daley (US), and Sarah Jasper (US) developed a method for the direct counting of bacteria in natural waters. Bacteria were rapidly stained with acridine orange, filtered onto a Nuclepore filter, and counted with epi- fluorescence microscopy (892).

 

Francisco Bolivar (MX), Raymond L. Rodriquez (US), Patricia J. Greene (US), Mary C. Betlach (US), Herbert L. Heynker (NL), Herbert Wayne Boyer (US), Jorge H. Crosa (US), and Stanley Falkow (US) used in vitro recombination techniques to construct the cloning vehicle pBR322. This plasmid quickly became one of the most popular cloning vehicles (196).

 

William G. Burton (US), Richard J. Roberts (US), Phyllis A. Myers (US), and Ruth Sager (US) discovered a site-specific single-stranded endonuclease from the eukaryote Chlamydomonas (288).

 

Argiris Efstratiadis (GR-US), Fotis Constantine Kafatos (DE), and Thomas Peter Maniatis (US) sequenced an entire cDNA insert, which confirmed the faithful propagation of the cDNA in E. coli and provided the first complete nucleotide sequence of an mRNA (543).

Gek Kee Sim (US), Argiris Efstratiadis (GR-US), C. Weldon Jones (US), Fotis Constantine Kafatos (DE), M. Koehler (US), Henry Morris Kronenberg (US), Thomas Peter Maniatis (US), Jerome C. Regier (US), B.F. Roberts (US), and Nadia Rosenthal (US) constructed a cDNA library and demonstrated the feasibility of using cDNA libraries of complex mRNA populations to obtain individual mRNAs (1738).

 

Elisabeth Ljungquist (SE) and Ahmad Iqbal Bukhari (PK-US) stated that a segment of DNA could transpose from one chromosomal location to another without leaving the original location, and that replicas flit to new sites in the genome without having a discernible independent existence (1212).

 

Robert Lenk (US), Laura Ransom (US), Yael Kaufmann (US), and Sheldon Penman (US) presented strong evidence suggesting an attachment of polyribosomes to the cytoskeleton via mRNA (1164).

 

Marie Lagueux (FR), Michel H. Hirn (FR), and Jules Alphonse Hoffmann (FR) found that ecdysone (a molting hormone) not only stimulates molting and metamorphosis in adult insects, but also regulates molts of the developing embryo. These observations “probably represent the best documented example of a transfer of steroid hormones of maternal origin to the embryo in egg-laying animals” (1123).

 

Holger W. Jannasch (US), Carl O. Wirsen (US), and Edward G. Ruby (US) retrieved undecompressed microorganisms from the deep sea and determined their physiological characteristics (969; 1618; 2043).

 

Per Hellung-Larsen (NL), Sune Frederiksen (NL), Lester Goldstein (US), Gary E. Wise (US), Christine Ko (US), Bernhard J. Benecke (NL), and Sheldon Penman (US) presented evidence for the presence of small nuclear RNA (snRNA) (128; 724; 843).

 

Eric Cundliffe (US) and Julian E. Davies (US) discovered that trichothecene fungal toxins inhibit initiation, elongation, and termination of eukaryotic protein synthesis (438).

 

James Edward Rothman (US), John Lenard (US) and Eugene Patrick Kennedy (US) showed that in Bacillus megaterium newly synthesized cell membrane phospholipids are all added first to the membrane’s cytoplasmic side then some are flipped to the exterior side (1608-1610).

Rosalind Coleman (US) and Robert M. Bell (US) had similar results with eukaryotes (Eucarya) (395; 396).

 

Tom D. Petes (US) and David Botstein (US) determined the mode of inheritance of ribosomal DNA by tetrad analysis in Saccharomyces cerevisiae. Of 14 tetrads analyzed, 12 clearly showed the ribosomal DNA forms segregating as a single Mendelian unit. Their interpretation of this result is that all of the approximately 100 copies of the ribosomal DNA genes of the yeast cell are located on one chromosome and that meiotic recombination within these genes is suppressed (1497). Note: This paper showed the way to locating a gene within a genome. One can use differences (polymorphisms) in DNA sequence as "DNA-sequence-based markers" to map genes.

Tom D. Petes (US) went on to map the location of Saccharomyces cerevisiae ribosomal DNA genes to the left arm of chromosome 12 (1495; 1496).  

Hans Eiberg (DK), Jan Mohr (DK), Dara Kennedy (CA), Natasa Plavsic (CA), Martha Zsiga (CA), Danuta Markiewicz (CA), Gita Akots (US), Cynthia Helms (GB), Thomas Gravius (US), Carol Parker (US), Kenneth Rediker (US), 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 (CA), Manuel Buchwald (CA), Helen Donis-Keller (US), Anthony P. Monaco (US), Corlee J. Bertelson (US), William Middleworth (US), Chris-Anne Colletti (US), John Aldridge (US), Kenneth H. Fischbeck (US), Richard Bartlett (US), Margaret A. Perick-Vance (US), Allen D. Roses (US), Louis M. Kunkel (US), Nancy S. Wexler (US), P. Michael Conneally (US), David Housman (US), and James F. Gusella (US) used restriction fragment length polymorphism (RFLP) for the first genetic mapping and positional cloning of human disease genes (cystic fibrosis, Duchenne muscular dystrophy, and Huntington's disease) (1073; 1353; 1910; 2016).

 

Philip J. Farabaugh (US), Ursula Schmeissner (CH), Murielle Hofer (CH), Jeffrey H. Miller (US), Donald Ganem (US), Ponzy Lu (US), and Albert Schmitz (CH) altered the amino acid composition of the lac repressor protein to determine which amino acids are necessary for the various functions of the complete protein (589; 1342).

 

Leona Samson (US), Hugh John Forster Cairns (GB-US-GB), Penelope Jeggo (US), Martine Defais (US), and Paul Schendel (US) measured the accumulation of mutants in Escherichia coli cells growing continuously in the presence of very low concentrations of mutagens. They showed that the cells could adapt to low levels of alkylating agents and manifest an increased resistance (adaptation) to killing and to mutagenesis by subsequent and higher concentrations of the alkylating. A model of chemically induced mutagenesis based on these findings is presented. It maintains that the observed mutation frequency is dependent on a "race" between these two error-free systems and the two mutagenic pathways agents (971; 1644; 1672). Peter Robins (GB) was an outstanding technician during this work.

Peter Karran (SE), Tomas Lindahl (SE), Beverly Griffin (GB), Bruce Demple (US), Barbara Sedgwick (GB), Peter Robins (GB), Nicholas F. Totty (GB), Michael D. Waterfield (GB), Ian Teo (GB), B. Li (), Michael W. Kilpatrick (GB), Tommie V. McCarthy (GB), Hiroko Kataoka (JP), Yoko Yamamoto (JP), Mutsuo Sekiguchi (JP), Yusaku Nakabeppu (JP), Toshiyuki Miyata (JP), Hidemasa Kondo (JP), Sadaaki, Iwanaga (JP), Shun-ichiro Kawabata (JP), and Yoshiyuki Mine (JP) showed that adaptation to killing results from the enhanced repair of alkylating damage by a DNA glycosylase, one that specifically recognizes certain alkylated bases and is encoded by a gene called alkA. The gene ada (for adaptive response) turned out to be novel in the DNA repair world. Ada protein is endowed with the ability to specifically recognize O⁶-methylguanine and O⁴-methylthymine in DNA. It plucks methyl groups from these (and only these) two positions of these (and only these) two alkylating bases in DNA, transferring them to a specific amino acid residue in the polypeptide. Expression of the ada and alkA genes, both of which are involved in the adaptive response of Escherichia coli to alkylating agents, is positively controlled by Ada protein, the product of the ada gene (481; 1015; 1022; 1023; 1390-1393; 1704; 1870; 1871).

 

Randi Leavitt (US), Sondra Schlesinger (US) Stuart Kornfeld (US), Trudy G. Morrison (US), Catherine O. McQuain (US), Dwight Simpson (US), Ron Gibson (US), Carolyn E. Machamer (US), Robert Z. Florkiewicz (US), John K. Rose (US), Robert W. Doms (US), Aino Ruusala (SE), Jonne Helenius (FI-US-CH), and Ari Helenius (FI-US-CH) have indicated that the glycosylation of proteins within the endoplasmic reticulum is important to their proper folding and intracellular transport (503; 690; 1149; 1247-1249; 1365).

James Edward Rothman (US) and Harvey Franklin Lodish (US) demonstrated that glycosylation of proteins in the endoplasmic reticulum occurs almost immediately as they appear on the lumenal side of the membrane (1611).

 

Urs Rutishauser (US), Jean-Paul Thiéry (FR), Robert Brackenbury (US), Ben-Ami Sela (IL), Gerald Maurice Edelman (US), and W. Einar Gall (US) isolated the neural cell adhesion molecule (NCAM), the first cell-cell adhesion molecule to be purified and characterized (220; 1627-1630; 1876).

Bruce A. Cunningham (US), John J. Hemperly (US), Ben A. Murray (US), Ellen A. Prediger (US), Robert Brackenbury (US), and Gerald Maurice Edelman (US) analyzed the cDNA and cloned the gene for neural cell adhesion molecule (NCAM) (439).

Masatoshi Takeichi (JP) while studying cell adhesion discovered that there are calcium-independent and calcium-dependent adhesion pathways. More importantly, the calcium-dependent mechanism could be protected from trypsinization by calcium. He realized that there is an important calcium-dependent adhesion molecule (1854). This was the first evidence of a cadherin molecule.

Chikako Yoshida (JP) and Masatoshi Takeichi (JP) identified E-cadherin as the first member of a protein family now known to regulate cell adhesion and, consequently, morphogenesis and tissue structure (2086).

 

Susumu Tonegawa (US), Christine Brack (CH), Nobumichi Hozumi (CH), and Rita Schuller (CH) cloned an immunoglobulin variable region gene from mouse embryo (1900).

Ora Bernard (CH), Nobumichi Hozumi (CH), and Susumu Tonegawa (US) determined the nucleotide sequences of the germ line gene as well as a corresponding somatically mutated and rearranged gene coding for a mouse immunoglobulin A, type light chain (145).

 

Arnold Kaplan (US), Daniel T. Achord (US), and William S. Sly (US) were the first to demonstrate that a hexose phosphate, specifically mannose-6-phosphate, is essential for the high affinity and saturable endocytosis of lysosomal hydrolases by cultured cells (1010).

 

Rodolfo R. Llinas (US) demonstrated a direct linkage between the inflow of calcium and the release of neurotransmitter at axon terminals (1213-1215).

 

Frank F. Vincenzi (US) and Martha L. Farrance (US) discovered calmodulin, the calcium activated regulatory protein (1946).

 

Neena B. Schwartz (US) and Cornelia P. Channing (US) presented evidence that porcine follicular fluid contains a non-steroidal substance(s), which they called inhibin, that can block the secretion of follicle stimulating hormone that is secondary to a natural or artificial luteinizing hormone surge. Inhibin is thus a hormone which participates in the regulation of reproductive cycles (1693).

 

Robert P. Casey (US), David Lars Njus (US), George Karoly Radda (GB), P. John Seeley (GB), Peter A. Sehr (GB), Michael F. Beers (US), Sally E. Carty (US), Robert Gahagen Johnson (US) and Antonio Georgio Scarpa (US) demonstrated that ATPase actively drives protons into the chromaffin vesicle and the proton gradient (creating pH and electrical gradients across the vesicle membrane) in turn drives catecholamine uptake (117; 326; 981; 982; 1422). This was the first demonstration of a chemiosmotic mechanism operating in any mammalian organelle other than the mitochondrion.

 

Brigit Rose (US), Ian Simpson (US), and Werner R. Loewenstein (US) demonstrated that calcium ions regulate gap junction permeability in leaves of the simple water plant Egeria densa (1592).

 

Wolfgang Schwarz (US), Philip T. Palade (US), and Bertil Hille (US) introduced the concept of use-dependent block of ion channels by local anesthetics (1694). The finding strongly influenced clinical medicine.

 

Enid W. Silverton (US), Manuel A. Navia (US), and David R. Davies (GB-US) used x-ray crystallographic diffraction data to produce a three-dimensional picture of the myeloma protein (1737).

 

Francis W. Ruscetti (US), Doris A. Morgan (US), and Robert C. Gallo (US) obtained long-term growth (over 13 months) of thymus-derived lymphocytes from numerous normal human bone marrow and peripheral blood cell samples by using a factor present in media obtained from mitogen-stimulated human peripheral blood lymphocytes. PHA, Con A, and pokeweed mitogens stimulated lymphproliferative responses in these cultures comparable to those of fresh peripheral blood cells. These proliferating cells were also able to release cell mediators, such as interferon and colony-stimulating activity. Further evidence for the T lymphocyte nature of these cultured cells was obtained from one-way mixed leukocyte cultures in which these cells responded to but were unable to stimulate allogeneic cells. The functional and morphologic characteristics of these cultured cells show that they are T cells that grow continuously in vitro (1625).

 

Lorenzo Moretta (IT), Susan R. Webb (US), Carlo E. Grossi (IT), Peter M. Lydyard (GB), and Max D. Cooper (US) give the first dissection of human T lymphocytes into phenotypically and functionally distinct subpopulations when they found that peripheral T lymphocytes express either receptors for the Fc portion of IgM or for the Fc portion of IgG. This made it possible to separate cells exerting helper or suppression functions on antibody production (1363).

 

Michael John Bevan (GB-US) asked whether cytotoxic T lymphocytes (CTL) from a normal mouse can respond quantitatively as well to antigen plus foreign H–2 as they do to antigen plus self H–2. These experiments were designed to test this influence. The results suggest that host H–2 antigens do exert an effect on the specificity of T-cell responses (160).

Note: Cell membrane structures controlled by genes in the major histocompatibility complex (H–2 in mice) are involved in most immune interactions between T lymphocytes and other cells.

 

Alan F. Williams (AU), Giovanni Galfrè (IT), and César Milstein (AR-GB) were the first to identify a CD4 (clusters of differentiation) antigen. They used W3/25 monoclonal antibody to identify this antigen on rat lymphocytes (2030).

Robert A.H. White (GB), Donald W. Mason (GB), Alan F. Williams (GB), Giovanni Galfrè (IT), and César Milstein (AR-GB) identified the W3/25 antigen as a CD4 marker on a subpopulation of lymphocytes, the T helper lymphocytes. This was also a first such identification (2017).

Ellis L. Reinherz (US), Patrick C. Kung (US), Gideon Goldstein (US), and Stuart F. Schlossman (US) were the first to identify a CD4 antigen on human lymphocytes (1556).

Patrick C. Kung (US), Gideon Goldstein (US), Ellis L. Reinherz (US), and Stuart F. Schlossman (US) used monoclonal antibodies to define distinctive human T cell surface antigens (1115).

 

Guenter Albrecht-Buehler (DE-CH-US) developed a technique he called a biological "cloud chamber" in which he studied cells as they migrated on a glass surface coated with colloidal gold particles. Because sister cells made symmetrical patterns (mirror image tracks) following division it suggested that cell migration is programmed (27).

 

Howard Michael Goodman (US), Maynard V. Olson (US), Benjamin D. Hall (US), Pablo Valenzuela (CL-US), Alejandro Venegas (CL), Fanyela Weinberg (US), Robert Bishop (US), and William J. Rutter (US) discovered transfer RNA (tRNA) introns in yeast (730; 1927).

 

Louise T. Chow (CN-US), Richard E. Gelinas (US). Tom R. Broker (US), Richard John Roberts (US), James M. Roberts (US), Daniel F. Klessig (US), Ashley R. Dunn (AU), John A. Hassell (US), James B. Lewis (US), Carl W. Anderson (US), John F. Atkins (IE), Susan M. Berget (US), Claire Moore (US), Phillip Allen Sharp (US), B. Sayeeda Zain (US), Arnold J. Berk (US), and Timothy J. Harrison (GB) all played a part in the fascinating discovery that in adenovirus 2, coding regions (exons) genes may be interrupted by non-coding regions (introns). This was the first indication that normal genes can exist as several, well-separated segments. The gene would produce a large mRNA which prior to translation must be cut and spliced (141; 142; 249; 365-367; 518; 1066; 1181). Note: This work represents the discovery of RNA splicing and genes in pieces; the intron and mRNA splicing.

Richard Breathnach (FR), Jean-Louis Mandel (FR), and Pierre M. Chambon (FR) discovered that eukaryotic genes have their coding sequences (exons) interrupted by noncoding sequences (introns) (228).

 

Matthew A. Harmey (GB), Gerhard Hallermayer (DE), Harald Korb (DE), and Walter Neupert (DE) discovered how proteins are transported into mitochondria (816; 1089).

Gottfried Schatz (AT-CH), Maria-Luisa Maccecchini (US), and Yvonne Rudin (CH) discovered how proteins are transported into mitochondria (1244; 1670).

 

Clay M. Armstrong (US) and Francisco Bezanilla (US) proposed a model, which became known as the ball-and-chain hypothesis, to explain the three-dimensional structure of voltage-gated channels in cell membranes (64).

 

Satoshi Ōmura (JP), Yuzuru Iwai (JP), Atsushi Hirano (JP), Akira Nakagawa (JP), Juichi Awaya (JP), Hisae Tsuchiya (JP), Yoko Takahashi (JP), and Rokurou Asuma (JP) isolated and characterized the antifungal antibiotic staurosporine from Streptomyces staurosporeus (1452).

Urs T. Ruegg (CH) and Gillian M. Burgess (GB) showed that this alkaloid— staurosporine— is cell permeable and exhibiting anti-cancer activity. It is a potent, non-selective inhibitor of protein kinases, including protein kinase C (1621).

Miguel Weil (GB), Michael D. Jacobson (US), Harriet S.R. Coles (GB), Tim J. Davies (GB), Richard L. Gardener (GB), Karl D. Raff (GB), and Martin C. Raff (CA-GB) reported that staurosporine induces apoptosis in all cells that possess an intact death pathway (2002).

 

Gerry C. Johnston (US), John R. Pringle (US), and Leland Harrison Hartwell (US) found in Saccharomyces cerevisiae that growth is integrated with the division cycle prior to budding, at the CDC28 and CDC33 (cell division cycle genes 28 and 33) step. This suggested that the growth cycle coupled to the cell cycle precisely at the initiation of the cell cycle (G₁ phase). They demonstrated that in yeast the cell cycle depends on the growth cycle and that the reverse dependency does not operate. In addition, they showed that at least one step in the cell cycle—the initiation step, or the G₁-S transition—depended on the cell's attaining a certain size (984).

 

Natalie M. Teich (US), Robin A. Weiss (US), Gail R. Martin (US), and Douglas R. Lowy (US) noted that murine leukemia virus (MLV) is not transcriptionally active in murine embryonal carcinoma stem cells, but that during differentiation into somatic cells MLV genes begin to be expressed (1869).

Daniel Wolf (US) and Stephen P. Goff (US) determined that the suppression of MLV in murine embryonal carcinoma stem cells is largely explained by the restriction factor TRIM28 binding to the MLV LTR via the zinc finger protein, ZFP809 (2052).

Chao-Nan Ting (US), Michael P. Rosenberg (US), Claudette M. Snow (US), Linda C. Samuelson (US), and Miriam H. Meisler (US) discovered that the activation of human salivary amylase genes in the human parotid gland is controlled by a retroviral insertion, which occurred during Old World primate evolution (1888).

 

Roy Curtiss III (US), Matsuhisa Inoue (US), Dennis A. Pereira (US), J. Charles Hsu (US), Laura Alexander (US), and Lynn Rock (US) developed the first safe strain of bacteria for use in recombinant DNA biotechnology. It was a strain of Escherichia coli K12 designated c1776 in honor of the American bicentennial (440).

 

Hugh Platt (GB), John G. Atherton (GB), D.J. Simpson (GB), C.E.D. Taylor (GB), R.O. Rosenthal (GB), Derek F.J. Brown (GB), and Tim G. Wreghitt (GB) isolated a previously unknown bacterium responsible for a major outbreak of a highly contagious genital infection in thoroughbred horses. The disease was christened Contagious Equine Metritis (CEM). To date it has not been found to fit any known taxonomic group (1513).

 

Steven Gillis (US) and Kendall A. Smith (US) reported they had succeeded in establishing long-term cultures of T cells using a lymphocyte-conditioned medium (701).

 

Giovanni Galfrè (IT), Shirley C. Howe (GB), César Milstein (AR-GB), Geoffrey W. Butcher (GB), and Jonathan C. Howard (GB) were the first to demonstrate the usefulness of monoclonal antibodies for identification, and eventually purification, of specific antigens (667).

 

Gordon Hisashi Sato (US), Sharon E. Hutchings (US), Reen Wu (US), Jennie P. Mather (US), David W. Barnes (US), and Richard A. Wolfe (US) showed that different cell lines require different mixtures of hormones and growth factors to grow in serum-free medium (98; 99; 931; 1297; 1659; 2053; 2066).

 

Axel Ullrich (US), John Shine (US), John Chirgwin (US), Raymond Pictet (US), Edmund Tischer (US), William J. Rutter (US), and Howard Michael Goodman (US) constructed recombinant bacterial plasmids containing complementary DNA prepared from rat islets of Langerhans messenger RNA, i.e., rat insulin genes (1920).

Lydia Villa-Komaroff (US), Argiris Efstratiadis (GR-US), Stephanie Broome (US), Peter Lomedico (US), Richard Tizard (US), Stephen P. Naber (US), William L. Chick (US), and Walter Gilbert (US) cloned double-stranded cDNA copies of a rat pre-proinsulin messenger RNA in Escherichia coli _X1776 with the result that it was expressed as proinsulin (1945).

Scientists at Genentech and City of Hope inserted synthetic genes carrying the genetic code for human insulin, along with the necessary control mechanism, into an E. coli bacterial strain, which is a laboratory derivative of a common bacterium, found in the human intestine. Once inside the bacteria, the genes were "switched-on" by the bacteria to translate the code into either "A" or "B" protein chains found in insulin. The separate chains were then joined to construct complete insulin molecules. This is from a 1978 press release.

David VanNorman Goeddel (US), Dennis G. Kleid (US), Francisco Bolivar (MX), Herbert L. Heynker (NL), Daniel G. Yansura (US), Roberto Crea (US), Tadaaki Hirose (US), Adam Kraszewski (US), Keiichi Itakura (US), and Arthur D. Riggs (US) induced Escherichia coli, a bacterium that normally populates the human intestinal tract, to produce human insulin. Unfortunately, their method could not produce insulin in quantities sufficient for commercial manufacturing (713).

Karen Talmadge (US), James F. Kaufman (US), and Walter Gilbert (US) were able to insert the gene for rat pre-proinsulin into Escherichia coli in such a way that the bacterium expressed the gene then processed the pre-proinsulin to proinsulin as it was excreted (1856).

Human insulin (Humulin) became the first recombinant DNA drug approved by the FDA (9).

Humalog, a fast acting, chemically modified human insulin was introduced in 1996. Humalog differs from human insulin in that the amino acids at positions 28 and 29 on the insulin-chain are reversed.

 

Fredrick R. Blattner (US), Bill G. Williams (US), Ann E. Blechl (US), Katherine Denniston-Thompson (US), Harvey E. Faber (US), Lesley-Anne Furlong (US), David J. Grunwald (US), Delight O. Kiefer (US), David D. Moore (US), James W. Schumm (US), Edward L. Sheldon (US), Oliver Smithies (GB-US), Philip Leder (US), David C. Tiemeier (US), and Lynn W. Enquist (US) were the first to use disabled lambda virus as a vector for cloning foreign DNA (182; 1150).

 

Mario Rizzetto (IT), Maria G. Canese (IT), Sarino Arico (IT), Osvaldo Crivelli (IT), Ferruccio Bonino (IT), Christian G. Trepo (IT), and Giorgio Verme (IT) discovered hepatitis delta virus (HDV) infections while studying chronic carriers of hepatitis B virus (1572). An HDV infection absolutely requires an associated HBV infection. The outcome of disease largely depends on whether the two viruses infect simultaneously (coinfection), or whether the newly HDV-infected person is a chronically infected HBV carrier (superinfection).

 

Peter Upcroft (AU), F. Ziemer (), Hagit Skolnik (IL), and George C. Fareed (US) used papovaviruses as vehicles for the transduction of foreign genes into mammalian cells (1923).

 

Michael F. Clark (GB) and Anthony N. Adams (GB) described how the new serodiagnostic method, enzyme-linked immunosorbent assay (ELISA), could be used to detect plant viruses. Morphologically different plant viruses were detected in purified preparations and in unclarified extracts of infected plants. Virus concentration in the samples was proportional to the color intensity of the enzyme- hydrolysed substrate (374).

Robert H. Yolken (US), HyunWha Kim (US), Thomas Clem (US), Richard G. Wyatt (US), Anthony R. Kalica (US), Robert Merritt Chanock (US), and Albert Zaven Kapikian (US) developed an enzyme-linked immunosorbent assay (ELISA) for the detection of the human reovirus-like agent of infantile gastroenteritis in human stools (2084).

 

 Robert A. Swanson (US), a venture capitalist, and biochemist Dr. Herbert W. Boyer (US), after a meeting in 1976, decided to start the first biotechnology company, Genentech.

 

Anton Lang (RU-US), Mikhail Khristoforovich Chailakhyan (RU), and I.A. Frolova (RU) demonstrated that graft-transmissible inhibitors of flower formation (antiflorigens) are formed in non-induced leaves (1132).

 

Harry L. Malech (US), Richard K. Root (US), and John I. Gallin (US) made neutrophils switch their direction, and thus found that microtubules orient and organize the internal structure of migrating cells (1266).

 

Howard Green (US), James G. Rheinwald (US), and Tung-Tien Sun (US) suggested that epithelial cells in general may not be independent cell types and that their poor cultivability may be due to failure to provide suitable fibroblast support. The existence of a number of established lines of epithelial origin that can grow without such support and of lines of fibroblastic origin which cannot support keratinocytes suggests that both epithelial dependence and the fibroblast supporting function can sometimes be lost in established cell lines (756).

 

Denis Gospodarowicz (US), John S. Moran (US), and Debra L. Braun (US) purified the fibroblast growth factor (FGF) and found it to be a potent endothelial mitogen (736). For the first time, large quantities of endothelial cells could be grown for use in experiments.

Daniele Brouty-Boye (US) and Bruce R. Zetter (US) were the first to report implications of interferons as possible anti-endothelial or antiangiogenic agents. The results were instrumental in the decision, some years later, to treat and cure life threatening childhood hemangiomas with daily low-dose, chronic interferon-alpha (253).

Thomas Maciag (US), Gayle A. Hoover (US), Michael B. Stemerman (US), and Robert Weinstein (US) showed that inclusion of an endothelial cell growth factor (ECGF) from bovine brain resulted in maximal proliferation of endothelial cells and achieved the 'Hayflick limit' the marker of cell senescence (1250).

Thomas Maciag (US), Julian L. Kadish (US), Leon M. Wilkins (US), Michael B. Stemerman (US), and Robert Weinstein (US) discovered that by withholding ECGF and fibronectin, they can spur endothelial cells in culture to roll up into tiny tubes. Within a month to six weeks, the tubes will branch into a complex network, creating the beginnings of a capillary tree right there in the culture dish (1251).

Joseph A. Madri (US), Stuart K. Williams (US), T. Wyatt (US), and Christine Mezzio (US) showed that collagens from the basement membrane, which sheaths the endothelial cells in a capillary, prompted rapid tube formation (1254).

Stephanie Taylor (US) and Moses Judah Folkman (US) showed protamine to be a specific inhibitor of angiogenesis. The compound inhibits the capillary proliferation observed in embryogenesis, inflammation, certain immune reactions, and the growth of solid tumors. This paper also reports the discovery that platelet factor-4 (PF-4) is an angiogenesis inhibitor (1866).

Susan C. Thornton (US), Stephen N. Mueller (US), and Elliot M. Levine (US) found that heparin synergized with the endothelial cell growth factor (ECGF), a seminal finding that led to the rapid identification of ECGF as FGF-1 (1884).

Yuen Shing (US), Moses Judah Folkman (US), Robert C. Sullivan (US), Catherine Butterfield (US), Joseph Murray (US), and Michael Klagsbrun (US) performed the first complete purification of a tumor-derived angiogenic endothelial growth factor. The factor turned out to be identical to basic FGF (1731). Heparin-affinity of FGF has turned out to be important for the function of the peptide. Before this paper, there were no molecules of any kind in the field of angiogenesis research and it was known primarily as a descriptive field.

Rosa Crum (US), Sandor Szabo (US), and Moses Judah Folkman (US) announced their discovery of angiostatic steroids: a new class of steroids that have only angiostatic function (433).

Farzan Rastinejad (US), Peter J. Polverini (US), and Noel P. Bouck (US) identified an inhibitor of angiogenesis in secretions of hamster cells and hamster-human hybrids whose activity was regulated by a cancer suppressor gene segregating transformants and revertants. The inhibitory activity was later identified as thrombospondin-1. This was the first example of control of the activity of an inhibitor of neovascularization as one function of a tumor suppressor gene that laid ground for further work on the genetic regulation of angiogenesis (1543).

Deborah J. Good (US), Peter J. Polverini (US), Farzan Rastinejad (US), Michelle M. Le Beau (US), Richard S. Lemons (US), William A. Frazier (US), and Noel P. Bouck (US) called attention to thrombospondin as an important angiogenesis inhibitor (727).

Donald Ingber (US), Takeshi Fujita (JP), Shoji Kishimoto (JP), Katsuichi Sudo (JP), Tsuneo Kanamaru (JP), Harold Brem (US), and Moses Judah Folkman (US) discovered the first non-toxic angiogenesis inhibitor that exhibited potent enough, wide-spectrum activity to warrant entry into human clinical trials. This established angiogenesis inhibition as a valid and generic approach for anticancer therapy (943).

Marsha A. Moses (US), Judith Sudhalter (US), and Robert S. Langer (US) reported the first purification of a cartilage-derived angiogenesis inhibitor (1368).

Kristina M. Dameron (US), Olga V. Volpert (US), Michael A. Tainsky (US), and Noel P. Bouck (US) were the first to connect specific mutated tumor suppressor genes, in this case p53, with induction and regulation of tumor angiogenesis. The mechanism involved here is through down-regulation of an endogenous angiogenesis inhibitor, namely thrombospondin-1. This study accelerated the field of natural inhibitors of angiogenesis and was instrumental in formulating the hypothesis that tumor angiogenesis is switched by a change in the balance of stimulators and inhibitors (448).

Peter C. Maisonpierre (US), Chitra Suri (US), Pamela F. Jones (US), Sona Bartunkova (US), Stanley J. Wiegand (US), Czeslaw Radziejewski (US), Debra L. Compton (US), Joyce McClain (US), Thomas H. Aldrich (US), Nick Papadopoulos (US), Thomas J. Daly (US), Samuel Davis (US), Thomas N. Sato (US), George D. Yancopoulos (US), Donald M. McDonald (US), Hao Zhou (US), Eben H. Oldmixon (US), Daniel J. Dumont (CA), Gérard Gradwohl (FR), Guo-Hua Fong (CA), Mira C. Puri (CA), Marina Gertsenstein (CA), Anna Auerbach (CA), Martin L. Breitman (CA), YuzuruTozawa (US), Urban Deutsch (DE), Karen Wolburg-Buchholz (DE), Yuko Fujiwara (US), Maureen Gendron-Maguire (US), Thomas Gridley (US), Hartwig Wolburg (DE), Werner Risau (DE), and Ying Qin (US) described angiopoietins 1 and 2 as natural antagonists and identified the Tie1 and Tie2 receptors as critical for embryonic angiogenesis (517; 1264; 1660; 1831).

Michael S. O'Reilly (US), Lars Holmgren (US), Yuen Shing (US), Catherine Chen (US), Rosalind A. Rosenthal (US), Marsha A. Moses (US), William S. Lane (US), Yihai Cao (US), E. Helene Sage (US), Moses Judah Folkman (US) identified a new natural inhibitor of angiogenesis, showed that its presence in the circulation is sufficient to hold metastases in check, and suggested that in vivo angiogenesis is regulated by the balance between circulating inducers and inhibitors of neovascularization. In addition, this work provided a theoretically satisfying explanation for the old clinical observation that some nests of metastatic tumor cells grow to clinical significance only after the large primary tumor from which they came has been removed (1436).

Robert J. d'Amato (US), Michael S. Loughman (US), Evelyn Flynn (US), Moses Judah Folkman (US) performed a study instrumental to initiating large numbers of oncology clinical trials using thalidomide as an antiangiogenic agent, including in multiple myeloma patients (443).

Chitra Suri (US), Pamela F. Jones (US), Sybil Patan (US), Sona Bartunkova (US), Peter C. Maisonpierre (US), Samuel Davis (US), Thomas N. Sato (US), and George D. Yancopoulos (US) identified angiopoietin-1, a ligand for the receptor tyrosine kinase Tie2, as another cytokine critical for embryonic angiogenesis (1830).

Michael S. O'Reilly (US), Thomas Boehm (US), Yuen Shing (US), Naomi Fukai (US), George Vasios (US), William S. Lane (US), Evelyn Flynn (US), James R. Birkhead (US), Bjorn R. Olsen (US), Moses Judah Folkman (US) discovered endostatin, a cleavage fragment of collagen XVIII (1435).

Lois E.H. Smith (US), John J. Kopchick (US), Wen Chen (US), Joanne Knapp (US), Fumi Konose (US), Douglas Daley (US), Eliot Foley (US), Roy G. Smith (US), and James M. Schaeffer (US) demonstrated that growth hormone controls neovascularization through insulin-like growth factor–1 (IGF-1), laying the groundwork for subsequent work showing that IGF-1 supports vascular endothelial growth factor (VEGF) proliferation and survival signaling (1756).

 

William Martin (US), Gina M. Villani (US), Desingarao Jothianandan (US), Kazuki Matsunaga (US), Robert F. Furchgott (US), Carl A. Gruetter (US), Barbara K. Barry (US), Dennis B. McNamara (US), Philip J. Kadowitz (US), Louis Joseph Ignarro (US), Darlene Y. Gruetter (US), William H. Baricos (US), Albert L. Hyman (US), Shoji Katsuki (JP), William P. Arnold (US), Chandra K. Mittal (US), Robert M. Rapoport (US), and Ferid Murad (US) began research which led to discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system (658; 659; 782; 783; 1024; 1294; 1300; 1301; 1542).

Shoji Katsuki (US), William P. Arnold (US), Chandra K. Mittal (US), and Ferid Murad (US) tested the hypothesis that nitroglycerin acts through the release of nitric oxide by allowing NO gas to bubble through a tissue preparation containing guanylate cyclase, a.k.a. guanylyl cyclase, a.k.a. guanyl cyclase. The production of cGMP increased. A new mode of action for drugs, to activate enzyme function was discovered. After more than 100 years of successful treatment of angina with nitroglycerin, the working principle was finally revealed. Nitroglycerin and related vasodilating compounds act by releasing nitric oxide, which relaxes smooth muscle cells (65; 1024).

 

Joe W. Kiceniuk (CA) and David R. Jones (CA) provided the first truly complete quantitative description of oxygen transport in the steady state at various swimming speeds of the rainbow trout. The relevant changes in ventilation, the cardiovascular system, and the blood gases had not been measured simultaneously until this study (1042).

 

Patrick J. Butler (CA), Nigel H. West (CA), and David R. Jones (CA) were the first to comprehensively characterize the basic cardiorespiratory parameters of a population of homing pigeons at calm rest and during steady wind tunnel flight under defined conditions (294).

 

John G. Bartlett (US), Andrew B. Onderdonk (US), Ronald L. Cisneros (US), and Dennis L. Kasper (US) carried out animal studies implicating Clostridium difficle as the major cause of antibiotic-associated colitis. It was later shown by others that this is also true in humans. This organism produces a protein cytotoxin whose cytopathology is poorly understood. Colitis is one of the most frequent and potentially severe adverse reactions associated with antibiotic therapy. Vancomycin is the drug of choice in treatment (102).

 

Michael R. Jacobs (ZA), Hendrik J. Koornhof (ZA), Roy M. Robins-Browne (AU), Carolyne M. Stevenson (ZA), Zoe A. Vermaak (GB), Ida Freiman (ZA), G. Bennie Miller (ZA), Maurice A. Witcomb (ZA), Margaretha Isaacson (ZA), Joel I. Ward (US) and Robert Austrian (US) reported pneumococci resistant to multiple antibiotics in Johannesburg, South Africa during July of 1977 (962).

 

Robert E. Weibel (US), Philip P. Vella (US), Arlene A. McLean (US), Allen F. Woodhour (US), Wallace L. Davidson (US), and Maurice Ralph Hilleman (US) developed a polyvalent pneumococcal vaccine (1998).

 

David Warshauer (US), Elliot Goldstein (US), Thomas G. Akers (US), William Lippert (US), M. Kim (US), George J. Jakob (US), Glenn A. Warr (US), and Mardel E. Knight (US) reported that influenza A viral infections can cause increased susceptibility to bacterial and fungal superinfections coincident with depressed metabolic and bactericidal activities of circulating and alveolar phagocytic cells (967; 1983).

 

Dhiman Barua (IN) and A.S. Paguio (PH) found that cholera appears more frequently among people with type O blood (105).

 

Allen C. Steere (US), Stephen E. Malawista (US), David R. Snydman (US), Robert E. Shope (US), Warren A. Andiman (US), Martin R. Moss (US), and Francis M. Steele (US) reported lyme arthritis, characterized by short, recurrent attacks of asymmetric oligo-articular pain and swelling of the large joints (1791).

Louis A. Magnarelli (US), John F. Anderson (US), Robert N. Philip (US), Elizabeth A. Caspar (US), Willy Burgdorfer (US), Alan G. Barbour (US), Stanley F. Hayes (US), Jorge L. Benach (US), Edgar Grunwaldt (US), and Jeffrey P. Davis (US) detected a treponema-like spirochete in and isolated it from adult Ixodes dammini, the incriminated tick vector of Lyme disease and showed antibody formation in patients with clinically diagnosed Lyme disease (280; 1258).

Allen C. Steere (US), Robert L. Grodzicki (US), Arnold N. Kornblatt (US), Joseph E. Craft (US), Alan G. Barbour (US), Willy Burgdorfer (US), George P. Schmid (US), Eric Henry Johnson (US), and Stephen E. Malawista (US) described the causative agent and named it Borrelia burgdorferi in honor of Willy Burgdorfer (1790). See Arvid Afzelius, 1910.

 

John C. Hobbins (US) and Maurice J. Mahoney (US) performed a total of 34 fetoscopic procedures in 28 patients whose fetuses were at risk for hemoglobinopathies (22 cases) or short-limbed dwarfism (three cases). An adequate sample of fetal blood for study of globin-chain synthesis was obtained in 23 of the 25 cases (92 per cent), and valuable diagnostic information was obtained in all three cases at risk for an anomalous fetus. Data from this series suggested that fetoscopy is associated with low maternal and fetal morbidity (894).

Maurice J. Mahoney (US), John C. Hobbins (US) and Leon E. Rosenberg (US) used ultrasonoggraphy for indirect definition and fetoscopy for direct viewing of fetal anatomy in the attempt to establish or exclude the presence of certain morphologic abnormalities in the second trimester (1262).

 

 Lawrence H. Einhorn (US) and John Donohue (US) treated fifty patients with disseminated testicular cancer using a three-drug combination consisting of cis-diamminedichloroplatinum, vinblastine, and bleomycin. This chemotherapy regimen produced 74% complete and 26% partial remissions. The authors believe this regimen represents a major advance in the management of patients with disseminated testicular cancer (549).

Frank M. Schabel, Jr. (US), Mary W. Trader (US), W. Russell Laster, Jr. (US), Thomas H. Corbett (US), and Daniel P. Griswold, Jr, (US) used cis-dichlorodiammineplatinum(II) in combination chemotherapy and cross-resistance studies with tumors of mice (1666).

Stephen D. Williams (US), Lawrence H. Einhorn (US), F. Anthony Greco (US), Robert Oldham (US), and Ronald Fletcher (US) treated 33 patients with VP-16-213 alone or in combination with cis-platinum, bleomycin, and frequently Adriamycin. All patients had prior chemotherapy, which in most was extensive. There were 14 complete and 15 partial remissions from advanced refractory germinal neoplasms (2032).

Stephen D. Williams (US), Robert Birch (US), Linda Irwin (US), F. Anthony Greco (US), Patrick J. Loehrer (US), and Lawrence H. Einhorn (US), from their experiments, concluded that etoposide with cisplatin and bleomycin is superior to vinblastine with cisplatin and bleomycin in the treatment of disseminated germ-cell tumors because of diminished neuromuscular toxicity and better efficacy among patients with advanced disease (2031).

 

Virgil Craig Jordan (GB), building on earlier work on oophorectomy and estrogen removal as a treatment for breast cancer, showed tamoxifen to inhibit growth of mammary tumors in mice, leading to its approval for treatment of breast cancer. It was also shown that tamoxifen was a selective estrogen receptor modulator (SERM), acting in opposition to estrogen in some tissues but acting like estrogen in others (993).

 

Isaiah J. Fidler (US) and Margaret L. Kripke (US) took individual cells from a tumor and transplanting them into mice showed that not all cells can form new tumors and only some cells within a tumor may be capable of metastasis (611).

 

A. Ja Lysenko (RU), Andrei E. Beljaev (RU), and V.M. Rybalka (RU) formulated a theory on the polymorphism of Plasmodium vivax sporozoites. They found that patterns of distribution of manifestations of tertian malaria among the population may readily be explained on the basis of the theory of polymorphism of sporozoites (1243; 1631).

 

Christoph Bernoulli (CH), Jean Siegfried (CH), G. Baumgartner (CH), Franco Regli (CH), Theodore Rabinowicz (US), Daniel Carleton Gajdusek (US), Clarence Joseph Gibbs, Jr. (US), David M. Asher (US), Paul W. Brown (US), Arwind Diwan (US), Paul M. Hoffman (US), George Nemo (US), Robert Rohwer (US), and Lon White (US) reported that Creutzfeldt-Jakob disease (CJD) was iatrogenically transmitted to patients undergoing brain surgery by electrodes previously used on a CJD patient. The electrodes had been sterilized (149; 665).

Elias E. Manuelidis (US), Jean N. Angelo (US), Edward J. Gorgacz (US), Jung H. Kim (US), and Laura Manuelidis (US) reported that CJD had been transmitted via a corneal transplant (1286).

 

John S. Najarian (US), David E. R. Sutherland (US), Arthur J. Matas (US), Michael W. Steffes (US), Richard L. Simmons (US), and Frederick C. Goetz (US) performed the first transplantation of human, insulin producing, islet cells (1389).

 

Vijay V. Kakkar (IN-GB), T.P. Corrigan (GB), D.P. Fossard (GB), I. Sutherland (GB), M.G. Shelton (GB), and J. Thirlwell (GB) investigated and verified the efficacy of low-dose heparin to prevent fatal postoperative pulmonary embolism (1002).

 

Thomas Dale Stewart (US), at Shanidar cave in Iraq, discovered that Shanidar I, a Neanderthal male (c. 47,000 BCE), has an underdeveloped right shoulder blade, collar bone, and upper right arm bone. He believes that Shanidar I was crippled, with a useless right arm, which had been amputated in life just above the elbow (1802). This is surely one of the earliest examples of surgery.

 

James F. Fixx (US) popularized jogging to promote physical fitness (627).

 

Thomas Richard Edmund Southwood (GB) reasoned that since ecological strategies evolve from the interaction of the habitat and organisms “a sort of ecological periodic table” might be constructed with a set of key habitat characteristics, or “habitat templets,” as the organizing elements (1773).

 

Rupert Riedl (AT) discusses a systems-analytical approach to complex systems/phenotype/constraint theory (1566).

 

Francois Jacob (US) wrote a 'perspective' essay that puts together many modern themes around the notion of "hierarchy" in evolutionary biology. He sees much of evolution as "tinkering," that is, working with available traits. "Tinkering" includes (but is not limited to) shifts in function (959).

 

Joseph H. Connell (US) and Ralph O. Slatyer (US) attempted a codification of mechanisms of succession in natural communities and their role in community stability and organization. They proposed that there were 3 main modes of successional development. These sequences could be understood in the context of the specific life-history theories of the individual species within an ecological community. The key factor distinguishing the three models is how the process of succession affects the original, pioneer species (i.e. their relative success in later-successional stages) (408).

 

Aldo Starker Leopold (US) in this comprehensive book summarizes what is known about the history, biology, and management of the California Quail. "The California Quail" is the definitive work on this beautiful bird (1165).

 

John Philip Grime (GB) suggested that evolution in plants might be associated with the emergence of three primary strategies, each of which may be identified by reference to several characteristics including morphological features, resource allocation, phenology, and response to stress. The competitive strategy prevails in productive, relatively undisturbed vegetation, the stress-tolerant strategy is associated with continuously unproductive conditions, and the ruderal strategy is characteristic of severely disturbed but potentially productive habitats (771). This is known as the CSR theory of plant strategies.

 

Marvin J. Allison (US), Enrique Gerszten (US), A. Julio Martinez (US), David M. Klurfeld (US), and Alejandro Pezzia (PE) discovered that a young female pre-columbian mummy of the Huari culture, c. 900, in Peru seems to represent one of the earliest cases of collagen disease, with many aspects compatible with systemic lupus erythematosus (SLE) (32).

 

Don W. Davis (CA), John Gray (CA), George L. Cumming (CA), and Halfdan Baadsgaard (CH-CA) determined the time constant for the decay of rubidium 87 to strontium 87. This became one of the standard radiometric dating methods. It has a 48.9 ± 0.4 billion-year half-life (458).

 

1978

“The question of interest is no longer whether human social behavior is genetically determined; it is to what extent.” Edward Osborne Wilson (2037).

 

“Finally, it must be acknowledged that the initial pursuit of ideas is more dependent upon the stimulus provided in an academic environment than upon research funding; as none was sought, received, nor required for this study to be undertaken. This may serve to emphasize how important it is to encourage and support young investigators in the pursuit of their ideas, which at the outset may well make few or little demands on the resources of many academic institutions.” Michael C. Brain (224).

 

Peter D. Mitchell (GB) was awarded the Nobel Prize in Chemistry for his contribution to the understanding of biological energy transfer through the formulation of the chemiosmotic theory.

 

Werner Arber (CH), Daniel Nathans (US), and Hamilton Othanel (US) were awarded the Nobel Prize in Physiology or Medicine for the discovery of restriction enzymes and their application to problems of molecular genetics.

 

Cristina Glad (SE) and Anders O. Grubb (SE) introduced a new simple and rapid method for immunochemical quantitation called immunocapillarymigration. It is based upon the attachment of antibodies to a porous insoluble support and the subsequent capillary migration of the antigen-containing solution in the porous support (709).

 

John Oró (US), E. Stephen-Sherwood (US), Joseph Eichberg (US), and Dennis E. Epps (US) reported the synthesis of phospholipids under primitive Earth conditions (1454).

 

Noam Lahav (IL), David White (US), and Sherwood Chang (US) experimentally produced peptide bonds under conditions where clay, water, and amino acids were subjected to cyclic variations in temperature and water content (1124).

 

 J. Denis McGarry (US), Guy P. Mannaerts (BE), and Daniel W. Foster (US) discovered that malonyl-CoA is not just a metabolic intermediate, but also a key signaling molecule for the regulation of long-chain fatty acid oxidation (1316).

 

Stephen C. Harrison (US), Arthur J. Olson (US), Clarence Schutt (GB), Fritz K. Winkler (DE), and Gerard Bricogne (GB) determined the atomic structure of a plant virus ( tomato bushy stunt virus) (821).

James M. Hogle (US), Marie Chow (US), and David J. Filman (US) presented the three-dimensional structure of poliovirus at 2.9 A resolution (901).

Michael G. Rossmann (US), Edward Arnold (US), John W. Erickson (US), Elizabeth A. Frankenberger (US), James P. Griffith (US), Hans-Jürgen Hecht (DE), 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) reported the first atomic resolution structure of an animal virus, human rhinovirus 14. It is strikingly similar to known icosahedral plant RNA viruses (1606).

 

James Ephraim Lovelock (GB), Lynn Margulis (US), and Andrew Watson (GB) proposed what became known as the Gaia hypothesis, suggesting that life stabilizes the Earth’s atmosphere which otherwise contains an extraordinary and unstable mixture of gases. Life on Earth not only contributes to the atmosphere, but also helps stabilize it—keeping it at a constant composition, and at a level favorable for life (1230-1232; 1234; 1988).

 

David Shortle (US) and Daniel Nathans (US) developed a method for generating viral mutants with base substitutions in preselected regions of the viral genome: local mutagenesis (1735).

 

Dietmar Kamp (DE), Regine Kahmann (DE), David Zipser (US), Tom R. Broker (US), and Louise T. Chow (CN-US) discovered that the host range of bacteriophage Mu is determined by G-loop inversion (1003).

 

Francis P. Tally (US), Nilda V. Jacobus (US), Sherwood Leslie Gorbach (US), Susanne S. Weaver (US), Gerald Paul Bodey (US), Barbara M. LeBlanc (US), Jean S. Kahan (US), Frederick M. Kahan (US), Robert T. Goegelman (US), Sara A. Currie (US), Marion Jackson (US), Edward O. Stapley (US), Thomas W. Miller (US), A.K. Miller (US), David Hendlin (US), Sagrario Mochales (ES), S. Hernandez (US), Harold Boyd Woodruff (US), Jerome Birnbaum (US), Georg Albers-Schönberg (US), Byron H. Arison (US), Otto D. Hensens (US), Jordan Hirshfield (US), Karst Hoogsteen (US), Edward A. Kaczka (US), Robert E. Rhodes (US), Frederick M. Kahan (US), Ronald W. Ratcliffe (US), Edward Walton (US), Linda J. Ruswinkle (US), Robert B. Morin (US), and Burton G. Christensen (US) determined the properties and the structure of the beta-lactam antibiotic thienamycin. It is a natural product of Streptomyces cattleya and shows activity against Pseudomonas and beta-lactamase-producing species (25; 999; 1855; 1993).

 

Elias James Corey (US), Eugene J. Trybulski (US), Lawrence S. Melvin, Jr. (US), Kyriacos Costa Nicolaou (CY-US), John A. Secrist (US), Robert Lett (US), Peter W. Sheldrake (US), John R. Falck (US), Daniel J. Brunelle (US), Martin F. Haslanger (US), Sunggak Kim (US), and Sung-eum Yoo (US) synthesized erythronolide B, an antibiotic produced by the bacterium Streptomyces erythreus. This antibiotic is a member of a group of antibiotics collectively called the erythromycins (415; 416).

 

A. González (), Antonio Jimenez (), D. Vazquez (), Julian E. Davies (CA), and Daniel Schindler (US), discovered the mode of action of hygromycin B, an inhibitor of translocation in eukaryotes (Eucarya) (726).

 

Aaron Klug (ZA-GB) determined the three-dimensional structure of chromatin by using high-resolution electron microscopy and x-ray crystallographic analysis of the nuclease digests of chromosomes (1068).

 

Jean Yin Yin Wang (CN-US) and Daniel Edward Koshland, Jr. (US) found that protein phosphorylation did occur in prokaryotes (1978). These findings initiated a line of research that led to a structure-function analysis of tricarboxylic acid cycle/glyoxylate shunt regulation.

 

Ira Tabas (US), Sondra Schlesinger (US), and Stuart A. Kornfeld (US) were able to isolate lipid-linked oligosaccharide intermediate from vesicular stomatitis virus-infected Chinese hamster ovary cells. They determined that the intermediate is a high molecular weight mannose-rich oligosaccharide and that as the viral glycoprotein matured in the cell, the excess mannose residues were removed, and the outer sugars were added. This indicated a single pathway for the formation of both high mannose and complex- type glycans on glycoproteins (1848).

Ellen Li (US), Ira Tabas (US), and Stuart A. Kornfeld (US) determined the complete structure of the lipid-linked oligosaccharide intermediate. The structure of the oligosaccharide is conserved from yeast to man. After the lipid-linked intermediate is transferred to the nascent protein, the oligosaccharide is processed to give rise to the completed complex oligosaccharide units (1189).

Stuart A. Kornfeld (US), Ellen Li (US), and Ira Tabas (US) characterized the major processing intermediates and proposed a scheme for the pathway of complex oligosaccharide biosynthesis (1099).

 

Paul C. Zamecnik (US) and Mary L. Stephenson (US) showed that when the tridecamer d(A-A-T-G-G-T-A-A-A-A-T-G-G), which is complementary to 13 nucleotides of the 3'- and 5'-reiterated terminal sequences of Rous sarcoma virus 35S RNA, was added to chick embryo fibroblast tissue cultures infected with Rous sarcoma virus, inhibition of virus production resulted (1799; 2096). Note: This is the discovery of antisense oligonucleotides.

Jonathan G. Izant (US) and Harold M. Weintraub (US) noted that experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene (956).

Carolyn A. Napoli (US), Christine Lemieux (US), Richard A. Jorgensen (US), Paul D. Cluster (IT), James English (GB), and Qiudeng Que (US), in an attempt to deepen the purple color of petunia flowers, introduced a pigment-producing gene under the control of a powerful promoter. Instead of the expected deep purple color, many of the flowers appeared variegated or even white. Jorgensen named the observed phenomenon cosuppression, since the expressions of both the introduced gene and the homologous endogenous gene were suppressed (994; 1397). Note: This was the discovery of a phenomenon now called post-transcriptional gene silencing (PTGS). PTGS appears to be a normal mechanism of eukaryotic cells.

Andrew Zachary Fire (US), Donna Albertson (US), Susan White-Harrison (US), Donald Moerman (US), SiQun Xu (CN-US), Mary K. Montgomery (US), Steven A. Kostas (US), Sam E. Driver (US), and Craig Cameron Mello (US) discovered RNA interference in animals. When they injected dsRNA — a mixture of both sense and antisense strands — into the nematode Caenorhabditis elegans. This injection resulted in much more efficient silencing than injection of either the sense or the antisense strands alone. Indeed, injection of just a few molecules of dsRNA per cell was sufficient to completely silence the expression of the homologous gene. Furthermore, injection of dsRNA into the gut of the worm caused gene silencing not only throughout the worm, but also in its first generation offspring. This process defends against viruses that try to insert themselves into DNA, and controls gene expression (618; 619). This represents the discovery of RNAi, the i standing for interference.

Lander Ingelbrecht (BE), Helena van Houdt (BE), Marc van Montagu (BE), and Anna Depicker (BE) found that in PTGS the homologous RNA transcript is made, but that it is rapidly degraded in the cytoplasm and does not accumulate (944).

Lori L. Wallrath (US) and Sarah C. Elgin (US) provided data suggesting that altered chromatin-packaging plays a role in position effect variegation (PEV) (1973). A euchromatic gene placed in the vicinity of heterochromatin by a chromosomal rearrangement generally exhibits position effect variegation (PEV), a clonally inherited pattern showing gene expression in some somatic cells but not in others.

Scott M. Hammond (US), Amy A. Caudy (US), and Gregory J. Hannon (US) found that the trans-acting factor responsible for PTGS in plants is double stranded RNA (dsRNA) (805).

Sayda M. Elbashir (DE), Winfried Lendeckei (DE), and Thomas Tuschi (DE), using a Drosophila in vitro system, demonstrated that 21- and 22-nucleotide RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) are generated by an RNase III–like processing reaction from long dsRNA. Chemically synthesized siRNA duplexes with overhanging 3′ ends mediate efficient target RNA cleavage in the lysate, and the cleavage site is located near the center of the region spanned by the guiding siRNA. Furthermore, they provided evidence that the direction of dsRNA processing determines whether sense or antisense target RNA can be cleaved by the siRNA–protein complex (551).

Thomas A. Volpe (US), Catherine Kidner (US), Ira M. Hall (US), Grace Teng (US), Shiv I. S. Grewal (US), and Robert A. Martienssen (US) proposed that double-stranded RNA (dsRNA) arising from centromeric repeats targets formation and maintenance of heterochromatin through interference RNA (RNAi) (1949). Note: It is hoped that therapies might, one day, be enhanced through RNAi, for example, using RNAi to switch off genes involved in drug resistance to make chemotherapy more effective.

 

Aaron Ciechanover (IL), Yaacov Hod (IL), Avram Hershko (IL), Keith D. Wilkinson (IL), Michael K. Urban (IL), Arthur L. Haas (US), Hanna Heller (IL), Irwin A. Rose (US), Alexander Varshavsky (RU-US), Daniel Finley (US), Esther Eytan (IL), Dvora Ganoth (IL), Tamar Armon (IL), Wolfgang Dubiel (DE), Katherine Ferrell (US), Greg Pratt (US), and Martin Rechsteiner (US) discovered that a small heat-stable polypeptide, ATP-dependent proteolysis factor1 (APF-1), is an essential component of the ATP-dependent proteolytic system of rabbit reticulocytes. They proposed that ubiquitin is the ATP-dependent proteolysis factor, which conjugates with cellular proteins and suggested that such conjugates are the active intermediates in ATP-dependent proteolysis. They found that in eukaryotic cells proteins with abnormal structure are more readily conjugated to ubiquitin than most normal proteins and that these ubiquitin conjugates decayed more extensively than the corresponding average labeled cellular proteins (368; 369; 509; 580; 863; 864; 2029).

 

Jack W. Lawler (US), Henry S. Slayter (US), and John E. Coligan (US) isolated, characterized, and named thrombospondin from human blood platelets. Platelet thrombospondin is an adhesive protein known to play a central role in the development of platelet aggregates (1141).

 

Stephanie Broome (US) and Walter Gilbert (US) developed a very sensitive method to detect as antigens the presence of specific proteins within phage plaques or bacterial colonies (252). This is especially useful in DNA recombinant experiments in which one might desire to identify a bacterial cell containing a fragment of a gene from a higher cell.

 

Peter L. Ey (AU), Stephen J. Prowse (AU), and Charles R. Jenkin (AU) isolated pure IgG1, IgG2a, and IgG2b immunoglobulins from mouse serum using protein A-sepharose (579).

 

Frederick Wayne Alt (US), Rodney E. Kellems (US), Joseph R. Bertino (US), and Robert Tod Schimke (US) purified cDNA sequences complementary to didydrofolate reductase mRNA of murine origin then used them to probe, to quantitate dihydrofolate reductase mRNA and gene copies in several different cell lines. When unstable cell lines were grown in the absence of 4-amino analogs of folic acid, e.g. methotrexate, loss of resistance to the drug was associated with a decrease in didydrofolate reductase gene copy number (38).

 

Howard J. Edenberg (US), Stephen Anderson (US), and Melvin L. DePamphilis (US) were among the first to point out that eukaryotic DNA polymerase alpha is important in DNA replication (540).

 

Joyce E. Heckman (US), Lanny I. Hecker (US), Steven D. Schwartzbach (US), W. Edgar Barnett (US), Barbara R. Baumstark (US), and Uttam L. RajBhandary (GB-US), using Neurospora crassa, were the first to sequence nucleic acid from mitochondria. Unique features of initiator tRNA were revealed (831). This work foreshadowed the discovery of numerous unexpected features of mitochondrial genomes.

 

Dominic L. Poccia (US), Dreania LeVine (US), and James Chuo Wang (US) discovered DNA topoisomerase I which nicks the unwinding DNA during replication to allow relief of the positive supercoils (1514).

 

Clyde A. Hutchison, III (US), Sandra Phillips (US), Marshall H. Edgell (US), Shirley Gillam (CA), Patricia Jahnke (CA), and Michael Smith (GB-CA) developed a technique for site-directed mutagenesis. They used a 12-nucleotide oligomer with a centrally positioned single nucleotide mismatch as primer, phi X174 DNA as template, and E. coli DNA polymerase I in which the 5'-exonuclease had been inactivated by subtilisin to construct a closed circular double-stranded DNA with the oligonucleotide in one strand. The specific mutations chosen for the experiment were the production and reversion of a known nonsense mutation, am3. The mutations involved the interconversion of a Trp codon, TGG, and an amber codon, TAG, by G-T and A-C mismatches (932).

 

Robert Tjian (CN-US) reported the first detailed mapping of DNA sequences bound by a transcription factor. He used an adenovirus–simian virus 40 (SV40) hybrid, which supported higher expression of a protein functionally like SV40 T antigen. He noted that the transcription-factor-binding site contained palindromic sequences (1891).

David R. Engelke (US), Sun-Yu Ng (US), Barkur S. Shastry (US), James J. Bieker (US), Paul L. Martin (US), Marcus D. Kretzschmar (US), Michael Meisterernst (DE), and Robert Gayle Roeder (US) were the first to isolate a eukaryotic chromosomal gene-specific transcription factor. It was from extracts of oocytes added to an egg cell-free system. They described many of the complex array of protein factors involved in transcription, e.g., transcription factors IIIA, IIIB, IIIC, and IIID, (TFIIIA), (TFIIIB), (TFIIIC), (TFIIID) (161; 565; 1105; 1723).

 

Horst T. Witt (DE) showed that an electrical potential is created across the chloroplast inner membrane in less than 10^-8 second after illumination (2044).

 

Roger Yate Stanier (CA), William R. Sistrom (US), Theo A. Hansen (NL), Brian A. Whitton (GB), Richard W. Castenholz (US), Norbert Pfenning (DE), Vladimir M. Gorlenko (RU), Elena N. Kondratieva (RU), Kjell E. Eimhjellen (NO), Roger Whittenbury (GB), Robert L. Gherna (US), and Hans Georg Trüper (DE) coined the word Cyanobacteria as a new name for the group previously known as the blue-green algae. They were therefore no longer algae but rather placed under the rules of the International Code of Nomenclature of Bacteria (1781).

 

Rial D. Rolfe (US), David J. Hentges (US), Benedict J. Campbell (US), and James T. Barrett (US) determined that the oxygen tolerance of anaerobes is due in large part to their possession of Fe- and Mn-containing superoxide dismutase enzymes (1588).

 

Annie C.Y. Chang (US), Jack N. Nunberg (US), Randal J. Kaufman (US), Henry A. Erlich (US), Robert Tod Schimke (US), and Stanley Norman Cohen (US) constructed a bacterial plasmid that contained and phenotypically expressed the mammalian genetic sequence for mouse dihydrofolate reductase. The Escherichia coli host for this vector was rendered resistant to the antimetabolic drug trimethoprim (346).

 

Albert Hinnen (US), James B. Hicks (US), and Gerald R. Fink (US) transformed a stable leu2- yeast strain to Leu2+ by using a chimeric ColE1 plasmid carrying the yeast leu2 gene. The ColE1DNA together with the yeast DNA integrated into the yeast chromosomes and once there behaved as a simple Mendelian element (885).

Jean D. Beggs (GB) constructed chimeric plasmids containing a yeast plasmid and fragments of yeast nuclear DNA linked to pMB9, a derivative of the ColEl plasmid from E. coli. These plasmids were used to develop a method for transforming a leu2 strain of S. cerevisiae to Leu+ with high frequency. The yeast transformants contained multiple plasmid copies, which were recovered by transformation in E. coli. The yeast plasmid sequence recombined intramolecularly during propagation in yeast (118).

Kevin Struhl (US), Dan T. Stinchcomb (US), Stewart Scherer (US), Ronald W. Davis (US), Chu-Lai (US), and John Anthony Carbon (US), using the methodology above provided the first evidence of replicators (DNA sequences required to direct replication initiation) in eukaryotic chromosomes (916; 1818).

 

Gert Kreibich (DE-US), Belinda L. Ulrich (US), David Domingo Sabatini (US), Milton Bernard Adesnik (US), Alain Amar-Costesec (BE), John A. Todd (US), Victoria M. Harnik-Ort (US), Kulkarni Prakash (US), Eugene E. Marcantionio (US), David R. Colman (US), Michael Geoffrey Rosenfeld (US), Cristina Crimaudo (US). Michael Hortsch (DE), Heinrich Gausepohl (DE), David I. Meyer (DE), Leander Lauffer (US), Pablo D. Garcia (US), Richard N. Harkins (US), Lisa M. Coussens (US), Axel Ullrich (US), Peter Walter (US), Marie-Madeleine Galteau (FR), Bénédicte Antoine (FR), and Hubert Reggio (FR) found that in the endoplasmic reticulum certain proteins are largely restricted to either the rough or smooth membranes (46; 431; 671; 817; 909; 1103; 1139).

 

Hao Wang Lee (KR), Pyung Woo Lee (KR), and Karl M. Johnson (US) isolated hantavirus, the etiological agent of Korean hemorrhagic fever, also referred to as hemorrhagic fever with renal syndrome (1155). Dr. Lee named it Hantaan virus for the Hantan River in Korea near where the prototype strain was obtained.

Jeffrey S. Duchin (US), Frederick T. Koster (US), Clarence J. Peters (US), Gary L. Simpson (US), Bruce Tempest (US), Sherif R. Zaki (US), Thomas G. Ksiazek (US), Pierre E. Rollin, Stuart Nichol (US), Edith T. Umland (US), Ronald L. Moolenaar (US), Susan E. Reef (US), Kurt B. Nolte (US), Margaret M. Gallaher (US), Jay C. Butler (US), Robert F. Breiman (US), and the Hantavirus Study Group provided the clinical description of hantavirus pulmonary syndrome. The disease is characterized by a brief prodromal illness followed by rapidly progressive, noncardiogenic pulmonary edema (511). The virus is now called Sin Nombre virus.

Sergey P. Morzunov (US), Heinz Feldmann (US), Christina F. Spiropoulou (US), Vera A. Semenova (US), Pierre E. Rollin (US), Thomas G. Ksiazek (US), Clarence J. Peters (US), and Stuart T. Nichol (US) performed a genetic analysis on a virus detected in autopsy tissues of a fatal hantavirus pulmonary syndrome-like case in Louisiana. They found a previously unrecognized hantavirus and named it Bayou virus (1367).

 

Hans J. Gross (DE), Horst Domdey (DE), Christine Lossow (DE), Peter Jank (DE), Manfred Raba (DE), Heidemarie Alberty (DE), and Heinz L. Sanger (DE) determined the nucleotide sequence and secondary structure of potato spindle tuber viroid. PSTV was the first pathogen of a eukaryotic organism for which the complete molecular structure has been established (772).

 

Walter Charles Cornelius Fiers (BE), Roland R. Contreras (BE), Guy Haegemann (BE), Raphaël Rogiers (BE), André Van de Voorde (BE), Hugo Van Heuverswyn (BE), Jacqueline Van Herreweghe (BE), Guido Volckaert (BE), Maarten Ysebaert (BE), Vermuri B. Reddy (US), Bayar Thimmappaya (US), Ravi Dhar (US), Kiranur N. Subramanian (US), B. Sayeeda Zain (US), Julian Pan (US), Prabhat K. Ghosh (US), Maria L. Celma (US), and Sherman M. Weissman (US) determined the entire nucleotide sequence, 5243 bases, for the genome of simian virus 40 (613; 1552).

 

Norman Edwin Gibbons (CA) and Robert George Everitt Murray (CA) proposed that all prokaryotes be subdivided into four divisions: Gracilicutes (typical gram-negative cell wall), Firmicutes (gram-positive cell wall), Tenericutes (lacking a cell wall), and Mendosicutes (lacking peptidoglycan in their walls) (687).

 

Jon G. Seidman (US), Marshall H. Edgel (US) and Philip Leder (US) cloned mouse immunoglobulin light chain structural gene sequences in a bacterial plasmid (1708).

 

Julian Davies (US) and David I. Smith (US) discovered that bacteria may become resistant to aminoglycosides by adenylating, phosphorylating, and acetylating sensitive enzymes (456).

 

Ernest Robert Sears (US) and Lotti M. Steintz-Sears (US) made available an almost complete set of twenty-one 44-chromosome lines in which each wheat chromosome was represented by a pair of telocentrics for both arms of the chromosome (1703). This material was of great benefit to wheat geneticists.

 

Robert Peter Gale (US), Robert S. Sparks (US), and David W. Golde (US) showed that liver macrophages originate from stem cells in the bone marrow (666; 716).

 

T. Stuart Walker (US) and Herbert H. Winkler (US) proposed that a process termed induced phagocytosis internalizes Rickettsia prowazekii. Active rickettsia can trigger the phagocytic process carried out by the host cell (1969).

 

Arthur J. Kornberg (US), John F. Scott (US), and LeRoy L. Bertsch (US) presented evidence for an unwinding enzyme in prokaryotes as part of the DNA replication mechanism. The enzyme would be named helicase (1090).

 

Georg Melchers (DK-DE), Maria Dolores Sacristán (DE), and Anthony A. Holder (DE) were the first to produce hybrid plants derived from fused protoplasts involving two species so different that they were genetically incompatible, e.g., potato and tomato (1327).

 

Hugh D. Robertson (US), Sidney Altman (CA-US), and John D. Smith (US) purified an endonucleolytic ribonuclease from E. coli extract. They found that the purified enzyme cleaved a single phosphodiester bond in the tRNA precursor molecule, removing all the extra nucleotides present at the 5'-end of the precursor molecule. This contrasted with what appeared to be non-specific exonucleolytic degradation at the 3'-end of the molecule. They named this new enzyme ribonuclease P (RNase P) (1576).

Benjamin C. Stark (US), Ryszard Kole (US), Emma J. Bowman (US), and Sidney Altman (CA-US) found that an RNA of high molecular weight co-purified with the enzymatic activity of RNase P, and they demonstrated that this RNA molecule (named M1 RNA) was essential for enzymatic activity (1782). Further work by other laboratories showed that RNase P is an essential enzyme in E. coli for the biosynthesis of all tRNAs and that both RNA and protein subunits were required in vivo.

Madeline F. Baer (US), Regina M. Reilly (US), George M. McCorkle (US), Tsong-Yuing Hai (US), Sidney Altman (CA-US), and Uttam L. RajBhandary (IN-US) found two regions of E. coli M1 RNA that are complementary to a sequence conserved in all tRNAs. They discovered that extensive pairing between the enzyme and its substrate is not essential for the enzymatic reaction (84).

 

John Collins (DE) and Barbara B. Hohn (CH) created cloning vectors, which were hybrids of lambda virus and plasmids. They called them ‘cosmids’ (398; 902).

 

Irving Kupfermann (US) and Klaudiusz Weiss (US) offered a definition of command neurons as cells whose activity is necessary and sufficient for a specific behavior (1119).

 

Erwin Neher (DE), Bert Sakmann (DE), and Joe Henry Steinbach (US) developed the extracellular patch clamp: a method for resolving currents through individual open channels in biological membranes (1407).

 

Kunihiro Matsumoto (JP), Akio Toh-e (JP), and Yasuji Oshima (JP) found that in Saccharomyces cerevisiae the polypeptide Gal80, the product of the gene GAL80, does not regulate Gal4, the product of gene GAL4. They found that Gal4 is preexisting, prior to the induction by galactose. These studies also demonstrated that not all gene regulation is controlled by a repressor-operator relationship.

 

Edwin D. Murphy (US), John B. Roths (US), and Eva M. Eicher (US) described the (lpr) lymphoproliferation, (gld) generalized lymphoproliferation, and (Yaa) Y chromosome-linked autoimmune accelerator mutations in mice. These single gene mutations mimic systemic lupus erythematosis (SLE) in man and are therefore valuable for biomedical research (1377-1379; 1612).

 

Francis Wiener (SE), Jack Spira (SE), Shinsuke Ohno (SE), Nechama Haran-Ghera (IL), and Georges Klein (SE) discovered that a trisomy for chromosome number 15 (and occasionally chromosome 17) is a common feature in mouse leukemias induced by radiation or by chemicals (2022-2024).

 

Antony G. Searle (GB), Colin V. Beechey (GB), James McGrath (US), Davor Solter (DE), Bruce M. Cattanach (GB), M. Kirk (GB), M. Azim Surani (GB), Sheila C. Barton (GB), Michael L. Norris (GB), Jeffrey R. Mann (US), Robin H. Lovell-Badge (GB), Jean-Paul Renard (FR), Charles Babinet (FR), Wolf Reik (GB), and Marilyn Monk (GB) demonstrated that a genomic contribution from both the mother and the father is essential for successful development during mammalian embryogenesis, e.g., paternal genes inherited from the father, are responsible for making the placenta; maternal genes, inherited from the mother, are responsible for making the greater part of the embryo, especially the head and brain. This sovereignty of the paternal genes over the development of the placenta was named paternal imprinting (also called genomic imprinting) (104; 330; 331; 1282; 1317-1319; 1355; 1558; 1701; 1702; 1769; 1826-1829).

Thomas M. De Chiara (US), Argiris Efstratiadis (GR-US), and Elizabeth J. Robertson (US) showed how insulin-like growth factor-II gene (IGF II) is expressed in the mouse fetus and the adult brain. Within the fetus it promotes the movement of metabolites across the placenta, promoting the acquisition of resources from the mother. The paternal copy of the gene is fully expressed, whereas the copy inherited from the mother is not (464; 465).

Marisa Bartolomei (US), Sharon Zemel (US), Shirley M. Tilghman (US), Denise P. Barlow (GB-AT), Reinhard Stöger (AT), Bernhard G. Hermann (DE), Kenkichi Saito (JP), Norbert Schweifer (AT), Thomas M. De Chiara (US), Elizabeth J. Robertson (US), and Argiris Efstratiadis (GR-US) reported that, in the mouse, three different genes are specifically and consistently expressed from only one parental copy: H19 and Igf2r from the maternal copy and Igf2 from the paternal copy (97; 103; 465).

Denise P. Barlow (GB-AT), Reinhard Stöger (AT), Bernhard G. Hermann (DE), Kenkichi Saito (JP), and Norbert Schweifer (AT) found, in contrast, the gene coding for a receptor for IGF II, the IGK II Type II receptor, shows a reversed pattern of expression. The maternal copy is expressed fully, whereas the paternal copy is not (97). Note: The result of imprinting is that individuals bearing two copies of either maternal or paternal alleles are unbalanced in terms of expression. They have severly impaired survival. The existence of genomic imprinting prevents the evolution of parthenogenesis in mammals, because a fetus with only maternally imprinted genes will perish.

 

Michael H. Wigler (US), Angel Pellicer (US), Saul J. Silverstein (US), and Richard Axel (US) developed an efficient method for introducing single copy mammalian genes into cultured-cells (2027).

 

Thomas Peter Maniatis (US), Ross C. Hardison (US), Elizabeth Lacy (US), Joyce Lauer (US), Catherine O'Connell (US), Diana Quon (US), Gek Kee Sim (US), and Argiris Efstratiadis (US) presented procedures for the creation of a complete library of human genomic fragments and a method for the cloning of human genes (1274).

 

Alexander W. Clowes (US) and Morris John Karnovsky (ZA-US) discovered that heparin, a well-known anticoagulant, also inhibits the proliferation of smooth muscle cells (385).

 

Linda M. Griffith (US) and Tom D. Pollard (US) provided evidence that microtubule-associated proteins (MAPs) mediate the interaction of actin-filament with microtubules (770).

 

Steven Gillis (US), Paul E. Baker (US), Francis Ruscetti (US), and Kendall A. Smith (US) maintained long-term culture of human antigen-specific cytotoxic T cell lines (699).

 

Sudhir Gupta (US) and Robert Alan Good (US) showed that there are subpopulations of human T lymphocytes. The distribution and quantitation of these subpopulations in peripheral blood, cord blood, tonsils, bone marrow, thymus, lymph nodes, and spleen was revealed (789).

 

Jørn Dyerberg (DK), Hans Olaf Bang (DK), Erik Stoffersen (DK), Salvador Moncada (GB), and John Robert Vane (GB) hypothesized that eicosapentaenoic acid (EPA) plays a role in prevention of thrombosis and atherosclerosis (523).

 

Jana Havrankova (CA), Donald E. Schmechel (US), Jesse Roth (US), Michael J. Brownstein (US), James L. Rosenzweig (US), Maxine A. Lesniak (US), Derek Le Roith (US), S. Anne Hendricks (US), Sharma Rishi (US), and Karin L. Becker (US) discovered that insulin (which was supposed to be produced only in the pancreas) is also made in the brain, as well as in one-celled organisms outside the human body (826; 1146; 1597).

 

Masatoshi Nei (US) developed a statistical method for estimating average heterozygosity and genetic distance from a small number of individuals. It was shown that, if the number of genetic loci examined is large, the number of individuals to be used can be very small. Nei provided a theoretical justification for the use of a small number of individuals at a time when electrophoretic study of evolution was popular (1408).

 

Douglas L. Coleman (US) identified obese (ob/ob) and diabetes (db/db): two mutant genes causing diabetes-obesity syndromes in mice. Cross-circulation (parabiosis) experiments suggested that the ob/ob gene encodes a circulating factor that regulates the nutritional state and that the db/db gene encodes the receptor for this factor (394). The syndrome produced by either or both homozygous recessive genotypes resembles morbid human obesity.

 

Patricia R. Bergquist (NZ) wrote an authoritative textbook on sponges (144). She is the leading authority on the systematics of Keratose sponges (Orders Dictyoceratida, Dendroceratida and Verongida). Recently (1994) Professor Bergquist was knighted in recognition of her important scientific and academic work. She is commemorated by Acarnus bergquistae Van Soest et al., 1991, Halichondria bergquistae Hooper et al., 1995, Monosyringia patricae Lévi, 1993, and Xestospongia bergquistia Fromont, 1992.

 

James M. Hughes (US), Dannie G. Hollis (US), Eugene J. Gangarosa (US), and Robert E. Weaver (US) recognized Vibrio cholera non O-group 1 (non-O1) as a human pathogen (927). It does not agglutinate in cholera O-group 1 antiserum (2019).

 

Michael J. Davis (US), Alexander H. Purcell (US) and Sherman Vance Thomson (US) isolated Xylella fastidiosa a gram-negative, rod-shaped bacterium consistently isolated from grapevines with Pierce's disease. Grapevines inoculated with the bacterium developed Pierce's disease, and the bacterium was re-isolated from the plants (459).

 

Anthony F. Purchio (US), Eleanor Erikson (US), Joan S. Brugge (US), Raymond L. Erikson (US), Marc S. Collett (US), Joan S. Brugge (US), and Paula J. Steinbaugh (US) were the first to isolate and define a polypeptide coded by an oncogene, the enzyme coded by the avian sarcoma virus src oncogene (this was after it was established that cancer-causing retroviruses carry oncogenes) (264; 397; 570; 1535). The protein product of this oncogene, which is a unique enzyme, drastically alters the biochemistry of the cell and diminishes its capacity for responding to regulatory signals from hormones. Of all the oncogenes now know, a substantial number seem to act in a similar way.

Arthur D. Levinson (US), Hermann Oppermann (US), Leon Levintow (US), Harold Elliot Varmus (US), and John Michael Bishop (US) provided evidence that the transforming gene of avian sarcoma virus encodes a protein kinase (pp60) associated with a phosphoprotein (1175).

Walter Eckhart (US), Mary Anne Hutchinson (US), Tony Hunter; Anthony Rex Hunter (US), Owen N. Witte (US), Asim Dasgupta (US), David Baltimore (US), and Bartholomew M. Sefton (US) identified phosphotyrosine kinase activity associated with polyoma virus middle T antigen, Abelson murine leukemia viral oncogene (Abl), and Rous sarcoma virus oncogene Src. They showed that these enzymes are essential for the malignant transformation of cells by the oncogenic proteins (526; 928; 2045). Note:As viral Src was derived from an evolutionarily conserved c-SRC cellular proto-oncogene, logic dictated that all vertebrate cells must contain at least one protein kinase that phosphorylates tyrosine.

Tony Hunter; Anthony Rex Hunter (US) and Bartholomew M. Sefton (US) found that pp60src (the product of the src gene of Rous sarcoma virus (RSV) phosphorylates tyrosine in vivo as well as in vitro. They suggested that pp60src is a protein kinase and that the modification of proteins by phosphorylation of tyrosine is essential to the malignant transformation of cells by Rous sarcoma virus (928). Note: This is the discovery of the first tyrosine kinase.

Richard C. Parker (US), John Michael Bishop (US), Harold Elliot Varmus (US), Alan M. Schultz (US), Louis E. Henderson (US), Stephen Oroszlan (US), Ellen A. Garber (US), Hidesaburo Hanafusa (US), Gregory S. Payne (US), and Ronald Swanstrom (US) used DNA copies of the Rous sarcoma virus oncogene v-src to probe the cellular DNA of various animals. A closely related homolog, cellular c-src, was found in the DNA from normal chickens, fish, mammals, humans, and even Drosophila. Subsequently, other viral oncogenes were shown to have related cellular forms that have been conserved from species to species during evolution. These retroviral oncogenes appear to be modified cellular genes captured by the virus from genomes of their vertebrate hosts. During provirus integration, all or part of the coding region of a cellular gene may be integrated within the sequences of the viral genome. Thus, the virus acts like a transducing phage, removing the cellular gene as part of its genome as it excises from the host DNA. The cellular gene is then packaged, along with viral sequences, into an infectious virus particle (1474; 1475; 1478; 1691; 1841).

David S. Dolberg (US) and Mina J. Bissell (US) re-examined the interaction of Rous sarcoma virus (RSV) with the avian embryo and confirmed that RSV is non-tumorigenic and non-teratogenic when microinjected into day 4 chicken embryos. In addition, they found that (1) the virus not only replicates in the embryo, but it also expresses an active src-specific protein kinase and (2) once the cells from the infected limbs are disrupted and placed in culture, they can express the transformed phenotype after a 24-h delay (501).

 

Michael D. Waterfield (GB), Geoffrey T. Scrace (GB), Nigel Whittle (GB), Paul Stroobant (US), Ann Johnsson (SE), Ake Wasteson (SE), Bengt Westermark (SE), Carl-Henrik Heldin (SE), Jung-San Huang (TW-US), Thomas F. Deuel (US), Russell F. Doolittle (US), Michael W. Hunkapiller (US), Leroy E. Hood (US), Sushilkumar G. Devare (US), Keith C. Robbins (US), Stuart A. Aaronson (US), and Harry N. Antoniades (US) identified the putative transforming protein of simian sarcoma virus as platelet-derived growth factor (PDGF) (504; 1987).

 

James Todd (US), Mark Fishaut (CA-US), R. Frank Kapral (US), and Thomas R. Welch (US) coined the phrase toxic-shock syndrome to describe an acute illness characterized by rapid onset of fever, hypotension, headache, myalgia, vomiting and diarrhea, mucous membrane hyperemia, laboratory evidence of multiple organ system dysfunctions, and an erythematous rash with subsequent desquamation particularly on the palms and soles. This syndrome is consistently associated with Staphylococcus aureus (1893).

The Centers for Disease Control (CDC) reported cases among young women of a newly recognized illness known as toxic-shock syndrome (TSS). Toxic-shock syndrome typically begins suddenly with high fever, vomiting, and profuse watery diarrhea, sometimes accompanied by sore throat, headache, and myalgias. The disease progresses to hypotensive shock within 48 hours, and the patient develops a diffuse, macular, erythematous rash with non-purulent conjunctivitis. In 33 of 45 (73%) patients cultured, Staphylococcus aureus was isolated from the throat, cervix, vagina, or rectum (8).

Kathryn N. Shands (US), George P. Schmid (US), Bruce B. Dan (US) Deborah Blum (US), Richard J. Guidotti (US), Nancy T. Hargrett (US), Roger L. Anderson (US), Dianne L. Hill (US), Claire V. Broome (US), Jeffrey D. Band (US), and David W. Fraser (US) noted that case-control studies of menstrual toxic-shock syndrome (TSS) clearly demonstrated that use of various brands and styles of tampons was by far the most important risk factor for TSS during menstruation (1721).

 

Peter G. Sargeaunt (GB), John E. Williams (GB), and J.D. Grene (GB) differentiated invasive from non-invasive Entamoeba histolytica by using isoenzyme electrophoresis (1656).

Matthias Leippe (DE), Egbert Tannich (DE), Rosa Nickel (DE), F. Gisou van der Goot (CH), Franc Pattus (FR), Rolf D. Horstmann (DE), and Hans Joachim Müller-Eberhard (DE-US-DE) discovered marked DNA differences between pathogenic and non-pathogenic isolates of Entamoeba histolytica (1162).

 

Stephen S. Hecht (US), Chi-Hong B. Chen (US), Norio Hirota (US), Raphael M. Ornaf (US), Tien C. Tso (US), and Dietrich Hoffmann (US) showed that nitrosamines derived from nicotine cause cancer in animal models. These substances were later shown to contribute to human lung and oral cancers (830).

 

David M. Goldenberg (US), Frank DeLand (US), Euishin Kim (US), Sidney Bennett (US), F. James Primus (US), John R. van Nagell, Jr. Norman Estes (US), Philip DeSimone (US), and Pam Rayburn (US) used radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning (718).

 

Hans Joachim Müller-Eberhard (DE-US-DE) showed that absence of the C3 complement component in blood predisposes an individual to recurrent infections (1376).

 

Donna S. Whitlon (US), James A. Sadowski (US), and John Weston Suttie (US) showed that warfarin exerts its anticoagulant activity by inhibiting the regeneration of vitamin K through blocking vitamin K epoxide reductase (2018).

 

Michael Klagsbrun (US) showed that human milk contains a mitogenic factor that stimulates DNA synthesis and cell division in mouse and human fibroblasts in vitro (1061).

 

Andre de Léan (CA), Peter J. Munson (US), and David Rodbard (US) developed a general computerized method to describe the dose-response curves to hormones, drugs, and neurotransmitters in terms of basal and maximal responses, ED50, and curve shape or steepness (470).

 

Martin C. Carey (US) and Donald M. Small (US) demonstrated that (a) metastable supersaturation is frequent in both normal and abnormal biles, (b) cholesterol gallstone patients have supersaturated gallbladder and hepatic biles without exception, and (c) the predominant driving force for cholesterol precipitation appears to be the absolute degree of cholesterol supersaturation (315).

 

Haralambos P. Gavras (US), Hans R. Brunner (CH), Gustave A. Turini (CH), Glen R. Kershaw (US), Charles P. Tifft (US), Sergio Cuttelod (US), Irene M. Gavras (US), Robert A. Vukovich (US), Doris N. McKinstry (US), Bernard Waeber (CH), Doris N. McKinstry (US), and Irene M. Gavras (US) found that chronic inhibition of the angiotensin-converting enzyme with captopril offers an efficient and well-tolerated approach to the treatment of hypertension (269; 674).

David W. Cushman (US), Hong Son Cheung (US), Emily F. Sabo (US), Bernard Rubin (US), and Miguel A. Ondetti (US) developed Captopril (Capoten), a remarkably effective antihypertensive drug designed and developed as a potent and specific inhibitor of angiotensin-converting enzyme, a zinc metallopeptidase that participates in the synthesis of a hypertensive peptide, angiotensin II, and in the degradation of a hypotensive peptide, bradykinin (441; 442). Captopril is a powerful oral agent for the treatment of high blood pressure, heart failure, and diabetic kidney disease. The ACE (angiotensin converting enzyme) inhibitors prevent the formation in the blood of a naturally occurring substance, angiotensin II, which raises blood pressure. An ACE inhibitor called bradykinin-potentiating factor (BPF), from the venom of snakes, was found to reduce blood pressure in rats. When eventually it could be purified, BPF was also shown to reduce blood pressure in patients. Various synthetic preparations were tested in rats, resulting in the introduction of Captopril.

 

Robert P. Heaney (US), Robert R. Recker (US), and Paul D. Saville (US) concluded that there is a specific, estrogen-related shift in calcium performance across menopause and that the reason for the positive effect of estrogen on balance and intake requirement is a combination of enhancement of intestinal absorption efficiency and improved renal calcium conservation (829).

 

Elaine K. Perry (GB), Bernard E. Tomlinson (GB), Garry Blessed (GB), Klaus Bergmann (GB), Peter H. Gibson (GB), and Robert H. Perry (GB) obtained results suggesting a close relationship between changes in the cholinergic system within the brain and Alzheimer's dementia (1489).

 

Anthony S. Fauci (US), Barton Haynes (US), and Paul Katz (US) discuss the epidemiology of the primary vasculitides in the spectrum of vasculitis (591).

 

Spreading from 2 countries in 1978 to at least 29 in 1988, chloroquine-resistant Plasmodium falciparum malaria has become a significant concern for travelers to Africa. The spread of chloroquine resistance has been documented by sporadic case reports and by isolated population surveys (4).

 

Joseph H. Connell (US) proposed that the commonly observed high diversity of trees in tropical rain forests and corals on tropical reefs is a nonequilibrium state which, if not disturbed further, will progress toward a low-diversity equilibrium community. This may not happen if gradual changes in climate favor different species (407).

 

Edward Osborne Wilson (US) wrote On Human Nature, a study of evolution and sociobiology for which he won the 1979 Pulitzer Prize for General Nonfiction (2037).

 

Richard Charles Lewontin (US) presents one of the best single treatments of the concept of adaptation (1184).

 

1979

“The only solid piece of scientific truth about which I feel totally confident is that we are profoundly ignorant about nature. Indeed, I regard this as the major discovery of the past hundred years of biology.” Lewis Thomas (1879).

 

"A good laboratory, like a good bank or a corporation or government, has to run like a computer. Almost everything is done flawlessly, by the book, and all the numbers add up to the predicted sums. The days go by. And then, if it is a lucky day, and a lucky laboratory, somebody makes a mistake; the wrong buffer, something in one of the blanks, a decimal misplaced in reading counts, the warm room off by a degree and a half, a mouse out of its box, or just a misreading of the day’s protocol. Whatever, when the results come in, something is obviously screwed up, and then the action can begin. The misreading is not the important error; it opens the way. The next step is the crucial one. If the investigator can bring himself to say, "But even so, look at that!" then the new finding, whatever it is, is ready for snatching. What is needed, for progress to be made, is the move based on the error." Lewis Thomas (1879).

 

“The history of medicine has never been a particularly attractive subject in medical education and one reason for this is that it is so unbelievably deplorable a story … Bleeding, purging, cupping and the administration of infusions of every known plant, solutions of every known metal, every conceivable diet including total fasting, most of them based on the weirdest imaginings about the cause of disease, concocted out of nothing but thin air—this was the heritage of medicine until a little over a century ago.” Louis Thomas (1879).

 

"The aim of molecular biology is to find, in the structures of macromolecules, interpretations of the fundamentals of life." Jacques Lucien Monod (996).

 

" There is no quicker way for a scientist to bring discredit upon himself…than to declare that science knows or soon will know the answers to all questions worth asking." Peter Brian Medawar (GB) (1323).

 

Allan MacLeod Cormack (ZA-US) and Godfrey Newbold Hounsfield (GB) were awarded the Nobel Prize in Physiology or Medicine for the development of computer assisted tomography (CAT scan).

 

John Edward Heuser (US), Thomas Sargent Reese (US), Michael J. Dennis (US), Yuh Nung Jan (US), Lily Yeh Jan (US), and Louise Evans (US) developed a high-resolution, deep-etching freeze-fracture technique using very rapidly frozen specimens (866).

 

Stuart G. Fischer (US) and Leonard S. Lerman (US) developed denaturing gradient gel electrophoresis to separate DNA fragments of identical length but different base composition and to identfy point mutations in DNA. Mutant fragments with single nucleotide differences could be separated in this gel system (620-622).

Richard M. Myers (US), Nadya Lumelsky (US), Leonard S. Lerman (US), Thomas Peter Maniatis (US), Stuart S. Fischer (US), Ezra Abrams (US), and Susan E. Murdaugh (US) further modified the method above making it possible to detect single base mutations in total human genomic DNA (15; 1381; 1383).

Richard M. Myers (US), Leonard S. Lerman (US), Thomas Peter Maniatis (US), and Kit Tilly (US), from the denaturing gradient gel electrophoresis, developed a method for saturation mutagenesis of regulatory DNA sequences, and to carry out the first single nucleotide saturation mutagenesis study of a eukaryotic promoter (1382; 1384).

 

Geoffrey M. Wahl (US), Michael Stern (US), and George R. Stark (US) described two techniques to increase the speed and reproducibility of nucleic acid hybridization to DNA immobilized on solid supports. The first involved a single chemical method to fragment DNA in situ in agarose gels to facilitate transfer to a solid support. The second described a means for accelerating hybridization rates 100-1,000-fold (1958).

 

Te Chang Yu (US), Russell D. Sinnhuber (US), and Jerry D. Hendricks (US) demonstrated that linolenic acid (C18:3 n-3) as the only source of essential fatty acids could support growth, reproduction, and viability of offspring of the rainbow trout, Salmo gairdner. In contrast to mammals, docosahexaenoic acid (C22:6 n-3) is the principal polyunsaturated fatty acid of all tissues of trout (2089).

 

Harry Towbin (CH), Theophil Staehelin (CH), and Julian Gordon (CH) devised a method for the electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets. The method allows detection of proteins by autoradiography and is simpler than conventional methods (1902).

 

John M. Chirgwin (US), Alan E. Przybyla (US), Raymond J. MacDonald (US), and William J. Rutter (US) developed a method for isolation of RNA from tissue, which contains a high level of RNAnase. The procedure entails rapid denaturation of nucleases with guanidinium thiocyanate and sedimentation of RNA through a CsCl cushion. The dense RNA is pelleted in the bottom of the tube, the DNA bands in the CsCl and proteins band in the top phase. The DNA may be saved and is not denatured during treatment. This is the method of choice when tissue is not limiting, and large amounts of RNA are required (363).

 

H. Chaim Birnboim (CA) and Janine Doly (CA) devised a simple, rapid procedure for extracting plasmid DNA from bacterial cells. The principle of the method is selective alkaline denaturation of high molecular weight chromosomal DNA while covalently closed circular DNA remains double-stranded (168).

 

Rupert Timpl (AT-DE), Heilwig Rohde (DE), Pamela Gehron Robey (US), Stephen I. Rennard (US), Jean-Michel Foidart (BE), and George R. Martin (US) isolated a high molecular weight non-collagenous glycoprotein that is also a major constituent of mouse EHS sarcoma. They determined that the protein, which they named laminin, consisted of at least two polypeptide chains joined to each other by disulfide bonds. Using purified antibody against laminin, they showed that the glycoprotein is produced by a variety of cultured cells and is a constituent of the basement membranes of these tissues (1887).

 

Charles Thomas Esmon (US) described a method for isolating a high molecular weight form of blood coagulation Factor V, which could be cleaved by thrombin to form both an activation intermediate and a stable, fully activated Factor V. Esmon was able to dissociate the intermediate and the activated Factor V with chelating agents. From these results, he proposed a scheme for the activation of Factor V in which the protein is cleaved by thrombin into two chains that are held together by noncovalent interaction (572).

 

Michael C. Pirrung (US) carried out the total synthesis of isocomene, a tricyclic sesquiterpene from the rayless goldenrod, Isocoma wrightii (1508; 1509).

 

Gert J. Kruger (ZA), Pieter Streicher Steyn (ZA), Robert J. Vleggaar (ZA), and Christiaan J. Rabie (ZA) had isolated asteltoxin and determined its structure (1106).

Michel Satre (FR) found that asteltoxin, produced by Aspergillus stellatus, exerts a potent inhibitory effect on the adenosine triphosphatase activity of Escherichia coli BF1 (1661).

Stuart Lee Schreiber (US) and Kunio Satake (US) carried out the complete synthesis of asteltoxin (1686-1688).

 

Jan Heeres (BE), Leo J. Backx (BE), Joseph H. Mostmans (BE), and Jan Van Cutsem (BE) synthesized ketoconazole and noted its usefullness as a new potent orally active broad-spectrum antifungal agent (835).

 

Al Claiborne (US), Douglas P. Malinowski (US), and Irwin Fridovich (US) discovered that Escherichia coli makes two catalases. One of these is only a catalase whereas the other is a dual catalase/peroxidase. These were named hydroperoxidase I and II respectively (370; 371).

 

Steven Clarke (US) and Daniel Edward Koshland, Jr. (US) were the first to identify the two major chemotaxis receptors in Escherichia coli membranes, the serine and aspartate receptors (Tsr and Tar) (376).

 

John M. Cheeseman (US) and Jack B. Hanson (US) discovered the role of the plasmalemma H1-ATPase in generating a nonequilibrium membrane potential and of potassium transporters, both “active” and “passive,” in dissipating it in corn roots (355).

 

W. Clark Still (US) carried out the total synthesis of periplanone B, a sex pheromone found in the female American cockroaches of the species Periplaneta americana (1803).

 

George Schmid (US), Tohru Fukuyama (JP), Kazuaki Akasaka (US), Yoshito Kishi (US), C.-L.J. Wang (US), Donald S. Karanewsky (US), David B. Collum (US), John H. McDonald III (US), W. Clark Still (US), Robert E. Ireland (US), Joseph D. Armstrong III (US), Jacques Lebreton (US), Robert S. Meissner (US), and Mark A. Rizzacasa (US) reported the first total synthesis of the ionophoric antibiotic, Monensin (400-402; 653; 654; 948; 949; 1677).

 

Avram Goldstein (US), Shinro Tachibana (US), Louise I. Lowney (US), Michael W. Hunkapiller (US), and Leroy Edward Hood (US) described the opioid properties of a tridecapeptide, the sequence of which corresponds to the NH2-terminal sequence of dynorphin, a novel porcine pituitary endorphin. They named it dynorphin-(1-13) (722).

 

Ramamoorthy Belagaje (US), Eugene L. Brown (US), Hans-Joachim Fritz (DE), Robert G. Lees (US), Har Gobind Khorana (IN-US), Takao Sekiya (JP), Michael J. Gait (GB), Michael J. Ryan (US), Kjeld E. Norris (DK), Tatsuo Takeya (JP), and Roland Contreras (BE) synthesized the final two segments of the tyrosine suppressor tRNA gene promoter. They used polynucleotide kinase and polynucleotide ligase to join 10 deoxyoligonucleotide segments to form the 62-nucleotide-long DNA corresponding to the promoter region of the tRNA gene. They joined the DNA duplexes to complete the total synthesis of the gene (119; 1711; 1713).

Takao Sekiya (JP), Roland Contreras (BE), Tatsuo Takeya (JP) and Har Gobind Khorana (IN-US) were able to successfully transcribe this synthetic gene (1712).

 

Andrew H. -J. Wang (US), Gray J. Quigley (US), Francis J. Kolpak (US), James L. Crawford (US), Jacques H. van Boom (NL), Gijs A. van der Marel (NL), and Alexander Rich (US) discovered the Z (left-handed) form of DNA (named for the zigzag backbone) (1975).

Fritz M. Pohl (DE) and Thomas M. Jovin (DE) had earlier suspected that such a form of DNA might exist (1517).

 

Wesley M. Brown (US), Matthew George, Jr. (US), Allan C. Wilson (NZ-US), Ellen M. Prager (US), and Alice Wang (US) found that mammalian and bird mitochondrial DNA mutates more rapidly than nuclear sequences (260; 261).

 

Shirley Gillam (CA) and Michael Smith (GB-CA) determined the optimum conditions and minimum oligodeoxyribonucleotide length of synthetic oligodeoxyribonucleotide necessary to produce a single defined point mutation in the DNA of the phage øX174 (698). This technique, called site-specific mutagenesis or site-directed mutagenesis, has become a very important method for determining the function of a particular protein or gene, by using single strands of viral DNA to mutate the genetic code at precise locations.

 

Patrick O. Brown (US), Craig L. Peebles (US), Alan Morrison (US), and Nicholas R. Cozzarelli (US) solved the problem of replicating circular DNA forming interlocking rings by their discovery of the enzyme topoisomerase II. This enzyme can cut both strands of a piece of DNA, pass another piece of DNA between the two ends, and then join the broken ends together again (259; 1364).

 

P. Anthony Weil (US), Donal S. Luse (US), Jeffrey Segall (US), and Robert Gayle Roeder (US) reconstructed a cell-free system capable of the correct initiation of transcription by RNA polymerase II (2003).

 

Michael Rush Lerner (US) and Joan Elaine Argetsinger Steitz (US) discovered small nuclear ribonucleoproteins (snurps) (1169).

Michael Rush Lerner (US), John A. Boyle (US), Stephen M. Mount (US), Sandra L. Wolin (US), Joan Elaine Argetsinger Steitz (US), John Rogers (US) and Randolph Wall (US) proposed that the small nuclear RNA (snRNA) known as U1 is the recognition component of the nuclear RNA splicing enzyme of eukaryotic organisms and forms base pairs with both ends of an intron so as to align them for cutting and splicing (1168; 1587).

Michael Rush Lerner (US), John A. Boyle (US), John A. Hardin (US), and Joan Elaine Argetsinger Steitz (US) presented evidence that patients with lupus erythematosus develop autoantibodies that completely inhibit the splicing reaction in which small nuclear RNA (snRNA) remove introns (1167).

Edward Michael de Robertis (UR-GB-CH-US), Susanne Lienhard (CH), and Ruth F. Parisot (CH) found that 5S RNA becomes concentrated in the nucleolus. Studies with lupus erythematosus antibodies showed that the migrating RNAs become associated with RNA-binding proteins (471).

Joan Elaine Argetsinger Steitz (US) led a group including Richard A. Padgett (US), Stephen M. Mount (US), Phillip Allen Sharp (US), Douglas L. Black (US), Benoit Chabot (US), David M. LeMaster (US), Volker Gerke (US), Kimberly L. Mowry (US), James P. Bruzik (US), Kevin Van Doren (US), David Hirsh (US), Ann L. Pinto (US), David A. Wassarman (US), Scott D. Seiwert (US), Erik J. Sontheimer (US), Woan-Yuh Tarn (US), Ti-Tao Yu (US), and Mei-Di Shu (US) that discovered spliceosomes, the particles that are the sites of splicing of pre-messenger RNA into the final mature mRNA and elucidated many of their roles (174; 175; 273; 338; 339; 681; 1371; 1463; 1507; 1710; 1771; 1859; 1860; 1984; 2090).

Paula J. Grabowski (US), Sharon R. Seiler (US), and Phillip Allen Sharp (US) recognized that a multicomponent complex they named spliceosome (splicing body) is unique to the splicing of messenger RNA precursors in vitro (750).

 

Philip R. Evans (GB), Peter J. Hudson (GB), and George W. Farrants (NO) worked out the molecular mechanism underlying allosteric regulation of the enzyme phosphofructokinase (577; 578).

 

Edwin Gerhard Krebs (US) and Joseph A. Beavo (US) found that the enzymes of glycogen metabolism could be regulated by phosphorylation/dephosphorylation through changes in cyclic 3’, 5’-AMP (1102).

 

Günter Klaus-Joachim Blobel (DE-US), Peter Walter (US), Chung Nan Chang (US), Barbara M. Goldman (US), Ann H. Erickson (US), and Vishwanath R. Lingappa (US) proposed the existence within integral membrane proteins of a stop-transfer sequence, which serves to interrupt translocation and thereby to retain the polypeptide chain in the lipid bilayer. They also proposed the existence of specific sorting-sequences, which would serve to route proteins to their destination following translocation across or orientation within the membrane (187).

C. Spencer Yost (US), Joe Hudspeth (US), and Vishwanath R. Lingappa (US) presented experimental evidence for the existence of such stop-transfer sequences (2087).

Hans Peter Hauri (CH) presented experimental evidence in support of the existence of sorting-sequences (825).

 

Lawrence W. Bergman (US), W. Michael Kuehl (US), Alan M. Tartakoff (US), Pierre Vassalli (CH), Sune Kvist (DE), Klas Wiman (SE), Lena Claesson (SE), Per A. Peterson (SE), Bernhard Dobberstein (DE), David G. Bole (US), Linda M. Hendershot (US), John F. Kearney (US), Barry E. Carlin (US), John Paul Merlie (US), Mary-Jane Gething (US), Karen McCammon (US), Joseph Frank Sambrook (GB-US-AU), Constance S. Copeland (US), Robert W. Doms (US), Eva M. Bolzau (US), Robert G. Webster (US), Ari Helenius (FI-US-CH), Klaus-Peter Zimmer (DE), Krystn R. Wagner (US), Glenn A. Healey (US), Ira Mellman (US), Thomas E. Kreis (US), Harvey Franklin Lodish (US), Deborah S. Keller (US), William E. Balch (US), Juha Koivu (FI), and Raili Myllylä (FI) determined that assembly of most oligomeric proteins occurs prior to their exit from the endoplasmic reticulum. Some oligomers are assembled cotranslationally and some posttranslationally (143; 195; 317; 413; 414; 502; 682; 1083; 1104; 1121; 1862).

Hugh R.B. Pelham (US) and R. John Ellis (US) suggested that a group of proteins might be involved in regulating proper protein folding and oligomeric assembly (559; 1482). The term “molecular chaperone” had been used as early 1978 to describe nucleoplasmin's role in overseeing histone–histone interactions.

 

Hamilton Othanel (US) reported that the sites recognized by many restriction endonucleases have twofold symmetry (1755).

 

Martin Frank Gellert (US), Kiyoshi Mizuuchi (US), Mary H. O'Dea (US), Haruki Ohmori (JP), and Jun-ichi Tomizawa (JP-US) discovered DNA topoisomerase II (DNA gyrase) an enzyme which introduces breaks in both DNA strands simultaneously to relieve the positive supercoils during unwinding associated with DNA replication (678).

 

Giuseppe Attardi (IT-US), Stephen T. Crews (US), Jerry Nishiguchi (US), Davin K. Ojala (US), James W. Posakony (US), Julio Montoya (ES), Thomas Christianson (US), David Levens (US), Murray Rabinowitz (US), James E. Hixson (US), William Walter Hauswirth, (US), David D. Chang (US), David A. Clayton (US), Enid F. Applegate (US), Barbara K. Yoza (US), and Daniel F. Bogenhagen (US) discovered that transcription in animal mitochondria, rather than initiating at each gene, begins at one promoter for each nucleotide chain of the DNA circle and transcribes the entire chain as a unit. In this sense, animal mitochondrial genomes consist of only two operons, one for each of the two nucleotide chains of the DNA circle (71; 192; 347-349; 890; 1357).

 

Thomas A. Kunkel (US), Ralph R. Meyer (US), Lawrence A. Loeb (US), Roel M. Schaaper (US), and Robert A. Beckman (US) performed experiments, which demonstrated that DNA polymerases are involved in the proofreading of DNA in eukaryotes (Eucarya) (1116; 1117).

 

Fred Heffron (US), Brian John McCarthy (US), Hisako Ohtsubo (JP), and Eiichi Ohtsubo (JP) reported that the genetic information contained within a transposon includes a transposase gene involved in a reaction cutting the transposon from one location in the genome and inserting it into a new one (836).

 

Yoshimi Takai (JP), Akira Kishimoto (JP), Ushio Kikkawa (JP), Terutoshi Mori (JP), and Yasutomi Nishizuka (JP) described a protein kinase (now protein kinase C) requiring calcium, phosphatidylserine, and diacylglycerol for complete activation (1853).

 

Peter Novick (US) and Randy Wayne Schekman (US) provided evidence that exocytosis may contribute to cell-surface growth in Saccharymyces cerevisiae (1427).

 

Randy L. Bell (US), Donald A. Kennerly (US), Nancy Stanford (US), and Philip Warren Majerus (US) provided evidence that arachidonate release from stimulated platelets involves a diglyceride lipase acting on the diglycerides produced by a phosphatidylinositol-specific phospholipase C (120).

Jørn Dyerberg (DK) and Hans Olaf Bang (DK) suggested for the first time a close relationship between platelet aggregation, bleeding time, and n-3 polyunsaturated fatty acids (522).

 

Walter Dallas (US) and Stanley Falkow (US), using E. coli minicells, determined the proteins encoded by the heat-labile enterotoxin (LT) gene were identified and the structure of LT was found to be similar to that of cholera toxin (447).

 

Joseph A. Martial (US), Robert A. Hallewell (US), John D. Baxter (US), and Howard Michael Goodman (US) used mRNA to clone complementary DNA for human growth hormone, i.e., chorionic somatomammotropin. The cloned DNA was inserted into E. coli using a plasmid vehicle with the result that the bacteria produced human growth hormone (1291).

 

Roger David Kornberg (US), Brad W. Baer (US), Paul Berg (US), Richard J. Bram (US), and Yahli Lorch (US) performed pioneering studies of the components involved in the regulation of eukaryotic gene expression (82; 137; 140; 225; 1094; 1223).

 

Lynna Hereford (US), Karen Fahrner (US), John Woolford, Jr. (US), Michael Rosbash (US), David B. Kaback (US), M. Mitchell Smith (US), Ólafur S. Andrésson (GB), and Kenneth Murray (GB) cloned the Saccharomyces cerevisiae genes encoding the four core histones, H2A, H2B, H3, and H4 (861; 1758; 1759).

Yahli Lorch (US), Janice W. LaPointe (US), and Roger David Kornberg (US) presented evidence that nucleosomes inhibit the initiation of transcription but allow chain elongation with displacement of histones (1224).

Paul S. Kayne (US), Ung-Jin Kim (US), Min Han (US), Janet R. Mullen (US), Fuminori Yoshizaki (US), and Michael Grunstein (US) found evidence that chromatin structure plays a key role in transcriptional silencing in Saccharomyces cerevisiae. These studies demonstrated that histone H4 mutants lacking their amino-terminal tails fail to silence HML and HMR (1028). This study led to the understanding that histone acetylation has a key role in transcriptional silencing.

Myeong-Sok Lee (US) and William T. Garrard (US) presented evidence that nucleosomes unfold to expose DNA during the transcription process (1156).

Joel N. Hirschhorn (US), Steven A. Brown (US), Chris D. Brown (US), and Fred Winston (US) found that the transcriptional activators Snf2/Swi2 and Snf5 activate transcription in yeast by altering chromatin structure. These proteins were envisioned to "function by removing or otherwise modifying nucleosomes" to allow transcription factors such as TATA-binding protein accessibility to their sites. (886).

Brian D. Stahl (US) and C. David Allis (US) expressed the popular concept that multiple types of histone modifications control transcription (1780).

 

Michael D. Grove (US), Gayland F. Spencer (US), William K. Rohwedder (US), Nagabhushanam B. Mandava (US), Joseph F. Worley (US), J. David Warthen, Jr. (US), George L. Steffens (US), Judith L. Flippen-Anderson (US), and J. Carter Cook, Jr. (US) discovered brassinosteroids (BRs), or brassins, which are a group of plant hormones. These steroid compounds were first found in rapeseed plant (Brassica napus) pollen. The best-known example of the brassinosteroids is brassinolide which controls plant development in response to light (776).

Takao Yokoda (JP) proposed a pathway for the synthesis of brassinosteroids (2083).

Jianming Li (US) and Joanne Chory (US) identified a plasma membrane receptor (BRI1) involved in brassinosteroid signal transduction (1190).

 

William G. Burton (US), Constance T. Grabowy (US), and Ruth Sager (US) showed that chloroplast DNA of Chlamydomonas is methylated and paternal DNA is not methylated (287).

 

Rolf Martin Zinkernagel (CH-US) and Peter Charles Doherty (AU-US) determined that infected host cells usually present microbial antigens on their surface in association with host structures encoded by the major histocompatibility (MHC) gene complex (2111).

 

J. Gregor Sutcliffe (US) described the complete nucleotide sequence of the Escherichia coli plasmid pBR322 and the strategy that was developed to ensure the accuracy of the results. The biological features encoded by the plasmid are interpreted through the sequence, as are features that enhance its value as a cloning vector (1832).

 

Har Gobind Khorana (IN-US) was the first to accomplish in vitro synthesis of a complete gene (tyrosine tRNA suppressor gene) (1040).

 

Jaime Renart (US), Jakob Reiser (US), and George R. Stark (US) developed a method (Western blotting) for detection of the protein products encoded by transcripts of genes. It is a rapid and sensitive method combining gel electrophoresis for fractionation, and electrophoretic transfer to a solid support for subsequent detection by specific antibodies (1559). Note: this is helpful in establishing how particular genes elicit specific phenotypes.

 

Michael H. Wigler (US), Raymond Sweet (US), Gee Kee Sim (US), Barbara Wold (US), Angel Pellicer (US), Elizabeth Lacy (US), Thomas Peter Maniatis (US), Saul J. Silverstein (US), and Richard Axel (US) made a conceptual breakthrough as they demonstrated that when a selectable gene is transfected into a mammalian cell together with a gene that is not subject to selection, both genes are incorporated into the genome of the host cell at the one site; and when selection for the selectable gene is applied, both genes are amplified synchronously (2028).

Michael H. Wigler (US), Angel Pellicer (US), Saul Silverstein (US), Richard Axel (US), and Gail Urlaub (US) demonstrate the feasibility of transforming mouse cells deficient in adenine phosphoribosyltransferase (aprt; AMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.7) to the aprt+ phenotype by means of DNA-mediated gene transfer. Transformation was affected by using unfractionated high molecular weight genomic DNA from Chinese hamster, human, and mouse cells and restriction endonuclease-digested DNA from rabbit liver (2026).

 

James F. Gusella (US), Aviva Varsanyi-Breiner (IL), Fa-Ten Kao (US), Carol Jones (US), Theodore Thomas Puck (US), Cheryl Keys (US), Stuart Holland Orkin (US), and David Housman (US) determined the precise localization of the human beta-globin gene complex on human chromosome 11 (791).

 

Charles Richard Madeley (GB) demonstrated the calicivirus using electron microscopy (1252). Calicivirus infections commonly cause acute gastroenteritis in humans.

 

Stephen M. Feinstone (US), Albert Zaven Kapikian (US), and Robert H. Purcell (US) used immune electron microscopy to identify a viral agent in the stools of patients with hepatitis A (594). This discovery quickly led to the development of tests to accurately detect antibodies to hepatitis A virus in the blood of those infected.

Philip J. Provost (US) and Maurice Ralph Hilleman (US) showed that cultured mammalian cells are permissive to human hepatitis A virus (HAV) replication (1530).

Jeffrey I. Cohen (US), John R. Ticehurst (US), Stephen M. Feinstone (US), Betsy Rosenblum (US), and Robert H. Purcell (US) showed that RNA transcripts derived from a genome-length cDNA clone of human hepatitis A virus are infectious when transfected into cultured cells (388).

Alan Werzberger (US), Barbara Mensch (US), Barbara Kuter (US), Leora Brown (US), John Lewis (US), Robert D. Sitrin (US), William Miller (US), Daniel Shouval (IL), Brian Wiens (US), Gary B. Calendra (US), John Ryan (US), Philip J. Provost (US), David R. Nalin (US), Bruce L. Innis (US), Rapin Snitbhan (TH), Prayura Kunasol (TH), Thanom Laorakpongse (TH), Weera Poopatanakool (TH), Christine A. Kozik (TH), Saroj Suntayakorn (TH), Tithinun Suknuntapong (TH), Assad Safary (TH), Douglas B. Tang (TH), and John W. Boslego (TH) developed safe and very effective vaccines for prevention of hepatitis A (945; 2014).

 

John B. Corliss (US), Jack Dymond (US), Louis Gordon (US), John M. Edmond (US), Richard von Herzen (US), Robert Ballard (US), Kenneth Green (US), David Williams (US), Arnold Bainbridge (US), Kathy Crane (US), and Tjeerd van Andel (US) discovered hydrogen sulfide oxidizing bacteria (chemolithotrophs) acting as primary producers at a depth of 2500 meters in an oceanic trench northwest of the Galápagos Islands. A community of giant clams and tube worms feeding on the sulfur oxidizing bacteria surrounds hot water vents in this area (417).

Jacob J. Blum (US), Irwin Fridovich (US), Bridget E. Laue (US), and Douglas C. Nelson (US) reported that sulfur oxidizing bacterial endosymbionts are housed within the specialized spongy tissue organs (trophosome) of the tubeworm, Riftia pachyptila, and gill filaments of the crab, Calyptogena magnifica. In these deep sea hydrothermal environments, the microbes oxidize the hydrogen sulfide to obtain energy, converting carbon dioxide into organic compounds, which then are available for the nourishment of the invertebrates which lack digestive tracts (188; 1138; 1461).

 

Dan T. Stinchcomb (US), Kevin Struhl (US), Ronald W. Davis (US), Bonita J. Brewer (US), Walton L. Fangman (US), Joel A. Huberman (US), Loretta D. Spotila (US), Kevin A. Nawotka (US), Suflan M. el-Assouli (SA), and Leslie R. Davis (US) identified autonomously replicating sequences (ARS). These are short DNA elements that can direct replication of linked DNA molecules, and that therefore have the properties expected of replication origins (244; 921; 1804).

Stephen P. Bell (US) and Bruce Stillman (US) discovered a complex of six proteins, known as origin recognition complex (ORC) which binds to yeast replication origins in an ATP-dependent fashion, providing an essential platform on which further steps in DNA replication are based (121).

John F.X. Diffley (GB) and Julie H. Cocker (GB) provided evidence that a multiprotein pre-replicative complex accumulates on yeast replication origins in the G1 phase of the cycle (494).

John F.X. Diffley (GB), Julie H. Cocker (GB), Simon J. Dowell (GB), and Adele Rowley (GB) show here that yeast replication origins exist in two chromatin states during the cell cycle. In the postreplicative state, genomic footprints closely resemble those produced in vitro by the purified ORC and ABF1 proteins, indicating that the binding of these proteins to replication origins is not sufficient to drive the initiation of DNA replication. An additional region of protection overlapping the ORC footprint characterizes the prereplicative state. This prereplicative complex appears near the end of mitosis and persists through G1. After entry into S phase, origins return to the postreplicative state. Similarities in temporal regulation of the prereplicative state and the Xenopus licensing factor suggest that mechanisms limiting DNA replication to once per cell cycle may be conserved among eukaryotes (495).

 

Paul E. Baker (US), Steven Gillis (US), and Kendall A. Smith (US) established the first monoclonal cytotoxic T cell lines (86).

 

Steven Gillis (US), Gerald R. Crabtree (US), and Kendall A. Smith (US) produced results which indicate that a major mechanism of glucocorticoid mediated immunosuppression may occur at the level of the T cell growth factor (TCGF)-producing cell, resulting in the control of clonal expansion of activated T cells via inhibition (700).

 

Goro Eguchi (JP) was among the first to show that genomic DNA does not undergo irreversible changes in most cases of cell differentiation (546). Antibody forming cells are an exception to this rule.

 

Kunio Yamazaki (US), Masahiro Yamaguchi (JP), L. Baranoski (US), Judith Bard (US), Edward A. Boyse (US), and Lewis Thomas (US) found that urine is a potent source of the major histocompatability complex (MHC)-determined odors that distinguish individual mice. They observed that mice can distinguish other mice that have the same genes for the major histocompatibility complex, a part of the immune system that identifies "self" as opposed to “nonself” (2077).

 

Felipe Cabello (CL) and Kenneth N. Timmis (DE) realized that the genetic determinants for certain virulence characteristics, such as hemolysins, toxins and adhesive factors, could be carried by plasmids (302).

 

Eugene C. Butcher (US), Roland C. Scollay (US), and Irving L. Weissman (US) discovered leukocyte adhesion molecules and their role in lymphocyte trafficking (291-293).

 

Mapuera virus (MPRV) was isolated from the salivary glands of an apparently healthy fruit bat (Sturnira lilium) captured in the tropical rain-forest of Brazil in 1979 (1012).

Ginny W. Henderson (GB), Carolyn Laird (GB), Evelyn Dermott (GB), and Bertus K. Rima (GB) characterized the Mapuera virus (846).

 

Thomas L. Hale (US) and Peter F. Bonventre (US) used transmission electron microscopy to demonstrate that epithelial cells via an active endocytic process internalize Shigella flexneri (796).

 

Carol C. Halpern (US), William S. Hayward (US), and Hidesaburo Hanafusa (US) found that retroviruses with an incomplete, defective src oncogene could still produce tumors in animals. Viruses subsequently isolated from the malignant tumors had assembled a complete src gene, indicating that they had become oncogenic by capturing the missing portion of the src gene from the host-cell DNA (800).

 

E. Tokunaga (JP), S. Sasakawa (JP), K. Tamaka (JP), H. Kawamata (JP), Carolyn M. Giles (GB), Elizabeth W. Ikin (GB), Joyce Poole (GB), David J. Anstee (GB), William J. Mawby (GB), and Michael J.A. Tanner (GB) report two Japanese blood donors who are the first homozygous MkMk individuals described; their red cells lack, as expected, known antigens of the MNSs blood group system and also have no demonstrable MN-active and Ss-active glycoproteins. Both MkMk individuals have a naturally occurring atypical antibody in their serum (1897).

 

Richard W. Ashford (GB) found an unidentified coccidian in stools of patients in Papua New Guinea (confirmed as Cyclospora cayetanensis in 1993) (68). The disease would come to be called cyclosporiasis.

Rosemary Soave (US), Jitender P. Dubey (US), Leticia J. Ramos (US), and Muriel Tummings (US) found the same parasite (Cyclospora cayetanensis) in the stools of patients with HIV (1762).

Ynés R. Ortega (US), Charles R. Sterling (US), Robert H. Gilman (PE), Vitaliano A. Cama (US), and Fernando Diaz (PE) named the organism Cyclospora cayetanensis (1455; 1456). Since then it has been identified as the cause of several outbreaks of diarrhea and fatigue in both immunocompetent and immunosuppressed individuals. Cyclospora infections are transmitted in water and on fruit, but the original source is not known.

Charles W. Hoge (US), David R. Schlim (US), Ramachandran Rajah (NP), Mervyn Shear (ZA), J. Gregory Rabold (US), Peter D. Echeverria (US), and Jennifer Triplett (US) confirmed the parasite to be a coccidian. The significant association of CLB (coccidian-like or cyanobacterium-like body) with prolonged diarrhea, and the low rate of other enteropathogens in CLB cases, strongly supports the hypothesis that CLB is a new pathogen (900).

Peter L. Chiodini (GB) supported the name Cyclospora cayetanensis (362).

Rosemary Soave (US) and Warren D. Johnson Jr. (US) reported trimethoprim-sulfamethoxazole to be effective in treating Cyclospora cayetanensis infections (1763).

 

Tateaki Wakamiya (JP), Thomas F. McCutchan (US), Martin P. Rosenberg (US), and Maxine Frank Singer (US) present the nucleotide sequence of a defective variant of simian virus 40 and show that the variant contains several large deletions, an inversion, and several DNA sequences derived from the permissive monkey cells in which the virus was propagated. From their data, they surmise that the recombinational events that resulted in the formation of the variant did not depend on extensive homology between recombining segments (1961).

 

N. Jerry Chatterton (US) and John E. Silvius (US) showed that starch synthesis in the soybean plant is programmed to provide enough starch to support respiration during the dark period, at the expense of growth (354).

 

Ernest Beutler (US) and Carol West (US) introduced a new anticoagulant preservative, citrate-phosphate-dextrose-adenine (CPDA-1), which extends the shelf life of whole blood and erythrocytes to 35 days (154).

Ernest Beutler (US) and Carol West (US) found they could modify this solution to get a shelf life of 42-49 days (155).

 

Jack Hirsh (AU-CA), Michael R. Buchanan (CA), Gregory W. Albers (US), John E. Atwood (US), David G. Sherman (US), Richard A. Hughes (GB), and Stuart J. Connolly (CA) established the value of aspirin in the prevention of stroke (24; 275; 887; 888).

Herschel R. Harter (US), John W. Burch (US), Philip Warren Majerus (US), Nancy Stanford (US), James Albert Delmez (US), Charles B. Anderson (US), and Carol A. Weerts (US) discovered the ability of low-dose aspirin to prevent thrombosis by blocking thromboxane synthesis in the treatment of people at risk of heart attack, stroke, and other ailments associated with blood clots (823). Thromboxane is a platelet-made molecule that causes the constriction of blood vessels and aggregation of platelets.

Philip Warren Majerus (US) found that aspirin blocks the thrombin-stimulated production of the icosanoid mediator thromboxane A2 in platelets by a unique mechanism. The acetyl group of aspirin covalently acetylates the enzyme cyclooxygenase, thereby permanently inactivating it. This effectively blocks production of all icosanoids (1265).

 

Robert T. Giaquinta (US) provided strong evidence for the phloem loading of sucrose being coupled to a proton transport mechanism driven by a vectorial plasmalemma ATPase (686).

 

G.Y. Wang (CN), T.A. Yin (CN), and He Guanqing (CN) reported that the level of selenium in the diet is related to prevention of Keshan disease (5-7; 785; 1977; 2082).

 

Judy C. Chang (US) and Yuet Wai Kan (CN-US) identified a gene mutation that causes beta-thalassemia (351).

Richard Anthony Flavell (GB-US), René Bernards (NL), Jan M. Kooter (NL), Ernie de Boer (NL), Peter F.R. Little (AU), Gillian Annison (GB), Robert Williamson (AU), Lex H.T. van der Ploeg (NL), Antonius W.T. Konings (NL), M. Oort (NL), Dirk Roos (NL), and Luigi F. Bernini (NL) showed that thalassemia, a group of inherited anemias, are the result of genetic defects. They went on to describe the exact nature of these genetic defects and the abnormal type of globin chain(s) they form (146; 629; 1929).

Yuet Wai Kan (CN-US), Kathleen Y. Lee (US), Mario Furbetta (IT), Andrea Angius (IT), and Antonio Cao (IT) then developed prenatal DNA tests for beta-thalassemia that are responsible for a dramatic reduction in the incidence of this disease in the Mediterranean region (1005).

 

Sven Hammarstrom (SE), Robert C. Murphy (US), Bengt Ingemar Samuelsson (SE), David A. Clark (US), Charles Mioskowski (FR), and Elias James Corey (US) determined the structure of leukotriene C (804).

Robert A. Lewis (US), K. Frank Austen (US), Jeffrey M. Drazen (US), David A. Clark (US), Anthony Marfat (US), and Elias James Corey (US) identified the slow reacting substances (SRS) released during an anaphylactic reaction as leukotrienes (1182). These slow-acting but extremely potent substances cause blood vessels to constrict and lung tissue to contract.

Sven-Erik Dahlén (SE), Per Hedqvist (SE), Sven Hammarström (SE), and Bengt Ingemar Samuelsson (SE) announced that slow reacting substance (SRS-A) is a combination of the leukotrienes LTC4, LTD4 and LTE4. They hypothesized SRS-A to be a biochemical mediator of the asthma response (445).

James W. Weiss (US), Jeffrey M. Drazen (US), E. Regis McFadden, Jr. (US), Peter F. Weller (US), Elias James Corey (US), Robert A. Lewis (US), and K. Frank Austen (US) conducted the first human experiments on themselves, proving that leukotrienes caused the biological reactions of asthma (2009). This work stimulated a new class of asthma medications, leukotriene inhibitors, to be developed.

 

Richard W. Burg (US), Brinton M. Miller (US), Edward E. Baker (US), Jerome Birnbaum (US), Sara A. Currie (US), Robert Hartman (US), Yu-Lin Kong (US), Richard L. Monaghan (US), George Olson (US), Irving Putter (US), Josefino B. Tunac (US), Hyman Wallick (US), Edward O. Stapley (US), Ruiko Oiwa (JP), and Satoshi Ōmura (JP) isolated a strain of Streptomyces avermitilis that produces the anti-parasitical compound avermectin (279).

William Cecil Campbell (IE-US) discovered a substance remarkably effective against parasites occurring in farm animals. The bioactive agent was purified and named avermectin, then later modified and called ivermectin. The drug knocked out parasites in animals; when tested on humans it had the same powerful effect on the parasite larvae linked to river blindness (onchocrciasis) and to elephantiasis (lymphatic filariasis) (307; 308). Note: Merck Research Laboratories, announced that it would distribute ivermectin, its modified version of avermectin, without charge wherever it was needed. That altruism has hugely helped to combat onchocerciasis – aka river blindness – lymphatic filariasis and other parasitic diseases in Africa, Latin America and Yemen. According to the World Health Organisation, 98 million people in 31 African countries receive annual treatment through the programme. Since 2009 the WHO’s focus on river blindness has shifted from treatment to elimination.

 

Scott B. Halstead (US) demonstrated the antibody dependence of dengue virus infection in subhuman primates—a complex, outbred experimental host—supports the hypothesis that the severity of dengue in humans is regulated by antibody (801).

 

Jon Lindstrom (US) and many other workers demonstrated that both myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused by an antibody-mediated autoimmune response to acetylcholine receptors (1202).

 

Gerald F.M. Russell (GB) described and named bulimia nervosa (1626).

 

Ellen Solomon (GB) and Walter Fred Bodmer (GB) estimated that the sickle variant gene first appeared 2785 generations (or about 69,625 years BP). This suggests that the origin of the sickle allele might well predate the origin of the major human racial groups, although its striking increase in frequency was much more recent (1768).

 

Edward G.D. Tuddenham (US), Norma C. Trabold (US), John A. Collins (US), and Leon W. Hoyer (US) purified Factor VIII of the blood coagulation "cascade," which led to the molecular identification of the protein (1912). Note: Factor VIII was first discovered in 1937. Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A.

 

David P. Lane (GB), Lionel V. Crawford (GB), Daniel I.H. Linzer (US), Arnold J. Levine (US), Albert B. DeLeo (US), Gilbert Jay (US), Ettore Appella (US), Garrett C. Dubois (US), Lloyd W. Law (US), and Lloyd John Old (US) discovered p53 as a cellular protein bound by the monkey oncogenic virus SV40, or as a transformation associated protein in chemically induced tumors; p53 was originally thought to be an oncogene. Later studies showed that p53 is a tumor suppressor gene that is mutated in the germline of individuals with the Li-Fraumeni cancer pre-disposition syndrome and in 50% of diverse human tumors (480; 1131; 1207). See, Li, 1969; Harris, 1996; Levine, 1997; Dameron, 1994

 

Hugo W. Rudiger (AT), Julie Marxen (AT), F.-Valentin Kohl (AT), Hans Melderis (AT), and Peter von Wichert (AT) found DNA adducts in cells incubated with the carcinogen benzo(a)pyrene (1620).

Frederica P. Perera (US), I. Bernard Weinstein (US), Michael B. Kastan (US), Bonnie J. Gowans (US), Michael W. Lieberman (US) and Bruce Nathan Ames (US) found DNA adducts more commonly in cells from older persons. The detection of DNA damage products would be useful for identification of carcinogens and in epidemiologic studies (48; 1019; 1488).

 

Andreas R. Gruentzig (DE) and David A. Kumpe (US) described recanalization of superficial femoral artery occlusions and of stenoses in the superficial femoral and pelvic arteries using the Gruentzig balloon catheter (angioplasty) (780).

Andreas R. Gruentzig (DE), Ake Senning, (SE) and Walter E. Siegenthaler (CH) described their technique of percutaneous transluminal coronary angioplasty (PTCA) as used in 50 patients (781).

 

Graeme Milbourne Clark (AU), Ingeborg Hochmair (AT), Blake S. Wilson (US), Peter A. Busby (AU), Lesley A. Whitford (AU), Peter John Blamey (AU), Alison M. Brown (AU), P.A. Gusby (AU), Richard C. Dowell (AU), Burkhard K.H. Franz (AU), Brian C. Pyman (AU), Robert Keith Shepherd (AU), Yit C. Tong (AU), Robert L. Webb (US), M.S. Hirshorn (AU), Janusz A. Kuzma (US), Dianne J. Mecklenburg (AU), David K. Money (AU), James F. Patrick (AU), Peter M. Seligman (AU), Louise M. Richardson (AU), Quentin R. Bailey (AU), Ingeborg J. Hochmair-Desoyer (AT), Erwin S. Hochmair (AT), Richard E. Fischer (AT), Kurt Burian (AT), Helmut K. Stigbrunner (AT), Charles C. Finley (US), Dewey T. Lawson (US), Robert D. Wolford (US), Mariangeli Zerbi (US), Donald K. Eddington (US), William M. Rabinowitz (US), and Michael F. Dorman (US) developed the modern cochlear implant, a device that restores hearing to individuals with profound deafness (289; 372; 373; 895-897; 2033-2035).

 

Karl Victor Hall (NO), Robert L. Kaster (US), and Arne Wøien (NO) developed a pivotal disc prosthetic heart valve. This prosthetic valve has no welds, joints, or bends that can eventually weaken the valve's structure (797). This is the Medtronic-Hall Valve.

 

Timothy Cooke (GB), D. George (GB), R. Shields (GB), Paul V. Maynard (GB), and Keith Griffiths (GB), in a single-center prospective cohort series trial, found that breast cancer recurrance rate was related to the presence or absence of estrogen. Breast cancer recurrence rates were significantly higher in patients whose tumors were estrogen receptor-negative, irrespective of whether they were pre- or post-menopausal. The highest recurrance rates were seen in patients with axillary metastatic nodal disease who were estrogen receptor-negative (412). See Beatson, 1896

 

John G. West (US), Donald D. Trunkey (US), and Robert C. Lim (US) performed a retrospective review of the results of trauma care in two different healthcare systems . They suggested that survival rates for major trauma can be improved by an organized system of trauma care that includes the resources of a trauma center (2015).

 

T. Andrew (GB) and W.A. Wallace (GB) showed that when treating an ingrowing toenail, the use of phenol cauterization compares favorably with Zadik's procedure in both onychogryphosis and ingrowing toenails (57).

James D. Greig (GB), J.H. Anderson (GB), A.J. Ireland (GB), and J.R. Anderson (GB) suggested that nail edge excision with phenolization is a logical and efective treatment for ingrowing toenails in which conservative treatment has failed and for those in which recurrence has followed previous surgical procedure (766).

A. M. C. Bos (NL), Marc W. A. van Tilburg (NL), Adriaan A. van Sorge (NL), and Jean H. G. Klinkenbijl (NL) found that partial nail avulsion with phenolization gave better results than partial avulsion with matrix excision. Local antibiotics did not reduce signs of infection or recurrence. Use of phenol did not produce more signs of infection than matrix excision (203).

 

David Frederick Attenborough (GB), beginning in 1979, produced and narrated a series of natural history films which have become benchmarks of quality in wildlife film-making. These films included: First Life, Life on Earth, The Living Planet, The Trials of Life, Life in the Freezer, The Private Life of Plants, The Life of Birds, The Life of Mammals, Life in the Undergrowth, Life in Cold Blood, Life on Land, The First Eden, Lost Worlds, and Vanished Lives.

 

Stephen P. Hubbell (US) studied patterns of tree abundance and dispersion in a tropical deciduous (dry) forest. He concluded that all species were either clumped or randomly dispersed, with rare species more clumped than common species. Breeding system was unrelated to species abundance or dispersion, but clumping was related to mode of seed dispersal (919).

 

Richard D. Alexander (US), John L. Hoogland (US), Richard D. Howard (US), Katharine M. Noonan (US), and Paul W. Sherman (US) explained that species in which sexes are the same size tend, with some exceptions such as horses, not to have harems. Species in which males are markedly bigger than females tend to have harems, or to practice some other form of polygyny (28).

 

Pere Alberch (US), Stephen Jay Gould (US), George F. Oster (US), and David B. Wake (US) formalized the notion of ‘ontogenetic trajectories’and proposed a formal lexicon of heterochrony terms (23).

 

Stephen Jay Gould (US) and Richard C. Lewontin (US) wrote this paper, which marks the beginning of the modern era of constraint theory and a critique of the adaptationist programme (749).

 

Richard Evans Schultes (US) and Albert Hofmann (US) wrote Plants of the Gods: Origins of Hallucinogenic Use, a very influential book (1690).

 

Guy Ourisson (FR), Pierre Albrecht (FR), and Michel Michel Rohmer (FR) noted that fossil triterpenes, the “geohopanoids,” ubiquitous and abundant in sediments, are useful in petroleum exploration. Their varied structures (>200 so far) are linked to conditions of deposition and extent of maturation. Their precursors, the biohopanoids,” are cholesterol surrogates stabilizing bacterial membranes, a role played in all living organisms by polyterpenoids. Biohopanoids form a phylogenetic series and may have played an important role in prebiotic chemistry (1460).

 

Mark E. Barley (AU), John S.R. Dunlop (AU), Joseph John Edmund Glover (AU), David I. Groves (AU), and Roger Buick (AU) concluded from their studies of sedimentary rocks in Western Australia that near 3.5 Ga there existed a shallow marine environment dominated by episodic island volcanism and hydrothermal activity (96; 778).

 

Luis Walter Alvarez (US), Walter Alvarez (US), Frank Asaro (US), Helen Michel (US), and Alessandro Montanari (IT) found convincing physical and chemical evidence that the great extinctions, which terminated the age of the dinosaurs, were related to the high-speed impact on Earth of a great asteroid estimated to have been about 10 km in diameter. The element of catastrophe was thus introduced into the studies of the evolution of life forms (42-44).

Alan K. Hildebrand (US), Glen T. Penfield (US), David A. Kring (US), Mark Pilkington (CA), Z. Antonio Camargo (MX), Stein B. Jacobsen (US), and William V. Boynton (US) discovered the Chicxulub (shick-zoo-loob) crater in the Yucatán Peninsula, supporting the asteroid impact theory (870; 1483; 1484).

Digby J. McLaren (CA) and Wayne D. Goodfellow (CA) presented a model for the environmental effects of large asteroid and comet impacts and some evidence for large impact events at most of the major extinction horizons (1321).

 

Tamara Anastasevna Ishchenko (RU) and R.N. Shylokov (RU) discovered fossil Marchantiales in lower Middle Devonian material from the USSR providing evidence that some major bryophyte divisions were well established by the Lower Devonian and that the bryophytes in general must have played a part in the initial colonization of land by plants (950).

 

John R. Horner (US) and Robert Makelar (US) reported several fossilized dinosaur nests, which proved to them that some dinosaur parents cared for their young and even led to more evidence for the warm bloodedness theory. They were discovered by Marion Brandvold (US) in terrestrial sediments of the Two Medicine Formation (Upper Cretaceous) near Choteau, Teton County, Montana (908).

John R. Horner (US) reported discoveries in the late Cretaceous (Campanian) sediments of the Two Medicine Formation of western Montana indicating that some dinosaur species, like some modern species of birds and crocodiles, nested in colonies. This suggests that they may have moved about in a herd (907).

 

Francois Lèvèque (FR) and Bernard Vandermeersch (FR), in 1979, found fossil remains of a Homo sapiens neanderthalensis; Homo neanderthalensis near Saint-Césaire in Southwestern France. The specimen has been dated between 34,000 and 31,000 BP (1173). This may well be the most recent Neanderthal known.

 

Knut R. Fladmark (CA) has been one of the most vocal supporters of the proposal that humans from Siberia may have traveled along the Pacific coastlines as they populated North and South America (628).

 

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; NP = Nepalese; NZ = New Zealander; NG = Nigerian; NO = Norwegian; PK = Pakistani; PA = Panamanian; PE = Peruvian; PH = Filipino; PL = Polish; PT = Portuguese; PR = Puerto Rican; RO = Romanian; RU = Russian; SA = Saudi Arabian; SN = Senegalese; CS = Serbian-Montenegrin; SK = Slovakian; Slovenian = SI; ZA = South African; ES = Spanish; LK = Sri Lankan; SE = Swedish; CH = Swiss; SY = Syrian; TW = Taiwanese; TH = Thai; TT = Trinidadian; TN = Tunisian; TR = Turkish; UG = Ugandan; UA = Ukrainian; UY = Uruguayan; VE = Venezuelan; ZW = Zimbabwean

 

 

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