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



“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 tRNAPHE 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 tRNAPHE 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 tRNAPHE 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