A Selected Chronological Bibliography of Biology and Medicine

 

Part 5A

 

c. 1948 — 1956

 

 

Compiled by James Southworth Steen, Ph.D.

Delta State University

 

Dedicated to my loving family

 

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

 

Please forward any editorial comments to: James S. Steen, Ph.D., Professor Emeritus, DSU Box 3262, Cleveland, MS 38733. jsteen08@bellsouth.net










 

c. 1948

Julius Hyman (US-GB) discovered that cyclopentadiene reacts with acetylene to give bicyclo [2.2.1] hepta-2, 5-diene (norbornadiene) as a stable product. It was then reacted with hexachlorocyclopentadiene (hex) to yield aldrin (1417).

 

1948

The surgeon who is his own physician, though he often has a fool for a colleague, has the happiness of working in an atmosphere of mutual confidence and admiration.” William Heneage Ogilvie (1338).

 

“It has become apparent over a period of years that even when a histologic diagnosis of malignant melanoma has been made in children the clinical behavior rarely has been that of a malignant tumor. The disparity in behavior of the melanomas of adults and children, despite the histologic similarity of the lesions occurring in the different age groups, is obviously a matter of fundamental importance …” Sophie Spitz (1690).

 

Arne Wilhelm Kaurin Tiselius (SE) was awarded the Nobel Prize in Chemistry for his research on electrophoresis and adsorption analysis, especially for his discoveries concerning the complex nature of the serum proteins.

 

Paul Hermann Müller (CH) was awarded the Nobel Prize in Physiology or Medicine for his discovery that dichloro-diphenyl-trichloroethane (DDT), also called 2,2-di (4-chlorophenyl)-1,1,1-trichloroethane, is a potent insecticide.

 

Lyman T. Aldrich (US) and Alfred Otto Carl Nier (US) provided absolute confirmation that 40Ar is the decay product of 40K when they measured significantly increased 40Ar/36Ar ratios on argon extracted from potassium-rich minerals relative to the atmospheric 40Ar/36Ar ratio (15). This set the stage for the rapid development of the K-Ar dating method. This dating technique is most useful between 10,000 and 3 billion years.

 

Bernard Leonard Horecker (US) and Arthur J. Kornberg (US) determined the precise extinction coefficients of both reduced diphosphopyridine nucleotide (DPNH) (cozymase I) and reduced triphosphopyridine nucleotide (TPNH) (reduced coenzyme II) at 340 nanometers. The values proved to be identical (875). This work made possible quantitative spectrophotometric measurements in reactions involving the pyridine nucleotides and became one of the most frequently cited papers in biochemical literature. Note: DPN became NAD and TPN became NADP.

 

Dorothy Mary Crowfoot-Hodgkin (GB) and Jack D. Dunitz (CH) determined the structure of calciferol (vitamin D) (377).

Gui-Dong Zhu (US) and William H. Okamura (US) synthesized vitamin D (1957).

 

Bernard Beryl Brodie (US) and Julius Axelrod (US) investigated the fate of acetanilide in the human body and concluded that it exerts its analgesic actions through N-acetyl-p-aminophenol (now known as acetaminophen) (226). In the early 1970s Johnson & Johnson marketed N-acetyl-p-aminophenol as Tylenol.

 

Daniel C. Pease (US) and Richard Freligh Baker (US) reliably prepared thin sections (0.1 to 0.2 micrometers thick) of biological material (80; 1397; 1398).

George Eugene Moore (US) described how radioactive di-iodofluorescein could be used to diagnose and localize brain tumors (1265).

Linus Carl Pauling (US) proposed the principle of transition-state stabilization to explain enzyme catalysis (1380).

 

Stanford Moore (US) and William Howard Stein (US) introduced partition chromatography on starch gel columns (1269). This technique was quickly modified using an ion-exchange resin (sulfonated cross-linked polystyrene), in 1951, and an automatic recording assembly to detect chemicals (amino acids) as they emerged from the column (1272; 1684). This apparatus for the first time allowed the complete amino acid analysis of protein hydrolysates.

 

Charles H. Lack (GB) reported that several workers had reported the lysis of fibrin clots by staphylococci, and this has been assumed to be due to a fibrinolysin produced by the bacteria (1033). Note: This fibrinolysis it turns out was due to staphylokinase.

 

Daniel Luzon Morris (US) discovered that a solution of anthrone in 95% sulfuric acid produces a characteristic blue color when added to twice its volume of a water solution of carbohydrates. The depth of color can be used for quantitative determination of sugars and polysaccharides even when these are chemically combined. The effective range is from 20-500 micrograms. Prior hydrolysis to convert sugars to the free state is not needed; thus, the reagent can be used for the quick determination of total carbohydrates in a mixture in terms of their glucose equivalent. Glycogen, starch, sucrose and other glucosides have been accurately measured (1277).

 

Elvin Abraham Kabat (US) and Manfred Martin Mayer (DE-US) wrote Experimental Immunochemistry, the first great text in immunochemistry (943). They revised it in 1961 to include, among other things, Mayer’s discoveries concerning the complement cascade.

 

Harry G. Albaum (US), and Milton Kletzkin (US) established conclusively the presence in Drosophila melanogaster adults of an ATP with the same physical, chemical, and physiological properties as vertebrate ATP (14).

 

Moses Kunitz (RU-US) described the isolation of deoxyribonuclease in crystalline form from beef pancreas (1028).

 

Morris Friedkin (US) and Albert Lester Lehninger (US) provided experimental proof that electron transport from NADH to oxygen is the direct source of the energy used for the coupled phosphorylation of ADP. Pure NADH was incubated aerobically with water-treated mitochondria, phosphate, and ADP in the absence of tricarboxylic acid cycle intermediates or any other added organic metabolite. (The hypotonic water treatment was necessary to make the mitochondria permeable to NADH.) The NADH was rapidly oxidized to NAD+ at the expense of molecular oxygen; simultaneously, up to three molecules of ATP were formed from ADP and phosphate. Such experiments indicated that at three points in the chain of electron carriers leading from NADH to oxygen, oxidation-reduction energy is transformed into phosphate-bond energy (629; 1072).

 

Benjamin Minge Duggar (US) discovered and introduced Aureomycin (chlortetracycline), the first of the tetracycline antibiotics. It is produced by Streptomyces aureofaciens (501). The tetracyclines block binding of aminoacyl-tRNA to the A-site of the ribosome in prokaryotes only.

 

Allan L. Grafflin (US), Dina E. Green (US), W. Eugene Knox (US), Betty N. Noyce (US), and Victor H. Auerbach (US) discovered that the process of beta-oxidation of fatty acids is localized in mitochondria (688; 994).

 

Peter Wilhelm Joseph Holtz (DE) and Hans-Joachim Schümann (DE) were the first to report the production of norepinephrine (noradrenaline) in the adrenal medulla (871).

 

Seymour Stanley Cohen (US) found that the nucleic acid of T2 phage is exclusively of the DNA type and that within 7-10 minutes following its infection of an Escherichia coli cell the metabolic activity of the host cell is directed to production of virus DNA in large amounts. He also found that the phosphorus contained within the newly synthesized viral DNA is largely derived from inorganic phosphorus in the culture medium (330-332).

 

August H. Doermann (US) discovered that with bacteriophages the infectivity associated with the original parental phage is lost at the outset of the reproductive process, since no infective phages whatsoever were found in any of the infected bacteria lysed artificially within the first ten minutes following infection. The time course that elapses between infection and the first intracellular reappearance of infective phage particles is called the eclipse (477-479).

 

Edward B. Lewis (US) studied position pseudoallelism in Drosophila (1109-1112).

 

Sol Sherry (US), William Smith Tillet (US), and L. Royal Christensen (US) discovered that some strains of hemolytic streptococci produce a streptococcal deoxyribonuclease that they named streptodornase (1618; 1766).

 

Jacques Lucien Monod (FR), Madeleine Jolit (FR), and Anne-Marie Torriani (FR) isolated lactase (beta-galactosidase) and amylomaltase from Escherichia coli strain ML (1260).

 

Alexander A. Krasnovsky (RU) discovered that in the presence of appropriate chemical reagents, chlorophyll a in solution is reversibly reduced in light (1023).

 

Stanford Moore (US), William Howard Stein (US), Christophe Henri Werner Hirs (US), Christian Boehmer Anfinsen, Jr. (US), Robert R. Redfield (US), Darrel H. Spackman (US), Derek G. Smyth (US), Warren L. Choate (US), Juanita Page (US), William R. Carroll (US), John Thomas Potts, Jr. (US), Arieh Berger (US), and Juanita Cooke (US) determined the primary structure for ribonuclease. This was the first enzyme to have its primary structure solved (36; 836-838; 1270; 1271; 1429; 1487; 1662; 1663; 1685; 1708; 1709).

Gopinath Kartha (US), Jake Bello (US), and David Harker (US) determined the tertiary structure of ribonuclease (953).

Harold W. Wyckoff (US), Karl D. Hardman (US), Norma M. Allewell (US), Tadashi Inagami (US), Louise N. Johnson (GB), Frederic Middlebrook Richards (US), William D. Carlson (US), Byungkook Lee (US), and Yukio Mitsui (JP) determined the tertiary structure of ribonuclease-S at 3.5 angstrom resolution (1500; 1940).

 

Philip Pacy Cohen (US) and Santiago Grisolia (CL) demonstrated the fixation of carbon into the carbonyl group of citrulline and into urea and concluded that citrulline is an obligate intermediate in the urea synthesis cycle (323).

Philip Pacy Cohen (US) and Santiago Grisolia (CL) concluded that in the synthesis of citrulline from ornithine, carbamyl-L-glutamic acid is an intermediate (322; 324).

 

E.S. Guzman Barron (US) and Theodore N. Tahmisian (US) provided sufficient evidence to establish that the Krebs cycle is present in the tissues of insects (97).

 

Koloman Laki (HU-US) and Laszlo Lorand (HU-US) partially purified the plasma protein that became known as the Laki-Lorand factor or fibrin-stabilizing factor, and presently as factor XIII (1036).

Renne Chen (US) and Russell F. Doolittle (US) found that the stabilization of fibrin clots by activated factor XIII involves two different sets of cross-linked chains (300).

 

Walter C. Schneider (US) developed a method for separating the various subcellular fractions by homogenizing tissues in isotonic sucrose and subjecting the homogenate to differential centrifugation (1591).

 

J. Walter Wilson (US) and Elizabeth H. Leduc (US) discovered the occurrence and formation of binucleate and multinucleate cells and polyploid nuclei in the mouse liver (1909).

 

Frank John Fenner (AU) studied the pathogenesis of ectromelia virus in mice (in which it causes fatal hepatitis) (578; 579). This work became a classic and has served as a model for such studies ever since.

 

Roy Markham (GB), Richard Ellis Ford Matthews (NZ), and Kenneth M. Smith (GB) purified and characterized an isometric plant virus, Turnip yellow mosaic virus. They showed that its infectivity depends on the presence of viral RNA, thus concluding that nucleic acid is essential for virus multiplication. For the first time RNA was shown to be capable of genetic behavior independent of DNA (1179).

 

Bernard David Davis (US), Joshua Lederberg (US), and Norton David Zinder (US) developed methodology for direct selection of bacterial auxotrophs (403; 405; 1070).

 

Ludmila Andreevna Kuprianova (RU) illuminated the pollen morphology of the monocotyledons (1029).

 

Harry Alfred Borthwick (US), Sterling Brown Hendricks (US), and Marion Wesley Parker (US) found that the action spectrum for floral induction in winter barley, a long-day plant, is very similar to that for the prevention of floral induction in soybean and cocklebur. In all three plants the active portion of the spectrum lies between 600 and 660 nm. The spectral sensitivity and energy requirements for stem elongation are very similar suggesting that the formation of flowers and stem elongation are linked to and dependent upon one another. They speculated that a light absorbing pigment is common to these processes (197). Sterling Brown Hendricks constructed an absorption curve for C-phycocyanin and found it to be remarkably like the action spectra for floral initiation and leaf growth (1370).

Harry Alfred Borthwick (US), Sterling Brown Hendricks (US), Marion Wesley Parker (US), Eben Henry Toole (US), and Vivian Kearns Toole (US) showed that the photoreceptor is very likely a photoreversible pigment in which absorption of red light (R) converts it into a form which absorbs far red light (FR) and vice versa. The wavelengths to which the seeds were last exposed, either R or FR, determine whether they were induced to germinate or inhibited (198).

Peter Herman Heinze (US), Albert Aloysius Piringer (US) and Harry Alfred Borthwick (US) determined that the photoperiodic pigment controls skin coloring in tomatoes (785; 1416).

Harry Alfred Borthwick (US), Sterling Brown Hendricks (US), Eben H. Toole (US), and Vivian Kearns Toole (US) discovered that the action spectra for promotion and inhibition of germination of Grand Rapids lettuce seeds seemed to be identical to the one that controlled flowering and stem and leaf growth. Maximum induction was at 660 nm with maximum inhibition at 710-750 nm (199). According to Hendricks, “One could hardly believe such an astounding result, showing that the control by light of a phenomenon at the start and termination of plant growth—the germination of the seed and the eventual flowering of the plant—were the same not only in a qualitative sense but on an absolute basis as well” (790).

Warren Lee Butler (US), Karl H. Norris (US), Harold William Siegelmann (US), and Sterling Brown Hendricks (US) worked out methods for detection, assay, and preliminary purification of the pigment controlling photoresponsive development of plants. They named the R-absorbing form of the pigment P655 and the FR-absorbing form P735 (256). Shortly thereafter the pigment was named phytochrome (Greek=plant color) with the R-absorbing form called Pr and the FR-absorbing form called Pfr (196; 1795).

 

David Pressman (US) and Geoffrey Keighley (US) attempted to create radiolabeled antibodies (1433).

David Pressman (US) and Leonhard Korngold (US) demonstrated that antibodies could be artificially complexed with a toxic material then act as a carrier of the toxin to a target cell. They showed that labeled antibodies against Wagner osteosarcoma were concentrated in vivo in these tumors (1014; 1434).

David Pressman (US), Eugene D. Day (US), and Monte Blau (US) introduced the paired labeling method in which both antibodies and a control preparation of IgG, each labeled with a different isotope are injected simultaneously into the same tumor-bearing animal. The measurement of radioactivity from each isotope in a dual channel scintillation counter allows one to distinguish the specific localization of antibodies in a tumor from the nonspecific accumulation of normal IgG, which is known to occur in the inflammatory and necrotic regions of the tumor (1432).

 

A. Stanley Holt (US) and Charles Stacy French (US) showed the isotopic composition of oxygen liberated by the Hill reaction from 18O-enriched water to follow that of water—thus proving that this reaction is a photochemical oxidation of water (870).

 

William Wayne Kielley (US) and Otto Fritz Meyerhof (DE-US) were the first to isolate sarcoplasmic reticulum as particulate material. It was found to possess ATPase activity stimulated by magnesium ions and inhibited by calcium ions (978).

 

William F. Loomis (US) and Fritz Albert Lipmann (DE-US) were the first to discover a chemical that will allow electron flow in oxidative phosphorylation but uncouple it from the phosphorylation of ADP to ATP. The uncoupling agent was 2,4 dinitrophenol (1142).

 

Alfred Ezra Mirsky (US), Hans Ris (CH-US), André Félix Boivin (FR), Roger Vendrely (FR), and Colette Vendrely (FR) reported that the amount of DNA per set of chromosomes is in general constant in different cell types of an organism. Moreover, the DNA content per chromosome set is a characteristic of each species and the DNA content of haploid and diploid nuclei is roughly in the ratio of 1:2 (188; 1239; 1506; 1813; 1814).

 

Gerald C. Mueller (US) and James A. Miller (US) were the first to demonstrate the oxidative metabolism of a carcinogen, 4-dimethylaminoazobenzene (DAB), in a cell-free system containing rat liver microsomes/ribosomes (1287).

Julius Axelrod (US) discovered a new class of enzymes, later called cytochrome P450 dependent monooxygenases (CYPs), which exert a profound influence in many areas of research, including metabolism of drugs, metabolism of normally occurring compounds, and investigations of carcinogenesis (67-73).

Allan H. Conney (US), Elizabeth C. Miller (US), and James A. Miller (US) provided the first evidence that certain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs), can promote their own metabolism through induction of microsomal proteins (345).

Tsuneo Omura (JP) and Ryo Sato (JP), David Y. Cooper (US), Otto Rosenthal (US), and Ronald W. Estabrook (US) discovered cytochrome P450 and suggested that this hemoprotein functions in the oxidation of certain chemicals (1341-1344). Note: Martin Klingenberg published a paper reporting the presence of a redox pigment in liver microsomes/ribosomes in 1958.

Anthony Y.H. Lu (US) and Minor Jesser Coon (US) determined that cytochrome P450 dependent monooxygenases (CYPs) are associated with an NADPH-dependent reductase (1151).

Masayuki Katagiri (JP), Bimal Naresh Ganguli (IN), and Irwin Clyde Gunsalus (US) were able to separate the methylene hydroxylase system from Pseudomonas putida into three fractions: a putidaredoxin reductase, putidaredoxin (an iron-sulfur protein), and a soluble cytochrome P-450 (P-450cam). The three enzymes were shown to function together to catalyze the hydroxylation of methylene carbon 5 of camphor (954).

Chang-An Yu (US), Irwin Clyde Gunsalus (US), Masayuki Katagiri (JP), Katsuko Suhara (JP), and Shigeki Takemori (JP) purified and crystallized cytochrome P-450cam and reported some of its general properties (1952). Eventually, Gunsalus and his colleagues published the amino acid sequence of bacterial cytochrome P-450 and solved its three-dimensional structure.

David A. Haugen (US) and Minor Jesser Coon (US) established beyond doubt the presence of at least two P-450 isoforms in liver (765). CYP enzymes mainly catalyze the initial step during conversion of organic xenobiotics into hydrophilic and excretable derivatives. Nucleophilic or chemically inert compounds such as aromatic and heterocyclic amines, aminoazo dyes, PAHs, N -nitrosamines, halogenated olefins, and others represent the great majority of human carcinogens. As these chemicals do not react directly with cellular constituents—they require enzymatic conversion into their ultimate carcinogenic forms—they are termed procarcinogens.

 

Richard W. Pohl (DE) was the first to demonstrate a circadian rhythm in a unicellular organism, Euglena gracilis. The recorded variables were photo accumulation in a beam of light, cell motility, and cell division (1419).

 

Elmer R. Roth (US), E. Richard Toole (US), and George Henry Hepting (US) determined that littleleaf disease in Southern pines results from a progressive deficiency of nitrogen brought about by complex interaction among certain soil conditions, feeder-root pathogens, land use practices, and stand density (1526).

 

Robert William Berliner (US) and Thomas J. Kennedy, Jr. (GB), in the normal dog, reported a constant rate of potassium excretion, dissociated from filtered load, occurring after salyrgan administration suggested a tubular secretory mechanism located, presumably, in the distal tubule. The presence of such a mechanism has been demonstrated by the intravenous administration of hypertonic potassium chloride solutions which yielded rates of potassium excretion considerably above the rates of filtration of potassium at the glomerulus (138).

 

Ignace H. Vincke (BE) and Marcel Lips (BE) isolated the first known rodent malarial parasite, Plasmodium berghei. It was found in the blood of a thicket rat in Katanga (now Zaire) Africa (1817).

 

William D. M. Paton (GB) and Eleanor J. Ziamis (GB) while developing muscle relaxants using anesthetized cats and rabbits discovered that decamethonium produces neuromuscular block, and hexamethonium produces ganglionic block. Hexamethonium, is the first effective drug for the treatment of high blood pressure. Although this ganglionic blocker is effective in reducing blood pressure in humans it has undesirable side effects because of its action on many different nerve reflexes (1373).

 

Raymond Perry Ahlquist (US) graded the reaction of a series of six sympathomimetic amines on vasoconstriction, the pupil, heart, gut and uterus. He found their action to be inhibitory or excitatory depending on the site of action. He concluded that the relative density and location of two types receptors (alpha and beta) determined opposing responses at different locations (10). Ahlquist conceived the theory that there must be two types of receiving mechanisms, or sites, in the cardiovascular system—one type prevailing in the heart, and the other in the blood vessels. These receptors, which receive "messages" from the sympathetic nervous system, were classified and named by him, alpha and beta. Because they are receptors for adrenaline and adrenaline-like substances, they are known as "adrenergic" receptors. Ahlquist further postulated that the predominant adrenergic receptors in the heart are of the beta type, and affect its contraction, its rate and its rhythm. See James Whyte Black, 1962.

 

Charles A. Owen, Jr. (US) and Jesse L. Bollman (US) discovered what would later be called factor VII of the blood clotting mechanism (1348).

Fritz Koller (CH), Emil A. Loeliger (NL) and Francois Henri Duckert (CH) identified the same factor, which they named factor VII (1003).

 

Peter Brian Medawar (GB) found that the brain performs quite poorly when challenged to set up a primary immune response to a locally introduced antigen, i.e., the brain is an immunologically privileged site (1210).

 

Bodil M. Schmidt-Nielsen (DK-US), Knut Schmidt-Nielsen (DK-US), Adelaide Brokaw (US), Howard Schneiderman (US), Humio Osaki (US), Herschel V. Murdaugh, Jr. (US), and Roberta O'Dell (US) suggested that urea must be actively secreted. At this time their studies could not determine the precise nephron segment where the secretion takes place (1294; 1578; 1579; 1583; 1586).

Satoshi Kawamura (JP), Juha P. Kokko (US), Akihiko Kato (US), and Jeff M. Sands (US) found in subsequent tubule perfusion studies conclusive evidence that urea was actively secreted in two different nephron segments: first, in the straight segment of the rabbit proximal tubule; and second, in the terminal portion of the rat inner medullary collecting duct (955; 956).

 

Seymour Solomon Kety (US) and Carl F. Schmidt (US) reported that the brain, which comprises only 2% of the body weight of man, receives for its nutrition one-sixth of the heart’s output of blood and consumes one-fifth of the oxygen utilized by the body at rest (976).

 

George Davies Snell (US) studied tissue transplantation among inbred strains of mice and coined the term histocompatibility antigens to describe those gene products responsible for tissue compatibility. The genes that code for these antigens he called histocompatibility genes (1668).

Peter A. Gorer (GB), Stewart D. Lyman (GB), and George Davies Snell (US) discovered the major histocompatibility complex in mice; later named the H-2 locus (683).

Frank Macfarlane Burnet (AU) and Frank John Fenner (AU), based on Ray David Owen’s observations and on studies of lymphocytic choriomeningitis virus by Erich Traub, postulated that immunological self-recognition is not genetically determined but rather is learned by the immune system during the organism’s embryonic stages, i.e., immunological tolerance develops during embryonic life. They predicted that antigen introduced prior to maturity of the immune mechanism would be mistaken for self then and throughout the life of the individual (249).

Diana Anderson (GB), Rupert Everett Billingham (GB-US), G.H. Lampkin (GB), and Peter Brian Medawar (GB) demonstrated mutual tolerance to skin grafts by freemartin cattle twins and speculated that actively acquired tolerance was responsible (30).

Rupert Everett Billingham (GB-US) and Peter Brian Medawar (GB) produced a primer to skin grafting in mammals. The impact of the paper has been greatly amplified in that it facilitated the later discovery of  actively acquired tolerance and the definition of the principal laws of transplantation tolerance (168).

Rupert Everett Billingham (GB-US), G.H. Lampkin (GB), Peter Brian Medawar (GB), and H.L.L. Williams (GB) while examining the fate of skin allografts in young cattle, with the objective of devising a test for distinguishing between fraternal and identical twins, found that skin grafts transplanted from one twin to the other were accepted, irrespective of the origin of the twins (167). Note: Cattle fetuses share a placenta, with the effect that the two blood systems communicate with each other and a free exchange of blood between the twins is possible.

Jean Baptiste Gabriel Joachim Dausset (FR) and André D. Nenna (FR) discovered isoagglutinins for the human leukocyte during a search for an immunologic etiology of leukopenia (400).

Peter Brian Medawar (GB) was the first to point out the immunologically privileged nature of the fetal allograft (1211).

Milan Hasek (CZ), in 1953, produced actively acquired donor specific tolerance to skin allografts in chickens by deliberately twinning chick embryos: using two embryonated hen's eggs he joined them by connecting their circulatory systems, ie., created a vascular bridge between them. When the chicks grew up he observed that they had lost the ability to form antibodies against the erythrocytes of their parabiotic partners . Note: This strongly supported Burnet's theory above.

Rupert Everett Billingham (GB-US), Leslie Brent (GB), and Peter Brian Medawar (GB) produced actively acquired donor specific tolerance to skin allografts in mice injected during late fetal life with donor hematolymphopoietic cells (164). Note: This strongly supported Burnet's theory above.

Jean Baptiste Gabriel Joachim Dausset (FR) reported the observation that the sera from 60 patients contained antibodies, which agglutinated lymphocytes from certain individuals. He noted that 90% of these patients had received multiple transfusions. Dausset concluded that transfusion was responsible for creating antibodies against leukocytes because of an immune response toward the donor (397).

Rupert Everett Billingham (GB-US), Leslie Brent (GB), and Peter Brian Medawar (GB) concluded that in mice the transplantation antigens are developed many days before birth (166).

Rupert Everett Billingham (GB-US), Leslie Brent (GB), and Peter Brian Medawar (GB) proposed that all the nucleated cells of different tissues of an individual have exactly the same antigenic make-up and that neonatal mice given foreign tissue would later treat it as selfimmunological tolerance— whereas older mice which had never experienced the same foreign material would treat it as non-self and respond immunologically (165).

Johannes Joseph van Rood (NL), J. George Eernisse (NL), Adriana van Leeuwen (NL), Rose Payne (US), and Mary R. Rolfs (US) found that pregnant mothers can be stimulated by their unborn child to produce human leukocyte agglutinins (HLA antibodies). The child and the mother must differ from one another in a leukocyte membrane antigen inherited from the father by the fetus (1396; 1804). Note: In 1967 the World Health Organization (WHO) named these human leukocyte antigens (HLA).

Jean Baptiste Gabriel Joachim Dausset (FR) introduced the first human histocompatibility antigen, MAC, named after the initials of three donors whose leukocytes did not agglutinate the test sera. This antigen is also known as HLA-A2. He showed that monozygotic twins exhibited identical agglutination patterns while dizygotic twins did not, which led him to hypothesize that leukocyte antigens are genetically controlled (398).

Johannes Joseph van Rood (NL) and J. George Eernisse (NL) discovered additional leukocyte antigens which they designated antigens 2 and 3 (1803).

Johannes Joseph van Rood (NL) and Adriana van Leeuwen (NL) were the first to use computers to make sense of the complex reactions produced by human antibodies, allowing identification of antigens currently known as HLA-B4 and 6, as well as leukocyte antigen grouping (1805).

Ruggero Ceppellini (IT), Emilia Sergio Curtoni (IT), Pier Luigi Mattiuz (IT), Vincenzo Miggiano (IT), Guido Scudeller (IT), and Antonio Serra (IT) coined the word haplotype to indicate the chromosomal combination of HLA alleles (283).

Results from a workshop in Torino during 1967 provided the first evidence that leukocyte antigens are the products of closely linked genes located on the same chromosome (283; 399; 1806).

Dennis Bernard Amos (US), and Fritz H. Bach (US) showed that the mixed leukocyte culture reaction was detecting the HLA-D locus (28).

John Richard Batchelor (GB) and Valerie C. Joysey (GB) analyzed the effect of graft incompatibility with respect to antigens of the HL-A system in 52 cases of cadaveric renal transplantation. It was concluded that prospective HL-A-antigen typing of donors and recipients should be carried out whenever possible, so that multiple incompatibilities can be avoided making graft survival more likely (103).

Jean Baptiste Gabriel Joachim Dausset (FR), Felix T. Rapaport (FR), Liliane Legrand (FR), Jacques Colombani (FR), and Aline Marcelli-Barge (FR) demonstrated the importance of HLA compatibility for the survival of skin grafts in unmodified human volunteers (401).

Thomas Earl Starzl (US), Kendrick Arthur Porter (US), Giuseppe A. Andres (US), Charles G. Halgrimson (US), Richard Hurwitz (US), Geoffrey Giles (US), Paul Ichiro Terasaki (US), Israel Penn (US), Gerhard T. Schroter (US), John R. Lilly (US), Selby John Starkie (GB), Charles W. Putnam (US), Max Ray Mickey (US), Miguel Kreisler (ES), Ekkehard D. Albert (US), and N. Tanaka (US) found that zero-HLA mismatching gives human kidney allografts their best chance for function, good histologic appearance, and least dependence on immunosuppression (1226; 1703).

Adriana van Leeuwen (DK), H. Riek Schuit (DK), and Johannes Joseph van Rood (NL) identified the first sera that could be used for HLA-DR typing. This formed the basis on which HLA-DR serology developed (1802). Note: HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31

Ans P.M. Jongsma (NL), Harry van Someren (NL), Andries Westerveld (NL), Ann Hagemeijer (NL), and Peter Pearson (NL) located the HLA genes on chromosome number 6 (940).

 

Austin Bradford Hill (GB) suggested that a statistical method of randomization be used to determine which treatment group each patient should be placed into in the streptomycin trial. It is because of Hill's efforts that the streptomycin trial is often cited as the first randomized controlled trial (RCT) in medical history; and that 1948 is celebrated as marking the beginning of a new era in modern medicine. See, Johannes Andreas Grib Fibiger, 1898.

In Britain, during the inter-war period, the Medical Research Council (MRC) collaborated with drug licensing bodies to systematize a methodology for making fair and reliable judgments about the efficacy of therapeutic interventions. By 1950 this methodology had evolved into the randomized controlled trial (RCT). It involved comparing different therapeutic interventions by casting lots to determine which patients would be assigned to which treatment groups. The MRC's Streptomycin Trial Committee was chaired by Philip D'Arcy Hart with Marc Daniels as Vice-Chairman and Austin Bradford Hill the statistician on the Committee (360; 816).

 

Francois Estrade (MG) was the first to successfully treat pneumonic plague (Yersinia pestis) patients. He used streptomycin (561).

Joseph E. Smadel (US), Theodore E. Woodward (US), C. Russell Amies (US), Kenneth Goodner (US), Fred R. McCrumb, Jr. (US), S. Mercier (), Jean-Marie Robic (FR) and M. Bouillot () successfully treated bubonic and pneumonic plague (Yersinia pestis) patients with the antibiotics chloramphenicol and terramycin (oxytetracycline) (1197; 1652).

 

Malcolm McCallum Hargraves (US), Helen Robinson (US), Robert J. Morton (US) described the lupus erythematosus cell which led to the subsequent discovery of antinuclear antibodies (758) and better understanding of the disease as one where immune complex deposition played a major role in tissue pathology and disease manifestations (741).

 

Sidney Farber (US), Louis Klein Diamond (US), Robert D. Mercer (US), Robert F. Sylvester (US), and James A. Wolff (US) described the temporary remission of acute leukemia in children following treatment with aminopterin (570).

 

Quentin Howieson Gibson (GB-US) was able to identify the pathway involved in the reduction of methemoglobin, thereby describing the first hereditary disorder involving an enzyme deficiency. As a result, the disease was named "Gibson’s syndrome" (664).

 

Martin Schneider (US), Edgar J. Poth (US), and William C. Levin (US) found that nitrogen mustard hydrochloride (mechlorethamine) has an antineoplastic effect in Hodgkin's lymphoma (1590).

Emil Frei, III (US), Emil J. Freireich (US), James F. Holland (US), and Donald Pinkel (US) were pioneers in the use of combination chemotherapy (Total Therapy V protocol), and supportive care of patients receiving combination chemotherapy for lymphoma and acute leukemia (623; 624; 864; 1413; 1414). Note: By the mid 1970s the cure rate for acute lymphoblastic leukemia (ALL) at St. Jude Children’s Hospital approached 90%.

Emil Frei III (US), Vincent T. DeVita, Jr. (US), John H. Moxley, III (US), Arthur A. Serpick (US), Paul P. Carbone (US), Robert C. Young (US), Bruce A. Chabner (US), Susan P. Hubbard (US), George P. Canellos (US), Brian J. Lewis (US), Dan L. Longo (US), Susan M. Hubbard (US), Margaret N. Wesley (US), Richard I. Fisher (US), Elaine S. Jaffe (US), and Costan Berard (US) made outstanding contributions to the concept of combination therapy in the treatment of Hodgkin’s lymphoma. They demonstrated that MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone) chemotherapy could cure advanced Hodgkin's lymphoma (452; 622; 1108; 1141; 1951).

Joseph V. Simone (US), Rhomes J.A. Aur (US), H. Omar Hustu (US), Manuel Verzosa (US), Donald Pinkel (US), Lorrie Furman (US), Bruce M. Camitta (US), Norman Jaffe (US), Stephen E. Sallan (US), J. Robert Cassady (US), Demetrius Traggis (US), Pearl Leavitt (US), David G. Nathan (US), and Emil Frei, III (US) combined chemotherapies in different phases and based on different toxicities, and including radiotherapy, developed a regimen that prolonged remission in 80% of patients with acute lymphocytic leukemia (642; 1636). Note: Collectively these papers—1964-1984— describe a major milestone in the modern chemotherapy era as they show the first demonstrations that a previously incurable advanced disease could be cured by combination chemotherapy and provided the rationale for the use of combination chemotherapy in medical oncology. This type of therapy became the standard drug regimen used to treat advanced lymphoma and acute leukemia.               

 

Eleanor de F. Baldwin (US), André Frédéric Cournand (FR-US), and Dickinson Woodruff Richards, Jr. (US) studied a large number and variety of cases of chronic pulmonary disease in man. The cases were found to fall into broad categories of pulmonary insufficiency: 1) the gross ventilatory, with restrictive or obstructive aspects, 2) the alveolar-capillary, with primary disturbances in respiratory gas exchange, 3) pulmonary emphysema, with various combinations of these factors, and 4) diffusional insufficiency or alveolar-capillary block, with the major interference at the alveolar-capillary interface (82-84).

 

Fred W. Stewart (US) and Norman Treves (US) reported a rare secondary malignancy in 6 cases of angiosarcoma in post-mastectomy lymphedema. They recognized that an edematous arm after radical mastectomy for breast cancer may suggest recurrent breast cancer, but that long-standing chronic edema without recurrent cancer may occasionally produce "a heretofore unrecognized and unreported sequel... long after the malignant breast neoplasm has apparently been arrested... a new specific tumor" (1721). The term Stewart-Treves syndrome is broadly applied to an angiosarcoma that arises in a chronically lymphedematous region due to any cause, including congenital lymphedema and other causes of secondary lymphedema unassociated with mastectomy. Lymphangiosarcoma is a misnomer because this malignancy seems to arise from blood vessels instead of lymphatic vessels. A more appropriate name is hemangiosarcoma.

 

Ward S. Fowler (US) measured physiological dead space in lungs by simultaneous and continuous measurement of volume flow and nitrogen content of gas expired following the change from breathing air to breathing 99.6% oxygen. The average volume of the physiological dead space in 45 healthy males at rest was 156 cc. The volume of physiological dead space is affected by, a) anatomical volume of the bronchial tree, and b) gas diffusion between terminal bronchioles and alveolar spaces and variation in the rate of inspiratory volume flow (605).

 

Derek Ernest Denny-Brown (NZ-GB-US) described bronchogenic carcinoma associated with primary degeneration of the dorsal root ganglion cells with primary degeneration of the muscles (447).

 

David H. Patey (GB) and Walter H. Dyson (GB) developed the modified radical mastectomy for breast cancer. This surgical procedure is less disfiguring than the radical mastectomy and eventually replaced it as the standard surgical treatment for breast cancer (1372).

 

The National Heart Institute, in 1948, initiated a study begun in Framingham, Massachusetts, known as the Framingham Study. This investigation involved 1,980 men and 2,421 women aged 30 to 62 who showed no signs of heart disease. Every two years, the participants underwent a complete physical examination. The study showed that high blood pressure, smoking, and high cholesterol levels are major factors in heart disease. Fifty years’ worth of data collected from the residents of Framingham has produced over 1,000 scientific papers; introduced the concepts of biologic, environmental, and behavioral risk factors; identified major risk factors associated with heart disease, stroke, and other diseases; created a revolution in preventive medicine; and forever changed the ways in which the medical community and the general population view the genesis of disease.

Thomas R. Dawber (US), William B. Kannel (US), Nicholas Revotskie (US), Joseph Stokes III (US), Abraham Kagan (US), and Tavia Gordon (US) Thomas R. analyzed several factors within the Framingham Study for possible association with the development of coronary heart disease. During the six years of follow-up of the population there was an inverse association with educational status, the incidence of new CHD being less at higher educational levels. There was no association between national origin and the risk of CHD. A suggestively low CHD incidence was noted in one of the eight Framingham precincts. This precinct differed from the others in some respects, but no explanation of this finding can yet be offered.

Smoking was associated with an increased incidence of nonfatal myocardial infarction and of death from CHD in men 45-62. It was not associated with an increased incidence of angina pectoris. Cholesterol levels were higher among cigarette smokers than among non-smokers and higher among those who had smoked and stopped than among those who had never smoked. Neither relative weight nor blood pressure showed a similar association with smoking.

Alcohol consumption per se was not associated with CHD although heavy alcohol intake was associated with heavy smoking (409).

William B. Kannel (US), Thomas R. Dawber (US), Abraham Kagan (US), Nicholas Revotskie (US), and Joseph Stokes, III (US) reported additional results from the Framingham study (948).

 

Derek Ernest Denny-Brown (NZ-GB-US) discovered bronchogenic carcinoma associated with primary degeneration of the dorsal root ganglion cells with primary degeneration of the muscles (447). This was named Denny-Brown’s syndrome II.

 

Edward Franklin Bland (US) and Richard Harwood Sweet (US) performed the first pulmonary-azygos shunt operation for relief of mitral stenosis (174).

 

Henry Hancock (GB) performed the first recorded successful operation for peritonitis due to abscess in the appendix (735).

 

Thomas Holmes Sellors (GB) performed the first successful pulmonary valvulotomy in humans (1608).

 

Harris B. Schumacker, Jr. (US) reported the excision of a small descending thoracic aortic aneurysm with reanastomosis of the aorta (1598).

 

Donald Dexter van Slyke (US) reported that in the first, circulatory phase of shock kidney, renal failure is attributable chiefly to decreased renal blood flow. In the 2d, organic damage, phase renal failure appears to be attributable to tubular reabsorption of glomerular filtrate. Means that may be taken during shock to forestall organic renal damage, and after shock to favor recovery from such demand are discussed (1809).

 

David H. Patey (GB) and Walter H. Dyson (GB) modified Halsted’s mastectomy operation by keeping the great pectoral muscle. The surgery is less traumatic and is followed by less postoperative complications (axillary retractable scar, painful syndrome, lymphedema, upper limb mobility limitation). Lymphedema was not constant, and the postoperative outcome was better with the preservation of the great pectoral and by changing the type of incision, which was oblique or transverse, and circumscribed the breast as an ellipse with poles on the xiphoid medial breast and axillary (1372).

Hedley J.B. Atkins (GB), John L. Hayward (GB), David J. Klugman (GB), and A.B. Wayte (GB), after 10 years of clinical trial, reported the superiority of radical mastectomy over wide excision (extended tylectomy) in patients with stage-two breast cancer (65).

John L. Madden (US), Souheil Kandalaft (US), and Roche-Andre Bourque (US-CA) established the current standard in radical mastectomy. Their contribution to the technique was the preservation of both pectoral muscles (1168).

 

Robert Edward Gross (US), in 1948, performed surgical closure of an aortopulmonary window in a 4-year-old girl who had dyspnea with slight exertion and a cardiac murmur that was consistent with a patent ductus (706). The patient made a satisfactory recovery.

 

Frank W. Preston (US) laid the mathematical foundation for discussions of species abundance patterns (1435-1437).

 

Louis Charles Birch (AU), using the rice weevil, Calandra oryzae, made the first comprehensive analysis of the demography of a population growing exponentially under carefully controlled conditions (169).

 

James Davidson (AU) and Herbert George Andrewartha (AU) used the method of partial regression to measure the degree of association between the numbers of thrips, Thrips imarginis, present during the spring and the weather experienced during the preceding months. The analysis showed that 78 per cent of the variance of the population could be related to: 1) the sum of effective temperatures between the date when the break of the dry season in autumn allows the seeds of the annual food-plants to germinate and the end of winter (31st August), 2) the amount of rainfall during September-October, 3) the temperature during the autumn and winter of the preceding year (402).

 

Thomas Park (GB) deliberately chose two closely related species, Tribolium confusum Duval and Tribolium castaneum Herbst, for his long-term study of interspecies competition. In three different experiments Park found that one of the two species always became extinct. Park’s experimental results supported the tenet that two nearly identical species cannot coexist on a single limiting resource (1368).

 

The World Health Organization (WHO) was founded.

 

1949

“The curiosity remains, though, to grasp more clearly how the same matter, which in physics and in chemistry displays orderly and reproducible and relatively simple properties, arranges itself in the most astounding fashions as soon as it is drawn into the orbit of the living organism. The closer one looks at these performances of matter in living organisms the more impressive the show becomes. The meanest living cell becomes a magic puzzle box full of elaborate and changing molecules, and far outstrips all chemical laboratories of man in the skill of organic synthesis performed with ease, expedition, and good judgment of balance. The complex accomplishment of any one living cell is part and parcel of the first-mentioned feature, that any one cell represents more an historical than a physical event. These complex things do not rise every day by spontaneous generation from non-living matter—if they did, they would really be reproducible and timeless phenomena, comparable to the crystallization of a solution, and would belong to the subject matter of physics proper. No, any living cell carries with it the experiences of a billion years of experimentation by its ancestors. You cannot expect to explain so wise an old bird in a few simple words.” Max Ludwig Henning Delbrück (441).

 

“It is impossible to exaggerate the importance of the variability of the bacterial cell or the desirability of studying the laws regulating it. Biochemically, bacterial cells are the most plastic of living material … The bacterial cell by reason of its small size and consequently relatively large surface, cannot develop by maintaining a constant chemical environment, but reacts by adapting its enzyme systems to survive and grow in changing conditions. It is immensely tolerant of experimental meddling and offers material for the study of processes of growth, variation and development of enzymes without parallel in any other biological material.” Marjory Stephenson (1715).

 

" A recognized fact which goes back to the earliest times is that every living organism is not the sum of a multitude of unitary processes, but is, by virtue of interrelationships and of higher and lower levels of control, an unbroken unity." Walter Rudolf Hess (812).

 

“Your patients . . . do not come to you to be cured; they come to be relieved of their pains and other symptoms and to be comforted. Forced to choose, they would usually prefer a kind doctor to an efficient one. Never forget that the patient and his relations are usually frightened and anxious – upset in the normal life to such an extent that they are prepared to call you into their lives and to tell you the most intimate facts about themselves, though you may be unknown to them except as a member of an honorable profession.” Hugh William Bell Cairns (260).

 

Walter Rudolf Hess (CH) for his discovery of the functional organization of the interbrain as a coordinator of the activities of the internal organs and Antonio Caetano de Abreu Freire Egas Moniz (PT) for his discovery of the therapeutic value of lobotomy in certain psychoses shared the Nobel prize for physiology and medicine.

 

Willard Frank Libby (US), Ernie C. Anderson (US), and James R. Arnold (US) developed the carbon-14 dating technique (1119; 1120). Carbon-14 has a half-life of 5730 years and is especially useful for dating objects from the last 40,000 years.

This is one of the most profound discoveries of the 20th century. J. Desmond Clark (GB) wrote that were it not for radiocarbon dating, "we would still be foundering in a sea of imprecisions sometime bred of inspired guesswork but more often of imaginative speculation” (309).

 

Joseph Reuben Spies (US) and Dorris C. Chambers (US) described several variations of a method for colorimetric analysis of unhydrolyzed proteins. The basic method was based on fundamental studies of the behavior of free and peptide-linked tryptophan. These studies included a method of alkaline hydrolysis which protects tryptophan from external destruction at temperatures up to 185°C without addition of antioxidants to the solution (1689).

 

Albert Kelner (US), working with Escherichia coli and conidia of Streptomyces griseus, discovered that light belonging to the visible range is capable of reactivating biological material that has been rendered inactive by ultraviolet radiation (UV) (963-968). This phenomenon is commonly referred to as photoreactivation. Note: Alexander Hollaender (US) and John T. Curtis (US) made the earliest known suggestion that there is likely to exist a natural DNA repair mechanism (863).

Renato Dulbecco (IT-US) discovered the same phenomenon in bacteriophages associated with their host cell (502; 503).

Claud Stan Rupert (US), Solomon H. Goodgal (US) and Roger M. Harriott (US) confirmed that photoreactivation really is a DNA repair process catalyzed by a specific enzyme with a strict requirement for visible light (1538).

Claud Stan Rupert (US) discovered an enzyme from baker’s yeast capable of catalyzing photoreactivation of bacterial cells, which had been inactivated by ultraviolet light (1537).

Rob Beukers (NL), J. Ijlstra (NL), Wouter Berends (NL), Adolf Wacker (DE), Hanswerner Dellweg (DE), Diether Jacherts (DE) and Dieter Weinblum (DE) determined that ultraviolet light produces dimers of thymine, thymine-cytosine, and cytosine in deoxyribonucleic acid (151-155; 1833-1835).

Richard Burton Setlow (US), William L. Carrier (US), Richard P. Boyce (US), Paul Howard-Flanders (US), David Pettijohn (US), and Philip Hanawalt (US) found that in Escherichia coli the onset of DNA synthesis is associated with thymine dimer removal. One step in the recovery of cells from the effects of UV may be the removal of the dimers from DNA (200; 1406; 1612). This helped explain what was called dark repair.

Ronald E. Rasmussen (US) and Robert B. Painter (US) presented evidence that this type of repair also operates in mammalian cells (1479).

Richard Burton Setlow (US), Jane K. Setlow (US), and William L. Carrier (US) determined the action spectrum for the splitting of thymine dimers and showed that wavelengths shorter than 254nm were most effective. Observing changes in the absorption spectrum of DNA could thus easily follow the dimerization and monomerization reactions in pure DNA. This simple measurement allowed them to determine the kinetics of dimerization and monomerization as a function of wavelength. They found that wavelengths around 280nm preferentially resulted in the formation of dimers, whereas wavelengths around 240nm preferentially split them (1610; 1611; 1613; 1614).

Daniel L. Wulff (US) and Claud Stan Rupert (US) went on to find evidence that both enzyme-catalyzed photoreactivation and short-wavelength direct reactivation operate on the same substrate, strongly suggesting that enzymatic photoreactivation effected the monomerization of pyrimidine dimers (1936).

Paul Howard-Flanders (US), Richard P. Boyce (US), and Lee Theriot (US) found that Escherichia coli K-12 contains three genetic loci (uvrA, uvrB, and uvrC) that control the excision of pyrimidine dimers and certain other mutagen products from DNA (884).

Norio Iwatsuki (JP), Cheol O. Joe (KR), and Harold Werbin (US) purified a photoreactivating enzyme. It is a low molecular weight, light-absorbing moiety, flavine adenine dinucleotide, with a chromophore (918). Subsequently it was settled that all photoreactivating enzymes have two chromophores.

Aziz Sancar (TR-US) and Claud Stan Rupert (US) cloned the E. coli phr gene, the first DNA repair gene to be cloned (1549).

Gwendolyn B. Sancar (US), Marilyn S. Jorns (US), Gillian Payne (US), Donald J. Fluke (US), Claud Stan Rupert (US), and Aziz Sancar (TR-US) were able to determine that the flavin cofactor of the photoreactivating enzyme (photolyase) is fully reduced in vivo and that, upon absorption of a single photon in the 300 –500 nm range, the photolyase chromophore donates an electron to the pyrimidine dimer causing its reversal to two pyrimidines (1550).

H.W. Park (US-CA), Aziz Sancar (TR-US), and Johann Deisenhofer (DE-US) solved the crystal structure of the E. coli photoreactivating enzyme (1361).

 

Rachmiel Levine (PL-CA-US), Maurice S. Goldstein (US), Bernice Huddlestun (US), Susan P. Klein (US) and Samuel Soskin (US) discovered the role of insulin in glucose metabolism. Contrary to the assumption that glucose molecules freely pass through the cell membrane, they proposed what became known as the Levine Effect or transport theory, in which they suggested that insulin serves as the key regulatory factor for the transport of glucose into the cells. They theorized that insulin stimulates the transport of glucose from blood to fat/muscle cells and thus lowers the blood glucose level (1103-1106).

  

Erwin Chargaff (AT-US), Ernst Vischer (US), Ruth Doniger (US), Charlotte Green (US), Fernanda Misani (US), and Stephen Zamenhof (US) demonstrated that contrary to common belief the four bases in DNA are not always present in equal molar concentrations. They discovered that the molar concentration of adenine is always the same as that for thymine, and the molar concentration of guanine is always the same as that for cytosine, however, the ratio of adenine to guanine and that of cytosine to thymine vary considerably from one DNA to another (291-293; 1819).

Gerard Robert Wyatt (CA) studied the base ratios in the DNAs of wheat germ, herring sperm, and insect viruses. His results confirmed the findings of Chargaff and his colleagues, even though he found an unusual base, 5-hydroxymethyl-cytosine, in the viruses. The molar ratio of cytosine plus 5-methyl-cytosine to guanine was 1:1 in these viruses (1937).

Gerard Robert Wyatt (US) and Seymour Stanley Cohen (US) discovered 5-hydroxymethylcytosine in the DNA of T-even phages (1938; 1939).

 

George Scatchard (US) pointed out that some proteins have attractions for small molecules and ions (1571).

Daniel Israel Arnon (PL-US) discovered that chloroplasts of Beta vulgaris (common beet) contain an enzyme, which requires copper as cofactor (48).

 

George W. Kenner (GB), Harold J. Rodda (GB), and Alexander Robertus Todd (GB) synthesized substrates for ribonuclease (972).

 

Joseph H. Burchenal (US), Aaron Bendich (US), George Bosworth Brown (US), George Herbert Hitchings (US), Cornelius P. Rhoads (US), C. Chester Stock (US), and Gertrude Belle Elion (US) synthesized a purine that inhibited mouse leukemia. This was the forerunner of 6-mercaptopurine (242).

Gertrude Belle Elion (US), Henry Vanderwerff (US), George Herbert Hitchings (US), M. Earl Balis (US), Daniel H. Levin (US), George Bosworth Brown (US), and Samuel Singer (US) confirmed that diaminopurine is an adenine antagonist. Diaminopurine, thioguanine, and 6-mercaptopurine were all found to be adenine and guanine antagonists (537; 539).

George Herbert Hitchings (US), Gertrude Belle Elion (US), and Samuel Singer (US) synthesized and developed 6-mercaptopurine (6-MP), also called purinethol, as an antitumor agent. They quantified the synergistic effects of purine antagonists with pyrimidine and folic acid antagonists (538; 839). Purinethol was used to treat childhood leukemia. Elion later developed thioguanine, also for the treatment of leukemia (536).

 

Howard Gest (US) and Martin David Kamen (US) discovered light-dependent production of hydrogen gas and nitrogen fixation by the bacterium, Rhodospirillum rubrum. The enzyme nitrogenase catalyzes both activities (659; 947).

 

Earl Reece Stadtman (US), Horace Alber Barker (US), G. David Novelli (US), and Fritz Albert Lipmann (DE-US) discovered phosphotransacetylase while elucidating the role of acetyl-CoA in fatty acid metabolism (1692-1694; 1696).

 

John F. Speck (US) and William H. Elliott (US) demonstrated that glutamine is synthesized by a specific enzyme, glutamine synthetase, in the presence of glutamic acid, ATP, Mg++, and ammonia (543; 544; 1686)