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, 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 (1473).

 

1948

"United wishes and good will cannot overcome brute facts, truth is incontrovertible. Panic may resent it. Ignorance may deride it. Malice may distort it. But there it is." Winston Spencer Churchill (320)s

 

“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 (1393).

 

“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 (1752).

 

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 (18). 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 (908). 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) (393).

Gui-Dong Zhu (US) and William H. Okamura (US) synthesized vitamin D (2031).

 

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) (235). 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 (89; 1452; 1453).

George Eugene Moore (US) described how radioactive di-iodofluorescein could be used to diagnose and localize brain tumors (1315).

Linus Carl Pauling (US) proposed the principle of transition-state stabilization to explain enzyme catalysis (1435).

 

Stanford Moore (US) and William Howard Stein (US) introduced partition chromatography on starch gel columns (1319). 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 (1322; 1746). 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 (1077). 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 (1327).

 

Elvin Abraham Kabat (US) and Manfred Martin Mayer (DE-US) wrote Experimental Immunochemistry, the first great text in immunochemistry (981). 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 (17).

 

Moses Kunitz (RU-US) described the isolation of deoxyribonuclease in crystalline form from beef pancreas (1072).

 

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 (649; 1116).

 

Benjamin Minge Duggar (US) discovered and introduced Aureomycin (chlortetracycline), the first of the tetracycline antibiotics. It is produced by Streptomyces aureofaciens (515). 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 (716; 1037).

 

Peter Wilhelm Joseph Holtz (DE) and Hans-Joachim Schümann (DE) were the first to report the production of norepinephrine (noradrenaline) in the adrenal medulla (904).

 

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 (344-346).

 

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 (495-497).

 

Edward B. Lewis (US) studied position pseudoallelism in Drosophila (1153-1156).

 

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 (1681; 1832).

 

Jacques Lucien Monod (FR), Madeleine Jolit (FR), and Anne-Marie Torriani (FR) isolated lactase (beta-galactosidase) and amylomaltase from Escherichia coli strain ML (1310).

 

Alexander A. Krasnovsky (RU) discovered that in the presence of appropriate chemical reagents, chlorophyll a in solution is reversibly reduced in light (1066).

 

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 (43; 869-871; 1320; 1321; 1485; 1543; 1722; 1723; 1747; 1770; 1771).

Gopinath Kartha (US), Jake Bello (US), and David Harker (US) determined the tertiary structure of ribonuclease (996).

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 (1557; 2011).

 

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 (337).

Philip Pacy Cohen (US) and Santiago Grisolia (CL) concluded that in the synthesis of citrulline from ornithine, carbamyl-L-glutamic acid is an intermediate (336; 338).

 

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 (107).

 

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 (1080).

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 (313).

 

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 (1651).

 

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 (1980).

 

Frank John Fenner (AU) studied the pathogenesis of ectromelia virus in mice (in which it causes fatal hepatitis) (597; 598). 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 (1223).

 

Bernard David Davis (US), Joshua Lederberg (US), and Norton David Zinder (US) developed methodology for direct selection of bacterial auxotrophs (419; 421; 1114).

 

Ludmila Andreevna Kuprianova (RU) illuminated the pollen morphology of the monocotyledons (1073).

 

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 (206). 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 (1425).

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 (207).

Peter Herman Heinze (US), Albert Aloysius Piringer (US) and Harry Alfred Borthwick (US) determined that the photoperiodic pigment controls skin coloring in tomatoes (818; 1472).

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 (208). 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” (823).

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 (267). Shortly thereafter the pigment was named phytochrome (Greek=plant color) with the R-absorbing form called Pr and the FR-absorbing form called Pfr (205; 1864).

 

David Pressman (US) and Geoffrey Keighley (US) attempted to create radiolabeled antibodies (1489).

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 (1057; 1490).

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 (1488).

 

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 (903).

 

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 (1021).

 

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 (1186).

 

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 (197; 1289; 1563; 1882; 1883).

 

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 (1337).

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 (76-82).

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 (359).

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 (1396-1399). 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 (1195).

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 (997).

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 (2024). 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 (798). 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 (1475).

 

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 (1584).

 

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 (150).

 

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 (1887).

 

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 (1428).

 

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 (13). 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 (1403).

Fritz Koller (CH), Emil A. Loeliger (NL) and Francois Henri Duckert (CH) identified the same factor, which they named factor VII (1046).

 

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 (1255).

 

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 (1344; 1638; 1639; 1643; 1646).

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 (998; 999).

 

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 (1019).

 

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 (1728).

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 (711).

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 (262).

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 (37).

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 (180).

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 (179). 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 (416).

Peter Brian Medawar (GB) was the first to point out the immunologically privileged nature of the fetal allograft (1256).

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 (176). 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 (413).

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 (178).

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 self— immunological tolerance— whereas older mice which had never experienced the same foreign material would treat it as non-self and respond immunologically (177).

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 (1451; 1873). 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 (414).

Johannes Joseph van Rood (NL) and J. George Eernisse (NL) discovered additional leukocyte antigens which they designated antigens 2 and 3 (1872).

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 (1874).

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 (296).

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 (296; 415; 1875).

Dennis Bernard Amos (US), and Fritz H. Bach (US) showed that the mixed leukocyte culture reaction was detecting the HLA-D locus (35).

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 (113).

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 (417).

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 (1271; 1765).

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 (1871). 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 (978).

 

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 (376; 849).

 

Francois Estrade (MG) was the first to successfully treat pneumonic plague (Yersinia pestis) patients. He used streptomycin (580).

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) (1241; 1712).

 

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 (791) and better understanding of the disease as one where immune complex deposition played a major role in tissue pathology and disease manifestations (774).

 

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 (589).

 

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" (685).

 

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 (1650).

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 (642; 643; 897; 1469; 1470). 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 (469; 641; 1152; 1185; 2023).

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 (662; 1696). 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 (91-93).

 

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" (1783). 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 (624).

 

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 (464).

 

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 (1427). See, Halsted, 1894

Umberto Veronesi (IT), Roberto Saccozzi (IT), Marcella Del Vecchio (IT), Alberto Banfi (IT), Claudio Clemente (IT), Mario De Lena (IT), Giuseppe Gallus (IT), Marco Greco (IT), Alberto Luini (IT), Ettore Marubini (IT), Giuseppe Muscolino (IT), Franco Rilke (IT), Bruno Salvadori (IT), Annamaria Zecchini (IT), and Roberto Zucali (IT), from their randomized controlled trial, concluded that breast-conserving surgery and radiotherapy are as safe as mastectomy in patients with small clinically node-negative breast cancer (1885).

 

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 (425).

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 (991).

 

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 (464). 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 (186).

 

Henry Hancock (GB) performed the first recorded successful operation for peritonitis due to abscess in the appendix (768).

 

Thomas Holmes Sellors (GB) performed the first successful pulmonary valvulotomy in humans (1670).

 

Harris B. Schumacker, Jr. (US) reported the excision of a small descending thoracic aortic aneurysm with reanastomosis of the aorta (1658).

 

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 (1878).

 

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 (1427).

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 (74).

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 (1212).

 

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 (734). The patient made a satisfactory recovery.

 

Frank W. Preston (US) laid the mathematical foundation for discussions of species abundance patterns (1491-1493).

 

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 (181).

 

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 (418).

 

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 (1423).

 

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 (458).

 

“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 (1777).

 

" 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 (845).

 

“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 (271).

 

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 (1162; 1163). 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” (323).

 

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 (1751).

 

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) (1006-1011). 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 (896).

Renato Dulbecco (IT-US) discovered the same phenomenon in bacteriophages associated with their host cell (516; 517).

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 (1596).

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 (1595).

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 (163-167; 1903-1905).

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 (209; 1462; 1674). 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 (1535).

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 (1672; 1673; 1675; 1676).

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 (2007).

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 (917).

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 (956). 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 (1608).

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 (1609).

H.W. Park (US-CA), Aziz Sancar (TR-US), and Johann Deisenhofer (DE-US) solved the crystal structure of the E. coli photoreactivating enzyme (1416).

 

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 (1147-1150).

  

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 (304-306; 1889).

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 (2008).

Gerard Robert Wyatt (US) and Seymour Stanley Cohen (US) discovered 5-hydroxymethylcytosine in the DNA of T-even phages (2009; 2010).

 

George Scatchard (US) pointed out that some proteins have attractions for small molecules and ions (1630).

Daniel Israel Arnon (PL-US) discovered that chloroplasts of Beta vulgaris (common beet) contain an enzyme, which requires copper as cofactor (56).

 

George W. Kenner (GB), Harold J. Rodda (GB), and Alexander Robertus Todd (GB) synthesized substrates for ribonuclease (1015).

 

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 (255).

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 (551; 553).

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 (552; 872). Purinethol was used to treat childhood leukemia. Elion later developed thioguanine, also for the treatment of leukemia (550).

 

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 (680; 985).

 

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 (1754-1756; 1758).

 

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 (557; 558; 1748).

 

Allan G. Gornall (CA), Charles J. Bardawill (CA), and Maxima M. David (CA) described a simple procedure for the determination of serum total protein, albumin, and globulin. The biuret reaction is approved as a simple, rapid, yet highly satisfactory and accurate method for the determination of the protein fractions in serum or plasma (714).

 

Dorothy Mary Crowfoot-Hodgkin (GB), Charles W. Bunn (GB), Barbara W. Rogers-Low (GB), and Annette Turner-Jones (GB) determined the three-dimensional structure of penicillin G, largely through computer analysis of x-ray diffraction data. They did this before organic chemists had even determined its primary chemical structure. Their work represents the first use of the electronic computer in direct application to a biochemical problem (392).

 

Sven Verner Furberg (GB), using x-ray diffraction data, was the first to correctly determine that the bases in DNA are at right angles to the helical sugar-phosphate backbone and parallel to one another (657-661).

 

William Howard Stein (US) and Stanford Moore (US) reported the complete amino acid analysis of beta-lactoglobulin and bovine serum albumin, determined by starch column partition chromatography (1771). See, E. Brand1945.

 

Pehr Victor Edman (SE) described the phenylisothiocyanate procedure for the successive chemical removal of individual amino acids from the amino terminus of a peptide chain (542; 543). This technique permitted the determination of a polypeptide’s amino acid sequence.

 

Leonard S. Lerman (US) discovered that immunoglobulin G
antibodies are bivalent (1127).

 

Selman Abraham Waksman (RU-US) and Hubert A. Lechevalier (US) reported the isolation of the antibiotic neomycin from Streptomyces fradiae (1915).

 

George Marmont (US) was the first to develop a voltage clamp. It was used to quantitatively measure ionic currents in cells (1225).

 

Henry Borsook (US), Clara L. Deasy (US), Arie Jan Haagen-Smit (NL-US), Geoffrey Keighley (US), Peter H. Lowy (US), and Tore Hultin (SE) discovered that ribonucleoprotein particles (now called ribosomes) are the sites of polypeptide bond formation (203; 204; 927).

 

Dana Irving Crandall (US) and Samuel Gurin (US) performed experiments, which finally clarified the enzymatic mechanisms of fatty acid oxidation (380).

 

Eugene Patrick Kennedy (US) and Albert Lester Lehninger (US) discovered that rat liver mitochondria contain the entire enzymatic apparatus of the citric acid cycle, whereas the enzymes of glycolysis are in the fluid portion of the cytoplasm. They noted that as mitochondria oxidize metabolites they simultaneously esterify phosphate groups. This represents the first experimental evidence of where oxidative phosphorylation resides within the cell (1013).

 

Alan Lloyd Hodgkin (GB) and Andrew Fielding Huxley (GB) determined that generation of the nerve impulse is accompanied by a leakage of potassium ions across the cell membrane with a resulting marked change in the membrane conductance, and that during the recovery the potassium ions are reabsorbed. They published equations, which allowed the prediction of the conductance changes and the form and amplitude of the action potential during impulse transmission and allowed them to restrict the number of possible kinds of ionic events, which might produce these changes. This work was the first to reveal the kinetic complexity and the ionic selectivity of permeability changes in nerve cells (882-886; 889).

Alan Lloyd Hodgkin (GB), Andrew Fielding Huxley (GB), and Bernard Katz (RU-GB) developed a model to explain the axon potential in the squid axon. The model was based on the movement of ions across a semipermeable nerve cell membrane (887; 888). This is often referred to as the sodium pump mechanism of nerve impulse transmission. See R.B. Dean, 1941.

 

Linus Carl Pauling (US), Harvey Akio Itano (US), Seymour Jonathan Singer (US), Ibert Wells (US), Max Ferdinand Perutz (AT-GB), and J. Murdoch Mitchison (GB) determined that the molecular defect that causes the human sickle cell anemia is due to chemically altered (mutant) hemoglobin molecules (1450; 1460). They used an electrophoretic method, developed by Sanger, which was later called protein fingerprinting.

Pauling got the idea for this research, in 1945, while listening to a report to a government committee, of which he was a member, charged with making recommendations for the direction of post-war medicine in the America. His brilliant insight is included here for your enjoyment.

“One of the members of the group, Dr. William Bosworth Castle, described some work that he was doing on the disease sickle cell anemia. When he mentioned that the red cells of patients with the disease are deformed (sickled) in the venous circulation but resume their original shape in the arterial circulation, the idea occurred to me that sickle cell anemia was a molecular disease, involving an abnormality of the hemoglobin molecule determined by a mutated gene. I thought at once that the abnormal hemoglobin molecules that I postulated to be present in the red cells of these patients would have two mutually complementary regions on their surfaces, such as to cause them to aggregate into long columns, which would be attracted to one another by van der Waals forces, causing the formation of a needle-like crystal which, as it grew longer and longer, would cause the red cell to be deformed and would thus lead to the manifestations of the disease” (1437).

John W. Harris (US) reported that David Waugh (US) identified microscopic hemoglobin tactoids as the actual physical basis of the sickling process (781).

 

Ezio Silvestroni (IT), Ida Bianco (IT), and Giuseppe Montalenti (IT) developed methods for identifying ß-thalassemia heterozygotes in populations and recorded their frequencies in different parts of Italy. In some regions heterozygote frequencies up to 10% were observed, and the strong geographic correspondence between the incidence of thalassemia and endemic malaria was noted, as documented by an Italian historian of science (1694).

John Burdon Sanderson Haldane (GB-IN) suggested that individuals heterozygous for the thalassemia allele might be resistant to malaria. Haldane and the individuals immediately above should be credited with originating the “malaria hypothesis" (757; 758).

Louis H. Miller (US), Simon J. Mason (US), David F. Clyde (GB), and Mary H. McGinniss (US) reported the resistance factor to Plasmodium vivax in blacks possessing the Duffy-blood-group genotype, Fya/Fyb (1282).

Jonathan Flint (GB), Adrian V. Hill (GB), Don K. Bowden (AU), Stephen J. Oppenheimer (GB), P.R. Sill (PG), Susan Wyber Serjeantson (AU), Joe Bana-Koiri (PG), Kuldeep Bhatia (PG), Michael P. Alpers (PG), Anthony J. Boyce (GB), David J. Weatherall (GB), and John B. Clegg (GB) supported the hypothesis that protection against malaria is the major factor responsible for the high frequencies of hemoglobinopathies in many parts of the world (614).

Stephen J. Allen (GB), Angela O'Donnell (GB), Neal D.E. Alexander (GB), Michael P. Alpers (GB), Timothy E.A. Peto (GB), John B. Clegg (GB), and David J. Weatherall (GB) determined that the homozygous state for alpha plus thalassemia offers considerable protection against the severe complications of Plasmodium falciparum malaria (26).

Sarah A. Tishkoff (US), Robert Varkonyi (US), Nelie Cahinhinan (US), Salem Abbes (TN), George Argyropoulos (US), Giovanni Destro-Bisol (IT), Anthi Drousiotou (CY), Bruce Dangerfield (ZA), Gerard Lefranc (FR), Jacques Loiselet (LB), Anna Piro (IT), Mark Stoneking (DE), Antonio Tagarelli (IT), Giuseppe Tagarelli (IT), Elias H. Touma (LB), Scott M. Williams (US), and Andrew G. Clark (US) suggested that malaria has influenced human evolution since the introduction of agriculture approximately 10,000 years ago (1835).

 

Harold Garnet Callan (GB), John Turton Randall (GB), and Stan G. Tomlin (GB) used electron microscopy to help provide the first descriptions of “pores” and “annuli” in nuclear envelopes. These studies described the structure of the nuclear membrane as a double membrane with pores possessing a large central channel (274; 275).

 

Paul Jackson Kramer (US) and Karl M. Wilbur (US), using radioisotopes, were the first to measure the uptake of phosphorus by mycorrhizal roots of trees (1064).

 

Pieter Korringa (NL) provided an incredibly complete picture of oyster reproduction and larval biology in the Oosterschelde (Netherlands). He considered the role of numerous physical factors, including light, temperature, wind, waves, salinity, and current velocity on both larval distribution and settlement intensity and conducted field manipulations of settlement surfaces to investigate the role of bottom characteristics on spatfall (1058).

 

Haldan Keffer Hartline (US), Henry G. Wagner (US), and Floyd Ratcliff (US) found that if one ommatidium of Limulus is receiving bright light and a neighbor is receiving dim light, the first ommatidium will inhibit the signal from its neighbor. The result is that the dimmer signal gets even dimmer and the result is an increased difference between the two which the eye would perceive as an increase in contrast (785; 787). This led to an understanding of the mechanisms of lateral inhibition. Lateral inhibition is a process that animals, including humans, use to better distinguish borders. When you look at the ocean horizon the ocean appears darker at the horizon, at the boundary between sea and sky. This apparent difference in light intensity is not actually there but is created by our visual receptors and is known as lateral inhibition.

Haldan Keffer Hartline (US), Henry G. Wagner (US), and Edward F. MacNichol, Jr. (US) recorded intracellular generator potentials in retinal nerve cells (786).

These discoveries convinced researchers that the retina (the innermost layer of the eye that is light sensitive) and optic nerves themselves process many nerve signals before the signals are transmitted to the brain.

 

Walter Rudolf Hess (CH) pioneered the use of electrical stimulation to probe structures deep in the brain. Studying cats, he discovered that, depending on the location of the electrode, sleep, sexual arousal, anxiety, or terror could be provoked by the flick of the switch and turned off just as abruptly (844).

 

Maurício Rocha e Silva (BR), Wilson Teixeira Beraldo (BR), and Gastão Rosenfeld (BR) described the release of an active peptide from serum globulin by trypsin or snake venoms. They named the peptide bradykinin because it caused a relatively slow contraction of the isolated guinea-pig ileum (1569).

 

Choh Hao Li (CN-US), Miriam E. Simpson (US), and Herbert McLean Evans (US) isolated electrophoretically pure follicle stimulating hormone (FSH) from sheep (1160).

 

Alfred Day Hershey (US) and Max Ludwig Henning Delbrück (DE-US) discovered that when Escherichia coli is simultaneously infected with two or more bacteriophages that differ from each other in two genetic characters there issue from the infected cell some recombinant phages that have obtained one of these two characters from one parent phage and the other of the two characters from the other parent phage. Phages can therefore engage in genetic recombination within the host cell (842).

 

Claude Ephraim ZoBell (US) and Frank H. Johnson (US) cultured bacteria brought up from great ocean depths and found that some are barophilic. These organisms are slow growing under these great pressures (2035).

 

Otto Heinrich Warburg (DE) defined the bacterial requirement for iron (1924). Prior to this work he had presented considerable evidence of the intracellular functions of iron.

 

Jacques Lucien Monod (FR) established the growth phases of a typical bacterial growth curve as lag, acceleration, exponential, retardation, stationary, and decline (1305).

 

Melvin M. Green (US) and Kathleen C. Green (US) were able to map mutations of the lozenge locus in Drosophila melanogaster into linear order (722).

 

Murray Llewellyn Barr (CA) and Ewart George Bertram (CA) discovered that interphase cells of cats can be characterized as being of male or female origin solely by the absence or presence of a densely staining bit of chromatin at the nuclear periphery. The dense body soon became known as the Barr body. Keith Leon Moore (CA), Margaret A. Graham (CA), and Murray Llewellyn Barr (CA) demonstrated the same phenomenon in humans (105; 1317; 1318). Mary Frances Lyon introduced the term Barr body. See, Lyon, 1962.

Pratima S. Karnik (IN) showed that phosphorylation of type 1 histone often accompanies aggregation of chromatin into heterochromatin, as is the case with the Barr body (994).

 

Boris Ephrussi (RU-FR), Hélène Hottinguer (FR), Jean Tavlitzki (FR), Anne-Marie Chimenes (FR), Philippe L'Héritier (FR), Piotr P. Slonimski (PO-FR) demonstrated non-Mendelian determinants in yeast. They described the isolation and characterization of the "petite" (or r^-) mutant. These initial studies demonstrated that the r^- trait was inherited by a non-Mendelian determinant, that normal strains could be converted in mass to r^- by acriflavine treatment, that r^- was irreversible, and that r^- mutants lacked cytochromes a, a3, and b and were deficient in respiration (572-574; 1708-1710; 1819).

 

Charles E. Palm (US) and Philip Garman (US) reported early cases of arachnid resistance to an organophosphate. The resistant species was Tetranychus urticae (red spider mite or two-spotted spider mite) (667; 1412).

 

Albert Frey-Wyssling (CH) and Kurt Mühlethaler (CH) published electron photomicrographs of chloroplasts in which the grana look like a scattered roll of coins (647).

 

Pierre Limasset (FR), Pierre Cornuet (FR) and Yves Gendron (FR) noted the absence of virus in the meristems of tobacco (Nicotiana tabacum) with virus diseases. Based on this finding, meristem culture has been extensively used to eliminate viruses, bacteria and fungi from plants (1172).

Georges Morel (FR) and Claude Martin (FR) regenerated whole virus-free plants of dahlia using meristems from plantations infected by three different viruses. This is the first successful micro-graft (1326).

Georges Morel (FR) produced virus-free cymbidiums (1324).

Georges Morel (FR) accomplished protocorm formation in cymbidiums (1325).

 

Cecil Edmund Yarwood (US) reported that 6-(1-methylheptyl)-2,4 dinitro-phenyl crotonate is a good fungicide for powdery mildew (2018).

Saul Rich (US) and James Gordon Horsfall (US) also introduced it in 1949 (1556).

 

John H. Lilly (US), John F. Stauffer (US), and Stanley D. Beck (US) were the first to develop an artificial diet for lepidopterous species (124; 125; 1171).

G. Michael Chippendale (US) and Stanley D. Beck (US) demonstrated the necessity of ascorbic acid in the diet of a lepidopterous insect (315).

 

Susumu Hagiwara (JP-US) performed a statistical analysis on the fluctuation of the interval of rhythmic excitation of neuronal firing (752; 753).

 

Kenneth Bryan Raper (US) and Charles Thom (US) wrote their monograph, Manual of the Penicillia (1532).

 

Edward Arthur Steinhaus (US) and Clarence G. Thompson (US) were the first to demonstrate that an insect pest can be controlled, under field conditions, using a virus spray containing the nuclear polyhedral virus of the alfalfa caterpillar (1774).

 

Alfred Sherwood Romer (US) spent much of his adult career investigating vertebrate evolution and wrote The Vertebrate Body, which is still a standard on the subject (1571).

 

Gustav Kramer (DE) demonstrated that certain diurnal bird migrants utilize the sun in orientation (1062; 1063).

 

Maurice J. Strauss (US), Ernest W. Shaw (US), Henry Bunting (US), and Joseph Louis Melnick (US) observed virus-like particles in skin papillomas then identified human papilloma virus (HPV) as the cause of warts (1791; 1792).

 

Leon Orris Jacobson (US), Edna K. Marks (US), Melba J. Robson (US), Evelyn O. Gaston (US), Raymond E. Zirkle (US), Egon Lorenz (DE), Delta E. Uphoff (US), T.R. Reid (US), Emma Shelton (US), Charles C. Congdon (US), Joan M. Main (US), and Richmond T. Prehn (US), using mice and rats, performed the first bone marrow transplants. They discovered that animals can be saved from the effects of an otherwise lethal dose of radiation by spleen shielding (Jacobson) or injecting them, after exposure, with extracts made from unexposed blood forming organs (355; 967; 968; 1189; 1190; 1214).

Charles Edmund Ford (GB), John L. Hamerton (GB), David W.H. Barnes (GB) and John Freeman Loutit (GB), showed that the recovery was brought about because living hematopoietic cells rapidly colonized the irradiated animals, replacing their dead lymphoid tissue (103; 622).

 

Curt Stern (DE-US) and Delta E. Uphoff (US) examined the genetic effects of low intensity irradiation and concluded, “Viewing all experiments together, it appears that radiation at low doses, administered at low intensity, induces mutation in Drosophila sperm. There is no threshold below which radiation fails to induce mutations.” This is now one of the cornerstones of radiation genetics (1779).

 

Robert Armstrong Nelson, Jr. (US), Manfred Martin Mayer (DE-US), Judith A. Diesendruck (US), and John T. Eagan (US) developed the TPI- (Treponema pallidum-Immobilization) Test, a highly sensitive, specific reaction for serodiagnosis of syphilis, based on the demonstration of immobilizing antibodies in patients' serum (1359).

 

Joseph E. Smadel (US), Theodore E. Woodward (US), Herbert L. Ley, Jr. (US), and Raymond Lewthwaite (US) successfully treated tsutsugamushi disease (scrub typhus) with chloramphenicol (Chloromycetin) (1713).

 

William A. Altemeier (US) and Wesley L. Furste (US) found that in experimentally induced Clostridium welchii infections the virulence of the bacterium was increased one thousand times by the presence in the wound of crushed muscle, and one million times by having crushed muscle and sterile foreign material (street dirt, cinders, etc.) in the wound (30).

Stephen D. Elek (GB) found in human volunteers that intradermal and subcutaneous inocula of more than one million Staphylococcus aureus were required to induce infections of the skin, but that in the presence of subcutaneous foreign bodies (infected silk sutures) pyogenic reactions occurred with much smaller doses of S. aureus (549).

 

Heinz Kruse (US), Philip Duryeé McMaster (US), Ernest Sturm (US), and Joshua L. Edwards (US) used dyed antigens to reveal that antigens are taken up by cells of the reticuloendothelial system throughout the body including Kupffer cells of the liver, as well as macrophages and reticular cells of the spleen and lymph nodes. In this manner they revealed certain of the sites from which the first stimuli to antibody formation arise (1069; 1248-1252).

 

Andre de Vries (US), Benjamin Alexander (US), Robert Goldstein (US), Eunice Addelson (US), and Elaine Promisel (US) characterized serum prothrombin conversion accelerator (SPCA) (437).

Benjamin Alexander (US), Robert Goldstein (US), Greta Landwehr (US) and Charles D. Cook (US) described Alexander’s syndrome, a congenital disorder of both sexes with onset in childhood or adult life. Like hemophilia but less severe this deficiency of serum prothrombin conversion accelerator (SPCA) results in hemophilia-like hemorrhagic diathesis with epistaxes, deep muscular hematomas, and internal hemorrhages (19).

Fritz Koller (CH), Emil A. Loeliger (NL) and Francois Henri Duckert (CH) identified the same factor, which they named factor VII (1046).

 

Kenneth M. Endicott (US), Theodore Gillman (US), Gerhard A. Brecher (US), Arthur T. Ness (US), F.A. Clarke (US), and Emil R. Adamik (US) found that the greatest iron uptake occurs in the duodenum (563).

Carl Vernon Moore (US) and Reubenia Dubach (US) determined that iron absorption occurs directly into the blood stream rather than through the lymphatics (1312; 1313).

 

Jessie L. Ternberg (US) and Robert Edward Eakin (US) demonstrated the presence in normal gastric juice of a protein fraction, apoerythein, which is absent from the gastric juice of pernicious anemia patients. This substance can combine with vitamin B12 (erythrotin) to form a vitamin-protein complex, erythein, in which the vitamin is resistant to digestive destruction. The substance is thus presumably identical with the “intrinsic factor” of Castle (1827). It has subsequently been shown that apoerythein is present in the saliva of both normal persons and pernicious anemia patients in amounts sufficient to account for that found in the gastric juice, but that the gastric juice of pernicious anemia patients contains a principle, which inactivates apoerythein, unless the gastric juice is first, treated with hydrochloric acid.

 

Geoffrey S.W. Organe (GB), William D.M. Paton (GB), and Eleanor J. Zaimis (GR) performed the first clinical trials of the anesthetic decamethonium (1400).

 

Joseph H. Burchenal (US), Shirley F. Johnston (US), Joan R. Burchenal (US), M.N. Kushida (US), Elaine Robinson (US), and Chester C. Stock (US) found that methotrexate could prolong survival in mice with leukemia (256).

Sidney Faber (US) used methotrexate to treat children with leukemia (588).

Robert H. Cress (US) and Nell L. Deaver (US) reported using methotrexate to manage psoriasis and arthritis (383).

Eugene J. van Scott (US) introduced the concept of "epithelial kinetics," the treatment of psoriasis with methotrexate (1876; 1877).

 

Philip Showalter Hench (US), Edward Calvin Kendall (US), Charles H. Slocumb (US), and Howard F. Polley (US) administered both Compound E (cortisone) and adrenocorticotropic hormone (ACTH) to fourteen patients suffering from rheumatoid arthritis. Both substances gave dramatically positive results (819; 820). See Valey Menken, 1941.

 

Philip Showalter Hench (US), Charles H. Slocumb (US), Arlie R. Barnes (US), Harry L. Smith (US), Howard F. Polley (US), and Edward Calvin Kendall (US) introduced Compound E (cortisone) in the treatment of rheumatic fever (821).

 

Lloyd D. Felton (US), utilizing pneumococcal polysaccharides, demonstrated a phenomenon known as "immunological paralysis" or immune tolerance (595).

 

Elizabeth Mapelsden Ramsey (US) and John W.S. Harris (US) made reconstructions of representative uteroplacental arteries, both human and monkey, at comparable stages of gestation, showing that there is very little qualitative difference in growth pattern during the first weeks after implantation. Checking of the monkey findings against their human counterparts, in operative and necropsy specimens, etc., they showned the monkey to be a valid experimental model with reproductive system anatomy and physiology closely similar to the human (782; 1510; 1512).

 

Charles Henry Sawyer (US), John W. Everett (US), and Joseph E. Markee (US) discovered the locus in the nervous system at which sex hormones alter the sensitivity to extrinsic stimuli and thus alter hypophyseal secretion. Their opinion was that the hypothalamus appeared to be the most likely site (gonadotrophin sex center) (1627).

 

Jerzy E. Rose (US) and Clinton Nathan Woolsey (US) completed a detailed lesion-retrograde degeneration mapping of the projections from the auditory region of the thalamus (medial geniculate body) to the auditory cortex in the cat (1576). They had completed similar studies on the projections of the mediodorsal nucleus to the orbitofrontal cortex in rabbit, sheep, and cat and on the relations between the anterior thalamic nuclei and the limbic cortex in the rabbit and cat (1574; 1575).

 

Donald Olding Hebb (CA) wrote The Organization of Behavior; A Neuropsychological Theory. His fundamental idea was to assume that the brain is constantly making subtle changes in the synapses, the points of connection where nerve impulses make the leap from one cell to the next. He argued that these synaptic changes were in fact the basis of all learning and memory. Hebb suggested that the selective strengthening of the synapses would cause the brain to organize itself into cell assemblies (subsets) of several thousand neurons in which circulating nerve impulses would reinforce themselves and continue to circulate. Hebb considered these cell assemblies to be the brain's basic building blocks of information. Each one would correspond to a tone, a flash of light, or a fragment of an idea. And yet these assemblies would not be physically distinct. Indeed, they would overlap, with any given neuron belonging to several of them. And because of that, activating one assembly would inevitably lead to the activation of others, so that these fundamental building blocks would quickly organize themselves into larger concepts and more complex behaviors. The cell assemblies, in short, would be the fundamental quanta of thought” (813). This hypothesis has been called Hebb's rule, Hebb's postulate, and cell assembly theory.

 

Lionel Sharples Penrose (GB) authored his very influential book, The Biology of Mental Defect. It is a thorough survey of the etiology of mental deficiency and an outstanding treatise on human genetics (1455).

 

Giuseppe Moruzzi (IT), Horace Winchell Magoun (US), Donald B. Lindsley (US), and John William Bowden (US) proposed that there is a diffuse system of ascending fibers arising in the reticular formation that is responsible for control of states of consciousness. They named it the ascending reticular activating system (the ARAS) (1175; 1334).

 

Harold Ridley (GB) achieved the first implant of an intraocular lens in 1949, although it was not until 1950 that he left an artificial lens permanently in place in an eye (1561). He had been experimenting with the correction of aphakia (the loss of the human lens from cataract surgery) by implanting artificial lenses into animals. As World War II broke out, he treated many fighter pilots whose eyes were injured by shattered plastic from the windshields of their fighter planes damaged during air combat. He discovered that if the tiny pieces of plastic were left in the eye, they were very well tolerated. A medical student, Peter Choyce (GB), suggested that he use polymethylmethacrylate or Perspex CQ, as the material for a human intraocular lens implant. Thus, the beginnings of the artificial lens implant to replace the cataractous lens removed at the time of cataract surgery.

 

John Frederick Joseph Cade (AU) observed the sedating effects of lithium in guinea pigs. He then determined that lithium was safe for human consumption by trying it himself. He administered lithium to ten manic patients, six schizophrenics, and three patients with major depressions. It didn’t affect the depressives and mildly calmed the schizophrenics, but it changed the manic patients dramatically (268). Note: Current hypotheses concerning its mechanisms include the interference with the phosphoinositide signaling pathway by either reducing the synthesis of second messengers involved in the pathway or inhibiting inositol monophosphatase activities; its neuroprotection against excitotoxicity caused by glutamate hyperactivity; the suppression of intracellular calcium mobilization; its stimulatory effect on ATP-dependent dopamine (prolactin-inhibiting hormone) uptake; its regulation of gene expression in long-term treatment; and the selective effect in G-protein subunit expressions in brain cells.

Lithium may be responsible for the reputed benefit of certain spring waters to patients with mental disease.

Johan August Arfwedson (Arfvedson) (SE), in 1817, discovered lithium. Its name is from the Greek word lithos meaning stone, apparently because it was discovered from a mineral source.

Priscilla White (US) introduced the "White Classification of Diabetic Pregnancies", which classified patients according to their level of risk and tailored their treatment protocol accordingly (1954).

Edward M. Trautner (DE-AU), Ron Morris (AU), Charles H. Noack (AU), and Samuel Gershon (AU) described the excretion and retention of ingested lithium and its effect on the ionic balance of man (1846).

 

Otto Steinbrocker (US), Cornelius H. Traeger (US), and Robert C. Batterman (US) summarized recommendations for uniform therapeutic criteria in treating rheumatoid arthritis (1772).

 

Richard Alan John Asher (GB) brought attention to the interaction between the brain and the thyroid gland, which can lead to madness (67). As a result, young and elderly psychiatric patients are now screened for thyroid malfunction.

Peter Garrard (GB), John R. Hodges (GB), Petrus Johannes de Vries (GB), Noel Hunt (GB), Angela Crawford (GB), and K. Sivasakthi Balan (GB) determined that some of the cases presenting as myxoedematous madness are thought to be the early descriptions of Hashimoto's encephalopathy, a rare neuroendocrine syndrome sometimes presenting with psychosis (668).

 

Ray E. Umbaugh (US) was the first to transfer a fertilized bovine embryo (1863).

Elwyn L. Willett (US), Wallace G. Black (US), Lester Earl Casida (US), William H. Stone (US), and P.J. Buckner (US) performed the first successful transfer of a fertilized bovine embryo that went to term (1971).

 

Robert A. Bruce (US), Frank W. Lovejoy, Jr. (US), Raymond Pearson (US), Paul N. G. Yu (US), George B. Brothers (US), and Tulio Velasquez (PE) aware of the tendency of people with coronary artery disease to experience angina (cardiac chest discomfort) during exercise, developed the first standardized method of "stressing" the heart, where serial measurements of changes in blood pressure, heart rate and electrocardiographic (ECG/EKG) changes could be measured under "stress-stress" conditions (243; 244).

Benedict Cassen (US), Clifton W. Reed (US), Lawrence Curtis (US), Leonard Baurmash (US), Herbert C. Allen, Jr. (US), and Raymond L. Libby (US) developed the first true radioisotope imaging system, the scintiscanner. It was a motor-driven scintillation detector coupled to a printer. The scanner was used to image the thyroid gland after the administration of radioiodine (23; 294).

William H. Sweet (US) and Gordon L. Brownell (US) suggested using the radiation emitted by positron annihilation to improve the quality of brain images by increasing sensitivity and resolution. They published a description of the first positron-imaging device to record three-dimensional data of the brain in their search for tumors. This was the beginning of positron emission tomography (PET) (1807).

Hal Oscar Anger (US) invented a type of gamma camera that is a scintillation camera, which permits visualization of radiotracer distribution in biological systems and makes possible dynamic studies (44).

Frank Mason Sones, Jr. (US) accidentally discovered that the coronary arteries can tolerate contrast dye. He and Earl K. Shirey (US) showed how to introduce contrast medium into the coronary arteries to permit radiography of these vessels. They subsequently began the development of a selective coronary angiographic procedure using image amplification and optical amplification with high-speed cinetechnique. Sones developed a catheter to enter selectively the coronary arteries. Selective coronary angiography became the standard of reference in the diagnosis of coronary artery disease. This work, begun in 1958, reports on over 1,000 selective coronary arteriographs performed by Sones and Shirey (1741).

Barry L. Zaret (US), H. William Strauss (US), Peter J. Hurley (US), T.K. Natarajan (US), and Bertram Pitt (US) devised a noninvasive scintiphotographic method for detecting regional ventricular dysfunction in man (2029).

Barry L. Zaret (US), Neil D. Martin (US), Harry P. Wells, Jr. (US), and Melvin Daniel Flamm, Jr. (US) performed noninvasive evaluation of regional myocardial perfusion with potassium 43. Their technique used patients at rest and those with exercise induced transient myocardial ischemia (1790; 2030).

Michel M. Ter-Pogossian (US), Michael E. Phelps (US), Edward J. Hoffman (US), and Nizar A. Mullani (US) developed the first positron-transmission-transaxial (PET) scanner which helps detect cancer, heart disease and other serious illnesses (1826). Note: Transaxial images of sections of organs containing positron-emitting radiopharmaceuticals are obtained. The detection system is a hexagonal array of 24 NaI (Tl) detectors connected to coincidence circuits to achieve the “electronic” collimation of annihilation photons. The image is formed by a computer-applied algorithm which provides quantitative reconstruction of the distribution of activity. Computer simulations, phantom and animal studies show that this approach is capable of providing images of better contrast and resolution than are obtained with scintillation cameras.

Tatsuo Ido (US), Chung-Nan Wan (US), Vito Casella (US), Joanna S. Fowler (US), Alfred P. Wolf (US), Martin Reivich (US), and David Edmund Kuhl (US) developed labeled 2-deoxy-D-glucose analogs. 18F-labeled 2-deoxy-2-fluoro-D-glucose, 2-deoxy-2-fluoro-D-mannose and 14C-2-deoxy-2-fluoro-D-glucose were major factors in expanding the scope of PET imaging (940).

Allen B. Nichols (US), H. William Strauss (US), Richard H. Moore (US), Timothy E. Guiney (US), Saadia Cochavi (US), George A. Beller (US), and Gerald M. Pohost (US) recorded acute changes in cardiopulmonary blood volume during upright exercise stress testing in patients with coronary heart disease (1364). Note: This is the origin of the modern noninvasive myocardial "stress test." George A. Diamond (US) and James S. Forrester (US) developed methodology to arrive at the patient's posttest likelihood of disease (472).

 

Donald D. Matson (US) developed the lumbo-ureteral shunt to drain overabundant cerebrospinal fluid into a hydrocephalic patient’s bladder via the ureter. This allowed the fluid to pass from the body along with urine. The kidney removed during this operation (Matson kidney) is often made available to patients in need of a kidney transplant (1231).

 

William Thornton Mustard (CA) and A. Lawrence Chute (CA), in 1949, successfully performed the world's first open-heart operation on a dog using rhesus monkey lungs to oxygenate the animal’s blood (1349).

William Thornton Mustard (CA), A. Lawrence Chute (CA), John Dowe Keith (CA), Anna Sirek (CA), Richard D. Rowe (CA), and Peter Vlad (CA), in 1952, used excised lungs from rhesus monkeys to oxygenate blood during pediatric surgery on a three-month-old girl with transposition of vessels. She only survived for a few hours (1350).

 

The US Navy Skin Bank, was established (833; 1850).

 

Ernest John Christopher Polge (GB), Audrey Ursula Smith (GB), and Alan S. Parkes (GB) were the first to demonstrate that the addition of an antifreeze like compound (glycerol) to cell cultures enhances their survivability when frozen and later thawed (833; 1477).

 

Rustom Jal Vakil (IN) reported on a clinical trial in which the ground roots of Rauwolfia serpentina were found to give a number of patients relief from essential hypertension (1867).

Nathan S. Kline (US) pioneered the introduction and use of Rauwolfia and other tranquilizing drugs for the treatment of schizophrenia in 1954 (1026).

 

Anton Julius Carlson (US) and Frederick Hoelzel (US) reported that observations made on 252 rats fed various diets in life span studies indicated that diverticulosis of the colon in ageing rats is produced by the lack of a suitable kind and amount of roughage in the diet (284).

 

Edward C. Tolman (US) hypothesized that there at least six kinds of learning: cathexes (which employs reinforcement); equivalence beliefs (reinforcement plus a traumatic experience); field expectancies (primarily Gestalt principles of learning and forgetting); field-cognition modes; drive discriminations; and motor patterns (probably Guthrie's principle of simple conditioning) (1840).

 

Aldo Starker Leopold (US) provided the intellectual and philosophical foundation for the discipline of wildlife ecology. His book of essays, A Sand County Almanac, gave form and voice to the land ethic that undergirds modern concepts of environmental sustainability. He fostered the idea that natural lands are more than a commodity, that nature is a human trust, and that there is inherent value in wilderness and wild things (1126).

 

Edward Smith Deevey, Jr. (US) reviewed the biogeography of the Pleistocene in an influential synthesis of existing knowledge. He coordinated climatic changes on both sides of the Atlantic Ocean (449).

 

1950

“Pasteur was not only the great scientist who was largely responsible for the creation of the science of microbiology, he was its high priest, preaching and fighting for the recognition of its importance in health and in human welfare.” Selman Abraham Waksman (688).

 

"Mother, mother I am ill,

Send for the doctor from over the hill;

In comes the Doctor, In comes the Nurse,

In comes the lady with the alligator purse.

Penicillin says the Doctor, Penicillin says the Nurse,

Penicillin says the lady with the alligator purse." This is a parody on a jump-rope-rhyme, which was written in response to the enormous popularity of penicillin.

 

Edward Calvin Kendall (US), Tadeus Reichstein (PL-CH) and Philip Showalter Hench (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects.

 

Otto Paul Hermann Diels (DE) was awarded the Nobel Prize in Chemistry for his synthesis of organic molecules including a dehydrogenated version of cholesterol.

Stanley Levey (US) and Elmer R. Jennings (US) introduced methodology—Levey-Jennings charts—to understand that random and systematic errors can be detected very effectively by means of statistical quality control (SQC) methods. The Levey-Jennings chart is the most important control chart in laboratory quality control. It can be used in internal and external quality control as well. It detects all kinds of analytical errors (random and systematic) and is used for the estimation of their magnitude (1134).

 William Grey Walter (US-GB) developed an automatic devise, which was so wired as to react in fashions that one usually associates with living creatures, i.e., a robot (1921).

James Hillier (CA-US) and Mark E. Gettner (US) devised one of the earliest ultramicrotomes (865; 866).

 

William E. Trevelyan (GB) developed an excellent technique for detection of reducing sugars on paper chromatograms. A developed chromatogram is dried and drawn through a solution of silver nitrate in aqueous acetone. The solvent is allowed to evaporate, and the paper sprayed with NaOH in aqueous ethanol. Reducing sugars produce dense black spots of silver at room temperature, unreacted silver hydroxide being then removed by immersing the paper in ammonia solution (1849).

 

Paul Fatt (GB) and Bernard Katz (RU-GB) originated the technique of using intracellular microelectrodes to record electrical potential and currents within the muscle fiber with which they discovered that in the absence of any form of stimulation, the end-plate region of the muscle fiber is not completely at rest, but displays electric activity in the form of discrete, randomly recurring <miniature> end-plate potentials. Each is only of the order of 0.5 mV in amplitude, but in other respects resembles the much larger end-plate potential evoked by the nerve impulse: it shows the same sharp rise and slow decay and has the character of a discrete all-or-none phenomenon though on a much smaller amplitude scale (590; 592).

Paul Fatt (GB) and Bernard Katz (RU-GB) concluded that in the synapse "small quantities of acetylcholine alter the end-plate surface in such a way that other ions can be rapidly transferred across it, not only sodium and potassium, but probably all free anions and cations on either side of the membrane. Apparently, we must think in terms of some chemical breakdown of a local ion barrier which occurs as soon as acetylcholine combines with it, and whose extent depends upon the number of reacting molecules" (591).

 

Maurice Ogur (US) and Gloria U. Rosen (US) described a method for the analytical extraction and quantitative estimation of RNA and DNA, enabling the utilization of u.v. absorbance as well as sugar and phosphorus estimation in the validation of the assay (1394).

 

Israel Doniach (GB), Alma Howard (GB), and Stephen R. Pelc (GB) were the first to apply autoradiography to the study of single cells. They established that most eukaryotic cells replicate their DNA in a narrow window of time course during the cell cycle called S phase (501; 914; 915).

Peter M.B. Walker (GB), Helen B. Yates (GB), and Hewson H. Swift (US), using spectrophotometric methods, discovered that doubling of eukaryotic cellular DNA occurs only during a portion of interphase (1809; 1919).

Alma Howard (GB) and Stephen R. Pelc (GB) devised the system whereby interphase of cell division is subdivided into G1, followed by S and G2 (916).

 

Emmett L. Durrum (US) introduced a micro-technique for the separation of amino acids, peptides and proteins. The technique is carried out by applying an electrical potential across the ends of strips of filter paper saturated with electrolyte solution. At some intermediate position of these strips, the mixture to be separated is applied. The course of separations is followed in the case of amino acids and peptides by ninhydrin treatment; in the case of protein separations by coagulation and selective dyeing in situ and in the case of radioactive components by autoradiography. Durrum introduced the mercury-bromophenol blue method for detection of protein spots on filter paper (523).

 

Phyllis Brewster (GB), Edward David Hughes (GB), Christopher Kelk Ingold (GB), and P.A.D.S. Rao () demonstrated that the stereochemical standards for sugars (L-glyceraldehyde) and amino acids (L-serine) possess the same configurations (230).

 

Louis Frederick Fieser (US) proposed that various substituents on the carbon atoms of the sugar molecule be designated alpha or beta, depending on whether they project above or below the plane in the Haworth structure (603).

 

Frank James Dixon (US), Samuel C. Bukantz (US), Gustave J. Dammin (US), and David W. Talmage (US) developed techniques to "tag" proteins and other molecules with radioactive iodine, a procedure still in use today. This method allows one to map and follow the progress of such molecules through the body to their ultimate location, where they can be quantitated, as a result, such antigen-antibody immune complexes and the inflammatory mediators they induce can be identified and linked with the diseases they cause (486-490).

 

Martin Seidman (US) and Karl Paul Link (US) synthesized o-nitrophenyl-beta-D-galactoside (ONPG) as a substrate for beta-galactosidase (1668). ONPG is cheap and colorless. Upon attack by beta-galactosidase it breaks down to colorless galactose and yellow o-nitrophenol. The yellow color can be determined quantitatively providing a sensitive test for the presence of beta-galactosidase. This test was important to the ultimate understanding of the lac operon.

 

Jacques Lucien Monod (FR), Aaron Novick (US), and Leo Szilard (HU-US) invented the chemostat, an instrument that achieves an automatic continuous culture of suspended cells (1383).

 

Andrew Alm Benson (US) identified early products of photosynthetic 14CO2 fixation by green algae and higher plants which separate readily on two-dimensional paper chromatograms. Exposure of X-ray film produced radioautographs revealing chemical properties and relative amounts of all the radioactive components of the extract. The radiochromatographic method facilitated identification of intermediates and delineation of their metabolic sequences in photosynthesis. Chemical identification of phosphoglyceric and malic acids as first products of CO2 fixation and of sugar phosphates, sugars, and amino acids are described (137).

Andrew Alm Benson (US), James Al Bassham (US), and Melvin Calvin (US) reported that the phosphate ester of sedoheptulose is part of the carbon assimilation pathway in photosynthesis (139).

Andrew Alm Benson (US) discovered that a phosphate of ribulose is part of this same mechanism (138).

 

James P. Martin (US) discovered that isolation and relative enumeration of fungi in soils and other natural materials containing organic residues was greatly improved using a combination of rose bengal at a concentration of about 1- 30,000 and streptomycin at 30 μg per ml in fungus plating media to prevent growth of bacteria and restrict size of colonies (1229).

 

Tracy Morton Sonneborn (US) led the way in developing methods in the general biology and genetics of Paramecium aurelia, including: collection from nature and identification; isolation; sterilization; culture; mutagenesis; cytology; genetics; control of growth rate, autogamy, conjugation, cytoplasmic transfer between mates, macronuclear regeneration, and in-breeding and cross-breeding; and work with mating types, killers and kappa, and surface antigens (770; 1742; 1743).

 

George Brecher (US) and Eugene P. Cronkite (US) developed a way to enumerate human blood platelets (225).

 

Howard Burlington (US) and V. Frank Lindeman (US) found that young roosters treated with DDT fail to develop normal male secondary sex characteristics, such as combs and wattles. The pesticide also stunts the growth of the animals' testes (259).

 

Paul Charpentier (FR) synthesized the phenothiazine derivative encoded 4560 RP, later to be known as chlorpromazine (Thorazine); the first effective drug for the treatment of schizophrenia and a commonly prescribed antipsychotic drug (307).

Jean Delay (FR) Pierre Deniker (FR), and Jean Marie Harl (FR) reported great success when they used chlorpromazine (Thorazine) on their patients (455; 457). In 1954 the U.S. Food and Drug Administration approved it.

Jean Delay (FR) and Pierre Deniker (FR) introduced the term “neuroleptic” (456). They defined “neuroleptics” as drugs which (i) induce a “psycholeptic state without hypnotic effect (i.e., indifference, affective and emotional neutrality), and decrease initiative and motor activity without gross alteration of vigilance and cognitive functions; (ii) control (treat) excitation, aggressiveness and agitation in manic and psychotic patients; (iii) improve (decrease) acute and chronic psychotic symptoms (hallucinations, delusions), ameliorate deficit symptoms of schizophrenia and control the symptoms induced by psychodysleptics; iv. induce neurovegetative and neurological side effects; and (v) exert their action at sub-cortical level (brain stem reticular formation, diencephalon).

 

M. Lourau (FR) and O. Lartigue (FR) discovered that diet can influence the biological effects produced by whole body X-irradiation (1192).

Jean-Francois Duplan (FR) found that cabbage in the diet offers a pronounced protection against whole body X-irradiation (522).

Harry Spector (US) and Doris Howes Calloway (US) reported that cabbage and broccoli reduce X-irradiation mortality (1749).

Doris Howes Calloway (US), Gordon W. Newell (US), William K. Calhoun (US), and A.H. Munson (US) confirmed previous findings that both cabbage and broccoli lowered mortality in irradiated animals. They found that several other carotene-containing foods also exerted some beneficial effects (276).

Kayoko Shimoi (JP), Shuichi Masuda (JP), Michiyo Furugori (JP), Syota Esaki (JP), and Naohide Kinae (JP) reported that some non-nutrient compounds such as lignans, indoles, coumarins and flavonoids protect mice from the effects of radiation (1683).

 

Alexander C. Finlay (US), Gladys Lounsberry Hobby (US), S.Y. P’an (US), Peter P. Regna (US), John B. Routien (US), Donald B. Seeley (US), Gilbert M. Shull (US), Ben A. Sobin (US), Isaiah Alexander Solomons III (US), John W. Vinson (US), and Jasper H. Kane (US) reported the isolation of the antibiotic terramycin (oxytetracycline) from Streptomyces rimosus (608).

 

József Baló (AT-HU) and Ilona Banga (AT-HU) discovered the pancreas elastase enzyme when they described the properties of a purified enzyme obtained from defatted pancreatic powder, distinct from trypsin and chymotrypsin, and capable of dissolving elastic fibers either in tissues or in test tubes (94).

 

Carl Widmer, Jr. (US) and Ralph T. Holman (US) discovered that linoleic acid fed to essential fatty acid deficient rats, is the precursor of arachidonic acid and that alpha-linolenic acid is the precursor of pentaene and hexaene acids (1960).

 

Otto Fritz Meyerhof (DE-US) and Harry Green (US) found that transphosphorylation occurs with biological phosphate compounds, with alkaline as well as with acid phosphatase, of animal origin, and that the transphosphorylation always goes from the phosphate of higher energy to those of lower energy (1267).

 

Charles Henry Sawyer (US), Joseph E. Markee (US), and John W. Everett (US) demonstrated that norepinephrine (noradrenaline) is involved in the release of gonadotropins (luteinizing hormone/LH or interstitial cell-stimulating hormone/ICSH and follicle stimulating hormone/FSH) from the anterior pituitary gland (1628).

 

Linus Carl Pauling (US), Robert Brainard Corey (US), Herman R. Branson (US), Harry L. Yakel, Jr. (US), and Richard E. Marsh (US) determined that the alpha-helix represents the secondary structure of many polypeptides (366; 1438; 1439; 1441-1443; 1446; 1448; 1449). Pauling and Corey also predicted the antiparallel pleated sheet (beta sheet) conformation as the secondary structure of some polypeptides (1440; 1444; 1445).

Linus Carl Pauling (US) introduced the use of molecular models, with precisely scaled representations of the atoms, as a method for solving molecular biology problems. On receiving the 1954 Nobel Prize in Chemistry he told the Swedish Academy. “The requirements are stringent ones. Their application to a proposed hydrogen-bonded structure of a polypeptide chain cannot in general be made by the simple method of drawing a structural formula; instead, extensive numerical calculations must be carried out, or a model must be constructed. For the more complex structures, such as those that are now under consideration for the polypeptide chain of collagen and gelatin, the analytical treatment is so complex as to resist successful execution, and only the model method can be used. In order that the principles of modern structural chemistry may be applied with the power that their reliability justifies, molecular models must be constructed with great accuracy. For example, molecular models on the scale of 2.5 cm = 1 angstrom unit, must be made with a precision better than 0.01 cm” (1436).

 

Martin Rivers Pollock (GB) observed that the enzyme penicillinase is induced by the presence of penicillin (1478).

 

André Michel Lwoff (FR), Antoinette Gutmann (FR), Louis Siminovitch (CA), and Niels Ole Kjeldgaard (DK), using Bacillus megatherium, rediscovered and explained lysogeny in bacteria (See, Bordet, 1921). They reasoned that in lysogeny the genes of the original infecting phage merged into the chromosome of the bacterium, where it behaved undetected like the neighboring genes along the string. Lwoff called this integrated form of the virus, prophage or provirus. In a rare cell the prophage would spontaneously disengage from the host chromosome and set into motion events, which would lead to the release of new phage particles. They discovered that virus in the lysogenic state can be induced to change to the lytic state by certain environmental factors. In 1953, Lwoff predicted that induction of prophage might be a good test for carcinogenic, and anti-carcinogenic agents (1198-1200; 1202).

Giuseppe Bertani (IT) confirmed the work of Lwoff and Gutmann in his work with three different temperate phages from a multiply lysogenic strain of E. coli, most notably phages P1 and P2 (160).

André Michel Lwoff (FR), Louis Siminovitch (CA), and Niels Ole Kjeldgaard (DK) found that ultraviolet light terminates the lysogenic state, which is then immediately followed by phage replication and lysis of the entire bacterial population (1203). This discovery made lysogeny more susceptible to detailed molecular analysis.

 

Esther M. Lederberg (US) isolated lambda virus from Escherichia coli K12. She demonstrated that it is a temperate virus and therefore capable of being induced. She also discovered that the lysogenic state of the host can be transmitted like a gene during bacterial crosses (1106; 1107).

Élie Wollman (FR) confirmed these findings (1987).

Melvin Laurance  (US) discovered lambda-mediated transduction of specific bacterial genes (specialized transduction) (1332).

 

Norton David Zinder (US), Joshua Lederberg (US), and Bernard David Davis (US) showed that bacteriophage virus particles could transfer bacterial genetic material from bacterium to bacterium without direct contact between the cells. They called this phenomenon transduction (420; 1111; 2033; 2034).

 

Thomas Foxen Anderson (US) found that bacteriophages lose their infectivity when subjected to osmotic shock, which ruptures the phage head and releases the phage DNA into the ambient medium. The implication was that the phage attaches to the host with its protein coat, called the capsid (39).

 

Kenneth M. Smith (GB) and Ralph Walter Greystone Wyckoff (US) discovered a distinct and major group of insect viruses, the spherical polyhedral viruses (1717).

 

Gilbert Julias Dalldorf (US) reports that newborne mice were essential for the clinical detection of coxsackieviruses and arboviruses prior to 1950 (404).

 

John R. Paul (US and Charles E. Rosenberg (US) report that rhesus monkeys were used exclusively for the clinical isolation of polioviruses prior to 1950 (1434).

 

William McDowell Hammon (US), in 1950, purified the gamma globulin component of the blood plasma of polio survivors. He proposed the gamma globulin, which contained antibodies to poliovirus, could be used to halt poliovirus infection, prevent disease, and reduce the severity of disease in other patients who had contracted polio (763).

Hammon (US), Lewis L. Coriell (US), Ernest H. Ludwig (US), Robert M. McAllister (US), Arthur E. Greene (US), Gladys E. Sather (US), and Paul F. Wehrle (US) found that the results of their large clinical trial were promising; the gamma globulin was shown to be about 80 percent effective in preventing the development of paralytic poliomyelitis. It was also shown to reduce the severity of the disease in patients who developed polio (764).

 

Lloyd Florio (US), Mabel Stewart Miller (US) and Edward R. Mugrage (US) isolated the Colorado tick fever virus from Dermacentor andersonii (the wood tick) (616).

 

Max Theiler (ZA) and Wilbur George Downs (US) report that embryonated eggs were used for clinical detection of influenza viruses prior to 1950 (1828).

 

Leslie Harold Collier (GB), beginning about 1950, developed a commercially feasible process for large-scale production of a stable freeze-dried vaccinia vaccine (352). Vaccinia vaccine was produced in large quantities, beginning in the 1950’s, for use by the Pan American Sanitary Organization and the World Health Organization. By 1979 the world was declared free of smallpox (1401).

Donald Ainslie Henderson (US) directed the decade-long World Health Organization global campaign that eradicated smallpox. He oversaw more than 700 advisors from 69 countries, as well as 200,000 national health staff and volunteers (617). According to the World Health Organization three-year-old Rahima Banu of Bangladesh was, on October 16, 1975, the last known case of smallpox in the world. This ended a 10-year vaccination campaign costing approximately $83 million. Smallpox is considered by many medical experts to be the most devastating and feared pestilence in human history (617).

Isao Arita (JP), as chief medical officer of the WHO World Smallpox Eradication Office, declares that smallpox (Variola) is officially eliminated; the last natural case was seen in Somalia in 1977. The victim, a twenty-three-year-old cook named Ali Maow Maalin, was successfully quarantined, and all of his contacts vaccinated (53). This represents the only microbial disease ever completely defeated.

Donald A. Henderson (US) also comments on this momentous accomplishment (822).

A laboratory outbreak of smallpox occurred during 1978 in a Medical School laboratory at the University of Birmingham. Two people in the same family died as the result of being infected (596). As of July 2014, no more cases have been reported.

 

Dorothy Hamre (US), Jack Bernstein (US), and Richard Donovick (US) were the first to report a chemical agent, which can block the replication of a virus. The agent is a thiosemicarbazone and it inhibits viruses from various families (766).

 

Luigi Luca Cavalli-Sforza (IT-US) and William Hayes (GB) were the first to isolate high frequency recombinant (Hfr) strains of bacteria (295; 803).

William Hayes (GB) discovered that bacterial conjugation is unidirectional, in which one organism acts as donor and the other organism as the recipient. Based on his experiments and those of others, principally the Lederbergs, Hayes theorized that some Escherichia coli carry a fertility factor (F⁺) whereas others lack it (F-). For a cross to be fertile, the presence of the fertility factor is required in at least one of the parents. Thus, the crosses F⁺ X F⁺ and F⁺ X F^- are fertile, whereas F- X F- is sterile. The fertility factor is transmissible from F⁺ to F- by a process requiring cell contact. F⁺ cells may spontaneously loose the fertility factor. Once lost it can only be regained from an F⁺ cell. He further proposed that the F⁺ cell transfers only part of its genome to the F- recipient, so that the resulting zygote is not a complete but a partial zygote, or merozygote.

William Hayes (GB) also announced that he had discovered a new sub strain of Escherichia coli, K12, which produced recombinants a thousand to ten thousand times more frequently than any previously known. He named it Hfr Hayes (Hfr = high frequency recombinant) (802-804; 1110; 1112).

William Hayes (GB), Joshua Lederberg (US), Luigi Luca Cavalli-Sforza (IT-US), and Esther M. Lederberg (US) discovered that bacteria have gender with the males containing a genetic element called a fertility factor (F factor), abbreviated F (802-804; 1112).

Joshua Lederberg (US) gave the name plasmid to all extrachromosomal genetic elements of bacteria (1108). Most of those found in eukaryotes (Eucarya) are now known to be intracellular symbiotic microorganisms.

Élie L. Wollman (FR) Francois Jacob (FR), and William Hayes (GB) discovered that the bacterial DNA of Escherichia coli Hfr cells is transferred with a definite directionality starting from what was called the origin and continuing back around to the integrated F factor. This injection follows a strict schedule, and, with any particular strain, the injection always starts at the same point. Because of their location on the chromosome it was logical that some genes would be transferred frequently, whereas others would be transferred only rarely. Usually the result is the formation of an incomplete zygote (merozygote). Using time of transfer of donor alleles, they were able to construct a time course map of the Escherichia coli chromosome (961; 1988; 1990).

Élie L. Wollman (FR) and Francois Jacob (FR) described the chromosome of Escherichia coli as a closed, or circular, structure. They described the F factor of Escherichia coli as a plasmid. They pointed out that the F factor is a self-replicating, nonessential, extra-chromosomal, genetic element that may be present or absent. The phenotypic characters acquired through possession of the F plasmid are dispensable since the plasmid is not a necessary cellular constituent. The F factor is capable of alternating between the integrated and autonomous state. Once a bacterium is cured of a plasmid (such as the change from F⁺ to F) the phenotypic character associated with the plasmid is irretrievably lost (960; 1989).

Yukinori Hirota (JP) and Teiji Iijima (JP) found that the F factor could be eliminated from F⁺ strains of bacteria by treatment with acridine dyes. Hfr clones are unaffected by the dye (868).

Francois Jacob (FR) and Élie L. Wollman (FR) proposed the term episome to describe genetic elements such as colicine, phage lambda, and F factor which can exist both in association with the chromosome and independent of it (965).

Francois Jacob (FR), Jacques Lucien Monod (FR), Edward Allen Adelberg (US), and Sarah N. Burns (US) discovered that occasionally an F factor picks up a small fragment of the bacterial chromosome when it disengages to become autonomous. They referred to these agents as F prime plasmids. These modified fertility factors exhibited a great increase in the frequency of their insertion into the bacterial chromosome. Furthermore, the chromosomal site at which the F prime factor became attached was invariably the same (10; 958).

Kunitaro Ochiai (JP), T. Yamanaka (JP), K. Kimura (JP), and O. Sawada (JP) demonstrated that antibiotic resistance could be transferred between strains of Escherichia coli and Shigella via extrachromosomal plasmids (R-factor) (1387).

Tomoichiro Akiba (JP), Kotaro Koyama (JP), Yoshito Ishiki (JP), Sadao Kimura (JP), and Toshio Fukushima (JP) reported that multiple drug resistance was developing in a single step in patients with enteric infections (16).

Robert Lavallé (FR) and Francois Jacob (FR) provided indirect radiobiological evidence suggesting that the F factor (plasmid) does contain DNA (1100).

Julius Marmur (US), Robert Rownd (US), Stanley Falkow (US), Louis S. Baron (US), Carl L. Schildkraut (US), and Paul Mead Doty (US) demonstrated conclusively that plasmids are DNA. They used the CsCl buoyant density separation of DNA based on nucleotide base composition to show that light density E. coli -like DNA appeared in Serratia marcescens (which has a somewhat heavier DNA) after transfer of the F-factor to Serratia (1226).

Tsutomu Watanabe (JP), Toshio Fukasawa (JP) and Keong Lyang (JP) showed that F factor plasmids can carry genes that endow the host cell with drug resistance, in some cases multiple drug resistance. Not only are these plasmids transferred to their own species but to a broad spectrum of taxonomically diverse genera. Today these are referred to as R plasmids. With the appearance of the R plasmids, drug resistance could spread like wildfire through the bacterial flora. Over a span of a few years these R plasmids made their appearance all over the world (1926; 1927).

Naomi Datta (GB) and Polyxeni Kontomichalou (GR) discovered genes conveying resistance to antibiotics in bacteria on small, infectious, supernumerary chromosomes called R factors (plasmids) (412).

Francois Jacob (FR), Sydney Brenner (ZA-GB), and Francois Cuzin (FR) proposed that the O locus of the F factor represents what they called a replicator, or site at which replication of the DNA molecule can be initiated by DNA polymerase enzyme. Each replication cycle of the autonomous (i.e., nonintegrated) F factor present in an F⁺ cell was thought to begin at that replicator site, in the same way in which replication of the bacterial chromosome was imagined beginning at its own replicators, and then to proceed around the DNA circle by means of a replicating Y-fork. The F replicator at the O locus has one additional quality, however: it is activated upon contact of the donor with a recipient cell. This activation engenders a new round of semiconservative DNA replication of the fertility-factor DNA, during which one of the two daughter duplexes is threaded, O locus first, into the conjugation bridge and driven toward the F- cell, while the daughter duplex remains in the donor cell. If the entire F genome is replicated in this way before the conjugation bridge is sheared the F- recipient will become an F+ cell (957).

Jun-ichi Tomizawa (JP-US) and Naoyo Anraku (JP-US) determined the time course of the integration process in merozygotes formed in the cross Hfr Cavilli Lac⁺ Tsx^s x F^- Lac^- Tsx^r. They concluded that most of the recombinants that arise from the conjugational merozygote are formed within a time span comparable to one bacterial generation period (1841-1843).

Stanley Falkow (US), Ron V. Citarella (US), John A. Wohlhieter (US), and Tsutomu Watanabe (US) found the spontaneous loss of one or more drug resistance characteristics carried by R-factors was correlated with either an apparent loss of particular density regions of the satellite DNA or a change in the relative amounts of the different fractions of the satellite DNA (586).

Stanley Norman Cohen (US), Annie C.Y. Chang (US), and Leslie Hsu (US) used cold calcium chloride to induce Escherichia coli to take up R-factor DNA (343).

Fred Heffron (US), Pat Bedinger (US), James J. Champoux (US), and Stanley Falkow (US) determined that the structural gene for plasmid-mediated ampicillin resistance resides upon a 3.2 X 10(6) dalton transposable sequence (TnA) flanked by short inverted repeated sequences that accompany its insertion. TnA was transposed to pMB8, a 1.8 X 10(6) dalton derivative of the colicingenic plasmid ColE1 (817).

 

Maurice Ralph Hilleman (US), Richard Patrick Mason (US), Edward L. Buescher (US), Frederick J. Flatley (US), Sally A. Anderson (US), Mary L. Luecking (US), and Doris J. Levinson (US) discovered what is now known as the "drifting" and "shifting" mutation of influenza virus, making it possible to predict the development of new strains of influenza and to develop vaccines effective against new strains (852-854; 860; 861).

 

Joseph Louis Melnick (US) isolated the Coxsackie virus and reported its properties, immunological aspects, and distribution in nature (1260).

Thomas Huckle Weller (US), John Franklin Enders (US), Margaret E. Buckingham (US), and John J. Finn, Jr. (US) linked a Coxsackie virus to the etiology of epidemic pleurodynia (1945).

 

Theodore A. Olson (US) was the first to demonstrate the link between specific genera of cyanobacteria and animal deaths resulting from the consumption of these cyanobacteria (285).

 

James B. Evans (US) and Charles F. Niven, Jr. (US) found that those strains of Staphylococcus aureus that produce food poisoning by means of an enterotoxin are usually coagulase positive (582).

 

John Nathaniel Couch (US) discovered the bacterial genus Actinoplanes. He established it as family Actinoplanaceae, in the order Actinomycetales (374).

 

Francis T. Haxo (US) and Lawrence Rogers Blinks (US) proposed that phycoerythrins are the chief photosynthetic pigments in red algae (801).

 

Shih-Yi Chen (CN), Boris Ephrussi (RU-FR), and Helene Hottinguer (FR) discovered that nuclear genes are necessary for proper functioning of mitochondria (314).

 

Folke Karl Skoog (SE-US) demonstrated, in vitro, that growth and development of plant organs is under chemical control (1706).

 Carlos O. Miller (US) and Folke Karl Skoog (SE-US) discovered that an old commercial preparation of herring sperm DNA is highly active in promoting cell division in pith tissue from the center of the tobacco (Nicotiana tabacum) stem. New DNA preparations did not yield the activity, but it was soon demonstrated that heating the DNA preparations in weakly acid solutions in the autoclave could generate the cell division activity.

Carlos O. Miller (US), Folke Karl Skoog (SE-US), Francis S. Okumura (US), Malcolm H. von Saltza (US), and Frank M. Strong (US) isolated, purified, and determined the structure of the compound responsible for the cell division activity of partially degraded DNA preparations. It was identified as 6-furfurylaminopurine (that is, N 6-furfuryladenine). The trivial name kinetin was given to this compound. This was the first example of a new class of plant growth substances that came to be known as cytokinins (1275; 1276).

The discovery of kinetin initiated intensive efforts to isolate and identify all naturally occurring compounds with equivalent activity in promoting cell division in plant tissues. D. Stuart Letham (NZ), James S. Shannon (NZ), Ian R. McDonald (NZ) and, almost simultaneously, Carlos O. Miller (US), successfully purified and identified a naturally occurring cytokinin from plant material and demonstrated that this compound was also an N 6-substituted adenine derivative. The isolation and identification of N 6-(trans-4-hydroxy-3-methyl-2-butenyl) adenine as the active cell division factor present in immature corn kernels was achieved by Letham. He gave this compound the trivial name of zeatin, and the compound that Miller had isolated from the same source was quickly shown to be identical to zeatin (1131; 1132).

 

Marion Wesley Parker (US), Harry Alfred Borthwick (US), and Laura E. Rappleye (US) determined that poinsettia will produce its showy red bracts just in time for Christmas if cuttings started at the beginning of October are kept in the dark for 14-16 hours daily (1424).

 

Marion Owenby (US) demonstrated that two species of the genus Trapopogonan were produced by polyploidization from hybrids. She showed that Trapopogonan miscellus found in a colony in Moscow, Idaho was produced by hybridization of T. dubius and T. pratensis. She also showed that T. mirus found in a colony near Pullman, Washington was produced by hybridization of T. dubius and T. porrifolius (1404).

 

Emma Lucy Braun (US) wrote Deciduous Forests of Eastern North America in which she describes the evolution of forest communities and their survival during periods of glaciation (223).

 

George Ledyard Stebbins, Jr. (US) published Variation and Evolution in Plants, the first book to provide a wide-ranging explanation of how evolutionary mechanisms operated in plants at the genetic level. Stebbins argued that evolution needed to be studied as a dynamic problem and that evolution must be considered on three levels: first, that of individual variation within an interbreeding population; second, that of the distribution and frequency of this variation; and third, that of the separation and divergence of populations as the result of the building up of isolating mechanisms leading to the formation of species (1766).

 

Miriam Elizabeth Simpson (US) and Choh Hao Li (CN-US) pointed out that hormonal coordination is necessary for the balanced development of tissue. ref

 

Paul Chatfield (US) and Charles Lyman (US) described fundamental physiological phenomena in the hibernating hamster Mesocricetus auratus that define the transition between the torpid and euthermic states. They described a dominant role for the sympathetic nervous system in stimulation of heart rate (HR) during rewarming. The increase in HR was preempted by a rapid rise in blood pressure achieved by differential vasoconstriction and restriction of circulation to the posterior parts of the body. Chatfield and Lyman proposed that arousal from hibernation is initiated by a waking stimulus, which causes a mass discharge from the hypothalamus and leads to an increase in body temperature (T_b), HR and blood pressure. Many of the contributions of Chatfield and Lyman's paper included some of the first descriptions of circulatory changes associated with arousal from hibernation (308).

 

Harry Harris (GB) studied familial patterns associated with 1241 diabetic propositi and concluded that diabetes tends to run in families (780).

 

Marie Cutbush (AU-GB-CA) and Patrick Loudon Mollison (GB) and Dorothy M. Parkin (GB) discovered and named the Duffy blood group system (400; 401).

Roger P. Donahue (US), Wilma B. Bias (US), James H. Renwick (US), and Victor A. McKusick (US) showed that segregation of the Duffy blood group is linked to a dominantly inherited microscopically visible secondary constriction (at an uncoiler locus) on the long arm of chromosome 1 in man (499).

 

John R. Haserick (US), Lena A. Lewis (US), and Donald W. Bortz (US) found a specific factor in the gamma fraction of serum associated with acute disseminated lupus erythematosus and responsible for inducing rosettes of leukocytes (791).

 

Floyd W. Denny (US), Lewis W. Wannamaker (US), William R. Brink (US), Charles H. Rammelkamp, Jr. (US), Edward A. Custer (US), Harold B. Houser (US), Edward O. Hahn (US), and John Holmes Dingle (US) performed a meticulous analysis of the role and timing of streptococcal infection in the causation of rheumatic fever. Their subsequent introduction of penicillin prophylaxis at the onset of streptococcal infection produced a sharp reduction in the incidence of rheumatic fever and rheumatic heart disease (463; 1508).

 

Jean Clark Dan (US-JP), A. Kitahara (JP), and T. Kohri (JP) described the acrosome reaction of sperm during the penetration of the egg in echinoderms, annelids, and mollusks. The acrosome reaction is characterized by two major physiological events: the exocytosis of the acrosomal vesicle and the extension of the acrosomal process (408-410).

Victor D. Vacquier (US), Gary W. Moy (US), Kirk S. Zigler (US), and Harilaos A. Lessios (US) isolated a protein associated with the inner acrosomal membrane and responsible for adhesion of sperm to sea urchin eggs. They named it bindin (1866; 2032).

Lewis G. Tilney (US), Daniel P. Kiehart (US), Christian Sardet (US), and Mary Tilney (US) determined that the acrosomal process is formed by the pH-dependent polymerization of actin (1833).

Charles G. Glabe (US) and Victor D. Vacquier (US) found that the bindin receptor in the vitelline coat of the sea urchin egg is a glycoprotein of more than 5 million daltons (693).

Charles G. Glabe (US) and William J. Lennarz (US) found that bindin mediates the species-specific adhesion of sperm to egg (692).

Jeffrey D. Bleil (US) and Paul M. Wassarman (US) found that in the mouse the bindin receptor is a zona pellucida component named ZP3 (191).

 

Emil Hans Willi Hennig (DE) published his Grundzüge einer Theorie der Phylogenetischen Systematik, which was translated in 1966 as Phylogenetic Systematics, then reprinted in 1979 (826; 827). Note: Hennig is considered the founder of phylogenetic systematics, also known as cladistics.

 

Kurt R. Reissmann (US) concluded that under experimental hypoxia, erythropoiesis is stimulated not by the partial pressure of oxygen in the bone marrow directly but by a humoral factor elicited by the hypoxemia (1548).

 

Eugene Roberts (US) and Sam Frankel (US) isolated and identified the inhibitor gamma-aminobutyric acid (GABA) in the brain (1566). GABA was already known to exist in plant and other animal tissues.

 

Karl Spencer Lashley (US) summarized his 33 years of research and theory on memory and the brain. He concluded that (1) memories are not localized but are instead distributed within functional areas of the cortex and (2) memory traces are not isolated cortical connections between inputs and outputs (1095).

 

William Clouser Boyd (US) blood typed people from all over the earth and separated them into 13 groups (210).

 

Robert W. Noyes (US), Arthur T. Hertig (US), and John Rock (US) used rapid changes in endometrial histologic patterns following ovulation to assign ‘dates’ which correlate well with other timing measures of ovulation in the study of human fertility. This methodology included a graph of histologic changes during the menstrual cycle, a series of representative photomicrographs, and clinical correlations among 300 patients (1386).

 

Frank Albert Bassen (US) and Abraham Leon Kornzweig (US) described Bassen-Kornzweig syndrome. Symptoms include abetalipoproteinemia, ataxia, atypical retinitis pigmentosa, diffuse disease of the central nervous system, and crenated red blood cells (112).

 

Norman R. Barrett (GB) first described the columnar metaplasia associated with chronic peptic ulcer of the esophagus and esophagitis (106).

Philip Rowland Allison (GB) and Alan Stewart Johnstone (GB) noted an association of columnar metaplasia with gastroesophageal reflux (27).

Andre P. Naef (CH), Luciano Ozzello (CH), Marcel Savary (CH), and Philippe Monnier (CH) were the first to systematically explore, describe, and photograph what today is the well-known pathology of progressively ascending columnar reparation of erosions due to gastroesophageal reflux and its association with adenocarcinoma (1304; 1351; 1626). This precancerous condition is frequently called Barrett’s esophagus.

 

Reed M. Nesbit (US) and William C. Baum (US) reported on the treatment of prostatic carcinoma through endocrine control. The initial successes become tempered by the knowledge that the benefits were not universal, that the degree and duration of response were variable and that eventually most patients experienced relapse and subsequent death from the primary disease (1362).

 

Richard J. Cross (US) and John V. Taggart (US) found that thin slices of rabbit kidney cortex are capable of accumulating p-aminohippurate (PAH) from a saline suspending medium against a considerable concentration gradient. This process appears to be closely related to the tubular excretion of PAH in the intact animal. Acetate, which exhibits a striking stimulatory effect on PAH accumulation, is suggested as a possible rate-limiting cellular component of the PAH transport mechanism (389).

 

Henri-Marie Laborit (FR) investigated the use of antihistamines, especially promethazine, to inhibit the reaction of the autonomic nervous system to physical stress in surgery (1076).

 

Wilfred Gordon Bigelow (CA), John C. Callaghan (CA), and John A. Hopps (CA) amputated a man's frostbitten fingers, in 1941. Contemplation of this operation later led them, along with William K. Lindsay (CA) and William F. Greenwood (CA), to begin animal experiments where they found that when dogs are cooled, open-heart surgery can be performed over long periods -- much longer than four minutes -- and they are likely to survive. They showed that at lower temperatures, the tissues of the body and brain didn't need as much oxygen and can survive without oxygenated blood for longer intervals (170; 171).

 

Alfred Blalock (US) and C. Rollins Hanlon (US) described a palliative procedure to improve arterial oxygen saturation in patients with complete transposition of the great arteries. A surgical atrial septectomy is accomplished through a right lateral thoracotomy, excising the posterior aspect of the interatrial septum to provide mixing of systemic and pulmonary venous return at the atrial level (185). Transposition of the great arteries is characterized by reversal of the aorta and pulmonary artery. The aorta receives the oxygen-poor blood from the right ventricle, but it's carried back to the body without receiving more oxygen. Likewise, the pulmonary artery receives the oxygen-rich blood from the left ventricle but carries it back to the lungs.

Ake Senning (SE) performed an operation for complete transposition of the great arteries in which venous return is directed to the contralateral ventricle by means of an atrial baffle fashioned in situ by using right atrial wall and interatrial septum. Therefore, the right ventricle supports the systemic circulation (1671).

Langford Kidd (CA) and William Thorton Mustard (CA) described the hemodynamic effects of a totally corrective procedure in transposition of the great vessels (1020).

William J. Rashkind (US) and William W. Miller (US) noted that best results are obtained in children well beyond 6 months of age when correcting transposition of the great vessels and therefore, it is imperative to provide early palliation that is effective until the optimal age for complete correction and that does not interfere significantly with subsequent surgery. They suggested creation of an interatrial communication as the best available choice to suit these requirements (1533).

William J. Rashkind (US) and William W. Miller (US) introduced balloon atrioseptostomy (BAS) as palliation for transposition of the great arteries (1534).

Sang C. Park (US), James R. Zuberbuhler (US), Williams H. Neches (US), Cora C. Lenox (US), and Richard A. Zoltun (US) introduced catheter blade atrial septostomy to be used in place of balloon atrial septostomy if the atrial septum is thickened (1422).

Jean Rubay (FR), Yves Lecompte (FR), Alain Batisse (FR), Yves Durandy (FR), Alain Dibie (FR), Georges Lemoine (FR), and Pascal Vouhe (FR) presented a surgical methodology for the anatomic repair of anomalies of ventriculo-arterial connection (REV) involving direct anastomosis of the pulmonary trunk to the right ventricle (1591).

 

Richard H. Lawler (US), James W. West (US), Patrick H. McNulty (US), Edward J. Clancy (US), and Raymond P. Murphy (US) surgically excised a (free) human kidney allograft then transplanted it to a recipient nephrectomy site. The recipient was not immunosuppressed (1101).

 

Vladimir Demikhov (RU) described more than 20 different techniques for heart transplantation (461).

James D. Hardy (US), Carlos M. Chavez (US), Frederick D. Kurrus (US), William A. Neely (US), Sadan Eraslan (US), M. Don Turner (US), Leonard W. Fabian (US), and Thaddeus D. Labecki (US) transplanted a chimpanzee's heart into a man. The heart was too small to support the circulation and failed after 2 hours (773).

Christiaan Neethling Barnard (ZA), on Dec. 3, 1967, performed the first successful transplantation of a human heart. He transplanted the heart of a 23-year-old woman killed in a motor vehicle accident into the chest of a middle-aged man, Louis Washkansky. The recipient lived for eighteen days, until the powerful drugs used to suppress rejection weakened him and he died of pneumonia (99-102).

 

Eugene M. Bricker (US) developed an intestinal conduit to convey urine from both kidneys to a watertight external appliance for patients following radical operations for pelvic cancer that involved the removal of the rectum as well as the bladder (231).

 

Lyle A. French (US), John J. Wild (US), and Donald Neal (US) provided research showing that ultrasound could detect differences in density between malignant and normal tissues (645).

 

Fritz Haber (US) and Heinz Haber (US) introduced the concept that parabolic flight would produce micro- gravity that could be used for medical research. It was calculated that a vertical parabola accurately flown by an aircraft with an initial air- speed of 450 mph and an initial pitch angle of 45° would generate 35 s of microgravity, long enough to investigate selected medical problems (749).

 

Hermann J. Schaefer (DE-US) concluded that data from balloon and suborbital rocket flights showed that galactic cosmic radiation increased rapidly with altitude between the ground and 70,000 feet. The recent discovery of very energetic heavy nuclei particles above 90,000 feet was also discussed.

He concluded “Without a doubt we must not fear that human beings above 90,000 feet altitude will be killed instantly or within a short time. The effect might rather be of the slow accumulating type which makes the clinical picture of the radium poisoning so uncanny and dreadful” (1632).

 

Nancy Catherine Keever (US) characterized succession in an old field after agricultural use had ceased. She observed a predictable shift in plant community composition following field abandonment, with horseweed (Erigeron canadense) dominating fields one year after abandonment, white aster (Aster pilosis) dominating in year two, and broom sedge (Andropogon virginicus) dominating in year three (Figure 5). She found that life history strategies of individual species, seed dispersal, allelopathy (biochemical production by a plant which alters growth and survival of other plants or itself), and competitive interactions among species, led to this predictable pattern of succession (1003).

 

The National Science Foundation was established in the United States.

 

1951

“I believe, therefore, that just as the role of iron in biological reactions is now made completely understandable by the work of Otto Warburg as being necessary for the catalysis of oxygen transfer, so the role of phosphate compounds in the organisms is made understandable by their importance for energy transfer.” Otto Fritz Meyerhof (1266).

 

"The Creator, if He exists, has a special preference for beetles, and so we might be more likely to meet them than any other type of animal on a planet that would support life." John Burdon Sanderson Haldane (GB-IN). A comment made by J.B.S. Haldane during a lecture on the biological aspects of space flight given in 1951. He was referring to the fact that 25% of all known animal species are types of beetles.

 

"To continue our 'Just So Story,' before our extremely remote ancestors could come ashore to enjoy their Eocene Eden or their Paleozoic Palm Beach, it was necessary for them to establish an enclosed aqueous medium which would carry on the role of seawater." James L. Gamble (664).

 

Max Theiler (ZA-US) was awarded the Nobel Prize in Physiology or Medicine for his discoveries concerning yellow fever and how to combat it.

 

Axel Hugo Theodor Theorell (SE) and Britton Chance (US) developed a rapid spectrophotometric method for measuring the formation and disappearance of the compound of alcohol dehydrogenase (ADH) and reduced nicotinamide adenine dinucleotide (NADH) without appreciable interference from the absorption of NADH (1829).

 

Thomas Foxen Anderson (US) developed the critical point drying method of dehydrating soft biological material to make it suitable for viewing with the scanning electron microscope. Carbon dioxide was used as the liquid which was brought to its critical point (40).

 

Oliver H. Lowry (US), Nira J. Rosebrough (US), A. Lewis Farr (US), and Rose J. Randall (US) devised a method for the determination of protein (1194). This has become the most cited paper in the biological sciences.

Marian M. Bradford (US) developed a rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding (216).

Samuel Natelson (US) was a great analytical chemist who pioneered in the development of microchemistry and its application to the understanding of electrolyte balance of the immature infant. His work has saved the lives of hundreds of thousands, if not millions, of infants (1356; 1357).

Jesse Philip Greenstein (US), Leon Levintow (US), Carl G. Baker (US), and Julius White (US) prepared the four pure stereoisomers of isoleucine. To do this they resolved mixtures of DL-isoleucine and DL-alloisoleucine into D- and L-isoleucine and D- and L-alloisoleucine with an enzymatic hog kidney preparation (723).

Alton Meister (US), Leon Levintow (US), Rembert B. Kingsley (US), and Jesse Philip Greenstein (US) used the enzymatic resolution procedure to prepare several enantiomorphic forms of amino acids. They then evaluated the purity of the resulting preparations with L- and D-amino acid oxidases and bacterial decarboxylases. They determined that their amino acid preparations contained less than 0.1% of the enantiomorph, thus proving that the enzymatic resolution procedure did indeed yield isomers of high optical purity (1259).

 

Dan H. Campbell (US), Ernst Luescher (CH), and Leonard S. Lerman (US) invented affinity chromatography on columns to purify enzymes and to purify and subdivide a population of heterogeneous antibodies (277; 1128; 1129).

Pedro M. Cuatrecasas (ES-US), Meir Wilchek (IL), and Christian Boehmer Anfinsen, Jr. (US) were early practitioners of affinity chromatography; a technique that frequently yields highly purified proteins in one step (399).

Pedro M. Cuatrecasas (ES-US) described the preparation of agarose and polyacrylamide bead derivatives for the purification of a variety of proteins and enzymes. The methodologies described permit the attachment of ligands directly or through extended hydrocarbon chains to immobilized supports (398).

 

Hans Henriksen Ussing (DK) and Karl Zerahn (DK) developed a short-circuit current technique to define the active transport of sodium as the source of electric current across the isolated frog skin i.e., the Ussing chamber (1865). Note: This single paper introduced a new research direction that has led to our understanding of many cellular models of ion transport physiology in numerous epithelial tissues of the body.

 

Arthur Nobile (US), William Charney (US), Preston L. Perlman (US), Hershel L. Herzog (US), Constance C. Payne (US), Maryann E. Tully (US), Margaret A. Jevnik (US), and Emanuel Benjamin Hershberg (US) succeeded in using bacteria to oxidize cortisone to prednisone and hydrocortisone to prednisolone. They found that these crude extracts of the corticosteroid prednisone were more than four times more effective than natural cortisones against arthritis in mice (1376; 1377). Note: Prednisone was soon used to prolong kidney transplant survival.

 

Gerty Theresa Cori, née Radnitz (CZ -US) and Joseph Larner (US) described the “debrancher” enzyme or amylo-1,6-glucosidase. This enzyme, which was found in muscle, catalyzes the hydrolysis of the 1,6-glucosyl linkages at the branch points. The hydrolysis of the branch points makes it possible for phosphorylase in the presence of excess phosphate (and low concentrations of 1-ester) to split glycogen almost completely (367).

 

Alexander Robertus Todd (GB) presented an argument that the ribonucleic acids exist as polynucleotides with recurring 3’—5’ glycosidic linkages (1837).

 

Robert Burns Woodward (US), Franz Sondheimer (US), and David Taub (US) performed the total synthesis of both cholesterol and cortisone (1999; 2000).

 

Luis E. Miramontes (MX), George Rosenkrantz (MX), and Carl Djerassi (AT-US), following the methods of Russel E. Marker (US), synthesized 19-nor-progsterone, a powerful synthetic progesterone (1288).

 

George Wallace Kenner (GB) carried out the total synthesis of natural ribonucleosides (1014).

 

Jordi Folch (ES-US) was the first to describe the presence of special proteins in rat brain myelin which could be solubilized in organic solvents (chloroform / methanol / water mixtures). These substances were named proteolipides and were considered as a novel lipoprotein but quite different from the other known lipoproteins (618).

 

W. Eugene Knox (US) showed that the amount of the liver enzyme L- tryptophan oxygenase, was greatly increased by treatment of living rats with the enzyme’s specific substrate. Some unrelated compounds caused lesser increases by a different mechanism, but only if the adrenal glands were present. The first mechanism was like the substrate induction of enzymes known in microorganisms. The second mechanism was a way hormones could act to affect metabolism by altering the amounts of specific enzymes in cells (1036).

 

Marco Rabinovitz (US) Melvin P. Stulberg (US), Paul Delos Boyer (US), Henry Arnold Lardy (US), and Harlene Wellman (US) reported that cellular respiration rates varied with the availability of inorganic phosphorus and phosphate acceptor (1094; 1500).

 

Giulio L. Cantoni (US) established the role of ATP in the enzymatic synthesis of a new metabolic intermediate (S-adenosyl methionine) which proved to be the methyl donor in numerous biological transmethylation reactions (282).

Giulio Leonardo Cantoni (US) showed that S-adenosyl-methionone formed from ATP and methionine can donate its methyl group to one of the hydroxyl groups of catecholamines (281).

 

Joseph Richard Stern (US), Seymour Korkes (US), Alice del Campillo (US), Irwin Clyde Gunsalus (US), and Severo Ochoa (ES-US) reported that propionyl-CoA was carboxylated to form methylmalonyl-CoA, which was then converted to succinyl-CoA (1048; 1780).

 

Elizabeth Lee Hazen (US) and Rachel Fuller Brown (US) isolated the antibiotic nystatin from Streptomyces noursei (806).

Elizabeth Lee Hazen (US), Rachel Fuller Brown (US), and Alice Mason (US) developed the first useful antifungal antibiotic. This was initially known as fungicidin, then Nystatin (named for "NY STATe Dept. of Health"), and finally Mycostatin. Mycostatin was isolated from Streptomyces noursei (807). Hazen and Brown were awarded U.S. patent #2,797,183 in 1957.

 

Alexander C. Finlay (US), Gladys Lounsberry Hobby (US), Frank A. Hochstein (US), Thomas M. Lees (US), Tulita F. Lenert (US), J.A. Means (US), S.Y. P’An (US), Peter P. Regna (US), John B. Routien (US), Ben A. Sobin (US), K.B. Tate (US), Jasper H. Kane (US), Quentin R. Bartz (US), John Ehrlich (US), James D. Mold (US), Mildred A. Penner (US), and Robert M. Smith (US) isolated the antibiotic viomycin from Streptomyces puniceus and Streptomyces floridae (111; 607). This antibiotic binds to RNA and inhibits prokaryotic protein synthesis and certain forms of RNA splicing.

 

Ann Bishop (GB) reported resistance of Plasmodium gallinaceum to proguanil in monkey and human malaria (182).

Ann Bishop (GB) reported the development of resistance to metachloridine (3-metanilamido-5-chloropyrimidine) in two clones of Plasmodium gallinaceum derived from single erythrocytic parasites and maintained by serial inoculation in young chicks. Resistance developed with equal facility and similarly in the two clones (183)

 

John Desmond Bernal (GB) proposed that one way in which organic subunits may spontaneously combine into larger molecules is by adsorption of the reacting molecules onto the highly ordered negatively charged aluminosilicates of clays. The clay surface performs a catalytic function (151; 152).

Alexander Graham Cairns-Smith (GB), P. Ingram (), and Gregory L. Walker () later proposed that under primitive Earth conditions organic polymers could have condensed on extremely thin layers of negatively charged aluminosilicates separated by layers of water (273).

 

Jacques Lucien Monod (FR) and Melvin Cohn (US) renamed the lactase Monod had isolated from Escherichia coli in 1948 as beta-galactosidase (349).

 

Martin B. Mathews (US), Albert Dorfman (US), and Saul Roseman (US) discovered that chondroitin sulfate is a substrate for hyaluronidase (1230).

 

Francis P.W. Winteringham (GB), Patricia M. Loveday (GB), and A. Harrison (GB) carried out the first comparative metabolic studies in which insects resistant to DDT (dichloro-diphenyl-trichloro-ethane or 2,2-di (4-chlorophenyl)-1,1,1-trichloroethane) were compared with those sensitive to it. They treated the insects with isotopically labeled (⁸²Br) DDT then analyzed the metabolites with paper chromatography and radiometric scanners (1981).

 

David Shemin (US) and Jonathan B. Wittenberg (US) used isotopically labeled acetates and determined that 26 of the carbons in protoporphyrin are derived from acetate (1679).

 

Jean-Marie Wiame (BE) and Michael Doudoroff (RU-US), while exploring oxidative assimilation in Pseudomonas saccharophila, discovered that both carbons of acetate, carbons 2 and 3 of lactate, and the two methylene carbons of succinate are largely assimilated, whereas the carbonyl carbons of lactate and succinate are mainly converted to carbon dioxide. This indicated that the acetyl moieties derived from various substrates are probably a major source of assimilated carbon (1959).

 

Wolf Vishniac (US), Severo Ochoa (ES-US-ES), L. Jonathan Tolmach (US), and Daniel Israel Arnon (PL-US) demonstrated that the photochemical reductive carboxylation of pyruvic acid to malic acid is driven by catalytic amounts of reduced NADP (TPN) (57; 1839; 1891).

 

Adele Millerd (AU), James Frederick Bonner (US), Bernard Axelrod (US), and Robert Bandurski (US) succeeded in obtaining from the mung bean (Phaseolus aureus), a cell-free preparation, which catalyzes the aerobic oxidation of all the members of the Krebs cycle. This strongly suggested that higher plants contain the Krebs cycle and oxidative phosphorylation (1287).

 

Feodor Felix Konrad Lynen (DE), Ernestine Reichert (DE), Luistraud Kröplin-Rueff (DE), Luise Wessely (DE), and Otto Wieland (DE) formulated the chemical reaction scheme for the beta-oxidation of fatty acids. Lynen named it the fatty acid cycle and noted that the key reaction consists of the thiolytic cleavage of the beta-keto acid by coenzyme A (1204-1206). See, Franz Knoop, 1904.

 

Efraim Racker (PL-AT-US) showed that the conversion of glyoxal to glycolic acid by glyoxylase proceeds through a carboxyl-S-glutathione intermediate. This is significant because it was the first time that an “energy-rich” thioester of biological relevance was identified (1502).

 

Bernard David Davis (US) elucidated the complete biosynthetic pathway of aromatic amino acids from a common precursor, shikimic acid (422).

 

Hans Weil-Malherbe (DE-GB-US) and A.D. Bone (GB) observed that glucose-6-phosphate inhibits hexokinase activity (1937).

Efraim Racker (PL-AT-US) proposed that glucose-6-phosphate, which inhibits hexokinase activity, acts as a control mechanism helping to explain the Pasteur effect (1503).

Robert Kellogg Crane (US) and Alberto Sols (ES) found that brain hexokinase has two binding sites. One is for ATP, while the other binds glucose-6-phosphate. They also found that α-glucose-1,6-diphosphate inhibits hexokinase (382).

 

Lester J. Reed (US), Betty G. DeBusk (US), Irwin Clyde Gunsalus (US), and Carl S. Hornberger, Jr. (US) crystallized and named alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase (1544). This chemical entity had been called the acetate-replacing/pyruvate oxidation factor.

Milon W. Bullock (US), John A. Brockman, Jr. (US), Ernest L. Patterson (US), Jack V. Pierce (US), and E.L. Robert Stokstad (US) synthesized DL-lipoic acid and established that it is 6,8-dithiooctanoic acid or 1,2-dithiolane-3-valeric acid (252).

Hayao Nawa (JP), William T. Brady (US), Masahiko Koike (JP), and Lester J. Reed (US) determined that the functional form of lipoic acid occurs when the carboxyl group of lipoic acid is bound in amide linkage to the epsilon-amino group of a lysine residue in the acyltransferase component of the alpha-keto acid dehydrogenase complexes (1358).

Masahiko Koike (US), Lester J. Reed (US), William R. Carroll (US), Prefulchandra C. Shah (US), Robert M. Oliver (US), Henry R. Henney, Jr. (US), Charles R. Willms (US), Tsuyoshi Muramatsu (US), Barid B. Mukherjee (US), and Eiji Ishikawa (US) dissected the pyruvate and alpha-ketoglutarate dehydrogenase complexes (PDH and KGDH respectively) into their component enzymes, characterized them, and reassembled the large functional units from the isolated enzymes. They found that functional units are composed of multiple copies of three enzymes: 1) a pyruvate and an alpha-ketoglutarate decarboxylase-dehydrogenase, 2) a dihydrolipoamide acetyltransferase and a succinyltransferase, and 3) a flavoprotein, dihydrolipoamide dehydrogenase. These three enzymes, acting in sequence, catalyze the decarboxylation of the alpha-keto acid, the subsequent reductive acylation of the lipoyl moiety, the acyl transfer to CoA, and the reoxidation of the dihydrolipoyl moiety with NAD-plus as the ultimate electron acceptor (825; 949; 1038-1041; 1545; 1979).

Flora H. Pettit (US), Lester J. Reed (US), and Tracy C. Linn (US) observed that the PDH complex, but not the KDGH complex, underwent a time-dependent inactivation in the presence of ATP. The PDH complexes are regulated by a phosphorylation-dephosphorylation cycle. Phosphorylation and concomitant inactivation of the complex is catalyzed by an ATP-dependent kinase, and dephosphorylation and concomitant reactivation are catalyzed by a magnesium ion-dependent phosphatase (1176; 1463).

 

Roger Moss Herriott (US) demonstrated that bacteriophage ghosts consist entirely of protein (834). Herriott wrote Alfred Day Hershey saying, “I’ve been thinking—and perhaps you have, too—that the virus may act like a hypodermic needle full of transforming principles; that the virus as such never enters the cell; that only the tail contacts the host and perhaps enzymatically cuts a small hole through the outer membrane and then the nucleic acid of the virus head flows into the cell” (837).

 

Salvador Edward Luria (IT-US) demonstrated that bacteriophage reproduce in an exponential fashion within the host cell (1196).

 

Jacques Lucien Monod (FR), Germaine Cohen-Bazire (FR), and Melvin Cohn (US) concluded that an enzyme inducer for beta-galactosidase does not induce because it is a substrate nor through its combination with pre-formed active enzyme, but rather at the level of another specific cellular constituent (1307; 1308). This paper disproved the hypothesis that the process of induction depends on an interaction of the inducer with the enzyme.

 

Gunnar Östergren (SE) explained the difference in chromosome movement seen in ordinary mitosis and the first division of meiosis by meticulous investigation of the first meiotic division in several plants where he found that a key difference lay in the arrangement of the kinetochore regions. In mitosis, the kinetochore is arranged on two opposite sides of the chromosome, but during the first meiotic division, the whole kinetochore is arranged on one side of the chromosome body. "Both the kinetochores of a bivalent can sometimes be seen to move actively towards the same spindle pole (during metaphase)", he wrote. "During these random movements the kinetochores of the paired chromosomes, sooner or later, happen to pull on their partners. This pull, in connection with the one-sided arrangement of the kinetochore on the chromosome body, results in an orientation of the partner kinetochores towards opposite spindle poles, i.e., it produces the co-orientation" (1402).

 

Jan Mohr (DK) discovered the Lutheran-secretor linkage in man as a linkage of the Lutheran blood group and the 'recessive' Lewis blood group. It was the first autosomal linkage identified in man (1301; 1302).

 

Myron K. Brakke (US) used density-gradient centrifugation in sucrose solutions to purify a plant virus (219; 220).

 

Thomas Foxen Anderson (US) described techniques for the preservation of three-dimensional structure in preparing specimens for the electron microscope (40).

 

Theodosius Grigorievich Dobzhansky (Ukrainian-US) found that Drosophila pseudoobscura exhibited regular seasonal variations in different types of chromosomal inversions (491; 492). These flies were well known for their inversion polymorphism.

Theodosius Grigorievich Dobzhansky (Ukrainian-US), Natasha P. Spassky (US), Howard Levene (US), and Olga Pavlovsky (US) were able to show that a variety of factors which vary with season, including temperature, food type and amount of intraspecific competition, affects the fitness of these chromosomal arrangements, thus accounting for the seasonal variation in inversion types. The reason the polymorphism is maintained is because the various inversion heterozygotes generally have higher fitness than their homozygotes (491; 493; 494; 1133).

 

Victor J. Freeman (US) discovered that a specific bacterial virus called beta-phage infects toxigenic diphtheria bacilli (640).

 

H. Herbert Fox (US) discovered that isoniazid (isonicotinic acid hydrazide) is antibacterial for Mycobacterium tuberculosis, M. bovis, M. africanum, and M. microti (626; 627).

Carl Muschenheim (US), Walsh McDermott (US), Richard B. Maxwell, Jr. (US), Charles M. Clark (US), DuMont F. Elmendorf, Jr. (US), William C. Cawthon (US), Clarence Jordahl (US), Roger DesPrez (US), and Kurt Deuschle (US) established the great efficacy of isoniazid drugs in the treatment of tuberculosis, meningitis and generalized miliary tuberculosis (1242; 1243; 1348).

Jack Bernstein (US), William A. Lott (US), Bernard A. Steinberg (US), Harry L. Yale (US), William Steenken, Jr. (US), Gordon M. Meade (US), Emanuel Wolinsky (US), and E. Osborne Coates, Jr. (US) introduced isoniazid (isonicotinic acid hydrazide) as a chemotherapeutic antimycobacterial agent (154; 1768).

Hans Meyer (CZ) and Josef Mally (CZ) were the first to synthesize isoniazid (isonicotinic acid hydrazide) (1265).

 

Leslie W. Mapson (GB) and David Rockwell Goddard (US) showed that tri-phospho-pyridine nucleotide (TPN; coenzyme II) serves as a hydrogen donor in the reaction of an enzyme they characterized and named glutathione reductase (1221; 1222).

 

Gottfried Samuel Fraenkel (DE-US) showed that, with some rare exceptions, insects have the same nutritional requirements as man (628; 629).

 

Edward Arthur Steinhaus (US) recognized the potential of Bacillus thuringiensis as a control agent for certain insect pests. He investigated its pathogenic characteristics, including the associated endotoxin (1773).

 

Solomon Zuckerman (GB) wrote a treatise in which he supported Waldeyer-Hartz's proposal of the absence of postnatal oogenesis in mammals (2037). Note: As of 2020, the validity of the dogma that oogenesis and folliculogenesis do not persist in the ovaries of adult mammalian females is controversial.

 

Ludwik Gross (Ludwig Gross) (PL-US) described the induction of leukemia in newborn mice by means of a cell-free extract of tissues from mice suffering with spontaneous leukemia (730). By showing that a virus causes mouse leukemia and can be passed naturally from generation to generation Gross gained the attention of scientists who had largely ignored the role of viruses in cancer, even though in 1908, researchers had suggested a viral cause by transmitting leukemia and sarcomas in chickens.

Ludwik Gross (Ludwig Gross) (PL-US) described the “vertical” transmission of mouse mammary carcinoma and chicken leukemia along with its possible implications for human pathology (731).

Bernice E. Eddy (US), Sarah Elizabeth Stewart (US), and William Berkeley (US) observed that tumor virus from mice caused a cytopathogenic effect in tissue culture (538).

Ludwik Gross (PL-US) and Sarah Elizabeth Stewart (US) independently observed sarcomas in mice following inoculation with extracts of murine leukemia virus (732; 733; 1784).

Sarah Elizabeth Stewart (US), Bernice E. Eddy (US), Alice M. Gochenour (US), Ninette G. Borgese (US) and George E. Grubbs (US) demonstrated that polyoma virus, which had caused the sarcomas in the 1953 study described above, replicates in tissue culture (1785).

Bernice E. Eddy (US), Sarah Elizabeth Stewart (US), Ralph D. Young (US) and G. Burroughs Mider (US) discovered that inoculation of the polyoma virus into newborn hamsters led to tumor induction with a shorter latent period than in adult mice (539).

GianPiero A. di Mayorca (IT-US), Bernice E. Eddy (US), Sarah Elizabeth Stewart (US), William S. Hunter (US), Charlotte Friend (US), and Aaron Bendich (US) discovered that SE polyoma virus DNA and intact polyoma virus are capable of infecting embryonic tissue cultures of both the mouse and the hamster. These new infectious molecules proved to be both the first infectious DNA isolated and the first cancer-inducing nucleic acid (471). The SE in SE polyoma is to honor Stewart and Eddy.

Wallace Prescott Rowe (US) and Worth I. Capps (US) found polyoma virus infection to be prevalent among wild mice (1587; 1588).

Michael J. Collins, Jr. (US) and John C. Parker (US) found the polyoma virus to be a common contaminant of transplantable murine tumors and stocks of murine leukemia viruses (353).

 

Preben Christian Alexander von Magnus (DK) reported the presence of noninfectious incomplete virus capable of interfering with influenza virus in chick embryos (1899-1901).

 

Povl Elo Christensen (DK), Henning R. Schmidt (DK), H.O. Bang (DK), Vera Andersen (DK), Bjarne Jordal (DK), and Oskar Jensen (DK), reported that Greenland experienced a measles epidemic in 1951. The virus was not endemic to this area, so it spred rapidly, eventually infecting 99.9% of the population. A rapid response using gamma globulin from Denmark doubtless reduced the number of fatalities (318; 319).

 

SchackAugust Steenberg Krogh (DK) and Torkel Weis-Fogh (DK) provided the first measures of metabolic rate and respiratory quotient in a flying locust (1068).

 

Chester W. Emmons (US) discovered that soil and pigeon habitats are both natural reservoirs of Cryptococcus neoformans (560; 561).

 

Sajiro Makino (JP) was the first to introduce the use of the peritoneal cavity of animals as a place for growing cells in culture. These are frequently referred to as ascites tumor cultures (1215).

 

Libbie Henrietta Hyman (US) recommended using the phylum name Aschelminthes to include the classes: Rotifera, Gastrotricha, Kinorhyncha, Nematoda, Priapulida, and Nematomorpha (938).

 

Stephen V. Boyden (GB) discovered that treatment of sheep erythrocytes with suitable concentrations of tannic acid renders them capable of adsorbing certain protein molecules from solution in saline. Red cells, which have adsorbed proteins in this way, are agglutinated after washing by the homologous antiprotein sera, even by high dilutions (211).

 

Oscar Davis Ratnoff (US) and Calvin Menzie (US) described a simplified method for the determination of fibrinogen in plasma which permits the accurate and rapid determination of the amount of fibrinogen in samples of normal plasma as small as 0.1 ml, one tenth the amount used in methods previously described (1540).

 

Bodil M. Schmidt-Nielsen (DK-US) and Knut Schmidt-Nielsen (DK-US) reported that the kangaroo rat possesses interesting adaptations to the desert life including: no sweat glands, nocturnal behavior, reduced surface temperature in the nasal passages, exceptionally concentrated urine, lack of the need to drink, and coprophagic behavior (1642).

 

Leon L. Miller (US), Chauncey G. Bly (US), Michael L. Watson (US), and William F. Bale (US) developed an isolated rat liver perfusion apparatus, which along with ¹⁴C labeled lysine, allowed them to demonstrate that the rat liver plays a dominant role in the synthesis of albumin, fibrinogen, and plasma globulins (1284).

Leon L. Miller (US) and William F. Bale (US) would show that the liver does not synthesize gamma globulin (1283).

 

Lawrence G. Brock (AU), Jack S. Coombs (AU), John Carew Eccles (AU), and Paul Fatt (AU) studied the chemical action at nerve synapses by means of microelectrodes inserted within the nerves themselves. They, along with P. Fatt (AU), were able to work out the chemical changes in considerable detail (233; 234; 362).

 

Viktor Hamburger (DE-US) and Howard L. Hamilton (US) presented their study of the normal development of the chick embryo. It summarizes the major developmental landmarks of the chick (761).

 

Otto von Dardel (SE) and Stephen Thesleff (SE) used choline esters of succinic acid or suxamethonium for muscle relaxation (1897).

 

Alfred Glücksmann (GB) proposed that cell death (apoptosis) occurs during the normal development and maintenance of the tissues and organs of vertebrates (698).

Rita Levi-Montalcini (IT-US), Viktor Hamburger (DE-US), Hertha Meyer (BR) and Stanley Cohen (US) were the first to describe and characterize nerve growth factor (NGF). They obtained it from mouse sarcoma cells and found that it elicited extensive growth of chick embryo neurons (339; 341; 342; 1135; 1136; 1138-1140). This was the first neurotrophin to be described and isolated.

Stanley Cohen (US) purified nerve-growth promoting protein from the mouse salivary gland and its neuro-cytotoxic antiserum (340).

Rita Levi-Montalcicni (IT-US) and Barbara Booker (US) showed that NGF is critical for the survival and maintenance of sympathetic and sensory neurons. Without it, these neurons undergo apoptosis (1137).

John F.R. Kerr (AU), Andrew H. Wyllie (GB), and Alistair R. Currie (GB) coined the term apoptosis to mean genetically orchestrated cell death not involving inflammation (1016).

David P. Martin (US), Robert E. Schmidt (US), Peter S. DiStefano (US), Oliver H. Lowry (US), Joyce G. Carter (US), and Eugene M. Johnson, Jr. (US) illuminated the fact that sympathetic neurons must synthesize protein and RNA to die when deprived of nerve growth factor (NGF) indicating that NGF, and presumably other neurotrophic factors, maintain neuronal survival by suppressing an endogenous, active death program (1227).

Thomas L. Deckwerth (US) and Eugene M. Johnson, Jr. (US) mapped the sequence of events in a neuron's death, showing that the cell-slaying program eventually reaches a point of no return (448).

 

Min Chueh Chang (CN-US) and Colin R. Austin (GB) independently found that sperm must undergo an incubation period within the female reproductive tract before they acquire fertilizing capacity (75; 298; 299). Austin would name this phenomenon sperm capacitation. Chang and his associates would subsequently show that capacitation is common among mammals.

 

Arthur Davis Hasler (US), Allan T. Scholz (US), and Robert W. Goy (US), and Warren J. Wisby (US) proposed the "imprinting hypothesis" to explain homing of fishes such as the salmon. This hypothesis states that recognition of the home stream results from a relatively rapid odor learning process during a sensitive period called the smoltification process (792; 793).

Hans Nordeng (NO) presented another hypothesis in which he speculated that smolts, which migrate to the ocean, release population specific odors called pheromones. It's these pheromones, in the end, that are used by mature adults as cues to guide them back to their home stream (1381). Evidence supporting both the imprinting and pheromone hypothesis has accumulated.

 

Min Chueh Chang (CN-US) found that of two million sperm deposited in the vagina of a rabbit only about 1% make it past the cervical barrier to the uterine cavity and only about 5,000 find their way past the utero-tubal junction. Fewer still reach the site of fertilization in the outer segment of the oviduct. These findings contradict the notion that swarms of sperm are necessary to penetrate the follicular cells surrounding the oocyte, the cumulus oophorus, and corona radiata. Chang showed that the physiological integrity of the individual sperm is the most important factor in its success in fertilizing the ovum. He found that a single sperm can penetrate the cumulus mass of cells and reach the zona pellucida, a thick mucoprotein membrane surrounding the ovum. Chang posited that every population of sperm is composed of some that are strong and others weak, morphologically defective, or aged. The larger the population the more likely a physiologically strong sperm is to reach the ovum (299).

 

Fred H. Allen, Jr. (US), Louis Klein Diamond (US), Bevely Niedziela (US), Robert Russell Race (US), and Ruth Sanger (US) discovered the Kidd blood group antigens and how they are inherited (22; 1501).

 

Frederick Heaf (GB) devised a single tuberculin test made with a multiple-puncture apparatus. The simplicity of the test and the elimination of the personal factor made it suitable for mass tuberculin surveys of large groups of population, particularly in undeveloped countries (808).

 

Frederic Crosby Bartter (US), Fuller Albright (US), Anne P. Forbes (US), Alexander Leaf (US), Eleanor Dempsey (US), and Evelyn Carroll (US) deduced that the common virilizing form of adrenal hyperplasia is fundamentally a type of adrenocortical insufficiency arising from a metabolic error in the biosynthetic pathway to corticol. They suggested that to compensate the pituitary secretes even more ACTH leading to the secretion of excessive amounts of other classes of adrenal steroids. They successfully treated this condition using cortisone (109).

 

John Julian Wild (GB-US) is considered by most to be the true founder of ultrasonic tissue diagnosis. Working with Donald Neal (US), an engineer, and John M. Reid (US) he published on unidirectional A-mode ultrasound investigations into the thickness of surgical intestinal material and later the diagnosis of intestinal and breast malignancies (1964; 1965).

John Julian Wild (GB-US), Harry D. Crawford (US) and John M. Reid (US) used echocardiography to identify a myocardial infarction in vitro using both M mode and 2D echo (1963).

 

Ralph Milton Waters (US) penned his important book on chloroform anesthesia, Chloroform—A Study After 100 Years (1928).

 

Harold Elford Johns (CA), Lloyd M. Bates (CA), Ed R. Epp (CA), Doug V. Cormack (CA), Sylvia Olga Fedoruk (CA), A. Morrison (CA), W.R. Dixon (CA), and C. Garrett (CA) reported that radioactive cobalt provided a continuous source with greater ability to treat internal tumors, with less damage to the intervening tissue. Clinical cobalt- 60 is still used in much of the developing world (975).

 

Hans Brücke (AT), Karl Heinz Ginzel (DE), Hans Klupp (DE), F.A. Pfaffenschlager (DE), and Gerhard Werner (DE) performed the first clinical trials of the anesthetic succinylcholine (suxamethonium chloride) (245). It is a nicotinic acetylcholine receptor agonist, used to induce muscle relaxation and short-term paralysis, usually to facilitate tracheal intubation. It is used as a paralytic agent for euthanasia/immobilization of horses. Despite its adverse effects, including life threatening malignant hyperthermia, hyperkalaemia, and anaphylaxis, it is perennially popular in emergency medicine because it arguably has the fastest onset and shortest duration of action of all muscle relaxants.

 

Derek Ernst Denny-Brown (NZ-GB-US) and Huntington Porter (US) reported the use of BAL (British anti-lewisite) treatment for Wilson’s disease (progressive hepatolenticular degeneration) (465). Named for Samuel Alex Kinnier Wilson (GB). This discovery was one of the first effective treatments for a neurological condition.

 

Sheldon S. Waldstein (US), Hans Popper (AT-US), Paul B. Szanto (US), and Frederick Steigmann (US) introduced the technique of liver biopsy using a needle (1917).

 

Brian McArdle (GB) first described glycogen storage disease type 5, following his examination of a male patient, 30 years of age, who reported the condition as having been present "all his life" (1237). Symptoms are muscular pain, fatigability, and muscle cramping following exercise.

Wilfred F.H.M Mommaerts (US), Barbara Illingworth (US), Carl M. Pearson (US), Richard J. Guillory (US), and Krikor Seraydarian (SY-US) found that this inborn abnormal accumulation of glycogen in muscle tissue is due to a phosphorylase B deficiency (1303).

 

Karl Beck (DE) described occlusion of the anterior spinal artery resulting in complex neurological signs as anterior spinal artery syndrome (123).

 

Hugh William Bell Cairns (GB) was the first to describe hydrocephalus following obstruction of the flow of cerebrospinal fluid secondary to tuberculous meningitis (272).

 

Archibald Denis Leigh (GB) described subacute necrotizing encephalomyelopathy (Leigh disease) (1118).

 

Richard Alan John Asher (GB) described and named Munchausen syndrome by proxy (Baron von Munchausen). This is a form of child abuse in which a parent, usually the mother, induces or reports physical symptoms in a child and fabricates a corresponding history that results in unnecessary medical evaluation and treatment (68; 69).

 

C. Miller Fisher (US) discovered that carotid bifurcation occlusive disease is the major preventable cause of stroke and transient ischemic attack (610; 611).

 

Poul Iversen (DK) and Claus Brun (DK) consider that continued studies of material removed by aspiration biopsy of the kidney may contribute materially to solution of the pathophysiologic problems of the heterogeneous group of renal diseases generally termed lower nephron nephrosis (954).

 

Charles A. Hufnagel (US) developed and implanted artificial valves in the descending aortas of dogs (924).

Charles A. Hufnagel (US), W. Proctor Harvey (US), Pierre J. Rabil (CA), Thomas F. McDermott (US), Paulo Diaz Vilkgas (US), and Hector Nahas (US) went on to perform the operation on humans (925; 926).

Nina Starr Braunwald (US), Theodore Cooper (US), and Andrew G. Morrow (US) reported the complete replacement of the mitral valve with a flexible polyurethane prosthesis (224).

Albert Starr (US) and M. Lowell Edwards (US) replaced the mitral valve in a human with a cage-ball valve (1760).

Donald N. Ross (ZA-GB) reported a homograft replacement of the aortic valve (1582).

Alain Carpentier (FR), Guy Lemaigre (FR), Ladislas Robert (FR), Séverine Carpentier (FR), and Charles Dubost (FR) performed the first implantation into the human heart of a valvular bioprosthesis, May 1968 in Paris (287).

 

René Küss (FR), J. Teinturier (FR), and Paul Milliez (FR) transplanted free kidneys and kidneys from guillotined donors using no immunosuppression. Their surgical techniques were pioneering and became popular (1075).

 

Fritz Zöllner (DE) and Horst Wullstein (DE), during the early 1950s, worked out the principles of the use of microscopy in operations on the eardrum and within the middle ear (745).

 

Ernst Walter Mayr (DE-GB-US) invented the concept of genetic revolution in which he concluded that the mere change of the genetic environment might change the selective value of a gene very considerably. Isolating a few individuals (the "founders" from a variable population which is situated amid the stream of genes which flows ceaselessly through every widespread species will produce a sudden change of the genetic environment of most loci (1234; 1235).

Robert K. Selander (US), W. Grainger Hunt (US), and Suh Y. Yang (US) showed how electrophoresis might be used in solving some long-standing evolutionary problems. They confirmed Ernst Walter Mayr’s theory (See, 1954 ref. above) that large genic differences accumulate before reproductive isolation between species is complete and found support for the idea of gene coadaptation. This was the first comparative study dealing with polymorphism at specific loci, and they employed a coefficient of genetic similarity to summarize their data, which were later used by others in developing new coefficients. They also presented the first estimates of levels of polymorphism and heterozygosity in an organism other than Drosophila and man (1669).

 

John Gordon Skellam (GB) develops the reaction-diffusion model of invasion biology. This model describes the dynamics of populations, which simultaneously develops and spreads, and provides that the invasion front moves with constant speed (1705).

 

Ralph Stefan Solecki (US) and coworkers examined the Shanidar cave in North Central Iraq for fossil remains. Nine partial Homo sapiens neanderthalensis; Homo neanderthalensis skeletons were removed (1737; 1738). The specimens have been dated between 25K-54K BP

 

1952

“The pseudo prestige of long and difficult words transcends the useful scientific term and diffuses widely through our papers. Simple things are made complicated, and the complex is made incomprehensible. Chaos reigns. The so-called medical literature is stuffed to bursting with junk, written in a hopscotch style characterized by a Brownian movement of uncontrolled parts of speech which seethe in restless unintelligibility.” William Bennett Bean (121).

 

“I believe that in art and science are the glories of the human mind. I see no conflict between them. In the past they flourished together during the great and happy periods of history and those men seem to me shortsighted who think that by suppressing science they will release other creative qualities.” Gerty Theresa Radnitz Cori (1347).

 

Archer John Porter Martin (GB) and Richard Laurence Millington Synge (GB) were awarded the Nobel Prize in Chemistry for their invention of partition chromatography.

 

Du Pont Chemical Company introduced the herbicide diuron, a substituted urea, as a pre-emergence to crops such as cotton (Gossypium spp.), alfalfa, grapes, fruit and nuts (1838).

 

Selman Abraham Waksman (RU-US) was awarded the Nobel Prize in Physiology or Medicine for his discovery of streptomycin, the first antibiotic effective against tuberculosis.

 

Georges Nomarski (PL-FR) devised and patented the system of differential interference contrast (DIC) for the light microscope that bears his name (1379; 1380).

Robert Day Allen (US), George B. David () and Georges Nomarski (PL-FR) defined the basic principles of the differential interference contrast (DIC) technique and the interpretation of images. They assisted the Zeiss Optical Company in developing a working model of the Nomarski differential interference microscope (25).

 

Emanuel Epstein (US) and C.E. Hagan (US) interpreted rates of absorption of rubidium ions by excised barley roots in terms of enzyme kinetics. The ion corresponds to the substrate, and a 'carrier' to the enzyme. Instead of catalysis through formation of an enzyme-substrate complex, the effect is ion transport across the membrane via transitory formation of a carrierion complex. Potassium and rubidium were found to be mutually competitive; sodium did not effectively compete with them (575).

 

Alexander Pavlovich Vinogradov; Aleksandr Pavlovich Vinogradov (RU), S.I. Zykov (RU), and I.K. Zadorozhny (RU) put the age of the earth at five to six billion years (1888).

 

Robert Cooley Elderfield (US) and Eleanor Werble (US) synthesized primaquine (pamaquine, or plasmoquine), an antimalarial drug (548).

Raymond J. Dern (US), Irwin M. Weinstein (US), George V. LeRoy (US), David W. Talmage (US), and Alf S. Alving (US) established that sensitivity to the hemolytic action of primaquine was due to an intrinsic abnormality of the erythrocytes of sensitive subjects (467).

 

Liese L. Abell (US), Betty B. Levy (US), Bernard Beryl Brodie (US), and Forrest E. Kendall (US) described a simple, rapid, and specific colorimetric method for the determination of total cholesterol in serum (2).

 

Ernest R.M. Kay (US), Norman S. Simmons (US), and Alexander L. Dounce (US) described an improved method of preparing DNA from various sources, making use of the detergent sodium dodecyl sulfate to deproteinize the protein component of DNA- protein complexes (1001).

 

Martin P. Schulman (US) and John Machlin Buchanan (US), by incubating radioactive glycine or carboxamide with pigeon liver homogenates or extracts, were able to show that carboxamide is utilized for hypoxanthine synthesis. They also found that units of ribose and phosphate were added to the carboxamide prior to ring closure (1657).

William J. Williams (US) and John Machlin Buchanan (US) found that carboxamide is incorporated into purines in yeast as well as in mammals (1977).

Edward David Korn (US) and John Machlin Buchanan (US) showed that 4-amino-5-imidazolecarboxamide, adenosine, and 2,6-diaminopurine can be converted to their ribosides by nucleoside phosphorylase in the presence of ribose 1-phosphate (1049). This information, combined with Greenberg’s observation that the riboside can be phosphorylated by adenosine triphosphate in pigeon liver preparations, provided a pathway for the conversion of free bases to their respective nucleotides via their nucleosides.

 

Prantosh K. Bhattacharyya (IN), Herbert E. Carter (US), Gottfried Samuel Fraenkel (DE-US), and Katharine R. Weidman (US) isolated, crystallized, and identified carnitine (168).

Gottfried Samuel Fraenkel (DE-US), Stanley Friedman (US), Prantosh K. Bhattacharyya (IN), and Jon Bremer (NO) established the role of carnitine as a carrier of acetyl groups through the mitochondrial membrane (227; 630; 650).

 

Walter Voser (CH), M.W. Mijovic (), Hans Heusser (CH), Oskar Jeger (CH), and Leopold Stefan Ruzicka (HR-CH) synthesized lanosterol and showed that it is structurally 4,4,14-trimethylcholestane; like both cholesterol and squalene (1598; 1902). In the 1953 paper Ruzicka mentions that in 1925 Edwin Alfred Rudolph (CH) in his doctoral thesis stated, “The hypothesis may be formulated that the steroids and the triterpenes have at least partially a common origin (1594).”

 

Hilary M. Grundy (CH), Sylvia A. Simpson (CH), James F. Tait (CH), Albert Wettstein (CH), Robert Neher (CH), Joseph von Euw (CH), Tadeus Reichstein (PL-CH), and Othmar Schindler (CH) identified, characterized, isolated, and named aldosterone; a highly active mineralocorticoid hormone from the beef adrenal gland (742; 1698-1700).

 

John Norman Porter (US), Reginal I. Hewitt (US), Clifford W. Hesseltine (US), George Charles Krupka (US), James A. Lowery (US), Wyeth S. Wallace (US), Nestor Bohonos (US), and James H. Williams (US) isolated the antibiotic achromycin (puromycin) from Streptomyces alboniger (1482).

Michael B. Yarmolinsky (US) and Gabriel L. de la Haba (US) discovered that puromycin inhibits the incorporation of amino acids into proteins (2017).

Puromycin causes the premature release of nascent polypeptide chains by its addition to the growing chain end in both prokaryotes and eukaryotes.

 

Frederick I. Dessau (US), Robert L. Yeager (US), Frederick J. Burger (US), James H. Williams (US), and William G.C. Munroe (CA) described pyrazinamide (aldinamide) as an antituberculosis agent (468; 2021; 2022).

H.J. Robinson (US), H. Siegel (US), and Joseph J. Pietrowski (US) were the first to clinically employ pyrazinamide as an antimycobacterial agent (1568).

 

Efraim Racker (PL-AT-US) and Isidore Krimsky (US) showed that during glycolysis the aldehyde group of glyceraldehyde 3-P reacts with an enzyme-bound sulfhydryl group, resulting in a thio-hemiacetal which is oxidized to an energy rich thioester, and that this thioester is phosphorylated by inorganic phosphate to 1,3 diphosphoglyceric acid (1504). This explanation of the mechanism by which a biological oxidation is coupled to ATP formation still ranks as one of the most important biochemical discoveries of all time.

 

Daniel M. Brown (GB), Alexander Robertus Todd (GB), Charles A. Dekker (US), and A. Michael Michelson (GB) described the precise phosphate-ester linkages that bond nucleotides together. They concluded that these linkages are always the same, with the phosphate group connecting the 5’ carbon of one deoxyribose residue to the 3’ carbon atom of the successive nucleotide. They reasoned that the polynucleotide chains of DNA are linear (237; 452).

 

Roy Markham (GB) and John D. Smith (GB) reported that the hydrolysis of RNA proceeded via a cyclic phosphate intermediate, which was then further hydrolyzed to produce a nucleoside 2'-monophosphate or 3'-monophosphate. A key development that led to this discovery involved the separation of complex mixtures of hydrolyzed RNA using a simple device, termed an 'electrophoresis apparatus'. The device was constructed from Whatman number 3 paper, several museum jars and various buffer solutions; the hydrolyzed ribonucleic acids were deposited onto the paper, and a power supply was attached to the device. Applying the current led to the separation of the complex mixture into its components; remarkably, relatively minor differences in the structure of the molecules in the mixture led to observable differences in mobility across the paper (1224).

 

Bernard David Davis (US) and Werner K. Maas (US) used temperature-sensitive pantothenate-requiring mutants to demonstrate that a mutation can alter an enzyme (423; 424).

 

Alexander L. Dounce (US) proposed that the order of amino acids in a specific protein is determined by an order of nucleotides in a corresponding nucleic-acid molecule (506; 507).

 

Jacques Lucien Monod (FR), Germaine Cohen-Bazire (US), Alwin Max Pappenheimer, Jr. (US), David Swenson Hogness (US), and Melvin Cohn (US) used the synthesis of beta-galactosidase in Escherichia coli to demonstrate that proteins are synthesized completely anew rather than by adding a few amino acids to a pre-existing protein (893; 1309).

 

Walter S. Vincent (US) analyzed the chemical properties of the nucleoli of starfish oocytes and found that the ribonucleic acid of the nucleolus differs from that of the cytoplasm in its content of guanine and uracil (1886).

Rachel McMaster-Kaye (US) and J. Herbert Taylor (US) discovered that chromosomal RNA and nucleolar RNA are distinct fractions (1253).

Jan-Erik Edström (SE), Wolfgang Grampp (SE), and Norberto Schor (AR), from base compositions and half-lives, suggested that the nucleolus is the source of ribosomal RNA (544; 545).

 

James M. McGuire (US), Robert L. Bunch (US), Robert C. Anderson (US), Harold E. Boaz (US), Edwin H. Flynn (US), Harold M. Powell (US), and James W. Smith (US) isolated erythromycin among the metabolic products of Streptomyces erythreus waksman, from soil obtained in the Philippines (1245). Erythromycin blocks the translocation reaction on ribosomes in prokaryotes only.

 

Fred W. Tanner, Jr. (US), Arthur R. English (US), Thomas M. Lees (US), and John B. Routien (US) isolated the antibiotic carbomycin from Streptomyces halstedii (1816).

 

C. Stacy French (US) and Victoria M.K. Young (US) demonstrated the fluorescence spectra of red algae and the transfer of energy from phycoerythrin to phycocyanin then on to chlorophyll a (644).

Louis Nicole Marie Duysens (NL) quantitatively determined the efficiency of excitation energy transfer from various accessory pigments (chlorophyll b; phycocyanin; phycoerythrin; fucoxanthin) to chlorophyll a. He was the first to use “P” for pigment designating a few chlorophyll a or bacteriochlorophyll molecules—later to be called P870 (526).

Bessel Kok (NL-US) found that there exists a photosystem containing a pigment (a special form of chlorophyll a) absorbing light maximally at around 700 nanometers. He called it P700 (1042-1044). This later became known as photosystem 1.

Bessel Kok (NL-US) and George Hoch (US) made the first explicit statement that there must be two photochemical reactions “the first sensitized by chlorophyll a and a direct photochemical bleaching of P700; the second sensitized by accessory pigment, acting indirectly via mediation of dark steps, and restoring P700” (1045). This paper, presented a year before publication, opened the modern era of thinking about photosynthesis.

Robert Lee Hill (GB), Fay Bendall (GB), Louis Nicole Marie Duysens (NL), Jan Amesz (NL), and Bert M. Kamp (NL) presented very strong evidence that the light reactions of photosynthesis contain two light absorbing photosystems working in series (527; 850).

Günter Döring (DE), Gernot Renger (DE), Joachim Vater (DE), and Horst Tobias Witt (DE) discovered photosystem 2 and noted that it contains a form of chlorophyll a absorbing light maximally around 680 nanometers (P680) (505).

 

Dilworth Wayne Woolley (CA-US), G. Schaffner (US), and Armin C. Braun (US) determined that a toxin produced by Pseudomonas tabaci causes wild fire disease in tobacco (Nicotiana tabacum) and is an antimetabolite of methionine (2001).

 

George Henry Hepting (US), E. Richard Toole (US), and Jack S. Boyce, Jr. (US) discovered the role of mating types in the life history of the oak wilt fungus (832).

 

Johannes M. Müller (CH), Emil Schlittler (CH), and Hugo J. Bein (CH) isolated from the Indian snakeroot (Rauwolfia serpentina) an alkaloid which has profound effects on the central nervous system. They named it reserpine (1339). Also called serpasil.

Louis Dorfman (US), Charles F. Huebner (US), Harold B. MacPhillamy (US), Emil Schlittler (CH), Arthur F. St. André (US), Andre Furlenmeier (CH), Robert A. Lucas (US), Johannes M. Müller (CH), Robert Schwyzer (CH), Ernest Wenkert (US), Liang H. Liu (US), Patrick A. Diassi (US), Frank L. Weisenborn (US), Christiane M. Dylion (US), Oskar Winterseiner (US), Eugene E. van Tamelen (US), and Paul D. Hance (US) worked out the structure of reserpine (473; 474; 503; 504; 920; 921; 1879; 1950).

Robert Wallace Wilkins (US) and Walter E. Judson (US) introduced the use of reserpine to treat high blood pressure in 1953. They reported on its outstanding sedative and tranquilizing effects (1970). Reserpine depletes post-ganglionic adrenergic neurons containing norepinephrine as their neurotransmitter. This action is responsible for the usefulness of reserpine in the treatment of hypertensive, nervous, and mental disorders. It is without doubt the most valuable tranquilizer ever isolated from plants.

Robert Burns Woodward (US), Frank E. Bader (CH), Horst Bickel (CH), Albert J. Frey (CH-US), and Richard W. Kierstead (CA) synthesized reserpine (1993; 1994).

 

Nathan Entner (US) and Michael Doudoroff (RU-US) studied the enzymatic oxidation of glucose in Pseudomonas saccharophila and identified glucose-6-phosphate, 6-phosphoglunonate, D-glyceraldehyde-3-phosphate, 3-phosphoglycerate, and pyruvate as intermediate products. A novel feature of this pathway is the conversion of 6-phosphogluconate to pyruvate and glyceraldehyde-3-phosphate. 2-keto-3-deoxy-6-phosphogluconate was postulated to be an intermediate in this reaction (571).

Joseph MacGee (US) and Michael Doudoroff (RU-US) proved that 2-keto-3-deoxy-6-phosphogluconate is an intermediate in this pathway (1210). This oxidative pathway became known as the Entner-Doudoroff pathway.

 

Harold R. Yust (US) and Frederick F. Shelden (US) reported that cyanide-resistant California red scale (Aonidiella aurantii) insects have a tissue-respiratory electron-transport system less dependent on cytochrome oxidase (2025). The resistance behaved as a single sex-linked gene.

 

Ursula Mittwoch (DE-GB) reported a male with Down syndrome whose meiotic chromosome count appeared to be 24 (1299). Note: At this time the diploid number of chromosomes in a normal human was thought to be 48 so she did not see this as unusual.

 

Sijiro Makino (JP) and Isao Nishimura (JP) were the first to expose cells to hypotonic solutions for the express purpose of enhancing chromosome analysis (1216).

Tao-Chiuh Hsu (US) developed a technique, which greatly improved the microscopic observation of chromosomes. It used a solution with a lower salt concentration than the cells it contains. This causes the cells to absorb water through their membranes and swell (but not burst). The swollen cells allow the chromosomes to readily separate, making them easier to count (919).

Joe-Hin Tjio (ID-NL-SE-US) and Johan Albert Levan (SE), using this technique, established the correct chromosome number of man to be 46 (1836).

Charles Edmund Ford (GB), and John L. Hamerton (GB) verified that man does possess 46 chromosomes (621).

 

Hugh Esmor Huxley (GB) demonstrated that the myofibrils of striated (skeletal) muscle cells contain two major types of myofilaments arranged in such a manner that they present bands (I and A), lines (Z and M), and the H zone. Each thick myofilament is surrounded by six thin myofilaments with cross bridges between adjacent thick and thin myofilaments (932-935).

 

Wolfgang Beerman (DE) interpreted chromosomal puffs in the midge Chironomus tentans as indicating gene activity and their tissue-specific patterns as indicating a differential genetic activity in different cell types, "the first direct cytological indication for the single elements of the genome reacting differentially to internal and external conditions” (130).

 

Howard K. Schachman (US), Arthur Beck Pardee (US), and Roger Yate Stanier (CA) demonstrated that Escherichia coli cells contain microsomal (ribosomal) particles (1631).

 

C. Cosar (FR), Leon Ninet (FR), Sylvie Pinnert-Sindico (FR), and Jean Preud’homme (FR) isolated the antibiotic spiramycin from Streptomyces ambofaciens (372; 1471). This antibiotic has been used to treat gonorrhea, trachoma, and sinusitis. It inhibits the incorporation of [14C] amino acids into protein without affecting RNA synthesis.

 

James Theodore Park (US), Jack Leonard Strominger (US) and Richard E. Thompson (US) initiated the biochemical investigations which ultimately determined that penicillin acts by inhibiting murein synthesis in the bacterial cell wall (1417-1421; 1796). This is the first discovery of the mode of action of a natural antibiotic.

 

Alfred Day Hershey (US) and Martha Cowles Chase (US) prepared virus particles that were isotopically labeled either in the protein or in the DNA by incubating the host bacteria in media containing appropriate labeled precursors. With such labeled virus particles, they showed conclusively that viral DNA rapidly enters the host cell whereas viral protein does not. These observations were later followed by the demonstration that the viral nucleic acid alone is infectious, in the absence of viral protein, and can lead to the formation of complete viral progeny in the host cell (840). Note: These results reorientated biologists to the importance of nucleic acids.

 

Joshua Lederberg (US) and Esther M. Lederberg (US) developed the replica plate technique to screen large populations of bacteria for rare mutants. This technique has remained one of the most important methodologies in the practice of bacterial genetics, finding wide application as an efficient way to isolate auxotrophic mutants (1113).

 

James S. Murphy (US) and Frederik B. Bang (US) observed in the chorioallantoic membrane of infected chicken embryos, influenza viruses produced in the form of "filaments and spheres which project from the free cell surface, i.e., viral budding (1345).

Hugh John Forster Cairns (GB-US-GB), Margaret Edney (AU), S. Fazekas De Saint Groth (AU), and Philip J. Mason (GB) discovered that influenza virus is not released from the host cell in a burst but rather is released in a slow trickle through the cell membrane, i.e, viral budding (269; 270).

 

Harriette Block Wasser (US) was the first to demonstrate an insect virus not associated with inclusion bodies (1925).

 

George W. Dick (GB), Stuart F. Kitchen (GB), and Alexander J. Haddow (GB) offered the first formal description of Zika virus (480). Note: Zika virus is a single-stranded RNA enveloped, spherical particle classified as a member of the family Flaviviridae, the genus Flavivirus. The virus belongs in the mosquito-borne cluster of the genus Flavivirus. As with arbovirus, it is transmitted by arthropods (mosquitoes), both Aedes aegypti (urban) and albopictus (rural). Zika virus was first isolated in 1947 from monkeys in Uganda. The first human cases were reported in 1952 in East Africa.

Zika virus received little attention until 2015 when a large outbreak of Zika virus illness followed by an increased number of babies born with microcephaly occurred in Brazil.

Alexander J. Haddow (GB), M.C. Williams (GB), John P. Woodall (GB), D.I. Simpson GB), and L.K. Goma (UG) suggested that Zika, primarily in nature, is in a sylvatic cycle of transmission between non-human primates and forest-dwelling mosquitoes (750). Note: Zika virus has re-emerged as a arthropod-borne RNA virus belonging to the Flaviviridae family, which also include the dengue virus (DENV), the West Nile virus (WNV), the Japanese encephalitis viruses (JEV) and the yellow fever virus (YFV).

Thais Dos Santos (US), Angel Rodriguez (US), Maria Almiron (US), Antonio Sanhueza (US), Pilar Ramon (US), Wanderson K. de Oliveira (BR), Giovanini E. Coelho (BR), Roberto Badaró (BR), Juan Cortez (US), Martha Ospina (CO), Raquel Pimentel (DO), Rolando Masis (HN), Franklin Hernandez (US), Bredy Lara (HN), Romeo Montoya (US), Beatrix Jubithana (SR), Angel Melchor (VE), Angel Alvarez (US), Sylvain Aldighieri (US), Christopher Dye (CH), Marcos A. Espinal (US), Cristiane N. Soares (BR), Patrícia Brasil (BR), Raquel Medialdea Carrera (GB), Patricia Carvalho Sequeira (BR), Ana Maria Bispo de Filippis (BR), Vitor A. Borges (BR), Fernando Theophilo (BR), Mark A. Ellul (GB), Tom Solomon (GB), Patricia Brasil (BR), Patricia Carvalho Sequeira (BR), Andrea D’Avila Freitas (BR), Heruza Einsfeld Zogbi (BR), Guilherme Amaral Calvet (BR), Rogerio Valls De Souza (BR), André Machado Siqueira (BR), Marcos Cesar Lima de Mendonca (BR), and Rita Maria Ribeiro Nogueira (BR) found Guillain-Barre’ syndrome and encephalitis associated with Zika virus infections during recent Zika virus epidemics (221; 1610; 1733).

Marli Tenorio Cordeiro (BR), Lindomar J. Pena (BR), Carlos A. Brito (BR), Laura H. Gil (BR), Ernesto T. Marques (BR), Carolyn B. Coyne (US), Helen M. Lazear (US), Bruno Hoen (FR), Bruno Schaub (FR), Anna L. Funk (FR), Vanessa Ardillon (FR), Manon Boullard (FR), André Cabié (FR), Caroline Callier (FR), Gabriel Carles (FR), Sylvie Cassadou (FR), Raymond Césaire (FR), Maylis Douine (FR), Cécile Herrmann-Storck (FR), Philippe Kadhel (FR), Cédric Laouénan (FR), Yoann Madec (FR), Alice Monthieux (FR), Mathieu Nacher (FR), Fatiha Najioullah (FR), Dominique Rousset (FR), Catherine Ryan (FR), Kinda Schepers (FR), Sofia Stegmann-Planchard (FR), Benoît Tressières (FR), Jean-Luc Voluménie (FR), Samson Yassinguezo (FR), Eustase Janky (FR), and Arnaud Fontanet (FR) showed that vertical transmission of Zike virus from mother to fetus is linked to increasing incidences of the congenital Zika syndrome in fetuses; including microcephaly, congenital malformation, and fetal demise (365; 379; 891).

 

William McDowell Hammon (US) and William Carlisle Reeves (US) were the first to isolate and identify the bunyavirus, etiological agent of California encephalitis in man (765). A very closely related virus causes La Crosse encephalitis.

 

Renato Dulbecco (IT-US) was the first to demonstrate that an animal virus can produce lytic plaques in a lawn of confluent animal cells (518). He and Marguerite Vogt (US) developed a method to plaque poliovirus in cell culture, i.e., to enumerate infectious virus particles in a stock of virus by detecting one focus of dead cells per infectious particle (519).

 

Marvin P. Bryant (US) isolated and characterized a small rumen spirochete of the genus Treponema, which could move through agar and compete with cellulolytic bacteria for use of the soluble sugars produced by the cellulolytic bacteria. This was the first published work on fermentation products of a spirochete (249).

 

René Jules Dubos (FR-US) states that the will-‘o’-the-wisp, perhaps better known as Jack O’ Lantern, is probably a microbial phenomenon and may result from the spontaneous ignition of phosphine in the presence of methane (513).

 

Salvador Edward Luria (IT-US), Mary Human (US), Giuseppe Bertani (US) and Jean-Jacques Weigle (CH-US) discovered the phenomenon of "restriction modification" (the modification of phage growing within an infected bacterium, so that upon their release and re-infection of a related bacterium the phage's growth is restricted) (161; 1197; 1936).

Daisy Dussoix (CH), Werner Arber (CH), Stanley Hattman (US), and Stuart Linn (US) showed that modification was a nonheritable alteration of DNA catalyzed by host-specific enzymes and that restriction was the result of the degradation of unmodified DNA by specific nucleases (49-51; 524). Note: This work led to the discovery of the class of enzymes now known as "restriction enzymes." These enzymes allowed controlled manipulation of DNA in the laboratory, thus providing the foundation for the development of genetic engineering.

 

Rhoda Benham (US), Margarita Silva (US), Libero Ajello (US), Lucille K. Georg (US), LaVerne B. Camp (US), and Harold E. Swartz (US) pioneered nutritional and physiological studies of the dermatophytes (15; 135; 676; 677; 1692; 1806). This greatly simplified the identification of the dermatophytes.

 

George Otto Gey (US), Ward D. Coffman (US), and Mary T. Kubicek (US) established the first permanent in vitro human cell line. The cells were derived from a human cervical carcinoma in a patient named Henrietta Lacks née Pleasant (US). Later these cells became known as the HeLa cell line (681; 682).

William F. Scherer (US), Jerome T. Sylverton (US), and George Otto Gey (US) used stable cell lines such as HeLa because these cell lines allow researchers to use genetically identical cells for experiments over long-term courses of repeated culturing in a manner not possible with primary cells (1635).

 

Curt Stern (DE-US), Gweneth L. Carson (US), M. Kinst (US), Edward Novitski (US), and Delta E. Uphoff (US) established that the average viability of heterozygotes for sex-linked lethals is 96.5% (1778).

 

Anthony D. Bradshaw (GB) found evidence in grasses for natural selection of genotypes tolerant to high concentrations of heavy metals (217).

 

Alexander Thomas Dick (AU) showed that an unknown dietary constituent besides molybdenum influences copper storage in livers of sheep (475). He subsequently found that inorganic sulfate is the component of alfalfa that lowers the blood molybdenum (476) and that sulfate is also the factor in alfalfa that, in combination with molybdenum, impairs liver copper storage (477; 478).

Neville F. Suttle (GB) pointed out that the formation of cupric tetrathiomolybdate, a highly insoluble complex, could occur in the sulfide-rich environment of the rumen (1801).

Alexander Thomas Dick (AU), D.W. Dewey (AU), and Jeff M. Gawthorne (AU) found that formation of copper thiomolybdates, particularly CuMoS4, in the rumen accounts for the poor absorption of copper when the intake of molybdenum is high (479).

George J. Brewer (US), Robert D. Dick (US), Virginia Johnson (US), Yuxan Wang (US), Vilma Yuzbasiyan-Gurkan (US), Karen J. Kluin (US), and Alex M. Aisen (US) used tetrathiomolybdate to treat Wilson's disease in human patients. This genetic disease results in accumulation of copper in tissues, and thiomolybdate counteracts copper toxicity by complexing with the cupric ion thus preventing its absorption (229).

 

Clinton Nathan Woolsey (US), Paul H. Settlage (US), Donald R. Meyer (US), W. Sencer (US), Teresa Pinto-Hamuy (CL), Ann M. Travis (US), William S. Coxe (US), Jean Francois Hirsch (FR), Robert M. Benjamin (US), Wally I. Welker (US), and Richard F. Thompson (US) mapped the primary and supplementary motor areas of the cerebral cortex and compared sensory and motor maps in both pre- and post-central cortical areas in primates and other animals (2002-2004).

 

Laurance W. Kinsell (US), John W. Patridge (US), Lenore A. Boling (US), Sheldon Margen (US), and George D. Michaels (US) demonstrated that the isoenergetic substitution of vegetable oils for animal fats significantly decreased serum cholesterol in humans (1022).

 

Alan M. Turing (GB) showed that developmental patterns could be generated by simple chemical reactions, together with diffusion, which marked a change in how the processes of development were viewed. In this work he made the first applications of computer modeling in biology (1853).

 

J.B. Cowey (GB) discovered the epidermal basement membrane of nemertean Amphiporus lactifloreus (ribbon worm) is composed of regularly disposed, inextensible fibers arranged in alternate left- and right-handed geodesic helices running around the body of the animal (378).

Robert S.B. Clark (GB) and J.B. Cowey (GB) presented a simple geometric model, based on the idea of a fiber-reinforced cylinder, to explain the mechanism underlying shape changes in ribbon worms and flatworms. The essential idea of this paper is that a structure composed of inextensible fibers could accommodate large extensibility (329).

 

Rosemary A. Biggs (GB), Alexander Stuart Douglas (GB), Robert Gwyn Macfarlane (GB), John Vivian Dacie (GB), W. Robert Pitney (GB), Clarence Merskey (ZA), and John Richard O'Brien (GB) identified and named Christmas factor (factor IX) as one of the materials necessary for normal blood clotting (175). Stephen Christmas, a five-year-old British boy was the first patient in whom this was recognized to be different from classical hemophilia. This disease is sometimes called hemophilia B.

Paul M. Aggeler (US), Sidney G. White (US), Mary Beth Glendening (US), Ernest W. Page (US), Tillie B. Leake (US) and George Bates (US) described this same condition almost simultaneously, in a 16-year old boy, calling the factor plasma thromboplastin component (PTC) (12).

Irving Schulman (US) and Carl H. Smith (US) also independently reported this metabolic disease (1656).

 

Ogden Carr Bruton (US) discovered the first scientifically established immunodeficiency disease. Bruton reported on a young patient who was missing the gamma fraction of serum resulting in his having recurrent bacterial infections (247). The disease was named Bruton’s agammablobulinemia in his honor and subsequently found to be X linked.

Ogden Carr Bruton (US), Charles Alderson Janeway (US), David Gitlin (US), and Leonard Apt (US) described collective observations of 3 patients, all boys, age 9 years. The syndrome was characterized by the commonality of multiple, recurrent, severe, septic bacterial infections; deficient antibody production to infecting microorganisms and vaccine immunizations; extremely low levels of serum gamma globulins despite normal serum total proteins; and successful treatment with injections of donor immune gamma globulin.

It was discovered that patients with agammaglobulinemia resist viral infections and demonstrate normal delayed-hypersensitivity responses (248; 972). These observations ultimately led to the recognition of the two main branches of interacting lymphocytes, the B and T cells.

Walter Hermann Hitzig (MX-CH), Z. Biro (CH), H. Bosch (CH), and H.J. Huser (CH) characterised the most severe inherited defect of immunity. This deficiency first became known as Swiss-type agammaglobulinaemia and subsequently as severe combined immunodeficiency or SCID (873).

 

Alexander Moisés Chédiak (CU) described a rare childhood autosomal recessive disorder that affects multiple systems of the body. Patients exhibit hypopigmentation of the skin, eyes, and hair; prolonged bleeding times; easy bruisability; recurrent infections; abnormal natural killer cell function; and peripheral neuropathy (309). Today it is called Chédiak-Higashi syndrome.

 

Julius B. Kahn, Jr. (US) and Jacob Hernerth Furth (AT/HU-US) discovered that anemia associated with acute death from radiation is due to erythrocytes entering the lymph ducts following the destruction of blood platelets (982).

Marion C. Woods (US), Frances N. Gamble (US), Jacob Hernerth Furth (AT/HU-US), and Robert R. Bigelow (US) found they could treat this radiation anemia by using transfusions of platelets (1991).

 

Karl Singer (US), Ben Fisher (US), and Meyer A. Perlstein (US) described and named acanthocytosis (1701).

 

Jean D. Benedict (US), Marcel Roche (US), T’sai Fan Yu (US), Edward J. Bien (US), Alexander Benjamin Gutman (US), and DeWitt Stetten, Jr. (US) first demonstrated overproduction of uric acid in gout. They found excessive incorporation of glycine ¹⁵N into uric acid in a gouty over excretor of uric acid (134).

Daniel J. McCarty, Jr. (US), and Joseph Lee Hollander (US), and Ralph Alfred Jessar (US) developed a simple technique using polarized light microscopy for urate crystal identification in synovial fluid (899; 1238; 1239).

Daniel J. McCarty, Jr. (US), Joseph Lee Hollander (US), Gonzalo Astorga (US), Eduardo-Castro-Murillo (US), and Arnold J. Rawson (US) found that acute gouty attacks were marked by phagocytosis of the crystals by mononuclear and polymorphonuclear leukocytes. The sensitivity and specificity of the procedure is such that it has been described as a pathognomonic test for gout (900; 901; 1238).

 

Carl W. Walter (US), in 1952, a researcher under Harvey Cushing (US) and William P. Murphy, Jr. (US) described a system in which the blood was collected into a collapsible bag of polyvinyl resin (1920). Murphy first used these on the front lines during the Korean War. This innovation opened the way for safe and easy preparation of multiple blood components from a single unit of whole blood.

 

Geoffrey Wingfield Harris (GB) and Dora Elisabeth Jacobsohn (DE-SE) showed that the anterior pituitary gland of mammals is regulated by hormones secreted by hypothalamic neurons into the hypothalamohypophyseal portal circulation. By contrast, the hormones of the posterior pituitary gland are secreted into the systemic circulation directly from the nerve endings of hypothalamic neurons (779). Note: This work founded the brain's role in hormonal regulation, helping to establish the field of neuroendocrinology.

Murray Saffran (CA), Andrew Victor Schally (PL-US), and Bruno G. Benfey (CA) coined the phrase corticotropin-releasing factor (CRF) for a product of the hypothalamus, which stimulates the adrenal release of ACTH (1601).

Roger Charles Louis Guillemin (FR-CA-US), Eiichi Yamazaki (FR), Marian Jutisz (PL-FR), and Edvart Sakiz (FR) discovered and crudely purified a hypothalamic thyroid stimulating hormone releasing factor (TSH-releasing factor) or thyrotropin-releasing factor (TRF) (744).

Roger Charles Louis Guillemin (FR-CA-US), Andrew Victor Schally (PL-US), Harry S. Lipscomb (US), Richard N. Andersen (US), and John M. Long (US) reported the presence in hog hypothalamus of (β-corticotropin releasing factor, α- and (β-melanocyte stimulating hormones, adrenocorticotropin, lysine-vasopressin and oxytocin (743).

Roger Cecil Burgus (US), Thomas F. Dunn (US), Darrell N. Ward (US), Wylie Vale (US), Max Amoss (US), Roger Charles Louis Guillemin (FR-CA-US), and Dominic M. Desiderio (US) concluded that ovine thyrotropin-releasing hormone from the hypothalamus has the structure pGlu-His-Pro-NH2 (257; 258).

Jan Bøler (US), Franz Enzmann (US), Karl August Folkers (US), Cyril Yarling Bowers (US), and Andrew Victor Schally (PL-US) found that the structure of L-pyroglutamyl-l-histidyl-l-proline amide (I) agrees with all known chemical and hormonal properties of the thyrotropin-releasing hormone from porcine hypothalami. This structural interpretation is probably applicable to other mammalian species and is chemically based on the chromatographic identity in seventeen diversified systems and is biologically based on a quantitative comparison of the hormonal activities of the natural and synthetic products. This formulation of structure represents the elucidation of the first of the hypothalamic hormones that have been sought for so long (198).

Raghaven M.G. Nair (US), John F. Barrett (US), Cyril Yarling Bowers (US), and Andrew Victor Schally (PL-US) concluded that porcine thyrotropin-releasing hormone (TRH) from the hypothalamus has the structure pGlu-His-Pro-NH2 (1354). Thus, TRH from two different species have the same structure and function.

Karl August Folkers (US), Franz Enzmann (DE), Jan Bøler (DE), Cyril Yarling Bowers (US), and Andrew Victor Schally (PL-US) synthesized porcine thyrotropin-releasing hormone (TRH) (619).

 

Francis Daniels Moore (US) published his research in the landmark text, The Metabolic Response to Surgery. This was the benchmark for the future of surgical metabolism and in nutrition for patients who are unable to eat (1314).

 

Bjorn Ibsen (DK) established the first hospital based intensive care unit. It was to treat patients with poliomyelitis during the 1952 epidemic. Ibsen examined some patients, studied their records, looked at specimens from four autopsies, and became convinced that the patients had died from lack of ventilation. He proposed to use hand-supplied positive pressure instead of the customary machine-generated negative pressure. This approach was found to be very successful. According to one account, in total, approximately 1,500 medical and dental students contributed 165,000 hours of life-preserving service, squeezing rubber bags (769). This radical and effective way of treating seriously ill patients launched the proliferation of intensive care units and led to the inauguration of the now flourishing specialty of critical care medicine.

Henry Cai Alexander Lassen (DK) highlighted several problems associated with high-pressure ventilation like that used during the epidemic of poliomyelitis. These included the deleterious effect of prolonged insufflation on cardiac output, problems with weaning, and the benefits of timing insufflation to coincide with spontaneous respiratory effort (1096).

Herb H. Webb (US) and Donald F. Tierney (US) produced the first study to identify both major factors currently thought to play a role in ventilator-induced lung injury: over distension, and ventilation at low lung volumes (1934).

Peter M. Suter (CH), H. Barrie Fairley (GB), and Michael D. Isenberg (US) describe the inter-relationship between lung mechanics, hemodynamics, oxygenation, and how to set positive end-expiratory pressure (PEEP) in individual patients (1799).

Paul E. Pepe (US) and John J. Marini (US) found that failure to recognize the hemodynamic consequences of auto-PEEP might lead to inappropriate fluid restriction or unnecessary vasopressor therapy. Although not apparent during normal ventilator operation, the auto-PEEP effect can be detected and quantified by a simple bedside maneuver: expiratory port occlusion at the end of the set exhalation period (1457).

Luciano Gattinoni (IT), Antonio Presenti (IT), Leonello Avalli (IT), Francesac Rossi (IT), and Michela Bombino (IT) found that there is heterogeneous distribution of diseased lung in ventilated patients with acute respiratory failure (ARF), with some areas retaining near-normal elasticity (671).

Didier Dreyfuss (FR), Paul Soler (FR), Guy Basset (FR), and Georges Saumon (FR) discovered that pulmonary edema and alveolar damage caused by mechanical ventilation are due to high inflation volume, and not airway pressure per se, and may be greatly attenuated by the addition of PEEP (512).

Keith G. Hickling (NZ), Seton J. Henderson (NZ), and Rodger Jackson (NZ) showed that limiting the inspiratory pressure and allowing hypercapnia ('permissive hypercapnia') can reduce the mortality of ventilated patients with adult respiratory distress syndrome (ARDS) (846).

Karl L. Yang (US), and Martin J. Tobin (US) found that rapid shallow breathing, as reflected by the f/VT ratio, was the most accurate predictor of failure, and its absence the most accurate predictor of success, in weaning patients from mechanical ventilation (2016).

Arthur S. Slutsky (CA) provided recommendations for mechanical ventilation in clinical practice and defined the state of the art of mechanical ventilation (1711).

Lorraine Trenmblay (CA), Franco Valenza (CA), Sergio P. Ribeiro (CA), Jingfang Li (CA), and Arthur S. Slutsky (CA) introduced the concept of 'biotrauma' into the field of mechanical ventilation, which raised the possibility that ventilation which over-distends the alveoli, or which causes repetitive opening and closing of the airways, causes the release of factors that may contribute to distal organ failure (1848). The Acute Respiratory Distress Syndrome Network (US) marshaled resources for a massive trial to test whether low tidal volume ventilation is beneficial. The results were unequivocal. In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use (52).

 

Roar Strøm (SE), Robert Milton Zollinger (US), and Edwin Homer Ellison (US) described a disease condition comprising a clinical triad of 1) hypersecretion of gastrin, 2) multiple, atypically located, often recurrent peptic ulcers, and 3) a non-insulin producing islet cell tumor of the pancreas (1794; 2036). It is called gastric hypersecretion-peptic ulceration-pancreatic tumor syndrome or Zollinger-Ellison-Strøm syndrome.

 

Bernard Lown (LT-US), William Francis Ganong, Jr. (US), and Samuel Albert Levine (US) described ECGs on 200 patients with short PQ intervals, a normal QRS complex, and a tendency to paroxysmal supraventricular tachycardia (1193). Today it is referred to as the Lown-Ganong-Levine syndrome.

 

William H. Sweet (US) and Manucher Javid (US) originated and encouraged the use of boron neutron capture therapy for brain tumors (1808).

 

Floyd John Lewis (US) and Mansur Taufic (US) performed the first successful open-heart surgery on a human. The patient was a five-year-old girl who had been born with a hole in her heart. Anaesthetized to stop her shivering, the girl was cooled by a special blanket until her body temperature reached 81 degrees F. At this temperature, she could survive without a pumping heart for ten minutes. Clamping the inflow to her heart so that it emptied of blood, Taufic and Lewis cut open her heart, which was still slowly beating, and quickly sewed the hole shut. With the repaired heart working properly for the first time in her life, the girl was then immersed in a bath of warm water to bring her body temperature back to normal. The operation was a success (1157). See, Daniel Hall Williams, 1893.

Clarence Walton Lillehei (US) and Richard L Varco (US) were the first to describe surgical anastomosis of the right pulmonary veins to the right auricle and the IVC to the left auricle by using an allograft aortic tube to connect the IVC and the left aorta (1166). This operation provided partial physiologic correction in patients with complete transposition of the great arteries.

 

Anthony Andreasen (GB) and Frank Watson (GB), showed that dogs can survive for almost 40 minutes without brain damage when all blood flow is stopped except that through the azygos vein (41).

Morley Cohen (US) and Clarence Walton Lillehei (US) applied these findings in their dog lab. They showed that dogs survive cardiac surgery when supplied with blood through the azygos vein-only; 10% of the normal supply (335).

Morley Cohen (US) and Clarence Walton Lillehei (US) hypothesized that when blood supply was low, the blood vessels dilated to receive a larger share of the blood, while the tissues absorbed a much higher proportion of the oxygen than under conditions of normal circulation.

Clarence Walton Lillehei would remark that, "The single most important discovery that made clinical open-heart surgery successful was the realization of the vast discrepancy between the total body flow that was thought necessary, and what was actually necessary.”

 

William P. Longmire, Jr. (US) and John M. Beal (US) performed a total gastrectomy with the formation of a new stomach (1184).

 

Charles Dubost (FR), Michel Allary (FR), and Nicolas Oeconomos (FR) performed the first successful resection of an abdominal aortic aneurysm, replacing it with a homograft. The graft used was the thoracic aorta taken 3 weeks previously from a 20-year-old woman. The patient's left common iliac artery then was anastomosed to the side of the graft (514).

 

Warren Herbert Wagner, Jr. (US) is widely regarded as the founder of modern day systematics for all groups of plants and animals and was the first to argue that phylogenetic reconstruction can be made explicit and rational. Today, the phrase 'Wagner [phylogenetic] tree' is part of the lingua franca of systematic biologists around the world (1907-1914). Wagner’s work led directly to the cladistic analysis of evolutionary relationships among plants.

 

George Mandler (US) and Seymour B. Sarason (US) tested a high anxiety (HA) and a low anxiety (LA) group on two intelligence test tasks. LA subjects performed better than HA subjects; failure reports unimproved the performance of LA subjects, whereas no further reference to the test situation was optimal for the HA subjects (1218).

 

1953

“Francis winged into the Eagle [a pub] to tell everyone within hearing distance that we had found the secret of life.” James Dewey Watson (1929).

 

“It has not escaped our notice that the specific pairing [of bases in the double helical structure] we have postulated immediately suggests a possible copying mechanism for the genetic material.” James Dewey Watson and Francis Harry Compton Crick (1930).

 

“Antibody for all three immunologic types [of polio virus] was induced by the inoculation of small quantities of…vaccines incorporated in a water-in-oil emulsion…Levels of antibody induced by vaccination are compared with levels that develop after natural infection… These studies…should not be interpreted to indicate that a practical vaccine is now at hand.” Jonas Edward Salk in referring to his work in developing a polio vaccine (1604).

 

"It is better to ask some of the questions than to know all the answers!" James Thurber (1830).

 

“The concept of evolution postulates that living organisms have common roots, and in turn the existence of common features is powerful support for the concept of evolution. The presence of the same mechanism of energy production in all forms of life suggests two other inferences, firstly, that the mechanism of energy production has arisen very early in the evolutionary process, and secondly, that life, in its present forms, has arisen only once.” Hans Adolf Krebs (1375).

 

Frederik (Frits) Zernike (NL) was awarded the Nobel Prize in Physics for his demonstration of the phase contrast method, which included his invention of the phase contrast microscope.

 

Hans Adolf Krebs (DE-GB) cited for his discovery of the citric acid cycle, and Fritz Albert Lipmann (DE-US) for his discovery of co-enzyme A and its importance for intermediary metabolism, were awarded the Nobel Prize in physiology and medicine.

 

Daniel Mazia (US), Philip A. Brewer (US) and Max Alfert (US) found that mercuric bromphenol blue, which had been used to visualize protein spots on filter paper, was suitable as a quantitative cytochemical stain for tissue sections. The stain permits sharp visual differentiation of structural details and it follows the Beer-Lambert laws and can be used for microphotometry. It reacts with various sites in proteins, to the extent of about one dye binding group per ten amino acid residues (1236).

 

Leland C. Clark Jr. (US), Richard Wolf (US), Donald Granger (US), and Zena Taylor (US) invented the first device to rapidly determine the amount of glucose in blood. It allows continuous recording of blood oxygen tensions by polarography. The “Clark Oxygen Electrode”, remains the standard for measuring dissolved oxygen in biomedical, environmental, and industrial applications. Allowing for the real-time monitoring of a patient's blood oxygen level, Clark's electrode has made surgery safer and more successful for millions of people throughout the world (328).

Leland C. Clark Jr. (US) and Champ Lyons (US) invented the first glucose biosensor (in fact the first biosensor of any type) (325).

 

Clair Cameron Patterson (US), George Tilton (US), and Mark Inghram (US) used uranium decay in rocks from Earth and in meteorites that struck Earth to date our solar system at 4.55 ± 0.07 billion years old (1429-1432).

 

Wallace Henry Coulter (US) and Joe Coulter (US) were granted a patent in 1953 for their discovery of The Coulter Principle. Their actual discovery in 1948 was a method for counting and sizing microscopic particles (including blood cells) suspended in a fluid. This method became widely used and formed the first viable basis for flow cytometry. From it grew an industry that forever changed the world of diagnostic medical research (375).

 

Stanley Lloyd Miller (US), working in Harold Clayton Urey’s (US) laboratory, showed that a wet mixture of methane, hydrogen, and ammonia, upon exposure to electrical discharge, formed traces of organic compounds, including organic acids including amino acids. These are regarded as exclusive products of living things (1285; 1286).

 

Raymond Urgel Lemieux (CA) synthesized sucrose (1123).

 

John R. Pappenheimer (US) proposed that water could flow across a semipermeable membrane as a result of the creation of osmotic gradients (1413).

 

Harvey F. Fisher (US), Eric E. Conn (US), Birgit Vennesland (DE-US), Frank Henry Westheimer (US), Frank A. Loewus (US) and Peter Ofner (US) showed that in dehydrogenase-catalyzed reactions, the hydrogen atom added to the pyridine ring is transferred directly from the substrate, without mixing with the hydrogen ions of the solution (613; 1183).

 

Alvin Nason (US) and Harold J. Evans (US) discovered nitrate reductase in Neurospora (1355).

Harold J. Evans (US) and Alvin Nason (US) identified the enzyme nitrate reductase (NR) in the leaves of vascular plants (soybean). Although NR had previously been described in Neurospora, this is the first report of NR in plants. The discovery of NR opened the field of study of plant nitrogen assimilation (581).

 

D. Amelung (), H.J. Huebener (), Ladislaus Róka (), and G. Meyerheim () discovered the enzymic interconversion of active 11-hydroxy glucocorticoids (cortisol, corticosterone) and inert 11-keto forms (cortisone, 11-dehydrocorticosterone) (33). Note: the enzyme is 11-beta hydroxysteroid dehydrogenase type 2

 

Francis A. Hochstein (US), Charles R. Stephens (US), Lloyd H. Conover (US), Peter P. Regna (US), Richard Pasternak (US), Philip N. Gordon (US), Frederick J. Pilgrim (US), Karl J. Brunings (US), and Robert Burns Woodward (US) determined the structure of Terramycin (881).

 

Henri-Géry Hers (BE) and T. Tusaka (BE) found that aldolase from liver extract is characterized by the ability to split both fructose-1-phosphate and fructose-1,6-diphosphate, whereas, the muscle aldolase is very poorly active on fructose-1-phosphate (835).

 

Eric J. Simon (US) and David Shemin (US) presented a method for the synthesis of succinyl coenzyme A (succinyl CoA) by addition of succinic anhydride to CoA in the presence of a weak base. The anhydride method is applicable to the synthesis of other acyl derivatives of CoA (1695).

 

Robert Burns Woodward (US) and Konrad Emil Bloch (US) suggested that the squalene chain might be folded—in a way unique at this time— to yield lanosterol as an intermediate in the synthesis of cholesterol (1995).

Robert G. Langdon (US) and Konrad Emil Bloch (DE-US) showed that squalene is a precursor to cholesterol in vivo (1089).

Rama Kant Maudgal (IN), Tche-Tsing Tchen (US), and Konrad Emil Bloch (DE-US) offered rigorous proof of this using chemically synthesized [¹³C] all-trans squalene (1233).

John Warcup Cornforth (AU-GB) demonstrated the conversion of squalene to lanosterol (368).

Tche-Tsing Tchen (US) and Konrad Emil Bloch (US) demonstrated the conversion of lanosterol to cholesterol (1822).

 

John Warcup Cornforth (AU-GB), Gordon D. Hunter (GB), George Joseph Popják (GB), and Irene Youhotsky Gore (GB) performed a complete carbon-by-carbon dissection of the cholesterol nucleus (369-371).

 

Albert Lester Lehninger (US) discovered that reduced NAD is the true substrate of oxidative phosphorylation. He also showed that the mitochondrium is the seat of oxidative phosphorylation and that the oxidation of ascorbic acid via cytochrome c is linked to ATP formation (1117).

 

Nathan Oram Kaplan (US) and Elizabeth Fondal Neufeld (US) described their discovery of a transhydrogenase from pig heart mitochondria that transfers hydrogen from TPNH (NADPH) to DPN (NAD) with an equilibrium constant of 1 (992).

Martin Klingenberg (DE), Werner Slenczka (DE), Lennart Danielson (SE), and Lars Ernster (SE) found that the mitochondrial transhydrogenase transfers electrons from NADH to NADP in an energy-dependent reaction (411; 1027).

Helen Freeman (GB), Kenju Shimomura (GB), Emma Horner (GB), Roger D. Cox (GB), and Frances M. Ashcroft (GB) reported that mice with mutations in the energy-dependent transhydrogenase fail to release insulin from pancreatic beta cells in response to increased glucose levels (639).

 

E. Myles Glenn (US) and Don H. Nelson (US) developed a chemical method for the determination of 17-hydroxy-corticosteroids and 17-ketosteroids in urine following hydrolysis with â-glucuronidase. The method was applicable to the study of steroid excretion rates, steroid metabolism, and various endocrinologic diseases in man (696).

 

Maurice Hugh Frederick Wilkins (GB), Rosalind Elsie Franklin (GB), Alexander Rawson Stokes (GB), Raymond George Gosling (GB), and Herbert Rees Wilson (GB) obtained the first high quality x-ray diffraction photographs of DNA. One of Franklin’s photographs revealed a dominant cross like pattern (B form), the telltale mark of a helix (637; 1969).

 

James Dewey Watson (US) and Francis Harry Compton Crick (GB) postulated a double-helix structure for deoxyribonucleic acid (DNA), which not only accounted for the molar equivalence of the bases and the characteristic x-ray diffraction pattern of DNA, but also suggested a simple mechanism by which genetic information can be precisely transferred from parent to daughter cells. Crick had also deduced the antiparallel nature of the molecule from the work of Rosalind Elsie Franklin (GB) and Maurice Hugh Frederick Wilkins (GB) (385; 637; 1930-1932; 1969). The structure worked out by Watson and Crick is now known as the B form.

On February 28, 1953, in the Cavendish Laboratory, at Cambridge University, Oxford England, “That morning, Watson and Crick knew, although still in mind only, the entire structure: it had emerged from the shadow of billions of years, absolute and simple, and was seen and understood for the first time. Twenty-angstrom units in diameter, seventy-nine billionths of an inch. Two chains twining coaxially, clockwise, one up the other down, a complete turn of the screw in 34 angstroms. The bases flat in their pairs in the middle, 3.4 angstroms and a tenth of a revolution separating a pair from the one above or below. The chains held by the pairing closer to each other around the circumference one way than the other, by an eighth of a turn, one groove up the outside narrow, the other wide. A melody for the eye of the intellect, with not a note wasted. Physically, the structure carried the means of replication—positive to negative, complementary. As the strands unwound, a double template was there in the base pairing, so that only complementary nucleotides could form bonds and drop into place as the daughter strands grew. Edna St. Vincent Millay wrote a sonnet which is, or so I thought in my youth, as good a poem about science as any since Lucretius’—the sonnet begins, ‘Euclid alone has looked on Beauty bare.’ Perhaps the experience ought to have been like that: one doubts, of course, that Crick and Watson altogether realized, that morning, what they had seen. ‘We have discovered the secret of life,’ Crick told everyone within earshot over drinks that noon at the Eagle. It was not the entire secret of life, yet truly for the first time at the ultimate biological level structure had become one with function, the antimony dialectically resolved. The structure of DNA is flawlessly beautiful” (980).

Roberta Ogilvie Day (US), John M. Rosenberg (US), Nadrian C. Seeman (US), Jung Ja Park Kim (US), Fred Leroy Suddath (US), Hugh B. Nicholas (US), and Alexander Rich (US) gave the first experimental evidence that Watson-Crick base pairs form when the molecule is constrained in a double helix. They did this by x-ray analysis, at 8-angstrom resolution, of two dinucleotide phosphate crystals, the RNA oligomers GpC and ApU (427; 1578).

 

Alfred Day Hershey (US) found that there are minor species of RNA with high turnover rates produced during phage infection of bacteria (838; 839).

 

Waldo E. Cohn (US) and Elliot Volkin (US) found that a specific phosphodiesterase from snake venom yields 5'-mononucleotides from RNA thus establishing the link on one side of the internucleotide bond (350).

Leon A. Heppel (US), Paul R. Whitfeld (AU), Russell J. Hilmoe (US), and Roy Markham (GB) proved that the linkage in ribonucleotides runs 5’ to 3’ (829; 830; 1955; 1956).

 

Luis Federico Leloir (AR), Carlos Eugenio Cardini (AR), and Jorge Chiriboga (PE) discovered the role of the sugar nucleotides in the synthesis of sucrose (283; 1120).

 

Hermann Niemeyer (CL), Robert Kellogg Crane (US), Eugene P. Kennedy (US), and Fritz Albert Lipmann (DE-US) found the acceptor effect in mitochondrial phosphorylation in studies of the action of thyroid hormones on mitochondrial activity. This means that ultimately, one of the controls in the mitochondrial production of ATP is ADP, the phosphoryl group acceptor (1369).

Robert Kellogg Crane (US) and Fritz Albert Lipmann (DE-US) explored the effect of arsenate on aerobic phosphate bond generation in mitochondrial suspensions. They concluded that by substitution for phosphate arsenate disrupts aerobic phosphorylation (381).

Arthur J. Kornberg (US) and William E. Pricer, Jr. (US) discovered the long-chain kinase, which catalyzes the ATP-requiring conversion of fatty acids—C8 to C18—to the corresponding acyl-CoA esters (1053).

 

Jack Gross (US) and Rosalind Venetia Pitt-Rivers (US) isolated the hormone 3:5:3'-triiodothyronine from ox thyroid gland and then synthesized it (729).

 

Heinrich Klüver (DE-US) and Elizabeth A. Barrera (US) introduced Luxol fast blue MBS stain as a method for staining myelin sheaths. When it was combined with Nissl stain cresyl violet, they found that both the myelin sheath and the nerve cell could be seen (1028).

 

Albert Kelner (US), using Escherichia coli strain B/r, demonstrated that ultraviolet light of 2537-angstrom wavelength damages DNA, which leads to inhibition of growth and ultimate death (1010).

 

Murray Strassman (US), Alice J. Thomas (US), and Sidney Weinhouse (US) discovered the first step in the pathway by which the yeast Torulopsis utilis converts pyruvate to valine (1788). This reaction is also the first step in the formation of acetoin (acetylmethylcarbinol), a property long used by bacteriologists as a diagnostic test to distinguish Aerobacter aerogenes from Escherichia coli.

Lester Orville Krampitz (US) established the role of acetolactate as an intermediate in the production of acetoin (1065).

Yeheskel S. Halpern (IL) and Harold Edwin Umbarger (US) showed that Aerobacter aerogenes synthesizes two enzymes that form acetolactate. One of them is synthesized when the pH of the growth medium falls below 6—the enzyme’s optimum—and forms acetoin, a neutral product of glucose catabolism. The other is synthesized when the pH is greater than 6—optimum near pH 8—and functions in the synthesis of valine (760).

 

Rosemary A. Biggs (GB), Alexander Stuart Douglas (GB), Robert Gwyn Macfarlane (GB) proposed two pathways to blood clotting according to whether tissue juices or extracts are present or absent; Extrinsic-tissue extracts are present, Intrinsic- tissue extracts are absent (173; 174).

 

William J. Harrington (US), Charles C. Sprague (US), Virginia Minnich (US), Carl V. Moore (US), Robert C. Aulvin (US), and Reubenia Dubach (US) reported observations to indicate that the thrombocytopenic factor may be a platelet agglutinin, and that those patients with idiopathic thrombocytopenia purpura who do not have platelet antibodies develop their disease solely because of a deficiency in platelet production (778).

 

Gilbert Burnett Forbes (US) described glycogen storage disease type 3. This is an autosomal recessive inheritable deficiency of amylo-1,6 glucosidase which results in storage of short chained glycogen molecules in the liver and skeletal musculature. Sequelae include hepatomegaly, cardiomegaly and muscle weakness (620).

 

Bernard Leonard Horecker (US), Pauline Z. Smyrniotis (US), and Hans Klenow (DK) discovered that the coenzyme of thiamin (vitamin B1) participates in the direct metabolism of carbohydrates when transketolase, which requires thiamin pyrophosphate, effects transfer of a 2-carbon unit from a 2-keto sugar to C-1 of various aldoses (909).

 

Selma E. Snyderman (US), L. Emmett Holt, Jr. (US), Rosario Carretero (US), and Kathryn Jacobs (US) established that pyridoxine and related compounds (vitamin B6) are essential for infants. Pyridoxine deprivation in two human infants resulted in an arrest of weight gain and failure of the ability to convert tryptophan to N¹-methylnicotinamide in both. In one subject, it resulted in convulsive seizures; in the other, it provoked a severe microcytic hypochromic anemia. All these symptoms and signs were corrected by the introduction of pyridoxine into the diet (1732).

 

Sidney Q. Cohlan (US) demonstrated that excessive intake of vitamin A (retinol) can cause congenital anomalies in the rat (348).

 

James B. Wyngaarden (US) and DeWitt Stetten, Jr. (US) investigated uricolysis in normal humans by intravenously injecting [1,3-15N] uric acid into Wyngaarden. They were able to show that 18% of the administered uric acid was degraded to other nitrogenous products such as urea and ammonia. The remainder was excreted as uric acid in his urine (2012).

 

Akiyasu Yasuma (JP) and Toyoki Ichikawa (JP) introduced the alloxan-Schiff and ninhydrin-Schiff histochemical reactions as tests for the presence of protein (2019).

 

Thalidomide was first synthesized at Chemie Grünenthal G.m.b.H., Stolberg, West Germany in 1953. Named Contergan, it was advertized as a sedative (1586; 1740).

 

Clifford George Pope (GB) and Muriel F. Stevens (GB) isolated crystalline diphtheria toxin (1479).

 

Louis Pillemer (US), Livia Blum (US), Jack Pensky (US), Leona Wurz (US), Irwin H. Lepow (US), Oscar A. Ross (US), Earl W. Todd (US), Alistair C. Wardlaw (US), and Chester M. Southam (US) discovered the alternative pathway for the activation of complement along with properdin, factors A and B (194; 1456; 1465-1467; 1745).

 

Suzanna E. Lewis (US), Edward Charles Slater (AU-NL), and Bertram Sacktor (US) demonstrated the presence of oxidative phosphorylation in insect tissues (1158; 1159; 1600).

 

Mabel Ruth Hokin (GB-US) and Lowell E. Hokin (GB-US) were the first to recognize that inositol phospholipids may play a role in transduction of signals initiated by first messengers. When they stimulated slices of pigeon pancreas with acetylcholine a remarkable movement of phosphorus into phospholipids was observed. This is called the phospholipid effect (894; 895).

Robert H. Michell (GB) was the first to propose that the phosphoinositide effect discovered by the Hokins plays a role in mobilization of cellular calcium (1268).

Robert H. Michell (GB), Christopher J. Kirk (GB), Lynne M. Jones (GB), C. Peter Downes (GB), and Judith A. Creba (GB) identified phosphotidylinositol-4, 5-biphosphate as the main phospholipid subject to a turnover in stimulated cells in connection with calcium mobilization (1269).

 

James Dewey Watson (US) and Francis Harry Compton Crick (GB) were the first to offer a molecular explanation for mutations (1931).

 

Max Alfert (US) and Irving I. Geschwind (US) described a selective staining method for the basic proteins of cell nuclei (20).

 

Clifford Grobstein (US) found that extracellular matrix (ECM) alone could induce mouse salivary gland tissue to differentiate (724).

Clifford Grobstein (US) demonstrated that the collecting ducts and nephrons arose from mutual induction between epithelial and mesenchymal tissues in embryonic kidneys (725).

Clifford Grobstein (US) proposed that the way one tissue induced another to develop might be through the presence of extracellular matrix (ECM) (726).

Stephen D. Hauschka (US) and Irwin R. Konigsberg (US) showed that myoblasts plated onto collagen (then the known major component of (ECM) would differentiate (799).

Stephen Meier (US) and Elizabeth D. Hay (US) undertook to determine whether physical contact with the substratum is essential for the stimulatory effect of extracellular matrix (ECM) on corneal epithelial collagen synthesis. They found that physical contact is necessary for induction of corneal epithelial collagen synthesis (1258).

Noreen E. Reist (US), Catherine Magill (US), U. Jack McMahan (US), and Robert M. Marshall (US) identified the ECM molecule agrin that was deposited by motoneurons and “spoke” to the postsynaptic muscle cells (1247; 1549).

Dale D. Hunter (US), Vandana Shah (US), John P. Merlie (US), and Joshua R. Sanes (US) discovered that ECM-localized laminin β2 directs differentiation of synapses during both regrowth and development (929).

Peter G. Noakes (US), Medha Gautam (US), Jacqueline Mudd (US), Joshua R. Sanes (US), John P. Merlie (US), Lisa Moscoso (US), Fabio Rupp (US), and Richard H. Scheller (US) performed knock-out studies which showed that both agrin and laminin β2 are critical during normal synaptic development in vivo (673; 1374). These discoveries confirmed that regenerating nerve axons take their cues for new synapse formation from the extracellular matrix (ECM) of muscle cells and not from the muscle cells themselves.

 

James F. Riley (GB) and Geoffrey B. West (GB) discovered that tissue mast cells are a main storage site of histamine (1562). This discovery helped lay the foundation for an understanding of allergic and inflammatory disease.

 

Susumu Hagiwara (JP-US), Hiroo Uchiyama (JP), Akira Watanabe (JP), and Takeyuki Wakabayashi (JP) described the myogenic rhythm intrinsic to cicada muscles (754-756).

 

Elis Wyn Knight-Jones (GB) sought to understand the role of settling behavior of larval barnacles on establishing the aggregated distribution of adults. He established that barnacle larvae recognize cues specifically associated with adult barnacles, are attracted to these cues, and therefore settle near conspecifics. The contact-dependent cue to which larvae respond appears to be a cuticular protein. He found that cyprid larvae, the specialized stage of barnacle larval development that is competent to settle, can prolong their planktonic lives and delaying metamorphosis into juveniles. The capacity to delay metamorphosis is considered adaptive because it increases the likelihood of locating suitable habitats and may promote genetic exchange among populations. Knight-Jones notes, “Isolated bare surfaces collect abnormally undiscriminating pioneer settlers, which are soon followed by gregarious individuals" (1030).

 

Jacques Lucien Monod (FR) and Germaine Cohen-Bazire (FR), using the bacterium Aerobacter aerogenes, presented evidence that the amino acid tryptophan can inhibit its own synthesis by activating its repressor at the gene level, i.e., enzyme repression (1306).

Arthur Beck Pardee (US), Harold Edwin Umbarger (US), Barbara Brown (US), Aaron Novick (US), Richard Alan Yates (US), Leo Szilard (HU-US), Georges N. Cohen (FR), Francois Jacob (FR), Jacques Lucien Monod (FR), John C. Gerhart (US), Earl Reece Stadtman (US), Gisele LeBras (FR), Huguette deRobichon-Szulmajster (FR), and Jean-Pierre Changeux (FR) produced additional examples of feedback control. Some of these are feedback inhibitions at the enzyme level. Others, like tryptophan, are feedback inhibitions at the gene level. A few are feedback controlled at both the enzyme and gene levels (300; 301; 679; 959; 1384; 1414; 1757; 1860-1862; 2020). See, Zacharias Dische 1940.

 

Nick Visconti (US) and Max Ludwig Henning Delbrück (DE-US) formulated a theory of genetic recombination in phages capable of accounting quantitatively for the recombinant frequencies obtained under various experimental conditions. This theory envisages that the vegetative phage genomes exist in an intracellular mating pool in which they undergo repeated pair-wise matings. Each mating leads to an exchange of genetic material by one or more crossovers between the two mated individuals.

From the vantage point of the Visconti-Delbrück theory, the fraction of progeny phages recombinant for two genetic markers introduced into a phage cross depends on two things: the linkage of the mutant genes in question and the number of mating events within the mating pool prior to lysis (1890).

 

Alfred Day Hershey (US), June Dixon (US), and Martha Cowles Chase (US) observed that a fraction of RNA molecules is rapidly synthesized and then degraded following the infection of Escherichia coli by T2 virus (841). Others would later show that this fraction was messenger RNA.

 

André Michel Lwoff (FR), Albert S. Kaplan (FR), and Evelyne Ritz (FR) established unequivocally that certain phage DNAs have the alternate possibility of being inserted in a prophage form into the chromosomes of their host. They can be transmitted from one cell generation to the next without external reinfection (1198; 1201).

 

Hans J. Schatzmann (CH) provided evidence that cardiac glycosides directly inhibit active transport of sodium and potassium ions through the red cell membrane (1634).

 

Hugh Esmor Huxley (GB) and Jean Hanson (US) were the first to identify the thick myofilaments in muscle cells as myosin and the thin ones as actin (771).

 

William Hayes (GB) found from the study of his Hfr strain of E. coli that the high-frequency donor character pertains only to a limited portion of the donor genome. He interpreted these findings to mean that the F plus Hfr change is attributable to a permanent alteration of the fertility factor. At the same time this engendered a loss of its own transferability to an F minus strain and a very much greater transferability of a limited sector of the donor genome (803; 805).

 

Shoei Iseki (JP) and Tatsuo Saki (JP) observed that infection of Salmonella by a temperate bacteriophage led to a change in somatic antigens of the host bacteria (948).

 

Joseph Louis Melnick (US) and William H. Gaylord, Jr. (US) described the intracellular development of poxviruses (674; 675; 1261).

 

Katherine Esau (RU-US) became one of the world’s leading authorities on plant anatomy upon the publication of her outstanding book, Plant Anatomy. Her later book, The Phloem, is considered the definitive text on structure and development of phloem (578; 579).

 

Ernest Robert Sears (US), working with wheat, described the processes of genetic analysis enabling the identification of chromosomes carrying specific recessive alleles. In the process, he discovered the hemizygous ineffective condition meaning the inability of a single copy of a recessive allele to pass the threshold necessary for expression. Two copies of the recessive allele are required for expression of the recessive phenotype (1664).

Ernest Robert Sears (US), working with wheat, created the most complete aneuploid series known in any organism. Using nullisomic effects seen in this series, he was able to show the genetic effects of each chromosome (1665).

 

Michael Abercrombie (GB) and Joan E.M. Heaysman (GB) coined the phrase contact inhibition to describe the inhibition of cellular locomotion, which commonly occurs when untransformed cell monolayers reach confluence (4; 5).

 

Thomas Huckle Weller (US) grew the virus of Varicella (chickenpox) and of Herpes zoster (shingles) in cultures of human tissue and found that they both produced the same type of cytopathogenic effect (1941).

 

Wallace Prescott Rowe (US), Robert Joseph Huebner (US), Loretta K. Gilmore (US), Robert H. Parrot (US), and Thomas G. Ward (US) recovered virus (adenovirus) from tissue cultures of human tonsillar and adenoid tissue (1590).

Robert Joseph Huebner (US), Wallace Prescott Rowe (US), Thomas G. Ward (US), Robert H. Parrott (US), and Joseph A. Bell (US) realized that these adenoidal-pharyngeal-conjunctival agents represented a newly recognized group of common viruses of the respiratory system (922).

Maurice Ralph Hilleman (US) and Jacqueline H. Werner (US) grew the adenovirus 4, a major cause of acute respiratory disease in humans, in polyploid tissue culture (864).

John Franklin Enders (US), Joseph A. Bell (US), John Holmes Dingle (US), Thomas Frances, Jr. (US), Maurice Ralph Hilleman (US), Robert Joseph Huebner (US), and Anthony Monck-Mason Payne (US) proposed the name adenoviruses for a newly recognized group of respiratory tract viruses (562).

Maurice Ralph Hilleman (US), Reuel Arthur Stallones (US), Ross L. Gauld (US), Mildred S. Warfield (US), Sally A. Anderson (US), and Jacqueline H. Werner (US) developed a vaccine for adenovirus types 4 and 7 to account for the vast majority of military recruits (862; 863; 1759).

 

Masahiko Kuroya (JP), Nakao Ishida (JP) and Takehiko Shiratori (JP) isolated what would be called Sendai virus from cases of pneumonitis in newborn infants in Sendai, Japan (1074).

 

Roger W. Reed (CA), Charles H. Rammelkamp, Jr. (US), Harold I. Griffeath (US), Robert S. Weaver (US), and Alan C. Siegel (US) concluded that type 12, group A, hemolytic Streptococcus is the most common etiological agent of acute hemorrhagic glomerulonephritis (1507; 1509; 1546; 1687).

 

Hermann Karl Felix Blaschko (DE-GB), Arnold D. Welch (GB), Nils-Åke Hillarp (SE), Sten Lagerstedt (SE), and Bodil Nilson (SE) were the first to isolate secretory vesicles (chromaffin vesicles) of adrenal medullary cells. Using centrifugation of adrenal medullary homogenates, they sedimented catecholamines, the major part of the hormones of this organ (187-189; 851).

 

Nicholas Avrion Mitchison (GB) provided the first evidence that transplantation immunity, the ability to maintain immunological individuality, is affected by regional lymph node cells (1294).

 

Paul György (US) found a specific mutant of Lactobacillus bifidus (var. Penn) isolated from the feces of a breast-fed infant that showed no growth in the usual medium satisfactory for most strains of L. bifidus. It required for its propagation the addition of a specific "growth factor" present in human milk. Cow's milk had only 1/30 to 1/100 of the activity of human milk (748).

 

Eugene Aserinsky (US) and Nathaniel Kleitman (US) found that rapid eye movements (REM) occur during some sleep periods and noted that dreaming typically occurs during REM sleep. Electroencephalograms (EEGs) showed that, during REM sleep, heart rate and breathing increased while brainwave activity was almost as high as that of the waking mind (65; 66). Note: Before REM, it was assumed that sleep was a passive state. After REM, scientists saw that the sleeping brain actually cycled between two distinct electrical and biochemical climates—one characterized by deep, slow-wave sleep, which is sometimes called “quiet sleep” and is now known as non-REM or NREM sleep, and the other characterized by REM sleep, also sometimes called “active” or “paradoxical” sleep.

 

William Grey Walter (GB -US) and his colleagues used their toposcope to extend temporal spectral analysis in which they visualized the spread of alpha waves across the surface of the brain in ways resembling the ebb and flow of tidal waves around the earth. Alpha activity has the peculiarity that it is most apparent when a human subject is at rest with eyes closed, and it disappears when the eyes are opened or if mental arithmetic is undertaken. Walter proposed that the alpha represented 'scanning' by the brain in search of local centers of activity when none was present, and that it stopped when a 'target' was found in the cortex. This 50-year-old hypothesis was and still is controversial, but there is at present none better (1922).

 

Franz K. Bauer (US), Benedict Cassen (US), Elsie Youtcheff (US), and Lucille Shoop (US) performed a clinical study comparing needle and jet gun injection (116).

 

Stephen William Kuffler (HU-US) discovered the center-surround receptive field of retinal ganglion cells, with antagonism between the effects of light falling on the central and surrounding portions of the field. It was immediately obvious, as Kuffler explicitly pointed out, that this receptive field organization would form the basis for spatial contrast enhancement (1070).

John E. Dowling (US) and Frank S. Werblin (US) presented an anatomical and physiological analysis of the mudpuppy (Necturus maculosus) retina. The principles of synaptic organization of the Necturus retina are like those of other vertebrates (509; 1951).

 

Robert L. Rosenthal (US), O. Herman Dreskin (US), and Nathan Rosenthal (US) described a new blood clotting factor in man, plasma thromboplastin antecedent (PTA). It was later designated Factor XI (1580; 1581).

 

George Brecher (US), Marvin Schneiderman (US), and Eugene P. Cronkite (US) discovered that in blood diluted with 1% ammonium oxalate, platelets become easily recognizable by phase microscopy. The “phase” method, based on the unequivocal identification of platelets, is highly reproducible and reflects the platelet level in the circulation (226).

 

Robert D. Langdell (US), Robert H. Wagner (US) and Kenneth M. Brinkhous (US) developed the Partial Thromboplastin Time Test (PTT), a one-stage procedure that measures the intrinsic coagulation activity of plasma. This test aids in the detection of blood clotting disorders (1087).

Robert R. Proctor (US) and Samuel I. Rapaport (US) developed the Activated Partial Thromboplastin Time Test (aPTT), a modification of the PTT test that dispenses with the variable of contact activation (1495).

Rosemary A. Biggs (GB) and Alexander Stuart Douglas (GB) developed the Thromboplastin Generation Test; an important advance enabling a more detailed analysis and localization of clotting factors (172).

 

Louis Lichtenstein (US) classified eosinophilic granuloma of bone along with Hand-Schuller-Christian disease (with the classic triad of exophthalmos, diabetes insipidus, and skull lesions) and Letterer-Siwe disease (lymphadenopathy, skin rash, hepatosplenomegaly, fever, anemia, and thrombocytopenia) as Histiocytosis X (1165).

 

Ralph J.P. Wedgwood (US), Charles D. Cook (US), and Jonathan Cohen (US) described dermatomyositis in children. It is a condition predominately affecting striated muscle and skin (1935).

 

Willys M. Monroe (US) and Arnold F. Strauss (US) observed schizocytes in the blood vessels of sections obtained at necropsy from two patients who had died of thrombotic thrombocytopenic purpura. They suggested that the abnormal blood vessels might be the site of red cell fragmentation and destruction (1311).

David Vérel (GB), Adam Lothian Turnbull (GB), George Ranken Tudhope (GB), and John H. Ross (GB) observed shortened red cell survival in a young patient with malignant hypertension with normal renal function in whom the red cell survival returned to normal when the malignant phase of hypertension had been treated (1884).

Michael C. Brain (GB), John V. Dacie (GB), and Dermot O’Brien Hourihane (GB) postulated that the hemolytic anemia found in patients with renal failure, thrombotic thrombocytopenic purpura, or disseminated carcinoma might be due to the effect on the red blood cells or their passage through the abnormal of partially occluded blood vessels found in these patients. Red cells could well be damaged when circulating through fibrin strands in small blood vessels (218).

 

George Eugene Moore (US), Lester Leland Bissinger (US), and Elsa C. Proehl (US) showed a strong causative link between chewing tobacco and cancers of the mouth (1316).

 

C.W. Miller (GB) designed a stationary linear accelerator to produce a beam of electrons with the length of the accelerator tube determining the power of the beam. This eliminated the need to replace a radioactive source. X-ray therapy (radiotherapy) using a linear accelerator now became possible (1277).

 

Louis Michon (FR), Jean Hamburger (FR), Nicholas Oeconomos (FR), Pierre Delinotte (FR), Gabriel Richet (FR), Jean Vaysse (FR), and Bernard Antoine (FR) were the first to perform a human kidney transplantation in which the donor was a living relative of the recipient (mother to son); no immunosuppression was used and the kidney functioned for three weeks prior to rejection (1270).

 

Ian Aird (GB), Hugh H. Bentall (GB), and John Alexander Fraser-Roberts (GB) found that there is a relationship between cancer of the stomach and the ABO blood groups with the highest incidence occurring in blood group A (14). Their published paper helped lead the way to our understanding of how disease is related to histocompatibility antigens.

 

Matthew Block (US), Leon O. Jacobson (US), and William F. Bethard (US) described twelve patients, most of whom developed overt acute leukemia, preceded for as long as five years by hematopoietic disorders manifested as a combination of anemia, neutropenia, and thrombocytopenia. These patients had problems with thrombocytopenic bleeding or infection related to neutropenia, and many progressed to florid acute myeloblastic leukemia, some in several months, others over several years.

This paper brought attention to “threshold” leucoses that can occur at any age, but which increase in incidence exponentially after age fifty years (193).

 

Virginia Apgar (US) developed a repeatable method, the Apgar score, based on observations made of the newborn immediately after birth, and is predictive of the motor and metal development of the child (46).

 

Jerome K. Sherman (US) and Raymond G. Bunge (US) introduced a simple method of preserving human sperm using glycerol, combined this with a slow cooling of sperm, and storage with solid carbon dioxide as a refrigerant. Sherman also demonstrated for the first time that frozen sperm, when thawed, were able to fertilize an egg and induce its normal development. He and Bunge demonstrated that successful pregnancies in humans could be produced using cryopreserved sperm (253; 1680).

 

Leland C. Clark, Jr. (US), Richard Wolf (US), Donald Granger (US), and Zena Taylor (US) introduced the first clinically practical polarographic oxygen electrode for measurement of arterial PO2 (327).

Leland C. Clark, Jr. (US) presented a relatively simple method to continuously monitor the oxygen tension of venous and arterial blood circulating in heart-lung machines (324).

Leland C. Clark, Jr. (US) and Champ Lyons (US) described “how to make electrochemical sensors (pH, polarographic, potentiometric, or conducto- metric) more intelligent” by adding “enzyme transducers as membrane enclosed sandwiches.” The concept was illustrated by an experiment in which glucose oxidase was entrapped at a Clark oxygen electrode using a dialysis membrane. The decrease in measured oxygen concentration was proportional to glucose concentration. Clark and Lyons coined the term “enzyme electrode” (326). Note: This is the invention of the first biosensor.

John W. Severinghaus (US) and A. Freeman Bradley, Jr. (US) described the first clinically practical electrode for measuring PCO2 in blood (1677).

 

Andrew Watt Kay (GB) developed a new and extremely consistent test for the presence of duodenal ulcer. It is based on the effect of increasing doses of histamine on the gastric secretion of hydrochloric acid (1000).

 

Frank Bernard Cockett (GB) and D.E. Elgan Jones (GB), after carrying out numerous cadaver limb dissections and investigations on their patients, using the new technique of arterial and venous injections, established that lower leg ulcers were caused not by varicose veins but by incompetent ankle perforating veins (332).

 

Michael Ellis DeBakey (US), Denton A. Cooley (US), E. Stanley Crawford (US), and George C. Morris, Jr. (US) developed Dacron as artificial arteries and Dacron-velour arteries as a surgical replacement of diseased arteries (441). They began using artificial arteries made of Dacron in 1953.

 

Robert M. Salassa (US), Warren A. Bennett (US), F. Raymond Keating Jr. (US), and Randall G. Sprague (US) describe and discuss postoperative deaths that were regarded as the result of acute postoperative adrenal cortical insufficiency associated with atrophy and functional suppression of the adrenal cortex induced by previous treatment with cortisone (1603).

 

Michael Ellis DeBakey (US) and Denton A. Cooley (US) performed the first successful removal and graft replacement of a fusiform aneurysm of the thoracic aorta, a swelling caused by a weakness in the arterial wall of the descending aorta in the chest (439).

 

Michael Ellis DeBakey (US) performed the first successful carotid endarterectomy for the treatment of stroke in 1953 but did not report it until 1975 (438). Carotid endarterectomy remains one of the principle surgical treatments of carotid artery stenosis.

 

William F. Enos (US), Robert H. Holmes (US), and James Beyer (US) described and analyzed the gross lesions found in the coronary arteries of United States soldiers killed in action in Korea (570).

 

Jeremiah Noah Morris (GB) James Austin Heady (GB), Philip Andrew Banks Raffle (GB), G.C. Roberts (GB), and J.W. Parks were epidemiologists and public health officials who revealed the health benefits of exercise. In a classic study they obtained early results from a study of London busmen; this revealed a substantial difference in risk between drivers (sedentary) and conductors (who ran up and down the stairs of London's double-decker buses). They followed thirty-five thousand drivers and conductors for two years and found that after they adjusted for all other variables, the drivers—no matter how healthy—were twice as likely to have a heart attack as the conductors (1331). Note: This was the first time that anyone had demonstrated a direct and measurable link between exercise and health.

Steven N. Blair (US), A.R. Hardman (GB) and Jeremy Noah Morris (GB) established that regular physical activity of 150 minutes/week of moderate intensity physical activity reduces the risk of numerous chronic diseases, preserves health and function (both physical and mental) into old age, and extends longevity (184; 1329; 1330).

 

Robert H. Whittaker (US) demonstrated that plant species distribute themselves along nutrient and environmental abiotic gradients (1957).

 

George Gaylord Simpson (US) originated the notion of the 'adaptive zone' and discusses the relation between adaptive zones and adaptive radiations at length. Here he relates the population/genetic/microevolutionary phenomena of concern to most of the ‘synthesists’ to macroevolutionary/deep time patterns evident in the fossil record (1697).

 

Sidney P. Colowick (US) and Stanley Oram Kaplan (US) founded Methods in Enzymology.

 

1954

“I believe with Schopenhauer that one of the strongest motives that leads men to art and science is escape from everyday life with its painful crudity and hopeless dreariness from the fetters of one’s own everyday desires…. A finely tempered nature longs to escape from personal life into the world of objective perception and thought.” Albert Einstein (547).

 

“A grain of slightly mad recklessness, Might, in this domain as in others, Be the price you have to pay for great and noble findings.” Claude Levi-Strauss (1141).

 

“There are men who express the age and the milieu in which they are educated but who, by the intensity of their imagination, the sweep of their knowledge and their astounding versatility, rise above their era and their neighbors so that they inhabit both time and eternity at once. When we analyze their minds, we can identify nearly all the component elements tracing this to family and that to school and the other to social climate and yet the compound is far more than the sum of all these elements; richer, intenser, different in quality as a diamond is different from carbon." Gilbert Highet (848).

 

“Metamorphosis is merely one type of polymorphism.” Vincent Brian Wigglesworth (1962).

 

Linus Carl Pauling (US) was awarded the Nobel Prize in Chemistry for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances.

 

John Franklin Enders (US), Thomas Huckle Weller (US), and Frederick Chapman Robbins (US) were awarded the Nobel Prize in Physiology or Medicine for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue.

 

John Desmond Bernal (GB), Peter C. Sylvester-Bradley (GB), S. Ichtiaque Rasool (US), Donald M. Hunten (US), William M. Kaula (US), Egon T. Degens (DE), Kenneth M. Towe (US), Edward Anders (US), Gustaf Olaf Arrhenius (SE-US), Bibhas Ranjan De (US), Hannes Olof Gosta Alfvén (SE-US), Anne Benlow (GB), Arthur Jack Meadows (GB), Manfred A. Lange (DE), and Thomas J. Ahrens (US) proposed that impact accretions from extraterrestrial objects represented a significant source of the Earth's atmospheric and biogenic elements (36; 62; 136; 153; 451; 1090; 1536; 1811; 1844).

 

David W. Green (GB), Vernon M. Ingram (GB) and Max Ferdinand Perutz (AT-GB) solved the phase problem in protein crystallography by the addition of heavy metals such as uranium to the crystal preparation (721).

 

Harold Horace Hopkins (GB), Narinder S. Kapany (GB), and Abraham Cornelis Sebastiaan van Heel (NL) independently devised an optical unit, which conveys optical images along a flexible glass axis. Hopkins and Kapany named it a fibrescope (907; 1870). This concept fostered endoscopes.

Basil Hirschowitz (US), C. Wilbur Peters (US), and Lawrence E. Curtis (US) produced the first fiber-optic, fully flexible endoscope (836).

 

I.D. Rattree (GB) and W.E. Stephen (GB), in 1954, introduced reactive dyes. These dyes are usually formed by condensation of cyanuric chloride with various amino dyes thus leaving two free chlorines. Procion yellow M-4R is an example and has been used to stain nerve tissue.

 

Herbert A. Sober (US), Frederick J. Gutter (US), Elbert A. Peterson (US), and Mary M. Wyckoff (US) invented cellulose-based ion exchangers to separate individual proteins from complex mixtures (1735; 1736).

 

Robert Burns Woodward (US), Arthur Allan Patchett (US), Derek Harold Richard Barton (GB), David A. J. Ives (US), and Ronald B. Kelly (US) accomplished the total synthesis of lanostenol (1998).

 

Robert Burns Woodward (US), Michael P. Cava (US), William D. Ollis (GB), A. Hunger (US), Hans U. Daeniker (CH), and Karl Schenker (CH) carried out a total synthesis of strychnine (1996; 1997).

Steven D. Knight (US), Larry E. Overman (US), and Garry Pairaudeau (US) would later carry out an updated total synthesis of strychnine (1029). Note: Strychnine is the major alkaloid isolated from the seeds of the trees Strychnos nux-vomica and Strychnos ignatii Bergius (Saint-Ignatiu’s bean), which are broadly distributed in the Asian tropics

 

Jerome Gross (US), and John Highberger (US), and Francis Otto Schmitt (US) demonstrated that various supramolecular forms of collagen can be reconstituted by self-assembly, and this led both to the determination of the dimensions of the collagen molecule (tropocollagen) and the quarter-stagger hypothesis, which accounted for the observed axial periodicity of the molecule (728).

Francis Otto Schmitt (US), Albert E. Rubin (US) , Dorthe Pfahl (US), Peter T. Speakman (US), Peter F. Davison (US), Lawrence Levine (US) and Maurice P. Drake (US) isolated and determined the primary structure of the noncollagen- like peptides (teleopeptides) at either end of the collagen molecule, which make it immunogenic and which are critical factors in fibrinogenesis, as well as in pathophysiology (1592; 1649).

 

Hartmut Hoffmann-Berling (DE) reported that water-glycerol extracted amnion fibroblasts contract upon addition of ATP (892). Subsequently Hoffmann-Berling showed that glycerinated epithelial cells, hen embryos, or Jensen tumor tissues could be contracted with ATP, similarly to the contraction of glycerinated muscle fibers. The idea that actin and myosin are present in mammalian cells, other than muscle, became a working hypothesis. By the middle of 1970s actin and myosin were acknowledged as regular components of non-muscle cells.

 

Ernst Klenk (DE) and Hildegard Debuch (DE) were the first to suggest the correct structure for plasmalogens (1025).

 

Jean Leclercq (FR) discovered that a small mealworm (Tenebrio molitor) needs carnitine as a "vitamin" (1105).

Irving B. Fritz (US) discovered that carnitine in muscle is active in increasing the oxidation of fatty acids by the liver, thereby increasing the energy supply to the liver and improving its function (653).

Irving B. Fritz (US) and Norman R. Marquis (US), over the next twenty years along with colleagues, proved that carnitine acts to transport fatty acids across barriers to the specific sites of fatty acid oxidation. In the case of the heart, carnitine is necessary for the utilization of this foodstuff and for optimal cardiac function (654; 655).

Salvatoro DiMauro (US) and Paola M. Melis DiMauro (US) were the first to describe an inherited defect in the fatty acid oxidation pathway (carnitine palmitoyltransferase 2 deficiency). This deficiency leads to myoglobinuria (483).

 

Jack Leonard Strominger (US), Herman Moritz Kalckar (DK-US), Julius Axelrod (US), and Elizabeth S. Maxwell (US) discovered how the cell generates uridine diphosphate glucuronic acid (UDPGA) from uridine diphosphate glucose (UDPG) using uridine diphosphate glucose dehydrogenase (83; 1795).

Julius Axelrod (US), Rudi Schmid (US), and Lydia Hammaker (US) then demonstrated that a deficiency of this microsomal fraction enzyme (uridine diphosphate glucose dehydrogenase) results in failure to detoxify bilirubin, which leads to jaundice (84).

 

Marthe Louise Vogt (DE-GB) identified the hypothalamus as a source of norepinephrine (noradrenaline) in the brain (1893).

 

Rollin Douglas Hotchkiss (US) extended transformation of bacterial characters beyond capsular qualities when he showed that DNA from Pen^r-S cells could convert Pen^s-R cells to Pen^r-S cells. He also demonstrated that bacterial cells are not equally susceptible to transformation during the entire division cycle. They enter a competent phase shortly after division and then return to a relatively noncompetent phase (910; 911).

 

Sarah Ratner (US) found that in the ornithine cycle, nitrogen is not transferred directly from ammonia to citrulline to form arginine but rather it is transferred by way of aspartic acid in the presence of ATP and magnesium. The aspartic acid complexes with citrulline to form argininosuccinic acid which in turn breaks down into arginine and fumaric acid (1537).

 

Ralph W. Brauer (US), George F. Leong (US), and Robert J. Holloway (US), using the isolated perfused rat liver, demonstrated that bile was secreted against pressures that exceeded the vascular perfusion pressure. Thus bile was not formed by hydrostatic filtration as was urine (222). Note: This study clearly demonstrated that the formation of bile was an energy dependent process.

Ivar Sperber (SE) was the first to articulate the “osmotic theory of bile formation.” He observed that when organic solutes, bile acids and other “cholephiles” were injected intravenously, they were concentrated in bile and stimulated bile flow. This led to his conclusion that the concentrative transport of solutes in bile created osmotic gradients that then stimulated the passive diffusion of water (and electrolytes) across the semipermeable canalicular membrane into bile (1750).

James L. Boyer (US) expressed a paradigm in biliary secretion, “It appears quite possible to assume osmotic filtration as a factor in bile formation. The primary event of bile formation would be the active transfer (from cells or through cells of bile acids and possibly other, though quantitatively less important compounds) into the bile capillaries.” (212)

Henry O. Wheeler (US) and subsequent investigators were able to characterize canalicular bile production and distinguish it from fluid secretion formed more distally by the bile duct epithelium (1953).

James L. Boyer (US) reported on the recognition that there were both “bile salt-dependent” [bile salt-dependent bile flow (BSDF)] and “bile salt-independent” [bile salt-independent bile flow (BSIF)] components of hepatocellular canalicular bile formation, and that there were considerable species differences with respect to the relative contribution of fluid secretion from the bile duct epithelium (213).

James L. Boyer (US) and J.R. Bloomer (US) estimated that man produced ~750mL of bile daily and that ~75% was formed at the level of the bile canaliculus in the adult. Approximately 50% of canalicular bile in man was found to be bile salt-dependent while a variable fraction (~25%) of the daily total production of bile came from the bile ducts in response to the release of secretin induced by meals (214).

Bennett L. Blitzer (US), James L. Boyer (US), Patricia S. Latham (US), Michael Kashgarian (US), Elizabeth S. Sztul (US), Daniel Biemesderfer (US), and Michael J. Caplan (US) used histochemical techniques to demonstrate that the sodium pump (Na⁺,K⁺-ATPase) was localized at the basolateral membrane of the hepatocyte similar to other classical epithelia (192; 1097; 1812). Note: This indicated that the liver was physiologically similar to other polarized epithelia with respect to the location of specific transport proteins.

M. Sawkat Anwer (DE-US), Dietmar Hegner (DE), Rebecca W. Van Dyke (US), Jeffrey E. Stephens (US), and Bruce F. Scharschmidt (US) determined that the inwardly directed sodium gradient, generated by the sodium pump, could be utilized as a secondary driving force when coupled to other solutes and provided a mechanistic explanation for the previously demonstrated dependence of hepatic uptake of conjugated bile salts on the presence of sodium ions (45; 1869).

Yukihiko Adachi (JP), Hikoaki Kobayashi (JP), Yoshiaki Kurumi (JP), Mika Shouji (JP), Motokazu Kitano (JP), Toshio Yamamoto (JP), Michael Muller (DE), Toshihisa Ishikawal (DE), Ulrike Berger (DE), Cornelia Klunemann (DE), Loth Larucka (DE), Antje Schreyerll (DE), Christoph Kannicht (DE), Werner Reutter (DE), Gerhart Kurzll (DE), Dietrich Keppler (DE), Toshiro Nishida (US), Zenaida Gatmaitan (US), Mingxin Che (US), Irwin M. Arias (US), Bruno Steiger (CH), Brigette O'Neill (CH), and Peter J. Meier (CH) showed that bile salts and other solutes were transported into bile largely by adenosine triphosphate (ATP)-dependent transport mechanisms rather than driven by the cellular electrical potential as originally believed (8; 1341; 1370; 1769).

 Domenico Alvero (US), Won Kyoo Cho (US), Albert Mennone (US), and James L. Boyer (US) used isolated bile duct units (IBDUs) to perform physiologic studies that characterized the role of hormones such as secretin, bombesin, vasoactive peptide (VIP), and others, as well as the function of ion transporters, in the generation of bicarbonate secretion from this epithelia (32; 316; 317).

 

Paul Berg (US) and Wolfgang Karl Joklik (AT-AU-US) discovered the enzyme that uses ATP to phosphorylate the four ribo- and deoxyribonucleoside diphosphates of RNA and DNA to their respective triphosphates; they dubbed the enzyme nucleoside diphosphokinase (146). This enzyme plays a critical role in generating the "building blocks" for RNA and DNA synthesis.

 

Howard J. Saz (US) and Lester Orville Krampitz (US) performed work with Micrococcus lysodeikticus, which strongly suggested that bacteria possess the tricarboxylic acid cycle (1629).

H. Earl Swim (US) and Lester Orville Krampitz (US) established that, in fact, Escherichia coli does possess the tricarboxylic acid cycle (1810).

 

Peter Dennis Mitchell (GB) gave the first adequate description of bacterial transport. He found that resting cells of Micrococcus pyogenes (Staphylococcus aureus) take up external 32Pi in exchange for internal phosphate by a reaction that is biased strongly to use of monovalent phosphate (1292).

 

William Chefurka (CA) provided conclusive evidence for the existence of an Embden-Meyerhof-Parnas type glycolytic pathway in an invertebrate (Musca domestica Linnaeus). This Embden-Meyerhof-Parnas pathway is virtually identical with those observed in vertebrate tissues (310). Chefurka also demonstrated that these houseflies possess the hexosemonophosphate shunt (311).

 

Carlton E. Schwerdt (US), Robley C. Williams (US), Wendell Meredith Stanley (US), Fred L. Schaffer (US), and Mary E. McClain (US) determined the morphology of type 2 poliomyelitis virus (MEF) by electron microscopy (1661).

 

Renato Dulbecco (IT-US) and Marguerite Vogt (US) applied the plaque method to a detailed study of the growth characteristics of the western equine encephalitis virus (WEE) along lines similar to those followed in bacteriophage work. The study concerned the one-step growth curve of the virus, both on a cell layer formed in vitro and on cells in suspension, and the distribution of virus yields from single infected cells. The growth curves of the WEE virus obtained both on a monolayer tissue culture and in a suspension of cells, showed a latent period varying from 2 to 3.5 hours, which was followed by a steep increase in virus production lasting over several hours. It was seen that individual infected cells release virus over a long period of time (520). Note: See Emory Leon Ellis, 1939, for one-step growth curve during infection by bacteriophage.

 

Yasuichi Nagano (JP), Yasuhiko Kojima (JP), and Y. Sawai (JP) saw an antiviral activity in rabbit skin after injection of inactivated vaccinia virus. They were the first to discover “facteur inhibiteur” (interferon) (1352; 1353).

Alick Isaacs (GB), Jean Lindenmann (CH), and Robin C. Valentine (GB) found that exposure of chick embryo chorioallantoic membranes to heat-inactivated influenza virus generated a factor that, when added to fresh membranes, rendered them immune to influenza virus infection (944; 945; 1174). This represents the second group to discover interferon, an inhibitor of viral replication. Lindenmann coined the name interferon.

Monto Ho (CN) and John Franklin Enders (US) were the third group to discover interferon (875). Note: After endogenous pyrogen, discovered in 1953, interferon was the second cytokine to be discovered.

Maurice Ralph Hilleman (US), George P. Lampson (US), Alfred A Tytell (US), Marjorie M. Nemes (US), and A. Kirk Field (US) demonstrated that certain nucleic acids stimulate interferon production in many types of cells, and detailed interferon’s ability to impede or kill many viruses, and correctly predicted its efficacy in the treatment of viral infections (e.g., hepatitis B and C), cancers (e.g., certain leukemias and lymphomas), and chronic diseases (e.g., multiple sclerosis). What’s more, Hilleman developed procedures to mass-produce and purify interferons (600-602; 855-859; 1083-1085; 1360; 1361; 1859).

 

John W. Gofman (US), Frank Glazier (US), Arthur Tamplin (US), Beverly Strisower (US), and Oliver de Lalla (US) established that the plasma lipids are transported in the form of a series of macromolecular complexes of lipids and proteins, the lipoproteins (699).

 

Susanna Harris (US), Tzvee N. Harris (US), James C. Roberts, Jr. (US), and Frank James Dixon (US) showed that the production of antibody could be transferred from one animal to another by way of cells (783; 1567).

 

Georgi Antonovich Gamow (RU-US) was among the first to deduce that DNA can act as a template for the orderly insertion of some twenty amino acids into a protein. “…the hereditary properties of any given organism could be characterized by a long number written in a four-digital system. On the other hand, the enzymes (proteins), the composition of which must be completely determined by the deoxyribonucleic acid molecule, are long peptide chains formed by about 20 different kinds of amino-acids and can be considered as long words based on a 20-letter alphabet. Thus, the question arises about the way in which four-digital numbers can be translated into such words” (665).

 

Ulf Svante Hansson von Euler-Chelpin (SE) and Otto Loewi (DE-US) proposed that adrenergic nerve transmitter is stored within intracellular granules (1182; 1898).

Eduardo Diego P. de Robertis (AR), H. Stanley Bennett (US), Antonio Van Ferreira (US), George Emil Palade (RO-US), and Sanford L. Palay (US) suggested that these synaptic vesicles might represent a transitory form of storage of the transmitter in synapses and similar structures. On stimulation such vesicles may move toward the cell membrane and give off their contents (434-436; 1407).

Sanford L. Palay (US) was even more explicit in proposing that the vesicles visible by electron micrographs were the structural source of the miniature, spontaneous pulses reported in a series of papers in 1954 (1410). Thus, the hypothesis of quantal transmitter release now had a structural correlate.

 

Keith Roberts Porter (US) was the first to describe a type of cell juncture called a desmosome or macula adherens (desmos = bond) (1483).

 

Hugh Esmor Huxley (GB-US), Jean Hanson (US), Andrew Fielding Huxley (GB), and Ralph M. Niedergerke (GB) proposed the sliding filament model of muscular contraction. According to this model force is generated between two types of muscle myofilament: one containing the protein actin, the other containing the protein myosin. The force causes the two types of myofilament to slide past each other and this, in turn, results in an overall shortening of the muscle (772; 930; 931; 936; 937).

 

Nicholas Avrion Mitchison (GB), James M. Weaver (US), Glenn H. Algire (US), and Richmond T. Prehn (US) discovered that sensitized cells and not antibodies are the primary agents of graft rejection (1295; 1296; 1933).

Nicholas Avrion Mitchison (GB), O. LeRoy Dube (US), Paul Andreini (US), and Marion L. Drasher (US) helped bring immunology to a turning point: the recognition that lymphocytes were important (42; 1297; 1298).

 

Robert J. Rutman (US), Abraham Cantarow (US), and Karl E. Paschkis (US) observed that rat hepatomas exhibited greater utilization of uracil than did normal rat livers (1597).

 

John Rodney Quayle (GB), R. Clinton Fuller (US), Andrew Alm Benson (US), and Melvin Calvin (US) observed enzymatic carboxylation of ribulose biphosphate in crude extracts from Chlorella (1499).

 

Daniel Israel Arnon (PL-US), Mary Belle Allen (US), Frederick Robert Whatley (GB), John B. Capindale (GB), and Lois J. Durham (US) found that the assimilation of carbon dioxide in isolated chloroplasts is indeed a reversal of the carbohydrate breakdown reactions (respiration). They further showed that ATP and reduced coenzyme (PNH2) provided the energy necessary for this reversal. When they illuminated isolated spinach chloroplasts in the presence of ADP and phosphate, ATP was formed. Since the yield of ATP in such experiments was rather high and comparable to the amount of light-induced electron flow, it was concluded that the formation of ATP must represent a major mechanism for the conservation of absorbed light energy, just as ATP formation is the major process by which the energy of respiration is conserved during electron transport in mitochondria. This process they named photosynthetic phosphorylation or photophosphorylation (24; 58-61).

Independently and nearly simultaneously Albert W. Frenkel (US) discovered that a very similar phosphorylation process occurs on illumination of membrane vesicles from the photosynthetic bacterium Rhodospirillum rubrum. These observations suggested that the formation of ATP from ADP and phosphate results from the energetic coupling of the phosphorylation to the photo-induced electron transport, in much the same way that oxidative phosphorylation is coupled to electron transport in mitochondria (646). This is the discovery of cyclic photophosphorylation in bacteria.

 

Aaron Novick (US) and Leo Szilard (HU-US) while analyzing the pathway of tryptophan synthesis in Escherichia coli discovered that the constitutive enzyme tryptophan synthetase in this pathway is subject to inhibition by tryptophan. Szilard referred to this as classic feedback control (1382; 1384). Henry James Vogel (US) later suggested that this type of pathway control be called enzyme repression (1892).

 

Paul Emanuel Polani (GB), William F. Hunter (GB), and Bernard Lennox (GB) noted that coarctation of the aorta is more common among Turner’s syndrome patients than among normal 46XX females (1476).

 

William H. Telfer (US), using the Cecropia silkworm, revealed for the first time a sex-limited blood protein whose concentration in the clear, liquid fraction of the yolk is four times higher than its maximum concentration in the blood during metamorphosis, and twenty times higher than that of the blood at the conclusion of egg formation. The protein thus appears to be transferred from blood to yolk against a concentration gradient (1824).

Thomas F. Roth (US) and Keith R. Porter (US) discovered the coated micropinocytotic vessicle, a generally distributed organelle exhibiting all the structured features that had been postulated for vitellogenesis transport across the oocyte membrane. They proposed that endocytosis is specific to a cargo and that the vesicle coat might be functioning in both selection and mechanical molding (1585; 1825).

 

Thelma B. Dunn (US) presented a review of the hematopoietic and reticuloendothelial system, including an examination of the peripheral blood and blood-forming organs, normal anatomy, non-neoplastic and neoplastic changes, a proposed classification of tumors and a survey of the literature (521).

 

José del Castillo (ES) and Bernard Katz (RU-GB) described impulse transmission across a synapse. They demonstrated that a chemical neurotransmitter substance is released from presynaptic terminals in discrete packets or quanta, each containing several thousand molecules (453).

 

Johannes Arne Gosta Rhodin (SE), working with mouse kidney tissue, discovered a new class of small, relatively simple cytoplasmic organelles, which he named microbodies (peroxisomes) (1554).

Pierre Baudhuin (FR), Henri Beaufay (BE), and Christian Rene de Duve (GB-BE-US) biochemically identified and purified an enzyme-containing organelle initially known as the microbody (114).

Pierre Baudhuin (FR), Miklós Müller (HU-US), Brian Poole (US), Christian Rene de Duve (GB-BE-US), and James F. Hogg (GB) showed the existence in some non-plant organisms of microbodies (peroxisomes) which, like plant glyoxysomes, contain enzymes of the glyoxylate cycle (115; 1340).

Christian Rene de Duve (GB-BE-US) and Pierre Baudhuin (FR) proposed that the new organelle be called a peroxisome, because it appeared to both generate and break down hydrogen peroxide (431).

Federico Leighton (CL), Brian Poole (US), Henri Beaufay (BE), Pierre Baudhuin (FR), John W. Coffey (US), Stanley Fowler (US), and Christian Rene de Duve (GB-BE-US) described the first large-scale preparation of peroxisomes (1119).

Sue Ellen Frederick (US), Eldon H. Newcomb (US), Eugene L. Vigil (US), and William P. Wergin (US) described structural details of plant microbodies in glutaraldehyde-osmium tetroxide-fixed cells, examined their relationship to similar structures reported in the literature, and speculated on their possible functions (638).

Paul B. Lazarow (US) and Christian Rene de Duve (GB-BE-US) discovered that peroxisomes (microbodies) can carry out fatty acid oxidation (1103).

 

Olga von H. Owens (US), Margaret Lewis Gey (US), and George Otto Gey (US) were the first to adapt a cell line to growth in suspension. The cells were a malignant lymphoblast line from the mouse (1405).

 

Betty Ben Geren (US) discovered that nonneuronal oligodendroglia (Schwann cells) are the source of the protective myelin wrapped around cerebral axons. She and Francis Otto Schmitt (US) presented the significance of the Schwann cell in the structure and function of peripheral nerve (678; 1648).

 

Loren C. Bryner (US), Jay V. Beck (US), Delmar B. Davis (US), Dean G. Wilson (US) and Ralph Anderson (US) recognized for the first time that there is a relationship between the presence of bacteria and the dissolution of metals in copper-leaching mining operations (232; 250; 251).

 

Ichiji Tasaki (US), Susumu Hagiwara (JP-US), and Akira Watanabe (JP) were the first to record action potentials from within Mauthner’s neuron in fish (catfish) (1818).

 

Helen K. Waltz (US), William W. Tullner (US), Virginia J. Evans (US), Roy Hertz (US), and Wilton R. Earle (US) demonstrated that in vitro tumor tissue—unlike in vitro normal tissue—tends to continue to produce its specialized products (1923).

 

Franklin Hollander (US) formally proposed the concept of a two-component, self-regenerating barrier. According to his hypothesis, the gastric mucous barrier is a composite of two integrated structural units. The layer of viscous mucus constituted the first line of defense and the second was the layer of columnar and cuboidal cells of the surface of crypt epithelium (898).

 

Leroy C. Stevens, Jr. (US) and Clarence Cook Little (US) bred a strain of mice (129Sv) with a high incidence of tumors that displayed a large realm of differentiated tissue such as teeth, hairs, muscles or endothelial structures, resembling classical human ovarian teratomas (1782). Note: By transplanting back into the murine peritoneum, G. Barry Pierce, Jr. (US) and Leroy C. Stevens, Jr. (US) obtained fluid ascitic tumors which contained thousands of free-floating structures that strikingly resembled day 5 or 6 mouse embryos, both in term of the appearance of cellular layers and their organization.

Leroy C. Stevens, Jr. (US) tested the developmental capacities of these embryonic structures and compared their morphogenetic potential to that of the embryos themselves. After isolating such embryo-like structures from ascites tumors, he transplanted them singly into the anterior chamber of a mouse eye. In one graft, Stevens noted a particularly well-developed embryo-like object, which had generated structures ‘’unmistakably similar to portions of normal embryo of about 9 days’’, with neuroepithelial cells, amnion, yolk sac epithelium and mesodermal cells (1781). Note: Stevens analyzed and described these granules and called them teratomatous ‘embryoid bodies'. He wrote: ‘..the embryoid bodies derived from the testicular teratomas of strain 129 mice have similarities in embryonic potency as well as in morphology to normal mouse embryos’. Note: This seminal finding opened the route towards using embryonic carcinoma cells, rapidly replaced by embryonic stem cells, to engineer modified mice via blastocyst injection (470).

G. Barry Pierce, Jr. (US), Frank J. Dixon, Jr. (US), and Ethel L. Verney (US) had previously observed the presence, in ascites tumors, of a central core of embryonal carcinoma (EC) cells surrounded by a layer of visceral yolk sac, which they had referred to as ‘granules’ (1464).

 

Ruth Sager (US) found mutations in Chlamydomonas, which behaved, in a non-Mendelian fashion suggesting that they resided within the chloroplasts (1602).

 

Richard Cawthon Starr (US) elucidated the sexuality of desmids and green algae. This was the first time the details of meiosis had been set forth for these groups (1761-1764).

 

Paul Charles Zamecnik (US), Elizabeth B. Keller (US), John W. Littlefield (US), and Jerome Gross (US) discovered that the microsomal (ribosomal) fraction of the cell contains the site of protein synthesis while the nucleus, mitochondria, and other organelles do not. In the process they developed the first cell-free system to carry out protein synthesis (1004; 1005; 1178; 1179; 2028).

Philip Siekevitz (US) and George Emil Palade (RO-US) reached a similar conclusion when they discovered that proteins destined to be secreted by pancreatic cells are synthesized on polyribosomes (polysomes) associated with the rough endoplasmic reticulum then continue from the microsome fraction to reach the pancreatic zymogen granules. They noted that the same sequence held true for individual purified secretory proteins (1688-1690).

Lucien G. Caro (US) and George Emil Palade (RO-US) examined the synthesis, intracellular transport, storage, and discharge of secretory proteins in and from the pancreatic exocrine cell of the guinea pig using light- and electron microscopical autoradiography with DL-leucine-4,5-H (3) as label. The autoradiographic observations show that, at approximately 5 minutes after injection, the label is localized mostly in cell regions occupied by rough surfaced elements of the endoplasmic reticulum; at approximately 20 minutes, it appears in elements of the Golgi complex; and after 1 hour, in zymogen granules. The evidence conclusively shows that the zymogen granules are formed in the Golgi region by a progressive concentration of secretory products within large condensing vacuoles (286).

James D. Jamison (US) and George Emil Palade (RO-US) provided direct evidence that secretory proteins are transported from the cisternae of the rough ER to condensing vacuoles via the small vesicles of the Golgi complex (970; 971).

 

Rollin Douglas Hotchkiss (US) and Julius Marmur (US) discovered that in bacteria the frequency of joint transformation of two gene regions depends on their proximity to one another. It was later discovered by others that the probability of joint transformation of two linked genes is, in fact, an excellent measure of the physical distance between them in the DNA molecule (912).

 

John Robert Raper (US), Carlene Allen Raper (US), Chiu-Sheng Wang (US), John H. Perkins (US), Thomas J. Leonard (US), Yigal Koltin (IL), Giora Simchen (IL), Philip J. Snider (US), Dana H. Boyd (US), Albert H. Ellingboe (US), Stanley Dick (US), Yair Parag (IL), Margery G. Baxter (US), Gladys S. Krongelb (US), James P. San Antonio (US), Philip G. Miles (US), and Richard B. Middleton (US) thoroughly elucidated the genetic mechanisms underlying the sexuality of the small wood-rotting basidiomycete, Schizophyllum commune (481; 554; 555; 1047; 1125; 1458; 1513-1531; 1729; 1730).

 

Norman Ernest Borlaug (US) helped develop disease-resistant, dwarf, wheat varieties, which are adaptable to growing conditions, and exceedingly high-yielding (200; 201). These wheats saved millions of lives by improving wheat production in Mexico in the 1940s and 1950s and later in Asia and Latin America.

William Steen Gaud (US), in 1968, referred to this as the “Green Revolution” (672; 1938).

 

Edmund Schulman (US) reported finding bristlecone pines (Pinus longaeva and Pinus aristata) thousands of years old (1654). He later found the oldest known specimen in this group and nicknamed it Methuselah. Its rings established its age at 4,723 years (1655). By combining ring patterns from living bristlecone pines with those of dead bristlecone tissue the historical record has been pushed back to 7000 BCE

 

Philip Levine (US), ElizabethA. Koch (US), Robert T. McGee (US), and Glen H. Hill (US) identified a low incidence blood antigen. The antibody was found in a mother in Caracas Venezuela, whose baby suffered from hemolytic disease of the newborn, and further investigation showed that the antigen being detected occurred in appreciable frequencies in certain South American Indian populations. The antigen was denoted Di^a, and the gene responsible for it, Di^d, behaved as a Mendelian dominant characteristic (1145).

 

John A. Sheedy (US), Herman F. Froeb (US), Hugh A. Batson (US), Charles C. Conley (US), Joseph P. Murphy (US), Richard B. Hunter (US), David W. Cugell (US), Robert B. Giles (US), Sol C. Bershadsky (US), John W. Vester (US), Robert H. Yoe (US), Carl N. Ekman (US), Joe L. Stockard (US), Robert K. Kiyasu (US), George Entwisie (US), and David P. Earle (US), while working with United Nations soldiers in Korea, described the clinical course, sequential physiologic derangements, and sequelae of epidemic hemorrhagic fever (534; 687; 1678). See Hao Wang Lee, 1978.

 

Zyun Hidaka (JP) reported that a virus causes tobacco stunt disease (847).

 

Robert C. Rend Orff (US) determined that a single cyst of Entamoeba coli is sufficient to establish an infection (1550).

 

Alice Timpe (US) and Ernest H. Runyon (US) classified nontuberculous mycobacteria (NTM) for the first time. Their classification was based on NTM growth rates, morphology, and colony pigmentation (1834).

 

Tando Misao (JP) and Yuzuru Kobayashi (JP) reported Rickettsia sennetsu on the Japanese island of Kyushu as the first documented cause of a disease resembling infectious mononucleosis. The disease was characterized by fever, weakness, anorexia, generalized lymphadenopathy, hepatosplenomegaly, and peripheral blood mononucleosis with atypical lymphocytes. The incubation period was ~14 days, and no fatalities were reported. The causative agent was isolated from patients’ peripheral blood, lymph nodes, and bone marrow and subsequently renamed Ehrlichia sennetsu and most recently Neorickettsia sennetsu (1290).

Human ehrlichioses are emerging tick-borne infections. Human ehrlichiosis describes infections with at least 5 separate obligate intracellular bacteria in 3 genera in the family Anaplasmataceae. These agents and infections (human monocytic ehrlichiosis [HME], caused by Ehrlichia chaffeensis; human granulocytic anaplasmosis [HGA], caused by Anaplasma phagocytophilum; and human ewingii ehrlichiosis, caused by Ehrlichia ewingii) and are causes of most human ehrlichioses.

 

John William Sutton-Pringle (GB) showed that the rapid wing-beats necessary for flight in insects are achieved by alternate sets of muscles, which are alternately stretch activated. This is referred to as the myogenic property of insect flight muscle (1802-1805).

 

David Lambert Lack (GB) amassed considerable evidence relating geographic trends in resource availability and clutch size in birds. He suggested that a species reduces its clutch to maximize the number of young that survive and fledge (1078).

William H. Muir (US), Albert C. Hildebrandt (US) and Albert J. Riker (US) obtained plant cultures from single-cells for the first time. These were obtained by shaking submerged callus cultures (1338).

Ludwig Bergmann (DE) separated single plant cells from cultures by filtration. He transferred the resulting cell suspension onto agar culture dishes. This was the first cloning of plant cells (148).

 

Paul D. Sturkie (GB) published his first edition of Avian Physiology (1797). Note: This work was related mainly to domestic birds and especially poultry, but later editions of the work, now titled Sturkie's Avian Physiology include studies of wild birds. Sturkie's research on the cardiovascular and hemodynamic controls of chickens and egg-laying hens had a notable impact on the poultry industry and breeding practices of farmers.

 

D. Eugene Becker (US), Stanley W. Terrill (US), Duane E. Ullrey (US), and Richard A. Notzold (US) performed extensive feed testing of carbohydrate sources to pigs ranging in age from 1 d to 16 wk. They were fed liquid diets containing casein and various sugars with ad libitum access. Seven pigs, 1 to 10d old, were fed each diet, six fed the sucrose diet died, five fed the fructose diet died, and only one fed the dextrose diet died. Among surviving pigs, those fed dextrose gained weight, whereas those fed sucrose or fructose lost weight. Pigs fed either sucrose or fructose also exhibited severe diarrhea. Of eight pigs 7 to 35 d of age, three of the eight pigs fed sucrose died, whereas mortality was minimal in pigs fed lactose, dextrose, dextrin or cornstarch. Although the surviving pigs fed sucrose gained body weight as effectively as those fed the other carbohydrate sources, the three pigs that died had severe diarrhea. This experiment suggested that at least some pigs by 7 d of age can effectively hydrolyze sucrose in the gut and can also utilize both glucose and fructose for energy. Pigs at 12-wks could effectively utilize sucrose (50% of dry diet), but depressed growth and moderate diarrhea resulted when the semi purified soybean meal diet contained 50% lactose (126-128).

Charles Bailey Mansfield Bailey (CA), Warren Dale Kitts (CA), Alexander J. Wood (CA), and Donald Midgely Walker (GB) found that small intestinal and pancreatic extracts from pigs at various ages showed that intestinal sucrase activity is extremely low in newborn pigs and increases 10-fold at 1 wk, 60-fold at 2 wks and 200-fold at 5 wks of age. Intestinal lactase activity, on the other hand, was high at birth but declined thereafter (88; 1918).

 

Bodil M. Schmidt-Nielsen (DK-US), Roy P. Forester (US), Lawrence Rabinowitz (US), and Bruno Truniger (CH) found evidence for active urea reabsorption somewhere along the distal tubule in the nephron (1640; 1641; 1645).

Taisuke Isozaki (US), Jill W. Verlander (US), and Jeff M. Sands (US) conclusively established that urea is actively reabsorbed in the initial portion of the rat inner medullary collecting duct (950).

 

A. McGehee Harvey (US), Lawrence E. Shulman (US), Philip A. Tumulty (US), C. Lockard Conley (US) and Edyth H. Schoenrich (US) presented clinical and pathological findings in 138 cases of systemic lupus erythematosus (SLE) together with a review of the literature emphasizing that with improved methods of diagnosis a broader concept of the character of this disease was necessary. Important features described were the episodic clinical course of the illness and the development of multiple serum protein abnormalities (790).

 

Norman Ashton (GB), Basil Ward (GB), and Geoffrey Serpell (GB) described an animal model of hypoxia-induced retinal neovascularization, allowing studies of the disease process, specifically the role of oxygen in vessel loss and the role of hypoxia in vessel growth (71).

Norman Ashton (GB) postulated that hypoxia triggers the production of soluble, secreted angiogenic factors (70).

Dorit Shweiki (IL), Ahuva Itin (IL), Dov Soffer (IL), and Eli Keshet (IL) found that hypoxia induces vascular endothelial growth factor (VEGF) release in the eye, leading to angiogenesis. These findings have great clinical relevance and have led directly to current attempts at treating vascular eye disease with VEGF antagonists (1685).

 

H. Brücke (DE) and H. Reis (DE) performed the first clinical trials of the anesthetic drug carbolonium (Imbretil) (246).

 

Harriet Pearson Dustan (US), Robert D. Taylor (US), and Arthur C. Corcoran (US) discussed patients treated with hydralazine who, after prolonged treatment with large doses, manifested a syndrome that, in its milder phase, resembled early rheumatoid arthritis; in its severer febrile aspect, it simulates systemic lupus erythematosis (525).

 

Isadore Lampe (US) and Robert S. MacIntyre (US) revealed the curability of medulloblastomas of the cerebellum by röntgentherapy (454; 1082).

 

Charles Alderson Janeway, Jr. (US), John M. Craig (US), Murray Davidson (US), William Downey (US), David Gitlin (US), and Julia C. Sullivan (US) described a fatal granulomatous disease of childhood that is due to severe quantitative and functional deficiencies of circulating neutrophils (973).

 

David B. Coursin (US) showed that an outbreak of convulsions in young infants in the United States was due to the low pyridoxine content in their diet (377).

 

R. Edgar Hope-Simpson (GB) showed conclusively that Herpes zoster did not come in epidemics and was not more abundant in years with Varicella (chickenpox) epidemics. Furthermore, he found that persons with a history of chickenpox who were at household risk of infection with zoster-varicella were completely cross-protected, whereas, had there been no cross-protection, 60% would have developed zoster-varicella. Hope-Simpson was thus convinced that Varicella and Herpes zoster (shingles) were caused by the same agent (905).

Thomas Huckle Weller (US), Marguerite B. Stoddard (US), Albert Hewett Coons (US), Helen M. Witton (US), and E. John Bell (US) supported Hope-Simpson’s conclusion (1944; 1948; 1949).

R. Edgar Hope-Simpson (GB) developed the latency hypothesis, a revolutionary proposal that Herpes zoster (shingles) is due to the reactivation of a latent Varicella (chickenpox) infection in a sensory ganglion (906). He further hypothesized that viral latency is maintained by immunosurveillance, which is boosted by periodic subclinical reactivations and exposure to exogenous virus, and that reactivation (i.e., HZ) appears when immunosurveillance falls below a critical threshold.

 

John Hans Menkes (US), Peter L. Hurst (US), and John L. Craig (US) described the clinical course of what the authors later termed maple syrup disease, a syndrome involving a rapidly progressive cerebral dysfunction commencing during the first week of life and marked by the excretion of urine having a characteristic ‘maple syrup’ odor (1264).

Dan Y. MacKenzie (GB) and Leonard I. Woolf (GB) reported that maple syrup urinary disease (also called branched-chain ketoaciduria) is an inborn error of the metabolism of valine, leucine, and isoleucine associated with gross mental deficiency (1211).

 

John Holmes Dingle (US), Harold S. Ginsberg (US), George F. Badger (US), William S. Jordan, Jr. (US), Sidney Katz (US), Eli Gold (US) and Alexander D. Langmuir (US) performed outstanding studies which have added significantly to our knowledge and ability to control acute respiratory diseases (484; 485; 690; 691; 979).

 

Harry H.G. Eastcott (GB), George White Pickering (GB) and Charles G. Rob (GB) reported a carotid endarterectomy. Most vascular surgeons consider this the first operation of this type (535).

 

Michael Ellis DeBakey (US) and Denton A. Cooley (US) performed the first successful resection and graft replacement of an aneurysm of the distal aortic arch and upper descending thoracic aorta (440).

 

Henry T. Bahnson (US), in 1953, is credited with the first successful repair of a ruptured aortic aneurysm (87).

 

Bernard Miller, Jr. (US), John Heysham Gibbon, Jr. (US), Victor E. Greco (US), C. Harold Cohn (US), and Frank F. Allbritten, Jr. (US) developed the left ventricular vent thus solving intra-cardiac air embolisms during open cardiotomy (1274).

 

H. Mitchell Perry, Jr. (US) and Henry A. Schroeder (US) reported a syndrome simulating collagen disease caused by hydralazine (Apresoline) (1459). Note: combined oral administration of hexamethonium chloride and hydralazine hydrochloride (called hyphex therapy) in adequate doses effectively controls severe and malignant forms of hypertension.

 

James Olds (US) and Peter Milner (US) described the rewarding effects of stimulating the septal region of the hypothalamus. It became known as the reward center (1395).

 

Mogens Abelin Schou (DK), Niels Juel-Nielsen (DK), Erik Robert Volter Strömgren (DK), Holger Voldy (DK), Geoffrey P. Hartigan (GB) and Poul Christian Baastrup (DK) made observations on small numbers of manic and depressed patients, which suggested that lithium treatment might ameliorate their disorders (85; 784; 1653). A longer-term study with more patients revealed several things. First, the start of long-term lithium treatment is associated with a marked (87 per cent) and long-lasting fall in the frequency of both manic and depressive recurrences. Secondly, the recurrences that do occur usually develop after interruption of the treatment. Thirdly, the prophylactic effect of lithium is equally good in unipolar and bipolar patients. And fourthly, the efficacy of lithium does not disappear with time or after interruption and subsequent resumption of the treatment (86; 1652).

 

Inge Edler (SE) and Carl Hellmuth Hertz (SE) borrowed a shipyard sonar machine made by Siemens used for detecting structural flaws in boat hulls. They are credited with performing the first human echocardiogram, which they termed ultrasound cardiography (UCG). Images were crude, but the posterior left ventricular wall and anterior mitral leaflet were visualized (although the valve was initially thought to be the anterior left atrial wall). This was the first successful imaging of any organ for medical purposes, (541).

Inge Edler (SE) described the use of the ultrasonic cardiogram for mitral valve diseases (540).

Sven Effert (DE) and Erwin Domanig (DE) identified left atrial masses using cardiac ultrasound (546).

 

John Cunningham Lilly (US), during 1953-1954, invented the isolation tank method for exploring consciousness. He found, "Within yourself you do have at least the circuitry to exert control over these systems. You can create a sense of well-being, or you can create a sense of fear out of the operation of your own bio-computer. That's the most important message we have regarding self-meta-programming. I saw that in the tank.

Somewhere, deep within the brain, was a mechanism capable of generating internal experiences completely independent of the outside world, and this settled the issue of what happens in profound physical isolation. The mind does not pass into unconsciousness; the brain does not shut down. Instead, it constructs experience out of stored impressions and memories. The isolated mind becomes highly active and creative” (1167-1170). This work led him to interspecies communication research projects between man and dolphin.

 

Richard M. Fenno (US) considered the requirements for a closed system to sustain humans in space then concluded that further progress could not be made until engineers could produce a sealed cabin that met the requirements outlined in this paper (599).

 

Peter Armitage (GB) and Richard Doll (GB) performed a re-analysis of age-related cancer death rates for adults in England and Wales. They demonstrated a nearly constant linear relationship between log transformed cancer mortality rates and age, thus indicating that the relationship between age and mortality rates was exponential, with a nearly constant power value across various types of cancer. From this, they inferred that cancers resulted from a sequence of independent “stages,” with the rate of occurrence of one or more stages increasing with age (55).

Peter Armitage (GB), William M. Court Brown (GB), Richard Doll (GB), Dieudonne J. Mewissen (GB) reported that radiation carcinogenesis was unequivocally established in human populations and described the nature of the dose-response relationship (54).

 

Lamont C. Cole (US) outlined, as had others before him, noted how population growth is critically affected by even the slightest variation in demographic parameters such as fecundity, survival to reproductive age and age at first reproduction. However, Cole took this several steps further. He noted that evolutionary fitness must be equally strongly affected by such variation, leading on to a discussion, from a theoretical standpoint, of which types of life cycles we should expect to find in nature. He stressed that life history traits should be viewed as putative adaptations to specific environments, and it is in this sense that Cole’s paper marks the start of modern life history theory (351).

 

H. Scott Gordon (CA) wrote a seminal research paper on the tragedy of the commons. This work marked the beginning of modern economics applied to fisheries (709).

Anthony Scott (CA) reminded us that “ ---- the important thing --- is that natural resources are the capital of a region, just as man-made equipment is; and that conservation is investment, just as augmenting the supply of machines is investment.” (1662)

 

Stanley A. Tyler (US) and Elso Sterrenberg Barghoorn (US) reported the discovery of fossil microscopic organisms in an outcropping of mid-precambrian rocks called the Gunflint Iron formation near Lake Superior in Ontario. Most of these fossils resemble present day bacteria and cyanobacteria. This was the first indisputable evidence of Precambrian life (1858).

Barghoorn, Tyler, and Preston Ercelle Cloud, Jr. (US) later confirmed these findings and discussed their significance (97; 330). Note: Other Precambriam fossil sites include: the Fig Tree Group, Africa; the Bulawayan Formation, Africa; the Gunflint Iron Formation, Minnesota/Canada; the Belcher Group, Hudson Bay; Bitter Springs, Australia; and the Ediacaran Sites, Australia.

 

Camille Arambourg (FR) and Robert Hoffstetter (FR) discovered Homo erectus mandibles with teeth at Ternifine, near the village of Palikao, east of Mascara, Oran, Algeria (47; 48). They were dated to c. 600K BP

 

c. 1955

“There's nothing like technical progress! Ideas come and go, but technical progress cannot be taken away.” Alfred Day Hershey, cited in an article by William F. Dove (508).

 

1955

Vincent du Vigneaud (US) was awarded the Nobel Prize in Chemistry for his work on biochemically important sulfur compounds, especially for the first synthesis of a polypeptide hormone.

 

Axel Hugo Theodor Theorell (SE) was awarded the Nobel Prize in Physiology or Medicine for his discoveries concerning the nature and mode of action of oxidation enzymes.

 

Gyula Takátsy (HU) initiated a new era - the era of microtechniques - in microbiology and other fields of natural science. To replace pipettes and test tubes he introduced the idea of using calibrated spiral loops for multiple serial dilution in plastic microwell plates (1813; 1814).

The reliability of this microtechnique led to its adoption as a standard method for serological testing at the Communicable Disease Center (663).

 

Charles J. M. Rondle (GB) and Walter T. J. Morgan (GB) described an updating of the earlier method of Elson and Morgan for the determination of hexosamines by treatment with acetyl acetone followed by addition of Ehrlich’s reagent. Emphasis is placed on the importance of using purified reagents and rigidly controlled conditions. Details are given of the accuracy likely to be obtained in any test or series of tests. Evidence is presented on the stability of the colored substances produced (1572).

 

Pierre Grabar (RU-DE-FR), Curtis A. Williams, Jr. (US) and Jeanine Courcon (FR) originated and named the technique of immunoelectrophoresis (715; 1972-1974).

 

Edward Fred Knipling (US) and Raymond C. Bushland (US) devised a novel pest control technique for the eradication of the screwworm (Cochliomyia hominivorax) in North and Central America, saving ranchers in the South and consumers billions of dollars over the past 70-plus years (266; 1031-1035).

 

Erik Odeblad (SE), Gunnar Lindström (SE), and Baidya Nath Bahr () described the factors leading to image contrast (differences in tissue relaxation time) (1389; 1390).

 Raymond V. Damadian (US), in 1970, discovered that there is a marked difference in relaxation times between normal and abnormal tissues of the same type, as well as between different types of normal tissues. This discovery led Damadian, Lawrence Minkoff (US), Michael Goldsmith (US), and Jason A. Koutcher (US) to adapt nuclear magnetic resonance to the imaging of tissues. Magnetic resonance imaging (MRI), as it came to be called, utilizes the relaxation differences between diseased tissues, such as cancer, and normal tissues. Any other type of imaging cannot exploit these relaxation differences. The exceptional contrast of MRI (10 to 30 times that of x-ray) is responsible for the extraordinary detail of the MRI image. This technique, also called field-focusing nuclear magnetic resonance (FONAR), has produced a revolution in diagnostic medicine (405-407).

Paul Christian Lauterbur (US), in 1972, conceived the theoretical basis for introducing gradients into the magnetic field thereby converting nuclear magnetic resonance information into 2D images. Along with David M. Kramer (US), Jeffrey S. Schneider (US), A. Markus Rudin (CH), and Ching-Ming Lai (US) he perfected the principle of zeugmatography—which adds to conventional NMR a three-dimensional gradient field and is used as a system of landmarks to localize each signal. NMR or magnetic resonance imaging (MRI) today can show the differences between soft tissues, distinguish between fluid in motion and at rest, measure the extent of damage from heart disease and stroke, and visualize normal and diseased tissues in nearly every part of the body (1061; 1079; 1098; 1099).

Peter Mansfield (GB) and Peter K. Grannell (GB) developed the use of gradients in the magnetic field and showed how the signals could be mathematically analyzed, which made it possible to develop a useful 3D imaging technique.

Mansfield found that it is possible to selectively image a two-dimensional slice of an object held in a graded magnetic field by delivering the blast of radio waves at a specific frequency. He developed techniques to manipulate the applied magnetic fields and algorithms to interpret the resulting cacophony of radio signals that enabled images to be pieced together in just a matter of seconds.

Mansfield's work has allowed researchers and clinicians to take snapshots of fast-moving events, such as the beating of the heart. It has also been vital in the development of brain scanning by functional MRI, in which mental activity can be tracked by monitoring changes in blood flow (1219; 1220).

 

Lloyd H. Conover (US) was granted a patent for his discovery of tetracycline (360).

Robert Burns Woodward (US) accomplished the total synthesis of tetracycline (1992).

 

Guy G.F. Newton (GB) and Edward Penley Abraham (GB) isolated, named, and determined the structure of the antibiotic cephalosporin C (7; 1363). This antibiotic is produced by the fungus Cephalosporium.

Giuseppi Brotzu (IT), c. 1945, was the first to use crude culture filtrates from Cephalosporium as a therapeutic agent. Patients with a variety of infections were treated successfully, especially typhoid fever. Brotzu forwarded a culture of Cephalosporium to Newton and Abraham at Oxford University for their study and subsequent great success.

 

Richard L. Potter (US) and Sondra Schlesinger (US) synthesized and characterized the four dNTPs (dTTP, dCTP, dGTP, and dATP) (1484).

 

Helmuth Hilz (DE), Phillips W. Robbins (US), and Fritz Albert Lipmann (DE-US) characterized "active sulfate" as 3'-phosphoadenosyl 5'-phosphosulfate (867; 1565).

 

José Luis Reissig (AR-US), Jack Leonard Strominger (US), and Luis Federico Leloir (AR) described a modification of the method of Aminoff et al. for the estimation of N-acetylamino sugars, which is less time-consuming and affords enhanced sensitivity, more stringent specificity, and less susceptibility to factors which might interfere with color development (1547).

 

Miklos Bodanszky (HU-US), Nina J. Williams (US), Miguel A. Ondetti (AR-US), and Seymour D. Levine (US) synthesized the 27-residue secretin peptide by solution phase stepwise addition methods (195; 196).

 

Leon A. Heppel (US), Paul R. Whitfeld (AU), and Roy Markham (US) announced an in vitro enzymatic method for the synthesis of ribo-oligonucleotides of known base sequence using pancreatic RNAase A and spleen phosphodiesterase (831).

 

Robert H. Daines (US) discovered that the sulfonamides possess a fungicidal quality (402; 403).

Allen R. Kittleson (US) was the first to synthesize these compounds (1023; 1024). The discovery of captan, a potent fungicide, and the related phthaliamides captafol, and folpet would be the outcome of these efforts.

 

Raymond Urgel Lemieux (CA) and George Huber (CA) showed that when a sugar such as N-acetylglucosamine incorporates a carbonium ion at the carbon-1 position, it tends to take up the same conformation that is forced on the N-acetylmuramic acid ring when lysozyme cleaves peptidoglycan. This is believed to represent an example of substrate activation by distortion, an idea long a favorite of enzymologists (1121).

 

Aaron Bunsen Lerner (US) and Teh H. Lee (US) isolated melanocyte-stimulating hormone (MSH) from the porcine anterior pituitary gland (1130). This isolate was later called alpha-melanocyte stimulating hormone (alpha-MSH).

Jerker Olof Porath (SE), Paul Roos (SE), Frank W. Landgrebe (GB), and G.M. Mitchell (GB) isolated melanocyte-stimulating hormone (MSH) from the porcine anterior pituitary gland (1480). This isolate was later called beta-melanocyte-stimulating hormone (beta-MSH).

 

John P. Decker (US) and Marco A. Tió (PR) firmly established that respiration of various plants increased following illumination (444-447). Note: In the 1959a paper Decker and Tió (PR) introduced the term photorespiration.

Hugo P. Kortschak (US), Constance E. Hartt (US), and George O. Burr (US) noted that some compounds other than 3-phosphoglyceric acid (3-PGA) were rapidly labeled during ¹⁴CO₂ assimilation by sugarcane leaves (263; 1059; 1060).

Yuri S. Karpilov (RU) independently reported similar early labeling of malate and aspartate during ¹⁴CO₂ assimilation by maize leaves (995).

Marshall Davidson Hatch (AU), C. Roger Slack (GB), Hilary S. Johnson (AU), and David J. Goodchild (AU) discovered and worked out the metabolic details of the C4 pathway for photosynthetic carbon assimilation (794-797; 1707).

W. John S. Downton (CA) and E. Bruce Tregunna (CA) showed that plants with low CO2 compensation values possess the newly discovered C4 pathway of photosynthesis1 and a unique type of leaf anatomy in which chloroplasts are concentrated around vascular bundles. These correlations permit rapid screening of taxa for photosynthetic pathway (511).

Bruce N. Smith (US) and Samuel Epstein (US) determined ¹³C/¹²C ratios for plant tissue from 104 species representing 60 families. Higher plants fall into two categories, those with low δ_PDBI¹³C values (—24 to —34‰) and those with high δ ¹³C values (—6 to —19‰). Algae have δ ¹³C values of —12 to —23‰. Photosynthetic fractionation leading to such values is discussed (1714).

 

Gabriel L. de la Haba (US), and Irwin Gordon Leder (US), and Efraim Racker (PL-AT-US) isolated and purified yeast transketolase, a key enzyme of the pentose phosphate pathway (433).

 

Arthur Karmen (US), Felix Wroblewski (US), and John S. LaDue (US) found that the serum glutamic oxalacetic transaminase activity in 88 normal humans varied from 0.41 to 1.36 micromoles per ml. per hour. Serum glutamic pyruvic transaminase activity in 39 samples was found to be between 0.21 and 1.01 micromoles per ml. per hour. Both transaminases showed much higher activity in whole blood hemolysates. A survey of transaminase activity in the blood of hospitalized patients revealed departure from the normal range of activity in several disease states, including acute myocardial infarction. Quantitative paper chromatography was the method used to measure enzyme activity (993).

 

Tage Astrup (DK) and Ida Strendorff (DK) isolated plasminogen activator (urokinase) from human urine. This is an enzyme that helps clear the urinary tract of blood clots (73).

 

Bert L. Vallee (CH-US) and Hans Neurath (AT-US) discovered that carboxypeptidase is a zinc metalloenzyme (1868).

 

John Langridge (AU) reported a temperature-sensitive leaky auxotroph in the thiamine pathway of Arabidopsis, a flowering plant. This was the first flowering plant found to contain an auxotroph mutant (1091).

George P. Rédei (HU-US) and S. Legong Li (US) reported auxotrophic mutants in Arabidopsis (1542).

 

Fred H. Mattson (US) and Lloyd W. Beck (US) demonstrated the high specificity of pancreatic lipase for triacylglycerol primary esters (1232).

 

Jarvis Edwin Seegmiller (US), Leonard Laster (US), and DeWitt Stetten, Jr. (US) investi- gated the involvement of 4-amino-5-imidazolecarboxamide in the biosynthesis of uric acid in humans. They found that approximately 20% of the 4-amino-5-imidazolecarboxamide is excreted unchanged, into the urine in the first 8 h. Between 20 and 23% was recovered in uric acid excreted in the 2–3 weeks following ingestion of the labeled compound, indicating the existence of a mechanism that converted 4-amino-5-imidazolecarboxamide to uric acid. Laster and Seegmiller then ingested unlabeled 4-amino-5-imidazolecarboxamide along with [15N]-glycine and showed that 4-amino-5-imidazolecarboxamide administration interferes with the synthesis of uric acid from glycine (1667).

 

Kenneth D. Gibson (US), Albert Neuberger (DE-GB), J.J. Scott (US), David Shemin (US), Rudi Schmid (CH-US), and William Graeme Laver (AU) showed that labeled delta-aminolevulinic acid is an excellent precursor of protoporphyrin. This led to a quick understanding of the biosynthetic pathway to all the porphyrins (683; 684; 1637).

 

Robert F. Schilling (US) invented a test of vitamin B-12 absorption, which plays a key role in nuclear hematology (1636).

 

George Emil Palade (RO-US) noted a particulate component of the cytoplasm. He confirmed its presence using two different fixatives, and described its abundance in embryonic, rapidly proliferating, and glandular cells. Thus, were born the particles of Palade, later known as ribosomes (1406). Palade saw that the particles were both on the endoplasmic reticulum (ER) and free in the cytoplasm.

Sanford L. Palay (US) and George Emil Palade (RO-US) found that the so-called Nissl bodies in neurons were none other than clumps of rough ER, which were distinct but connected to sections of “a granular reticulum” or smooth ER. This helped draw a distinction between rough and smooth ER (1411).

George Emil Palade (RO-US) and Philip Siekevitz (US) found that the structures we now call ribosomes are rich in ribonucleic acids. They concluded that Albert Claude's biochemical fraction called microsomes (see, Claude, 1943) were none other than the in vitro version of the endoplasmic reticulum (ER) (1408; 1409).

 

Christian Rene de Duve (GB-BE-US), Berton Charles Pressman (US), Robert Gianetto (CA), Robert Wattiaux (BE), and Francoise Appelmans (BE) proposed the existence of a new group of subcellular organelles with lytic properties, the lysosomes, and hinted at the existence of another subcellular organelle, the future peroxisome (432).

Alex Benjamin Novikoff (UA-US) Henri Beaufay (BE-US) and Christian Rene de Duve (GB-BE-US) discovered lysosomes (1385).

Werner Straus (US) confirmed this discovery (1789).

Christian Rene de Duve (GB-BE-US) developed what became known as analytical fractional centrifugation (428; 430; 1573). This paved the way for many discoveries concerning subcellular particles. See, Schneider, 1948.

Christian Rene de Duve (GB-BE-US) and Pierre Baudhuin (FR) used centrifugation to isolate lysosomes and, later, microbodies which they called peroxisomes because they oxidized cellular organics with the release of hydrogen peroxide (429; 431).

Pierre Baudhuin (FR), Henri Beaufay (BE), and Christian Rene de Duve (GB-BE-US) confirmed the identification of lysosomes as pericanalicular dense bodies and showed that the peroxisomes correspond to the particles known as microbodies (114).

 

Gunther Siegmund Stent (US) and Clarence R. Fuerst (US) found that if phosphorus 32 is incorporated into the DNA of bacteriophage its lethality increases with concentration of the radioactive isotope and decreases with temperature (1775).

 

Leonard T. Skeggs, Jr. (US), Walton H. Marsh (US), Joseph R. Kahn (US), Kenneth L. Lentz (US), Norman P. Shumway (US), and Kenneth R. Woods (US) determined the amino acid sequences and biological relationships of hypertensin (angiotensin) I and II (1124; 1703; 1704).

David F. Elliott (GB) and William Stanley Peart (GB) determined the amino-acid sequence in hypertensin from oxen (556).

 

Howard Walter Florey (AU-GB) isolated the antibiotics cephalosporin P, cephalosporin N (really a penicillin and previously isolated), and cephalosporin C (615).

 

Gilbert M. Shull (US), Joseph L. Sardinas (US), Roger L. Harned (US), Phil Harter Hidy (US), and Eleanore Kropp LaBaw (US) isolated the antibiotic D-cycloserine (oxamycin) from Streptomyces lavendarles, Streptomyces orchidacens and Streptomyces garyphalus (777; 1684).

 

John Vandeputte (US), Jacques L. Wachtel (US), and Eric T. Stiller (US) isolated the antibiotic amphotericin B from Streptomyces nodusus (1881).

 

Herman Hoeksema (US), James L. Johnson (US), and Jack W. Hinman (US) isolated the antibiotic novobiocin from Streptomyces niveus (890).

 

Susan Ross (CA) isolated the antibiotic oleandomycin from Streptomyces antibioticus (1583).

 

Alfred Ammann (US), David Gottlieb (US), Thomas D. Brock (US), Herbert E. Carter (US), and George B. Whitfield (US) isolated the antifungal antibiotic filipin from Streptomyces filipinensis (34).

 

Gunther Siegmund Stent (US) and Max Ludwig Henning Delbrück (DE-US) were the first to hypothesize that DNA replicates by a mechanism Stent called semi-conservative (459; 1151; 1776).

 

Francis Harry Compton Crick (GB) sent a letter to a select group of his fellow scientists calling themselves The RNA Tie Club. Crick himself was a member along with George Gamov (RU-US), the self-appointed president. In this letter we have the earliest record, in print, of the hypothesis that the genetic code is degenerate and that there existed in cells an adaptor molecule, which would seek out an amino acid, react with it, and somehow bring it into the polypeptide being made. Arguably his letter displays the remarkable insight of a man who was, along with Linus Carl Pauling (US) and Jacques Lucien Monod (FR), one of the major architects and premier theorists of the molecular biology revolution. Since it is rare in print, excerpts are included here, “In this note I propose to put on paper some of the ideas which have been under discussion for the last year or so, if only to subject them to the silent scrutiny of cold print. It is convenient to start with some criticisms of Gamov’s paper…as they lead naturally to the further points I wish to make…Another proof…depends on the A chain of two species of insulin. (Frederick Sanger. Personal communication, and in press.) The sequences are identical except that one (sheep) has Gly where the other (bovine) has Ser. The change occurs roughly in the middle of the chain. Both sequences cannot be coded by a Gamov scheme, since changing one pair of bases necessarily alters at least two amino acids, and this cannot be corrected without making further changes in the base sequence…Thus to code both species of insulin A chains is impossible. A third method to disprove Gamov’s scheme, given sufficient data, is to count neighbors. This is particularly useful in a scheme, which does not distinguish between neighbors-on-the-right and neighbors-on-the-left.

Using the data from the two insulin chains and beta-corticotropin one finds 10 amino acids having 8 neighbors or more. Gamov’s scheme (see his table III) allows only 8 amino acids to have more than 7 neighbors. Thus, coding would be impossible…

I have set out these at length, not to flog a dead horse, but to illustrate some of the simplest ways of testing a code. It is surprising how quickly, with a little thought, a scheme can be rejected. It is better to use one’s head for a few minutes than a computing machine for a few days!

The most fundamental objection to Gamov’s scheme is that it does not distinguish between the direction of a sequence; that is, between Thr. Pro. Lys. Ala. and Ala. Lys. Pro. Thr.…There is little doubt that Nature makes the distinction, though it might be claimed that she produces both sequences at random, and that the wrong ones—not being able to fold up—are destroyed. This seems to me unlikely.

This brings us face to face with one of the most puzzling features of the DNA structure—the fact that it is non-polar, due to the dyads at the side; or put another way, that one chain runs up while the other runs down. It is true that this only applies to the backbone, and not to the base sequence, as Delbrück has emphasized to me in correspondence. This may imply that a base sequence read one way makes sense, and read the other way makes nonsense. Another difficulty is that the assumptions made about which diamonds are equivalent are not very plausible… [Gamov’s idea] would not be unreasonable if the amino acid could fit on to the template from either side, into cavities which were in a plane, but the structure certainly doesn’t look like that. The bonds seem mainly to stick out perpendicular to the axis, and the template is really a surface with knobs on, and represents a radically different aspect on its two sides…

What, then are the novel and useful features of Gamov’s ideas? It is obviously not the idea of amino acids, nor the idea of the bases sequence of the nucleic acids carrying the information. To my mind Gamov has introduced three ideas of importance:

(1) In Gamov’s scheme several different base sequences can code for one amino acid…This degeneracy seems to be a new idea, and, as discussed later, we can generalize it.

(2) Gamov boldly assumed that code would be of the overlapping type…Watson and I, thinking mainly about coding by hypothetical RNA structures rather than by DNA, did not seriously consider this type of coding.

(3) Gamov’s scheme is essentially abstract. It originally paid lip service to structural considerations, but the position was soon reached when coding was looked upon as a problem, independent as far as possible of how things might fit together…Such an approach, though at first sight unnecessarily abstract, is important.

Finally, it is obvious to all of us that without our President the whole problem would have been neglected and few of us would have tried to do anything about it.

I want to consider two aspects of the DNA structure. Firstly, its dimensions; secondly its chemical character.

The dimensional side is soon disposed of. In the paracrystalline form of DNA (Structure B) we have one base every 3.4 angstroms in the fiber direction. A fully extended polypeptide chain measured about 3.7 angstroms from one amino acid to the next. Therefore, it is argued that not more than one base pair can, on the average, be matched with an amino acid. If we go up the outside of the helix the position is worse, since the distance per base pair is now greater, perhaps twice as great.

I want to point out that this argument, though powerful, is not completely watertight.

As regards chemical character, I want to consider not only the DNA structure, but also any conceivable form of RNA structure. Now what I find profoundly disturbing is that I cannot conceive of any structure (for either nucleic acid) acting as a direct template for amino acids, or at least as a specific template. In other words, if one considers the physical-chemical nature of the amino acid chains we do not find complimentary features on the nucleic acids. Where are the knobby hydrophobic [water-repelling] surfaces to distinguish valine from leucine and isoleucine? It is true that a Teller scheme, in which the amino acids already condensed act effectively as part of the template, might be a little easier, but a study of known sequences from this point of view is not encouraging.

I don’t think that anybody looking at DNA or RNA would think of them, as templates for amino acids were it not for other, indirect evidence.

What the DNA structure does show (and probably RNA will do the same) is a specific pattern of hydrogen bonds, and very little else. It seems to me, therefore, that we should widen our thinking to embrace this obvious fact. Two schemes suggest themselves. In the first small molecules (phospholipids? ions chelated on guanine?) [He was imagining small structures that might attach.] could condense on the nucleic acid and pad it suitably, and the resulting combination would form the template. I shall not discuss this further here. In the second, each amino acid would combine chemically, at a special enzyme, with a small molecule, which, having a specific hydrogen-bonding surface would combine specifically with the nucleic acid template. This combination would also supply the energy necessary for polymerization. In its simplest form there would be 20 different kinds of adaptor molecule, one for each amino acid, and 20 different enzymes to join the amino acid to their adaptors. Sydney Brenner, with whom I have discussed this idea, calls this the adaptor hypothesis, since each amino acid is fitted with an adaptor to go on to the template.

The usual argument presented against this latter scheme is that no such small molecules have been found, but this objection cannot stand. For suppose, as is probable, that the small adaptor molecules are in short supply. Then consider the experiment in which all amino acids except one, (say leucine) is supplied to an organism, so that protein synthesis stops. Why do not the intermediaries—the (amino acid + adaptor) molecules—accumulate? Simply because there is very little of them, and no more amino acid can combine with these adaptors until the amino acids, to which they are at that moment attached, have been made into proteins, thus releasing the adaptor molecule. Thus, under these conditions free amino acids accumulate, not amino acids-plus-adaptor molecules.

In any case it seems unlikely that totally free amino acids actually go on to the template, because a free energy supply is necessary, especially when one bears in mind the entropy contribution needed to assemble the amino acids in the correct order. Free energy must be supplied to prevent mistakes in sequence being made too frequently.

The adaptor hypothesis implies that the actual set of twenty amino acids found in proteins is due either to a historical accident or to biological selection at an extremely primitive stage. This is not impossible, since once the twenty had been fixed it would be very difficult to make a change without altering every protein in the organism, a change that would almost certainly be lethal. It is perhaps surprising that an occasional virus has not done this, but even there a number of steps would be required…

It is also conceivable that there is more than one adaptor for one amino acid, and the number 20 may be simply an accident (in any case we need a code for end chain, so perhaps 21 would be more reasonable) …

The adaptor hypothesis allows other general types [codes]; for example, depending on the sequence of four base pairs. The insulin A chain data makes this unlikely, but it is difficult to prove rigorously.

I have tacitly dealt with DNA throughout, but the arguments would carry over to some types of RNA structure. If it turns out that DNA, in the double-helix form, does not act directly as the template for protein synthesis, but that RNA does, many more families of codes are of course possible. (Incidentally the protein sequences we use to test our theories—insulin, for example—are probably RNA-made proteins. Perhaps a special class of DNA-made proteins exists, almost always in small quantities (and thus normally overlooked), except perhaps where there are giant chromosomes.)

In particular base pairing may be absent in RNA or take a radically different form…without a structure for RNA one can only guess.

Altogether the position is rather discouraging. Whereas on the one hand the adaptor hypothesis allows one to construct, in theory, codes of bewildering variety, which are very difficult to reject in bulk, the actual sequence data, on the other hand, gives us hardly any hint of regularity, or connectedness, and suggests that all, or almost all sequences may be allowed. In the comparative isolation of Cambridge I must confess that there are times when I have no stomach for decoding” (980).

 

Mahlon Bush Hoagland (US) described how the energy is supplied to form peptide bonds during cellular protein synthesis (876; 878).

 

Severo Ochoa (ES-US-ES), Marianne Grunberg-Manago (FR), and Priscilla J. Ortiz (US) were the first to carry out a cell-free synthesis of RNA. While investigating an aspect of energy metabolism they made the unexpected observation that one of the reactants, adenosine diphosphate (ADP), had been polymerized by cell juices into a chain of adenylates resembling RNA. They discovered that this polymerization is catalyzed by a magnesium ion requiring polynucleotide phosphorylase, which they subsequently purified from Azotobacter vinelandii (739; 740). They quickly prepared additional polynucleotides and discovered that the nature of the product depended on the kind and variety of the nucleotide diphosphates present during the synthesis (741; 1388).

 

Oliver Smithies (GB-US) invented starch gel electrophoresis for high-resolution separation of soluble proteins (1719-1721).

Ulrich E. Loening (GB) demonstrated that gels made from polymerized acrylamide and bisacrylamide ('polyacrylamide gels') had sufficient resolving power to separate high-molecular-weight pieces of RNA (1181).

David C. Schwartz (US) and Charles R. Cantor (US) described a new approach, named 'pulse-field gradient gel electrophoresis,' which used short pulses from perpendicular electrical fields to separate large pieces of DNA. Pulse-field gel electrophoresis has since allowed biologists to undertake massive genotyping studies, as well as molecular epidemiological analyses of pathogens (1659).

 

Dorothy Mary Crowfoot-Hodgkin (GB), Alan W. Johnson (GB), Alexander Robertus Todd (GB), Ray Bonnett (GB), Jennifer Kamper (GB), Maureen MacKay (GB), Jenny Pickworth (GB), Kenneth N. Trueblood (US), John G. White (US), June Lindsey (GB), John H. Robertson (GB), Clara Brink Shoemaker (GB), Ian O. Sutherland (GB), E. Lester Smith (GB), and Richard J. Prosen (US) used computer aided x-ray diffraction analysis to determine the structure of cyanocobalamin (vitamin B12) with full stereochemical and conformational detail (199; 394-397).

 

Mary Ellen Jones (US) Leonard B. Spector (US), and Fritz Albert Lipmann (DE-US) showed that in the ornithine cycle, citrulline is formed by a reaction between ornithine and carbamoyl phosphate (977).

 

Edmond Henri Fischer (US), Edwin Gerhard Krebs (US), Earl Wilbur Sutherland, Jr. (US), Walter D. Wosilait (US), Donald Paul Wolf (US), John D. Scott (US), Jacques G. Demaille (FR), Dean A. Malencik (US), Sonia R. Anderson (US). Michael F. Cicirelli (US), Nicholas K. Tonks (US), Curtis D. Diltz (US), and James E. Weiel (US) discovered reversible protein phosphorylation as a biological regulatory mechanism. They characterized a group of enzymes, called protein kinases that change proteins from their inactive to active form by triggering the chemical bonding of a phosphate group to the protein. This phosphorylation is the underlying switch that starts and stops a variety of cell functions, from breakdown of fats to the generation of chemical energy in response to hormonal and other signals. They determined that adenosine triphosphate (ATP) is typically the donor of the phosphate group (321; 609; 1067; 1217; 1663; 1800; 1986).

 

James Gray (GB) and Geoffrey J. Hancock (GB) explained how spermatozoa are propelled by flagellar bending waves. This paper was a lasting success because it provided an easy-to-understand solution to a complicated hydrodynamic problem, and because it provided a quantitative prediction of the swimming speed that was almost identical to the swimming speed measured in Gray’s accompanying paper on the movement of sea-urchin spermatozoa (719; 720).

 

Niels Kaj Jerne (GB-DK) used the natural selection theory to explain the immune response. He postulated a large set of natural globulins that had been diversified in some random fashion. The function of antigen was to combine with those globulins with which it made a chance fit and then to transport these selected globulins into an antibody-forming cell. The cell would then make identical copies of the globulin presented to it. Although incorrect, this theory pointed the way to the clonal selection theory (974).

Frank Macfarlane Burnet (AU) and David W. Talmage (US) introduced the clonal selection theory of immunity, a modification of Jerne’s theory of antibody production. They independently hypothesized that antibodies sit on the surface of lymphocytes and that each lymphocyte bears only one kind of antibody (260; 261; 1815).

Peter Medawar (GB) said, "Perhaps Burnet's greatest contribution to biology is that he made immunologists rethink the mechanism of the immunological response in terms of the population dynamics of lymphoid cells and to abandon forever a Lamarckian interpretation of the immunological response." (1257)

 

Herbert H. Moorefield (US), and Clyde W. Kearns (US) found that resistance to dichloro-diphenyl-trichloro-ethane (DDT); also named 2,2-di (4-chlorophenyl)-1,1,1-trichloroethane, in insects is due to enzymatic dehydrochlorination (1323).

 

Seymour Benzer (US) brought the new concept of the molecular gene to bear directly on genetic experimentation. Benzer’s point of departure was a finding he made in 1953 that appeared to be of only mild interest to his fellow phage workers at the time: one class of closely linked r mutations of T-even phage, which Hershey had previously termed rII, possess another phenotype in addition to their typical r plaque morphology on agar plates seeded with the ordinary Escherichia coli strain. Phages carrying such rII mutations cannot grow at all on special Escherichia coli strains known collectively as K strains. On K strains the r⁺ wild-type phage, as well as other r mutants that do not belong to the rII class, can grow perfectly well. Benzer realized that this conditionally lethal growth defect of rII mutants could serve as a powerful selective agent for detecting the presence of a very small proportion of rII⁺ phages within a large population of rII mutants. It is known that K strains owe their inability to propagate rII phage mutants to the incorporation of the genome of another phage into their chromosome. That other phage is lambda.

Benzer proceeded with the construction of a fine-structure genetic map of the T4 genome. For this purpose, he crossed members of his rII mutant collection two-by-two and collectively scored for the frequency of rII⁺ wild-type recombinants produced by plating the phage progeny of each cross on plates seeded with an Escherichia coli K strain. In this way he hoped to detect very rare recombinants between adjacent genetic sites, since the limit of resolution of this method would have allowed him to find rII⁺ recombinants in frequency as low as 0.0001%—a frequency so low that, if the nonselective method of simply hunting for r⁺ plaques on ordinary, rII permissive Escherichia coli were employed, 10⁶ progeny r plaques would have to be inspected for every r⁺ recombinant found. Among the first set of 60 mutants, Benzer found some pairs that produced no r⁺ recombinants at all when crossed. He reasoned that such mutants must carry recurrences of a mutation at precisely the same site of the phage genome; they must be exact alleles.

It is assumed that genetic recombination is equally probable at all points of the phage DNA that represents that genome. His genetic map of the rII region showed that genetic recombination is a process that can separate genetic sites represented by contiguous nucleotides on the phage DNA molecule. He found that most genetic recombination (crossing over) occurs within genes rather than between genes (140).

Benzer changed our concept of the gene, by demonstrating that it has a fine structure consisting of a linear array of sub-elements. When Benzer did this work most geneticists thought the gene to be indivisible and to be the smallest unit of recombination, mutation, and function (141).

 

Georges N. Cohen (FR) and Howard V. Rickenberg (DE-GB-AU-US) were the first to describe the beta-galactosidase or lac transport system in Escherichia coli (334).

Peter Dennis Mitchell (GB) postulated that lactose transport occurs in symport (cotransport) with protons and that a proton electrochemical gradient is the immediate driving force for accumulation against a concentration gradient (1293). This is called a symport.

Ian C. West (GB) and Peter Dennis Mitchell (GB) offered proof of Mitchell’s 1963 proposal of a symport (1952).

 

Howard V. Rickenberg (DE-GB-AU-US), Georges N. Cohen (FR), Gérard Buttin (FR) and Jacques Lucien Monod (FR) discovered and named bacterial permeases in Escherichia coli. They realized that the genes for beta-galactosidase (gene z) and permease (gene y) are controlled as a unit by a third gene, which they called I, because it controls inducibility. These were recognized as the membrane enzymes, which control the entry of specific families of molecules into the cell. The genes are simultaneously induced by galactosides (333; 334; 1559).

Irving Zabin (FR), Adam Képès (FR), and Jacques Lucien Monod (FR) added the gene for thiogalactoside transacetylase to the two genes whose expression is governed by the I gene (2026; 2027). The gene for producing this enzyme was later found to be part of the lactose operon.

Arthur Beck Pardee (US) independently discovered bacterial permeases at a slightly later date (1415).

Benno Müller-Hill (DE), Howard V. Rickenberg (DE-GB-AU-US), Kurt Wallenfels (DE), Claude Burstein (FR), Melvin Cohn (FR), Adam Kèpés (FR), and Jacques Lucien Monod (FR) discovered that lactose is metabolized in part by beta-galactosidase to its isomer 1-6-beta-D-galactosido-glucose (allolactose). It is this allolactose, which is the natural inducer of the lac operon (264; 1343).

C. Fred Fox (US) and Eugene P. Kennedy (US) isolated the product of the lacY gene. They changed its name from Lac permease to M (membrane) protein (625; 1012).

Charles Gilvarg (US) demonstrated the existence of specific transport systems for metabolites (named permeases by Monod) (689; 1559).

 

Milislav L. Demerec (Yugoslavian-US) and Zlata Hartman (US) applied the gene mapping strategy based on phage transduction of bacterial genes to genes involved in tryptophan synthesis. They found that the genes are arranged on the bacterial chromosome in the same order as the biochemical steps that they control (460).

 

Armin Dale Kaiser (US), George Streisinger (HU-US), Victor Bruce (US), Robert S. Edgar (US) and Georgette Harrar Denhardt (US), using genetic crosses, determined that the T-even bacteriophages contain only one linkage group (983; 1793).

 

Mary B. Mitchell (US), working with Neurospora, provided the first proof of gene conversion, a process by which DNA sequence information is transferred from one DNA helix (which remains unchanged) to another DNA helix, whose sequence is altered. This conversion is due to inappropriate base mismatch repair during recombination (1291).

 

Henry Bernard Davis Kettlewell (GB) used the interaction of birds with the melanic and mottled forms of the peppered moth (Biston betularia) to investigate whether birds eat cryptic day-resting moths, and whether they do so differentially with respect to morph. They demonstrated that they do both (1017; 1018). This study is one of the most cited examples of evolution being observed in action. The study confirmed a proposal by James William Tutt (GB) that the original, non-melanic form was well camouflaged on the bark of lichen encrusted trees until industrial pollution darkened the trunks of the trees thus favoring the survival of the black form (f. carbonaria) (1856).

 

Britton Chance (US) and Graham R. Williams (US) applied the oxygen electrode and difference spectrophotometry to give evidence for the sites where the reactions of oxidative phosphorylation occur within mitochondria (297).

 

Harry Eagle (US) made the first systematic investigation of the essential nutritional requirements of eukaryotic cells in culture and found that animal cells could propagate in a defined mixture of small molecules supplemented with a small proportion of serum proteins (528-533).

 

Edward L. Pratt (US), Selma E. Snyderman (US), Mung W. Cheung (US), Patricia Norton (US), L. Emmett Holt, Jr. (US), Arild E. Hansen (US), and Theodore C. Panos (US) established the dietary requirement of a normal infant for the amino acid threonine (1486).

 

Rosalind Elsie Franklin (GB) proposed the arrangement of protein subunits in tobacco mosaic virus (TMV) based on x-ray diffraction studies (635).

Francis Harry Compton Crick (GB) and James Dewey Watson (US), assuming a triplet code, deduced that viral protein coats must be composed of many identical protein subunits since the viral nucleic acid in the smaller viruses does not contain enough information to produce a shell to cover all the viral nucleic acid (386; 387).

Donald L.D. Caspar (US) used x-ray diffraction patterns of tomato bushy stunt virus (TBSV) to show a high degree of structural symmetry (292).

Donald L.D. Caspar (US) and Aaron Klug (ZA-GB) put forth principles of icosahedral virus structure (293).

 

Fred L. Schaffer (US) and Carlton E. Schwerdt (US) purified then crystallized MEF-1 poliomyelitis virus particles (1633). This was the first time an animal virus was crystallized.

 

Heinz Ludwig Fraenkel-Conrat (DE-US) and Robley Cook Williams (US) conducted a classic group of experiments, which demonstrated that tobacco mosaic virus could be reconstituted in the test tube from its isolated protein and RNA components. On simple remixing, infectious virus particles are formed that are structurally indistinguishable from the original virus. Therefore, all information necessary for constructing the virus is inherent in its parts, which self-assemble spontaneously in solution (631; 632; 634).

Alfred Gierer (DE) and Gerhard Schramm (DE) independently reached the same conclusion (686).

Heinz Ludwig Fraenkel-Conrat (DE-US), Beatrice Singer (US), and Robley Cook Williams (US) mixed viral coat proteins and RNA from two different viruses prior to infecting tobacco plants (Nicotiana tabacum). They found that the lesions on the tobacco plants are entirely dependent on the source of RNA in the reconstituted virus (633).

 

Rudolfo A. Arribaizaga (AR) reported a new epidemic disease due to an unidentified agent. It was characterized by nephrotoxic, leukopenic and enanthematous hyperthermia. It was most likely Argentine hemorrhagic fever, an endemo-epidemic disease caused by Junín virus (63).

 

Rosalind M. Taylor (US), Herbert S. Hurlbut (US), Telford Hindley Work (US), James R. Kingston (US), and Thomas E. Frothingham (US) discovered Sindbis virus: A newly recognized arthropod transmitted virus (1821).

 

Conrad Gasser (CH), E. Gautier (CH), Annemarie Steck (CH), Rudolf Ernst Siebenmann (CH), and R. Oechslin (CH) were the first to describe hemolytic-uremic syndrome (HUS). They characterized it as a disorder that usually occurs when an infection in the digestive system produces toxic substances that destroy red blood cells, causing kidney injury (670).

 

Oscar D. Ratnoff (US) and Joan E. Colopy (US) discovered the Hageman blood clotting factor (Factor XII), named for John Hageman (GB) (1538; 1539).

 

Joshua Lederberg (US) classified the various bacterial recombination processes as: sexuality, transduction (which includes transformation), lysogeny and lysogenic conversion (1109).

 

Neal B. Groman (US) discovered that the virus-toxin relationship for toxigenic strains of Corynebacterium diphtheriae is an absolute one. That is, strains, which harbor the virus, produce the toxin, and those free of the virus do not produce toxin. Thus, the virulence of the organism is directly dependent upon the presence of the beta phage in its chromosomes (727).

 

Daniel A. Boroff (US) demonstrated that most botulism toxin is released from the bacterial cells by autolysis as the culture ages (202).

 

Theodore Thomas Puck (US) and Philip I. Marcus (US) devised the now standard method for cloning animal cells in vitro. Their new methods allowed cultures to be propagated from single human cells, enabling the kind of detailed genetic studies previously only possible for bacterial cell (1497).

 

Philip L. Townes (US) and Johannes Friedrich Karl Holtfreter (DE-US) proposed that differential cell adhesion might be one of the key elements underlying epithelial morphogenesis. In this classic study, the epidermis and neural tube were isolated from early amphibian embryos and dissociated into single cells, and the two populations of cells were mixed together in explant culture. Over time, the two cell populations sorted out so that the epidermal cells reformed an epidermis with the correct polarity on the outside of the explant, and the neural cells reformed a neural tube with the correct polarity on the inside of the explant (1845).

 

Dennis J. Crisp (GB) studied the effect of water flow on the settlement of barnacle larvae. He addressed a now central issue in marine larval ecology, namely if and how microscopic larvae can actively select final settlement sites on shores and sea beds exposed to water flows more than 100× faster than larval swimming speeds. Crisp focused on the local flow speed at the scale of the settling larva (c. 0.5 mm), rather than the free-stream flow speed away from the seabed. He was perhaps the first to explicitly point out the significance of the velocity gradient of water (the boundary layer), which is always present close to any surface, to aquatic organisms (388).

 

Victor Loosanoff (RU-US), James B. Engle (US), and Charles A. Nomejko (US) accumulated one of the most extensive long-term data sets on fluctuations of marine populations: their classic study of oysters and starfish in Long Island Sound (1187; 1188).

 

Peter S.B. Digby (GB) was able to measure accurately the thoracic temperature of insects as small as houseflies and the variation of temperature across the thorax in slightly larger flies. Temperature excess (the difference between body temperature and ambient air temperature) varied directly with radiation strength. For insects of breadth greater than 0.3-cm. spectral composition of radiation over the normal sunshine range was of negligible importance to the temperature excess. The effect of color on the temperature excess was slight. Temperature excess varied inversely as the square root of the wind speed above speeds of 20-30 cm./sec. and tended to become independent at lower speeds, with the transition between forced and natural convection. The latter condition will be more important close to the ground. Evolution of insects from the type of the Orthoptera to the Diptera and Hymenoptera has been associated with the attainment of greater temperature excess for given body size (482).

 

Libbie Henrietta Hyman (US) treated Deuterostomata, Enterocoela, and enterocoelous coelomates as synonymous and inclusive of the four phyla Chaetognatha, Echinodermata, Hemichordata, and Chordata (939).

 

Artemij Vasilevich Ivanov (RU) created the phylum Pogonophora (beard worms) to contain protostomate worms found mostly in the abyssal depths of the oceans (952; 953). They were originally thought to be deuterostomes.

 

Göran C.H. Bauer (SE), Arvid Carlsson (SE), and Bertil Lindquist (SE) discussed, reviewed, and reevaluated the use of isotopes of calcium, phosphorus, and sodium in studying the metabolism of the skeleton in normal and pathological states in humans and animals (mainly rats). They found that these isotopes are taken up by the skeleton then released again independently of true anabolic and catabolic processes. Besides maintaining the normal architecture of the bones, their resorption process is mainly responsible for the role of the skeleton in the calcium homeostasis of the body (117-119).

 

Grace A. Goldsmith (US), Harold L. Rosenthal (US), Janis Gibbens (US), Walter G. Unglaub (US) performed sxperiments comparing a “corn” versus “wheat” based diet. After several weeks and urinary excretion assessments, findings show that those subjects fed a “corn” based diet developed a niacin deficiency at a much faster rate, most likely due to the low tryptophan content of corn and an inhibitory factor in corn which results in an amino acid imbalance (700).

 

Lillian G. Alonso (US) and Thomas H. Maren (US) examined the effect of food restriction on body composition of hereditary obese mice. In these animals, drastic weight reduction through food restriction, while leading to a normalization of body weight, fails to reduce body fat to proportions comparable to those found in lean control animals of equal weight, and it is regularly accompanied by a loss in body proteins (28).

 

Rex L. Huff (US), David D. Feller (US), Oliver J. Judd (US), and George M. Bogardus (US) measured the cardiac output in man using iodine-131 human serum albumin (923).

 

John W. Saunders, Jr. (US), Mary T. Gasseling (US), Janice E. Errick (US), Eugene Bell (US), Edgar Zwelling (US), Cecelia Reuss (US), M. David Gfeller (US), Jack M. Cairns (US), Richard N. Feinberg (US), Mary A. Repo (US), John F. Fallon (US), Arthur B. Maccabe (US), Jeffrey A. MacCabe (US), Marilyn Pickett (US), Dolores J. McWhinnie (US), and Leo Rubin (US) laid the foundation for our understanding of pattern formation in the vertebrate limb. Their experiments suggested that the apical ectodermal ridge (AER) is not only required for limb outgrowth, but it also provides signals that allow specific structures to form at different proximo–distal levels of the limb axis (131; 132; 576; 577; 587; 593; 594; 669; 1207-1209; 1254; 1593; 1611-1619; 1621-1625).

John W. Saunders, Jr. (US) and Mary T. Gasseling (US) identified a region at the posterior margin of the wing bud—later termed the zone of polarizing activity (ZPA)—which, when transplanted to an anterior position in the wing-bud margin, caused a mirror-image duplication of digits (1620).

Cheryl Tickle (GB), Dennis Summerbell (GB) and Lewis Wolpert (GB) proposed that the zone of polarizing activity (ZPA) releases a diffusible morphogen, establishing a gradient such that the posterior-most digit arises closest to the source of the morphogen, and the more anterior digits emerge at sites with progressively lower morphogen concentrations (1831).

Robert D. Riddle (US), Randy L. Johnson (US), Ed Laufer (US), and Cliff Tabin (US) showed that the zone of polarizing activity (ZPA) signal is Sonic hedgehog and that retinoic acid, which can convert anterior limb bud tissue into tissue with polarizing activity, concomitantly induces Sonic hedgehog expression in the anterior limb bud (1560). Sonic hedgehog is the best-established example of a morphogen that diffuses to form a concentration gradient and has different effects on the cells of the developing embryo depending on its concentration.

Gail R. Martin (US), Philip H. Crossley (US), George Minowada (US), Craig A. MacArthur (US), Jin-Kwan Han (KR), Lee A. Niswander (US), Astrid Vogel (DE), Cheryl Tickle (GB), and Iain Booth (GB) subsequently attributed the signaling activity of the apical ectodermal ridge (AER) to molecules of the fibroblast growth factor (FGF) family (390; 391; 767; 1228; 1371-1373).

 

Gertrude Falk (US) examined the maturation of renal function during postnatal development in rats. She examined several of the basic functions of the kidney in adult and neonatal rats and compared the glomerular filtration rate, rates of excretion of a water load and salt load, and the ability to concentrate urine when deprived of food and water for 24 h. This study set the standard for how to carefully characterize immature renal function and the response of the neonate to environmental stress (585).

 

Felix Wroblewski (US) and John S. LaDue (US) reported their work on the release of glutamic oxaloacetic transaminase (GOT) with liver injury. They measured serum glutamic oxalacetic transaminase (SGOT) activity in 10 patients with jaundice from parenterally transmitted hepatitis and in 5 patients with jaundice without any recognized parenteral risk factors. SGOT levels were elevated in all patients and returned to normal with recovery from the acute illness (2006). Prior to this work liver cell injury or inflammation was often difficult to diagnose.

 

Jerome W. Conn (US) and Lawrence H. Louis (US) noted that patients with periodic severe muscular weakness, intermittent tetany with parathesis, polyuria, polydipsia and hypertension also showed in their blood a retention of sodium, diuresis of potassium, and increased capacity for carbon dioxide. Aldosterone was found in their urine in excess. They named the new disease primary aldosteronism and found tumor of the adrenal cortex (adenoma) to be the cause (356-358). This condition is also called hyperaldosteronism.

 

Richard J. Havel (US), Howard A. Eder (US), and Joseph H. Bragdon (US) described an accurate and efficient method for determination of the composition of the different types of lipoproteins in human blood (800). This article is the origin of the terms: very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).

 

Rudolf Altschul (CA), Abram Hoffer (CA), and J.D. Stephen (CA) discovered the cholesterol-lowering properties of nicotinic acid. At that time, nicotinic acid was the only drug effective in lowering both cholesterol and triglycerides (31).

William B. Kannel (US), Thomas R. Dawber (US), Abraham Kagan (US), Nicholas Revotskie (US), Joseph Stokes, III (US), Gary D. Friedman (US), William E. Glennon (US), Patricia M. McNamara (US), Naphtali Brand (US), John J. Skinner, Jr. (US), William P. Castelli (US), Tavia Gordon (US), and Marthana C. Hjortland (US) examined the risks of developing atherosclerotic disease that are associated with cholesterol. They focused on the four different fractions of lipoproteins that are involved in the transport of cholesterol in the bloodstream. These fractions are defined as very-low-density lipoprotein (VLDL), intermediary-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). They concluded that “a relatively large amount of cholesterol in the low-density lipoprotein fraction is atherogenic, whereas that in the high-density fraction appears protective…. The previous position that virtually all of the lipid information pertaining to coronary heart disease resided in the serum total cholesterol must be accordingly modified” (710; 987-991).

Roy N. Barnett (US), Ann D. Cash (US), and Siegfried P. Junghans (US) obtained human serum cholesterol measurements using 12 different commercially available “kits” and compared them to the Abell-Kendall method. They concluded that only two of the 12 “kits” being marketed at the time of the study were acceptable for clinical use. To ensure precision they evaluated by using replicate determinations and linearity by measuring a series of samples with varying concentrations of the constituent being measured (104).

Osmo Turpeinen (FI), Matti Miettinen (FI), Matti J. Karvonen (FI), Paavo Roine (FI), Maija Pekkarinen (FI), E. J. Lehtosuo (FI), and Paavali Alivirta (FI) performed an intervention trial in two mental hospitals to test the hypothesis that the incidence of coronary heart disease could be reduced by dietary means. Practically total replacement of dairy fats by vegetable oils resulted in a substantial reduction of this disease (1855).

Matti Miettinen (FI), Matti J. Karvonen (FI), Osmo Turpeinen (FI), Reino Elosuo (FI), and Erkki Paavilainen (FI) showed in men, that the use of the cholesterol-lowering diet was associated with considerably and significantly reduced mortality from coronary heart disease. Total mortality was also consistently lower on this diet, although the differences were too small for statistical significance (1272).

William T. Friedewald (US), Robert I. Levy (US), and Donald S. Frederickson (US) pioneered a very popular method for estimation of the concentration of LDL-cholesterol (LDL-C) in both clinical and research laboratories (648).

Michael Stuart Brown (US) and Joseph Leonard Goldstein (US) worked out the steps involved in the uptake of cholesterol, in the form of low-density lipoprotein (LDL), in blood plasma by the cells of the body. The LDL particles bind to their receptors and are then internalized by endocytosis. An endocytotic vesicle forms which subsequently fuses with a lysosome where the lipoprotein is degraded. The receptors return to the cell membrane. They discovered that the gene mutated in familial hypercholesterolaemia is the gene for low-density lipoprotein-receptors (LDL-receptors). Individuals with inherited high cholesterol levels were found to have either low levels or deficient forms of the low-density lipoprotein receptor (LDL-receptor) involved in the removal of cholesterol from the blood (238; 240; 241; 701-703). Note: This discovery led to the development of new drugs that lower blood cholesterol levels and reduce the risk of heart disease.

Osmo Turpeinen (FI), Matti J. Karvonen (FI), Maija Pekkarinen (FI), Matti Miettinen (FI), Reino Elosuo (FI), and Erkki Paavilainen (FI) concluded that the use of the serum-cholesterol-lowering diet exerted a substantial preventive effect on coronary heart disease (1854).

Luis F. Soria (US), Erwin H. Ludwig (US), Howard R.G. Clarke (US), Gloria L. Vega (US), Scott M. Grundy (US), and Brian J. McCarty (US) discovered a familial form of autosomal dominant hypercholesterolemia defective at apoB-100 caused by mutations in the apoB gene (1744).

Charles C. Allain (US), Lucy S. Poon (US), Cicely S.G. Chan (US), W. Richmond (US), and Paul C. Fu (US) developed an automated method for total serum cholesterol using three enzymes: cholesteryl ester hydrolase was used for hydrolysis of cholesteryl esters, cholesterol oxidase for oxidation of cholesterol to form hydrogen peroxide, and peroxidase for oxidative coupling to develop color with 4-aminoantipyrine and phenol (21).

Michael S. Brown (US) and Joseph L. Goldstein (US) demonstrated a defect in binding of low-density lipoproteins to cells from subjects with the homozygous form of familial hypercholesterolemia. This finding appears to explain the previously reported failure of lipoproteins to suppress the synthesis of 3-hydroxy-3-methylglutaryl coenzyme a reductase and hence may account for the overproduction of cholesterol that occurs in these cultured cells (239).

George J. Miller (GB) and Norman E. Miller (GB) discovered the relationship between coronary heart disease and plasma levels of high-density lipoprotein. The body cholesterol pool increases with decreasing plasma-high-density-lipoprotein (HDL) but is unrelated to the plasma concentrations of total cholesterol and other lipoproteins. They proposed that a reduction of plasma-HDL concentration might accelerate the development of atherosclerosis, and hence ischemic heart disease by impairing the clearance of cholesterol from the arterial wall (1278).

Ray H. Rosenman (US), Richard J. Brand (US), C. David Jenkins (US), Meyer Friedman (US), Reuben Straus (US), and Moses Wurm (US) issued the Coronary heart disease in Western Collaborative Group Study (CHD). It occurred in 257 subjects during eight to nine years of follow-up (average, 8 1/2 years) in a prospective study of 39- to 59-year-old employed men. Incidence of CHD was significantly associated with parental CHD history, reported diabetes, schooling, smoking habits, overt behavior pattern, blood pressure, and serum levels of cholesterol, triglyceride, and β-lipoproteins. The type A behavior pattern was strongly related to the CHD incidence, and this association could not be explained by association of behavior pattern with any single predictive risk factor or with any combination of them (1579).

George G. Rhoads (US), Christian L. Gulbrandsen (US), and Abraham Kagan (US) compared levels of major lipoproteins between 264 men with and 1,755 men without coronary heart disease (CHD) in a defined population of American Japanese men in Hawaii. The inverse relation between high-density lipoprotein (HDL) and disease was as strong as the direct relation for low-density lipoprotein (LDL). The protective effect of HDL could not be explained by other risk factors (1551).

Akira Endo (JP), Masao Kuroda (JP), Yoshio Tsujita (JP), Kazuhiko Tanzawa (JP), Noritoshi Kitano (JP), Akira Yamamoto (JP), and Hiroshi Sudo (JP) became the first to discover a statin (compactin). These are drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), which are important in the pharmacologic management of hypercholesterolemia (564-568; 1852; 2015).

 Isao Kaneko (JP), Yoko Hazama-Shimada (JP), and Akira Endo (JP) found that inhibition by compactin was very specific to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) (986).

Akira Endo (JP) discovered monacolin K (lovastatin), a drug which inhibits the synthesis of cholesterol and lowers cholesterol levels in the blood (564).

Karl August Folkers (US), J. Lan Tucker (US), Richard Willis (US), Li-Jun Xia (CN), Chun-Qu Ye (CN), and Hiroo Tamagawa (JP) found that lovastatin decreases coenzyme Q levels in rats and humans (1978).

Michael J. Dawson (GB), John E. Farthing (GB), Peter S. Marshall (GB), Robert F. Middleton (GB), Melanie J. O’Neill (GB), Alan Shuttleworth (GB), Chari Stylli (GB), Robert Murray Tait (GB), Pam M. Taylor (GB), Howard G. Wildman (GB), Antony D. Buss (GB), David Langley (GB), Michael V. Hayes (GB), Philip J. Sidebottom (GB), Rona M. Highcock (GB), Stephen J. Lane (GB), Panayiotis A. Procopiou (GB), Nigel S. Watson (GB), James D. Bergstrom (GB), Marc M. Kurtz (GB), Deborah J. Rew (GB), Allison M. Amend (GB), John D. Karkas (GB), Richard G. Bostedor (GB), Vinay S. Bansal (GB), Christiana Dufresne (GB), Frank L. Van Middlesworth (GB), Otto D. Hensens (GB), Jerrold M. Liesch (GB), Deborah L. Zink (GB), Kenneth E. Wilson (GB), Janet C. Onishi (GB), James A. Milligan (GB), Gerald F. Bills (GB), Louis Kaplan (GB), Mary Nallin-Omstead (GB), Rosalind G. Jenkins (GB), Leeyuan Huang (GB), Maria S. Meinz (GB), L. Quinn (GB), Richard W. Burg (GB), Yu-Lin Kong (GB), Sagrario Mochales (GB), Marina Mojena (GB), Isabel Martin (GB), Fernando Pelaez (GB), Maria T. Diez (GB), and Albert W. Alberts (GB) announced the discovery of a new class of natural products they found in two different fungi. Each research group gave the family a different name—squalestatins and zaragozic acids respectively (149; 426; 1686).

Allan Baxter (GB), Belinda J. Fitzgerald (GB), Julie L. Hutson (GB), Alun D. McCarthy (GB), Joanne M. Motteram (GB), Barry C. Ross (GB), Meenu Sapra (GB), Michael A. Snowden (GB), Nigel S. Watson (GB), Robert J. Williams (GB), and Carolyn Wright (GB) discovered that zaragozic acid A (squalestatin S1) has a very high affinity for squalene synthase and could lower serum cholesterol levels in the marmoset (120).

Kyriacos Costa Nicolaou (CY-US), Alan Nadin (US), James E. Leresche (US), Susan La Greca (US), Tatsuo Tsuri (US), Eddy W. Yue (US), Zhen Yang (US), Yoshimitsu Naniwa (US), and Francesco De Riccardis (US) carried out the total synthesis of zaragozic acid A, a potent reducer of serum cholesterol (1365-1368).

The Scandinavian Simvastatin Survival Study Group performed a multicenter clinical trial during the 1990s in Scandivavia. The objective of the study was to assess the effect of a cholesterol-lowering drug called simvastatin on mortality and morbidity in a group of 4444 patients with coronary heart disease, aged between 35 and 70 years. The patients presented with moderate hypercholesterolemia between 5.5 and 8.0 mmol/L. The results of the trial showed that simvastatin had a lowering effect on mortality and morbidity of patients suffering from coronary heart disease (738).

Frank Martin Sacks (US), Marc Alan Pfeffer (US), Lemuel A. Moye (US), Jean L. Rouleau (US), John D. Rutherford (US), Thomas G. Cole (US), Lisa Brown (US), J. Wayne Warnica (US), J. Malcolm O. Arnold (US), Chuan-Chuan Wun (US), Barry R. Davis (US), and Eugene Braunwald (US) found that cholesterol-lowering therapy with statins reduces the risk of coronary events and stroke in patients with previous coronary artery disease and low-density lipoprotein levels >125 mg/dL. The reduction in coronary events with statin therapy was greater in women and patients with higher pre-treatment levels of cholesterol (1599).

Andreas Arti (AT), Gunther Marsche (AT), Sophie Lestavel (AT), Wolfgang Sattler (AT), and Ernst Malle (AT) observed that increased HDL cholesteryl ester uptake and reduced cellular cholesterol efflux (acute-phase versus native HDL) suggest that displacement of apolipoprotein A-I by serum amyloid A results in considerable altered metabolic properties of its main physiological carrier. These changes in the apolipoprotein moieties appear (at least in the in vitro system tested) to transform an originally antiatherogenic into a proatherogenic lipoprotein particle (64).

Christine Kim Garcia (US), Kenneth Wilund (US), Marcello Arca (IT), Giovanni Zuliani (IT), Renato Fellin (IT), Mario Maioli (IT), Sebastiano Calandra (IT), Stefano Bertolini (IT), Fausto Cossu (IT), Nick Grishin (US), Robert Barnes (US), Jonathan C. Cohen (US), and Helen H. Hobbs (US) discovered an autosomal recessive form of hypercholesterolemia caused by mutations in the LDL receptor adaptor protein (666).

Gregory G. Schwartz (US), Anders G. Olsson (SE), Michael D. Ezekowitz (US), Peter Ganz (US), Michael F. Oliver (GB), David Waters (US), Andreas Zeiher (DE), Bernard R. Chaitman (US), Sally Leslie (US), and Theresa Stern (US) reported that in patients with recent acute coronary syndrome, atorvastatin 80 mg daily reduced the risk of recurrent ischemia in the following 16 week period. This study did not demonstrate a significant reduction in death, cardiac arrest, or nonfatal acute myocardial infarction with statin therapy, as compared to placebo (1660).

The Medical Research Council/Brtish Heart Foundation Heart Protection Study is much the largest trial in the world of cholesterol-lowering therapy and of antioxidant vitamin supplementation in people at increased risk of heart disease.

Between July 1994 and May 1997, 20,536 individuals were recruited in 69 hospitals from within various prior disease categories (coronary disease, other occlusive arterial disease, diabetes, hypertension) and other categories (women, the elderly, those with average or below average cholesterol levels) where there was uncertainty as to how worthwhile, and safe, are these treatments.

Half of the participants were randomly allocated to receive 40 mg daily simvastatin to lower blood cholesterol levels, and half to receive dummy "placebo" tablets. In addition, within each of these two groups (using a "factorial" design), half were allocated to receive antioxidant vitamins (600 mg E, 250 mg C and 20 mg beta-carotene daily), and half to receive placebo capsules.

Compliance with the study treatments was good, resulting in large average reductions in blood levels of total cholesterol (1.2 mmol/l) and LDL cholesterol (1.0 mmol/l), and large increases in antioxidant vitamin levels. During the scheduled treatment period, there were approximately 4500 major vascular events (which included 2000 coronary events and 1000 strokes) and 3000 deaths (1500 from vascular causes and 1500 from other causes).

Consequently, the MRC/BHF Heart Protection Study provides reliable evidence about the effects of these cholesterol-lowering treatments and antioxidant vitamin supplements on mortality and major morbidity in a wide range of circumstances (735-737).

Marianna Abifadel (FR), Mathilde Varret (FR), Jean-Pierre Rabès (FR), Delphine Allard (FR), Khadija Ouguerram (FR), Martine Devillers (FR), Corinne Cruaud (FR), Suzanne Benjannet (FR), Louise Wickham (FR), Daniele Erlich (FR), Aurelie Derré (FR), Ludovic Villéger (FR), Michel Farnier (FR), Isabel Beucler (FR), Eric Bruckert (FR), Jean Chambaz (FR), Bernard Chanu (FR), Jean-Michel Lecerf (FR), Gerald Luc (FR), Philippe Moulin (FR), Jean Weissenbach (FR), Annick Prat (FR), Michel Krempf (FR), Claudine Junien (FR), Nabil G. Seidah (FR), and Catherine Boileau (FR) identified a familial hypercholesterolemia 3, which is caused by mutations in the proprotein convertase subtilisin/kexin type 9 (PCK9) gene (6).

Christopher P. Cannon (US), Eugene Braunwald (US), Carolyn H. McCabe (US), Daniel J. Rader (US), Jean L. Rouleau (US), Rene Belder (US), Steven V. Joyal (GB), Karen A. Hill (US), Marc A. Pfeffer (US), and Allan M. Skene (US) found that high-dose atorvastatin was associated with a 16% reduction in death or major cardiovascular events compared to standard pravastatin therapy following an acute coronary syndrome. The protective effect of intensive lipid-lowering was evident in the first 30 days of therapy and was consistent across pre-specified subgroups (280).

Jiandie Lin (US), Ruojing Yang (US), Paul T. Tarr (US), Pei-Hsuan Wu (US), Handschin Christoph (US), Siming Li (US), Wenli Yang (US), Liming Pei (US), Marc Uldry (US), Peter Tontonoz (US), Christopher B. Newgard (US), and Bruce M. Spiegelman (US) identified a molecular mechanism in the liver that explains how eating foods rich in saturated fats and trans-fatty acids causes elevated blood levels of "bad" cholesterol and triglycerides, increasing the risk of heart disease and certain cancers (1173).

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators noted that in patients with recent stroke or TIA, high-dose atorvastatin significantly reduces the risk of fatal stroke compared to placebo. Atorvastatin was also associated with a significant reduction in risk of cardiovascular events (943).

Isabelle Aeberli (US), Michael B. Zimmermann (US), Luciano Molinari (US), Roger Lehmann (US), Dagmar l’Allemand (US), Giatgen A. Spinas (US), and Kaspar Berneis (US) reported that in school-age children, greater total and central adiposity are associated with smaller low density lipoprotein particle size and lower high density lipoprotein cholesterol. Overweight children consume more fructose from sweets and sweetened drinks than do normal-weight children, and higher fructose intake predicts smaller low density lipoprotein particle size (11).

Fred A. Kummerow (DE-US) showed that cholesterol is not responsible for heart failure. Excessive oxidation of cholesterol is responsible for the increased synthesis of sphingomyelin in the arterial wall, which increases calcification of the coronary arteries, which inhibits the blood flowing through them. In addition, the presence of oxidized LDL and oxysterols in excessive amounts causes an increase in thromboxane synthesis in the platelets. A deficiency of sphingomyelin and enhancement of thromboxane can lead to heart failure and sudden death (1071). See, Poulletier de la Salle, c.1758.

 

Miguel Layrisse (VE), Túlio Arends (VE), R. Dominguez Sisco (VE), Philip Levine (US) and Elizabeth A. Robinson (US) discovered and characterized the Diego blood group antigen (1102; 1146).

 

Elizabeth Mapelsden Ramsey (US) and Garman H. Daron (US) found: 1) the placenta is an organ well adapted for study of those basic functions of metabolic exchange usually associated with systemic capillary beds alone, 2) that the analogy between the intervillous space of the primate placenta and a systemic capillary has been demonstrated from morphological and physiological standpoints, 3) that the endometrial blood vessels show their protean adaptability to changing functional demands during the menstrual cycle and pregnancy, and 4) that the circulatory mechanics of both the maternal and the fetal placental vasculature and their interaction at the level of the intervillous space were described (1511).

 

George V. Taplin (US), Orsell Meredith, Jr. (US), and Harold Kade (US) devised a radioactive (iodine-131 tagged) rose bengal uptake-excretion test for liver function using external gamma-ray scintillation counting techniques(1817).

Earl K. Dore (US), George V. Taplin (US), and DeLores E. Johnson (US) used radioiodinated hippuran to measure kidney function with scintillation detectors (502).

 

 Sidney C. Truelove (GB) and Leslie J. Witts (GB) showed the value of cortisone treatment in patients with ulcerative colitis (though with a warning that penicillin and sulfonamides should be used to prevent pyogenic complications) (1851).

 

Arthur Clifton Guyton (US), Arthur W. Lindsey (US), and Berwind N. Kaufmann (US) pioneered the use of analog computers and systems analysis to study the circulatory system. They found that venous return acts as a determinant of cardiac output. They also analyzed the various factors that influence venous return, demonstrating mathematically and experimentally in dogs, that venous return is proportional to the mean circulatory filling pressure minus the right atrial pressure, or the "pressure gradient for venous return." They also noted, however, that venous return increased to a greater extent than was predicted to occur as a result of increased mean circulatory filling pressure because of the effect of elevated venous pressure to reduce the impedance to venous return (747).

Arthur Clifton Guyton (US), Thomas G. Coleman (US), and Harris J. Granger (US) presented their computer model of the cardiovascular system. This was the first large-scale computer model that integrated the many factors influencing the peripheral circulation, the heart, the endocrine systems, the autonomic nervous system, the kidneys, and body fluids (746).

 

Richard Fikentscher (DE) and Kurt Semm (DE) presented an insufflation device for diagnostic work on the fallopian tubes (604-606). Note: this device, associated with laporascopy, was later used in a variety of operations.

 

Joseph J. Bunim (US), Maurice M. Pechet (US), and Alfred J. Bollet (US) subjected metacortandralone and metacortandracin, synthetic steroids, to clinical trial. Biological experiments in animals conducted by the investigators who prepared these steroids indicated that the compounds possess three to four times the activity of cortisone or hydrocortisone. The antirheumatic, anti-inflammatory, metabolic, and endocrinologic effects of metacortandralone were studied in seven patients with rheumatoid arthritis. The patients were selected by the following criteria: (1) arthritis of more than two years' duration, (2) unequivocal activity of the disease process, (3) joint changes that were partially or completely reversible, and (4) therapy previously administered that was of conventional type and produced unsatisfactory results (254).

 

Dwight E. Clark (US) highlighted the possibility that irradiation might be an etiological factor in carcinoma of the thyroid in children and adolescents as suggested by Duffy and Fitzgerald, who found that 10 of 28 patients, 18 years of age or younger, seen at the Memorial Hospital had been subjected to irradiation to the thymus gland some time between the 4th and 16th month of life. Simpson, Hempelmann, and Fuller studied the frequency of neoplasms in 1,400 of 1,722 children who had received x-ray therapy to the thymic area between 1926 and 1951 and found that the number of cases of thyroid cancer was markedly higher in the treated group than in either the untreated siblings or the general population (322).

 

Robert D. Langdell (US), Robert H. Wagner (US) and Kenneth M. Brinkhous (US) developed the first effective therapy for hemophilia: intravenous infusions of factor VIII (1088).

 

William M. Lougheed (US), William H. Sweet (US), James Clarke White (US), and William R. Brewster, Jr. (US) were the first to use hypothermia for neuroprotection during surgery (1191).

 

Cristopher S. Welch (US) was the first to transplant a liver. He described transplanting livers into the right paravertebral gutters of immunocompetent mongrel dogs. The allografts atrophied rather quickly, which Welch attributed to rejection (1940).

 

Charles G. Rob (GB-US) and Harry H.G. Eastcott (GB) reported the first successful surgical reconstruction of a tuberculous aortic aneurysm. They used an Orlon cloth graft (1564).

 

Frank Bernard Cockett (GB) extended the bypass graft principle to the aorta. He probably performed the first aortic bypass graft for treatment of aortic thrombosis without removing the aorta in 1955 (90).

 

Michael Ellis DeBakey (US), Denton A. Cooley (US), and Oscar Creech, Jr. (US) performed the first successful resection and graft replacement of an aneurysm of the ascending aorta and the first successful resection of a dissecting aneurysm of the thoracic aorta (442).

 

Denis Graham Melrose (GB), B.B Dreyer (ZA), Hugh H. Bentall (GB), and John B.E. Baker (GB) solved the problem of the heart beating during open-heart surgery. Using potassium citrate and then potassium chloride, they succeeded in stopping the heart safely in anesthetized dogs on a heart-lung machine (1263).

Hans J. Bretschneider (DE) introduced cold cardioplegia. This consists of protecting the asystolic heart during surgery by introducing an iced (4 degrees Celsius) solution of dextrose, potassium chloride, and other ingredients into coronary circulation via specialized cannulae (228).

David J. Hearse (GB), David A. Stewart (GB), and Mark V. Braimbridge (GB), using the isolated hearts of rabbits and rats, established optimum concentrations of potassium chloride to stop the heart, and ways of preserving the heart while starved of blood. This was achieved by bathing the heart in a solution of precise concentration of various salts and reducing the temperature to below 28 degrees C. This cold cardioplegia is used routinely today in open-heart operations (809-811).

Conrad R. Lam (US), Thomas E. Geoghegan (US), and Alfredo Lepore (US) coined the term cardioplegia in describing cardiac arrest via acetylcholine (1081).

 

Henry K. Beecher (US) found that placebos have a high degree of therapeutic effectiveness in treating subjective responses, decided improvement, interpreted under the unknowns technique as a real therapeutic effect, being produced in 35.2 ± 2.2% of cases. This is shown in over 1,000 patients in 15 studies covering a wide variety of areas: wound pain, the pain of angina pectoris, headache, nausea, phenomena related to cough and to drug-induced mood and tension, and the common cold, a wide spread of human ailments where subjective factors enter. The relative constancy of the placebo effect over a fairly wide assortment of subjective responses suggests that a fundamental mechanism in common is operating. The evidence is that placebos are most effective when the stress is greatest. This supports the concept of the reaction phase as an important site of drug action. Placebos have not only remarkable therapeutic power but also toxic effects. These are both subjective and objective. The reaction (psychological) component of suffering has power to produce gross physical change (129).

 

1956

“A child’s world is fresh and new and beautiful, full of wonder and excitement. It is our misfortune that for most of us that clear-eyed vision, that true instinct for what is beautiful and awe-inspiring, is dimmed and even lost before we reach adulthood. If I had influence with the good fairy who is supposed to preside over the christening of all children I would ask that her gift to each child in the world be a sense of wonder so indestructible that it would last throughout life, as an unfailing antidote against the boredom and disenchantments of later years, the sterile preoccupation with things that are artificial, the alienation from the sources of our strength.” Rachel Carson (288; 289).

 

André Frédéric Cournand (FR-US), Werner Theodor Otto Forssmann (DE) and Dickinson Woodruff Richards (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning heart catheterization and pathological changes in the circulatory system.

 

Stellan Hjertén (SE), Östen Levin (SE), and Arne Vilhelm Kaurin Tiselius (SE) introduced column chromatography on hydroxyapatite (874).

 

Philips S. Chen, Jr. (US), Taft Y. Toribara (US), and Huber Warner (US) presented a method for phosphorus determination sufficiently sensitive to dispense with microtechniques and special glassware and apparatus (312).

 

Kenneth Burton (GB) studied and modified the color reaction of Dische (1930) between diphenylamine and deoxyribonucleic acid (DNA). The principal modifications were to add acetaldehyde and to perform the reaction for several hours at 30°C instead of for 3-10 min. at 100°C. Using this modified reaction, the author studied the conditions for the quantitative extraction of DNA from bacteria (265).

 

Meso-2,3-dimercaptosuccinic acid (DMSA), also called succimer, is a sulfhydryl-containing, water-soluble, non-toxic, orally administered metal chelator which has been in use as an antidote to heavy metal toxicity. More recent clinical use and research substantiates this compound’s efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances (1273). Note: DMSA was first synthesized by V. Nirenburg (RU) in the Urals Polytechnic Institute, commissioned by one of the electrical enterprises of Sverdlovsk, which consumed many tons of mercury and was looking for a medicine to prevent poisoning of personnel.

 

Audrey M. Glauert (GB), George Ernest Rogers (AU), and Richard H. Glauert (GB) showed that the epoxy resin Araldite is a highly effective embedding agent for electron microscopy (694; 695).

 

Herbert E. Carter (US), Robert H. McCluer (US), and Edward Doyle Slifer (US) were the first to present evidence for the existence of glycosylated glycerides when they isolated two lipocarbohydrate fractions from wheat flour (290).

 

Peter A. Tavormina (US), Margaret H. Gibbs (US), and Jesse W. Huff (US) discovered that mevalonic acid is incorporated quantitatively into cholesterol in cell-free systems with an accompanying loss of carbon dioxide (1820).

 

Raymond Urgel Lemieux (CA) and George Huber (CA) synthesized sucrose (1122).

 

Edmund C. Kornfeld (US), Eugene J. Fornefeld (US), G. Bruce Kline (US), Marjorie J. Mann (US), Dwight E. Morrison (US), Reuben G. Jones (US), and Robert Burns Woodward (US) synthesized lysergic acid (1056).

 

Linus Carl Pauling (US) and Robert Brainard Corey (US) were the first to emphasize, based on general structural considerations, that three hydrogen bonds likely existed between cytosine and guanine derivatives in DNA (1447).

Henry M. Sobell (US), Ken-Ichi Tomita (JP), and Alexander Rich (US) used co-crystals of cytosine and guanine derivatives to conclusively demonstrate that these derivatives are held together by three hydrogen bonds (1734).

 

Douglas N. Rhodes (GB) and Andrew G.H. Lea (GB) were the first to demonstrate the occurrence of different species of phospholipids (1552; 1553).

 

Horace Albert Barker (US) published a generalized pathway for the formation of methane from acetate, methanol, or carbon dioxide (98).

 

Paul Berg (US) explained how acetyl-CoA is produced from acetate in a two-step reaction: 1) ATP + acetate yields acetyl adenylate + PPi, 2) acetyl adenylate + CoA yields acetyl-CoA + AMP (143; 144).

 

Hans Adolf Krebs (DE-GB) and Hans Leo Kornberg (GB-US) described the glyoxylate cycle. The purpose of this cycle is to enable plants and microorganisms to utilize fatty acids or acetate, in the form of acetyl-CoA, as sole carbon source, particularly for the net biosynthesis of carbohydrate from fatty acids. The glyoxylate cycle bypasses the CO₂-evolving steps of the tricarboxylic acid cycle. Animals lack this shunt across the tricarboxylic acid cycle (1054; 1055).

 

Hans Noll (US), Hubert Bloch (US), Jean Asselineau (FR), and Edgar Lederer (FR) determined that the chemical structure of the cord factor of Mycobacterium tuberculosis is trehalose dimycolate (1378).

 

Anthony San Pietro (US) and Helga M. Lang (US) discovered the ability of isolated chloroplasts to catalyze the light driven accumulation of NADPred (1607).

 

Alexander Rich (US) and David R. Davies (US) discovered that some single stranded RNA molecules can react with one another to form a double helix (1555).

 

Kenneth Burton (GB) developed a colorimetric method for the quantitative determination of deoxyribonucleic acid (DNA). Acidified diphenylamine reacts with DNA producing a dark blue color with a maximum absorbance at 660 nm (265). This method allows laboratories without a UV spectrophotometer to make DNA determinations.

 

Mack H. McCormick (US), W. Max Stark (US), Gail E. Pittenger (US), Robert C. Pittenger (US), and James M. McGuire (US) isolated vancomycin from Streptomyces orientalis (1240).

 

Ernest L. Patterson (US), Harry P. Broquist (US), Alberta M. Albrecht (US), Malcolm H. von Saltza (US), and E.L. Robert Stokstad (US) discovered a new pteridine (ptyeroylglutamic acid) in human urine required for the growth of the trypanosomid flagellate Crithdia fasciculate (1433).

 

David Libermann (FR), Maurice Moyeux (FR), Noël Rist (FR), and Francoise Grumbach (FR) discovered the antibacterial agent ethionamide (ethylthiosonicotinamide) (1164).

 

Vincent C. Barry (IE), Michael L. Conalty (IE), and Ethna E. Gaffney (IE) reported the chemotherapeutic activity of anilinoaposafranines and their derivatives (108). They are most effective as antimycobacterial agents.

 

Hans Joachim Müller-Eberhard (DE-US-DE), and Henry George Kunkel (US) determined that gamma globulin and myeloma proteins contain a carbohydrate moiety (1342).

 

Henry Arnold Lardy (US) and Robert E. Parks, Jr. (US) proposed that ATP at high concentrations inhibits 6-phosphofructokinase activity. This inhibition would stop glycolysis and thereby modulate glycolysis (1092; 1093).

 

Edward C. Heath (US), Jerard Hurwitz (US), and Bernard Leonard Horecker (US) demonstrated that xylulose 5-phosphate is cleaved phosphorolytically to acetyl phosphate and triose phosphate by a thiamine pyrophosphate-dependent enzyme they called phosphoketolase during the bacterial fermentation of pentoses (812).

 

John L. Graves (US), Birgit Vennesland (DE-US), Merton Franklin Utter (US), and R.J. Pennington (GB) determined the mechanism of the reversible carboxylation of phosphoenolpyruvate (718).

 

Lemuel D. Wright (US), Emlen L. Cresson (US), Helen R. Skeggs (US), Gloria D.E. MacRae (US), Carl H. Hoffman (US), Donald E. Wolf (US), and Karl August Folkers (US) discovered and established the chemical structure of mevalonic acid (2005). This led to the identification of mevalonic acid as a source of the pyrophosphate of isopentenol which acts as the metabolic isoprenoid unit used in a series of ATP-dependent reactions to produce squalene.

 

Edna B. Kearney (US) and Thomas P. Singer (US) recovered succinate dehydrogenase from various animal tissues and Proteus vulgaris (1002).

 

Parithychery R. Srinivasan (US), Harold T. Shigeura (US), Milon Sprecher (US), David B. Sprinson (US) and Bernard David Davis (US) demonstrated that three of the carbon atoms of shikimic acid come from phosphoenolpyruvate and the other four from erythrose-4-phosphate (1753).

 

Richard E. Strange (GB), F.A. Dark (GB), and Leonard H. Kent (GB) described N-acetylglucosamine and N-acetylmuramic acid as the two major constituents of the glycan portion of bacterial cell walls (1786; 1787).

 

Carroll Milton Williams (US) is credited with being the first to suggest that juvenile hormone analogs would make good insecticides (1975; 1976).

 

Paul Berg (US), Francis Harry Compton Crick (GB), Mahlon Bush Hoagland (US), Robert William Holley (US), Kikuo Ogata (JP), Paul Charles Zamecnik (US), Hiroyoshi Nohara (JP), Jack P. Preiss (US), Mary Louise Stephenson (US), Jesse Friend Scott (US), Liselotte I. Hecht (US), E. James Offengand (US), Fred H. Bergmann (US), and Marianne Dieckmann (US) obtained experimental evidence to support Crick’s "adaptor theory". Their results suggested that during the synthesis of polypeptides, amino acids (AA) are first activated by ATP to form high energy AA-AMP complexes that are then bonded to low molecular weight RNA molecules (sRNA or tRNA) which escort them to the microsomal (ribosomal) site (142; 145; 147; 384; 814-816; 877; 879; 880; 902; 1392; 1487)

 

Elliot Volkin (US) and Lazarus Astrachan (US) isolated an RNA with unexpected properties, which is produced when bacteria are infected with coliphage. This RNA has a high turnover rate, the ratios of its four bases resembles the phage DNA, not the bacterial, and it is neither microsomal (ribosomal) RNA, nor is it soluble (transfer) RNA (72; 1894-1896). Some years later Sydney Brenner realized that this RNA must be the messenger RNA for protein synthesis.

 

Seymour Stanley Cohen (US) discovered that cytosine is replaced by glucosylated hydroxymethylcytosine in the DNA of T-even bacteriophage (347).

 

Arthur J. Kornberg (US), Israel Robert Lehman (US), Maurice J. Bessman (US), and Ernest S. Simms (US) discovered and purified DNA polymerase I (first polymerase recognized) of Escherichia coli. This enzyme’s activities include polymerization, pyrophosphorolysis, pyrophosphate exchange, and two independent exonucleolytic hydrolyses, one of which degrades in the 3’—5’ direction and the other in the 5’—3’ direction. Remarkably all these activities are contained within one polypeptide chain (162; 1115). Later it was discovered that DNA polymerase I of E. coli plays an essential role in processing the nascent Okazaki fragments produced during the discontinuous replication of the lagging strand at the replication fork to prepare them for ligation. The multisubunit DNA polymerase III holoenzyme is the enzyme that catalyzes the synthesis of the E. coli chromosome.

Maurice J. Bessman (US), Arthur J. Kornberg (US), Israel Robert Lehman (US), and Ernest S. Simms (US) showed that naturally synthesized nucleotides containing cytosine or thymine join through a 5' linkage (162; 1052; 1244).

Arthur J. Kornberg (US) offers a brief history of the discovery of DNA polymerase, written as an introduction to his 1956b paper above (1050; 1051).

 

Harold Edwin Umbarger (US) discovered that high levels of isoleucine inhibit the pathway used to produce isoleucine (1860).

Richard Alan Yates (US) and Arthur Beck Pardee (US) discovered that aspartate transcarbamylase is inhibited by the presence of pyrimidine nucleotides, which are the end products of the pathway containing this enzyme. They observed that when cytosine is plentiful, the enzyme is blocked (2020).

 

Vernon Martin Ingram (DE-GB-US) modified chromatographic techniques developed by Seymour Jonathan Singer (US) to carry out what Ingram called protein fingerprinting to analyze the alpha and beta chains of hemoglobin. He discovered that sickle cell hemoglobin differs from normal hemoglobin in that each beta chain has a single amino acid substitution at position 6: normal hemoglobin has a glutamic acid; sickle cell hemoglobin has a valine. This discovery suggested that mutations might result from a very slight change in hereditary material (941; 942). This was the first concrete evidence that genes specify the amino-acid sequence of proteins.

John A. Hunt (US) and Vernon Martin Ingram (DE-GB-US) found that the mutation in hemoglobin C turned out to be a substitution of a single amino acid at the same position as the hemoglobin S mutation. In the case of hemoglobin C, the change was glutamic acid to lysine, a net change of 2 charge units (928).

 

Donald L.D. Caspar (US) and Rosalind Elsie Franklin (GB) independently established the location of ribonucleic acid within the protein capsid of tobacco mosaic virus (291; 636).

 

Rollin Douglas Hotchkiss (US) discovered that at high DNA concentrations (e.g. 10^-4 mg/ml) DNA transformation plateaus. It has been deduced that the pneumococci have a limited number of DNA receptors, for which all DNA molecules compete (911).

 

Francois Jacob (FR) and Élie L. Wollman (FR) produced the first timed course map of a bacterial chromosome by mechanically shearing mating pairs. They used Escherichia coli Hayes K12 (962-964).

Palmer D. Skaar (US) and Alan Garen (US) performed a very similar mechanical shearing experiment using Escherichia coli (1702).

 

Francois Jacob (FR) and Élie L. Wollman (FR) demonstrated that the transfer of a phage-bearing chromosome (lysogenic state) to a sensitive cell often resulted in the maturation and aggressive growth of the phage resulting in lysis. On the other hand, the introduction of a sensitive chromosome (no integrated virus) into a lysogenic bacterium does not result in this induction (962).

 

Rose Litman (US) and Arthur Beck Pardee (US) discovered that addition of 5-bromouracil to the culture medium of T2-infected bacteria results in the appearance of a very greatly increased proportion of mutants among the phage progeny (1177).

 

Robert Jack Downs (US) and Harry Alfred Borthwick (US) found that, “the photochemical reaction controlling germination and flowering and growth of herbaceous plants also controls onset of dormancy and the elongation of new structures of woody plants” (510).

 

Sterling Brown Hendricks (US), Harry Alfred Borthwick (US), and Robert Jack Downs (US) used data from experiments with pinto beans, lettuce, and Lepidium (peppergrass) to calculate what fraction of the photoperiodic pigment is in the active form at any time and how efficiently each form absorbs and uses radiant energy (824).

 

Anton Lang (RU-US) and James L. Liverman (US) found that gibberellin and indoleacetic acid are capable of inducing flowering in Hyoscymus niger and long-day plants respectively (1086; 1180).

 

Theodore Thomas Puck (US) and Harold W. Fisher (US) selected mutants with altered growth requirements from cultures of HeLa cells. They also demonstrated that, if the molecular environment is carefully controlled, mammalian cell stocks could be cultivated with genetic stability comparable to that of microorganisms (1496).

 

Albert Tyler (US), Alberto Monroy (US), Chi Yueh Kao (US), and Harry Grundfest (US) discovered that polyspermy in starfish is prevented by an electrical change at fertilization—now called fertilization potential (1857).

Laurinda A. Jaffe (US) and Meredith C. Gould (US) reported that electrical polyspermy blocks operate in many animal species, including frogs, clams, and marine worms, but not in the several mammals that have been studied (hamster, rabbit, mouse) (969).

Yasuhiro Iwao (JP) and Laurinda A. Jaffe (US) demonstrated that it is the sperm, which sense the voltage (955).

 

Wesley Kingston Whitten (AU) showed that tubal mouse ova at the eight-cell could be developed consistently to blastulse, when cultured in the egg white–saline mixture used by Hammond for the actual collection of ova (1958).

 

Gaylord R. Hartsough (US), John R. Gorham (US), Dieter Burger (US), Robert W. Leader (US), James B. Henson (US), David D. Porter (US), Frank J. Dixon (US), Austin E. Larsen (US), Bernard M. Wagner (US), and George A. Padgett (US) discovered the Aleutian disease of mink virus (AMDV) and its relationship to immunologically mediated glomerulonephritis and myeloma (712; 788; 789; 828; 1104; 1481). Note: Aleutian disease, also known as mink plasmacytosis, is a disease which causes spontaneous abortion and death in minks and ferrets. It is caused by Carnivore amdoparvovirus 1 (also known as Aleution disease virus, ADV), a highly contagious parvovirus in the genus Amdoparvovirus. In man, microangiopathy similar to that in mink with Aleutian disease was found to have AMDV-specific antibodies and AMDV DNA.

 

Robert Merritt Chanock (US) isolated—from infants with croup—a virus producing sponge-like syncytial areas in monkey kidney tissue culture. He called it CA virus (Croup-Associated Virus) (302). Later the Committee on Viral Nomenclature classified CA virus as parainfluenza virus.

Charles B. Smith (US), Jose G. Canchola (US), and Robert Merritt Chanock (US) demonstrated parainfluenza 1 in tissue culture using the hemadsorption technique (1715).

 

Winston H. Price (US), William Pelon (US), William J. Mogabgab (US), Irving A. Phillips (US), and Willard E. Pierce (US) discovered human rhinoviruses (1454; 1494).

 

Stewart H. Madin (US), Charles J. York (US), and Delbert C. McKercher (US) isolated the infectious bovine rhinotracheitis virus (1213).

 

John A. Morris, Jr. (US), Robert E. Blount (US), Robert E. Savage (US), Robert Merritt Chanock (US), and L. Finberg (US) were the first to isolate the respiratory syncytial virus (the first pneumovirus) (303; 1328). Note: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia in children under 1 year of age in the United States. RSV is a negative-sense, single-stranded RNA virus of the family Paramyxoviridae.

 

Tikvah Alper (GB), and P. Howard-Flanders (GB) showed that bacterial sensitivity to radiation could be modified by the presence or absence of oxygen (29).

 

Theodore Sall (US), Stuart Mudd (US), John C. Davis (US), Akira Yoshida (JP), Masaatsu Koike (JP), and Atsushi Takagi (JP) demonstrated, using the electron microscope, the presence of cellular granules in bacteria. These were later to be called metachromatic granules (1336; 1605; 1606).

 

Eugen Barbu (FR), Ki Yong Lee (FR), R. Wahl (FR), Andrei Nikolaevitch Belozersky (RU), Alexander S. Spirin (RU), Noboru Sueoka (US), Julius Marmur (US), and Paul Mead Doty (US) showed that the base compositions of DNAs varied widely among the different bacterial species—while the RNAs hardly varied at all (96; 133; 1798).

 

Montrose J. Moses (US) identified the synaptonemal complex (1335).

 

Virginia J. Evans (US), Jay C. Bryant (US), Mary C. Fioramonti (US), William T. McQuilkin (US), Katherine K. Sanford (US), Wilton R. Earle (US), and Benton B. Westfall (US) were the first to succeed in growing animal cells in a completely defined medium. The cells were L cells grown in medium NCTC109 (583; 584).

 

Theodore Thomas Puck (US) and Philip I. Marcus (US) produced the first single cell survival curve for eukaryotic cells exposed to X irradiation (1498).

 

Walter H. Cottle (US), Loren Daniel Carlson (US), and Arnold C.L. Hsieh (CN) discovered that one of the ways in which rats adapt to cold by increased heat production is to alter their endocrine secretions, specifically an increase in the level of noradrenaline (norepinephrine) (373; 918).

 

Evelyn M. Witkin (US) presented evidence that bacteria have a mechanism in place to repair damaged DNA. This repair mechanism is affected by such parameters as time, temperature, and protein synthesis (1983).

Miroslav Radman (BE), Evelyn M. Witkin (US), Martine Defais (BE), Perrine Caillet-Fauquet (BE), and Maurice S. Fox (US) first suggested the SOS DNA repair mechanism in bacteria (450; 1505; 1506; 1984; 1985).

 

Peter Henry Andrews Sneath (GB) pioneered the study of bacterial taxonomy using numerical taxonomy techniques (1724-1727).

 

Stephen Wilhelm (US), Edward C. Koch (US), Lee C. Benson (US), James E. Sagen (US), Richard C. Storkan (US) and T. Carpenter (US) discovered that chloropicrin and methyl bromide are excellent soil fumigants to eliminate the parasite causing verticillium wilt of strawberries (1966-1968).

 

Joseph R. Goodman (US), Roger E. Moore (US), and Richard F. Baker (US) showed that phagocytes ingest bacteria by completely enveloping them with the cell membrane of the ingesting cell (707; 708).

 

Ernest Robert Sears (US) produced leaf rust resistance in Triticum aestivum (wheat), a susceptible species, by transferring a chromosome into it from Aegilops umbellulata (goat-grass), a species resistant to the rust (1666).

 

Robert E. Snodgrass (US) produced an excellent book on the anatomy of the honeybee, Apis mellifera Linn (1731).

 

Ari van Tienhoven (NL-US), H. Charles Thomas (US), and Lester J. Dreesen (US) found that a drug (sulfamethazine), which was introduced to treat diseases of poultry (coccidiosis and fowl cholera), was to have the side effect of stimulating comb and testes growth in Leghorn chicks (1880).

 

Charlotte Friend (US) characterized a murine virus, which induces erythroleukemia accompanied by anemia. This virus was named the Friend leukemia virus (FLV) in her honor (651; 652). FLV would later be classified as a retrovirus.

Frank J. Rauscher, Jr. (US) discovered a virus which induced erythrocytopoiesis and leukemia in mice (1541).

Herbert T. Abelson (US) and Louise S. Rabstein (US) discovered what became known as the Abelson murine leukemia virus (3).

 

B.R. Eaton (GB), John A. Morton (GB) Margaret M. Pickles (GB, K.E. White (GB) discovered a new antibody, anti-Yta, characterizing a blood-group antigen of high incidence (536).

 

Curt Paul Richter (US) discovered mineralocorticoid-induced sodium hunger, i.e., the hormone (aldosterone) not only acts to conserve and redistribute sodium in the body, but also to generate the behavior of salt ingestion (1558).

 

Frederic Crosby Bartter (US), Grant W. Liddle (US), Leroy E. Duncan, Jr. (US), Joan K. Barber (US), and Catherine S. Delea (US) reasoned that extracellular fluid volume is a major determinant of aldosterone secretion (110). This deduction ultimately led several groups to the discovery that the aldosterone regulatory influence of extracellular volume is mediated by the renin-angiotensin system.

 

Rosa M Campbell (GB), David P. Cuthbertson (GB), Christine M. Matthews (GB), and Arthur S. McFarlane (AU-GB) reasoned that from the urinary excretion curves of 131-Iodine of separately labelled pure proteins by the rat and from total activities in the extravascular compartment the metabolic breakdown of albumin and γ-globulin occurs in the intravascular compartment, but these proteins are metabolized independently (279).

 

Edmund Brisco Ford (GB) defined polymorphisms as “the occurrence together in the same habitat of two or more (inherited) discontinuous forms of a species, in such proportions, that the rarest of them cannot be maintained merely by recurrent mutation” (623).

 

 

Bodil M. Schmidt-Nielsen (DK-US), Knut Schmidt-Nielsen (DK-US), T. Richard Houpt (US), and Stig Axel Jarnum (DZ) reported that the camel’s adaptations to the desert climate include: highly variable body temperature, an insulating layer of fur, toleration of 24 -36 percent loss of body weight as water loss (man can tolerate 12-18 percent), constant blood volume during dehydration, and large water volume intake without water intoxication (1644; 1647).

 

Joe-Hin Tjio (ES-SE) and Johan Albert Levan (ES-SE) were the first to establish with certainty that the diploid chromosome number of man is 46 (1836).

 

Norman Bier (GB) introduced the plastic contact lens (169).

 

Edward Hamlin, Jr. (US) and Austin L. Vickery, Jr. (US) provided pioneering descriptions of needle biopsy diagnosis, radiation effects, thyroiditis and thyroid tumors. Vickery was a long-standing champion of the core needle biopsy procedure for the diagnosis of thyroid diseases, particularly thyroiditis in children, and a strong advocate of a conservative approach to the therapy of papillary thyroid carcinoma (762).

 

Rosalyn Sussman Yalow (US), Solomon Aaron Berson (US), Arthur Bauman (US), Marcus A. Rothschild (US), and Katharina Newerly (US) while investigating the distribution of insulin in humans, discovered that people develop antibodies to injected animal insulin. To investigate this phenomenon, the researchers undertook to develop a tool for measuring circulating insulin levels. The radioimmunoassay was the result (155-159; 2013; 2014).

Charles N. Hales (GB) and Philip J. Randle (GB) described a radioimmunoassay for insulin employing a solid phase reagent of guinea pig insulin antibody pre-precipitated with rabbit antiguinea pig γ-globulin serum. Sensitisation of the assay by pre-incubation with unknown or standard prior to addition of radiolabelled hormone is described (759).

 

Jack Levin (US) and Frederick Barry Bang (US) discovered that the lysate of amebocytes from the hemolymph of the horseshoe crab, Limulus polyphemus, clots in the presence of liposaccharides in the cell walls of gram-negative bacteria. This discovery led to the development of an in vitro assay for pyrogens contaminating injectable products. This Limulus Amebocyte Lysate (LAL) assay replaced the Rabbit Pyrogen Test (95; 1142-1144).

 

Charles E. Smith (US), Margaret T. Saito (US), and Susan A. Simons (US) established the usefulness of serology in the diagnosis and prognosis of coccidioidomycosis (1716).

 

Gregory Goodwin Pincus (US), Min Chueh Chang (CN-US), Meyer X. Zarrow (US), Elsayed Saad Eldin Hafez (US), and Anne Merrill (US) discovered that 19-norsteroids prevent ovulation in women. This represents the origin of the contraceptive pill (1468).

 

Charles P. Emerson (US), Shu Chu Shen (US), Thomas Hale Ham (US), Eleanor M. Fleming (US) and William Bosworth Castle (US) concluded that the function of the spleen in hereditary spherocytosis may be normal and the inherited defect is limited to the red cells (559).

 

Jean-Louis Beaumont (FR), Jacques P. Caen (FR), Jean Bernard (FR), and Charles E. Blatrix (FR) noted that aspirin, in relatively small doses, results in a prolongation of bleeding time (122; 190).

Harvey J. Weiss (US) and Louis M. Aledort (US) showed that prolongation of bleeding time course by aspirin (3 grams/day for two and one quarter days) is associated with a marked impairment of collagen-induced platelet aggregation (1939).

 

William A. Silverman (US), Dorothy H. Andersen (US), William A. Blanc (US), and Douglas N. Crozier (US) performed a controlled clinical trial to evaluate the relative effectiveness of two prophylactic antibacterial regimens in premature infants. It resulted in an unexpected and inexplicable outcome: kernicterus (and death) occurred significantly more often among infants who received penicillin/ sulfisoxazole (1693).

Gerard B. Odell (US) reported observations demonstrating how the administration of drugs to prevent infection in jaundiced neonates could result in higher mortality and morbidity from bilirubin toxicity because the drugs reduced the albumin’s binding capacity for bilirubin (1391).

 

Herman Moritz Kalckar (DK-US), Elizabeth P. Anderson (US), Kurt J. Isselbacher (US), and Kiyoshi Kurahashi (JP) found that the enzyme defect in the most serious form of galactosemia is in the uridyl transferase (951; 984).

Herman Moritz Kalckar (DK-US), Elizabeth P. Anderson (US), Kiyoshi Kurahashi (JP), and Kurt J. Isselbacher (US) developed a blood test for uridyl transferase, which allowed early detection of severe galactosemia thus preventing the associated severe mental retardation and other developmental defects (38).

 

Patricia V. Johnston (US), Ogden C. Johnson (US), and Fred A. Kummerow (DE-US) reported clear evidence of a link between high intake of trans fats and clogged coronary arteries (976). Note: This report was not only criticized, it was dismissed.

Walter Willett, a professor of epidemiology and nutrition at the T. H. Chan School of Public Health at Harvard, credited Professor Kummerow with inspiring him to include trans fats for analysis as part of Harvard’s highly influential Nurses’ Health Study, the results of which were published in 1993. Not until 2004 did the American Heart Association accept that Kummerow was correct. and not until 2015 did the Food and Drug Administration finally decree trans fats unsafe to eat (462; 751).

 

Clinton Nathan Woolsey (US) and Ann M. Travis (US) showed that after bilateral removal of all neocortex in stages, monkeys could show considerable recovery of motor function and become capable of locomotion if given adequate post-operative physical therapy (1847).

 

George Henry Alexander Clowes, Jr. (US), Amos L. Hopkins (US), and William Evans Neville (US) designed and made a large flat multi-layered ethylcellulose membrane blood oxygenator; used clinically on several patients (331).

 

Thomas Huckle Weller (US), John C. MacAulay (US), John M. Craig (US), Pat Wirth (US), Margaret G. Smith (US), Wallace Prescott Rowe (US), Janet W. Hartley (US), Samuel Waterman (US), Horace C. Turner (US), and Robert Joseph Huebner (US) discovered cytomegalovirus (1589; 1718; 1942; 1947).

Margaret G. Smith (US), Wallace Prescott Rowe (US), Janet W. Hartley (US), Samuel Waterman (US), Horace C. Turner (US), Robert Joseph Huebner (US), Thomas Huckle Weller (US), John C. MacAuley (US), John M. Craig (US), and Pat Wirth (US) isolated human cytomegalovirus (CMV) strains (1589; 1718; 1947). Newborns, or adults with compromised immune systems, are most likely to present with mononucleosis-like symptoms of infection.

Thomas Huckle Weller (US) and James B. Henshaw (US) delineated virologic and clinical features of congenital cytomegalic inclusion disease in 17 infants, diagnosed by isolation of cytomegalovirus from urine or liver biopsy material. Cytomegalovirus is incriminated as a cause of intra-uterine infection, persistent viruria (viruses in the urine), and the most common cause of congenital infective brain damage. They emphasized the great breadth of clinical manifestations induced by cytomegalovirus (CMV), attempting a synthesis of the natural history of CMV-host relationships (1946).

Thomas Huckle Weller (US) emphasized the broad clinical implications of infection produced by cytomegalovirus (1943).

Joseph Louis Melnick (US), Betty L. Petrie (US), Gordon R. Dressman (US), Joyce Burek (US), Charles H. McCollum (US), and Michael Ellis DeBakey (US) reported that evidence of cytomegalovirus (CMV), a common virus infecting a high percentage of people without causing symptoms, was present in the cells comprising the vessel walls of 11 patients with atherosclerosis, or hardening of the arteries. Cytomegalovirus, which causes cells to multiply, often becomes dormant in the body for years after infection. This study suggested that early in life, cytomegalovirus might initiate the lesions that later cause atherosclerosis (1262).

Ervin Adam (US), Joseph Louis Melnick (US), Jeffrey L. Probstfield (US), Betty L. Petrie (US), Joyce Burek (US), Kent R. Bailey (US), Charles H. McCollum (US), and Michael Ellis DeBakey (US) reported that patients with heart disease have higher-than-normal levels of antibodies to cytomegalovirus. The report supported their earlier finding that cytomegalovirus may play a major role in the development of atherosclerosis (9).

 

Warren E.C. Wacker (US), David D. Ulmer (US), and Bert L. Vallee (US) demonstrated that blood levels of metalloenzymes could be used to diagnose myocardial infarction (1906).

 

Vincent Paul Dole (US) developed an efficient method to measure the concentration in plasma of non-esterified fatty acids, those fatty acids bound to protein (498).

 

Alexander Solomon Wiener (US), Lester J. Unger (US), Laura Cohen (US), and Josiane D. Feldman (AT) discovered the blood group I antigen in man (1961).

 

Newton E. Morton (US) detected and estimated the linkage between the genes for elliptocytosis and the Rh blood type in man (1333).

 

B.R. Eaton (GB), J.A. Morton (GB), M.M. Pickles (GB), and K.E. White (GB) found a new antibody, anti-Yta, characterizing a blood-group antigen of high incidence (536).

 

James T. Bradbury (US), Raymond G. Bunge (US), and Rita A. Boccabella (US) reported their success in finding female chromatin in oral smears from Klinefelter’s syndrome “males.” This test improved the diagnosis of Klinefelter’s, especially in teen age patients (215).

 

Vincent P. Collins (US), R. Kenneth Loeffler (US), and Harold Tivey (US) reported that linear exponential growth, determined by measurement of pulmonary metastases and expressed as ‘Doubling Time,’ is a characteristic of the individual cancer, governing the duration before and after diagnosis. The evidence for an age-related ‘Period of Risk’ for childhood tumors is a supporting application (354).

 

Bruce Glick (US), Timothy S. Chang (CN-US), and R. George Jaap (US) discovered that removal of the bursa of Fabricius— named for Giralamo Fabrizi (IT), 1533-1619 —from chickens leads to impaired immune function, i.e., the lack of antibody formation (697). Note: The bursa is a hind-gut lymphoid organ in birds that like the thymus, was also without known function at this time.

Jacques Francis Albert Pierre Miller (FR-AT-AU) demonstrated that the thymus is responsible in some manner for cell-mediated immune responses, such as delayed hypersensitivity and rejection of transplanted tissues. He also found that if the thymus is removed at a sufficiently early stage, a young animal is unable to develop antibody resistance to foreign molecules (1279).

Jacques Francis Albert Pierre Miller (FR-AT-AU) found that neonatal thymectomy in mice leads to severe depletion in the lymphocyte population and severe impairment of the immune response in the mature animal to Salmonella typhi H antigen and to allogeneic and heterospecific skin grafts (1280).

Jacques Francis Albert Pierre Miller (FR-AT-AU), K. Robert McIntire (US) and Stewart S. Sell (US) proposed that the thymus is the source of immunocompetent lymphocytes (1246).

Robert Alan Good (US), Olga K. Archer (US), James C. Pierce (US), Max Dale Cooper (US), Raymond D.A. Peterson (US), Agustin P. Dalmasso (US), Carlos Martinez (US), Ben W. Papermaster (US), Ben R. Burmester (US), T.N. Frederickson (US), H. Graham Purchase (US), Mary Ann South (US), Michael J. Kellum (US), David E.R. Sutherland (US), Ann E. Gabrielsen (US), Jacques Francis Albert Pierre Miller (FR-AT-AU), Christine K. Wennersten (US), Katarina Isakovic (US), Stanley B. Smith (US), and Byron Halsted Waksman (US) discovered that the removal of the thymus gland from neonatal mice, rabbits, and chickens results in a severe reduction in immune response (363; 364; 704-706; 946; 947; 1281; 1461).

Max Dale Cooper (US), Raymond D.A. Peterson (US), and Robert Alan Good (US) definitively showed there are two populations of lymphocytes in the chicken's body: those originating and migrating from the bursa and those originating and migrating from the thymus. Thus, the two major classes of lymphocytes—t lymphocytes, from the thymus, and b lymphocytes, from the bursa—were delineated (363).

Nabih I. Abdou (US) and Nancy L. Abdou (US) found that human bone marrow contains bursal cells and probably very few or no thymus cells (1).

Note: The above findings ushered in the modern era of the study of the cellular basis of the immune response.

 

Frederick P. Moersch (US) and Henry W. Woltman (US) described and named the stiff-man syndrome (1300).

Michele Solimena (IT), Franco Folli (IT), Suzanne Denis-Donini (IT), Giancarlo C. Comi (IT), Guido Pozza (IT), Pietro De Camilli (IT), and Aurelio M. Vicari (IT) presented evidence that stiff-man syndrome is an autoimmune disease (1739).

Fredric Austin Gorin (US), Barbara A. Baldwin (US), Robert C. Tait (US), Rajiv Pathak (US), Masud Seyal (US), and Emiliano Mugnaini (US) determined that stiff-man disease is characterized by autoantibodies that react with cell bodies and axon terminals of gamma-aminobutyric acid (GABAergic) neurons (713). Neurons that output GABA are called GABAergic neurons, and chiefly function as inhibitors at receptors in the adult vertebrate.

 

Edgar Zwillung (US) and Louis A. Hansborough (US) discovered that a typical polydactylous limb develops from the combination of mutant mesoderm and normal ectoderm in chick embryos (2038).

 

Fritz Fuchs (DK) and Povl Riis (DK) were the first to examine amniotic fluid to diagnose genetic disease. They determined fetal sex from cells found in amniotic fluid, based on the presence or absence of the Barr body (656). This may be the first prenatal sex determination.

Henry M. Parrish (US), Frank R. Lock (US), and Mary E. Roundtree (US) reported the lack of congenital malformations in normal human pregnancies after transabdominal amniocentesis (1426).

Mark W. Steele (US), W. Roy Breg, Jr. (US), Cecil B. Jacobson (US), and Robert H. Barter (US) found that chromosomal abnormalities could be detected in the fetus, by karyotyping, without harm to the pregnancy (966; 1767). This initiated the concept that cytological prenatal diagnosis may eventually lead to prenatal treatment. The Jacobson-Barter paper marked the beginning of prenatal genetic diagnostic procedures for detection of fetal chromosomal and enzymatic disorders.

 

Trevor P. Telfer (GB), Kenneth William Ernest Denson (GB), Donald R. Wright (GB), Cecil Hougie (US), Emily M. Barrow (US) and John B. Graham (US) discovered a previously unknown clotting factor, now known as Factor X. This discovery provided the missing link in the blood-clotting cascade, connecting the intrinsic and extrinsic pathways to the final steps in clot formation (466; 913; 1823).

 

Charles M. Plotz (US) and Jacques M. Singer (US) described a latex fixation test for the serologic diagnosis of rheumatoid arthritis which improves on standard tests depending on erythrocyte agglutination by using biologically inert polyvinyl toluene and polysterene latex particles of uniform size (1474).

 

Noel R. Rose (US), Ernest Witebsky (DE-US), Kornel Terplan (US), John R. Paine (US), Richard W. Egan (US), Deborah Doniach (GB), Peter N. Campbell (GB), Rupert Vaughn-Hudson (GB), and Ivan Maurice Roitt (GB) established Hashimoto’s chronic thyroiditis as an autoimmune disease when they discovered its association with thyroglobulin autoantibodies (278; 500; 1570; 1577; 1982). Hakaru Hashimoto (JP) first described this lymphoid goiter or struma in 1912.

 

Björn Sigurdsson (IS) described benign myalgic encephalomyelitis (1691).

 

Miller Fisher (US) described external ophthalmoplegia, ataxia and areflexia due to a vascular cause (Miller Fisher syndrome) (612).

 

Lealdes McKendree Eaton (US) and Edward H. Lambert (US) described a myasthenia-like reaction associated with small-cell carcinoma of the bronchus (Eaton–Lambert syndrome) (537).

 

Jan Gosta Waldenström (SE), Martin J. Brodie (GB), Michael R. Moore (GB), and Abe Goldberg (GB) found that the porphyrias could in all cases be localized to one specific enzyme within the heme biosynthetic pathway (236; 1916). In acute intermittent porphyria, the defect has been shown to lie at the level of porphobilinogen deaminase. In hereditary coproporphyria the defect lies at the level of coproporphyrinogen oxidase, in variegate porphyria at protoporphyrinogen oxidase, and in the exceptionally rare plumboporphyria at ALA dehydratase. The resultant overproduction of coproporphyrinogen and protoporphyrin respectively in these diseases can account for their photocutaneous manifestations.

In the nonacute porphyrias, the expression is both hepatic and erythropoietic. The deficient enzymes are in congenital erythropoietic porphyria, uroporphyrinogen cosynthetase, erythropoietic protoporphyria, ferrochelatase; and PCT, uroporphyrinogen decarboxylase.

 

Hans C. Engell (DK), Erik Kyvsgaard (DK), and Inge H. Rygg (DK) developed a low volume disposable pumpless bubble oxygenator (569). This machine was soon used as a substitute lung for children with cystic fibrosis, respiratory distress syndrome (RDS), and cyanotic heart disease (CHD).

 

Bernice Grafstein (CA-US) reported that propagation of cortical spreading depression (CSD) depends on the liberation of potassium ions from depolarized neurons. She also demonstrated that recovery from spreading depression is an oxidative, energy-dependent process (717). This conclusion is now central to concepts of the way in which acute brain injury evolves, both in experimental models and now increasingly in patients receiving neurocritical cares.

 

Donald Walter Gordon Murray (CA), Walter Roschlau (CA), and William Lougheed (CA) performed the first successful transplant of a human heart valve homograft (1346).

 

Denton A. Cooley (US) and Michael Ellis DeBakey (US) performed the first successful resection and graft replacement of an aneurysm of the ascending aorta (361).

 

Michael Ellis DeBakey (US), Oscar Creech, Jr. (US), and George C. Morris, Jr. (US) were the first to perform a successful resection with graft replacement of an aneurysm of the thoracoabdominal portion of the aorta between the chest and abdomen. This procedure was done with a graft replacement of the arteries leading from the aorta to the liver, spleen, stomach, gastrointestinal tract, and kidneys (443).

 

Michael Boris Shimkin (US), Matthew H. Griswold (US), and Sidney J. Cutler (US) made the case for early diagnosis and treatment of cancer when, from 1935 to 1951, they examined a total of 75,494 cancer cases in the state of Connecticut. The state had 2,000,000 residents in 1950. They found that the five-year survival rate improved due to earlier diagnosis of the cases. The improvement has occurred in cancer that is diagnosed when it is clinically localized and when it involves regional areas, but not when it is disseminated. The most marked improvement is recorded for cancers of the colon and rectum in both sexes, and of the uterine cervix in women (1682).

 

Min Chiu Li (US), Roy Hertz (US), Donald B. Spencer (US), and Delbert M. Bergenstal (US) were the first to cure a solid tumor by chemotherapy. They used the drug methotrexate to treat a patient with choriocarcinoma, a rare cancer of the reproductive tissue that mainly affects women (843; 1161).

 

Denham Harman (US) theorized that aging in man results from damage to macromolecules by free radicals (775).

Harman later came to the conclusion that mitochondria were producing as well as being damaged by free radicals, but that exogenous antioxidants don't enter the mitochondria. And that it is mitochondria that determine lifespan (776).

 

William L. Brown, Jr. (US) and Edward Osborne Wilson (US) described character displacement as the situation in which, when two species of animals overlap geographically, the differences between them are accentuated in the zone of sympatry and weakened or lost entirely in the parts of their ranges outside this zone. The characters involved in this dual divergence-convergence pattern may be morphological, ecological, behavioral, or physiological (242).

 

English country names and code elements taken from the International Organization for Standardization:

DZ = Algerian; US = American; AR = Argentinian; AU = Australian; AT = Austrian; AT/HU = Austro/Hungarian; BA = Bosnian-Herzegovinian; BE = Belgian; BR = Brazilian; GB = British; BG = Bulgarian; CM = Cameroonian; CA = Canadian; TD = Chadian; CL = Chilean; CN = Chinese; CO = Colombian; CR = Costa Rican; HR = Croatian; CU = Cuban; CY = Cypriot; CZ = Czechoslovakian; DK = Danish; DO = Dominican; NL = Dutch; EC = Ecuadorian; EG = Egyptian; EE = Estonian; ET = Ethiopian; FI = Finnish; FR = French; DE = German; GR = Greek; GT = Guatemalan; GU = Guamanian; HN = Honduran; HU = Hungarian; IS = Icelander; IN = Indian; ID = Indonesian; IR = Iranian; IQ = Iraqi; IL = Israeli; IE = Irish; IT = Italian; JP = Japanese; KE = Kenyan; KR = South Korean; KW = Kuwaiti ; LV = Latvian; LB = Lebanese; LT = Lithuanian; LU = Luxembourgian; MK= Macedonian; MG = Malagasy; MT = Maltese; MY = Malaysian; MX = Mexican; NA = Namibian; NZ = New Zealander; NG = Nigerian; NO = Norwegian; PK = Pakistani; PA = Panamanian; PE = Peruvian; PH = Filipino; PL = Polish; PT = Portuguese; PR = Puerto Rican; RO = Romanian; RU = Russian; SV = Salvadoran; SA = Saudi Arabian; SN = Senegalese; CS = Serbian-Montenegrin; SK = Slovakian; ZA = South African; ES = Spanish; LK = Sri Lankan; SR = Surinamian; SE = Swedish; CH = Swiss; SY = Syrian; TW = Taiwanese; TH = Thai; TN = Tunisian; TR = Turkish; UG = Ugandan; UA = Ukrainian; UY = Uruguayan; VE = Venezuelan; ZW = Zimbabwean

 

 

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