A Selected Chronological Bibliography of Biology and Medicine

 

Part 4B

 

1937 — 1947

 

 

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










 

1937

"Now my own suspicion is that the Universe is not only queerer than we suppose, but queerer than we CAN suppose." John Burdon Sanderson Haldane (665).

 

"What does it matter to Science if her passionate servants are rich or poor, happy or unhappy, healthy or ill? She knows that they have been created to seek and to discover, and that they will seek and find until their strength dries up at its source. It is not in a scientist's power to struggle against his vocation: even on his days of disgust or rebellion his steps lead him inevitably back to his laboratory apparatus." Eve Curie Labouisse (FR) in her biography of Madame Curie (907).

 

Clinton Joseph Davisson (US) and George Paget Thomson (GB) were awarded the Nobel Prize in Physics for their experimental discovery of the diffraction of electrons by crystals.

 

Walter Norman Haworth (GB) for his investigations on carbohydrates and vitamin C and Paul Karrer (RU-CH) for his investigations on carotenoids, flavins, and vitamins A and B2 were awarded the Nobel Prize in Chemistry.

 

Albert Imre Szent-Györgyi (HU-US) was awarded the Nobel Prize in Physiology or Medicine for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid.

 

William S. Koffman (US) developed a rapid photoelectric method for the determination of glucose in blood and urine (755).

 

Arthur James Ewins (GB) and Montague Alexander Phillips (GB), in 1937, synthesized sulfapyridine, which was the first sulfonamide used with great success in the treatment of pneumonia (528; 529).

Ralph Campbell Lindsay Batchelor (GB), Robert G. Lees (GB), Marjorie Murrell (GB), and George Ian Hector Braine (GB) discovered that gonorrhea can be successfully treated using sulfapyridine (79).

 

Yasushige Ohmori (JP) reported a method for the determination of alkaline phosphatase in the blood (1154).

 

Tadeus Reichstein (PL-CH) discovered a steroid hormone from the adrenal cortex which he named substance M (cortisol) (1275).

 

Hermann Karl Felix Blaschko (DE-GB), Derek Richter (DE), and Hans Schlossmann (DE) discovered an adrenaline-degrading enzyme, initially called adrenaline oxidase, today monoaminooxidase (132; 133).

 

Esmond Emerson Snell (US), Frank Morgan Strong (US), William Harold Peterson (US), and M. Swaminathan (IN) introduced microbial assays to estimate the concentration of growth factors, including vitamins (1475; 1549).

 

Hans Molisch (DE) coined the word allelopathy to describe both the beneficial and the deleterious chemical interactions of plants and microorganisms (1099). Note: in recent years the term has been used more often to signify a negative impact of one plant on another through their production and release of chemical compounds.

 

Vilém Laufberger (CZ) isolated a crystallizable protein from horse spleen, which contained over 20 per cent by dry weight of iron. He named it ferritine (ferritin) and speculated that it served as a depot for iron in the body (932).

Arthur L. Schade (US) and Leona Caroline (US) identified transferrin as an abundant plasma iron transport protein (1383). Both ferritin and transferrin sequester iron to keep it nonreactive.

M. Edward Kaighn (US), Alfred M. Prince (US), Michael K. Skinner (US), Michael D. Griswold (US), Kathleen R. Zahs (US), Violeta Bigornia (US), and Christian F. Deschepper (US) reported that transferrin is actively secreted by hepatocytes, Sertoli cells of the testes, and distinct cells at the blood/brain barrier (827; 1451; 1757).

Kevin M. Shannon (US), James W. Larrick (US), Samuel A. Fulcher (US), Kathy B. Burck (US), John Pacely (US), Jack C. Davis (US), and David B. Ring (US) determined that transferrin receptor, TFR1, is found on rapidly dividing cells, on activated lymphocytes, and on erythroid precursors. TFR1 binds diferric transferrin to internalize it (1424).

Hiromi Gunshin (US), Bryan Mackenzie (US), Urs V. Berger (US), Yoshimi Gunshin (US), Michael F. Romero (US), Walter F. Boron (US), Stephan Nussberger (US), John L. Gollan (US), and Matthias A. Hediger (US) determined that most iron enters the body by way of the duodenum where it is pumped through enterocytes by a proton-coupled metal-ion transporter (648).

Alexander Krause (DE), Susanne Neitz (DE), Hans-Jürgen Mägert (DE), Axel Schulz (DE), Wolf-Georg Forssmann (DE), Peter Schulz-Knappe (DE), Knut Adermann (DE), Christina H. Park (US), Erika V. Valore (US), Alan J. Waring (US), Thomas Ganz (US), Christelle Pigeon (FR), Gennady Ilyin (FR), Brice Courselaud (FR), Patricia Leroyer (FR), Bruno Turlin (FR), Pierre Brissot (FR), and Olivier Loréal (FR) discovered hepcidin, a peptide hormone produced in the liver, that has primary responsibility for modulating iron availability to meet iron needs (885; 1175; 1210).

Cindy N. Roy (US), David A. Weinstein (US), and Nancy C. Andrews (US) proposed a central role for hepcidin in anemia of chronic disease, linking the inflammatory process with iron recycling and erythropoiesis (1341).

Elizabeta Nemeth (US), Marie S. Tuttle (US), Julie Powelson (US), Michael B. Vaughn (US), Adriana Donovan (US), Diane McVey Ward (US), Tomas Ganz (US), Jerry Kaplan (US), Ivana de Domenico (US), Charles Langelier (US), Wesley L. Sundquist (US), and Giovanni Musci (IT) found that hepcidin binds to cell-surface ferroportin, triggering its tyrosine phosphorylation, internalization, and ubiquitin-mediated degradation in lysosomes. By removing ferroportin from the plasma membrane, hepcidin shuts off cellular iron export. This is particularly important in the intestine, where inactivation of basolateral ferroportin leads to retention of iron in the intestinal epithelium, and in iron-recycling macrophages of the reticuloendothelial system, where inactivation of ferroportin interrupts release of iron recovered from senescent erythrocytes (385; 1136).

George C. Shaw (US), John J. Cope (US), Liangtao Li (US), Kenneth Corson (US), Candace Hersey (US), Gabriele E. Ackermann (US), Babette Gwynn (US), Amy J. Lambert (US), Rebecca A. Wingert (US), David Traver (US), Nikolaus S. Trede (US), Bruce A. Barut (US), Yi Zhou (US), Emmanuel Minet (US), Adriana Donovan (US), Alison Brownie (US), Rena Balzan (MT), Mitchell J. Weiss (US), Luanna L. Peters (US), Jerry Kaplan (US), Leonard I. Zon (US), and Barry H. Paw (US) found that precise regulation of iron transport in mitochondria is essential for heme biosynthesis, hemoglobin production, and Fe-S cluster protein assembly during red cell development. Mitoferrin functions as the principal mitochondrial iron importer essential for heme biosynthesis in vertebrate erythroblasts (1425).

Tomas Ganz (US) found that induction of hepcidin in inflammation and consequent iron sequestration augments innate immune defenses against invading pathogens. The resulting decrease in plasma iron levels eventually limits iron availability to erythropoiesis and contributes to the anemia associated with infection and inflammation (590).

Thomas T. Chen (US), Li Li (US), Dong-Hui Chung (US), Christopher D.C. Allen (US), Suzy V. Torti (US), Frank M. Torti (US), Jason G. Cyster (US), Chih-Ying Chen (US), Frances M. Brodsky (US), Eréne C. Niemi (US), Mary C. Nalamura (US), William E. Seaman (US), and Michael R. Daws (US) reported that ferritin receptors are present on lymphocytes and other cell types but their physiologic function has not been fully defined (287).

 

Alwin Max Pappenheimer, Jr. (US) isolated, crystallized, and characterized diphtheria toxin (1174). This was the first bacterial toxin to be obtained in pure crystalline form.

 

William Charlton (GB), Walter Norman Haworth (GB), Stanley Peat (GB), Edmund Langley Hirst (GB), Frederick A. Isherwood (GB), Fred Smith (GB), William Zev Hazzid (GB), and Israel Lyon Chaikoff (GB-US) settled the basic structural features of the starch, and glycogen molecules (283; 696; 699; 700).

 

Otto Fritz Meyerhof (DE-US) proposed that the splitting of ATP might supply energy to initiate the succession of events in muscular activity (1076).

 

Otto Fritz Meyerhof (DE-US), Walter Schulz (DE), Philipp Schuster (DE), Paul Ohlmeyer (DE-US), and Walter Möhle (DE) found that the oxidation of D-3-phosphoglyceraldehyde to D-3-phosphoglyceric acid requires phosphate, diphosphopyridine nucleotide (DPN), and adenosine diphosphate (ADP). It yields adenosine triphosphate (ATP), and reduced diphosphopyridine nucleotide (DPNH) (1081-1083).

 

Alexander Logie du Toit (ZA) championed continental drift and was the first to realize that the southern continents had at one time formed the super continent Gondwanaland (455).

 

Eugene I. Rabinowitch (US) and Joseph Weiss (US) provided evidence that chlorophyll a can be oxidized by light and ferric compounds (1245).

 

Michael Heidelberger (US), Kai O. Pedersen (SE), and Elvin Abraham Kabat (US) determined the molecular weight of antibodies (706; 822). They were measuring mostly immunoglobulin gamma.

 

Rudolf Schoenheimer (DE-US) and David Rittenberg (US) found that the degradation and synthesis of saturated fatty acids proceeds two carbon atoms at a time and saturated fatty acids can be converted to mono-unsaturated fatty acids and vice versa. When mice were fed fatty acids labeled with deuterium, most of the deuterium was recovered in the fat tissues rather than being immediately utilized, i.e., newly ingested fat is stored whereas older fat is used. When water labeled with deuterium was administered to mice, it was found that 50 percent of the hydrogen atoms of cholesterol were derived from the hydrogen atoms of the water. Body fat is not static, as was previously thought, but rather in a dynamic turnover state even when adequate fat is supplied in the diet (1299; 1395).

Rudolf Schoenheimer (DE-US), David Rittenberg (US), Marvin Fox (US), Albert S. Keston (US), and Sarah Ratner (US) used heavy nitrogen (N15) labeled amino acids to trace the fate of amino nitrogen and found that there was rapid changing and shifting, even though the overall movement might be small. In their words, “It is scarcely possible to reconcile our findings with any theory which requires a distinction between these two types of nitrogen. It has been shown that nitrogenous groupings of tissue proteins are constantly involved in chemical reactions; peptide linkages open, the amino acids liberated mix with others of the same species of whatever source, diet, or tissue. This mixture of amino acid molecules, while in the free state, takes part in a variety of chemical reactions: some re-enter directly into vacant positions left open by the rupture of peptide linkages; others transfer their nitrogen to deaminated molecules to form new amino acids. These in turn continuously enter the same chemical cycles, which render the source of the nitrogen indistinguishable. Some body constituents like glutamic acid and aspartic acid and some proteins like those of the liver, serum, and other organs are more actively involved than others in this general metabolic pool originating from interactions of dietary nitrogen with the relatively larger quantities of reactive tissue nitrogen” (1394; 1396-1398).

This work on fats and proteins led to a biochemical generalization concerning the biochemical constituents of the body: The large, complex macromolecules are constantly involved in rapid chemical reactions with their smaller component units, a continuing and constant process of degradation and resynthesis. This generalization overthrew the prevailing opinion that the dietary constituents are used only for repair and for energetic purposes.

 

Ernest Francois Auguste Fourneau (FR), Jacques Gustave Marie Tréfouël (FR), Frederico Nitti (FR), Daniel Bovet (CH-FR-IT), and Thérèse Tréfouël, née Boyer (FR) discovered the antibacterial activity of diasone (Diamidin), 4-4’ diaminodiphenyl sulfone, dihydrostreptomycin (DDS). It is also called dapsone (565).

Guy Henry Faget (US), Frederick A. Johansen (US), Sister Hilary Ross (US), R.C. Pogge (US), J.F. Dinan (US), Bernard M. Prejean (US), and C.G. Eccles (US) of the National Leprosarium, United States Marine Hospital #66, pioneered sulfone drug therapy. Dr. Faget and his staff demonstrated the efficacy of sulfone drugs, including Promin, Diasone, and Promizole in the treatment of Hansen's disease (leprosy) (531-534).

James A. Doull (US) carried out clinical trials on the efficacy of using diasone (Diamidin), 4-4’ diaminodiphenyl sulfone, and dihydrostreptomycin for the treatment of leprosy. It is also called DDS or dapsone. The trials were successful and even today it is still used in combination with antibiotics for treatment of Hansen’s disease (leprosy) (451).

 

André Pirson (DE) discovered that manganese is essential for oxygenic photosynthesis (1212; 1213).

 

Albert Francis Blakeslee (US), Amos G. Avery (US), and Albert Levan (SE) discovered that the plant alkaloid colchicine—isolated from autumn crocus and other members of the genus Colchicum—can induce mutations in cells by interfering with cell division. It prevented chromosomes, once doubled, from being partitioned into daughter cells (129; 955).

 

James Frederick Bonner (US) and James English, Jr. (US) discovered a plant wound hormone, which stimulates cell division. They called it traumatin. Chemically it is 1-decene-1, 10-dicarboxylic acid (160).

Don C. Zimmerman (US) and Carol A. Coudron (US) determined that the wound hormone results from a non-enzymatic oxidation of 12-oxo-trans-10-dodecenoic acid, the first compound in the jasmonic acid pathway (1764).

 

Charles E. Clifton (US) reported that both sodium azide and 2,4-dinitrophenol inhibit oxidative assimilation, therefore, suggesting an inhibition of energy transfer to the energy-requiring assimilatory reactions (304).

Henry Arnold Lardy (US) and Paul H. Phillips (US) gave the first clear evidence that 2,4-dinitrophenol interferes with the energy-coupling mechanism with the result that oxidation and glycolysis run rampant, while the energy is lost as heat rather than being conserved for work (927).

Jacques Lucien Monod (FR) proved that agents, which uncouple oxidative phosphorylation, such as 2,4-dinitrophenol, completely blocked the shift from one substrate to the other. This suggested that the shift required synthesis of another enzyme thus requiring considerable energy (1100).

 

M.I. Nakhimovskaia (RU) was the first to survey the soil for the presence of actinomycetes antagonistic to bacteria. Of 80 isolates studied, 47 could suppress bacterial growth, but only 27 released antagonistic substances into the medium (1130).

 

Selig Hecht (PL-US) explained that when the eyes are exposed to light visual purple (rhodopsin) is converted into a nerve stimulator and retinene (retinal) (yellow). New visual purple is synthesized from vitamin A (retinol) obtained from the blood stream (703).

 

Harry N. Holmes (US) and Ruth E. Corbet (US) crystallized vitamin A (retinol) from liver oil of mackerel and other fishes (759).

 

Thaddeus Robert Rudolph Mann (PL-GB) found that in plant tissues the highest concentration of hematin (iron protoporphyrin) occurred in the meristematic tissues and concluded that these higher concentrations correlated with higher metabolic activity (1022; 1023).

 

Aleksandr Evseyevich Braunstein (RU) and Maria Grigorievna Kritzmann (RU) reported that in minced pigeon-breast muscle, the alpha-amino group of glutamic acid is transferred reversibly to pyruvic acid (to form alanine) or to oxaloacetate (to form aspartic acid) thus effecting a transamination reaction. This discovery provided a metabolic linkage between the ornithine cycle and the citric acid cycle (187).

Philip Pacy Cohen (US) pointed out problems of earlier papers on transamination then refined and made precise the study of transamination. Cohen originated the term transaminase for the enzyme catalyzing transamination (308; 309).

 

Herman Moritz Kalckar (DK-US), Vladimir Aleksandrovich Belitzer; Vladimir Aleksandrovich Belitser (RU), and Elena T. Tsibakova; Elena T. Tsibakowa (RU) independently supplied evidence that phosphorylation is coupled to respiration. They showed that when various intermediates in the tricarboxylic acid cycle were oxidized by buffered suspensions of freshly minced liver, kidney, or muscle tissue, inorganic phosphate present in the medium disappeared. Concomitantly, there was an increase in the concentration of organic phosphate compounds, such as glucose 6-phosphate and fructose 6-phosphate, whose phosphate groups are derived from ATP. When the tissue suspensions were deprived of oxygen or poisoned with cyanide, uptake of inorganic phosphate did not take place. It was therefore concluded that phosphorylation of ADP is coupled to aerobic respiration as a mechanism for energy recovery.

Belitzer and Tsibakova reported that the phosphorylation of creatine in pigeon heart muscle is coupled to the oxidation of any one of a number of metabolites (e.g., citrate, alpha-ketoglutarate, succinate, pyruvate, lactate, malate, fumarate) and that approximately two molecules of creatine phosphate are synthesized per atom of oxygen consumed (103; 828; 830; 834).

 

Erwin Paul Negelein (DE) and Hans Joachim Wulff (DE) crystallized alcohol dehydrogenase from yeast (1134).

 

Mortimer Louis Anson (US) crystallized carboxypeptidase (34).

 

Robert A. Fulton (US) and Horatio C. Mason (US) produced the first evidence for the absorption and translocation of a bulky insecticidal molecule foreign to the plant, when they found that derris applied to the first two leaves of bean plants reduced the attack by the Mexican bean beetle (Chrysomelidae) on leaves subsequently produced (586). This was evidence that the insecticide had spread to become systemic.

 

Conrad Arnold Elvehjem (US), Robert James Madden (US), Frank Morgan Strong (US), and Dilworth Wayne Woolley (CA-US) demonstrated that lack of sufficient nicotinic acid (vitamin B3 or nicotinamide) in a dog’s diet leads to a disease called black-tongue (510; 511). Pellagra is the human equivalent of black-tongue.

 

Joseph Gilbert Hamilton (US) used radioactive sodium to perform the first medical physiology studies of the dynamics of sodium transport in the human. Both test subjects were leukemia patients (671).

 

Homer William Smith (US) discovered that since inulin is completely filterable at the glomerulus and not reabsorbed, excreted, or synthesized by the renal tubules it can be used to measure glomerular filtration (1458).

 

Kenneth Vivian Thimann (GB-US) and Frits Warmolt Went (NL-US) suggested that depending on its concentration auxin might produce inhibitory effects in one tissue and stimulation in another, different tissues being characterized by a series of overlapping optimal concentration curves (1570; 1677).

 

George S. Avery, Jr. (US), Paul R. Burkholder (US) and Harriet B. Creighton (US) found that methyl 3-indole acetate, potassium 3-indole acetate, gamma-3-indole butyric acid, methyl gamma-3-indole butyrate, potassium gamma-3-indole butyrate, alpha-naphthalene acetic acid, potassium alpha-naphthyl acetate, methyl alpha-naphthyl acetate, ethyl alpha-naphthyl acetate, beta-3-indole propionic acid, and potassium beta-3-indole propionate are effective in promoting growth curvatures of the Avena coleoptile (Went method) (50).

 

Edward Calvin Kendall (US) and Dwight Joyce Ingle (US) characterized the relation between the adrenal gland and salt and water metabolism, a phenomenon that subsequently became the basis for a bioassay system that led to the recognition that the adrenal cortex secretes a mineralocorticoid hormone (aldosterone) (850).

 

Dwight Joyce Ingle (US) and Edward Calvin Kendall (US) found that administration of adrenalcortical extracts or purified glucocorticoids to intact rats causes atrophy of the adrenal glands. Adrenal atrophy could be avoided by simultaneous administration of pituitary extracts (798; 801).

Dwight Joyce Ingle (US), Choh Hao Li (CN-US), and Herbert McLean Evans (US) established that the changes in adrenal size and activity are mediated by the pituitary hormone adrenocorticotropin (800; 802; 803). Note: The elucidation of the feedback mechanism between the adrenal cortex and the pituitary became the model for similar studies.

 

Alan Lloyd Hodgkin (GB) demonstrated the dependence of nerve conduction on the electronic spread of depolarization induced by local current from the region of the action potential to that ahead of it to cause enhanced excitability and excitation (748; 749).

 

Edward Holbrook Derrick (AU), Frank Macfarlane Burnet (AU), and Mavis Freeman (AU), worked on an outbreak of febrile disease among abattoir workers, described Q fever (Nine-Mile Fever) and Derrick designated Rickettsia burnetii (Coxiella burnetii) as the etiological agent (225-228; 423; 424). The Q stands for query and not Queensland as some writers have reported.

Gordon E. Davis (US) and Herald Rea Cox (US) identified a new rickettsial disease, which they called Nine Mile Fever (named for Nine Mile Creek where the ticks were collected). It is synonymous with Q fever (381).

 

Fred R. Beaudette (US) and Charles B. Hudson (US) were the first to isolate a coronavirus. The source was chickens with infectious bronchitis (90).

David Arthur John Tyrrell (GB) and M.L. Bynoe (GB) used cultures of human ciliated embryonal trachea to propagate the first human coronavirus in vitro (1595).

Jane Parry (GB) reported that severe acute respiratory syndrome (SARS) is likely caused by a strain of coronavirus (1178). It was later called SARS-Associated Coronavirus (SARS-CoV).

Victor M. Corman (DE), Isabelle Eckerle (DE), Tobias Bleicker (DE), Ali Muhammad Zaki (SA), Olfert Landt (DE), Monika Eschbach-Bludau (DE), Sander van Boheemen (NL), Robin Gopal (GB), Tobias M. Ballhause (DE), Theo M. Bestebroer (NL), Doreen Muth (DE), Marcel A. Müller (DE), Jan Felix Drexler (DE), Maria Zambon (GB), Albert D. Osterhaus (NL), Ron A.M. Fouchier (NL), and Christian Drosten (DE) first reported a novel coronavirus called “Middle East Respiratory Syndrome Coronavirus” (MERS-CoV) in 2012 in Saudi Arabia (351).

 

Gilbert Julias Dalldorf (US), Margaret Douglass (US), and Horace Eddy Robinson (US) demonstrated the ability of one virus to modify the course of infection by another (infection with lymphocytic choriomeningitis virus protected monkeys from infection by poliomyelitis) (370-373).

 

Charles Armstrong (US) announced successful passage of a fresh human strain of poliomyelitis virus (Lansing strain) from the monkey to Eastern cotton rats (Sigmodon hispidus hispidus) (35).

Charles Armstrong (US) successfully transfered the Lansing strain of poliomyelitis virus from the Eastern cotton rat to the white mouse (36).

 

Eugene Wollman (FR) and Elisabeth Wollman (RU-FR) noted that immediately after being infected bacteriophages pass through a noninfectious stage (1728).

August H. Doermann (US), for the first time, methodically investigated the complete life cycle of a bacteriophage and rediscovered the virus eclipse phase, the time elapsed between successful infection of the host cell and the start of new virus production. During this phase no infectious particles were present within the host cell (441).

 

Thomas Milton Rivers (US) devised a set of postulates, like Koch’s, which were very useful in establishing the causal role of a virus in disease. River’s postulates, applicable to both animal and plant viruses, can be stated as follows:

1) The viral agent must be found either in the host’s body fluids at the time of the disease or in the cells showing specific lesions.

2) The viral agent obtained from the infected host must produce the specific disease in a suitable healthy animal or plant or provide evidence of infection in the form of antibodies (substances produced by vertebrates in response to a virus) against the viral agent. It is important to note that all host material used for inoculation must be free of any bacteria or other microorganisms.

3) Similar material from such newly infected animals or plants must in turn be capable of transmitting the disease in question to other hosts (1300).

 

Thomas Francis, Jr. (US), Thomas P. Magill (US), Jonas E. Salk (US), Monroe D. Eaton (US), Gordon Meiklejohn (US), Frederick M. DavenPort (US), C. Henry Kempe (US), William G. Thalman (US), Edwin H. Lennette (US), George Keble Hirst (US), Elsmere R. Rickard (US), William F. Friedewald (US), Theodore C. Eickhoff (US), Jerome L. Schulman (US), and Edwin D. Kilbourne (US) were major participants in the development of influenza vaccines (379; 483; 503; 570; 571; 745; 746; 1062; 1063; 1412).

 

Arthur Quinton Wells (GB) discovered and characterized the acid-fast bacillus Mycobacterium microti as the cause of an epizootic, chronic infection of the field vole, i.e., vole tuberculosis (1672).

 

Robert Lee Hill (GB), Fay Bendall (GB), and Ronald Scarisbrick (GB) discovered that light-induced oxygen evolution can be observed in cell-free granular preparations extracted from green leaves. Illumination of such preparations in the presence of artificial electron acceptors, such as ferricyanide or reducible dyes, caused evolution of oxygen and simultaneous reduction of the electron acceptor —this later became known as the Hill reaction. Carbon dioxide was apparently not required, nor was it reduced to a stable form that accumulated, suggesting that the photoreduction of carbon dioxide to hexose is a later step in photosynthesis. Electrons are being induced to flow away from water molecules to an acceptor, thus yielding molecular oxygen from the water. Yet in animal tissues electrons arising from organic substrates flow toward molecular oxygen, which is reduced to water. Clearly, the direction of electron flow is opposite to that in respiration. The energy of this reversed electron flow, which takes place only on illumination, comes from the absorbed light (730-735). The 1960 paper was the first to describe a ‘Z’-scheme for the two light reactions of photosynthesis.

 

H. Close Hesseltine (US) presented evidence indicating that pregnancy and diabetes mellitus are predisposing conditions for mycotic vulvovaginitis (723).

 

John Burdon Sanderson Haldane (GB-IN) introduced the concept of genetic load which was defined as the proportion of the population that die each generation because of the action of selection on a genetic system (664).

 

Tracy Morton Sonneborn (US) demonstrated the mechanism for inheritance of mating type in Paramecium aurelia. He determined that a single gene controlled mating type. This was the first gene to be demonstrated in the ciliates (1482-1485).

 

Gladwyn Kingsley Noble (US) and Adolf H. Schmidt (US) discovered that two groups of snakes, the pit vipers (Crotalidae) and the boas (Boidae) use thermal radiation from a warm-blooded animal such as a mouse to guide their striking motion (1145).

Theodore Holmes Bullock (US) and Friedrich P.J. Diecke (US) showed that pit vipers could detect long-wavelength infrared radiation (221).

 

Frank Fraser Darling (GB) did a classic field study of red deer and wrote A Herd of Red Deer. This research would be instructive reading for any aspiring field biologist (378).

 

Theodosius Grigorievich Dobzhansky (Ukrainian-US) authored Genetics and the Origin of Species in which he concluded that genetic mutations generate numerous variations thus providing the raw material for natural selection. This book also made a deep impression on naturalists by relating systematics to genetics (437).

 

Walter Michel (DE) was the first to produce artificial heterokaryons. He fused plant protoplasts from different species and genera (1084).

 

William Jacob Robbins (US), Mary A. Bartley (US) and Frederick Kavanagh (US) showed that vitamin B1 (thiamine) promotes the growth of tomato root tips and fungi in culture (1304; 1305). This was the first time that a vitamin was shown to be necessary for plant or fungal growth.

William Jacob Robbins (US) and Mary Stebbins (US), had by 1949, kept tomato roots through 131 consecutive passes in a solution of mineral salts, cane sugar, and thiamine or thiazole. A period of over twenty years!

 

Charles Drechsler (US) discovered that the fungus Arthrobotrys dactyloides throttles its nematode prey with nooses of three cells held out on a short stalk. A nematode worm passing through one of these traps triggers its closure. The cells triple in volume in a tenth of a second, constricting and ensnaring the worm for consumption (453).

 

Alfred Edwards Emerson (US), based on his work with termites, wrote the first of many articles defending the use of behavioral traits as taxonomic characters (512).

 

Per Fredrik Thorkelsson Scholander (SE-NO-US), Laurence Irving (US), Wilhelm Bjerknes (NO), Edda Bradstreet (US), Stuart W. Grinnell (US), Herschel V. Murdaugh, Jr. (US), Bodil M. Schmidt-Nielsen (DK-US), J.W. Wood (US), William L. Mitchell (US), Harold Theodore Hammel (US), David Hugh LeMessurier (AU), Edvard A. Hemmingsen (NO-US), and Walter F. Garey (US) investigated the physiology of deep diving mammals and found that: seals exhale prior to a dive, thus decreasing the nitrogen content of their lungs and avoiding the “bends.” The oxygen-carrying capacity of the blood is much greater in a seal than in man. The seal’s blood volume is relatively large, and both blood and muscles contain much larger amounts of hemoglobin, and thus hold more oxygen, than in mammals in general. A seal’s most characteristic response to an experimental dive is to slow the heart down to a few beats per minute (diving bradycardia is typical of all animals investigated; that is mammals, birds, reptiles, amphibians, and even fishes which had been taken out of water); the blood is diverted to the most vital organs, notably the central nervous system and eyes. The muscles, which can function anaerobically through the formation of lactic acid, receive no blood and thus acquire an oxygen debt that is repaid when oxygen is again available at the termination of the dive.

For these investigations Scholander developed new methods for continuous recording of the respiratory metabolism of diving animals (124; 807; 808; 1120; 1399-1406; 1408; 1409).

 

Julia Bell (GB) and John Burdon Sanderson Haldane (GB) described the first example of linkage in humans in X-linked pedigrees transmitting both hemophilia and color blindness (104).

 

Max Theiler (ZA-US) isolated and characterized a new virus disease, spontaneous encephalomyelitis of mice (1568).

 

Jacob Furth (US) and Morton Kahn (US) were the first to allude to cancer stem cell (CSC) or tumor-initiating cell principles. Using cell lines, they provided the first quantitative assay for the assessment of the frequency of the malignant cell maintaining the hematopoietic tumor. They showed that a single leukemic cell can transmit the systemic disease when transplanted into a mouse (587).

Robert Bruce (CA) and Hugo Van der Gaag (CA) used the spleen colony-forming assay (CFU-S) to show that only a small subset of primary cancer tissue can proliferate in vivo (210).

Tsvee Lapidot (CA), Christian Sirard (CA), Josef Vormoor (CA), Barbara Murdoch (CA), Trang Hoang (CA), Julio Caceres-Cortes (CA), Mark Minden (CA), Bruce Paterson (CA), Michael A. Caligiuri (US), Dominique Bonnet (CA) and John E. Dick (CA) showed that when isolated from acute myeloid leukemia (AML) patients, only a small fraction of the tumor cells with a characteristic marker signature is able to establish leukemia in recipient mice (164; 924).

Muhammad Al-Hajj (US), Max S. Wicha (US), Adalberto Benito-Hernandez (US), Sean J. Morrison (US), Michael F. Clarke (US), Sheila K. Singh (CA), Cynthia Hawkins (CA), Ian D. Clarke (CA), Jeremy A. Squire (CA), Jane Bayani (CA), Takuichiro Hide (CA), R. Mark Henkelman (CA), Michael D. Cusimano (CA), and Peter B. Dirks (CA) revealed that the cancer stem cell (CSC) concept extends beyond hematopoietic malignancies. They showed that human breast and brain tumors are not homogeneous, but rather contain a small subset of cells that can be prospectively isolated and are able to initiate phenotypically heterogeneous cancers in vivo (10; 1448).

 

Hans Popper (AT-US), Emil Mandel (AT), and Helene Mayer (AT) developed the creatinine clearance test for assessing kidney function (1220).

 

William Warrick Cardozo (US) concluded that sickle cell anemia is inherited following Mendelian law and is more frequent among black people or people of African descent (256).

 

Samuel Soskin (US) and Rachmiel Levine (PL-CA-US) espoused the concept of a hepatic threshold for glucose, defined as the blood glucose level at which glucose production and utilization by the liver exactly balance each other. They believed that the hepatic threshold for glucose is elevated in diabetes and lowered by insulin (1490).

 

Ludvig G. Browman (US) showed that the exposition of rats to continuous light interrupts the estral cycle inducing the state of persistent estrous (198).

Virginia Mayo Fiske (US) reported on the effect of light on sexual maturation, estrous cycles, and anterior pituitary in the rat (548).

 

Fuller Albright (US), Allen M. Butler (US), Aubrey Otis Hampton (US), and Philip H. Smith (US) described a syndrome (later to become Albright’s syndrome) distinguished by precocious puberty in girls, cystic bone disease, and brownish pigmentation of the skin (12).

 

Raphael Issacs (US), using careful cytological study of the cell types in lymphosarcoma leukemia, found that the cells are not lymphocytes, but lymphosarcoma cells, so that the condition is true lymphosarcoma cell leukemia (809).

 

Abraham Albert Hijmans van den Bergh (NL) and Wilhelm Grotepass (NL) gave the first clinical and biochemical picture of variegate porphyria (VP) (1602).

Jan Gosta Waldenström (SE) described over one hundred patients with acute intermittent porphyria (AIP), most of who originated from a small village in Northern Sweden (1639). AIP is characterized by recurrent episodes of abdominal pain, vomiting, constipation, hypertension, tachycardia, and neurologic involvement including muscle weakness, mental changes, and even seizures.

Since this early observation, specific inherited deficiencies of enzymes within the heme synthetic pathway have been delineated that allow improved understanding of classification, pathogenesis, and genetic screening.

L. James Strand (US), Bertram F. Felsher (US), Allan G. Redeker (US), and Harvey S. Marver (US) determined that acute intermittent porphyria is characterized as an autosomal dominant condition resulting from decreased levels of porphobilinogen deaminase (PBG) or hydroxymethylbilane synthase (HMB) (1537).

 

Robert Alexander McCance (GB), Elsie M. Widdowson (GB), Norman M. Keith (GB), Arnold E. Osterberg (GB), and Harry E. King (GB) observed that renal potassium clearances in excess of glomerular filtration rate often occurred (846; 1041). This implied tubular secretion of potassium.

 

Robert Alexander McCance (GB) and Elsie M. Widdowson (GB) concluded that no physiologic mechanism of iron excretion exists. Consequently, absorption alone regulates body iron stores (1042).

 

Vittorio Erspamer (IT), Maffo Vialli (IT), Giuseppe Boretti (IT), and Biagio Asero (IT) isolated and characterized a hormone substance from enterochromaffin cells they named enteramine (524-526).

Maurice M. Rapport (US), Arda Alden Green (US), and Irvine Heinly Page (US) isolated and chemically characterized this vasconstrictor indole (5-hydroxytryptamine) and named it serotonin (1264-1267).

Betty Mack Twarog (US), Irvine Heinly (US), A.H. Amin (GB), Tom B.B. Crawford (GB), John Henry Gaddum (GB), and John Henry Welsh (US) determined that serotonin was a neurotransmitter in invertebrates and the central nervous system of higher animals (26; 1593; 1594; 1674-1676).

Dilworth Wayne Woolley (US) and Elliott Shaw (US) suspected that serotonin might be a neurotransmitter involved in mental illness (1743; 1744).

 

James Wenceslas Papez (US) published work on the limbic circuit and conceived a mechanism of emotion (hypocampo-thalamo-cingulate-hippocampal circuit) associated with this region of the brain (1173). Note: Limbic means border.

Paul D. MacLean (US) coined the phrase limbic system and distinguished three limbic circuits based on function; emotions related to self-preservation (amygdala and hippocampus), emotions related to pleasure (cingulate gyrus and septum), and emotions related to social cooperation (parts of the hypothalamus and anteriorthalamus) (1012; 1013).

Paul D. MacLean (US) proposed that our skull holds not one brain, but three, each representing a distinct evolutionary stratum that has formed upon the older layer before it, like an archaeological site: the triune brain. The three levels are 1) the Reptilian Brain, 2) the Limbic System (Paleomammalian brain), and 3) the Neocortex (Neomammalian brain) (1014).

 

Tracy Jackson Putnam (US) and Hiram Houston Merritt (US) were the first to discover that phenytoin (PHT) (also diphenylhydantoin) is a therapeutically effective substance when it counteracts electrically induced hyperexcitability and convulsions in the cat. They reported their clinical trial of sodium diphenyl hydantoinate made in 200 patients with frequent convulsive seizures which had not been relieved by the previous modes of therapy. In 142 such patients who have received the treatment for periods varying from two to eleven months, grand mal attacks were relieved in 58 per cent and greatly decreased in frequency in an additional 27 per cent; petit mal attacks were relieved in 35 per cent and greatly decreased in frequency in an additional 49 per cent, and psychic equivalent attacks were relieved in 67 per cent and greatly decreased in frequency in 33 per cent. There were no fatalities (1072; 1241).

 

Riojun Kinosita (JP-US) found that liver tumors could be readily induced by ingestion of dimethylaminoazobenzene, a dye known as " butter-yellow " (861).

 

Wade H. Marshall (US), Clinton Nathan Woolsey (US), and Archibald Philip Bard (US) used the cathode ray oscilloscope and the evoked potential technique to develop detailed mapping of the somatic sensory area of the cerebral cortex of the cat and monkey (1028; 1029; 1749).

 

Walter Edward Dandy (US), in 1937, performed he first direct surgical approach and clipping of a cerebral aneurysm (375).

 

James Barrett Brown (US) achieved permanent survival of skin grafts exchanged between human monozygotic twins (204).

 

Edward Thomas Campbell Milligan (GB), C. Naunton Morgan (GB), Lionel E. Jones (GB), and R. Officer (GB) devised one of the most popular hemorrhoidectomy operations. It was named the Milligan-Morgan technique in their honor (1092). Note: It was associated with significant post-operative pain.

Antonio Longo (IT) invented a circular stapling device for treatmet of hemorrhoidal disease. The level of pain associated with this treatment was less than that of the Milligan-Morgan procedure .

Brian J. Mehigan (GB), John R.T. Monson (GB), and John E. Hartley (GB) performed one of the first randomized trials assessing post-operative pain in patients undergoing stapled hemorrhoidectomy versus the older excisional approach. They found that stapled hemorrhoidectomy is associated with a significant improvement in post-operative pain (1061).

 

Alfred Wiskott (DE), Robert Anderson Aldrich (US), Arthur G. Steinberg (US), and Donald C. Campbell (US) described a syndrome characterized by a triad of eczema, profound thrombocytopenia, and frequent infections due to immunological deficiency. It is a sex-linked recessive disorder with a defect in both T and B cell function (16; 1724). It is often called Wiskott-Aldrich syndrome.

 

Thomas Hale Ham (US) established that in chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria (PNH) the lysis is affected by complement. He demonstrated a dose-response relationship (limited because hemolysis disappears with even very little dilution of serum), and that inhibition or destruction of complement or components of complement abrogated the lytic reaction (669).

 

F.J. Neuwahl (GB) and C.C. Fenwick (GB) introduced an extract of Bulgarian belladonna (deadly nightshade) as a treatment for post-encephalitic Parkinsonism (1139; 1140).

 

Geoffrey Keynes (GB) perfected and championed the treatment of breast cancer with breast-sparing surgery followed by radiation therapy. After surgery to remove the tumor, long needles containing radium are inserted throughout the affected breast and near the adjacent axillary lymph nodes (855; 1052).

 

Helga Tait Malloy (CA) and Kenneth A. Evelyn (CA) described a method for the accurate photoelectric determination of both direct and indirect bilirubin in serum, in which protein precipitation and consequent loss of bilirubin by adsorption have been eliminated (1020).

 

Erwin Chargaff (AT-US) and Kenneth B. Olson (US) discovered that protamine can neutralize heparin’s function as an anticoagulant (282).

Bernard J. Miller (US), John Heysham Gibbon, Jr. (US), and Mary Gibbon (US) used protamine to reverse the anticoagulation effects of sodium heparin during open-heart surgery (1089).

Clarence Walton Lillehei (US), Morley Cohen (US), Herbert E. Warden (US), and Richard L. Varco (US) used controlled cross-circulation to correct a ventricular septal defect in an 11-year-old boy. The boy's anesthetized father served as the oxygenator. Blood flow was routed from the patient's caval system to the father's femoral vein and lungs, where it was oxygenated and then returned to the patient's carotid artery. The cardiac defect was repaired with a total pump time course of 19 minutes. Over the ensuing 15 months, Lillehei operated on 45 patients with otherwise irreparable complex interventricular defects; most of these patients were less than 2 years old. Although cross-circulation was a major advance, it was not adopted for widespread use because it posed a serious risk to the "donor” (974).

Clarence Walton Lillehei (US) and Richard A. DeWall (US), in 1955, advanced the concept of a heart-lung machine. They called it a helix reservoir bubble oxygenator, which bubbled oxygen through the blood during the operation (975).

John W. Kirklin (US), James W. Dushane (US), Robert T. Patrick (US), David E. Donald (US), Peter S. Hetzel (US), Harry G. Harshbarger (US), and Earl H. Wood (US) began a successful series of open-heart surgeries utilizing an extracorporeal circulation machine (a modified Mayo-Gibbon-IBM pump oxygenator) (863).

These early versions of heart-lung machines were cumbersome and dangerous —often leaking blood, damaging blood cells and causing air embolisms (602).

Clarence Walton Lillehei (US), Vincent L. Gott (US), Richard A. DeWall (US), and Richard L. Varco (US) used a pump oxygenator while correcting a pure mitral regurgitation with suture plication of the commissures under direct vision. Heart-lung machines had come of age (976).

 

Arne Torkildsen (NO), in 1937, performed the first ventriculocisternostomy to relieve obstructive hydrocephalus. This is the surgical formation of an opening between the ventricles of the brain and the cerebellomedullary cistern (1585).

 

Andrew W. Contratto (US) and Samuel A. Levine (US) studied 180 cases of aortic stenosis, unassociated with other significant valve disease, 53 of which were examined post mortem. Among the cases an early history of rheumatic fever was common. A loud basal systolic murmur, a systolic thrill near the aortic area, and calcification of the valve were common. Disturbances in conduction such as bundle branch block and auriculoventricular block were common. Angina pectoris occurred in 22.7 % of the cases. There were 21 instances of syncope (335).

 

William H. Lang (GB) positioned Cooksonia pertonii as the earliest known land-living vascular plant found in England and one of the earliest in the world (921).

Dianne Edwards (GB) and E. Catherine W. Rogerson (GB) discovered Cooksonia pertonii near Brecon Beacons, England in rock 420 M (497; 498).

 

Ales Hrdlicka (CZ-US) proposed that America had been peopled from Asia via the Bering Strait (778).

 

Dorothy Anne Elizabeth Garrod (GB), Dorothea Minola Alice Bate (GB), Theodore Doney McCowan (GB), and Arthur Keith (GB) reported the discovery at Mugharet et-Tabun, Mount Carmel, southeast of Haifa, Israel of a fossilized female skeleton likely to be Homo sapiens neanderthalensis; Homo neanderthalensis. They also discovered Homo remains from roughly the same time period in a nearby cave named Mugharet es-Skhül (592; 1049). These specimens are dated at 30-60 K BP

 

The National Cancer Institute was formed.

 

c. 1938

James Gordon Horsfall (US) introduced chloranil as a fungicide for legume seed treatment (769).

 

1938

Richard Johann Kuhn (DE) was awarded the Nobel Prize in Chemistry for his work on carotenoids and vitamins. He was caused by the authorities of his country to decline the award but later received the diploma and the medal.

 

Corneille Jean Francois Heymans (BE) was awarded the Nobel Prize in Physiology or Medicine for the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration.

 

William Thomas Astbury (GB), and Florence Ogilvy Bell (GB) presented the first x-ray diffraction pictures of DNA. They were of calf thymus DNA sent to them by Torbjörn Oskar Caspersson, the Swedish biochemist (40-42).

 

Max Ferdinand Perutz (AT-GB), John Desmond Bernal (GB), Isadore Fankuchen (US), Michael George Rossmann (US), Ann F. Cullis (GB), Hilary Muirhead (GB), Georg Will (GB), and Anthony C.T. North (GB) were among the first to report the tertiary and quaternary structure of a protein—hemoglobin and chymotrypsin. Perutz began this work as part of his Ph.D. thesis in 1937 (120; 1192-1199).

Guilio Fermi (GB), Max Ferdinand Perutz AT-GB), Boaz Shaanan (IL), and Roger Fourme (FR) determined the crystal structure of human deoxyhemoglobin at 1.74 Å resolution (542).

 

Donald Dexter van Slyke (US), Alma Hiller (US), Robert T. Dillon (US), and Douglas A. MacFadyen (US) announced the discovery of the amino acid hydroxylysine, which they isolated from gelatin (1608).

James R. Weisiger (US), Elizabeth A. Jacobs (US), John Clark Sheehan (US), and William A. Bolhofer (US) later synthesized hydroxylysine (1428; 1667).

 

Albert Neuberger (DE-GB) discovered that ovalbumin, a protein from chicken egg white, contains a carbohydrate moiety. This marks the beginning of modern glycoprotein research (1138).

 

Virginia Clementine Irvine (US), Sydney Charles Bausor (US), Percy W. Zimmerman (US), Alfred E. Hitchcock (US), and Frank Wilcoxon (US) demonstrated that beta-naphthoxyacetic acid is an auxin (81; 806; 1766).

 

K.K. Chen (US), Charles L. Rose (US), and E. Brown Robbins (US) showed that nicotinic acid is at least several hundred times less toxic in mice, rats, and guinea pigs than nicotine. Nicotinic acid is devoid of action upon the autonomic ganglia. Nevertheless, repeated administration of large doses, 2 gm. daily, in dogs has resulted in poisoning and deaths (285).

 

Arthur Stoll (CH) and Albert Hoffman (CH-US), in 1938, produced lysergic acid diethylamide (LSD) while trying to synthesize a new drug for the treatment of headaches (it is one of the most potent psychoactive drugs known) (1533). Pamela A. Pierce (US) and Stephen J. Peroutka (US) showed that lysergic acid diethylamide (LSD) blocks or inhibits the action of the brain’s neurotransmitter serotonin (1208).

 

David Keilin (PL-GB) and Edward Francis Hartree (GB) described the mechanism of the decomposition of hydrogen peroxide by catalase (845).

 

Felix Haurowitz (CZ-US) discovered the drastic change in crystalline shape of deoxyhemoglobin from hexagonal plates to elongated prisms as oxygen is taken up (698). This is sometimes cited as the first observation of an allosteric reaction.

 

Lionel Ernest Howard Whitby (GB) reported that 2- (p-aminobenzene sulphonamide) pyridine is chemotherapeutically active in experimental infections in mice against pneumococci of Types I, II, III, V, VII, VIII and especially against Types I, VII, and VIII. It was as active as sulphanilamide against hemoltyic Streptococcus and Meningococcus (1682).

Maxwell Finland (RU-US), Elias Strauss (US), and Osler L. Peterson (US) reported that the sulfonamide, “Sulfadiazine was used in the treatment of 446 patients with various infections. It appeared to be highly effective in the treatment of…pneumococcic, staphylococcic and…pneumonias; meningococcic infections; acute infections of the upper respiratory tract including sinusitis; erysipelas; acute infections of the urinary tract, particularly those associated with Escherichia coli bacilluria, and acute gonorrheal arthritis…. Toxic effects…were relatively mild and infrequent” (545).

 

Emil L. Smith (US) demonstrated that chlorophyll is bound to proteins (1457).

 

Cornelis Adrianus Gerrit Wiersma (NL-US) identified the lateral giant interneuron as key to triggering the tail flip escape in response to a sharp tap on the animal's abdomen (1693; 1694).

Franklin B. Krasne (US) made one of the first attempts to analyze the synaptic basis for the release of an animal's fixed action pattern. In this case the neural controls of the crayfish escape response. More complex than a simple reflex, this response results from a 'decision' reached by the animal in response to a specific sort of stimulus. Once triggered, the response orchestrates the behavior of the animal's entire body. These escape behaviors are often found to be subject to simple forms of learning, including habituation, dishabituation, and sensitization. For crayfish escape, the relevant question was whether habituation of the escape response occurred because the afferent pathway to the lateral giant interneuron, or the lateral giant interneuron itself, became less excitable with repeated stimulation, or because increasingly strong inhibition was imposed on the lateral giant interneuron circuit from elsewhere in the nervous system.

Krasne completed the general outline for the afferent path to the lateral giant interneuron, and therefore for the entire escape circuit. This was one of the first, if not the first, polysynaptic circuits for a fixed action pattern that had been so described. Second, he demonstrated that much, but not all, of behavioral habituation of the escape response could be accounted for by synaptic depression within one limb of the afferent path that carries nervous signals to the lateral giant interneuron (882).

 

Archibald Vivian Hill (GB) found that, even in "isometric" contractions, the muscle fibers initially shorten. He proposed that skeletal muscles have two distinct components in series with each other: a contractile component that shortens when stimulated and an elastic component that lengthens under tension. Hill proposed an empirical relation for the force-velocity curve that emphasized the hyperbolic form of the data. This equation is still commonly used today: (force + a) (velocity + b) = (forcemax + a) b, where a and b are constants. The functional importance of the Hill equation is that it allowed scientists to clearly distinguish between slow-twitch and fast-twitch muscles and, using this relationship, develop force-power curves and determine peak power (728).

 

John T. Manter (US) created an elegant force plate design which stands out from others because it was the first to record forces in three axes – vertical, fore–aft and lateral – and therefore is the prototype of the modern force plate used in biomechanics research as well as clinical orthopedics. His work appears to be the first to combine simultaneous measurements of individual foot forces and film to use the modern inverse dynamics approach to estimate the muscle forces acting at individual joints and for measuring mechanical work. Manter's inverse dynamics analysis of cat walking led him to conclude that some muscles may act isometrically (1027).

 

Herman Moritz Kalckar (DK-US) provided evidence for the production of phosphoenolpyruvate (PEPA) from fumaric or malic acids, observations that later provided an important clue to the mechanisms involved in the formation of glucose from non-carbohydrate sources in animal tissues (829).

 

William Cumming Rose (US) and Eldon E. Rice (US) determined that ten amino acids are essential in the diet of the rat and dog (histidine, isoleucine, leucine. threonine, lysine, methionine, phenylalanine, tryptophan, valine, and arginine). The rat was found to survive in the absence of arginine, but its growth was suboptimal (1315; 1327).

 

James Gordon Horsfall (US), Robert O. Magie (US), and Ross F. Suit (US) discovered that the Bordeaux mixture harms tomatoes by closing the leaf pores, weakening the cuticle around the pores, and hardening the lamella within the leaves and stunting the plants (770).

 

Peter Wilhelm Joseph Holtz (DE), Rudolf Heise (DE), and Kathe Lüdtke (DE) determined that epinephrine (adrenaline) is made from norepinephrine (noradrenaline) in the chromaffin cells of the adrenal medulla (764).

 

Johannes Van Overbeek (US) reported that certain nongeotropic mutants in maize did not show the usual inequality of auxin distribution (1606).

 

Lewis Charles Chadwick (US) and Donald C. Kiplinger (US) discovered that auxins promote rooting of stem cuttings of ornamental plants (270).

 

Rudolf Signer (CH), Torbjörn Oskar Caspersson (SE), and Einar Hammarsten (SE) reported that the physical properties of calf thymus DNA suggested that the molecule is rod shaped, with a length approximately 300 times its width, and a molecular weight between 500,000 and 1,000,000 (1444).

 

Albert Edward Gillam (GB) and Isidore Morris Heilbron (GB), William Edward Jones (GB), Edgar Lederer (FR), and Franz H. Rathmann (FR) discovered that vitamin A (retinol) in the retinas of fresh water fishes differs from that found in other animals. This form is called vitamin A2 (607; 941).

 

W. William Sebrell (US) and Roy F. Butler (US) used canine experiments to show that some pellagra patients who resisted treatment with nicotinic acid were in fact simultaneously suffering from riboflavin (vitamin B2) deficiency (1416). Joseph Goldberger (SK-US) and George A. Wheeler (US) had called this condition pellagra sine pellagra but did not appreciate its underlying cause.

 

Samuel Lepkovsky (US), John C. Keresztesy (US), Joseph R. Stevens (US), Paul György (US), Richard Johann Kuhn (DE), Gerhard Wendt (DE), Akiyoshi Ichiba (JP), and Kimiyo Michi (JP) isolated and crystallized pyridoxine (vitamin B6) (661; 795; 853; 900; 948).

Samuel Lepkovsky (US) and Elmer Nielsen (US) isolated a green pigment-producing compound in urine of pyridoxine-deficient rats (949).

Samuel Lepkovsky (US), Elisabeth Roboz (US), and Arie Jan Haagen-Smit (NL-US) isolated a yellow compound from the urine of pyridoxine- deficient rats. This yellow compound was shown to be identical with Musajo’s xanthurenic acid, a 4,8-dihydroxyquinoline-2-carboxylic acid. Xanthurenic acid was shown to originate in dietary tryptophane (950).

 

William C. Langston (US), William J. Darby (US), Carroll F. Shukers (US), and Paul L. Day (US) found that vitamin M (folic acid) is essential for the rhesus monkey (Macaca mulatta) (922).

 

Wilhelm Siegmund Feldberg (DE-GB) and Charles Halliley Kellaway (GB) discovered that cobra venom contains a substance that causes the contraction of smooth muscle in the guinea pig. They determined that it is distinct from histamine, another known factor in inflammatory reactions. Relative to histamine, this new mediator has a longer duration of action and thus was called the slow reacting substance (SRS) (537).

Walter E. Brocklehurst (GB) refined its name to "slow reacting substance of anaphylaxis," or SRS-A (193). See Dahlen, 1980.

Robert C. Murphy (US) Sven Hammerstrom (SE), and Bengt Ingemar Samuelsson (SE) elucidated the structure of the "slow reacting substance of anaphylaxis" (SRS-A) as a derivative of arachidonic acid, leukotriene (1121).

 

Georg Charles de Hevesy (HU-SE), Jakub (Jacob) Karol Parnas (PL), Tadeusz Baranowski; Tadeush Baranowski (PL), A. Jerzy Gutke (PL), Pawel Ostern (PL), and Tadeusz W. Korzybski (PL) conducted experiments with tissues, eggs, milk, and yeast fermentations using synthetic radioactive adenylic acid, in which it was possible to trace radioactive phosphorus. After a period of incubation, a considerable portion of the active phosphorus was found in the sugar phosphoric acid esters fraction. Evidence indicated that this also occurs in bacteria, muscle, and yeast cells (386; 875; 1177). These experiments are likely the first to use radioactive phoshorus in biological studies.

Wilhelm Kiessling (DE) and Otto Fritz Meyerhof (DE-US) found that adenylic acid and its allied phosphates act as coenzymes in the transfer of phosphates from phosphopyruvic acid to glucose (857; 858). Among these adenosine nucleotides are: adenylic acid, adenosine diphosphate and adenosine triphosphate, diadenosine pentaphosphoric acid, diadenosine tetraphosphoric acid, and the pyrophosphate. All apparently function as phosphate carriers in cellular glycolysis.

 

Saul Hertz (US), Arthur Roberts (US), and Robley Evans (US), using animal studies in rabbits, demonstrated the principle that radioactive iodine (RAI) could be used to investigate thyroid gland physiology. They demonstrated the tracer capabilities of RAI and its delineation of function of the thyroid gland. Roberts’ produced I-128 at the MIT laboratory, while Hertz and Roberts solely administered and analyzed the biodistribution of the radioisotope in the rabbits (722). Note: Sadly, because of his academic position, Evans was able to force his name be included as one of the authors although he did nothing to justify such.

Joseph Gilbert Hamilton (US) and Mayo H. Soley (US) published the first paper on the diagnostic uses of iodine-131 in patients (672).

In early 1941, Hertz administered 77.7 MBq (2.1 mCi) of MIT cyclotron-produced RAI, the first therapeutic treatment of radioiodine to a patient, Elizabeth D, with a chasing dose of stable iodine in the form of Lugol solution to prevent a possible thyroid storm. As proof of concept, it was a success as shown by histology. Saul Hertz (US) and Arthur Roberts (US), published the first clinical trial of RAI to successfully diagnose and treat Graves’ disease (721). Note: Saul Hertz was also a pioneer in promoting the use of radioisotopes to treat cancer (1575).

John J. Livingood (US) and Glenn Theodore Seaborg (US) discovered iodine-131 and cobalt-60 (987; 988).

Carlo Perrier (IT), Emilio Gino Segre (US) and Glenn Theodore Seaborg (IT-US) discovered technetium-99m (sodium pertechnetate). It is used to image the skeleton and heart muscle in particular, but also for brain, thyroid, lungs, liver, spleen, kidney, gall bladder, bone marrow, salivary and lachrymal glands, heart blood pool, infection and numerous specialized medical studies (1191; 1415; 1417). Note: Technetium was the first artificially synthesized chemical element that does not occur in nature.

Samuel M. Seidlin (US), Leo D. Marinelli (US), and Eleanor Oshry (US) used iodine-131 to treat a patient with thyroid cancer (1420).

Herbert C. Allen, Jr. (US), Raymond L. Libby (US), and Benedict Cassen (US) invented the radioisotope scanner for body organ imaging. Cassen assembled the first automated scanning system in 1950. 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 (20).

George E. Moore (US) used iodine-131 labeled diiodofluorescein to "probe" the brain for tumors at surgery (1102).

 

Robert Doerr (DE) stated that Herpes simplex virus infection in man resulted from the endogenous production of a virus-like agent by the cell under the influence of certain stimuli and were not caused by exogenous infection. Once the agent had been produced, it would act on the cells of susceptible animals (not man) as a true virus (442). Note: Doerr had come perilously close to understanding the true nature of latency.

Frank Macfarlane Burnet (AU) and Stan W. Williams (AU) stated that “Herpes simplex infections, however, once contracted, seem to persist for life. The virus remains for the most part latent; but under the stimulus of trauma, fever, and so forth it may at any time be called into activity and provoke a visible herpetic lesion” (232).

 

Stephen Bartlett (GB), Anda G. Cotton (GB), Isaac Walker Rupel (US), Gustav Bohstedt (US), Edwin Bret Hart (US), Edwin C. Owen (GB), James Andrew Buchan Smith (GB), and Norman Charles Wright (GB) clearly established that bacteria of the rumen synthesize protein from nonproteinaceous material and can obtain nitrogen from sources such as urea. Significant amounts of protein are made available to the ruminant when the bacteria die and are digested (74; 1160; 1352).

 

Barbara McClintock (US) and Hermann Joseph Muller, Jr. (US) defined telomeres as special structures required for chromosome stability (prevention of fusion) (1047; 1112). Note: Later, it was shown that telomeres are repeated simple sequence elements that are added by an enzyme, telomerase, which is not normally expressed in somatic cells. In each cell division, telomeres shorten. When they become sufficiently truncated they cause the cells to enter senescence and die, limiting the number of divisions a cell can undergo and suppressing tumor development.

 

Herbert Göpfert (DE) and Hans Schaefer (DE) used extracellular electrodes to record, during synaptic transmission, the proper electrical response of the post-synaptic membrane, or endplate potential (616).

 

Albert Claude (BE-US) reported RNA rich particles in the cytoplasm (295-297).

 

Torbjörn Oskar Caspersson (SE), Jack Schultz (US), Lennart Aquilonius (SE), and Jean Louis Auguste Brachet (BE) collected considerable evidence about the location of the nucleic acids within cells. Their work indicated that there is a correlation between high levels of protein synthesis and high levels of RNA synthesis. Caspersson also noted that most of the cytoplasmic RNA is concentrated in particles (176; 177; 259-265; 1413).

 

Edgar G. Anderson (US) and Leslie Hubricht (US) developed the concept of introgressive hybridization—usually termed “introgression”—and gave it its name. As the name implies, introgression refers to the gradual infiltration of germplasm of one species into another through repeated backcrossing (30).

 

Theodosius Grigorievich Dobzhansky (RU-US) and Alfred Henry Sturtevant (US) published the first account of the use of inversions in constructing a chromosomal phylogenetic tree (438).

 

William Ernest Castle (US), from his genetic studies in mice, concluded that albinism has no influence on body size (267).

 

Marcus Morton Rhoades (US) discovered the Dotted mutator gene in maize. It was found on a single ear of corn where it produced a phenotype of variegated endosperm characterized by purple dots on a colorless background (1280).

 

Salome Gluecksohn-Schoenheimer (US) used chronological histological examination to follow development of the tailless mutant in the house mouse. She concluded that abnormalities in the tailless mouse likely trace back to a malformation of the primitive gut region in an early stage of embryogeny (611).

Leslie Clarence Dunn (US) and Salome Gluecksohn-Schoenheimer (US) performed breeding experiments on the tailless phenotype in the house mouse. Their results are interpreted as due to an effect of the t1 allele on segregation, possibly through causing additional equational divisions in spermatogenesis (467).

 

Barbara S. Burks (US) recorded the first case of autosomal linkage in man. It involved tooth deficiency and hair color (224).

 

Warren Weaver (US) is credited with being the first person to use the phrase molecular biology in its modern context. In his 1938 report to the Rockefeller Foundation he said, "Among the studies to which the Foundation is giving support is a series in a relatively new field, which may be called molecular biology” (1662). See, Karl Friedrich Wilhelm Ludwig, 1858.

 

Francis Gano Benedict (US), Per Fredrik Thorkelsson Scholander (US), Raymond Hock (US), Vladimir Walters (US), Laurence Irving (US), and Robert E. Smith (US) established, by insulation measurements, the general rule that arctic mammals have warmer furs than do tropical mammals. Natural selection seemed not to have packed more metabolic capacity into a gram of an arctic mammal than into a gram of a similar-sized tropical mammal. Brief mention was made that a small mammal, the arctic weasel, showed an extraordinarily high rate of heat production when exposed to cold; this species' metabolic rate was well above the regression line of the ‘mouse to elephant’ curve. This ‘oddity’ and similar observations on other small, cold-stressed mammals helped to pave the way for the discovery of the thermogenic role of brown adipose tissue (BAT). The discovery of this specialized heat-generating tissue cast metabolic adaptation to cold by mammals (no avian equivalent of BAT is known) in a new light. They noted that the problem for tropical mammals is neither overheating nor cooling, but both (107; 1407; 1470).

 

Chief Medical Officer (GB) reported jaundice in a small group of individuals who had received injections of measles convalescent serum (1153). This very likely represents the first recorded cases of serum hepatitis.

Hans Voegt (DE) determined the viral etiology of infectious hepatitis (hepatitis A) by inoculating psychiatric patients from the mental hospital in Breslau (1624).

Paul Bruce Beeson (US) published the classic description of transfusion-transmitted hepatitis. He linked the occurrence of jaundice in seven cases to blood or plasma transfusions the patients had received a few months prior, providing the quintessential description of transfusion-transmitted hepatitis (93).

Joseph Stokes, Jr. (US) and John R. Neefe (US) showed that immune globulin (concentrated antibodies obtained from pooled human plasma) provided protection against illness among children at a summer camp who had been exposed to hepatitis A by either preventing or attenuating the hepatitis A infection (1532). “Since then, immune globulin has been used widely for post-exposure prophylaxis” (359).

Frederick O. MacCallum (GB) introduced the terms "hepatitis A" for viral hepatitis A (previously called infectious hepatitis, infectious jaundice, or campaign jaundice) and "hepatitis B" for viral hepatitis B (previously called serum hepatitis) (1008).

Saul Krugman (US), Joan P. Giles (US), and Jack Hammond (US) confirmed the work of MacCallum (894).

Frederick O. MacCallum (GB), using human volunteers, differentiated hepatitis A, which is spread by contaminated food and water, from hepatitis B, which is spread by blood (1008).

Jan Gosta Waldenström (SE) reported the association of liver cirrhosis and hypergammaglobulinemia, which is now recognized as chronic active hepatitis or autoimmune hepatitis (AIH) (1642; 1643).

Maurice Payet (SN-FR), Robert Camain (FR), Pierre Pene (FR), Paul E. Steiner (US), and Jack N.P. Davies (US) suggested that hepatitis could be the cause of primary hepatic carcinoma (PHC) (380; 1184; 1521).

Dhirendra Nath Gupta (IN) and Hans F. Smetana (US), in 1955, documented that hepatitis E virus was the etiological agent responsible for an outbreak of disease in New Delhi, India (649). Note: Hepatitis E (HVE) is a liver disease caused by the hepatitis E virus: a non-enveloped, positive-sense, single-stranded ribonucleic acid (RNA) virus.

Saul Krugman (US), Robert Ward (US), Joan P. Giles (US) and Jack Hammond (US) carried out a series of experiments which showed that hepatitis B is infectious and can spread from person to person by contact and sexual intimacy (606; 893-895; 1655). Note: Hepatitis B is not just a serious problem for gay men in Western society. It poses one of the greatest problems for global public health, the major epidemic areas being Asia and Africa, especially below the Sahara.

Baruch Samuel Blumberg (US) and Nancy M. Riddell (US) discovered an antibody present in the blood of a person infected with hepatitis, which would react with the blood of an Australian aborigine. They named the antigen Australian antigen (Au) in the 1965 article (150; 154).

Baruch Samuel Blumberg (US), Betty Jane S. Gerstley (US), David A. Hungerford (US), W. Thomas London (US), and Alton Ivan Sutnick (US) identified and named the antigen with which this antibody (Au) reacted as (HBV) surface antigen (HBsAg) of the hepatitis B virus. The 1967 paper contains the first suggestion that Australia antigen (Au) is the hepatitis virus (151; 991).

Saul Krugman (US), Joan P. Giles (US), and Jack Hammond (US) separated disease caused by the hepatitis A virus (HAV) from that caused by hepatitis B virus (HBV) (894). This led to virologic and serologic breakthroughs that have resulted in an increasing understanding of HBV, HBV infection and HBV disease.

Alfred M. Prince (US) describes the background for the finding of a hepatitis B virus specific antigen and the establishment of its identity with the 'Australia antigen' discovered by Blumberg (1235).

Richard J. Hirschman (US), N. Raphael Shulman (US), Lewellys F. Barker (US), and Kendall O. Smith (US), using electron microscopy, revealed morphologically similar virus-like particles both in sera from patients with hepatitis and from healthy apes. Australia antigen appears to be hepatitis virus itself, and a single virus group may be responsible for both infectious and serum hepatitis (742).

Kazuo Okochi (JP), Seishi Murakami (JP), K. Ninomiya (JP), and M. Kaneko (JP) found that Australian antigen (Au) can be transmitted by transfusion and that it leads to the development of hepatitis in some of the people who receive it, and that some transfused patients develop anti-Au antibodies (1155; 1156).

Manfred E. Bayer (US), Baruch Samuel Blumberg (US), Barbara Werner (US), David Surrey Dane (GB), Colin H. Cameron (GB) and Moya Briggs (GB) isolated and identified the Au (hepatitis B virus) particle using the electron microscope (82; 377). Dane’s group identified 42nm particles. Bayer’s group identified particles of approximately 20nm size. Particles of both sizes contain Au antigen.

June D. Almeida (GB) and Anthony P. Waterson (GB) proposed that the effect of hepatitis B antigen was immune mediated (24). Note: Hepatitis B surface antigen is a protein on the surface of the hepatitis B virus that causes the immune system to produce antibodies.

John Harley Walsh (US), Rosalyn Sussman Yalow (US), and Solomon Aaron Berson (US) used radioimmunoassay to detect the Australian antigen associated with hepatitis (1650).

Lewellys F. Barker (US), N. Raphael Shulman (US), Roderick Murray (US), Richard J. Hirschman (US), Frank Ratner (US), William C. L. Diefenbach (US), and Herman M. Geller (US) noted that there is evidence that transmission of serum hepatitis is associated with transmission of virus-like particles, approximately, 20 millimicrons in diameter, containing the Australia or serum hepatitis (SH) antigen, which is currently referred to as the hepatitis associated antigen (HAA) (71).

Baruch Samuel Blumberg (US) and Irving Millman (US) developed a vaccine against hepatitis B virus (153; 1093).

James A. Smith (), Eugene O. Ogunba (NG), Thurmul I. Francis (), Alfred M. Prince (US), Dick Metselaar (UG), George W. Kafuko (UG), Louis G. Mukwaya (UG), Chung-M. Ling (US), Lacy R. Overby (US), Francisco J. Muniz (AR), Don W. Micks (US), Baruch Samuel Blumberg (US), William Wills (US), Irving Millman (US), W. Thomas London (US), Gerard Saimot (Sengalese), Christian Brochard (US) and Rita Dechene (US) detected hepatitis B surface antigen (HbsAg) in mosquitoes collected in the field areas where HbsAg is common in the human population (155; 1117; 1237; 1459; 1717).

Alfred M. Prince (US), George F. Grady (US), Charles Hazzi (US), Betsy Brotman (US), William J. Kuhns (US), Richard W. Levine (US), and Stephen J. Millian (US) reported that most postransfusion hepatitis was due to a virus other than HBV or Hepatitis A (HAV) (1236).

William S. Robinson (US), David A. Clayton (US), Richard L. Greenman (US), and Larry I. Lutwick (US) determined that the hepatitis B virus is a double stranded DNA virus (1308; 1309).

Baruch Samuel Blumberg (US), Bernard Larouzé (FR), W. Thomas London (US), Barbara Werner (US), Jana E. Hesser (US), Irving Millman (US), Adrien Gérard Saimot (FR), Maurice Payet (SN-FR), Edward D. Lustbader (US), and Marc Sankalé (SN) established that there is a striking association of hepatitis B virus with primary hepatic carcinoma (PHC) (152; 929).

Marianna M. Newkirk (US), Aylward E.R. Downe (CA-US), Jerome B. Simon (US), William Wills (US), Bernard Larouzé (FR), W. Thomas London (US), Baruch Samuel Blumberg (US), Irving Millman (US), M. Pourtaghra () and J. Coz () found that both the North American bedbug (Cimex lectularius) and the tropical bedbug (Cimex hemipterus) can be carriers of hepatitis B virus (1141; 1716).

Philippe Maupas (FR), Pierre Coursaget (FR), Alain Goudeau (FR), Jacques Drucker (FR), Marc Sankale (FR), J. Linhard (FR), G. Diebolt (FR) and Wolf Szmuness (PL-US) reported that there is an association of hepatitus B virus with hepatocellular carcinoma (1035; 1556).

Maurice Ralph Hilleman (US), William J. McAleer (US), Eugene B. Buynak (US), and Arlene A. McLean (US) transformed the hepatitis B surface protein, discovered by Baruch Blumberg and known as the Australia antigen, into an effective vaccine (738). Note: Hepatitis B plays an important role in cancer of the liver. The hepatitis B vaccine holds hope that it may be the first anti liver-cancer vaccine.

June Goodfield (GB) reported that hepatitis B is probably the major cause of liver cancer in the world currently (614).

Soo Bin Park (CN) reported that a preventative vaccine for hepatitis E infection (HEV 239) was approved for use in China (1176).

 

Harry Plotz (US) grew the measles virus in the Macacus rhesus monkey, transferred it to chick embryo culture, and then induced the disease in monkeys (1218). This work essentially proved the viral etiology of measles.

John Franklin Enders (US) and Thomas C. Peeples (US) grew the measles (rubeola) virus in several cell lines including human kidney tissue culture and observed that it induced the formation of multinucleated syncytia with a foamy appearance in cell culture. It was during these experiments that foamy virus (a retrovirus) was discovered (520).

 

Erich Traub (DE-US) showed that if you inject lymphocytic choriomeningitis virus into embryonic mice in utero, they grow up without making antibodies to it, even though it is very foreign. Mice infected as adults give a normal immune response (1589). Ray David Owen (US) would later call this phenomenon tolerance. See Owen, 1945.

 

Venezuelan equine encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV), and Western equine encephalitis virus (WEEV) are members of the genus Alphavirus (family Togaviridae) transmitted by mosquitoes. Enzootic strains of EEEV and WEEV typically circulate among birds, whereas, VEEV circulates among rodents in forest or swamp habitats. Epizootic strains of VEEV, typically belonging to subtypes IAB and IC, circulate among equine amplification hosts in agricultural habitats, but are not known to persist in permanent foci.

C.E. Beck (US), Ralph W.G. Wyckoff (US), Vladimir Kubes (US), and Francisco A. Ríos (US) were first to isolate the etiological agent of Venezuelan equine encephalitis (VEE). It came from specimens obtained during an equine epizootic in Venezuela in 1936 (92; 896).

LeRoy D. Fothergill (US), John Holmes Dingle (US), Sidney Farber (US), and Marion L. Connerley (US) isolated EEEV from the brain tissue of several humans thus proving that it can infect man (562).

Leroy D. Fothergill (US), John Holmes Dingle (US), and Jacksolt Cabot Fellow (US) confirmed birds as playing a role in the transmission cycle of EEEV (563).

Beatrice F. Howitt (US) isolated the virus of equine encephalitis from the brain of a child (776).

William Trager (US) was the first to successfully grow an arbovirus (equine encephalomyelitis) in insect tissue culture. He maintained fragments of tissue from the mosquito, Aedes aegypti for two to three weeks depending upon the tissue (1586).

Beatrice F. Howitt (US) isolated WEEV from a man infected with it during an epidemic in California. This proved that humans are susceptible (777).

William McDowell Hammon (US), William Carlisle Reeves (US), Bernard Brookman (US), Ernest M. Izumi (US), and Claude M. Gjullin (US) determined that the viruses responsible for western equine and St. Louis encephalitis came from a species of mosquito called Culex tarsalis (677).

Rebecca R. Rico-Hesse (US), John T. Roehrig (VE), Dennis W. Trent (VE), and R.W. Dickerman (VE) reported that subtype IE VEEV strains have historically been considered enzootic and the mosquito Culex (Melanoconion) taeniopus is the proven enzootic vector for enzootic strains of this subtype (1293). Epizootic IAB and IC VEEV strains are thought to periodically emerge and then undergo extinction when they kill or immunize most equids.

Christina Ferro (CO), Jorge Boshell (CO), Abelardo C. Moncayo (US), Marta Gonzalez (CO), Marta L. Ahumada (CO), Wenli Kang (US), and Scott C. Weaver (US) found that enzootic and epizootic VEEV strains typically use mosquitoes from different species as vectors. Enzootic strains are believed to be transmitted almost exclusively by mosquitoes of the Spissipes section of the subgenus Melanoconion within the genus Culex (543).

Michael J. Turell (US), Joseph R. Bearman (US), Gary W. Neeley (US), Peter J. Bosak (US), Lisa M. Reed (US), Wayne J. Crans (US), Michael R. Sardelis (US), David J. Dohm (US), Benedict Pagac (US), and Richard G. Andre (US) reported that during some years, EEEV is transmitted to mammalian hosts by bridge vectors, mosquitoes that feed on both birds and mammals. Bridge vectors for EEEV include Coquilletidia perturbans and members of the genera Aedes, Ochlerotatus, and Culex. EEEV can also be found in the introduced species Aedes albopictus (the Asian tiger mosquito), and limited evidence suggests this mosquito might be a particularly efficient vector (167; 1380; 1591).

William Reisen (US) states that Culex tarsalis is the most important mosquito vector of arboviruses in western North America, responsible for maintenance, amplification and epidemic transmission of St. Louis and western equine encephalitis viruses in irrigated and riparian habitats. This species is also a vector of Llano Seco, Turlock, Gay Lodge, and Hart Park viruses, and several species of avian malaria. Cx. tarsalis is an efficient experimental vector of Japanese and Venezuelan equine encephalitis viruses. Culex tarsalis appears to be the most important vector of WEEV with a variety of mammals as incidental hosts (1278).

Henry R. Shinefield (US) and Thomas E. Townsend (US) presented evidence that in humans, WEEV can cross the placenta (1442).

There is currently a VEEV vaccine available for both humans and horses. The live attenuated vaccine known as TC-83 is a strain of VEEV that was passed 83 times in guinea pig heart cells. There is also an inactivated form of the vaccine known as C-84 derived from the TC-83 strain. Currently only the C-84 vaccine is licensed for use in horses in the U.S. although countries such as Mexico and Colombia still produce the live vaccine for horses.

 

Lowell Jacob Reed (US) and Hugo Muench (US) proposed a simple method of estimating fifty per cent endpoints in experimental biology, e.g., using the dilution by which half the animals are affected (1272).

 

Bodo van Borries (DE), Ernst August Friedrich Ruska (DE), Helmut Ruska (DE), and Gerhard Piekarski (DE) applied the electron microscope to the study of bacteria and viruses for the first time (1205-1207; 1600; 1601).

 

Edgar William Todd (GB) discovered that streptococci produce at least two different hemolysins, streptolysin O and streptolysin S (1582).

 

B. Saenz (CU), Alfonso Armenteros (CU), and Grau Trjana (CU) discovered that the spirochete Treponema pallidum carateum (herrejoni) is the etiological agent of Mal del Pinto. Their studies were based on earlier studies—1927—by Salvador Gonzalez Herrejon (MX) (1361).

 

M. Ruiz Castañeda (MX) showed that large numbers of Rickettsiae mooseri appear in the lungs of rats following intranasal inoculation (266).

 

Herald Rea Cox (US) described the successful cultivation of Rickettsia in the yolk sac of the developing chick embryo (357). The family Coxiellaceae and the genus Coxiella, which contain the organism that causes Q fever, are named for him.

 

Samuel Rickard Christophers (GB) and James D. Fulton (GB) were the first to investigate the metabolism of malarial parasites (290).

 

Sterling Howard Emerson (US) studied the self-incompatibility system of Oenothera organensis and found that pollen rejection is a function of the style under control of a locus with multiple alleles (516).

 

Dirkje E. Reinders (NL) found that auxin present in concentrations as low as 1mg/liter stimulated water uptake in potato discs along with an increase in respiration and loss in dry weight (1277).

 

John Nathaniel Couch (US) discovered that scale insects and the fungus Septobasidium have a mutually reliant relationship, but that together they destroy their host tree (355).

 

Gottfried Samuel Fraenkel (DE-US) and John W.S. Pringle (GB) showed that the halteres, which replace the second pair of wings in the adult fly, function as miniature gyroscopes or balance organs (566).

 

Hans Spemann (DE) proposed the first cloning experiment, transferring a nucleus from an adult cell to an enucleated egg. In 1928, he used the nucleus from a 16-cell salamander embryo to create an identical twin (1493).

Robert W. Briggs (US) and Thomas J. King (US), working on the frog Rana pipiens, successfully transplanted living nuclei in multicellular organisms. They transplanted blastula nuclei into enucleated eggs, which then developed into normal embryos (192).

John Bertrand Gurdon (GB) transplanted intestinal epithelium-cell nuclei from Xenopus tadpoles into enucleated frog eggs and managed to produce 10 normal tadpoles. The logical consequence of Gurdon's success — that the nuclei of differentiated cells retain their totipotency — provided a key conceptual advance in developmental biology (650; 651). This work proved that genes are not lost or changed during cell differentiation — they are just differentially expressed. It became clear that their cytoplasmic environment profoundly influences the genes expressed in a nucleus.

John Burdon Sanderson Haldane (GB-IN) used the word clone (from Greek for "twig") to describe Gurdon's frog experiments of 1962 (666).

John Bertrand Gurdon (GB) removed the nuclei from fertilized frogs’ eggs, replaced them with nuclei taken from cells of the gut of a single tadpole, and grew several frogs with identical genetic constitutions—an animal clone (652; 653).

Steen Malte Willadsen (DK-GB-CA-US) cloned sheep from early embryo cells. He is credited with being the first to clone a mammal using nuclear transfer (1700).

Keith H.S. Campbell (GB), Jim McWhir (GB), William A. Ritchie (GB), and Ian Wilmut (GB) cloned identical lambs from differentiated, 9-day old embryo cells (253). Note: One of these cloned animals was nicknamed "Dolly."

Ian Wilmut (GB), Angelika E. Schnieke (GB), Jim McWhir (GB), Alex J. Kind (GB), and Keith H. Campbell (GB) reported the birth of live lambs from three new cell populations established from adult mammary gland, fetus and embryo, i.e., the lambs were clones of adults. The fact that a lamb was derived from an adult cell confirms that differentiation of that cell did not involve the irreversible modification of genetic material required for development to term. The birth of lambs from differentiated fetal and adult cells also reinforces previous speculation that by inducing donor cells to become quiescent it will be possible to obtain normal development from a wide variety of differentiated cells (1718).

Samantha A. Morris (US) and George Q. Daley (US) discuss current strategies to manipulate the identity of abundant and accessible cells by differentiation from an induced pluripotent state or direct conversion between differentiated states. They contrast these approaches with recent advances employing partial reprogramming to facilitate lineage switching, and discuss the mechanisms underlying the engineering of cell fate (1104; 1105).

 

William Swan Ferguson (GB), A.H. Lewis (GB), and Stephen John Watson (GB) discovered that trace quantities of molybdenum in the diet of ruminants causes diarrhea. The disease is called teart (540).

 

Lucy Wills (GB) and Barbara D.F. Evans (GB) determined that tropical macrocytic anemia could be treated successfully using autolyzed yeast extract and/or injections of crude liver extract but not with the purified liver extract (vitamin B12) used to treat pernicious anemia (1715).

 

Hugh R. Butt (US) and Albert M. Snell (US) reported that their clinical trials indicated a rough inverse relationship between prothrombin levels and coagulation time (235). This led to the use of vitamin K for the treatment of hemorrhage in humans.

Hugh R. Butt (US), Albert M. Snell (US), and Arnold E. Osterberg (US) reported the first successful correction of a vitamin K deficiency in a patient with biliary obstruction (and intraluminal bile acid deficiency). They showed that a crude vitamin K preparation was absorbed and effective only when given together with conjugated bile salts (236).

 

Maurice Bolks Visscher (US), Raymond C. Ingraham (US), Richard L. Varco (US), Charles W. Carr (US), Robert B. Dean (US), Dorothy Erickson (US), E. Stanton Fletcher, Jr. (US), Harry P. Gregor (US), Marian Sedin Bushet (US), and Dorothy Erickson Barker (US) demonstrated how the intestine handles electrolytes. They established that both anions and cations can be absorbed against a diffusion gradient and that there is a lengthwise gradient of absorption and secretion in the small intestine. They determined that there is a substantial two-way traffic of sodium between blood and lumen of the small intestine and colon and that there is a gradient of decreasing traffic from duodenum to colon.

Chyme is brought to isotonicity and neutrality in the duodenum and upper jejunum by a brisk flow of electrolytes in both directions across the intestinal mucosa. In the ileum there is net absorption of sodium, chloride, and water, with secretion of bicarbonate replacing chloride in the lumen. The colon performs the essential function of maintaining the volume of extracellular fluid by net absorption of the sodium that escapes absorption in the ileum. Ingraham and Visscher presented compelling evidence for the independence of absorptive and secretory fluxes (804; 1622; 1623).

 

Henry Hubert Turner (US) described a series of young women with failure of sexual maturation, short stature, and neck webbing. These are the clinical symptoms of what later became known eponymically as Turner’s syndrome. Turner believed the symptoms were due to a defect in the anterior pituitary gland (1592). Today, we know the underlying cause is a 45, XO karyotype.

Charles Edmund Ford (GB), Ken W. Jones (GB), Paul Emanuel Polani (ES-GB), J. Carlos De Almedia (BR), and Joseph H. Briggs (GB) discovered that gonadal dysgenesis (Turner’s syndrome) in humans is associated with a 45,XO karyotype (558).

Malcolm A. Ferguson-Smith (GB) reported that about half of the patients with Turner’s phenotype have the karyotype 45,X0. In the remaining cases, mosaicism or rearrangement of the sex chromosome is seen. Structural aberrations can affect one of the X chromosomes (deletions of Xp or Xq, ring X, isoXq) or the Y (deletion of Yp or Yq, ring Y). The variability in the cytogenetic findings could explain some of the phenotypic differences. Karyotype/phenotype correlations in such patients indicate that many genes are involved in the formation of the full Turner phenotype (541).

 

Alexander Benjamin Gutman (US) and Ethel Benedict Gutman (US) pointed out the increased serum activity of acid phosphatase in metastasizing prostate carcinoma and demonstrated the usefulness of measuring serum acid phosphatase levels in the diagnosis and management of patients with prostatic malignancy (656).

 

David Bruce Dill (US) noted that reductions in maximal heart rate were as great as 40 to 50 beats per minute at an altitude of 17,500 feet; documented the phenomenon of hemoconcentration during both acute and chronic exposure to high altitude; discovered that the ability of some animals to adapt to high altitudes is more the result of quality than the quantity of their circulating hemoglobin; and showed that one way the human body adapts to higher temperature is by producing more perspiration which contains less salt per unit volume (429).

 

Mogens Fog (GB) performed animal experiments on cerebral blood circulation, showing elements of its regulatory mechanism. He found autoregulation of cerebral blood flow: the fact that normally the cerebral vessels constrict when the blood pressure increases and dilate when the pressure decreases (549).

Niels A. Lassen (DK) found support for the autoregulation of cerebral blood flow (CBF) in man by collecting several series of studies of induced hyper and hypotension, showing that within limits (and with unchanged arterial carbon dioxide) CBF was in fact unchanged. In patients with essential hypertension the autoregulatory plateauthe limits of pressures between which flow is maintained constant—is shifted toward higher pressures. The cerebral resistance vessels appeared to be adapted (hypertrophied?) to the higher pressure (930).

Svend Strandgaard (DK) found that the shift of cerebral autoregulation in chronic hypertension has been seen quite clearly, and there has been presented evidence suggesting that it may return to the normal pressure range after prolonged effective treatment (1538).

Svend Strandgaard (DK), Eric T. Mackenzie (GB), Dipankar Sengupta (IN), Jack O. Rowan (GB), Niels A. Lassen (DK), and A. Murray Harper (GB) studied flow increase with more marked hypertension to pressures above the ‘upper limit’ of autoregulation.This flow increase and the concomitant abnormal protein permeability of the blood brain barrier is probably an initiating event in acute hypertensive encephalopathy (1539).

R. Palvölgyl (HU) helped lead the way in studies of metabolic regulation of cerebral blood flow (1172). Note: One can by measuring blood flow in a given area reveal if it is active or inactive. We can map the areas of the brain in animals or in man during sensory perception movements, vocalization, etc.

 

Sid Robinson (US) in his doctoral dissertation performed the first study ever done describing the effect of age and of strenuous physical training on the aerobic capacity of man. Here for the first time appeared the relationship between age and maximal heart rate as approximately 220 minus age, a finding confirmed many times since (1307).

 

Dorothy Hansine Andersen (US) was the first to clearly identify fibrocystic disease of the pancreas (29).

Paul A. di Sant’ Agnese (US), Robert C. Darling (US), George A. Perera (US), and Ethel Shea (US) discovered that patients with cystic fibrosis (CF) lose excess salt in their sweat (425). Note: An adage from northern European folklore: ‘Woe to that child which when kissed on the forehead tastes salty. They are bewitched and soon will die’ (1671).

Lewis E. Gibson (US) and Robert E. Cooke (US) developed the sweat test to measure the concentration of chloride that is excreted in sweat. It is used to screen for cystic fibrosis (CF). Due to defective chloride channels (CFTR), the concentration of chloride in sweat is elevated in individuals with CF (604).

John R. Riordan (CA), Johanna M. Rommens (CA), Bat-sheva Kerem (CA), Noa Alon (CA), Richard Rozmahel (CA), Zbyszko Grzelczak (CA), Julian Zielenski (CA), Si Lok (CA), Natasa Plavsic (CA), Jia-Ling Chou (CA), Mitchell L. Drumm (CA), Michael C. Iannuzzi (CA), Francis S. Collins (CA), Lap-Chee Tsui (CA), Janet A. Buchanan (CA), Danula Markiewicz (CA), Tara K. Cox (CA), Aravinda Chakavarti (CA), Manuel Buchwald (CA), Georg Melmer (CA), Michael Dean (CA), Jeffrey L. Cole (CA), Dare Kennedy (CA), Noriko Hidaka (CA), and Martha Zsiga (CA) identified the cystic fibrosis gene, cloning and characterizing it with complementary DNA (852; 1297; 1313). Note: Cystic fibrosis is inherited as an autosomal recessive.

 

Jerome W. Conn (US), Louis Harry Newburgh (US), Margaret W. Johnston (US), and Elizabeth S. Conn (US) were among the first to clearly recognize the relationship between obesity and adult-onset diabetes by showing the resumption of normal carbohydrate tolerance after attainment of normal weight in twenty of twenty-one patients (331).

 

Charles Fisher (US), Walter Robinson Ingram (US), and Stephen Walter Ranson (US) showed that the hypothalamus is connected with the posterior lobe of the hypophysis by means of a large unmyelinated fiber tract that runs by way of the infundibular stem. The components of this tract play an important role in regulating the secretory activity of the neural hypophysis (546).

 

Walter Russell Brain (GB) and H.M. Turnbull (GB) described exophthalmic ophthalmoplegia or malignant exophthalmos as a separate entity from Grave’s exophthalmos (180).

 

Arthur Schüller (AT-GB-AU) was the first to adapt radiology to the diagnosis of epilepsy in children (1411). Note: two weeks after this paper was published Arthur and his wife fled from the Nazis to Oxford, England. Their two sons were captured and sent to concentration camps.

 

Julius Lempert (US) performed successful surgery for hearing restoration, now called Lempert's fenestration operation (946).

Samuel Rosen (US) mobilized the footplate of the stapes to restore hearing in otosclerosis--a procedure attempted by Jean Kessel (DE) in 1876 (1337).

John J. Shea, Jr. (US) developed the modern technique of footplate mobilization, soft tissue grafting of the oval window, and ossicular replacement. Shea is also credited with the first stapedotomy (1426; 1427).

 

Frederic Edward Mohs (US) developed the Mohs micrographic surgery (MMS) technique in 1938 to remove skin cancer lesions. The Mohs procedure is considered the best method for treating certain types of skin cancer, especially of the head and neck, with cure rates approaching 100% (1098). Occasionally called chemosurgery.

 

Walter Edward Dandy (US) discovered the cause of hydrocephalus then devised an operative treatment for repairing it (376).

 

John G. Kidd (US), Francis Peyton Rous (US), and Isaac Berenblum (US) showed that tumorigenesis is identified as a multistage disease, and it is shown that chemicals induce cancer in two distinct steps of initiation and promotion. A nonspecific irritant (wounding) was shown to promote tumorigenesis after initiation with a suboptimal dose of carcinogen (tarring or application of Shope papillomavirus to rabbit ears) (111; 856).

 

Harvey Williams Cushing (US), Louise Charlette Eisenhardt (US), and Edward B. Schlesinger (US) published their milestone monograph on Meningiomas. Their Classification, Regional Behaviour, Life History and Surgical End Results (367).

 

Herbert Faulkner Copeland (US) proposed the four-kingdom classification of all life forms. The four kingdoms are Monera, Protista, Plantae and Animalia. The kingdom monera is comprised of the unicellular organisms. The protists, plants and animals are the eukaryotic organisms. The fungi were placed in the group of plants which was considered as the drawback of the four-kingdom classification (346; 347).

 

The Congress of the United States passed the Federal Food, Drug, and Cosmetic Act of 1938. This act contained provisions dealing with prohibition of economic adulteration of food, mandatory food standards, truth in food labels or labeling, labeling of imitation foods as such, required labeling of foods with manufacturer’s name, address, net quantity of contents, name of the food, and ingredients of the food (329).

 

Harry Hatton (FR) and Joseph H. Connell (US) investigated the correlation between population age structures and severity of physical factors in the environment. They found that under very harsh conditions the population might be composed of a single dominant year class (332; 333; 697).

Harry Hatton (FR) authored a paper on the distribution of intertidal plants and animals at Saint Malo which must be regarded as the most important forerunner of intertidal "supplyside" ecology. In this work, which deals with two species of barnacles, a limpet, and three species of algae, Hatton addressed not only the problem of zonation, but also physical and biological factors (e.g., waves, water currents, exposure, substratum type, substratum orientation) that determined horizonal patterns of recruitment and mortality (697).

 

Heinrich Klüver (US) and Paul C. Bucy (US) performed experimental lesion studies in monkeys, which demonstrated that large temporal lobe lesions that included the amygdala resulted in dramatic postoperative changes in behavior, including flattened affect, visual agnosia, hyperorality, and hypersexuality (868).

 

South African fishermen, in 1938, netted a coelacanth off the coast of South Africa. It was identified as belonging to a group or subclass of fishes known as the Crossopterygia, or lobe-finned fish, which passed the heyday of their evolutionary history some 200 millions of years ago and were thought to be extinct. It was named Latimeria chalumnae to honor Miss Marjorie Courtenay-Latimer, a museum curator, in East London, South Africa. Almost immediately living specimens were filmed in their habitat (315; 1460; 1611).

 

Robert A. Broom (ZA) reported on and named the discovery of Australopithecus robustus: Paranthropus robustus (formerly Parathrops crassidens) by a schoolboy, Gert Terblanche, in 1938 at Kromdraai in South Africa. It had a body like that of A. africanus, but a larger and more robust skull and teeth. It existed between 2-1.5 M. The massive face is flat or dished, with no forehead and large brow ridges. It has relatively small front teeth, but massive grinding teeth in a large lower jaw. Most specimens have sagittal crests. Its diet would have been mostly coarse, tough food that needed a lot of chewing. The average brain size is about 530 cc. Bones excavated with robustus skeletons indicate that they may have been used as digging tools (195; 196).

 

Zeitschrift für Tierpsychologie (Journal of Animal Psychology), nowadays Ethology was founded.

 

1939

“The man who can see the miraculous in a poem, who can take pure joy from music, who can break bread with comrades, opens his window to the same refreshing wind off the sea. He too learns a language of men.

But too many men are left unawakened." (387).

 

 "Already I was beginning to realize that a spectacle has no meaning except it be seen through the glass of a culture, a civilization, a craft.” Antoine de Saint Exupéry (387).

 

"Upon this gilded age, in its dark hour

Rains from the sky a meteoric shower

Of facts…they lie unquestioned, uncombined,

Wisdom enough to teach us of our ill

Is daily spun, but there exists no loom

To weave it into fabric." Edna St. Vincent Millay (1088).

 

“As man is now changing the composition of the atmosphere at a rate which must be very exceptional on the geological time scale, it is natural to seek for the probable effects of such a change. From the best laboratory observations, it appears that the principal result of increasing atmospheric carbon dioxide … would be a gradual increase in the mean temperature of the colder regions of the Earth.” Guy Stewart Callendar (243).

 

“The fungi in their reproduction and inheritance follow the same laws that govern these activities in higher plants and animals.” Bernard Ogilvie Dodge (439).

 

Adolf Friedrich Johann Butenandt (DE), for his work on sex hormones, and Leopold Stefan Ruzicka (HR-CH), for his work on polymethylenes and higher terpenes, were awarded the Nobel Prize in chemistry. Butenandt was caused by the authorities of his country to decline the award but later received the diploma and the medal but not the money.

 

Gerhard J. Domagk (DE) was awarded the Nobel Prize in Physiology or Medicine for the discovery of the antibacterial effects of prontosil. (Caused by the authorities of his country to decline the award, but later received the diploma and the medal.)

 

Siemens AG (DE) produced the first commercial transmission electron microscope.

 

Werner E. Bachmann (US), J. Wayne Cole (US), and Alfred L. Wilds (US) accomplished the total synthesis of equilenin, a sex hormone from pregnant mares. This was particularly significant because it confirmed many of the assumptions about the configuration of the steroid ring structure (52).

 

Chester Wilson Emmons (US), Alexander Hollaender (US), Edgar Knapp (DE), A. Reuss (DE), Otto Risse (DE), and Hans Schreiber (DE) found that the maximum mutagenic response of bacteria to ultraviolet radiation corresponds with the peak absorption wavelengths for nucleic acid (518; 869). This represented strong circumstantial evidence for the concept that genes consist of nucleic acid.

 

Frank E. Gardner (US), Paul C. Marth (US), and Lawrence P. Batjer (US) pioneered the use of 1-naphthalene-acetic acid for pre-harvest drop control in apples (591).

 

Vincent du Vigneaud (US), Joseph P. Chandler (US), Arden W. Moyer (US), Dorothy M. Keppel (US), Mildred Cohn (US), George Bosworth Brown (US), Jay R. Schenck (US), and Sofia Simmonds (US) through their studies of the amino acid methionine and related compounds, explained how the body shifts a methyl group from one compound to another. By such shifts the body sometimes completes the construction of a complicated molecule (457-459).

 

Hermann Karl Felix Blaschko (DE-GB) was the first to propose a biosynthetic pathway to produce catecholamines such as the hormone epinephrine (adrenaline) (131).

Walter L. Halle () had proposed a very similar pathway in 1906 (668).

Toshiharu Nagatsu (US), Morton Levitt (US), and Sidney Udenfriend (US) confirmed Blaschko’s pathway (1125).

 

Linus Carl Pauling (US) and Carl George Niemann (US) discredited the theory that the amino acids of proteins exist in a cage like structure. Their evidence supported a chain structure (1182).

 

Jordi Folch (US) and Donald Dexter van Slyke (US) identified phosphatidyl serine (Folch and van Slyke 1939).

 

Henry Eyring (US) and Allen Edwin Stearn (US) suggested that denaturation of proteins involves breaking of salt linkages (formed by the mutual attraction of oppositely charged ions) and of covalent bonds (possibly the disulfide bonds of cystine units) (530).

Rufus Lumry (US) and Henry Eyring (US) proposed a feasible mechanism to account for protein denaturation (996).

 

A. Calvin Bratton (US) and Eli Kennerly Marshall, Jr. (US) developed a method for the quantitative determination of sulfonamides in blood and tissues. This method was important because it permitted a rational basis for dosage (185).

 

Samuel M. Ruben (US), William Zev Hassid (RU-GB-US), Martin David Kamen (CA-US), and Don DeVault (US) used the short-lived radioactive carbon, C11, as an indicator, to study the assimilation of C*O2 by barley. They found that leaves kept illuminated or in complete darkness for less than two and one-half hours formed radioactive carbohydrates. Leaves kept in the dark for over two and one-half hours did not form radioactive carbohydrates. This work with carbon 11 paved the way for isotope tracer research in plants (1344; 1346).

 

Georg Borgström (SE-US) found that plant shoots exposed to ethylene exhibited positive geotropism associated with the predicted auxin distribution. Ethylene must in some way influence the transverse movement of auxin (166).

 

Paul Jackson Kramer (US) found that, “Most, and possibly under some circumstances all, of the water absorbed by transpiring plants is absorbed as a result of forces set in motion by loss of water in transpiration.” Water absorption in plants occurs slowly by osmotic means at night when transpiration is negligible and results in “root pressure” in the vascular system often leading to formation of droplets around the margins of leaves (guttation). During the day water is absorbed by forces originating in the shoot because of the dehydration caused by transpiration, and these forces extend through the living tissues of the root into the soil water (879).

 

Ferenc Bruno Straub (GB) isolated and purified dihydrolipoyl dehydrogenase from heart muscle tissue. It uses flavine adenine dinucleotide (diaphorase or coenzyme factor) as its prosthetic group (1540).

 

Otto Heinrich Warburg (DE) and Walter Christian (DE) isolated an enzyme, glyceraldehyde-3-phosphate dehydrogenase, which catalyzes the oxidation of glyceraldehyde-3-phosphate to 1,3-diphosphoglyceric acid. They demonstrated that this reaction required the presence of inorganic phosphate and oxidized DPN (NAD), which was converted to reduced DPN (NAD) during the reaction. The reduced coenzyme subsequently donated hydrogens to acetylaldehyde to produce ethyl alcohol (350; 1652).

Otto Heinrich Warburg (DE), Walter Christian (DE), and Theodor Bücher (DE), isolated an enzyme which converts 1,3-diphosphoglyceric acid + adenosine diphosphate (ADP) to 3-phosphoglyceric acid + adenosine triphosphate (ATP) (218; 1653). This was a particularly important discovery because for the first time it linked the release of chemical energy by oxidation to the substrate level synthesis of adenosine triphosphate (ATP), i.e., substrate level phosphorylation.

Erwin Paul Negelein (DE) and Heinz Brömel (DE) determined that during glycolysis when glyceraldehyde-3-phosphate is acted upon by glyceraldehyde-3-phosphate dehydrogenase in the presence of inorganic phosphate the immediate product is 1,3-diphosphoglyceric acid (1132; 1133).

Jane Harting (US) and Sidney F. Velick (US) determined that acetyl phosphate formation and transfer is catalyzed by glyceraldehyde-3-phosphate dehydrogenase (691; 692).

Leon A. Heppel (US) determined that K+ and Na+ can cross an animal cell membrane (712-714).

John Robert Raper (US) and Arie Jan Haagen-Smit (NL-US) discovered that hormones are used to control sexual behavior in species of Achlya, a common genus of aquatic fungi (1253-1263).

Trevor McMorris (US) and Alma Barksdale (US) isolated and characterized hormone A of Achlya. It was found to be a sterol and renamed antheridiol, the first steroid hormone found in either plants or the fungi (1055).

 

Daniel Israel Arnon (PL-US) and Perry R. Stout (US) discovered that molybdenum is essential for growth in all plants (37).

 

George Wells Beadle (US) proposed the "Teosinte Hypothesis," in which maize was domesticated from teosinte by human selection (83).

Paul Mangelsdorf (US) later suggested that maize was the product of hybridization between an undiscovered wild maize and Tripsacum, the "Tripartite Hypothesis" (1021). Most scientists currently support the “Teosinte Hypothesis.”

 

Harry E. Warmke (US) and Albert Francis Blakeslee (US) described the sex mechanism in polyploids of Melandrium (1656).

 

John Charles Walker (US) found that internal black spot in beets is a disease due to a soil boron deficiency (1644).

 

Juda Hirsch Quastel (GB-CA) carried out one of the earliest studies of brain metabolism when he focused on the energy-yielding oxidative processes in slices and homogenates of brain (1243).

 

Vladimir Aleksandrovich Engelhardt (RU) and Militsa Nikolaevna Liubimova (RU) discovered that Kühne’s myosin, isolated in 1864, possesses an ATPase activity believed to catalyze the hydrolysis of ATP and thereby directly link muscle contraction with ATP hydrolysis (521).

 

Frank A. Brown, Jr. (US) and Ona Cunningham (US) demonstrated the influence of the hormone from the sinus gland in the eyestalk of crustaceans on normal viability and ecdysis (201). See, Zeleny, 1905.

 

George Widmer Thorn (US), Lewis L. Engel (US), Harry Eisenberg (US), Samuel S. Dorrance (US), and Emerson Day (US) found that bilaterally adrenalectomized dogs, fed a constant diet of low sodium and chloride content, may be maintained in excellent condition, by means of the subcutaneous implantation of pellets of crystalline desoxy-corticosterone acetate. This demonstrated that Addison’s disease is due to a deficiency of adrenal cortical hormone (1572; 1573).

 

Thomas H. Jukes (US), Dilworth Wayne Woolley (CA-US), Harry A. Waisman (US), and Conrad Arnold Elvehjem (US) discovered that pantothenic acid prevents a type of dermatitis in chickens (820; 1745).

Paul György (US) and C. Edward Poling (US) found that a greying of the hair in rats is caused by a deficiency of pantothenic acid (662).

Floyd S. Daft (US), William Henry Sebrell (US), Sidney H. Babcock, Jr. (US), and Thomas H. Jukes (US) found that a deficiency of pantothenic acid in rats produces hemorrhagic adrenal necrosis (368; 369).

William D. Salmon (US) and Ruben William Engel (US) reported that a deficiency of pantothenic acid causes lesions in the adrenal glands of rats (1362).

 

Alan Lloyd Hodgkin (GB), Andrew Fielding Huxley (GB), Howard J. Curtis (US), and Kenneth Stewart Cole (US) directly measured the action potential within the nerve fiber (cells) (318; 366; 750). “We have recently succeeded in inserting micro-electrodes into the giant axons of squids…. A small action potential was recorded from the upper end of the axon and this gradually increased as the electrode was lowered, until it reached a constant amplitude of 80-95 mv…. The axon appeared to be in a completely normal condition, for it survived and transmitted impulses for several hours…. These results…prove that the action potential arises at the surface” (750).

 

Eric T. Stiller (US), John C. Keresztesy (US), Joseph R. Stevens (US), Stanton A. Harris (US), and Karl August Folkers (US) discovered the molecular structure of pyridoxine (vitamin B6) and synthesized it (688; 689; 1530). Its molecular structure is designated 2-methyl-3-hydroxyl-4, 5-di (hydroxymethyl)-pyridine. This vitamin is necessary for the synthesis and breakdown of amino acids, the building blocks of protein; aids in fat and carbohydrate metabolism; aids in the formation of antibodies; maintains the central nervous system; aids in the removal of excess fluid of premenstrual women; promotes healthy skin; reduces muscle spasms, leg cramps, hand numbness, nausea & stiffness of hands; and helps maintain a proper balance of sodium & phosphorous in the body.

A deficiency of vitamin B6 may result in nervousness, insomnia, skin eruptions, loss of muscular control, anemia, mouth disorders, muscular weakness, dermatitis, arm and leg cramps, loss of hair, slow learning, and water retention.

 

Vladimir Aleksandrovich Belitzer; Vladimir Aleksandrovich Belitser (RU), Elena T. Tsibakova (RU), and Severo Ochoa (ES-US-ES) made the first quantitative measurements of phosphorus and oxygen in the respiratory chain and determined that the P:O ratio is greater than one. Ochoa concluded that the P:O ratio during the oxidation of pyruvate to carbon dioxide is 3 (103; 834; 1150; 1151).

 

W.J. Schmidt () gave the first evidence of fibrous organization in the living spindle with his observations of developing sea-urchin eggs made in 1937, and reinterpreted in 1939, with a polarizing microscope (1390).

Shinya Inoué (JP) gave the definitive visual demonstration of the existence of spindle fibers in untreated living cells (805).

 

George Otto Gey (US) and Frederick B. Bang (US) were the first to report a cytopathic effect caused by a virus in cell culture. The agent was lymphopathia venera virus (601).

 

Morris Frank Shaffer (US) and John Franklin Enders (US) developed a quantitative virus indicator system using counts of foci on the chorioallantoic membrane of the chick (1423).

 

Ernest Everett Just (US) wrote The Biology of the Cell Surface (821).

 

Johannes Friedrich Karl Holtfreter (DE-US) showed that if embryonic amphibian cells from different tissues are dissociated then mixed together the cells re-associate into tissue specific masses—so called histotypic aggregates (761-763). This is an application to vertebrates of Wilson’s discovery with sponges. See, Wilson, 1907.

 

Sven Otto Hörstadius (SE) described the differences in the early development of regulative eggs (each blastomere can give rise to a whole embryo) and mosaic eggs (isolated blastomeres produce only fragments of an embryo, i.e., determinate cleavage). He discovered the existence of a double gradient of animalization and vegetalization in the echinoderm egg (771; 772).

 

Carey H. Bostian (US) and Phineas W. Whiting (US) worked out the mechanism for sex determination in the hymenopterean, Habrobracon. Homozygosity or hemizygosity at a multiply allelic locus produces a male while heterozygosity at this same locus produces a female (168; 1687; 1688). Whiting went on to show that nine different alleles are known for this locus (1689).

 

Henry Arnold Lardy (US) and Paul H. Phillips (US) developed a medium for the preservation of animal sperm (926).

 

Schack August Steenberg Krogh (DK) found that the kidneys of whales and seals can produce urine with a salt concentration higher than seawater, thus they are able to drink seawater to replace the water lost from their tissues to the surrounding ocean (891).

 

Wendell H. Griffith (US) and Nelson J. Wade (US), based on their experimental results in rats, suggested that choline is essential for the maintenance of the normal structure of tissues as well as for its lipotropic action. A deficiency of choline is characterized by an extreme toxic state in which there is a marked hemorrhagic enlargement and degeneration of the kidneys, a regression of the thymus, and an enlargement of the spleen. The deficiency is prevented by amounts of choline too small to influence the deposition of liver fat. The requirement for choline is greater in young than in older rats (633).

 

Emory Leon Ellis (US) and Max Ludwig Henning Delbrück (DE-US) demonstrated the one-step growth curve for phage. It showed that the progeny of the infecting phage particle appear only after a period of constant phage titer (508).

 

James R. Dawson (US), Israel J. Kligler (IL) and Hans Bernkopf (IL) cultivated rabies virus in the chick embryo (383; 866).

 

Joseph I. Schleifstein (US) and Marion B. Coleman (US) were the first to recognize Yersinia enterocolitica as a human pathogen (1386).

Robert E. Black (US), Richard J. Jackson (US), Theodore F. Tsai (US), Michael Medvesky (US), Mehdi Shayegani (US), James C. Feeley (US), Kenneth I.E. MacLeod (US), and Adah M. Wakelee (US) first characterized Yersinia enterocolitica as food-borne (126).

Riitta Saario (FI), Rauli Leino (FI), Riitta Lahesmaa (FI), Kaisa Granfors (FI), Auli Toivanen (FI), Timo Yli-Kerttula (FI), Reijo Luukkainen (FI), Riitta Merilahti-Palo (FI), and Jouko Seppälä (FI) found that mild or inapparent infections of Yersinia enterocolitica may trigger autoimmune disorders such as thyroiditis and reactive arthritis, especially in individuals harboring the HLAB27 histocompatability allele (1359; 1584).

 

Mary E. Caldwell (US) and Dwight L. Ryerson (US) recovered members of the bacterial genus Arizona from cold-blooded animals (242).

 

René Jules Dubos (FR-US) and Roland D. Hotchkiss (US) isolated the antibiotics tyrocidin and gramicidin from Bacillus brevis, a common soil bacterium. Tyrocidin is toxic to all living cells; gramicidin, which is active both in the test tube and in animals against gram-positive bacteria, is, however, limited to external use because it destroys erythrocytes. Gramicidin was the first antibiotic to be produced commercially and employed clinically. It is still in use today (462-464).

 

Walter John Dowson (GB) named the bacterial genus Xanthomonas, but it had been known as a group for some time and its characteristics described (452).

 

Ian H. MacLean (GB), Keith B. Rogers (GB), and Alexander Fleming (GB) reported the first cases where microorganisms (Pneumococcus) had developed resistance to sulfonamide (1011).

 

Hans Gaffron (DE) found that if certain unicellular green algae are deprived of oxygen, they cease to be capable of ordinary photosynthesis but become capable of reducing carbon dioxide in light if hydrogen is provided as a substitute reductant to replace water (588).

 

George Henry Hepting (US) identified the previously undescribed cause of wilt disease in mimosa as Fusarium. This was one of the first reports of tree disease caused by a fungal species in this taxonomic group (715).

 

Carl G. Hartman (US), Chester Henry Heuser (US) and George Linius Streeter (US) followed macaque monkey embryonic development from the two-cell stage to the end of the embryonic period. Theirs is the first such complete description in a primate (693; 725).

 

Carl Pfaffman (US) described directionally sensitive cat mechanoreceptors (1201).

 

Irvine H. Page (US)  found that arterial hypertension had developed in animal kidneys in which cellophane had been wrapped around the kidneys to prevent the development of renal cortical collateral circulation. The reaction of tissue to cellophane was extraordinary. Contact for relatively short periods (three to thirty days) is enough to evoke a proliferative reaction which continues for a time, at least, after the cellophane has been dispersed by the omentum (1165).

 

A Committee for the Standardization of Blood Pressure Readings defined diastolic and systolic pressures as: “The systolic pressure is the highest level at which successive sounds are heard…. The point where the loud clear sounds change abruptly to the dull and muffled sounds should be taken as the diastolic pressure. The American Committee recommend that if there is a difference between this point and the level at which the sounds disappear completely the latter reading should be regarded also as a measure of the diastolic pressure” (1271).

 

A. Calvin Bratton (US), Eli Kennerly Marshall, Jr. (US), Dorothea Babbitt (US), and Alma R. Hendrickson (US) developed a clinical test (Bratton-Marshall test) to determine the tissue level of sulfonamide. A diazonium cation was reacted with a chromogenic coupling reagent, and the colored azo product was measured by absorption spectrophotometry (186).

 

Abner Wolf (US), David Cowen (US), and Beryl Paige (US) described human toxoplasmosis occurring in infants as an encephalomyelitis which they verified by transmission to animals (1727).

 

Norman Macdonnell Keith (US), Henry P. Wegener (US), and Nelson W. Barker (US) created four groups for hypertensive retinopathy, ranging from the benign group 1 to the so-called malignant hypertension as belonging to Group 4. They described the prognosis of people with differing severity of retinopathy. They showed that 70% of those with grade 1 retinopathy were alive after 3 years whereas only 6% of those with grade 4 survived (847). Note: Several other diseases can result in retinopathy that can be confused with hypertensive retinopathy. These include diabetic retinopathy, retinopathy due to autoimmune disease, anemia, radiation retinopathy, and central retinal vein occlusion.

 

Karl Sune Detlof Bergström (SE), Rune Eliasson (SE), Hans Dunér (SE), Ulf Svante Hansson von Euler-Chelpin (SE), Jan Sjövall (SE), and Bengt Pernow (SE) performed the first study on the cardiovascular effects of the pure prostaglandins in humans (116; 117).

 

Konrad Schäfer (DE) and Hildegard Gisela Gennerich (DE) started the study of platelet antigens when they proved the presence of AB blood-group antigens on human platelets (1384).

 

Andrew W. Brown (US), I.P. Bronstein (US), and Ruth Kraines (US) discovered that thyroid therapy diminishes mental retardation due to “cretinism,” “thyroid deficiency” and “hypothyroidism.” In this work “cretin,” “thyroid deficiency” and hypothyroidism” are used interchangeably (200).

 

Henry Stanley Banks (GB), in 1939, used sulfonamide for treating meningococcal meningitis (69).

 

F. Thiébaut (FR), J. Lemoyne (FR), and L. Guillatjmat (FR) described what became known as Refsum’s syndrome (Sigvald Bernhard Refsum), as a congenital condition consisting of retinitis pigmentosa, deafness, ataxia and peripheral neuropathy (1569). Note: This rare disorder was the first example of an inherited disorder in fatty acid oxidation. It is characterized by phytanic acid accumulation in the blood and tissues.

Sigvald Bernhard Refsum (NO) gave the first description of heredopathia atactica polyneuritiformis (HAP) or Refsum's syndrome as an autosomal recessive neurological disease that results in the over-accumulation of phytanic acid in cells and tissues. The disease usually begins in late childhood or early adulthood with increasing night blindness due to degeneration of the retina (retinitis pigmentosa). If the disease progresses, other symptoms may include deafness, loss of the sense of smell (anosmia), problems with balance and coordination (ataxia), dry and scaly skin (ichthyosis), and heartbeat abnormalities (cardiac arrhythmias) (1274).

 

Robert Edward Gross (US) and John Perry Hubbard (US) were the first to carry out a successful ligation of a patent ductus arteriosus (a fetal blood vessel between the pulmonary artery and the aorta) (639). The operation was performed on August 28, 1938. The patient made an uneventful recovery.

John C. Munro (US) had justified and described (but did not perform) an operation for ligation of the ductus arteriosus to repair patent ductus arteriosus (1119).

 

Brian Thaxton King (US) and Joseph Dominic Kelly (US) described an operation to restore the function of the vocal cords (849; 860).

 

Percival Bailey (US), Douglas Nisbet Buchanan (US), and Paul Clancy Bucy (US) wrote the first serious and detailed study of intracranial tumors of infancy and childhood (57).

 

A. Gordon Ide (US), Norman H. Baker (US), and Stafford L. Warren (US) found that tumors transplanted into the ears of rabbits elicited a vascular network. This was early evidence of the phenomenon of angiogenesis, or new blood vessel growth, which would later become a target for antiangiogenesis cancer therapies. They made the seminal suggestion that tumors might produce a vessel growth-stimulating substance (796).

Glenn H. Algire (US), Harold W. Chalkley (US), Frances Y. Legallais (US), and Helen D. Park (US) postulated that the growth advantage of a tumor cell over its normal counterpart might not be due to "some hypothetical capacity for autonomous growth inherent within the [tumor] cell," but rather to its ability to continuously induce angiogenesis — that is, the formation of new blood vessels. They watched blood vessels migrate toward tumors in wound chambers. This was the first demonstration that tumors actively attract new blood vessels (17-19).

Isaac C. Michelson (GB) gave the first description of an angiogenic activity, regulated by oxygen, elaborated by the retina and mediating abnormal, retinopathic vessel growth (1087). Michelson's 'factor X' was eventually identified as vascular endothelial growth factor (VEGF) and confirmed to be the underlying causal factor of retinopathies.

Melvin Greenblatt (US), Philippe Shubik (GB-US), Robert L. Ehrmann (US), and Mogens Knoth (US) showed that tumor transplants stimulated the proliferation of blood vessels via a true diffusible substance that could, in theory, be identified (502; 629).

Moses Judah Folkman (US) introduced the concept that angiogenesis inhibitors could be used in the treatment of cancer (553).

Moses Judah Folkman (US), Ezio Merler (US), Charles Abernathy (US), and Gretchen Williams (US) isolated just such a tumor angiogenic factor (TAF) from tumor extracts and proposed that the growth of malignancies might be prevented if TAF activity were blocked (552; 554; 555).

Michael A. Gimbrone, Jr. (US), Stephen B. Leapman (US), Ramzi S. Cotran (US), and Moses Judah Folkman (US) reported that small balls of living tumor cells do not increase in size when suspended in the anterior chamber of the eye where they are deprived of vascularization. When such dormant balls of cells are moved from the anterior chamber to a nearby spot in the eye where they can attract vessels from the iris, they then grow exponentially. This is the first paper to provide direct evidence that the progressive growth of a tumor can indeed be dependent on angiogenesis (610).

David W. Leung (US), George Cachianes (US), Wun Jing Kuang (US), David V. Goeddel (US), and Napoleone Ferrara (US) purified and subsequently identified the gene encoding vascular endothelial growth factor (VEGF) which is a secreted protein that can stimulate both vascular endothelial cell proliferation in vitro and angiogenesis in vivo (953).

K. Jin Kim (US), Bing Li (US), Jane Winer (US), Mark Armanini (US), Nancy Gillett (US), Heidi S. Phillips (US), and Napoleone Ferrara (US) demonstrated that monoclonal antibody specific for vascular endothelial growth factor (VEGF) inhibited the growth of the tumors, but had no effect on the growth rate of the tumor cells in vitro (859).

Douglas Hanahan (US) and Moses Judah Folkman (US) found that tumors appear to activate the angiogenic switch by changing the balance of angiogenesis inducers and countervailing inhibitors (682).

 

Julian Sorell Huxley (GB) introduced the concept of the cline in evolutionary variation (792). Cline is the gradual and continuous variation in genetic character over an extensive geographical area because of adjustments to changing conditions.

 

Hans Hass (AT) was among the first to introduce worldwide audiences to the beauties of coral reefs, stingrays, octopuses and sharks — especially sharks, which he considered the most beautiful and most maligned ocean creatures. He published his first book of underwater photographs, Underwater Hunting, in 1939 and released his first underwater film, Stalking Under Water, a year later (695).

 

c. 1940

It was established by consensus that the clear majority of proteins are built up from a mixture of no more than 20 amino acids. From 1819 through 1936 only 20 amino acids had been found to be constituents of proteins based on isolation from protein hydrolysates.

 

1940

“Men think themselves free, because they are conscious of their volitions and of their desires and are oblivious to the causes which dispose them to desire and to will.” Charles Scott Sherrington (1439).

 

Samuel M. Ruben (US) and Martin David Kamen (CA-US) isolated carbon-14, which has a half-life of 5730 years. It quickly became one of the most useful of all isotopes in biochemical research and has also been turned to historical and archaeological use. Carbon-14 did not become widely available for metabolic studies until after World War II (836).

 

Alfred Otto Carl Nier (US) published the description of a mass spectrometer for routine isotope abundance measurements and suggested that the apparatus was sufficiently accurate to measure the 13C/12C ratio if separated 13C was used as a tracer in biological investigations (1143).

 

Charles Dubois Coryell (US) introduced the terms exergonic and endergonic to denote free-energy changes in chemical reactions (353).

 

Paul Hermann Müller (CH) discovered that 1,1,1-trichloro-2, 2-bis (p-chlorophenyl) ethane or dichloro-diphenyl-trichloroethane (DDT) is a potent insecticide with low toxicity for higher organisms (1114-1116). This compound was originally synthesized in 1873 by Othmar Zeidler (Othmar Ziedler) (DE) for his Ph.D. thesis work. He knew nothing of its biological activity (1761).

 

Ammonium sulfamate was introduced as a herbicide for control of woody plants in 1940 (727).

 

Andrei Nikolaevitch Belozersky (RU) found that both DNA and RNA are always present in bacteria (106).

 

Doris Elaine Dolby (GB), Leslie Charles Nunn (GB), and Ida Smedley-MacLean (US) discussed the possibility that linoleic acid could be a physiological precursor to arachidonic acid (443).

 

Roger J. Williams (US) and Randolph T. Major (US) determined the structure of pantothenic acid (1714).

Eric T. Stiller (US), Stanton A. Harris (US), Jacob Finkelstein (US), John C. Keresztesy (US), and Karl August Folkers (US), achieved the total synthesis of pure pantothenic acid (1529).

 

Robert Edward Eakin (US), Esmond Emerson Snell (US), Roger John Williams (US), and William A. McKinley (US) isolated from raw egg white a protein called injury-producing protein, which they named avidin (473-475). This protein forms a strong union with biotin (vitamin H) and prevents its absorption from the intestinal tract.

 

Moses Kunitz (RU-US) described the isolation of bovine ribonuclease in crystalline form (904).

 

Leslie A. Epstein (US); Leslie A. (Epstein) Falk and Ernst Boris Chain (DE-GB) showed that lysozyme is an enzyme, that its substrate is peptidoglycan of bacterial cells, and that it hydrolyzes a beta-1, 4-glycosidic bond in the glycan backbone chain (522).

 

Heinz Ludwig Fraenkel-Conrat (DE-US), Choh Hao Li (CN-US), Miriam E. Simpson (US), and Herbert McLean Evans (US) biologically characterized then isolated the luteinizing hormone (LH), also known as interstitial cell-stimulating hormone (ICSH) in males (567; 568; 968).

 

Edward Lawrie Tatum (US) and George Wells Beadle (US) isolated and crystallized what was called the v+ hormone from a bacterial culture supplied with tryptophan (1560).

 

Willard F. Verwey (US) was the first to describe staphylococcal protein A (SPA). He characterized it as a protein antigen present in type A staphylococci (coagulase-positive, alpha toxin positive, mannitol fermenting, and pathogenic; i.e., S. aureus) but not in the type B staphylococci (those lacking these characteristics) (1615).

Arne Grov (NO), Berit Myklestad (NO), and Per Oeding (NO) proposed the designation protein A (641).

Arne Forsgren (SE) and John Sjoquist (SE) showed that the well-recognized ability of all human sera to agglutinate S. aureus, which had been attributed to the universal presence of so-called natural antibodies, did not in fact represent an immune reaction. They showed that purified SPA bound to the Fc fragment of the immunoglobulin molecule, not to the antigen-binding Fab fragment (560). SPA became a valuable agent for immunochemistry and immunoassays.

 

Zacharias Dische (FR) discovered that the phosphorylation of glucose in erythrocytes is prevented by addition of phosphoglycerate. This may be the first example of end-product (negative feedback) inhibition (435).

 

Ferenc Brunó Straub (HU) reported the crystallization of lactic dehydrogenase from beef heart muscle (1541).

 

Wilbur Paul Wiggert (US), Milton Silverman (US), Merton Franklin Utter (US), and Chester Hamlin Werkman (US) were the first to obtain soluble enzyme preparations capable of fermenting carbohydrates from bacteria (1696). This opened the way for bacteria to be used as experimental material in the study of metabolic pathways.

Merton Franklin Utter (US) and Chester Hamlin Werkman (US) demonstrated that bacteria have fermentative pathways involving many of the same reactions as yeast and muscle (1597; 1598).

 

Otto Gsell (CH) performed the first important trial of sulphatiazole (642).

 

Donald Devereux Woods (GB) and Paul Gordon Fildes (GB) postulated that sulphanilamide acts by blocking the utilization of p-aminobenzoic acid by bacteria. This represents the origin of the essential metabolite inhibition hypothesis (1735-1737).

 

Sydney Dattilo Rubbo (AU) and Jeffrey M. Gillespie (AU) proved that p-aminobenzoic acid is a vitamin for bacteria (1342).

Edward Nielsen (US), J.J. Oleson (US), Conrad Arnold Elvehjem (US), Gustav Julius Martin (US) and Stefan Ansbacher (US) proved that for rats p-aminobenzoic acid is a vitamin (1032; 1142).

 

Dilworth Wayne Woolley (CA-US), Gertrude Gavin (CA), and Earle W. McHenry (CA) demonstrated that inositol is a vitamin in the diet of mice and rats (595; 1740-1742).

 

Andrew J. Krog (US), and Charles G. Marshall (US) used a swab technique to establish the bactericidal action of Zephiran, a quaternary ammonium compound, against bacteria commonly found on eating and drinking utensils. A one-minute exposure to a 1: 5,000 dilution was apparently sufficient to reduce bacteria surviving on tumblers to less than 100 per rim (890).

 

Ernst Boris Chain (DE-GB), Howard Walter Florey (AU-GB), Arthur Duncan Gardner (GB), Norman G. Heatley (GB), Margaret Augusta Jennings (GB), Jena Orr-Ewing (GB), A. Gordon Sanders (GB), Edward Penley Abraham (GB), and Charles M. Fletcher (GB) developed the cultural and chemical methodology to produce pure penicillin from Penicillium and found that it displayed potent in vivo antimicrobial activity against certain pathogens. This purified antibiotic was first used clinically on an Oxford, England policeman suffering from staphylococcal pyemia (4; 272).

Anne Miller (US), in 1942, became the first American civilian patient to be successfully treated with penicillin. She was lying near death at New Haven Hospital in Connecticut, after miscarrying and developing an infection that led to blood poisoning.

Kenneth Bryan Raper (US), working at the Northern Regional Research Laboratory, isolated Penicillium chrysogenum strain NRRL 1951 from a moldy cantaloupe brought to him by a Peoria, Illinois housewife in 1943. This strain could produce large quantities of penicillin in submerged culture and subsequently became the parent of most all strains used in the production of penicillin. Once larger quantities of the antibiotic were available it was used to treat war casualties starting in Tunisia and Sicily in 1943.

 

Selman Abraham Waksman (RU-US) and Harold Boyd Woodruff (US) isolated the antibiotic actinomycin D from Streptomyces antibioticus. This antibiotic, the first ever isolated from actinomyces, is too toxic for use in animals (1637; 1638). Actinomycin D binds to DNA and blocks the movement of RNA polymerase (prevents RNA synthesis) in both prokaryotes and eukaryotes.

 

Gustav A. Kausche (DE) and Helmut Ruska (DE) took the first electron photomicrographs of chloroplasts (842).

 

Linus Carl Pauling (US) proposed his version of the template mechanism for antibody synthesis. This introduced the concept of complementariness in association with biological macromolecules (1179).

Linus Carl Pauling (US) and Max Ludwig Henning Delbrück (DE-US) suggested that the surface of a gene somehow acts as a positive mold, or template, for the formation of a molecule of complementary (negative) shape (1181).

 

Karl Landsteiner (AT-US), Alexander Solomon Wiener (US), Philip Levine (RU-US) and Rufus E. Stetson (US) discovered that if a rabbit is injected with the blood of a rhesus monkey, (Macacus rhesus), its blood in turn develops an immune substance which will agglutinate not only the monkey’s blood but also that of about 85 percent of humans. Thus, there must be in some human blood a substance which is also present in the monkey; for convenience they called it “Rh” (from rhesus).  Levine and Stetson published in a first case report the clinical consequences of non-recognized Rh factor, hemolytic transfusion reaction, and hemolytic disease of the newborn in its most severe form (920; 959). Landsteiner and Wiener elaborated on the hemolytic transfusion reactions (918; 919; 1690).

Ronald Aylmer Fisher (GB) and Robert Russell Race (GB) postulated that the blood Rh factor is controlled by three pairs of closely linked genes leading to the possibility of 27 different Rh genotypes. They proposed a new nomenclature using the symbols C, c, D, d, E, e to designate the six antigens and anti-C, anti-c, anti-D, etc. to designate the antibodies specific for these antigens (Fisher's CDE hypothesis). In the 1944 paper, Race also showed that in addition to the supposedly normal form of anti-Rh (anti-D) antibody, which agglutinated D-positive red cells directly, when they were suspended in a saline medium, there existed a variant, known as incomplete antibody (547; 1246). The D or Rh0 antigen is by far the most antigenic of all the Rh factors therefore anti-D antiserum is typically used in Rh blood typing.

This real factor found in rhesus macaque was classified in the Landsteiner-Wiener antigen system (antigen LW, antibody anti-LW) in honor of the discoverers (49).

 

Louis Klein Diamond (US) and Alexander Solomon Wiener (US) also discovered incomplete antibodies at about the same time (426; 1691).

 

Øjvind Winge (DK) and Otto Laustsen (DK) showed that in the yeast Saccharomyces cerevisiae colonial characteristics, cell shape, and fermentative ability are under the control of genes that segregate during the reductive division (1720).

 

William C. Snyder (US) and Hans N. Hansen (US) proposed a system of taxonomy for Fusarium section Elegans, in which the 10 species, 18 varieties, and 12 forms of Wollenweber and Reinking are placed in one species, Fusarium oxysporum, on the sole basis of morphology (1476). Note: Fusarium species are parasites or pathogens on nearly all plants, including trees, in all parts of the world, and produce mycotoxins making some plant products hazardous to animals and humans.

 

Charles Clemon Deam (US) produced his Flora of Indiana; a 1,236-page creation resulting from Deam personally collecting specimens in all 1,016 townships in Indiana. This flora has excellent keys; Indiana distributional maps for all species and especially observational and/or critical notes about most. Deam's wife Stella faithfully worked alongside her husband as a research assistant (389).

 

Helmut Ruska (DE), Ubald Kottmann (DE), Edgar Pfankuch (DE), Gustav Adolf Kausche (DE), Salvador Edward Luria (IT-US), Thomas Foxen Anderson (US), Constantin Levaditi (FR), and Paul Bonet-Maury (FR) were the first to take electron photomicrographs of virus (bacteriophage), establishing their particulate nature and proving that specific bacteriophages have characteristic morphologies (878; 954; 999; 1202; 1354-1356).

 

Richard O. Roblin, Jr. (US), James H. Williams (US), Philip S. Winnek (US), and Jackson P. English (US) discovered sulfadiazine, which later proved especially good at treating epidemic cerebrospinal meningitis (1310)

 

The parent L strain cell culture was derived from normal subcutaneous areolar and adipose tissue of a 100-day-old male C3H/An mouse by Wilton R. Earle (US) in 1940. National Centre for Cell Science (NCTC) clone L929 is a clone of strain L (also known as L929) that was subsequently derived in March 1948. Strain L was one of the first cell strains to be established in continuous culture, and clone 929 was the first cloned strain developed. Clone 929 was established (by the capillary technique for single cell isolation) from the 95th subculture generation of the parent strain. The cells were treated with 20 methylcholanthrene and produced sarcomas when injected into C3H strain mice.

 

Kenneth C. Smithburn (US), Thomas P. Hughes (US), Alexander W. Burke (US), J. Harland Paul (US), and Henry R. Jacobs (US) isolated the virus of West Nile Fever from the blood of an African native of Uganda (1473; 1474). In recent years West Nile virus has spread beyond its traditional boundaries, causing illness in birds, horses, and humans in Europe and now the United States.

Costin Cernescu (RO), Simona Maria Ruta (RO), Gratiela Tardei (RO), Camelia Grancea (RO), L. Moldoveanu (RO), E. Spulbar (RO), and Theodore F. Tsai (CN-RO) reported 800 cases hospitalized during the viral meningoencephalitis epidemic caused by the West Nile virus in Southern Romania (268). This report is significant because it exhibits the increased neurotropic nature of the virus.

 

Ralph T. White (US) and Samuel R. Dutky (US) determined that type A white milky disease of insects and type B white milky disease of insects are caused by Bacillus popilliae and Bacillus lentimorbus, respectively (1686).

 

Edward Penley Abraham (GB) and Ernst Boris Chain (DE-GB) described a substance from Escherichia coli that could inactivate penicillin. They named it penicillinase (beta-lactamase) (3).

 

Karl Meyer (US), Gladys Lounsberry Hobby (US), Eleanor Chaffee (US), and Martin Henry Dawson (US) discovered hyaluronidase in the supernatant fractions of cultures of hemolytic streptococci (1075).

 

Paul W. Miller (US), Walter Beno Bollen (US), Joseph E. Simmons (US), H.N. Gross (US), and Howard P. Barss (US) described Xanthomonas corylina (Xanthomonas campestris) as the causative agent of bacteriosis in filbert (1091).

 

Friedrich Seidel (DE), Eberhard Bock (DE), and Gerhard Krause (DE), working with the golden-eyed fly, Chrysopa (Neuroptera) discovered the existence of a primary embryonic inductor in insects, which is associated with a specific germ layer, the ectoderm. Inductive stimuli originate in the ectoderm, and the underlying mesoderm responds with specific differentiations (1418; 1419). These were primarily Bock’s discoveries.

 

Soichi Fukuda (JP) discovered the prothoracic gland while studying the induction of pupation in the Chinese bivoltine race of silkworm (Bombyx) and the Japanese bivoltine race. This gland was found to be the source of internal secretion, which at a critical period releases into the blood a substance responsible for pupation (581-585).

 

John Henry Comstock (US) reported that the wing shape and vein pattern in insects is species-specific and is useful taxonomically (326).

 

Gavin Rylands de Beer (GB) refuted the theory that the embryonic development of an organism repeats the adult stages of the organism’s evolutionary ancestors (384).

 

Ruben A. Stirton (US) and George Gaylord Simpson (US) published phylogenetic studies of the North American horse. These are among the best and most complete phylogenetic studies ever written (1447; 1531).

 

Edmund Briscoe Ford (GB) defined genetic polymorphism (559).

 

Lewis Victor Heilbrunn (US) and Floyd J. Wiercinski (US) demonstrated the contractile effect of calcium ions when injected into frog muscle cells (708; 710).

Lewis Victor Heilbrunn (US) put forward the calcium ion release theory of muscle contraction in 1943, stating that calcium ion released from internal storage sites into the muscle cytoplasm by electrical or chemical stimuli, was assumed to activate the contractile material (709).

 

Adalbert Farkas (IL) and Joseph Aman (IL) were the first to report resistance of a plant pathogen to an organic fungicide (535).

 

Thaddeus Robert Rudolph Mann (PL-GB) and David Keilin (PL-GB) determined that sulphanilamide is a potent inhibitor of carbonic anhydrase (1024).

William B. Schwartz (US) found that sulphanilamide produces an increased sodium, potassium and water excretion in patients with congestive heart failure; this likely resulted from inhibition of carbonic anhydrase in cells of the renal tubules (1414).

 

William Bloom (US), Margaret A. Bloom (US), Lincoln V. Domm (US), and Franklin C. McLean (US) were the first to demonstrate the importance of estrogens in laying down bone minerals in bone metabolism. They recorded the transformation of osteoblasts into osteoclasts (144-148).

 

Valy Menkin (US) demonstrated that adrenal cortical extract or Compound E (cortisone) would suppress inflammation in laboratory animals (1066; 1070). See, Philip Showalter Hench, 1949.

 

Fuller Albright (US) and John D. Stewart (US) pointed out the role of steatorrhea in depleting the body of fat-soluble vitamins (14).

 

Erik Waaler (NO) described agglutination by rheumatoid sera of sheep cells sensitized with a sub-agglutinating coating of gamma globulin. This represents the discovery of the rheumatoid factor (RF). RF is an antibody directed to the Fc part of antibodies of the human IgG class. This and the description of the same phenomenon by Harry Melvin Rose (US), Charles Ragan (US), Elizabeth Pearce (US), and Miriam Olmstead Lipman (US) laid the foundation of one of the most important tests in rheumatology. Charles M. Plotz (US) and Jacques M. Singer (US) refined the test (1217; 1314; 1627).

Albert Tannenbaum (US) examined the effects of underfeeding on the initiation and growth of induced skin and subcutaneous tumors and spontaneous breast and lung tumors. He concluded that initiation and growth of tumors may be controlled by different factors and should therefore be studied separately. He showed that in underfed mice fewer tumors are formed and at a later time (retarded initiation) than in full-fed animals, that the rate of growth of tumors developing in underfed animals appears to be the same as that of tumors developing in full-fed animals, and that the rate of growth of tumors developing in full-fed animals diminishes when these animals are subsequently underfed (1558).

Albert W. Hetherington (US), Stephen Walter Ranson (US), Bal K. Anand (US), and John R. Brobeck (US) by using lesioning studies paved the way to the " classic " teaching of hypothalamic control of feeding behavior by two competing systems, one in the lateral hypothalamic area (LHA) and the other in the ventromedial hypothalamus (VMH). Lesions of the LHA resulted in cessation of feeding behavior and severe anorexia, while those of the VMH resulted in hyperphagia and obesity (27; 28; 724). Note: It was first found over a hundred years ago that hypothalamic injuries led to the rapid onset of obesity in patients (211; 578).

 

Ralph Rossen (US), Herman Kabat (US), John P. Anderson (US), Lawrence M. Weinberger (US), Mary H. Gibbon (US), and John Heysham Gibbon, Jr. (US) determined that the cerebral cortex in humans is damaged irreversibly by relatively short periods of ischemia (a few minutes), while lower centers, such as the medulla, can survive for longer periods of temporary interruption in their supply of blood. They noted that a cessation of blood flow to the cerebral cortex for 6.8 seconds caused a loss of consciousness (1339; 1665).

 

Derek Ernest Denny-Brown (NZ-GB-US), W. Ritchie Russell (GB), Hugh John Forster Cairns (GB-US-GB), and Denis Williams (GB) did extensive research on cerebral concussion, post-concussion syndrome, closed head injury, disability from head injury, “shell-shock” and the effect on the head of high explosives (240; 400-405; 417-419; 1711).

 

Douglas R. Drury (US), George E. Boxer (US), and DeWitt Stetten, Jr. (US) observed that the livers of diabetic or starved animals exhibited a large decrease in capacity to synthesize fatty acids (172; 454).

 

John Christian Krantz, Jr. (US), Jelleff C. Carr (US), Sylvan E. Forman (US), and William E. Evans, Jr. (US) introduced cyprome ether as an anesthetic (881).

 

Hugh G. Grady (US) and Harold L. Stewart (US) first identified the type 2 cell of the pulmonary alveolus as the cell of origin of the common alveologenic tumors of the lungs of mice (621).

 

Oscar V. Batson (US) found it possible to explain most cases of aberrant malignant metastases, aberrant pyogenic metastases and aberrant embolism following air injections by the demonstrated role of the vertebral vein system (80).

 

Henk Verbiest (NL) identified lateral spinal stenosis of the lumbar nerve canal (1612; 1613). His first description of lateral spinal stenosis was in 1940.

 

Robert Fiske Griggs (US) was perhaps the first to place plant rarity into an ecological context, acknowledging that plants do not statically interact with their surrounding environment. He also observed a geographic component to rare species distributions: some occur only in very restricted sites while others are more widespread, but sparsely populated. Griggs speculated the former were relics that had previously covered a larger area but had become “slowly dying vestiges of races once widespread." In addition, he proposed that “habitat choice” or specificity was an ecological determinant of rare species occurrence and that certain types of habitats (e.g. rock outcrops, oceanic islands, and river margins) consistently harbored rare plant assemblages. The most resounding theory produced from this seminal paper was the notion that many plants are rare because they are poor competitors, predominantly existing in early successional or “ecologically young” environments where competitive pressures are low (634).

 

Marcel Ravidat (FR), Jacques Marsal (FR), Georges Agnel (FR), and Simon Coencas (FR) discovered the cave at Lascaux, France where man produced representational art on the walls. It contains a great collection of Paleolithic art 10-15 K BP years old (1).

 

There occurred a widespread epidemic of rubella (German measles) in Australia.

 

1941

“Nothing is more flatly contradicted by experience than the belief that a man, distinguished in one of the departments of science is more likely to think sensibly about ordinary affairs than anyone else.” Wilfred Batten Lewis Trotter (1590).

 

“The first [quality] to be named must always be the power of attention, of giving one's whole mind to the patient without the interposition of anything of oneself. It sounds simple but only the very greatest doctors ever fully attain it. ... The second thing to be striven for is intuition. This sounds an impossibility, for who can control that small quiet monitor? But intuition is only interference from experience stored and not actively recalled. ... The last aptitude I shall mention that must be attained by the good physician is that of handling the sick man's mind.” Wilfred Batten Lewis Trotter (1590).

 

“The mind likes a strange idea as little as the body likes a strange protein and resists it with similar energy. It would not perhaps be too fanciful to say that a new idea is the most quickly acting antigen known to science. If we watch ourselves honestly we shall often find that we have begun to argue against a new idea even before it has been completely stated.” Wilfred Batten Lewis Trotter (1590).

 

“The various systems of doctrine that have held dominion over man have been demonstrated to be true beyond all question by rationalists of such power—to name only a few—as Aquinas and Calvin and Hegel and Marx. Guided by these master hands the intellect has shown itself deadlier than cholera or bubonic plague and far crueler. The incompatibility with one another of all the great systems of doctrine might surely be expected to provoke some curiosity about their nature.” Wilfred Batten Lewis Trotter (1590).

 

Albert Hewett Coons (US), Hugh J. Creech (US), R. Norman Jones (US), and Ernst Berliner (DE) attached fluorescent dyes to antibodies then used them to detect antigens; the so-called direct fluorescent antibody technique. The first fluorescent dye they used was B-anthryl isocyanate, which gives a blue fluorescence. Later they used fluorescein, to detect pneumococcal antigens. It gives a green fluorescence. This discovery made it possible to trace antigen and antibody within cells (342; 343).

Albert Hewett Coons (US) and Melvin H. Kaplan (US) improved the ability of the technique to localize antigens in tissue cells (344). This immunofluorescent technique is so important because it permits the detection of antibodies, antigens, and virtually any antigenic substance.

 

Archer John Porter Martin (GB) and Richard Laurence Millington Synge (GB) introduced liquid-liquid partition (column) chromatography which depends on the establishment of an equilibrium between two liquid phases (e.g., chloroform and water), one of which (water) is immobilized by being held by a solid support (e.g., silica gel), as the other (chloroform) flows through the column. Note: both high-pressure gas-liquid partition chromatography (GLC) and high-pressure liquid chromatography (HPLC) were first proposed in this paper (1031).

Fritz Prior (AT) and Erika Cremer (DE) developed gas chromatography (GC). Prior, in 1947, succeeded in separating oxygen and carbon dioxide on a charcoal column - a technical achievement for which he received his PhD (362; 1238).

Anthony T. James (GB) and Archer John Porter Martin (GB) developed high-pressure gas-liquid (partition) chromatography (GLC). They used the new column with great success to separate a variety of natural products (812).

 

Douglas K. McClean (GB) found that some streptococci can produce hyaluronidase (spreading factor) (1044).

 

Francis Peyton Rous (US) and George W. Wilson (US) concluded from experimental studies on dogs that loss of blood volume, not loss of erythrocytes, was the important consideration in hemorrhage. Even after gross hemorrhage, these workers were able to restore the blood pressure to normal, and maintain it at the normal level, by replacing the blood they had removed with an equal quantity of plasma (1340).

Edwin Joseph Cohn (US), Laurence E. Strong (US), Walter L. Hughes, Jr. (US), Dwight J. Mulford (US), John N. Ashworth (US), Marshall Melin (US), and F.H. Laskey Taylor (US) developed a cold ethanol fractionation of plasma; the process of breaking down plasma into components and products. Albumin, a protein with powerful osmotic properties, plus gamma globulin and fibrinogen were isolated and became available for clinical use (313; 314).

Walter L. Tatum (US), Alvin John Elliott (US), and Naurice M. Nesset (US) established the efficacy of the use of albumin as a substitute for blood in transfusion (506; 1563).

Alvin John Elliott (US) and Naurice M. Nesset (US) perfected a sterile evacuated bottle containing chemical preservatives for the collection and preservation of blood (505).

Douglas B. Kendrick, Jr. (US) reported on the use of human albumin to treat traumatic shock. “. . .This patient was 20 years of age and was admitted to the hospital 16 hours after injury. He had a bilateral compound continued fracture of the tibia and fibula. He had fractures of five ribs with associated pleural damage, pneumothorax and subcutaneous emphysema. At the time of admission, his blood pressure was 76/30. Two bottles of albumin, consisting of approximately 25 grams, were injected over 30 minutes. The blood pressure after injection was 106/70 . . . his blood pressure remained above 130 . . . he has had no evidence of circulatory failure since the albumin was administered . . . this patient appeared quite groggy and irrational when I first saw him, but 12 hours later he was very clear mentally and appeared to be feeling better" (851).

Isidor Schwaner Ravdin (US) reported on the effectively of using Cohn’s albumin to treat victims of the Pearl Harbor attack for burns and shock. Injected into the blood stream, albumin absorbs liquid from surrounding tissues, preventing blood vessels from collapsing; the finding associated with shock. "All seven patients were given albumin, and all showed prompt clinical improvement, including one whose state was so critical that the administration of albumin to him was debatable. There was no question as to his response: He was unconscious in the morning when he was given 250 grams of albumin. In the afternoon, he was talking, but was disoriented. The following morning, he was given the same amount of albumin. Twenty-four hours later, the edema had disappeared, and he was taking food by mouth" (1268).

 

Samuel B. Barker (US) and William H. Summerson (US) developed a colorimetric method for identifying lactic acid in biological materials. It is applicable to a wide variety of biological materials following deproteinization (72).

 

Ernst Klenk (DE) isolated a product from a cerebroside fraction and named it neuraminic acid (865). The predominant form in mammalian cells being N-acetylneuraminic acid.

 

Cecil James Watson (US) and Samuel Schwartz (US) developed the Watson-Schwartz Test for the qualitative detection of porphobilinogen in urine. This test is to identify patients who carry the genetic trait for hepatic porphorias associated with neurologic lesions. It is a bedside urine test, which can distinguish between cases of porphobilinogen (porphyria) and urobilinogen (pellagra) (1659).

 

Roger Adams (US) isolated and synthesized tetrahydrocannabinol and several of its analogues (6). Tetrahydrocannabinol is the active chemical in cannabis and is one of the oldest hallucinogenic drugs known.

Hugh Brown (US), Lisa M. Eubanks (US), Claude J. Rogers (US), Albert E. Beuscher, IV (US), George F. Koob (US), Arthur J. Olson (US), Tobin J. Dickerson (US), Kim D. Janda (US) presented evidence that tetrahydrocannabinol has an anticholinesterase action which may implicate it as a potential treatment for alzheimer's and myasthenia gravis (202; 527).

 

Leonard Francis LaCour (GB) introduced the acetic orcein method for staining chromosomes (912).

 

Henry Mcllwain (GB) found that iodinin produced by Chromobacterium iodinum (Brevibacterium iodinum) is antimicrobial (1053).

 

Edward Lawrie Tatum (US) and Arie Jan Haagen-Smit (NL-US) identified the v+ vitamin of Drosophila as l-kynurenine (1561). Kynurenine is ubiquitous in insects, despite its extremely low concentration. It is in the metabolic pathway, which leads to the production of brown pigments (skotommins).

Adolf Friedrich Johann Butenandt (DE), Wolfhard Weidel (DE), Ruth Weichert (DE), and Waldemar Derjugin (DE) determined the structure of kynurenine (234).

L-Kynurenine is a metabolite of the amino acid L-tryptophan used in the production of niacin.

Gilles J. Guillemin (AU), Bruce J. Brew (AU), Vincent Meininger (FR), Stephen J. Kerr (AU), Ka Ka Ting (AU), Lucie I. Bruijn (ZA-GB-US), Timothy M. Miller (US), Don W. Cleveland (US), M. Flint Beal (US), Wayne R. Matson (US), Kenton J. Swartz (US), Paul H. Gamache (US), Chai K. Lim (AU), George A. Smythe (AU), Roland Stocker (AU), Nicholas Stoy (GB), Gillian M. Mackay (GB), Caroline M. Forrest (GB), John Christofides (GB), Mark M. Egerton (US), Trevor W. Stone (GB), L. Gail Darlington (GB), Maria Zamanakou (GR), Anastasios E. Germenis (GR), and Vaios Karanikas (GR) demonstrated the kynurenine pathway to be involved in many diseases and disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, AIDS dementia complex, malaria, cancer, depression and schizophrenia, where imbalances in tryptophan and kynurenines have been found (88; 212; 643-645; 977; 1534; 1581; 1758).

Pieter J. Hoekstra (NL), G.M. Anderson (NL), Pieter W. Troost (NL), Cees G.M. Kallenberg (NL), and Ruud B. Minderas (NL) associated kynurenine with tics in humans (752).

Yiquan Chen (AU) and Gilles J. Guillemin (AU) reported that the kynurenine pathway is an effective mechanism in modulating the immune response and in inducing immune tolerance. This is achieved by accelerating the degradation of tryptophan and the generation of kynurenines (288).

 

Hershel K. Mitchell (US), Esmond Emerson Snell (US), and Roger John Williams (US) isolated folic acid from spinach (folium = leaf (Lat.)) and named it. They showed it to be a growth factor for Streptococcus lactis R (S. faecalis) (1096). It is also called folate, pteroylglutamic acid, and vitamin B9, vitamin M.

Robert B. Angier (US), James H. Boothe (US), Brian L. Hutchings (US), John H. Mowat (US), Joseph Semb (US), E.L. Robert Stokstad (US), Yellapragada SubbaRow (IN-US), Coy W. Waller (US), Donna B. Cosulich (US), Marvin J. Fahrenbach (US), Martin E. Hultquist (US), Erwin Kuh (US), Elmore H. Northey (US), Doris R. Seeger (US), Jackson P. Sickels (US), and James M. Smith, Jr. (US) synthesized folic acid and determined its structure (32; 33).

 

Samuel M. Ruben (US), Merle Randall (US), Martin David Kamen (CA-US), and James Logan Hyde (US) used C18O2 and H218O containing 18O (heavy oxygen) to show that all oxygen liberated in photosynthesis originated in water; none came from carbon dioxide, and that the oxygen of CO2 enters organic compounds (1347). Because 18O is not radioactive, Ruben used a mass spectrometer to find out where the oxygen from the water went.

Alexander Pavlovich Vinogradov; Aleksandr Pavlovich Vinogradov (RU) and Rufina Vladimirovna Teis (RU) reached a similar conclusion (1620; 1621).

 

Robert Emerson (US) and Charlton M. Lewis (US) determined that a minimum of 10-12 quanta of light energy is needed for each molecule of oxygen released in photosynthesis (513; 514).

 

Samuel M. Ruben (US) and Martin David Kamen (CA-US) identified phosphoglyceric acid (PGA) as the first stable product of photosynthesis (1345).

 

Selig Hecht (PL-US), Simon Shlaer (US), and Maurice Henri Pirenne (US) revealed that a retinal rod could be excited by a single photon (704; 705).

 

Robert B. Dean (US) and Schack August Steenberg Krogh (DK) published articles in which the concept of the sodium pump was set forth (390; 892). Dean coined the phrase ion pump in his 1941 article.

 

Feodor Felix Konrad Lynen (DE) and Marvin J. Johnson (US) proposed a key role for inorganic phosphate in the mechanism underlying the Pasteur effect (816; 1003).

 

Fritz Albert Lipmann (DE-US) presented the general hypothesis for energy transfer in living cells, to which Herman Moritz Kalckar (DK-US) also made important contributions. Lipmann postulated that ATP functions in a cyclic manner as a carrier of chemical energy from the degradation or catabolic reactions of metabolism, which yield chemical energy, to the various cellular processes that require an energy input. ATP is generated from ADP by coupled or linked phosphorylation reactions at the expense of energy yielded by degradation of fuel molecules. The ATP so generated is postulated to donate its terminal phosphate group to specific acceptor molecules, to energize them for carrying out various energy-requiring functions in the cell, e.g., the biosynthesis of cell macromolecules (chemical work), the active transport of inorganic ions and cell nutrients across membranes against gradients of concentration (osmotic work), and the contraction of muscles (mechanical work). As the energy of ATP is delivered to these energy-requiring processes, the ATP undergoes cleavage to ADP and inorganic phosphate. The ADP is then rephosphorylated at the expense of energy-yielding oxidation of fuels to yield ATP, thus completing the cellular cycle. The terminal phosphate group of the ATP was thus visualized as undergoing constant turnover, being continuously transferred to acceptor molecules and continuously replaced by phosphate groups that become energized during the catabolic degradation of cell fuels. He gave the energy-rich phosphate bond its name and invented the mark, ~, called the squiggle, as in —O~P— by which it is shown (831; 982).

 

Konrad Emil Bloch (US) and Rudolf Schoenheimer (DE-US) carried out isotope tracer studies which demonstrated that creatine is synthesized by the transfer of an amidine group from arginine to glycine, with the formation of guanidinoacetic acid which is then methylated to give creatine (143).

 

Barry Commoner (US) and Kenneth Vivian Thimann (GB-US) found that concentrations of 10-5 M of iodoacetate could halt coleoptile growth but produce no effect on cellular respiration. They assumed that only a small fraction of respiration might be involved in growth (325).

 

Albert Imre Szent-Györgyi (HU-US), Ilona Banga (AT-HU), Tamas Erdös (HU), Mihály Gerendás (HU), Wilfred F.H.M. Mommaerts (US), and Ferenc Brunó Straub (HU), demonstrated that artificial fibrils made from myosin and another protein, which they named actin, contracted when ATP was added. The combination of actin with myosin was named actomyosin (68; 1550; 1552-1554).

Ferenc Brunó Straub (HU) separated the active components of muscle contraction into actin and myosin (1551; 1552).

George Feuer (HU), F. Molnár (HU), E. Pettkó (HU), and Ferenc Brunó Straub (HU) found that water extraction of an acetone-dried muscle residue yielded an actin solution with low viscosity, monomeric or globular (G) actin, that upon addition of salts (at physiological concentrations) polymerized to a highly viscous gel, filamentous or fibrous (F) actin (544).

Ferenc Brunó Straub (HU) and George Feuer (HU) reported that G-actin contains bound ATP and during polymerization of actin the ATP is hydrolyzed to bound ADP and Pi. Straub postulated that the transformation of G-actin-ATP to F-actin-ADP plays a role in muscle contraction (1542).

Hans Hermann Weber (DE) and Hildegard Portzehl (DE) prepared single muscle fibers from glycerol treated psoas muscles that developed tension equal to the intact muscle and reproduced the entire contraction-relaxation cycle of the muscle. Thus, it was proven without doubt that the interaction between actin, myosin and ATP is the basic mechanism for the contraction-relaxation cycle in skeletal muscle (1663).

Wolfgang Kabsch (DE), Hans Georg Mannherz (DE), Dietrich Suck (DE), Emil F. Pai (DE), and Kenneth C. Holmes (DE) were the first to crystallize G-actin and determine its structure (826).

 

John Desmond Bernal (GB) and Isidor Fankuchen (US) obtained clear x-ray diffraction patterns of tomato bushy stunt virus (TBSV) and tobacco mosaic virus (TMV) (119).

Dorothy Mary Crowfoot-Hodgkin (GB) and Gerhard M.J. Schmidt (IL) obtained an x-ray diffraction pattern using a single crystal of tobacco necrosis virus (364).

 

Johannes van Overbeek (NL), Marie E. Conklin (US) and Albert Francis Blakeslee (US) discovered that the addition of coconut milk (Cocos nucifera) causes a drastic increase in the growth of plant embryos and tissue cultures (1607).

 

John Bellows Alsever (US) and Robert B. Ainslie (US) developed an anticoagulant solution for storing test erythrocytes. It consists of 2.05 % glycoside, 0.42 % sodium chloride, 0.8 % tri-sodium citrate, and 0.055 % citric acid in distilled water (25).

 

Harold A. Campbell (US), Mark Arnold Stahmann (US), Charles Ferdinand Huebner (US) and Karl Paul Gerhard Link (US) isolated and identified 3,3’-methylene bis- (4-hydroxycoumarin), later called dicumarol, as the anticlotting agent in spoiled clover hay which was causing cattle to bleed excessively (sweet clover disease). This contributed to our understanding of the mechanism of blood clotting and provided a method for the improved treatment of thromboembolic conditions (251; 1512).

Miyoshi Ikawa (US), Mark Arnold Stahmann (US), Karl Paul Gerhard Link (US), and Ivan Wolff (US) synthesized comparable compounds including warfarin (Coumadin). It is one of the drugs used today to treat deep vein thrombosis as well as to limit the danger of blood clots in patients with artificial valve replacements. Large doses are used in rat poison because it leads to uncontrollable internal bleeding (797; 1513).

 

George Wells Beadle (US) and Edward Lawrie Tatum (US), who had previously collaborated in efforts to establish the chemical identity of substances I and II in the synthesis of Drosophila eye pigment, developed a new experimental approach for the study of the genetic control of metabolic reactions. They had become discouraged over the difficulties they encountered with Drosophila as an object for biochemical studies and turned their attention to a fungus, the bread mold Neurospora crassa. According to Beadle: “With the new organism our approach could be basically different. Through control of the constituents of the culture medium we could search for mutations in genes concerned with the synthesis of already known chemical substances of biological importance. We soon found ourselves with so many mutant strains unable to synthesize vitamins, amino acids and other essential components of protoplasm that we could not decide which ones to work on first.”

George Wells Beadle (US) and Edward Lawrie Tatum (US) described various methods of inducing, identifying and characterizing large number of gene mutations in the red bread mold Neurospora that are concerned with the synthesis of vitamins, amino acids and other essential metabolites.

Genetic crosses between the Neurospora wild-type and the many mutants isolated and characterized in this manner revealed that most of them owe their growth factor requirement to the mutation of a single gene in the Neurospora genome. Furthermore, detailed biochemical study of the aberrant metabolism of the mutants showed that most of them carry a block at a single step in the reaction sequence leading up to the synthesis of the amino acid, vitamin, purine, or pyrimidine required for growth.

George Wells Beadle (US) and Edward Lawrie Tatum (US) proposed what Norman Harold Horowitz (US) would call the one-gene one-enzyme theory of gene action (767). This proposal was based on their studies of mutants of the mold Neurospora crassa. The approaches they developed were extremely important not only for study of the gene-enzyme relationship but also for the analysis of the pathways of intermediary metabolism. Wild-type, i.e., unmutated, Neurospora can grow on a simple medium containing glucose as sole carbon source and only ammonia as nitrogen source. However, exposure of Neurospora spores to x-rays yields some mutant cells no longer capable of growing on this simple medium. Such mutant cells will grow normally if the medium is supplemented with the specific metabolite whose biosynthesis was impaired by the mutation. For example, some mutants of Neurospora are unable to grow unless the medium contains arginine, suggesting that an enzyme required in the synthesis of arginine from ammonia is genetically defective in these mutants. For lack of arginine such mutant cells cannot manufacture their proteins.

The mutant cells can utilize arginine for protein biosynthesis and show normal growth only when this amino acid is supplied in the medium. Further studies show that not all mutants of Neurospora defective in the capacity to make arginine are identical; they differ with respect to the specific step in the pathway of arginine biosynthesis that is genetically defective.

The one-gene-one-enzyme theory had nothing to say about how the gene manages to direct the formation of the enzyme under its dominion. Above all, it did not include the idea that the gene directs the assembly of amino acids into a polypeptide chain of given primary structure. Elucidation of the physical nature of the gene and of its role as the information element of the enzyme-cannot-make-enzyme paradox was to be the work of molecular genetics, the birth of which, it should be noted, was rendered valuable midwife service by the one-gene-one-enzyme theory (84-87).

 

Kenneth Mather (GB) coined the term polygene and describes polygenic traits in various organisms (1034).

 

Albert Bruce Sabin (PL-US) and Robert Ward (US) showed that it was very rare to find poliovirus in nasal tissues. Moreover, poliovirus was present not only in the nervous system but also in the digestive system. This meant that the virus entered the body through the mouth, passed into the digestive system, and was then distributed by the blood to the nervous system (1360).

 

Carl Peter Henrik Dam (DK), Johannes Glavind (DK), Sigurd Orla-Jensen (DK), Anna D. Orla-Jensen (DK), Simon Black (US), Ralph S. Overman (US), Conrad Arnold Elvehjem (US), and Karl Paul Gerhard Link (US) have shown that Escherichia coli, Enterobacter aerogenes, and other intestinal microorganisms synthesize large amounts of the B complex vitamins; thiamin, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, folic acid, inositol, and vitamin K (127; 374).

 

Tracy Morton Sonneborn (US) explained the complex life cycle of Paramecium including macronuclear regeneration and cytoplasmic exchange and the finding that autogamy—the uniparental nuclear reorganization that periodically occurs in many paramecia—is sexual (1486; 1487).

William F. Diller (US) was the first to report autogamy in Paramecium aurelia (430).

 

Herbert J. Dutton (US), Winston M. Manning (US), and Benjamin Minge Duggar (US) were the first to demonstrate that light energy absorbed by accessory pigments (e.g., fucoxanthol) is transferred to chlorophyll a (470; 471).

 

Paul G. Smith (US), John Charles Walker (US), and William J. Hooker (US) proved for the first time that improper nutrition in plants is an important factor for initiation and eventual severity of vegetable diseases (1469; 1645-1648).

 

Ake Gustaffsson (SE) produced agriculturally superior new strains of cereals by selection from mutants produced by x-irradiation (654; 655).

 

Philip Levine (RU-US), Lyman Burnham (US), Eugene M. Katzin (US), and Peter Vogel (US) pointed out the great clinical importance of the anti-Rh antibody as a frequent cause of erythroblastosis fetalis (957; 958; 960). Note: The antibodies probably act as opsonins promoting macrophage engulfment and lysis of red cells. Affected newborns die shortly after birth from bilirubin neurotoxicity.

Louis Klein Diamond (US) successfully used umbilical vein replacement transfusion to treat erythroblastosis fetalis (427).

Alvin Zipursky (CA), John Pollock (CA), Rebecca Yeow (CA), Lyonel G. Israels (CA), and Bruce Chown (CA) developed anti-Rh gamma globulin vaccine to prevent erythroblastosis fetalis (289; 1767).

 

Frank Macfarlane Burnet (AU), Mavis Freeman (AU), Alan V. Jackson (AU), and Dora Lush (AU) proposed that descendants of cells reacting to antigen would produce antibodies specific to the antigen (229).

 

Sally Hughes-Schrader (US) and Hans Ris (CH-US) discovered holokinetic (diffuse centromere) chromosomes (787).

 

George Keble Hirst (US), Laurella McClelland (CA) and Ronald Hare (CA) discovered that influenza virus will spontaneously agglutinate chicken erythrocytes in saline. Antibodies to the virus will inhibit the agglutination. This became a direct means of recognizing the presence of this virus and measuring its titer in cell culture (743; 744; 1046). The reaction became known as the Hirst reaction.

Martin Goldfield (US), Sunthorn Srihongse (US), and John P. Fox (US) reported agglutination of human erythrocytes for a few enterovirus serotypes (613).

Leon Rosen (US) subdivided the adenoviruses for convenience of typing into several groups on the basis of the type of erythrocyte they agglutinated and the conditions of such agglutination (1335; 1336). Note: Later, it was found that these same subgroups also shared other characteristics such as antigenic relationships, epidemiologic behavior, and relative oncogenicity for laboratory animals.

 

William McDowell Hammon (US), William Carlisle Reeves (US), Bernard Brookman (US), Ernest M. Izami (US), Claude M. Gjullin (US), Margaret Gray (US), Pedro Galindo (US), and Gladys E. Sather (US) performed quantitative studies of the natural history of arboviruses in vector arthropods (673-680).

 

Stuart Mudd (US) and Thomas Foxen Anderson (US) used the electron microscope to visualize the combination of antibodies with the flagellar and somatic antigens of bacteria (1110).

 

Dorsey W. Bruner (US) and Philip R. Edwards (US) demonstrated that Salmonella paratyphi A grown in media containing suppressive antisera of one sort can shift to one of four different antigenic phases (213).

 

Marjorie Griffen Macfarlane (GB) and Bert Cyril James Gabriel Knight (GB) discovered that the alpha toxin of Clostridium welchii is an enzyme (phospholipase C) which cleaves phosphatidylcholine (1009).

 

Louis Gershenfeld (US), Vera Elaine Milanick (US), and David Perlstein (US) discovered that acidity decreases the antibacterial efficiency of many quaternary ammonium compounds so decidedly that they are completely ineffective at pH 3, and only weakly bactericidal at pH 4 (597; 598).

 

Zelma Baker (US), Robert W. Harrison (US), and Benjamin F. Miller (US) discovered that quaternary ammonium compounds are not very selective in their germicidal efficiency (62).

 

William Trager (US) was the first to grow the malarial parasite (Plasmodium) in vitro in a procedure which proved repeatable (1587; 1588).

 

William Porter MacArthur (GB) identified cysticercosis as a cause of epilepsy (1007).

 

John Holmes Dingle (US), Lewis Thomas (US), and Allan R. Morton (US) established the efficacy of sulfadiazine in the treatment of meningococcal meningitis (434).

 

Jacob Earl Thomas (US) developed a method for collection of bile under physiologic conditions by using a special cannula (1571).

 

Charles Brenton Huggins (CA-US), Clarence Vernard Hodges (US), and Roland E. Stevens (US) demonstrated the effects of castration, of estrogens, and of androgens on serum phosphatase levels in patients with extensive metastatic carcinoma of the prostate. They reported large clinical improvements in a significant number of these patients after orchiectomy and estrogen treatment. This was the first indication that a major type of cancer could be controlled by purely chemical means (785; 786). Note: This became known as "hormone therapy."

 

Fuller Albright (US), Patricia H. Smith (US), and Anna M. Richardson (US) described post-menopausal osteoporosis (13).

 

Eric George Lapthorne Bywaters (GB) and Desmond Beall (GB) were the first to describe a syndrome found in many air raid casualties. The syndrome was observed in patients who were buried for several hours with pressure on a limb. They went into shock some time later, and then, despite fluid replacement, developed renal damage and died within a week. (238).

Eric George Lapthorne Bywaters (GB), George E. Delory (GB), Claude Rimington (GB), and John Smiles (GB) found that the protein, myoglobin, was leaked into the circulation from crushed muscles. This blocked the tiny ducts in the kidneys, preventing urine and waste products from being filtered from the blood. They used animal models to show that alkaline fluids by mouth or intravenously protected the kidney and kept the patient alive until the blocked renal tubules healed (239).

 

Paul Hamilton Wood (GB) attributed the somatic symptoms of Da Costa’s syndrome (effort syndrome, or soldier’s heart) to psychoneurosis arising from fear (1730; 1731).

 

Bernhard Zondek (DE-IL) reported that menstruation in women could be delayed (producing a limited amenorrhea) up to 70 days by the administration of estrogenic hormone. He realized that this had clinical significance (1769).

 

Frank W. Foote, Jr. (US) and Fred W. Stewart (US) initially diagnosed and described the related pattern of infiltrating lobular neoplastic breast disease in women. It is also referred to as lobular carcinoma in situ (LCIS). This has been considered a special type of premalignancy ever since (556).

 

Paul E. Steiner (US) and Clarence C. Lushbaugh (US) presented maternal pulmonary embolism by amniotic fluid as a cause of obstetric shock and unexpected deaths in obstetrics (1522).

 

Paul Owen (NO) noted the correlation between diet and coronary thrombosis. ref

 

Ernest Rupel (US) and Robert Brown (US) performed the first nephroscopy by placing a rigid cystoscope through a nephrostomy tract so that stones could be removed during open surgery (1351).

 

Robert Edward Gross (US) and William E. Ladd (US) wrote Abdominal Surgery of Infancy and Childhood, the first textbook on surgery in children (913).

 

1942-1953

Polio continued to ravage the U.S., peaking in 1952 with about 60,000 cases (870).

 

1942

“At that subtle moment when man glances backward over his life, Sisyphus returning toward the rock, in that slight pivoting he contemplates that series of unrelated actions which becomes his fate, created by him, combined under his memory’s eye and soon sealed by his death. Thus, convinced of the wholly human origin of all that is human, a blind man eager to see who knows that night has no end, he is still on the go. The rock is still rolling.

I leave Sisyphus at the foot of the mountain! One always finds one’s burden again. But Sisyphus teaches the higher fidelity that negates the gods and raises rocks. He too concludes that all is well. This universe henceforth without a master seems to him neither sterile nor fertile. Each atom of that stone, each mineral flake of that night-filled mountain, in itself forms a world. The struggle itself toward the heights is enough to fill a man’s heart. One might imagine Sisyphus happy.” Albert Camus (254).

 

“To think that physics or chemistry ought to be defined in terms of matter or physiology in terms of life is more than an egregious blunder; it is a threat to the existence of science. It implies that people know what matter is without studying physics or chemistry, and what life is without studying physiology.” Robin George Collingwood (319).

 

Harold H. Strain (US), Winston M. Manning (US) and Garrett Hardin (US) showed that chlorofucine, later known as chlorophyll c, is not an artifact (1535; 1536).

 

Jordi Folch (ES-US) showed that cephalin is not a single lipid but rather a mixture of at least three lipids (phosphatidyl ethanolamine, serine and inositol). Folch was the first to have elucidated the structure of phosphatidyl serine (550; 551).

 

Vincent du Vigneaud (US), Klaus Hofmann (CH-US), and Donall B. Melville (US) http://walkbackintime1940s.weebly.com/medical-advances.html deduced the complicated two-ring structure of biotin (456; 460).

 

Albert Dorfman (US), Sam Berkman (US), and Stewart Arment Koser (US) discovered the role of pantothenic acid in pyruvate metabolism (444).

 

Paul Delos Boyer (US), Henry Arnold Lardy (US), and Paul H. Phillips (US) discovered the K+ activation of pyruvate kinase. This was the first demonstration of a potassium ion requirement for an enzyme reaction (173; 175).

 

Stewart Arment Koser (US), Marjory H. Wright (US), and Albert Dorfman (US) discovered the role of biotin in aspartic acid biosynthesis (876).

 

Douglas K. McClean (GB) and Idwal Wyn Rowlands (GB) discovered hyaluronidase in mammalian sperm (1045). This enzyme dissolves the cement substance of follicle cells that surround mammalian eggs and facilitates passage of sperm to eggs.

 

Otto Fritz Meyerhof (DE-US) presented what has become known as the Embden-Meyerhof-Parnas pathway (1077).

 

Konrad Emil Bloch (US) and David Rittenberg (US) used isotope labeling techniques to show that acetate contributes in a major way to the synthesis of fatty acids, as well as, both the aliphatic side chain and to the tetracyclic moiety of sterol molecules (140-142; 1298).

Henry N. Little (US) and Konrad Emil Bloch (US) predicted that a two-carbon metabolite of acetate is the principal if not the sole building block of cholesterol (986).

 

Dean Burk (US) found that the metabolism of the regenerating liver, which grows more rapidly than most tumors, is not cancer metabolism, but perfect aerobic embryonic metabolism (223).

 

Forrest W. Quackenbush (US), Fred A. Kummerow (US), and Harry Steenbock (US), using experiments in rats, suggested that the requirement for linoleic, arachidonic, and linolenic acids during pregnancy and lactation is double that needed during the growth of young animals. They found that linoleic acid is necessary for satisfactory milk production (1242).

 

Herman Moritz Kalckar (DK-US) and Sidney P. Colowick (US) discovered that muscle extracts of myokinase (adenylate kinase) catalyze the reaction ATP + AMP 2ADP. This is a vital reaction because it returns AMP to ADP, which can be phosphorylated to ATP. The absence of adenylate kinase leads to phosphate accumulating as AMP (321; 832).

 

Karl Landsteiner (AT-US) and Merrill Wallace Chase (US) announced that delayed hypersensitivity could be transferred with cells (284; 917). Their findings resulted in a clear separation of the class of immune responses initiated by cells from those mediated by circulating immunoglobulins.

 

Anna M. Kulka (US) showed that soluble antigen-antibody complexes would induce smooth muscle contraction in vitro (902; 903).

 

Edgar William Todd (GB) demonstrated that streptolysin O has a powerful lytic action on leukocytes when tested at low oxygen tension (1583).

 

Max B. Lurie (US) and Peter Zappasodi (US) provided evidence that mononuclear phagocytes while unable to damage the tubercle bacillus in non-immune individuals acquired the ability to destroy it in immune individuals (1002).

 

Harold Joel Conn (US) described the genus Agrobacterium with Agrobacterium tumefaciens as the type species (330).

 

Gladys Lounsberry Hobby (US), Karl Meyer (US), and Eleanor Chafee (US) established that under certain conditions penicillin is bactericidal and that it kills growing, but not resting cells (747).

 

Harold E. Clark (US) and Kenneth R. Kerns (US) used 1-naphthalene-acetic acid to induce synchronous flowering in pineapples (Ananas comosus) (293).

 

Roland E. Slade (GB), William Gladstone Templeman (GB), Wilfred A. Sexton (GB), Percy W. Zimmerman (US), Alfred E. Hitchcock (US), John F. Lontz (US), Ezra Jacob Kraus (US), Franklin D. Jones (US), Philip S. Nutman (GB), H. Gerard Thornton (GB), Juda Hirsch Quastel (GB-CA), Paul C. Marth (US), John W. Mitchell (US), and C.J. Marmoy (GB) discovered that certain chlorophenoxyacetic acids act as hormone herbicides. This included 2,4-D, MCPA, and 2,4,5-T (817; 818; 884; 992; 1030; 1148; 1455; 1565; 1756; 1765).

Amchem Corp. introduced 2,4-D (2,4-dichlorophenoxyacetic acid) as the first in a series of phenoxyacetic acid herbicides to control broadleaf weeds in corn (Zea mays), wheat (Triticum spp.), barley (Hordeum vulgare), sorgham, sugar cane (Saccharum officinarum), grass pastures, and in turf. Robert Pokorny (US) reported production of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) (1219).

 

Samson R. Dutky (US) developed a way to produce spores of Bacillus popilliae to provide effective suppression of the Japanese beetle by inducing bacterial milky spore disease —the first commercial microbial pesticide (469).

 

Sidney Fay Blake (US) and Alice C. Atwood (US) authored Geographical Guide to Floras of the World, which is a valuable bibliographical resource (128).

 

Sheldon C. Reed (US), Carroll Milton Williams (US), and Leigh E. Chadwick (US) found that individual flies from various inbred strains of Drosophila can beat their wings at 12,000 to 14,000 beats per minute during sustained flight until exhaustion sets in after as much as three hours, or more than 2 million double wing beats (271; 1273).

 

Gordon Lynn Walls (US) wrote an important book on the eye of reptiles entitled, The Vertebrate Eye and Its Adaptive Radiation. He emphasized the profound differences between the eye of snakes and lizards and suggested that snakes evolved from nocturnal lizards (1649).

 

Ernst Gutmann (CZ), Ludwig Guttmann (DE), Peter Brian Medawar (GB), and John Zachary Young (GB) damaged peripheral nerves of young and adult rabbits and dogs so that their axons would be severed, leading to degeneration of the distal part. They then followed the progress of regrowth from the cut stump over time. In most cases, no regeneration was seen for 3-7 days. Axons then appeared to grow at a constant rate of 3-5 mm per day. Surprisingly, however, functional recovery was not detectable for 2-3 weeks after the first axons had reached the end organ. Monitoring of functional recovery was one of the unique dimensions of this paper. Their clear demonstration that regeneration and functional recovery were very different served as a powerful impetus for further work (657).

Frank Kingsley Sanders (GB) and John Zachary Young (GB) performed experiments suggesting that physical constrictions in the Schwann cell guides through which regeneration occurred were important determinants of the limitation of axon diameter. Knowing that these constrictions increased with time after denervation, they stressed the importance of performing nerve repair surgery as soon as possible following injury (1369).

Ernst Gutmann (CZ) and John Zachary Young (GB) showed that the Schwann cell guides critical for regeneration through the distal nerve also play critical roles in accurate reinnervation of muscle fibers (658).

 

George Linius Streeter (US), from 1942 to 1951, wrote Developmental Horizons in Human Embryos, a landmark achievement in the embryology of humans. He placed embryos in Horizons and titled each of them with Roman numerals. Later, Ronan O’Rahilly (IE-US) changed Horizon to Stage and titled each with Arabic numbers that are used today and are known as the Carnegie stages. Stage 1 (Horizon l) was defined as fertilization and Stage 23 (Horizon XXIII) was defined as the end of the embryonic period when the embryo is approximately eight weeks post fertilization age, has a greatest length of approximately 30 mm, and possesses about 4,000 definitive, permanent structures (1149; 1543; 1545-1547).

Erich Blechschmidt (DE), between 1942 and 1972, constructed a very precise series of color-coded, 3D reconstructions of human embryos including every organ and cavity at representative stages (134; 135).

Erich Blechschmidt (DE) and Raymond Frank Gasser (DE) described the growth movements that occur during the formation of specific tissues. Fields were described that explain the movements taking place as the cells; tissues and organs change their shape and position. It is remarkable that the movements in any given region are consistent at every level of magnification (i.e., cells, tissues and organs) (136).

 

George Linius Streeter (US) discussed embryological defects and their relation to spontaneous abortion in man (1544).

 

William Cumming Rose (US), Julius E. Johnson (US), William J. Haines (US), M. Jane Oesterling (US), Morton Shane (US), Madelyn Womack (US), Leonard C. Smith (US), Byron E. Leach (US), Minor J. Coon (US), Haines B. Lockhart (US), G. Frederick Lambert (US), Donald T. Warner (US), Aleck Borman (US), Robert L. Wixom (US), and Eugene E. Dekker (US) demonstrated that humans require eight amino acids in their diet (isoleucine, leucine, threonine, lysine, methionine, phenylalanine, tryptophan, and valine) as opposed to the ten required by rats and dogs. They noted that all essential amino acids must be supplied in the L-isomeric form except for methionine, which can be used in either the D-, or the L- form. They even calculated the minimum daily requirement for each of these essential amino acids. Cystine was found to spare part of the methionine requirement and tyrosine spare part of the phenylalanine requirement. Glycine, glutamic acid, urea, and ammonium salts could all supply nitrogen necessary for synthesis of the non-essential amino acids (1316-1326; 1328-1334).

 

C.S. Swaminath (IN), Henry Edward Shortt (GB), and L.A.P. Anderson (GB) demonstrated transmission of Leiahmania donovani (the causative agent of kala-azar) by sandflies (1548).

 

Rudolf Schoenheimer (DE-US) and Hans T. Clarke (US) applied radioactive tracers to the study of the biosynthesis of cell structures and concluded that the body is in a state of dynamic equilibrium with the continual release and uptake of chemical substances to and from a metabolic pool (1393).

 

Charles H. Rammelkamp, Jr. (US) and Chester S. Keefer (US) developed a method for determining the concentration of penicillin in body fluids and exudates (1251). At this time penicillin was a rare and precious commodity.

 

George Keble Hirst (US) used penicillin to thwart bacterial contamination during the isolation of influenza virus from unfiltered throat washings inoculated into the amniotic sac of the developing chick embryo (744).

 

William Smith Tillett (US), Margaret J. Cambier (US), Harold Dunn (US), William H. Harris, Jr. (US), and James E. McCormack (US) studied penicillin therapy in cases of pneumococcal pneumonia and concluded that: 1) tissue levels of penicillin are more important than serum levels, 2) it is not the total daily dose of penicillin which results in recovery from the disease, but its duration of therapy, 3) during recovery the patient develops type-specific antibodies by the seventh to the tenth day after infection, and 4) if penicillin therapy is interrupted before the 7-10 day period following infection the patient will relapse and experience a recurrence of the disease (1576-1580). These results represent the first clear-cut demonstration of a seminal principle of antibiotic therapy, namely, that the antibiotic serves to limit the growth of the infectious agent until the appropriate immune responses of the host can be marshaled and result in its eradication.

On March 14, 1942, John Bumstead (US) and Orvan Walter Hess (US) became the first doctors in the world to successfully treat a patient (Anne Miller) with penicillin. Miller was suffering from a septic abortion.

Wallace E. Harrell (US) established clinical efficacy and pharmicokinetics of Penicillin (originally for treatment of syphilis). ref

 

Elvin Abraham Kabat (US), Dan H. Moore (US), and Harold Landow (US) demonstrated that certain diseases are associated with a cerebrospinal protein pattern in which the gamma globulins are proportionally the predominant fraction (824; 825).

Elvin Abraham Kabat (US), Murray Glusman (US), and Vesta Knaub (US) found that immunoglobulin gamma (IgG) is the main component of the gamma fraction in normal cerebrospinal fluid (823).

 

Hans Popper (AT-US), Frederick Steigmann (US), and Hattie A. Dyniewicz (US) discovered that vitamin A deficiency leads to liver damage (1221).

 

Wilhelm Siegmund Feldberg (DE-GB) and Alfred Fessard (FR) made the first experimental demonstration of the electrogenic action of acetylcholine (536).

 

Harold R. Griffith (CA) and G. Enid Johnson (CA) were the first to produce muscular paralysis by the injection of a purified preparation of curare (intocostrin) as an adjuvant to surgical anesthesia. They used it to facilitate access to the abdomen during an appendectomy (631).

 

Harry Fitch Klinefelter, Jr. (US), Edward Conrad Reifenstein, Jr. (US), and Fuller Albright (US) described a clinical syndrome characterized by gynecomastia, aspermatogenesis without A-Leydigism, and increased excretion of follicle-stimulating hormone. This condition would become known as Klinefelter’s syndrome (867).

Patricia Ann Jacobs (GB) and John A. Strong (GB) reported a case of human intersexuality having a possible XXY sex-determining mechanism (810).

Charles Edmund Ford (GB), Ken W. Jones (GB), Orlando J. Miller (GB), Ursula Mittwoch (GB), Lionel Sharples Penrose (GB), Michael A.C. Ridler (GB), and Alec Shapiro (GB) discovered that patients with Klinefelter’s syndrome possess a 47, XXY karyotype (557).

The majority of Klinefelter’s individuals have an extra female chromosome, resulting in a 47,XXY karyotype. Other patterns of chromosomal aberration such as XXYY, and some mosaic patterns may result in the same syndrome. It is the most frequent type of intersexuality, occurring in one per 500-700 live male births.

 

Aura E. Severinghaus (US) described XY sex chromosome complements in an XY female (1422).

 

Julian Sorell Huxley (GB) brought together several major ideas about evolution present in the population genetics of the early 20th century to form his modern synthesis. The ideas included genetic variation, natural selection, and particulate (Mendelian) inheritance. This ended the eclipse of Darwinism and supplanted a variety of non-Darwinian theories of evolution (793).

 

Clinton Nathan Woolsey (US) and Edward M. Walzl (US) selectively stimulated localized regions of auditory nerve fibers in the cochlea of the cat and mapped the patterns of evoked responses on the auditory cortex of the brain’s temporal lobe. This was the first demonstration of tonotopic (cochleotopic) organization of the auditory cortex (1752).

Clinton Nathan Woolsey (US) and David Fairman (US) found a second tonal map ventral to the first with the sound spectrum in reverse order (1747).

Harlow W. Ades (US) found a secondary acoustic area in the posterior ectosylvian gyrus of the cat (7).

 

Walter Mann (US), Charles Philippe Leblond (CA-US), and Stafford L. Warren (US) used radio-iodine to show that in physiological conditions iodine is first incorporated into the thyroid gland as diiodotyrosine and from there is slowly transformed into thyroxine (1025).

 

Werner Kuhn (CH) and Kaspar Ryffel (CH) hypothesized that the production of hypertonic urine by the kidney might result from a concentration mechanism by counter-current between descending and ascending limbs of Henle's loops (901).

Heinrich Wirz (CH), Bartholomew Hargitay (CH), and Werner Kuhn (CH) proposed that the mammalian kidney concentrates urine by means of a counter-current mechanism. “These findings indicate that the concentration of the urine occurs without steep osmotic gradients. The loops of Henle are an example of a hairpin counter-current system. They prepare a hypertonic surrounding for the collecting ducts so that the contents of the collecting ducts are being concentrated by losing water in this hypertonic milieu.” The tubular urine becomes osmotically concentrated in its descending limb, diluted in its ascending limb, and finally concentrated in the collecting ducts by the diffusion of water into the hyperosmotic medullary interstitium (684; 1721-1723).

Carl W. Gottschalk (US) and Margaret Mylle (US) determined the hydrostatic pressure in renal tubules and small vessels of the rat kidney (619).

Carl W. Gottschalk (US), Margaret Mylle (US), William E. Lassiter (US), Karl J. Ullrich (US), Bodil Schmidt-Nielsen (DK-US), Roberta O’Dell (US), and Gundula Pehling (US) used the micropuncture technique on various mammalian species with different kidney anatomies under three different conditions to show virtual equality of osmolarity in collecting ducts and at the bend of the thin loops of Henle during antidiuresis. These experiments provided definitive proof that urine is concentrated by countercurrent multiplication (618; 620; 1596).

William E. Lassiter (US), Carl W. Gottschalk (US), and Margaret Mylle (US) found a large net addition of urea to the fluid in the loop of Henle, indicative of urea recycling in the renal medulla (931).

 

Heinrich Pette (DE) coined the word panencephalitis when he realized that some forms of viral encephalitis having a different name in different regions of the globe were in fact worldwide (1200).

 

Fuller Albright (US), Charles H. Burnett (US), Patricia H. Smith (US), and William Parson (US) described pseudohypoparathyroidism, a hypoparathyroidism in which there is evidence that the cause of the disturbance is the failure of the target organ(s) to respond to the hormone (11).

 

Harry Keil (US) was the first to propose that discoidal lupus erythematosus and systemic lupus erythematosus are forms of the same disease, and that they could even present transitional forms. It was also Keil who clearly outlined the differential diagnosis of cutaneous manifestations to distinguish between lupus erythematosus and dermatomyositis (844).

 

Paul Klemperer (AT-US), Abou D. Pollack (US), and George Baehr (US) found that “the apparent heterogeneous involvement of various organs in disseminated lupus had no logic until it became apparent that the widespread lesions were identical in that they were mere local expressions of a morbid process affecting the entire collagenous tissue system…. A similar widespread alteration of collagen has also been noted in certain cases of diffuse scleroderma.” They defined the collagen diseases as chronic or acute processes, localized in connective tissue, especially in its intercellular components but with multiple locations throughout the organism. Due to this last phenomenon they coined the phrase diffuse diseases of collagen (864).

 

Arnold Rice Rich (US) and John E. Gregory (US) demonstrated that the lesions of periarteritis nodosa, rheumatic carditis, and pneumonitis, and some forms of glomerulonephritis are caused by the anaphylactic type of hypersensitivity (630; 1282; 1284-1290).

 

Karl Theodore Dussik (AT) and Friederich Dussik (AT) are generally regarded as the first physicians to have employed ultrasound in medical diagnosis. They located brain tumors and the cerebral ventricles by measuring the transmission of ultrasound beam through the head, employing a transducer on either side (468).

George D. Ludwig (US) and Francis W. Struthers (US) were among the first to use pulse-echo ultrasound on animal tissues. They investigated the detection of gallstones using ultrasound, the stones being first embedded in the muscles of animals (995).

 

Edward A. Gall (US) and Tracy Burr Mallory (US) made an early attempt to classify lymphomas based on their analysis of 618 cases (589).

 

John Silas Lundy (US) opened the first post-anesthesia recovery room in the world. Here patients were provided with specially trained personnel to monitor their recovery from the anesthetic agent (997).

 

George Walton Duncan (US) and Alfred Blalock (US) demonstrated shock due to crush injury (466).

 

While treating victims of the Cocoanut Grove fire in Boston, Massachusetts General Hospital physicians demonstrated the efficacy of a new approach to burn treatment and the value of new blood bank and emergency-response plans (345).

 

Albert Richard Behnke, Jr. (US), Benjamin G. Feen (US), and Walter C. Welham (US) presented data supporting the concept that the comparatively low specific gravity of fat makes the measurement of the specific gravity of the body mass valid for the estimation of fat content (100).

 

Conrad Hal Waddington (GB) induced an extreme environmental reaction in the developing embryos of Drosophila. In response to ether vapor, a proportion of embryos developed a radical phenotypic change, a second thorax. At this point in the experimental bithorax is not innate; it is induced by an unusual environment. Waddington then repeatedly selected Drosophila for the bithorax phenotype over some 20 generations. After this time, some Drosophila developed bithorax without the ether treatment.

Waddington introduced genetic canalisation (canalization) as a measure of the ability of a population to produce the same phenotype regardless of variability of its environment or genotype. In other words, it means robustness. The term canalization was coined by Waddington, who used the word to capture the fact that developmental reactions, as they occur in organisms submitted to natural selection...are adjusted to bring about one definite end-result regardless of minor variations in conditions during the reaction (1628).

Waddington, coined the term epigenetics, which was derived from the Greek word “epigenesis” to attempt to explain the complex, dynamic interactions between the developmental environment and the genome that led to the production of phenotype (1629). Note: A current definition of epigenetics is: “The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence” (1357).

Carl Clarence Lindegren (US) reviewing data on inheritance in Neurospora, said that two-thirds of new variants do not show Mendelian segregation (978).

Conrad Hal Waddington (GB) carried out a similar experiment by inducing the cross-veinless phenocopy in Drosophila using heat shock, with 40% of the flies showing the phenotype prior to selection. Again, he selected for the phenotype over several generations, applying heat shock each time, and eventually the phenotype appeared even without heat shock (1630).

Waddington defined genetic assimilation as a process “by which a phenotypic character, which initially is produced only in response to some environmental influence, becomes, through a process of selection, taken over by the genotype, so that it is formed even in the absence of the environmental influence which had at first been necessary” (1631).

Janine Beisson (US) and Tracy Morton Sonneborn (US) showed that an experimentally modified organization of the cilia on Paramecium can be inherited through many asexual and sexual generations (101).

John S. Griffith (US) and Henry R. Mahler (US) suggested that the modification of DNA by methylation (or demethylation) may be important in long-term memory function. They called this the DNA ticketing theory of memory. The authors state that, “Contrary to usual opinions, it is possible to have a biochemically plausible theory in which memory is stored in coded form in the DNA of nerve cells(632).

Gerald Maurice Edelman (US) and Vernon Benjamin Mountcastle (US) proposed the theory called neural Darwinism or the theory of neural group selection (TNGS). It assumed that morphogenesis of the brain with its myriad connections was initially constrained by homeotic genes and the like but then was subject to epigenetic events that resulted in enormous individual variation at the finest ramifications of neuroanatomy (495; 496).

Jim van Os (NL), Jean-Paul Selten (NL), David St. Clair (GB), Mingqing Xu (CN), Peng Wang (CN), Yaqin Yu (CN), Yourong Fang (CN), Feng Zhang (CN), Xiaoying Zheng (CN), Niufan Gu (CN), Guoyin Feng (CN), Pak Sham (CN), and Lin He (CN) found that human adults prenatally exposed to famine conditions have been reported to have significantly higher incidence of schizophrenia (1502; 1605).

Rebecca C. Painter (NL), Tessa J. Roseboom (NL), Otto P. Bleker (NL), Bastiaan T. Heijmans (NL), Elmar L. Tobi (NL), Aryeh D. Stein (US), Hein Putter (NL), Gerard J. Blauw (NL), Ezra S. Susser (US), P. Eline Slagboom (NL), and Lambert H. Lumey (US) presented data reinforcing the concept that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life (707; 1166).

 

Pilar Cubas (ES), Coral A. Vincent (DE), and Enrico Coen (GB) characterized a naturally occurring mutant of Linaria vulgaris, originally described more than 250 years ago by Linnaeus, in which the fundamental symmetry of the flower is changed from bilateral to radial. They showed that the mutant carries a defect in Lcyc, a homologue of the cycloidea gene, which controls dorsoventral asymmetry in Antirrhinum. The Lcyc gene is extensively methylated and transcriptionally silent in the mutant. This modification is heritable and co-segregates with the mutant phenotype. Occasionally the mutant reverts phenotypically during somatic development, correlating with demethylation of Lcyc and restoration of gene expression. It is surprising that the first natural morphological mutant to be characterized should trace to methylation, given the rarity of this mutational mechanism in the laboratory. This indicates that epigenetic mutations may play a more significant role in evolution than has hitherto been suspected (365).

Maria Pia Cosma (ES), Tomoyuki Tanka (GB), and Kim Nasmyth (GB) found that crucial determinants of gene expression patterns are DNA-binding transcription factors that choose genes for transcriptional activation or repression by recognizing the sequence of DNA bases in their promoter regions. Interaction of these factors with their cognate sequences triggers a chain of events, often involving changes in the structure of chromatin, that leads to the assembly of an active transcription complex (354).

Marc F. DeCristofaro (US), Bryan L. Betz (US), Checo J. Rorie (US), David N. Reisman (US), Weidong Wang (US), and Bernard E. Weissman (US) discovered the SWI/SNF (SWItch/Sucrose Non-Fermentable) complex in the yeast, Saccharomyces cerevisiae. The protein interactions of the SWI/SNF complex with the chromatin allows binding of transcription factors and therefore an increase in transcription (391).

By regulating chromatin structure and DNA accessibility, chemical changes influence how the genome is made manifest across a diverse array of developmental stages, tissue types, and disease states. Epigenetic modifications fall into two main categories: DNA methylation and histone modifications. In vertebrates, DNA methylation occurs almost exclusively in the context of CpG dinucleotides, and most CpGs in the genome are methylated. Chemical modifications to histone proteins and cytosine bases provide heritable epigenetic information that is not encoded in the nucleotide sequence (123). The epigenome is a multitude of chemical compounds that can tell the genome what to do.

 

Charles Sutherland Elton (GB) was a community ecologist. He did important early studies on food webs. His speculations on interaction of population dynamics and selection foreshadowed the founder effect principle (509).

 

Ernst Walter Mayr (DE-GB-US) wrote Systematics and the Origin of Species from the Viewpoint of a Zoologist in which he gave systematics the first adequate integration of taxonomy, genetics, and natural history. Here he also produced the biological species concept, stating that species are “groups of actually or potentially interbreeding populations which are reproductively isolated from other such groups.” The 1942 book contains the first statement of the founder principle (1036-1038). See, Aristotle, c. 350 BCE on species.

 

Raymond L. Lindeman (US), while studying the cycling of nutrients through a lake, realized that organisms are ecologically linked to their abiotic environment. The lake was an integrated system of the biotic and abiotic, to which he gave the name ecosystem. His trophic-dynamic viewpoint was an attempt to demonstrate how the day-to-day processes within a lake affected the long-term changes of ecological succession (981).

 

Edward Smith Deevey, Jr. (US) described the biostratonomy of Linsley Pond in Connecticut. From his data he could read the 12,000-year history of the changes of conditions and communities within the pond, changes in the climate above it, and some of the activities of human population around it (392).

 

1943

“We shall not cease from exploration
And the end of all our exploring
Will be to arrive where we started
And know the place for the first time.” Thomas Stearns Eliot
(504).

 

Henrik Carl Peter Dam (DK) for his discovery of vitamin K and Edward Adelbert Doisy (US) for his discovery of the chemical nature and synthesis of vitamin K were awarded the Nobel Prize in physiology and medicine.

 

George Charles de Hevesy; Georg Charles von Hevesy (HU-DE-SE-DE) was awarded the Nobel Prize in Chemistry for introducing metabolic tracer methodology using radioactive lead and phosphorus (174).

 

Edward Joseph Conway (IE) determined that the oceans during the geological period when the original vertebrates evolved (Ordovician) had salinity very similar to the oceans of today (336). This is strong evidence against the blood-reflects-the-early-seas hypothesis.

 

Paul D. Boyer (US), Henry A. Lardy (US), and Paul H. Phillips (US) showed that pyruvic kinase from rabbit muscle was dependent upon a univalent cation (174).

Gene Miller (US) and Harold J. Evans (US) showed that pyruvic kinase from peas behaved like the enzyme from animals requiring univalent cations for activity (1090).

 Andrew J. Hiatt (US) and Harold J. Evans (US) examined the acetic thiokinase from spinach leaves and arrived at a similar conclusion (726).

Ronald Nitsus (US) and Harold J. Evans (US) demonstrated a specific requirement of potassium for the synthesis of nitrate reductase in Neurospora and showed that potassium was essential for the starch synthetases from several plants (1144). Note: Even though rubidium, ammonium, and sometimes cesium often activated enzymes in vitro, they concluded that potassium was the only non-toxic element that accumulated in cells in sufficient concentrations to fulfill the physiological role of a univalent cation activator for a large group of enzymes.

 

Winston M. Manning (US) and Harold H. Strain (US) discovered chlorophyll d (1026).

A. Stanley Holt (CA) and Harold V. Morley (CA) determined the chemical structure of chlorophyll d (760).

 

Julius Hyman (US-GB) produced mono- and bis-adducts of hexachlorocyclopentadiene (hex) by reacting it with cyclopentadiene (1216).

Clyde W. Kearns (US), Lester Ingle (US), and Robert Lee Metcalf (US) tested these products and found that the mono-adduct’s (chlordene) insecticidal potency was about one-fourth that of dichloro-diphenyl-trichloro-ethane (DDT) or 2,2-di (4-chlorophenyl)-1,1,1-trichloroethane but that it was too volatile to be useful (843).

Julius Hyman (US-GB) and Randolph Riemschneider (DE) solved this problem by chlorinating the reactive double bond thus producing chlordane (794; 1294).

 

Leslie James Burrage (GB) and James Crosby Smart (GB), in 1943, showed that it is the gamma isomer of benzene hexachloride that is insecticidal (233; 1454). See Michael Faraday, 1825 and Van der Linden, 1912.

 

Andre Lardon (CH) and Tadeus Reichstein (CH) were the first to successfully synthesize compound A (11-dehydrocorticosterone) (925).

 

Bernard Beryl Brodie (US) and Sidney Udenfriend (US) devised simple, precise, methods for the estimation of Atabrine in biological fluids and tissues (194).

 

Wallace E. Herrell (US), Edward N. Cook (US), Luther Thompson (US), and Dorothy H. Heilman (US) established the clinical efficacy and pharmacokinetics of penicillin (711; 718).

 

Charles E. Clifton (US) reported that penicillin can be produced in good yield in continuous flow cultures, and that such a method is commercially feasible (305).

 

Britton Chance (US) deduced the mechanism of peroxidase action in detail. His results strongly supported the theory that enzymes combine with their substrate forming a temporary enzyme-substrate complex (274).

 

Frederick W. Barnes, Jr. (US), Rudolf Schoenheimer (DE-US), Konrad Emil Bloch (US), Charles Tesar (US), and David Rittenberg (US) established that purine compounds of the tissues and the excreta are rapidly synthesized from simple metabolic units and not from preformed substances such as arginine, urea, and histidine (73; 139; 1567).

 

Barry Commoner (US), Seymour Fogel (US) and Walter H. Muller (US) demonstrated that auxin would promote water absorption against an osmotic gradient. The effect is inhibited by iodoacetate (324).

 

Alfred Alexander Harper (GB) and Herbert Stanley Raper (GB) discovered pancreozymin (cholecystokinin), a hormone released from the small intestine, which stimulates the secretion of pancreatic enzymes (687). Note: later discovered that pancreozymin also stimulates the release of bile from the gall bladder.

 

Choh Hao Li (CN-US), Herbert McLean Evans (US), Miriam E. Simpson (US), George Sayers (US), Abraham White (US), and Cyril Norman Hugh Long (GB-US) isolated the adrenocorticotropic hormone (ACTH) from the pituitary gland of sheep then tested its biological activity (962; 1381).

Choh Hao Li (CN-US), Irving I. Geschwind (US), Anthony L. Levy (US), J. Ieuan Harris (US), Jonathan S. Dixon (US), Ning G. Pon (US), and Jerker O. Porath (SE) isolated and determined the properties of alpha-corticotropin (ACTH) from sheep pituitary glands (965).

Paul H. Bell (US), Robert G. Shepherd (US), Stuart D. Willson (US), Katherine S. Howard (US), David S. Davies (US), Selby B. Davis (US), E. Ann Eigner (US), and Nancy E. Shakespeare (US) isolated then determined the structure of porcine beta- corticotropin (ACTH) (105; 773; 1438).

Choh Hao Li (CN-US), Irving I. Geschwind (US), R. David Cole (US), Ilse Dorothea Raacke (US), J. leuan Harris (US), and Jonathan S. Dixon (US) determined the entire amino acid sequence of the alpha-corticotropin hormone (ACTH) of the anterior pituitary gland (964).

 

Otto Heinrich Warburg (DE) and Walter Christian (DE) isolated and crystallized aldolase (zymohexase) from muscle (1654).

 

Samuel M. Ruben (US) hypothesized that in photosynthesis the reduced pyridine nucleotide and the ATP needed to reverse the Embden-Meyerhof-Parnas pathway are generated by coupling to the light-dependent reduction of water (1343).

 

Michael Doudoroff (RU-US), Nathan Oram Kaplan (US), and William Zev Hassid (RU-GB-US) demonstrated that a glucosyl moiety of sucrose is transferred by enzyme to phosphorous. This was the first demonstration of such a sugar transfer. Glucose-1-phosphate and fructose were found to be the products of this sucrose breakdown by the bacterium Pseudomonas saccharophila. They found that this reaction was easily reversed leading to the synthesis of sucrose; the first such synthesis discovered (450).

 

Robert Emerson (US) and Charlton M. Lewis (US) determined that during photosynthesis in Chlorella quantum yields, as measured by oxygen release, are high when exposed to 400-440 and 560-580 nanometer ranges of light with a dip at about 490 nanometers (515).

 

Otto Fritz Meyerhof (DE-US) and Renate Junowicz-Kocholaty (US) re-determined the equilibrium constant for the isomerase and aldolase reactions in the presence and absence of inorganic phosphate, cozymase, and Warburg's oxidizing enzyme. They found that their values agreed with those previously determined and that equilibrium is not influenced by the presence of inorganic phosphate, cozymase, or Warburg's enzyme. They were also unable to detect the formation of any substance that would break down into glyceraldehyde phosphate and phosphate (1079).

 

Carl Ferdinand Cori (CZ-US) and Gerty Theresa Cori, née Radnitz (CZ-US), using liver tissue extract, presented evidence for the enzyme which forms the one to six glycosidic linkages in amylopectin (348).

Walter Norman Haworth (GB), Stanley Peat (GB), Edward J. Bourne (GB), Alan Macey (GB), and Susan A. Barker (GB) presented evidence for this same enzyme in higher plants (169; 170; 701; 1188).

 

David Nachmansohn (RU-DE-US), Richard Threlkeld Cox (US), Christopher W. Coates (US), and Adao L. Machado (BR) found that the production of very strong currents by electric eels relates to the breakdown of phosphocreatine (1122).

David Nachmansohn (RU-DE-US) and Adao L. Machado (BR) proved that electric tissue contains enzymes capable of utilizing the energy of ATP for the acetylation of choline by choline acetylase (1123). This was the first time ATP had been shown to drive a synthetic reaction other than phosphorylation.

 

Juan M. Muñoz (AR) and Luis Federico Leloir (AR) demonstrated fatty acid oxidation in cell-free liver systems (945; 1118).

Albert Lester Lehninger (US) showed that ATP is required for the oxidation of fatty acids and gave evidence that the fatty acid is enzymatically activated at the carboxyl group. He also found that fatty acids are oxidized to yield two-carbon units that can enter the tricarboxylic acid cycle (943).

 

Donald Dexter van Slyke (US), Robert Allan Phillips (US), Paul B. Hamilton (US), Reginald M. Archibald (US), Palmer H. Futcher (US), and Alma Hiller (US) identified glutamine as source material for urinary ammonia (1609).

 

Alfred Ezra Mirsky (US) and Arthur Wagg Pollister (US) demonstrated that histones are common to all somatic nuclei (1094).

 

Salvador Edward Luria (IT-US) Max Ludwig Henning Delbrück (DE-US), and Thomas Foxen Anderson (US) were the first to see bacterial ribosomes. They did not, at the time, know what they were (1001).

 

Salvador Edward Luria (IT-US) and Max Ludwig Henning Delbrück (DE-US) published a paper entitled Mutations of Bacteria from Virus Sensitivity to Virus Resistance. This paper represents the birth of bacterial genetics. With their paper, Luria and Delbrück did for bacterial genetics what Mendel had done for general genetics—namely, to show for the first-time what kind of experimental arrangements, what kind of data treatment, and, above all, what kind of sophistication are required for obtaining meaningful and unambiguous results (1000).

Bacteriophages (phages) are subcellular parasites that infect, multiply within, and kill bacteria. The T1 (T one) phage, active on Escherichia coli—with which Luria and Delbrück were working— has a head and a tail and occupies about one-thousandth the volume of its Escherichia coli host. It is too small to be seen with a light microscope. Upon collision of such a T1 phage particle with an Escherichia coli cell, the particle is fixed to the cell surface by interaction with a T1-phage receptor site; such sites form part of the Escherichia coli cell wall. The interaction of a phage particle with its phage receptor site has the same high degree of specificity as the interaction of the active site of an enzyme with its substrate. Once fixed to the receptor site, the T1 phage particle invades the Escherichia coli cell and destroys it. Imagine an experiment in which about 105 Escherichia coli cells are spread on the surface of a nutrient agar plate containing 1010 T1 phage particles. Upon incubation of that plate, the agar surface will most likely remain completely blank: not a single Escherichia coli colony can be expected to appear on that plate, since every bacterium of the inoculum will be infected, and hence killed, by one or more of the 1010 phage particles on the plate.

The point of departure of Luria and Delbrück’s paper was the observation that, upon spreading about109, rather than only about 105, Escherichia coli cells upon agar containing an excess of T1 phage particles, the chances are rather good that a few Escherichia coli colonies will appear on the agar surface. If one of these few surviving colonies is picked, and a sample of the cells making up the colony replated on agar containing T1 phage, it will be found that all these cells grow into colonies. All the bacteria in one of the few surviving colonies are T1-resistant or Tonr. By convention of genetic nomenclature, Ton designates the infectious agent and the superscripts r or s designate resistance or sensitivity of the host. The T1 resistant bacteria retain their Tonr character upon further cultivation in the absence of any T1 phage, as can be demonstrated by spreading samples of the Tonr culture growing in the T1-free medium on T1-containing agar. Thus, the Tonr bacteria perpetuate and pass on to their descendants the property of resistance to the phage, in contrast to the T1 sensitivity passed on by the normal Tons Escherichia coli cells. The physiological basis of the T1 resistance resides in the structure of the bacterial cell wall, in that the cell wall of Tonr bacteria does not feature the T1 receptor sites, to which the phage particles attach before they infect and kill the Tons cell. Hence the T1 phage particles cannot attach to, and, therefore, cannot kill the Tonr cells. Since the few Tonr cells isolated by plating the original Escherichia coli culture on the T1-containing agar have clearly descended from the Tons ancestors that make up the bulk of the population, they must represent stable variants of the normal Tons type. That is, an element of the bacterium that controls the synthesis of the T1 receptor sites in the cell wall of the normal Tons cell has changed in some way in the Tonr variant so that these receptor sites are no longer formed.

Such instances of the appearance of stable bacterial variants resistant to one or another antibacterial agent had been well known to bacteriologists for many years when Luria and Delbrück designed an experiment that was to enable them to decide between the following two fundamentally different views of the origin of stable Tonr variants in cultures on Tons Escherichia coli: 1) the Tonr character is induced as a consequence of the exposure of the Tons bacterial culture to T1 phage, 2) the Tonr character pre-exists in a few cells before exposure of the bacterial culture to T1 phage (1000). This great experiment is often referred to as the fluctuation test. It gave proof that mutations are usually not induced by the environment.

Luria and Delbrück’s statistical proof of the spontaneous nature of bacterial mutation and measurement of mutation rate represents not only the beginning of bacterial genetics, but also the first of several fortunate choices of experimental material that were to aid the further development of this field. Their finding of spontaneous mutation to phage resistance turns out to have depended on their use of the T1 phage, a phage that is a virulent bacteriophage. Had they chosen one of the phage types that came to be known as temperate bacteriophages, they would have had to conclude (wrongly) that the bacterial variants acquire their resistant character by contact with the antibacterial agent (1000).

 

Carl Clarence Lindegren (US) and Gertrude Lindegren (US) discovered heterothallism with two mating types in Saccharomyces (979).

 

Frederick Kroeber Sparrow (US) authored Aquatic Phycomycetes Exclusive of the Saprolegniaceae and Pythium, the first comprehensive systematic treatment of the aquatic Phycomycetes (1492).

 

Jacob S. Light (US) and Horace L. Hode (US) were probably the first to report clinical cases of rotaviral gastroenteritis (972; 973).

 

Curt Stern (DE-US) and Elizabeth White Schaeffer (US) demonstrated isoalleles while using the recessive cubitus interruptus (ci) allele in Drosophila (1524).

 

J. Bruce Hamilton (GB) clearly showed from clinical and laboratory observations that keratitis can be due to the Herpes simplex virus (670). Keratitis has multiple causes, one of which is an infection of a present or previous Herpes simplex virus secondary to an upper respiratory infection, involving cold sores.

Samuel N. Key, 3rd. (US), W. Richard Green (US), Eddy Willaert (US), Ann R. Stevens (US), and Samuel N. Key, Jr. (US) reported keratitis due to the protozoan, Acanthamoeba castellani (854). Amoebic infection of the cornea is the most serious corneal infection, usually affecting contact lens wearers. It is usually caused by Acanthamoeba.

Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteria involved are Staphylococcus aureus and for contact lens wearers, Pseudomonas aeruginosa. Pseudomonas aeruginosa contains enzymes that can digest the cornea.

 

Ragnar Granit (FI-SE) proposed a physiological theory of color perception. “The mechanism of color reception is organized by the peripheral visual apparatus, the number of color-sensitive elements is relatively limited, and these elements represent widely different regions of the visible spectrum (622).” He also made the first ganglion cell recordings from a mammalian retina, the cat retina (623).

 

Albert Claude (BE-US) used differential centrifugation to isolate a mitochondrial fraction from liver (298).

 

H. Nakamura (JP) and H. Tsumagari (JP) were the first to describe the tobacco stunt disease (1128).

 

Victor Assad Najjar (LB-US) and L. Emmett Holt, Jr. (US) discovered that bacteria in the bowel of man are synthesizing thiamine (vitamin B1) which is being absorbed into the blood stream (1126).

 

Robert Edward Hungate (US) described an anaerobic cellulose digesting bacterium from the rumen of cattle (789).

Frank Baker (GB), S.T. Harris (GB), Ralph M. Pearson (GB), and John Allan B. Smith (GB) used histochemical and histophysical methods to identify cellulose cleaving microorganisms in the rumen of cattle and sheep, and in the caeca of the horse, guinea pig, rabbit, and hen. They observed that each host species tends to harbor a characteristic microbiota (59; 60; 1185-1187).

Robert Edward Hungate (US) described his the roll-tube technique (Hungates's technique) for culturing strict anaerobes such as Clostridium cellobioparus (790).

 

Valy Menkin (RU-US) produced the first papers on the soluble factors from "pus" being pyrogenic. He injected rabbits with supernatants from leukocytes removed from sterile peritonitis (44; 1067-1069).

Paul Bruce Beeson (US) discovered a factor released from polymorphoneuclear leukocytes into the blood, which behaved as an endogenous mediator of fever. It would later be known as interleukin-1 (94). Note: For the next 40 years, the intravenous bolus injection of supernatants from leukocytes into rabbits with indwelling rectal thermometers was the most rapid and most reliable bioassay for what would later come to be called interleukin-1 (IL‐1).

Elisha Atkins (US) and W. Barry Wood, Jr. (US) demonstrated a protein that circulated during endotoxin fever and termed the activity "endogenous pyrogen." (45)

Igal Gery (US), Richard K. Gershon (US), and Byron Halsted Waksman (US) isolated a lymphocyte activating factor (LAF) produced by monocytes, which behaved as a mitogen for T-lymphocytes. This represents a rediscovery of the substance, which would later be known as interleukin-1 (IL-1). The operational definition of IL-1 became a soluble substance of monocytic origin, which augments murine thymocyte mitogenesis (599; 600).

Ralph F. Kampschmidt (US), Herbert F. Upchurch (US), Carl L. Eddington (US), and Larry A. Pulliam (US) discovered that a factor released from leukocytes stimulates the acute-phase response. This mediator would later be called interleukin-1 (837).

Stanley Cohen (US), Pierluigi E. Bigazzi (US), and Takeshi Yoshida (US) coined the term cytokine to specify molecules involved in signaling between cells engaged in immune responses (311; 312). Note: interferons, interleukins, colony stimulating factors, tumor necrosis factors, and transforming growth factor-beta are examples.

Doris A. Morgan (US), Francis W. Ruscetti (US), and Robert Charles Gallo (US) showed that a cell-free supernatant fraction from phytohemagglutinin stimulated human peripheral lymphocytes and could induce continuous proliferation of human T cells. It was called T cell growth factor (TCGF) (1103). Note: TCGF would later be called interleukin-2.

Charles A. Dinarello (US), Lois Renfer (US), and Sheldon M. Wolff (US) reported the purification of human leukocytic pyrogen (LP) and estimated that 5–10 ng/kg produced a fever (433). Note: LP and endogenous pyrogen are former interchangeable terms for the pyrogenic property of IL‐1. No other cytokine is as potent as IL‐1 in producing a fever in humans thus providing evidence that IL‐1β is the real "endogenous pyrogen." Endogenous pyrogen has been shown to be released by normal peripheral blood mononuclear cells (PBMC), human monocytic leukemia cells, and lymphoma cells.

Steven Gillis (US), Mary M. Ferm (US), Winny Ou (US), Kendall A. Smith (US), and Paul E. Baker (US) described for the first time the biological and biochemical characteristics of the T cell growth factor (TCGF) now known as interleukin-2 (61; 608; 1461; 1465).

Lucien A. Aarden (CH), K. Theodor Brunner (CH), and Jean Charles Cerottini (CH) later agreed that a single class of molecules was responsible for activity in several in vitro immune response assay systems including the antibody response and further agreed that this molecule (TCGF), which could trigger T cell replication, should be referred to as interleukin-2 (IL-2) (2).

Kendall A. Smith (US), Kevin J. Gillbride (US), and Margaret F. Favata (US) provided evidence that lymphocyte activating factor (LAF) promotes the concentration-dependent release of T cell growth factor (TCGF). The extent to which T cells proliferate is determined by the concentration of TCGF. Thus a mechanism to control the extent of T cell clonal expansion was provided (1464).

Kendall A. Smith (US), Lawrence B. Lachman (US), Joost J. Oppenheim (US), and Margaret F. Favata (US) found that lymphocyte activating factor 1 (LAF1) = interleukin 1 (IL-1) promotes the production of T cell-derived T cell growth factor (TCGF) = interleukin 2 (IL-2) (1466).

Donald Bunjes (DE), Conny Hardt (DE), Martin Rollinghoff (DE), and Hermann Wagner (DE) found that cyclosporin A suppresses the production of cytotoxic T cells by impairing the release of interleukin 1 and interleukin 2 (222).

Richard J. Robb (US), Allan Munck (US), and Kendall A. Smith (US) determined that TCGF interacts with activated T cells via a receptor through which it initiates the T cell proliferative response (1302).

Richard J. Robb (US) and Kendall A. Smith (US) discovered that T cell growth factor (TCGF) is a protein, which exists in various forms due to variable glycosylation (1303).

Warren J. Leonard (US), Joel M. Depper (US), Takashi Uchiyama (JP), Kendall A. Smith (US), Thomas A. Waldmann (US), and Warner C. Greene (US) partially characterized the membrane receptor for human interleukin-2 (947).

Stephen C. Meuer (DE), Rebecca E. Hussey (US), Ann C. Penta (US), Kathleen A. Fitzgerald (US), Beda Martin Stadler (CH), Stuart F. Schlossman (DE-US), and Ellis L. Reinherz (US) determined the cellular origin of human interleukin 2 (IL 2) to be T4+ and T8+ T lymphocytes (1074).

George H.A. Clowes, Jr. (US), Barbara C. George (US), Claude Alvin Villee, Jr. (US), and Calvin A. Saravis (US) reported that a peptide in the circulation of patients with sepsis or trauma promoted muscle wasting. This peptide would later be known as interleukin-1 (306).

Tadatsugu Tanaguchi (JP), Hiroshi Matsui (JP), Takashi Fujita (JP), Chikako Takaoka (JP), Nobukazu Kashima (JP), Ryota Yoshimoto (JP), Junji Hamuro (JP), Steven C. Clark (US), Suresh K. Arya (US), Flossie Wong-Staal (CN-US), Michiko M. Matsumoto-Kobayashi (US), and Robert M. Kay (US) cloned the gene which codes for human interleukin-2 (294; 1557).

Takashi Fujita (JP), Tadatsugu Taniguchi (JP), Hiroshi Matsui (JP), Chikako Takaoka (JP), Nikki J. Holbrook (US), Kendall A. Smith (US), Albert J. Fornace (US), Claudette M. Comeau (US), Robert L. Wiskocil (US), and Gerald R. Crabtree (US) determined the entire nucleotide sequence for the human interleukin-2 gene and flanking regions (580; 758).

Kendall A. Smith (US), Margaret F. Favata (US), and Stephen Oroszlan (US) described laboratory techniques useful in the production of monoclonal antibodies against human interleukin 2 (IL-2). These anti-lymphokines should be excellent tools to explore the molecular and biologic properties of these immunoregulatory molecules (1463).

Doreen A. Cantrell (GB), Kendall A. Smith (US), Stefan C. Meuer (DE), Rebecca E. Hussey (US), James C. Hodgdon (US), Oreste Acuto (GB), Thierry Hercend (FR), Stuart F. Schlossman (US), and Ellis L. Reinherz (US) discovered that after T cell stimulation by antigen the concentration of interleukin-2, the concentration of interleukin-2 receptors on T cells, and the duration of the interleukin-2 reaction with its receptor are all critical if the T cell is to be stimulated to divide (255; 1073; 1462).

Kenji Nakanishi (JP), David I. Cohen (US), Marcia A. Blackman (US), Ellen A. Nielsen (US), Junichi Ohara (JP-US), Toshiyuki Hamaoka (JP), Marian E. Koshland (US), and William Erwin Paul (US) demonstrated that interleukin-2 helps B cells to start secreting antibodies (1129).

Lee J. Siegel (US), Mary E. Harper (US), Flossie Wong-Staal (CN-US), Robert Charles Gallo (US), William G. Nash (US), and Stephen James O’Brien (US) located the human gene for interleukin-2 on chromosome 4q and the feline gene for interleukin-2 on chromosome B1 (1443).

Charles A. Dinarello (US) proposed that interleukin-1 acts as the “master molecule” inducing the entire spectrum of physiologic, hematologic, metabolic and immunologic upheaval of the host response to infection, trauma and immunologic activation (431).

Toshio Hirano (JP), Tetsuya Taga (JP), Naoko Nakano (JP), Kiyosi Yasukawa (JP), Shinichiro Kashiwamura (JP), Kazuo Shimizu (JP), Koichi Nakajima (JP), Kwang H. Pyun (JP), and Tadamitsu Kishimoto (JP) purified to homogeneity and characterized human B cell differentiation factor (BCDF or BSFp-2) (740).

Toshio Hirano (JP), Kiyoshi Yasukawa (JP), Hisashi Harada (JP), Tetsuya Taga (JP), Yasuo Watanabe (JP), Tadashi Matsuda (JP), Shin-ichiro Kashiwamura (JP), Koichi Nakajima (JP), Koichi Koyama (JP), Akihiro Iwamatsu (JP), Susumu Tsunasawa (JP), Fumio Sakiyama (JP), Hiroshi Matsui (JP), Yoshiyuki Takahara (JP), Tadatsugu Taniguchi (JP), and Tadamitsu Kishimoto (JP) reported the molecular cloning, structural analysis, and functional expression of the cDNA encoding human B cell differentiation factor (BSF-2). The primary sequence of BSF-2 deduced from the cDNA reveals that BSF-2 is a novel interleukin consisting of 184 amino acids. They named it interleukin-6 (IL-6). This factor was found to induce final maturation of B cells into antibody producing cells (741). Since this work, IL-6 has been found to be a multifunctional cytokine exerting a biological influence on various tissues and cells including hematopoietic progenitors, hepatocytes, nerve cells, epidermal keratinocytes, and kidney mesangium cells.

Julie B. Stern (US) and Kendall A. Smith (US) found that the activation of the T cell antigen receptor rendered the cells responsive to interleukin-2 (IL-2), but did not move them through the cell cycle. Interleukin-2 (IL-2) stimulated G1 progression to S phase, or lymphocyte blastic transformation. During IL-2 promoted G1 progression, expression of the cellular proto-oncogene c-myb was induced transiently at six to seven times basal levels, maximal levels occurring at the midpoint of G1 (1525).

Brad J. Brandhuber (US), Tom Boone (US), William C. Kenney (US), and David B. McKay (US) grew crystals of interleukin-2 and determined its three-dimensional structure (183; 184).

Hugh D. Campbell (AU), William Q.J. Tucker (AU), Yvonne Hort (AU), Mary E. Martinson (AU), Garry Mayo (AU), Elaine J. Clutterbuck (AU), Colin J. Sanderson (AU), and Ian G. Young (AU) carried out molecular cloning, nucleotide sequencing, and expression of the gene encoding human eosinophil differentiation factor (interleukin-5) (252).

Stefan Ehlers (DE) and Kendall A. Smith (US) compared neonatal and adult T cells revealing that both populations expressed the genes for interleukin-2 (IL-2) and its receptor, but only adult T cells were capable of transcribing mRNAs for IL-3, IL-4, IL-5, IL-6, interferon gamma, and granulocyte/macrophage colony-stimulating factor. However, neonatal T cells could be induced to undergo functional differentiation in vitro, thereby acquiring the capacity to express the lymphokine gene repertoire characteristic for adult T cells. These data suggest that the T cells generated from neonatal blood by a primary stimulation in vitro are functionally indistinguishable from the T cells in adult blood that presumably have undergone primary stimulation in vivo (499).

Paulo Vieira (PT-FR), Rene de Waal-Malefyt (US), Minh-Ngoc Dang (US), K.E. Johnson (US), Robert A. Kastelein (US), David F. Fiorentino (US), Jan E. de Vries (NL), Maria-Grazia Roncarolo, Timothy R. Mosmann (US), and Kevin W. Moore (US) demonstrated the existence of human cytokine synthesis inhibitory factor (CSIF) interleukin-10 (IL-10). IL-10 of human and murine origin exhibit a strong sequence homology to the open reading frame in Epstein-Barr virus, BCRFI. Human IL-10 and the BCRFI product inhibit cytokine synthesis (1617).

Antanina Zmuidzinas (US), Harvey J. Mamon (US), Thomas M. Roberts (US), and Kendall A. Smith (US) found that interleukin-2-triggers Raf-1 expression, phosphorylation, and associated kinase activity increase through G1 and S in CD3-stimulated primary human T cells (1768).

Patricia G. McCaffrey (US), Chun Luo (US), Tom K. Kerppola (US), Jugnu Jain (US), Tina M. Badalian (US), Andrew M. Ho (US), Emmanuel Burgeon (US), William S. Lane (US), John N. Lambert (US), Tom Curran (US), Gregory L. Verdine (US), Anjana Rao (US), and Patrick G. Hogan (US) purified nuclear factor of activated T cells (NFATp) from murine T cells and isolated a complementary DNA clone encoding NFATp (1040). Nuclear factor of activated T cells (NFAT) is a transcription factor that regulates expression of the cytokine interleukin-2 (IL-2) in activated T cells. The DNA-binding specificity of NFAT is conferred by NFATp, a phosphoprotein that is a target for the immunosuppressive compounds cyclosporin A and FK506.

Hal M. Hoffman (US), James L. Mueller (US), David H. Broide (US), Alan A. Wanderer (US), and Richard D. Kolodner (US) were the first to identify the genetic basis of four human diseases, including NLRP3, the gene responsible for cryopyrin associated periodic syndromes (CAPS). They identified four distinct mutations in a gene that segregates with the disorder in three families with familial cold autoinflammatory syndrome (FCAS) and one family with Muckle–Wells syndrome

(MWS). This gene, called either CIAS1(cold-induced autoinflammatory syndrome 1) or NLRP3 (NOD-like receptor protein 3), is expressed in peripheral blood leukocytes and encodes a protein (cryopyrin) with a pyrin domain (754). Note: The existence of the inflammasome was only possible with the discovery of cryopyrin. The discovery of cryopyrin provided the basis for the understanding of a broad class of acute and chronic inflammatory diseases, uniquely mediated by interleukin‐1β and now known as "auto‐inflammatory diseases."

Charles A. Dinarello (US) reported that interleukin-1 was later categorized into IL-1α and IL-1β, which are members of a family of 11 molecules, including agonists and antagonists (432).

Roy A. Black (US), Shirley R. Kronheim (US), Janet E. Merriam (US), Carl J. March (US), Thomas P. Hopp (US), Matthew J. Kostura (US), Michael J. Tocci (US), Guadalupe Limjuco (US), Jayne Chin (US), P. Cameron (US), A.G. Hillman (US), N.A. Chartain (US), John A. Schmidt (US), D.P. Cerretti (US), C.J. Kozlosky (US), B. Mosley (US), N. Nelson (US), K. Van Ness (US), T.A. Greenstreet (US), C.J. March (US), S.R. Kronheim (US), T. Druck (US), L.A Cannizzaro (US), Nancy A. Thornberry (US), Herbert G. Bull (US), Jimmy R. Calaycay (US), Kevin T. Chapman (US), Andrew D. Howard (US), Douglas K. Miller (US), Susan M. Molineaux (US), Jeffrey R. Weidner (US), John Aunins (US), Keith O. Elliston (US), Julia M. Ayala (US), Francesca J. Casano (US), Gloria J.-F. Ding (US), Linda A. Egger (US), Erin P. Gaffney (US), Oksana C. Palyha (US), S. M. Raju (US), Anna M. Rolando (US), J. Paul Salley (US), Ting-Ting Yamin (US), Terry D. Lee (US), John E. Shively (US), and Malcolm MacCross (US) found that interleukin‐1β likely evolved after interleukin‐1α. The distinctive characteristic of interleukin‐1β is a complex pathway by which the inactive precursor is cleaved by caspase‐1 within the cell into an active cytokine and secreted. Activation of caspase‐1 takes place via a protein complex called the inflammasome (125; 269; 877; 1574).

 

Robert Williams (GB), G.J. Harper (GB), and Arnold Ashley Miles (GB) developed a slide agglutination reaction using human plasma to identify coagulase positive staphylococci (1712).

Wilson Smith (GB) and James H. Hale (GB) determined that pathogenic strains of Staphylococcus aureus and of the albus variety regularly produce coagulase while nonpathogenic strains do not (1471).

 

Tracy Morton Sonneborn (US) showed that various cases of non-Mendelian inheritance could be classified into distinct groups, most involving interactions between nuclear genes and the cytoplasm (1488; 1489).

 

Maxwell E. Power (US) began his very important contribution to insect neuroanatomy by studying the distribution of nerve tracts and specific fibers in the brain of Drosophila as well as its thoracico-abdominal nervous system (1230-1232).

 

Carroll Milton Williams (US), and Muriel Voter Williams (US) demonstrated the neuromuscular network in the thorax that controls the wing-beat in Drosophila (1710).

 

Wilton R. Earle (US), Emma Shelton (US), Mary P. Clapp (US), Edward L. Schilling (US), Thomas H. Stark (US), Nancy P. Straus (US), Mary F. Brown (US), and Anderson Nettleslip (US) were the first to establish a permanent mammalian cell line in vitro. The cells were originally derived from an explant of subcutaneous tissue from the C3H strain of mice and after many subculturings designated the L strain. They found they could alter the morphology and growth characteristics of these cells by treatment with a carcinogen. When these altered cells were injected into healthy mice, tumors were produced. Earle and Nettleship (US) noted that all these normal cells maintained in vitro, even those not treated with a carcinogen, eventually became malignant and reverted (transformed) to a more primitive morphology (476-480; 1137; 1429).

Katherine K. Sanford (US), Wilton R. Earle (US), and Gwendolyn D. Likely (US) grew single isolated animal cells in vitro, thus proving that it is possible for a single somatic animal cell to give rise to a clonal population. The cell was from the murine L cell line and almost certainly transformed. The cloned cell line was designated NCTC-929 or L929 (1370).

Katherine K. Sanford (US), Gwendolyn Likely Hobbs (US), and Wilton R. Earle (US) found that clone L929 cells were still capable of giving rise to a low percentage of sarcomas when injected into strain C3H mice even after 10 years of being subcultured. A second finding was that these cells induced an immune reaction in the strain C3H mouse (1371).

 

Clinton Nathan Woolsey (US) discovered a second somatic sensory receiving area in the cortex of the cat, dog, and monkey (1746).

Edgar Douglas Adrian (GB) independently made the same discovery at a slightly later time in the Shetland pony (8).

 

Min Chueh Chang (CN-US) discovered that applying ice to the scrotum of sheep causes severe disintegration of sperm from the lower end of the epididymis. He referred to this as cold shock (276).

 

Paul Hahn (US) observed that within 1 minute after injection of 250 units of the anticoagulant heparin into lipemic dogs, the lipemia (due principally to chylomicrons, the lowest density lipoproteins in blood) had totally cleared, as observed visually in samples of drawn blood (663).

Norman Gulack Anderson (US) and Blake Fawcett (US) found that heparin injection causes the appearance in plasma of a "lipemia clearing factor" or "antichylomicronemic substance" that can clear lipemic plasma in vitro (31).

Edward David Korn (US) found that the “clearing factor” is, in fact, a heparin-activated lipoprotein lipase that occurs in and is released by heparin from heart and adipose tissues. It hydrolyzes the triacylglycerols of lipoproteins but not simple oil emulsions; the latter could, however, be converted to substrate by complexing with a high-density lipoprotein (872-874).

 

Jan Gosta Waldenström (SE) described three patients with an elevated erythrocyte sedimentation rate (ESR) who had hyperproteinemia and petechiae of their lower extremities without evidence of malignancy (1640). Although he coined the term purpura hyperglobulinaemica, this entity is now recognized as benign hypergammaglobulinemic purpura of Waldenström (BHPW).

 

James Purdon Martin (GB) and Julia Bell (GB) were the first to describe the fragile X syndrome (Martin-Bell syndrome) (1033).

Herbert A. Lubs (US) reported the fragile site on the X chromosome (994).

Annemiske J.M.H. Verkerk (NL), Maura Pieretti (US), James S. Sutcliffe (US), Ying-Hui Fu (US), Derek P. Kuhl (US), Antonio Pizzuti (US), Orly Reiner (US), Stephen Richards (US), Maureen F. Victoria (US), Fuping Zhang (US), Bert E. Eussen (NL), Gert-Jan B. van Ommen (NL), Lau A.J. Blonden (NL), Gregory J. Riggins (US), Jane L. Chastain (US), Catherine B. Kunst (NL), Hans Galjaard (NL), Charles Thomas Caskey (US), David L. Nelson (US), Ben A. Oostra (NL), and Stephen T. Warren (US) identified a gene for fragile X syndrome (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region and determined that its transcriptional silence is due to heavy methylation (1209; 1614).

Eric J. Kremer (AU), Melanie A. Pritchard (AU), Michael Lynch (AU), Sui Yu (AU), Katherine Holman (AU), Elizabeth Baker (AU), Stephen T. Warren (AU), David Schlessinger (AU), Grant R. Sutherland (AU), and Robert I. Richards (AU) determined that fragile X syndrome is caused by a massive expansion and concomitant methylation of a CCG repeat located in the 5’-untranslated region of the FMR1 gene, which results in transcriptional silencing of the gene (889; 1291). Fragile X syndrome is one of the most common forms of inherited mental retardation.

 

John Freeman Loutit (GB) and Patrick Loudon Mollison (GB) devised a disodium-citrate-glucose mixture as a blood preservative, which made possible the storage of whole blood for up to three weeks (993).

 

Thomas Gibson (GB) and Peter Brian Medawar (GB) defined the immunologic nature of skin allograft rejection in humans, confirmed subsequently with controlled rabbit experiments (605; 1056). See, Digby, 1661

Peter Brian Medawar (GB), Leslie Brent (GB), Rupert Everett Billingham (GB-US), and Elizabeth M. Sparrow (GB) established the immunological basis of the allograft reaction including an explanation of the second-stage phenomenon, i.e., an animal which has been grafted with foreign skin from the same donor on two successive occasions will reject the second graft more rapidly than the first (188; 1056-1059).

Peter Brian Medawar (GB) observed that presensitization of a recipient with leukocytes from the graft donor accelerated skin graft rejection, whereas erythrocytes had no effect. He therefore concluded that the search for histocompatibility antigens (coined in 1948) should be focused on the white cells, not the red cells, of the blood (1058).

 

F. Gerard Allison (CA) described restless legs syndrome and offered a treatment (23).

 

Edwin Bennett Astwood (US) found that hyperthyroidism could be successfully treated with thiourea and thiouracil (43).

 

Jay Tepperman (US), John Raymond Brobeck (US), and Cyril Norman Hugh Long (US) described hypothalamic hyperphagia in the albino rat (1566).

 

Diphtheria outbreaks accompanied war and disruption in Europe: in 1943, there were 1 million cases in Europe, with 50,000 deaths (not including the USSR) (1065).

 

Leo Kanner (AT-US) first used autism in its modern sense in English when he introduced the label early infantile autism in a report of 11 children with striking behavioral similarities (838).

 

David Lambert Lack (GB) wrote The Galapagos Finches (Geospizinae) a Study in Variation; Darwin’s Finches; The Life of the Robin; and Swifts in a Tower, all important contributions to ornithology and an introduction of competition theory into animal ecology, stressing the importance of ecological isolation in speciation, and providing a cogent model for adaptive radiation. Darwin's Finches, is a landmark work in which the differences in bill size of finches, which inhabit the Galapagos Islands, are interpreted as adaptations to specific food niches, an interpretation that has since been abundantly confirmed. Darwin's finches are a group of about 18 species of passerine birds(908-911). Note: "The person who more than anyone else deserves credit for reviving an interest in the ecological significance of species was David Lack... It is now quite clear that the process of speciation is not completed by the acquisition of isolating mechanisms but requires also the acquisition of adaptations that permit co-existence with potential competitors ."(1039)

 

1944

“From Type III Pneumococcus a biologically active fraction has been isolated…which in exceedingly minute amounts is capable…of inducing the transformation of unencapsulated R variants of Pneumococcus Type II into fully encapsulated cells of the same specific type as that of the heat-killed microorganisms from which the inducing material was recovered…. The active fraction…consists principally…of a highly polymerized, viscous form of desoxyribonucleic acid.” Oswald Theodore Avery (51).

 

Joseph Erlanger (US) and Herbert Spencer Gasser (US) shared the Nobel Prize in Physiology or Medicine for their determination of how different nerve fibers (cells) conducted their impulses at different rates. All else being equal, the velocity of the impulse varies directly with the thickness of fiber.

 

Raphael Consden (GB), Arthur Hugh Gordon (GB), and Archer John Porter Martin (GB) developed the technique of paper chromatography and stated that, “the separation depends on the differences in partition coefficient between the mobile phase and the water-saturated cellulose, instead of differences in adsorption by the cellulose” (334).

 

Lyman Creighton Craig (US) developed liquid-liquid countercurrent distribution as a separation and purification technique (360).

 

Charles M. Brewer (US) reported that the phenol coefficient technique is unsatisfactory for evaluating quaternary ammonium compounds because the results are to inconsistent (189).

 

Norton Nelson (US) reported a modification of the Somogyi method for glucose determination in biological material. Somogyi’s copper reagents were adapted for colorimetric use by omitting iodide and iodate in their preparation. The author developed a new arsenomolybdate reagent which, when used with Somogyi’s micro reagent, gave satisfactory stability and reproducibility of color (1135).

 

George A. Buntin (US) produced the first samples of toxaphene, a potent insecticide that could kill a wide range of cotton (Gossypium spp.) insect pests. Pilot plant production began in 1945 (1216).

 

Vincent du Vigneaud (US), Glen W. Kilmer (US), Julian R. Rachele (US), and Mildred Cohn (US) determined that all the sulfur and none of the carbon in newly formed cysteine originate from methionine (461).

 

Robert Burns Woodward (US) and William von Eggers Doering (US) performed the total synthesis of quinine from very simple molecules (1738; 1739).

 

Stanton A. Harris (US), Donald E. Wolf (US), Ralph Mozingo (US), R. Christian Anderson (US), Glen E. Arth (US), Nelson R. Easton (US), Dorothea Heyl (US), Andrew N. Wilson (US), and Karl August Folkers (US) achieved the first synthesis of biotin (690).

Henry Arnold Lardy (US), Richard L. Potter (US), and Conrad Arnold Elvehjem (US) found that the function of biotin is to fix carbon dioxide in heterotrophic organisms (928).

Pat N. Confalone (US), Giacomo Pizzolato (US), Enrico G. Baggiolini (US), Dianne Lollar (US), and Milan R. Uskokovic (US) carried out a total synthesis of biotin, an essential vitamin that functions as an indispensable coenzyme in a range of biocarboxylation reactions related to crucial physiological processes such as glucogenesis and fatty acid synthesis (327; 328).

 

Albert Schatz (US), Elizabeth Bugie (US), and Selman Abraham Waksman (RU-US) isolated a new antibacterial substance they designated streptomycin. It was isolated from two strains of actinomycetes related to an organism described as Actinomyces griseus (1385; 1635). It was first used on humans May 12, 1945. Waksman is credited with coining the word antibiotic (against life) (1633). See, Papacostas, 1928. Notes: the advent of the streptomycin era revolutionized the treatment of tuberculosis. Prior to the entry of the antibiotic into pharmacotherapy, this chronic malady was treated with rest, fresh air, and supportive care, with minimal therapeutic intervention. Streptomycin prevents the transition from initiation complex to chain elongating ribosome and causes miscoding in prokaryotes only.

Frederick A. Kuehl, Jr. (US), Karl August Folkers (US), Robert L. Peck (US), Alphonse Walti (US), and Charles E. Hoffhine, Jr. (US) crystallized then determined the structure of streptomycin (898; 899).

 

Oswald Theodore Avery (CA-US), Colin Munro MacLeod (US), and MacLyn McCarty (US) discovered that genetic information is contained in, and transmitted by DNA (51). Avery was 67 years old when this paper appeared. It is a mystery to many that he was never awarded the Nobel Prize. Erwin Chargaff (AT-US) commented, “the ever-rarer instance of an old man making a great scientific discovery. It had not been his first. He was a quiet man; and it would have honored the world more, had it honored him more” (281).

 

Bernice E. Eddy (US) reported that based on serological typing reactions seventy-five varieties of pneumococcal capsules had been discovered (493; 494).

 

Eugene F. Jansen (US), and Doris J. Hirschmann (US) discovered the antibiotic subtilin, produced by Bacillus subtilis. It was later shown by others to be antagonistic chiefly to gram-positive bacteria. It also inhibits Mycobacterium spp. and several pathogenic higher fungi (813).

 

Albert Edward Oxford (GB) isolated the antibiotic diplococcin from milk streptococci (1163).

 

Maud Leonora Menten (CA), Josephine Junge (US), and Mary H. Green (US) coined the phrase active site as it refers to the site of enzyme activity (1071).

 

Fritz Kubowitz (DE) and Paul Ott (DE) reported isolating pyruvate kinase from human muscle (897).

 

David Rockwell Goddard (US) demonstrated that cytochrome oxidase operates with the cytochrome c from plants (612).

Allen H. Brown (US) and David Rockwell Goddard (US) had shown that cytochrome oxidase is photoreversibly inhibited by carbon monoxide (199).

 

Sidney Weinhouse (US), Grace S. Medes (US), and Norman F. Floyd (US) proved the correctness of Georg Franz Knoop's hypothesis that ketone bodies are synthesized from two carbon fragments that are generated by the oxidation of fatty acids in the liver (1666).

Grace S. Medes (US), Sidney Weinhouse (US), and Norman F. Floyd (US) proved decisively that beta-oxidation of a fatty acid occurs with some of the product undergoing oxidation via the tricarboxylic acid (TCA) cycle and the residue condensing into ketone bodies, acetoacetic acid and beta-hydroxybutyric acid (1060).

See, Knoop, 1904.

 

Folke Karl Skoog (SE-US) produced in vitro cultures of tobacco tissue to study adventitious shoot formation (1452).

Folke Karl Skoog (SE-US) and Cheng Tsui (US) achieved the formation of adventitious shoots and roots with in vitro cultures of tobacco tissue (1453).

 

Reginald Ernest Balch (GB-CA) and Frederick Theodore Bird (CA) provided one of the first reports on the use of a virus to control an arthropod pest, i.e., the European spruce sawfly (63).

 

Charles H. Gray (US), Edward Lawrie Tatum (US), Raymond R. Roepke (US), Raymond L. Libby (US), and Margaret H. Small (US) described bacterial mutants in Escherichia coli which they characterized as auxotrophs, from the Greek aux-, increase (not from the Latin auxi-, help), and trophe, food. The normal or wild-type cells he called prototrophs, from protos, first, or minimal.

In order to isolate rare bacterial mutants that have a nutritional requirement for their growth with which the parent Escherichia coli can dispense, they followed essentially the same procedure that had yielded the Neurospora mutants in 1940. For this procedure large numbers of Escherichia coli cells were plated on nutrient agar—that is, on complete medium. The colonies, which appeared after overnight incubation on the complete medium, were then picked, and part of each bacterial clone was tested to ascertain whether it would grow on a minimal medium—that is, agar containing a synthetic medium deficient in all components except the minimum necessary to grow the prototroph. In this way Gray and Tatum found that, whereas most colonies consisted of bacterial clones capable of growing on both media, about 1% of the colonies that grew on the complete medium were made up of bacteria that were unable to grow on the minimal medium. That is, these rare colonies were made up of clones of nutritional Escherichia coli mutants, which require for their growth some factor present in the complete medium but absent from the minimal medium.

The exact nature of the growth requirement of any particular auxotrophic mutant strain could be established by placing samples of the auxotrophic bacterial clone into a series of minimal media to which various putative growth factors, such as amino acids, vitamins, purines, and pyrimidines, had been added. The growth requirement is then inferred to be that substance whose addition to the minimal medium is necessary and sufficient to allow growth of the auxotroph.

Gray and Tatum established that many of their Escherichia coli auxotrophs responded to the addition of just one single factor to the minimal medium. (By convention the auxotrophic mutants are designated with a minus sign and a three-letter abbreviation for the specific synthetic deficiency, e.g., Thr -, Pro -,Trp -. The prototrophic condition carries a plus sign, e.g., Thr +, Pro +, Trp +. It is noted that the minus or plus superscripts affixed to these symbols mean inability or ability to synthesize the substances represented by the three-letter abbreviation, and not, as with sugar-fermentation mutants, inability or ability to utilize the substance as a source of carbon and energy) (625; 1312).

 

Monroe D. Eaton (US), Gordon Meiklejohn (US), William van Herick (US), Marilla Corey (US), Leonard Hayflick (US), and Michael F. Barile (US) discovered the etiology of primary atypical pneumonia (280; 481; 482; 484). Note: The infectious agent was initially referred to as a pleuropneumonia like organism (PPLO).

Robert Merritt Chanock (US), Louis Dienes (US), Monroe D. Eaton (US), D.G. Edward (GB), Eyvind Antonius Freundt (DK), Leonard Hayflick (US), J. Francois Hers (FR), Keith E. Jensen (US), Chien Liu (US), Barrie Patrick Marmion (GB-AU), Harry E. Morton (US), Maurice A. Mufson (US), Paul F. Smith (US), Norman L. Somerson (US), and David Taylor-Robinson (GB) proposed Mycoplasma pneumoniae as binomial nomenclature name for atypical pneumonia organism (Eaton Agent) (279).

 

Victor Assad Najjar (LB-US), George A. Johns (US), George C. Medairy (US), Gertrude Fleischmann (US), and L. Emmett Holt, Jr. (US) discovered that bacteria in the large intestine of man are synthesizing riboflavin (vitamin B2) which is being absorbed into the blood stream (1127).

 

Roger Buvat (FR) noted that in vitro plant tissue would, with time, tend toward dedifferentiation (237).

 

Lothar Szidat (CL) found eggs of the fish tapeworm, Diphyllobothrium latum, in the intestines of two human bodies preserved in a peat bog in East Prussia since the early glacial period, i.e., Weichselian at 10- 110 Ka (1555).

 

J. Zed Young (GB), Paul Alfred Weiss (AT-US), and Helen B. Hiscoe (US) discovered that axoplasm of neurons is continuously flowing down nerve fibers at the rate of 0.2 mm per day (1668; 1755).

 

Raymond Bridgman Cowles (US) and Charles Mitchill Bogart (US) found that reptiles were voluntarily active only between the temperature extremes of 16 and 42 C. Nocturnal reptiles not only tolerate but prefer temperatures somewhat lower than those of diurnal reptiles. Reptiles were able to avoid extensive temperature fluctuations. Defecation is most frequent at body temperatures of 37 to 38 C. Close approximation of the maximum temperatures tolerated voluntarily and the critical maximum, which immobilizes the animals was somewhat less than 6 C. It is suggested that reptilian relicts tend to survive on islands or peninsulas owing to the relatively slight temperature fluctuations characteristic of maritime climates. For similar reasons relicts would tend to survive in tropical regions. Desert reptiles are capable of rapidly absorbing heat. Thermotaxis through behavior is one of the outstanding characteristics of desert reptiles (356).

 

William Hugh Feldman (US) and Horton Corwin Hinshaw (US) were the first to demonstrate successful in vivo treatment of tuberculosis with streptomycin (538; 739).

 

William Christopher Stadie (US), Benjamin C. Riggs (US), and Niels Haugaard (US) wrote a series of papers on the oxygen poisoning of enzymes and tissues at hyperbaric pressures (1503-1511).

 

Aristides Azevedo Pacheco Leão (BR), while studying the epileptiform after discharge response of the cerebral cortex to electric stimulation in rabbits, discovered the spreading depression reaction—a response of the dorsolateral neocortex to electric or mechanical stimuli applied to its surface. This visible aura frequently precedes migraine headaches (934-936).

 

John Friend Mahoney (US), Richard C. Arnold (US), Burton L. Sterner (US), Ad Harris (US), Margaret R. Zwally (US) described the use of penicillin to treat syphilis (1018). One long-term result of this discovery was the virtual elimination of tertiary syphilis of the brain, once a leading cause of insanity throughout the world.

 

Theodore B. Steinhausen (US), Clarence E. Dungan (US), Joseph B. Fürst (US), John T. Plati (US), S. Willard Smith (US), A. Perry Darling (US), E. Clinton Wolcott, Jr. (US), Stafford L. Warren (US), and William H. Strain (US) introduced the use of ethyl iodophenylundecylate (Pantopaque) compounds as contrast media to perform radiographic diagnosis (1523).

 

John McMichael (GB), Edward P. Sharpey-Schafer (GB), Rajane M. Harvey (US), M. Irené Ferrer (US), Richard T. Cathcart (US), Dickinson Woodruff Richards (US), André Frédéric Cournand (FR-US), Richard A. Bloomfield (US), Bernard Rapoport (US), J. Pervis Milnor (US), Walter K. Long (US), J. Gilmer Mebane (US), Laurence B. Ellis (US), and M. Rita Lavin (US) established that digitalis glucosides act favorably only upon ventricles over-dilated, with excessive filling pressures and inadequate emptying; that in such hearts it acts rapidly to increase the energy of contraction, increase stroke volume, and promote adequate emptying, thus relieving the congestive state; that it performs with regular as well as irregular cardiac rhythms (149; 694; 1054).

 

Arnold Rice Rich (US) clarified the pathogenesis of the spread of the tubercle bacilli in the body (1283).

 

Maurice Ralph Hilleman (US) demonstrated that the Chlamydia are bacteria rather than viruses (736; 737).

 

Dale Rex Coman (US) showed that cells from squamous cell carcinoma exhibit decreased mutual adhesion (322).

 

James Gray (GB) in his studies of the mechanics of the tetrapod skeleton points out among other things that, in locomotion, limbs can function either as struts, providing force along their long axis, or as levers, providing a moment of force to supply torque around the attachment point (626).

 

Roger Wolcott Sperry (US) severed optic axons in adult and immature anurans then noted that they reconnected to the optic tectum (the principal visual center) and visual function eventually returned, indicating that reflex relations in the brain had been correctly restored. To test how the restored vision had come about, regeneration was combined with a perturbation of the visual field produced by rotation of the eye. Control animals that had undergone regeneration of the optic nerve without rotation of the eye always showed correct responses when tested. Incorrect responses by those in which the eye had been rotated could not be attributed to any inherent defect in the regeneration process itself, and any functional process such as learning could not correct them, even if they were of a maladaptive nature. Sperry inferred from these experiments that “the ingrowing optic fibers must possess specific properties of some sort by which they are differentially distinguished in the [brain] according to their respective retinal origins” (1494).

Roger Wolcott Sperry (US) created various experimental environments in test subjects: 1) excising the optic chiasma and rerouting the optic nerves (which are usually completely crossed in the amphibians that he used) to connect each eye to the ipsilateral lobe of the optic tectum, 2) transplant one eye to the opposite side, thus reversing its dorsal-ventral orientation without changing its nasal-temporal orientation, or vice versa. In these animals, the visuomotor responses were altered from normal in the direction that would have been predicted from their eye orientations. Histological studies showed a disorderly progression of the optic axons along the nerve, with almost all of them crossing to the contralateral tectum and only a scattering selecting the route to the side to which they would originally have connected. Thus, it was evident that the regenerating axons were not passively following their old trajectories, and hence their final orderly reconnection to the optic tectum must have been determined by an intrinsic property reflecting the specific location of their cell bodies in the retina. Sperry inferred that the specific local properties would have been produced originally in the embryo “through a field differentiation of the retina” (1495).

 

Jan Gosta Waldenström (SE) described two patients with oronasal bleeding, lymphadenopathy, normochromic anemia, increased erythrocyte sedimentation rate, thrombocytopenia, hypoalbuminemia, low serum fibrinogen, and increased numbers of lymphoid cells in the bone marrow. Prolonged bleeding after lymph node biopsy and bone marrow aspiration, lobar pneumonia, and retinal hemorrhages were observed. His initial description remains to this day characteristic of the clinical presentation and laboratory abnormalities of Waldenström's macroglobulinemia related to excess IgM (1641).

 

John Rock (US) and Miriam Menkin (US) announced the first successful human in vitro fertilization (IVF) experiment (1311).

 

Grantly Dick-Read (GB) developed the concept of natural childbirth: that by elimination of fear and tension, labor pain could be minimized and anesthetics, which can be hazardous to both mother and child, rendered unnecessary (428).

 

Hugh William Bell Cairns (GB), Walpole Sinclair Lewin (GB), Edward S. Duthie (GB), and Honor V. Smith (GB) introduced intrathecal administration of penicillin in treatment of pneumococcal meningitis (241).                            David H. Rosenberg (US) and Philip A. Arling (US) were the first to successfully treat meningitis with intravenous and intrathecal penicillin (1338). Since then, penicillin has remained the drug of choice for the treatment of meningococcal meningitis.

 

Dwight Emary Harken (US), when the Normandy invasion took place in 1944, became a lieutenant-colonel in the medical corps and acquired a good reputation for removing bullets and shrapnel from the chests of 134 wounded soldiers—78 within or in relation to the great vessels and 56 in or in relation to the heart—without losing a single patient (686).

 

Hans Asperger (AT) published the first definition of Asperger’s Syndrome in 1944. In four boys, he identified a pattern of behavior and abilities that he called “autistic psychopathy,” meaning autism – self and psychopathy – personality disorder. The pattern included “a lack of empathy, little ability to form friendships, one-sided conversation, intense absorption in a special interest and clumsy movements” (39).

                                                           

Paul Jackson Kramer (US) and John P. Decker (US) determined that the eventual transformation of pine forests to hardwood forests results from the inability of pine seedlings to grow in the low light intensities under deciduous trees (880). Note: This work is one of the first explanations of the succession of plant species in natural communities.

 

Maurice Ralph Hilleman (US) helped to develop a vaccine against Japanese B encephalitis to protect American troops in the World War II Pacific theater of operations. Hilleman’s vaccine was never widely tested. It was given to thousands of U.S. soldiers in wartime and likely prevented disease in many of them. Later, other vaccines replaced it (1065). Note: The mosquito, Ochlerotatus japonicus, is the suspected vector of Japanese encephalitis in Asia and West Nile virus in the United States.

 

1945

“…But I would like to sound one note of warning. Penicillin is to all intents and purposes non-poisonous so there is no need to worry about giving an overdose and poisoning the patient. There may be a danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.

The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant." Alexander Fleming (GB) (564).

 

Artturi Ilmari Virtanen (FI) was awarded the Nobel Prize in Chemistry for his research and inventions in agricultural and nutrition chemistry, especially for his fodder preservation method.

 

Alexander Fleming (GB), Ernst Boris Chain (DE-GB), and Howard Walter Florey (AU-GB) were awarded the Nobel Prize for physiology and medicine for the discovery of penicillin and its curative effect in various infectious diseases.

 

Erwin Schrödinger (AT) wrote his little book What is Life?, which had a profound effect on physical scientists. Since many of these physical scientists were suffering from a general professional malaise in the immediate post-war period, they were eager to direct their efforts toward a new frontier, which according to Schrödinger was ready for some exciting developments. He tantalized physicists by suggesting that while the study of the gene would not elude the laws of physics, as established up to that date, it was likely to involve other laws of physics hitherto unknown. Their knowledge of biology was generally confined to stale botanical and zoological lore, and having one of the founding fathers of the new physics put the question, what is life? Provided for them an authoritative confrontation with a fundamental problem worthy of their mettle. Schrödinger’s book became a kind of catalyst of the revolution in biology that, when the dust had cleared, left molecular biology as its legacy. It is in this book that Schrödinger proposes the existence of an aperiodic solid polymer with potential as a miniature code containing information which is transmitted from one generation to the next.

Schrödinger emphasizes that all living organisms are thermodynamically open systems and their increase in orderliness is paid for by a net increase of disorder in their environments (1410).

 

Paul H. Leslie (GB) showed how one simple mathematical technique can be used to make all the important demographic projections and how this technique can be applied to basic life table data of the sort that a laboratory or field ecologist usually obtains (952).

 

Robley Cook Williams (US) working with the electron microscopist Ralph Walter Greystone Wyckoff, Sr. (US) developed the technique of metal shadow casting. This allows tiny objects to take on a three-dimensional quality when viewed through the electron microscope (1713).

 

Gösta Karpe (DK) made electroretinography a useful clinical method (840).

 

Gordon R. Baldock (GB) and William Grey Walter (GB-US) developed automated spectral analysis of EEG traces. A standard method for EEG analysis since its discovery has been to measure the power in various frequency bands, including alpha and delta, also beta (15-30 Hz), and theta (3-7 Hz). Walter used his skills in analog electronics to build a device that displayed the frequency content in an EEG trace, even as the trace was displayed with an ink-writing oscillograph, a pen whose fluctuations left a trace on moving paper that became the mainstay of electroencephalographers (64; 65).

 

Gerhard Schmidt (US) and Siegfried Joseph Thannhauser (US) presented a method for the determination of desoxyribonucleic acid, ribonucleic acid, and phosphoproteins in animal tissues (1389).

 

Willard A. Krehl (US), Lester J. Teply (US), Padman S. Sarma (US), and Conrad Arnold Elvehjem (US) presented evidence that tryptophan is very likely a metabolic precursor to niacin (vitamin B3) (887; 888).

 

Harland Goff Wood (US), Nathan Lifson (US), and Victor Lorber (US) demonstrated the pathway of carbon dioxide incorporation into specific carbon atoms of glucose derived from rat hepatic glycogen (1729).

 

Percy Wragg Brian (GB), Harold George Hemming (GB), and J.C. McGowan (GB) reported that griseofulvin is antifungal because it inhibits Botryti allii and produces distortions in its germ tubes (190).

Albert Edward Oxford (GB), Harold Raistrick (GB), and Paul Simonart (GB) discovered griseofulvin as a product of Penicillium griseofulvum (1164).

James C. Gentles (GB) reported the successful treatment of dermatophytosis in guinea pigs with griseofulvin (596). It was introduced for clinical use in 1959.

 

Alastair Campbell Frazer (GB) and Herbert G. Sammons (GB) demonstrated that the formation of mono- and diglycerides from triglycerides results from the action of pancreatic lipase (pancreatic triacylglycerol lipase) both in vitro and in vivo, with no free glycerol appearing during the first five hours of the reaction (572).

 

Clause Silbert Hudson (US), Nelson K. Richtmyer (US), and James W. Pratt (US) elucidated the structure of sedoheptulose (781; 1233; 1292).

 

Linus Carl Pauling (US) speculated that the biological action of a protein is related to the shape of the surface into which the polypeptide folds (1180).

 

Erwin Brand (US), Leo J. Saidel (US), William H. Goldwater (US), Beatrice Kaseel (US), and Francis J. Ryan (US) reported the first complete amino acid analysis of a protein by chemical and microbiological methods. The protein was beta-lactoglobulin (182). Beta-lactoglobulin is the major whey protein in the milk of ruminants and some non-ruminants.

 

Choh Hao Li (CN-US), Herbert McLean Evans (US), Miriam E. Simpson (US), and Kai O. Pederson (US) isolated and determined the properties of anterior hypophyseal growth hormone known as somatotropin or growth hormone (GH) from the ox (963; 967).

Choh Hao Li (CN-US) and Harold Papkoff (US) prepared and tested the properties of growth hormone from human and monkey pituitary glands (966).

 

Frederick Sanger (GB), Hans Tuppy (GB), Edward Owen Paul Thompson (GB), Andrew P. Ryle (GB), Leslie F. Smith (GB), Ruth Kitai (GB), and Henry Brown (GB) developed a method for determining the nature and amount of the amino-terminal amino acid residues in a protein by using dinitrofluorobenzene. When they applied this methodology to insulin they concluded that each 12,000-molecular weight unit contained two amino-terminal glycine residues and two amino-terminal phenylalanine residues. Sanger postulated that, “The presence of four alpha amino groups suggests that the submolecule is built up of four open polypeptide chains bound together by cross-linkages, presumably chiefly disulfide linkages. It is, of course, possible that other chains may be present in the form of a ring structure with no free amino groups”. They later found that insulin was likely to be composed of two polypeptide chains, succeeding in determining the exact amino acid sequences for both chains of bovine insulin. This was the first demonstration that proteins contain a precise amino acid sequence (203; 1358; 1372-1379).

Donald Frederick Steiner (US), Ronald E. Chance (US), Robert M. Ellis (US), William W. Bromer (US), Ole Hallund (DK), Arthur Harold Rubenstein (US), Sooja Cho (US), Claudia Bayliss (US), Jeffrey L. Clark (US), Chris Nolan (US), Emanuel Margoliash (IL), Bradley Aten (US), Philip E. Oyer (US), James D. Peterson (US), and Franco Melani (US) found that insulin is synthesized first in the islet cells as a single-chained precursor, proinsulin. In the pancreatic duct proinsulin is subsequently converted to the two-chained form by the enzymatic removal of a segment from its middle after the formation of the three disulfide bonds (275; 1064; 1146; 1517-1520). This represents the first evidence for the existence of a novel family of endoproteolytic processing enzymes called proprotein convertases. See Roebroek, 1986.

 

Otto Fritz Meyerhof (DE-US) demonstrated the need for ATPase during glycolysis (1078).

 

Walter C. Schneider (US) described methodology by which DNA, RNA, and cellular protein can be separated from one another (1391; 1392).

 

Fritz Albert Lipmann (DE-US) discovered how pyruvate is oxidized to the intermediate formation of a reactive two-carbon fragment (active acetate) by studying a model system. He showed that pigeon-liver extracts, in the presence of added ATP, also affected the acetylation of the amino group of the drug sulfanilamide with acetate as the source of potential active acetate. He found that this reaction required—in addition to thiamine pyrophosphate—the presence of a heat-stable dialyzable factor, which he named cofactor coenzyme A (A for acetylation) (983).

Fritz Albert Lipmann (DE-US), Nathan Oram Kaplan (US), G. David Novelli (US), L. Constance Tuttle (US), and Beverly M. Guirard (US) tested coenzyme A for vitamin activity and indeed found that it contains pantothenic acid (Greek, pantothen, from every side) (984).

Joseph Richard Stern (US), Severo Ochoa (ES-US-ES), G. David Novelli (US), Fritz Albert Lipmann (DE-US), Willard B. Elliott (US), George Kalnitsky (US), and Feodor Felix Konrad Lynen (DE) reported the synthesis of citrate from acetate, ATP, CoA, and oxaloacetate in pigeon liver, yeast, Escherichia coli, and kidney tissue. It was shown that citrate rather than cis-aconitate or isocitrate is the product of the "acetate"-oxaloacetate condensation (507; 1147; 1526-1528). This is citrate synthase.

Fritz Albert Lipmann (DE-US), Nathan Oram Kaplan (US), G. David Novelli (US), L. Constance Tuttle (US), and Beverly M. Guirard (US) isolated coenzyme A (985).

G. David Novelli (US) and Fritz Albert Lipmann (DE-US) confirmed the catalytic function of coenzyme A in citric acid synthesis using cell-free extracts of Saccharomyces cerevisiae and Escherichia coli (1147).

Seymour Korkes (US), Joseph Richard Stern (DE-US), Irwin Clyde Gunsalus (US) and Severo Ochoa (ES-US-ES) elucidated the enzymatic synthesis of citrate from pyruvate and oxaloacetate in Escherichia coli (871).

Fritz Albert Lipmann (DE-US), Nathan Oram Kaplan (US), G. David Novelli (US), L. Constance Tuttle (US), and Beverly M. Guirard (US) isolated coenzyme A (985).

Feodor Felix Konrad Lynen (DE), Ernestine Reichert (DE), and Luistraud Kröplin-Rueff (DE) established the precise chemical mechanism by which coenzyme A carries acyl groups. They isolated an active form of acetate from yeast and showed it to consist of a thioester of acetic acid with the thiol or sulfhydral group of coenzyme A. The function of coenzyme A is to serve as a carrier of acyl groups in enzymatic reactions involved in fatty acid oxidation, fatty acid synthesis, pyruvate oxidation, and biological acetylations (1004-1006).

James Baddiley (GB), Eric M. Thain (), G. David Novelli (US), and Fritz Albert Lipmann (DE-US) worked out the structure of coenzyme A (54).

Severo Ochoa (ES-US-ES), Joseph Richard Stern (DE-US), Morton C. Schneider (US), and Feodor Felix Konrad Lynen (DE) demonstrated that acetyl-CoA is the substance that reacts with oxaloacetate to form citrate in the presence of the condensing enzyme crystallized by Severo Ochoa’s laboratory (1152; 1528).

Horace Albert Barker (US) and Earl Reece Stadtman (US) found that coenzyme A participates in the metabolism of fatty acids (70).

Sydney Kaufman (US), D. Rao Sanadi (), and John W. Littlefield (US) showed that coenzyme A also participates in the conversion of alpha-ketoglutarate to succinate and that succinyl coenzyme A is an intermediary stage (841; 1368).

Roscoe O. Brady (US) and Earl Reece Stadtman (US) detected three distinctly different thioltransacetylases in pigeon liver extracts; namely, thioltransacetylase A which catalyzes the transfer of the acetyl group of acetyl-CoA to reduced lipoic acid, 2-mercaptoethanol, and to a lesser extent to some other mercaptans, thioltransacetylase B which catalyzes the acetylation of 2-mercaptoethanol and 2-mercaptoethylamine, and a hydrogen sulfide thioltransacetylase that catalyzes the acetylation of hydrogen sulfide with the formation of thioacetic acid (179).

John Gilbert Moffatt (US) and Har Gobind Khorana (IN-US) synthesized coenzyme A (1097). NAD and lipoic acid were found to be requirements for coenzyme A activity. See, Lester J. Reed.

 

Herman Moritz Kalckar (DK-US) and Manya Shafran (US) discovered that phosphorolytic cleavage of nucleosides is like that of glycogen, e.g. ribose-hypoxanthine + Pi is converted to ribose-1-P + hypoxanthine. The equilibrium of this reaction lies to the left. This was the first demonstration of enzymatic synthesis of a nucleoside (833; 835).

 

Gerty Theresa Cori, née Radnitz (CZ-US), Milton Wilbur Slein (US), and Carl Ferdinand Cori (CZ-US) crystallized glyceraldehyde-3-dehydrogenase from skeletal muscle (349).

 

Winston H. Price (US), Carl Ferdinand Cori (CZ-US), and Sidney P. Colowick (US) demonstrated that hexokinase activity is promoted by insulin but checked by another hormone in extracts from the anterior lobe of the pituitary gland, i.e., the hypophysis (1234). Note: This first demonstration of a regulatory effect of hormone on enzyme opened a whole new field of investigation.

 

David Shemin (US) and David Rittenberg (US) observed that if 15N-labelled glycine molecules are given to human subjects it leads to hemin (ferriprotoporphyrin) molecules in which all four nitrogens are 15N. Serendipitously they found that the data allowed them to calculate the average life span of a human erythrocyte at 127 days (1432-1434).

David Shemin (US), Irving M. London (US), David Rittenberg (US), Jonathan B. Wittenberg (US), Kenneth D. Gibson (US), William Graeme Laver (AU), Albert Neuberger (DE-GB), Helen M. Muir (GB), John C. Wriston, Jr. (US), Leon Lack (US), Charlotte S. Russell (US), and Tessa Abramsky (US) elucidated the basic aspects of heme (pyrrole ring) biosynthesis and showed that glycine and succinyl-CoA are the source of all the heme (603; 989; 990; 1111; 1430; 1431; 1436; 1437; 1726; 1754).

Roland G. Westall (GB), Gerry H. Cookson (GB) and Claude Rimington (NO) found that a patient suffering from acute intermittent porphyria was excreting a monopyrrole (porphobilinogen). Porphobilinogen was postulated to be a "pyrrolic intermediate" in the synthesis of a group of organic pigments, which includes hemoglobin and chlorophyll (337; 338; 1679).

Samuel I. Beale (US), Simon P. Gough (US), and Sam Granick (US) discovered the C5 pathway in which the first pyrrole ring of the four pyrrole rings in chlorophyll can be made by an alternative route for the synthesis of 5-aminolevulinate which starts from glutamate (in contrast to the synthesis from glycine and succinyl-CoA) (89).

 

Gunnar Östergren (SE) formulated the concept of selfish DNA. Speaking of non-coding B chromosomes, he stated that: “I think reasonable support may be given to the view that in many cases these chromosomes have no useful function at all to the species carrying them, but they often lead an exclusively parasitic existence” (1159).

 

Norman Harold Horowitz (US) and Jerry S. Hubbard (US) postulated how complex sequential metabolic pathways may have arisen as the result of selective pressure, i.e., the retrograde model.

Suppose that a contemporary cellular pathway makes a required substance such as an amino acid through the sequence A to B to C to D to E, in which A is a simple inorganic substance and E is the final organic product. Initially E was plentiful in the environment and was absorbed directly by primitive aggregates. Later, as E became scarce because of use, chemical selection favored pre-cells that could make E from D, a slightly less complex organic substance still found in abundance in the environment. As D became exhausted, selection favored assemblies that developed the pathway C to D, in which the even simpler substance C could be absorbed and used as raw material to make D. This process continued until the entire synthetic pathway, based on an essentially inexhaustible inorganic substance, was established (766; 768).

 

Milislav L. Demerec (Yugoslavian -US) and Ugo Fano (US) collected the group of seven bacteriophages later to be called the T-set. Their host is E. coli strain B. They were numbered consecutively as they were collected (most likely from sewage or feces) (398; 819). Of the seven, the so-called T-even strains (T2, T4, and T6), which are similar structurally, antigenically, and genetically, proved the most useful for biochemical and genetic studies.

 

Alan Lloyd Hodgkin (GB) and Andrew Fielding Huxley (GB) were able to measure the resting and action potentials in single nerve fibers (cells) (751).

 

Keith Roberts Porter (US), Albert Claude (BE-US), and Ernest F. Fullam (US) produced the first electron micrograph of an intact eukaryotic cell. The cell was a cultured fibroblast originating from a chick embryo, which was grown by Porter on polyvinyl film, then peeled off and transferred to a wire specimen grid. The cell was fixed with osmium tetroxide, washed and then dried to prevent evaporation in the electron microscope's vacuum chamber. Magnified 1600 times, this first electron micrograph of a cell reveals mitochondria, the Golgi apparatus and a lace-like reticulum which Porter later named the endoplasmic reticulum. The electron microscope used for this historic image was an RCA EMB model, operated by Fullam at the Interchemical Corporation in New York City (1225).

George Emil Palade (RO-US), Keith Roberts Porter (US), Frances Kallman (US) and Fritiof Stig Sjöstrand (SE) developed methods for fixation and thin sectioning that enabled many intracellular structures to be seen for the first time (1167; 1168; 1226; 1449).

Keith Roberts Porter (US), working with Albert Claude (BE-US), named the endoplasmic reticulum (1223).

H. Stanley Bennett (US), Keith Roberts Porter (US), and George Emil Palade (RO-US) identified the sarcoplasmic reticulum (109; 1227).

George Emil Palade (RO-US) and Keith Roberts Porter (US) found that an endoplasmic reticulum similar to that previously described in cultured material is present in situ in all cell types examined. The observations showed in addition that the endoplasmic reticulum is a network of cavities which may enlarge into relatively vast, flattened vesicles here described as cisternae (1170). Porter and Palade described the transverse channels so vital to conduction.

Keith Roberts Porter (US) and Joseph Blum (US) developed the ultramicrotome. The invention took place in 1952 (1224).

 

Fritiof Stig Sjostrand (SE), Leonard G. Worley (US), Ernest Fischbein (US), and Jennie E. Shapiro (US) discovered the ciliary rootlet as an anatomical structure (1450; 1753). The cross-linking between the rootlets and other cytoskeletal elements indicate its important role as an anchor and support structure for the cilia.

 

Hermann Joseph Muller, Jr. (US) made an exceptionally farsighted interpretation of Oswald Theodore Avery’s work on the transformation of pneumococci (51). Muller stated, “There were, in effect, still viable bacterial ‘chromosomes’ or parts of chromosomes floating free in the medium used. These might, in my opinion, have penetrated the capsuleless bacteria and in part at least have taken root there.

A method appears to be provided whereby the gene constitution of these forms can be analyzed, much as in the crossbreeding tests on the higher organisms. However, unlike what has so far been possible in higher organisms, viable chromosome threads could also be obtained from these lower forms for in vitro observation, chemical analysis, and determination of the genetic effects of treatment” (1113). Note: Given as a Pilgrim's Trust Lecture before the Royal Society of London 1 November 1945.

 

Max Ludwig Henning Delbrück (DE-US) organized the first annual summer phage course at Cold Spring Harbor, New York. This course persuaded many young scientists to adopt phage as a tool for solving problems of a biological nature, especially the problem of defining a gene and its relationship to DNA.

 

Michael Doudoroff (RU-US) proposed that the utilization of sugars is controlled by permeability mechanisms involving sugar-specific carrier proteins (447; 448).

 

Salvador Edward Luria (IT-US) discovered that bacteriophages can sport host-range mutants. These host-range mutants are able to overcome the resistance of phage-resistant mutant bacteria because the structure of the attachment organs of the mutant phage differs in some subtle way from that of the wild-type phage (998).

Alfred Day Hershey (US) reported the isolation of r (rapid lysis) and h (host-range) phage mutants. This along with Luria’s work demonstrated to existence of various mutant forms (719).

 

Max Ludwig Henning Delbrück (DE-US) developed a technique permitting the assay of the relative proportion of h and h plus types in a single plating of a bacteriophage suspension. h is a mutant T2 phage that can infect and grow on cells normally resistant to the T2 phage. The wild-type T2 phage is h plus which is capable of infecting normal cells but not Tto resistant cells (395).

 

Edward B. Lewis (US) designated that in genetics there are two different types of position effects, S-type (stable) and V-type (variegated) (961).

 

Josef Fried (US) and Oscar Paul Wintersteiner (US) isolated the antibiotic streptothricin from Actinomyces lavendulae (577).

 

Herman C. Lichstein (US) and Virginia F. van de Sand (US) isolated the antibiotic violacein from Chromobacterium violaceum (970).

 

Balbina A. Johnson (US), Herbert Anker (US) and Frank L. Meleney (US) first described the antibiotic bacitracin, which they isolated from Bacillus licheniformis. It was found to be to toxic for internal use (814).

 

André Félix Boivin (FR), Albert Delauney (FR), Roger Vendrely (FR), and Yvonne Lehoult (FR) reported a transformation phenomenon in Escherichia coli, which was very similar to Oswald Theodore Avery’s 1944 transformation in Pneumococcus (156; 157).

 

Barbara McClintock (US) determined that the chromosomes of Neurospora and their behavior in the ascus are typically eukaryotic. She outlined the details of meiosis and described the seven chromosomes, noting that despite their small size they are individually recognizable by their distinctive morphology at pachytene. Pachytene pairing in a translocation heterozygote with the ascus types resulting from different modes of segregation when the translocation was heterozygous were described (1048).

 

Donald Frederick Poulson (US) studied embryonic development in Drosophila melanogaster by using deficiencies involving the entire X chromosome or reasonably large portions thereof. The results of one such deficiency, known as Notch-8, were detailed. “The most striking feature of such eggs is that they contain very little or no endoderm or mesoderm... the process of germ layer formation has been interfered with seriously... The ectoderm proliferates especially along the ventral mid-line and produces what appears to be a semblance of the early nervous system” (1228).

Donald Frederick Poulson (US) clearly demonstrated that the closely coordinated yet separate developmental steps involved in Drosophila embryogenesis are under the control of specific genes (1229).

Christopher Q. Doe (US) and Corey S. Goodman (US) studying the neural ectoderm of grasshoppers suggested a mechanism that we now know as lateral inhibition. Using laser micro beams to ablate one or more ectodermal cells in a group, they found that neuroblasts are specified by cell interactions. Initially, each undifferentiated cell within a sheet of neural ectodermal cells has an equal chance of becoming a neuroblast, but only one cell within a group takes on this role. Interactions between the cells of a group allow this one cell to enlarge into the neuroblast, which somehow prevents its neighboring cells from taking on the same identity; these cells instead become support cells or die (440).

Kristi A. Wharton (US), Kristen M. Johansen (US), Tian Xu (US) and Spyros Artavanis-Tsakonas (US) presented the primary structure of the major embryonic Notch transcript, which shows homology to the epidermal growth factor (EGF) and other proteins containing EGF-like repeats. Hydropathy plots suggest that the putative Notch protein may span the membrane. They relate these findings to the developmental action of Notch and speculate that the locus may be involved in a cell-cell interaction mechanism that is essential for the differentiation of the ectoderm into neural and epidermal precursors (1680).

 

Philippe l'Héritier (FR) and Georges Teissier (FR) reported the symptoms exhibited by Drosophila when infected with sigma virus (906).

 

Mikhail Petrovich Chumakov (RU), in 1944, was the first to identify and establish the viral etiology of the disease the Soviets called Crimean Hemorrhagic Fever. He passed the virus through human volunteers but was unable to isolate it (292).

David I. H. Simpson (IE), E.M. Knight (), Ghislaine Courtois (BE), Miles C. Williams (GB), M. Paul Weinbren (ZA), and John W. Kibukamusoke (AU) isolated and named Congo virus from several Congolese and Ugandan patients exhibiting a severe febrile illness (1445). The virus was eventually named Crimean-Congo hemorrhagic fever virus (CCHF), a member of the genus Nairovirus, family Bunyaviridae.

Jordi Casals (ES-US) found the Crimean virus indistinguishable from Congo virus, which was isolated in 1956 from a febrile child in Stanleyville (now Kisangani, Democratic Republic of the Congo), leading to the current designation, CCHF virus (258). CCHF produces high mortalities, up to 60%, and has been found in over 30 countries.

 

Kenneth Bryan Raper (US) and Charles Thom (US) wrote their monograph, Manual of the Aspergilli (1262).

 

Georgiana B. Deevey (US) and Edward Smith Deevey, Jr. (US) wrote a paper on the hematology of the black widow spider. This paper was the first to use life table analysis in the study of an arachnid (394).

 

Colin Munro MacLeod (US), Richard G. Hodges (US), Michael Heidelberger (US), and William G. Bernhard (US) conceived, produced, and field-tested a type-specific pneumococcal vaccine (1016).

 

Charles H. Rammelkamp, Jr. (US), with the Commission on Acute Respiratory Diseases and the New York State Department of Health, helped determine the relationship between epidemics of acute bacterial pneumonia and influenza (702). This is the basis for the influenza surveillance by the Centers for Disease Control, which follows pneumonia prevalence as a surrogate for influenza.

 

Robert Royston Amos Coombs (GB), Arthur Ernest Mourant (GB), and Robert Russell Race (GB) found that erythrocytes which had been sensitized with incomplete anti-Rh antibodies and then washed free of unbound human globulin could be agglutinated by an anti-human globulin serum prepared by immunizing a rabbit with human gamma globulin or whole human serum (339; 340). Erythrocytes sensitized by nonagglutinating incomplete anti-Rh antibodies will agglutinate when mixed with anti-globulin antibodies, i.e., the Direct Coombs Test. Suspected cases of erythroblastosis fetalis may be tested in this manner.

 

Ray David Owen (US) was the first to apply the term tolerance to an immunological phenomenon. He used it to describe results in his studies on binovular twin cattle sharing a common placenta (freemartin cattle). Owen noted that “erythrocyte precursors from each twin fetus had become established in the other and had conferred on their new host a tolerance towards … foreign cells that lasted a lifetime.” These twins of different sex were in fact red-cell chimeras or genetic mosaics (1161; 1162). Note: This observation demonstrated that self was “learned” by the immune system during development and paved the way for research involving induction of immune tolerance and early tissue grafting.

 

Michael Francis Addison Woodruff (GB) and Bernard Lennox (GB) confirmed the freemartin concept in man when they found a pair of twins, one male the other female, who shared elements of different red cell types. Postulating a shared placental circulation between the two, they cross skin grafted them successfully (1734).

 

Sheila Callender (GB), Robert Russell Race (GB), and Zafer V. Paykoc (GB) discovered the Lutheran blood group antigen in humans (244).

 

Robert Franklin Pitts (US) and Robert S. Alexander (US) showed that the hydrogen ion secreted by the renal tubules is responsible for acidifying the urine of mammals (1215).

Robert Franklin Pitts (US), William D. Lotspeich (US), Martha Barrett (US), and Ilse Langer (US) defined the properties of renal bicarbonate transport by examining the relationship between bicarbonate reabsorption and excretion at varying plasma bicarbonate levels. A renal threshold for bicarbonate excretion was defined at 24mM. They established the kidney’s ability to generate significant transepithelial carbon dioxide gradients, which were explained by a lack of effective carbonic anhydrase activity in the lumen of distal nephron segments. They noted a relationship between bicarbonate transport and excretion of acid, based on the observation that during acidosis the excretion of titratable acid varied inversely with the amount of bicarbonate administered (1214).

 

George H. Chambers (US), Eleanor V. Melville (US), Ruth S. Hare (US), and Kendrick Hare (US) found that in conscious dogs the secretion of the antidiuretic hormone (vasopressin) depends on the osmotic pressure of the blood plasma (273).

 

George Washington Corner (US), Carl G. Hartman (US), and George W. Bartelmez (US) described the development, organization, and breakdown of the corpus luteum in the rhesus monkey (Macacus rhesus) (352).

 

George Gaylord Simpson (US) placed all apes in one family, the Pongidae and all members of the genus Homo, extinct and extant, in a separate family, the Hominidae (1446).

 

Lars Leksell (SE) presented clear evidence that the activity in the muscle-spindle afferents can be modified by stimulating the small gamma motor neurons connected to the specialized muscle of the spindle receptor (intrafusal muscle). This provided the first definitive demonstration of the central control of receptors. The gamma motor neurons control spindle discharge by direct excitation of the receptor-muscle fibers. The spindle afferents, in turn, act back upon the alpha motor neurons controlling the extrafusal muscle (944).

 

Gordon R. Baldock (GB) and William Grey Walter (GB-US) developed automated spectral analysis of EEG traces. A standard method for EEG analysis since its discovery has been to measure the power in various frequency bands, including alpha and delta, also beta (15-30 Hz), and theta (3-7 Hz). Walter used his skills in analog electronics to build a device that displayed the frequency content in an EEG trace, even as the trace was displayed with an ink-writing oscillograph, a pen whose fluctuations left a trace on moving paper that became the mainstay of electroencephalographers (64; 65).

 

Anthonie van Harreveld (US) produced experimental evidence that after removal of part of the innervation of a muscle, the remaining motor units grow by adopting muscle fibers, which originally belonged to the dennervated motor units (1604).

Harvey Frederic Hoffman (GB) provided histopathological evidence of local reinnervation in partially dennervated muscle (753).

 

Clinton Nathan Woolsey (US), John L. Hampson (US), and Clinton R. Harrison (US) mapped the somatic sensory projections to the cerebellar cortex and the organization of projections from the cerebral cortex to the cerebellar cortex in the cat and dog (681; 1748).

 

Stanley E. Bradley (US), Franz J. Ingelfinger (US), Geraldine P. Bradley (US), and John J. Curry (US) developed a method for measuring hepatic blood flow (178).

 

Paul Bruce Beeson (US), Emmett S. Brannon (US), and James V. Warren (US) found when they made observations on the sites of removal of bacteria from the blood of patients with bacterial endocarditis colony counts were highest in arterial blood. Blood from the antecubital veins gave colony counts only slightly lower than arterial blood. In the femoral veins, on the other hand, there were appreciably fewer organisms. This difference is attributed to the type of tissues drained by the two veins. Colony counts in blood from the superior and inferior venae cavae were also lower than arterial counts, the ratio being comparable to that found in femoral vein blood. In the renal veins colony counts were only slightly below the arterial level indicating that few organisms are removed from the blood during passage through the kidneys. The greatest reduction in bacterial content was found in hepatic vein blood. In 3 of the 6 subjects this reduction amounted to more than 95 per cent, and in all subjects the difference was very considerable. Mixed venous blood in the right auricle of the heart gave colony counts that were usually one-half to two-thirds as high as in corresponding samples of arterial blood. An interesting finding in these studies was a remarkable constancy of the bacterial content of arterial blood, during periods of 1 or 2 hours. Even though considerable portions of the bacteria, which leave the heart in arterial blood, appear to be removed during a single circuit of the body, the number of bacteria in successive samples of arterial blood shows little change. This indicates that in bacterial endocarditis organisms are discharged into the blood from the endocardial vegetations at a comparatively even rate, rather than in a haphazard fashion because of the breaking-off of infected particles (95).

 

Derek Ernst Denny-Brown (NZ-GB-US) and Daniel Sciarra (US) described nervous system changes associated with porphyria (399).

 

Cecil James Watson (US), Samuel Schwartz (US), Violet Hawkinson (US), Moisés Grinstein (US), and Robert Anderson Aldrich (US) revealed that in most cases of porphyria the excreted porphyrins are derived from the liver, suggesting a defect in heme synthesis within this organ (635; 1660).

Cecil James Watson (US), Rudi Schmid (US), Samuel Schwartz (US), Robert A. Aldrich (US), Violet Hawkinson (US), and Moisés Grinstein (US) noted the exception, a rare condition resulting from a defect in hemoglobin synthesis in maturing normoblasts of the bone marrow (15; 1387; 1388).

Cecil James Watson (US), Victor Perman (US), Francis A. Spurrell (US), Harvey H. Hoyt (US), and Samuel Schwartz (US) named the rare condition congenital erythropoietic porphyria (1658).

 

Alfred Blalock (US), Helen Brooke Taussig (US), and Vivien Theodore Thomas (US) perfected what became known as the blue baby operation (Blalock-Taussig shunt)—subclavian artery attached to the pulmonary artery— to correct a defect of the large artery that supplies blood to the lungs. This defect allows so little blood to be pumped through the narrow passage that the oxygen intake is painfully curtailed. Blalock performed the operation on a human for the first time in 1946. Prior to this Vivien Theodore Thomas had performed this operation many times on dogs. Dr. Blalock, in collaboration with Dr. Taussig, developed procedures for the correction of several congenital heart lesions or anomalies of the great vessels of the heart, leading to morbus ciruleus, among them patent ductus arteriosis, tetrology of Fallot (blue baby syndrome), tricuspic atresia, and coarctation of the aorta (130; 1269).

 

Hunter H. Comly (US) reported on cyanosis in infants caused by nitrates in well-water (323).

 

David Glendenning Cogan (US) reported a disorder characterized by recurrent inflammation of the front of the eye (the cornea) and often fever, fatigue, and weight loss, episodes of dizziness, and hearing loss. It can lead to deafness or blindness if untreated (307). It was later named Cogan syndrome.

 

Carl F. Vilter (US), Tom D. Spies (US), and Muiv B. Koch (US) reported that cases of sprue (celiac disease or gluten-sensitive enteropathy) and nutritional macrocytic anemia respond to treatment with pteroylglutamic acid (PGA, vitamin M, folic acid, or folate) (1619).

 

Robert Edward Gross (US), in 1945, reported the first successful case of surgical relief for tracheal obstruction from a vascular ring (636).

 

Clarence Crafoord (SE) and Gustav Nylin (SE), on October 19, 1944, reported the first successful end-to-end anastomosis of the aorta after resection of an aortic coarctation (358).

Robert Edward Gross (US) and Charles A. Hufnagel (US) successfully replaced a longer segment of a resected coarctation with a preserved arterial homograft with methods devised by Charles Hufnagel for the preservation of human homografts. In infants this narrowing of the aorta is typically proximal to its junction with the ductus arteriosus. The adult type is at or distal to the junction. This condition is usually fatal (637; 638; 640).

 

By the end of World War 2, the estimated death toll from hepatitis was 16 million cases. The US Army identified 150,000 cases whereas 4 million were ‘the census data’ in the German military and civilian populations (1157).

 

1946

“Adapt or perish, now as ever, is Nature’s inexorable imperative.” Herbert George Wells (1673).

 

“Essential to a great discoverer in any field of nature would seem an intuitive flair for raising the right question…to ask something which the time is not yet ripe to answer is of little avail.” Charles Scott Sherrington (1440).

 

“There is a romance of science which stimulates the mind and satisfies the soul; it also happens to be the surest approach to one's understanding of the truth.” Issac Berenblum (112).

 

James Batcheller Sumner (US) for his discovery that enzymes can be crystallized and John Howard Northrop (US) and Wendell Meredith Stanley (US) for their preparation of enzymes and virus proteins in a pure form were awarded the Nobel Prize in Chemistry.

 

Hermann Joseph Muller, Jr. (US) was awarded the Nobel Prize in Physiology or Medicine for the discovery of the production of mutations by means of x-ray irradiation.

 

Edward Mills Purcell (US), Henry C. Torrey (US), Robert V. Pound (US), Felix Bloch (CH-US), William Webster Hansen (US), and Martin Packard (US) found that when certain nuclei were placed in a magnetic field they absorbed energy in the radiofrequency range of the electromagnetic spectrum, and re-emitted this energy when the nuclei transferred to their original state. This is nuclear magnetic resonant absorption (NMR) (137; 138; 1239; 1240). Note: Yevgenii Konstantinovich Zavoiskii; Yevgeny Konstantinovich Zavoisky (RU) was the first person to build a magnetic resonance spectrometer. Zavoiskii observed the first nuclear magnetic resonance (NMR) signal, but his magnetic field did not have sufficient homogeneity to generate signals with reproducible frequency or amplitude. He thus demonstrated that NMR was possible but difficult to do. He also observed the first reproducible magnetic resonance signal—from electron paramagnetic resonance (EPR), from which reproducible signals were easier to obtain (1759; 1760).

 

Richard R. Ernst (CH) and Hans Primas (CH) designed and built advanced electronic equipment for improved nuclear magnetic resonance (NMR) spectrometers. In parallel, they developed the theoretical background for the optimum performance of the instruments (523).

 

Albert Claude (BE-US) developed differential centrifugation for isolating and purifying cell parts. He and others would use this technique to separate ribosomes, mitochondria, lysosomes, peroxisomes, and the Golgi complex into distinct fractions. This paper contains the first full explanation of the fractionation of mammalian cells by differential centrifugation (299).

George Hall Hogeboom (US), Walter Carl Schneider (US), and George Emil Palade (RO-US) significantly improved this methodology by carrying out the centrifugation in a concentrated solution of sucrose. This technique was considered to have made the method of isolating mitochondria complete (757).

 

Erwin Brand (US) proposed that the first three letters in the name of an amino acid be used as an abbreviation for that acid, there being a few exceptions (181).

 

George Hall Hogeboom (US), Albert Claude (BE-US), and Rollin Douglas Hotchkiss (US) showed that the site of intracellular respiration is the mitochondrion (756).

George Emil Palade (RO-US) produced the first electron photomicrographs of mitochondria, which revealed their cristae and outer membrane. He postulated that their structure was related to the function of such enzymes as succinic acid dehydrogenase and cytochrome c oxidase. These photomicrographs revealed that the enzymes of respiration reside within the inner membrane of the mitochondrion (1167).

George Emil Palade (RO-US) used images from electron micrographs to characterize the mitochondrial structure as follows: "A characteristic pattern of organization was found with the help of the electron microscope in sectioned animal mitochondria irrespective of the species providing the specimen and of the cell type examined.

Each mitochondrion was found to possess:

1) A limiting membrane.

2) A mitochondrial matrix that appears structureless at present levels of resolution.

3) A system of internal ridges (cristae mitochondriales) that protrude from the inside surface of the membrane towards the interior of the organelles. In many mitochondria the cristae are perpendicular to the long axis of the organelles and occur in series within which they lie parallel to one another at more or less regular intervals.

In favorable electron micrographs the mitochondrial membrane appears to be double and the cristae appear to be folds of a second, internal mitochondrial membrane." (1169)

 

Kenneth Bailey (GB) discovered tropomyosin (56).

Setsuro Ebashi (JP), Fumiko Ebashi (JP), Ayako Kodama (JP), Makato Endo (JP), Iwao Ohtsuki (JP) and Takeyuki Wakabayashi (JP) isolated troponin (native tropomyosin) and found that when skeletal muscle is stimulated by depolarization of the muscle membrane the level of calcium ions in the muscle increases and this increases the amount of calcium ions bound to troponin. The sensitivity of calcium ion binding to calcium ion concentration, together with the observation that at low calcium ion levels the actin-myosin interaction is inhibited but that this inhibition is reversed at higher calcium ion levels, clearly indicated that regulation of actin-myosin activity must relate to the binding of calcium ions by troponin (485-488; 491; 492).

Setsuro Ebashi (JP), Ayako Kodama (JP), Makato Endo (JP), Iwao Ohtsuki (JP), Marion L. Greaser (US), John Gergely (US), James A. Spudich (GB-US), Hugh Esmor Huxley (GB-US), and John T. Finch (GB) proposed a mechanism to explain how the interaction of calcium with troponin and tropomyosin modulates the interaction of actin and myosin during skeletal muscle contraction (489; 490; 627; 1501).

Setsuro Ebashi (JP) and Makoto Endo (JP) used biochemical data to estimate the relative numbers of actin, tropomyosin, and troponin molecules in the F-actin filament (488).

 

Philip Pacy Cohen (US) and Mika Hayano (US) were the first to successfully set up a cell-free system for urea synthesis (310).

 

Lindsay H. Briggs (NZ), Harry T. Openshaw (GB), and Robert Robinson (GB) determined the structure of strychnine (191; 1306).

Cornelis Bokhoven (DE), Jean Chaques Schoone (DE), and Johannes Martin Bijvoet (DE) used crystallographic techniques to solve the structure of strychnine (159).

 

Jörgen Lehmann (SE) discovered the anti-tubercular agent para-aminosalicylic acid (PAS) (942). This drug when used along with streptomycin—discovered by Waksman—provided the first effective treatment of tuberculosis.

 

Harry Most (US), Irving M. London (US), Charles A. Kane (US), Paul H. Lavietes (US), Edmund F. Schroeder (US), and Joseph M. Hayman, Jr. (US) successfully used chloroquine for treatment of acute attacks of vivax malaria (1107).

 

Otto A. Bessey (US), Oliver H. Lowry (US), and Mary Jane Brock (US) described a method for determining alkaline phosphatase in blood serum (121).

 

Alma Joslyn Whiffen (US), J. Nestor Bohonos (US), and Robert L. Emerson (US) isolated the antifungal/antiprotozoal/antimammalian antibiotic cycloheximide (actidione) from Streptomyces griseus (1681). Cycloheximide blocks the translocation reaction on ribosomes.

 

John C. Sonne (US), John Machlin Buchanan (US), and Adelaide M. Delluva (US) determined that during the in vivo synthesis of inosinic acid (a purine) carbon dioxide is the precursor of carbon atom 6; formate, of carbon atoms 2 and 8; and the carboxyl carbon of glycine, of carbon atom 4 (216; 217; 1478; 1479).

Jon L. Karlsson (IS), Horace Albert Barker (US), David Shemin (US), and David Rittenberg (US) determined that carbon atom 5 and nitrogen atom 7 of inosinic acid are derived from the alpha carbon and nitrogen of glycine (839; 1435).

John C. Sonne (US), I-hsiung Lin (US), and John Machlin Buchanan (US), demonstrated that two nitrogen atoms are derived from the amide nitrogen of glutamine and that aspartic acid (or glutamic acid) contributes one nitrogen to the synthesis of the purine ring (1480; 1481).

Bruce Levenberg (US), Standish C. Hartman (US), and John Machlin Buchanan (US) demonstrated that within purines nitrogen 1 is derived from aspartic acid nitrogen and nitrogen atoms 3 and 9 from the amide nitrogen of glutamine (956).

 

Robert Allan Phillips (US), Andrew Yeomans (US), Vincent P. Dole (US), Lee E. Farr (US), Donald Dexter van Slyke (US), and David Hogan (US) developed a simple method, based on specific gravity, for determining erythrocyte concentration in whole blood and protein concentration in blood plasma (1204).

 

Solomon Spiegelman (US) and Martin D. Kamen (US) suggested that copies of the information encoded within DNA are transmitted into the cell’s cytoplasm for protein synthesis (1497; 1498). This had great significance for future research into messenger RNA.

 

Maclyn McCarty (US) isolated, purified, and described for the first time the existence and properties of bovine pancreatic deoxyribonuclease (1043).

Johann Salnikow (US), Ta-Hsiu Liao (US), Stanford Moore (US), and William Howard Stein (US) isolated, and then determined the composition and amino acid sequences of the tryptic and chymotryptic peptides of bovine pancreatic deoxyribonuclease A (969; 1363).

 

Carroll Milton Williams (US) began a series of experiments with the silkworm, Hyalophra (Platysamia) cecropia, which led to discoveries that at low temperatures the pupal brain becomes competent to secrete hormone. At high temperatures, which typically follow low temperatures in the seasons, specialized cells in the competent brain secrete a hormone, which reacts with the prothoracic glands causing them to secrete a growth, and differentiation hormone. This growth and differentiation hormone reacts with the pupal tissues to terminate diapause thus leading to development of an adult.

He also found that a brain hormone produced by larvae early in the spinning process promotes the secretion of the prothoracic gland growth and differentiation hormone which promotes pupation (1701-1709).

 

Philip Rodney White (US) was the first to attempt the production of a defined medium for the culturing of eukaryotic cells. The cells survived but did not multiply (1684; 1685).

 

Max Rubin (US) and Herbert R. Bird (US) discovered that an acid precipitate of a water extract of dried cow manure stimulates the growth of chicks. This would later be known as vitamin B12 (1348-1350).

 

Georgi Frantsevitch Gause (RU) isolated the antibiotic litmocidin from Proactinomyces cyaneus antibioticus (594).

 

Selman Abraham Waksman (RU-US), Albert Schatz (US), and H. Christine Reilly (US) isolated the antibiotic grisein from Streptomyces griseus (1634; 1636).

 

Herman C. Lichstein (US) and Virginia F. van de Sand (US) isolated the antibiotic prodigiosin from Serratia mercescens (971).

 

Karl Sune Detlof Bergström (SE), Axel Hugo Theodor Theorell (SE), and Hans Davide (SE) isolated the antibiotic pyolipic acid from Pseudomonas aeruginosa (118).

 

Georgi Frantsevitch Gause (RU) isolated the antibiotic colistatin from a yellow, aerobic, sporulating bacillus (593).

 

Gaston Ramon (FR) and Rémy Richou (FR) isolated the antibiotic subtiline from Bacillus subtilis (1252).

 

Louis de Saint-Rat (FR) and Henri R. Olivier (FR) isolated the antibiotic endosubtilysin from Bacillus subtilis (388).

 

Jackson W. Foster (US) and Harold Boyd Woodruff (US) isolated the antibiotic bacillin from Bacillus subtilis (561).

 

Edwin A. Johnson (US) and Kenneth L. Burdon (US) isolated the antibiotic eumycin from Bacillus subtilis (Marburg strain) (815).

 

Robert K. Callow (GB) and Philip Montagu d’Arcy Hart (GB) isolated the antibiotic licheniform from Bacillus licheniformis Weigmann emend. Gibson. It is especially effective against species of myxobacteria (245).

 

Edgar S. McFadden (US) and Ernest Robert Sears (US) discovered that the amphiploid between Triticum turgidum (wheat) and Aegilops squarrosa (goat-grass) is phenotypically very close to Triticum spelta (wheat). This confirmed earlier inference from hybrids involving Aegilops cylindrica (goat-grass) that the seven pairs of chromosomes (genome) in hexaploid but absent in tetraploid wheat had been derived from Aegilops squarrosa (goat-grass) (1050).

 

Carl Lamanna (US), Henning W. Eklund (US), Olive E. McElroy (US), Adolph Abrams (US), Gerson Kegeles (US), and George A. Hottle (US) crystallized the exotoxin of Clostridium botulinum Type A and characterized it as a protein of the globulin type (5; 916).

Carl Lamanna (US) and Harold N. Glassman (US) isolated type B botulinus toxin in amorphous form (915).

 

Jean Louis Auguste Brachet (BE) hypothesized that proteins are synthesized on ribonucleoprotein granules within the cytoplasm (177).

 

Linus Carl Pauling (US) proposed that enzymes might work by causing their substrate to assume the configuration of a transition form (1183).

 

Jonathan D. Green (US) and Geoffrey Wingfield Harris (GB) postulated the existence of growth-hormone-releasing hormone (GHRH) (628).

Jean Rivier (US), Joachim Spiess (US), Michel Thorner (US), Wylie W. Vale (US), Roger Charles Louis Guillemin (FR-CA-US), Paul Brazeau (US), Peter Bohlen (US), Frederick Esch (US), Nicholas Ling (US), and William B. Wehrenberg (US) isolated, sequenced, and synthesized GHRH. They found that the full biological activity of GHRH peptides resides in the 29 residues ending at the amino terminus (646; 1301).

Michael J. Cronin (US), Alan D. Rogol (US), Robert M. MacLeod (US), Donald A. Keefer (US), Ivan S. Login (US), Joao L.C. Borges (US), Michael O. Thorner (US), Louise M. Belezikjian (US), and Wylie W. Vale (US) determined that the stimulatory effect of GHRH on GH release occurs via stimulation of cyclic AMP production (102; 363).

 

André Gratia (BE) and Pierre Frédéricq (BE) discovered colicine, a killer substance, produced by some strains of Escherichia coli (573; 624).

Pierre Frédéricq (BE) and M. Betz-Bareau (BE) showed that colicines behave as genetic factors independent of the chromosome (574-576).

 

James P. Duguid (GB) suggested that penicillin acts by interfering with the formation of a normal bacterial cell wall (465).

Joshua Lederberg (US) used penicillin to induce the formation of bacterial protoplasts (938).

Ian M. Dawson (GB) presented electron photomicrographs illustrating the physical appearance of the cell wall of Staphylococcus aureus (382).

Milton R.J. Salton (US) and Robert W. Horne (GB) isolated and purified bacterial cell walls for chemical analysis and characterization (1365-1367).

Milton R.J. Salton (US) demonstrated that the substrate for the lysis of Micrococcus lysodeikticus by lysozyme is the cell wall (1364).

Claes Weibull (US) observed that cells of Bacillus megaterium are transformed into wall-less, fragile, protoplasts when treated with lysozyme (1664).

Jean-Marie Ghuysen (BE) recounted how the molecular structure of bacterial cell walls was elucidated through a series of experiments utilizing various bacteriolytic enzymes, which attack specific molecular structures (938).

Mary Lynne Perille Collins (US) and Milton R.J. Salton (US) were among the first to utilize detergents to solubilize bacterial membrane proteins (320).

 

Joshua Lederberg (US) and Edward Lawrie Tatum (US) demonstrated sexual recombination in Escherichia coli strain K-12. This recombination behavior strongly suggested that bacteria, like higher organisms, contain genes. Up to this point in time no bacterium of any sort had been shown to have genes. Lederberg was to name this phenomenon conjugation (937; 939; 940; 1562).

 

Max Ludwig Henning Delbrück (DE-US), Alfred Day Hershey (US), Raquel Rotman (US), and William T. Bailey, Jr. (US) presented evidence suggesting that when bacteria are simultaneously infected by two different varieties of bacteriophage the burst of daughter phage shows characteristics derived from both parents, as though phage genes have recombined inside the host bacterium. This represents the discovery of genetic recombination in bacteriophage and the birth of phage genetics (396; 719; 720).

 

Kenneth M. Smith (GB) reported that two distinct viruses, tobacco vein distorting and tobacco mottle, when co-infecting tobacco (Nicotiana tabacum) plants, caused the tobacco rosette disease. This is considered the discovery of the first luteovirus-associated aphid-transmitted virus complex (1467; 1468).

 

Kenneth C. Smithburn (US), Alexander John Haddow (GB), and Alexander Francis Mahaffy (CA) isolated the Bunyamwera (BUN) virus from Aedes mosquitoes in 1943 at the Enteebe East Africa Research Institute in Uganda. It would become the type virus for the Bunyaviridae family (1472).

 

Jacques Lucien Monod (FR) and Alice Audureau (FR) demonstrated that Escherichia coli mutabile possesses the genetic information to produce the enzymes which allow utilization of lactose, whether lactose is present or not (1101).

 

Edward Lawrie Tatum (US) was the first to intentionally produce mutations in bacteria. He exposed Acetobacter and Escherichia coli to x-rays (1559).

 

Evelyn M. Witkin (US) showed that Escherichia coli cells can inherit different degrees of sensitivity to radiation (1725).

 

Carl Clarence Lindegren (US) and Gertrude Lindegren (US) discovered that haplophase cultures of Sacharomyces cerevisiae contain two mating types which they designated a and alpha (980).

 

Marcus Morton Rhoades (US) discovered the nuclear gene, iojap, a mutator gene that affects plastids. This is one of the first known cases of nuclear-cytoplasmic interaction. These alterations are heritable via the cytoplasm (1281).

 

Harold H. McKinney (US) was the first to report that oat mosaic disease has a viral etiology (1051).

 

A. Orlando (BR) and Karl Martin Silberschmidt (BR) demonstrated that the whitefly, Bemisis tabaci, serves as a vector for abutilon mosaic virus (1158).

 

Louis Pillemer (US), Ruth Wittler (US), and Donald B. Grossberg (US) crystallized the toxin of Clostridium tetani and characterized it as a protein (1211).

 

Margaret T. Dyar (US) and Erling J. Ordal (US) found that bacteria die rapidly when the negative charge on their surface is neutralized by the positive charge on a quaternary ammonium compound. This suggested a relationship between surface charge and disinfecting power (472).

 

Ernest Aubrey Ball (US) excised Nasturtium and Tropaeolum shoot tips and grew them in a test tube. He excised the shoot tips with scalpels made of razor blade corners spot-welded onto sewing needles, which could be inserted into wooden holders. He also regenerated plantations of lupin (Lupinus) by culturing their shoot tips with leaf primordia (66; 67).

 

Harold H. Mitchell (US) and Richard J. Block (US) discovered how the relationship of the amino acid constitution of a protein, or of the protein component of a food product, to its nutritive value for the growing rat can be best revealed (1095).

 

George Henry Hepting (US) and Elmer R. Roth (US) discovered the pitch canker disease of southern pines and identified the specific causal fungi (717).

George Henry Hepting (US) found that pines inoculated with pitch canker fungus produced oleoresin flow with desirable results (716).

 

Otto Rahn (DE-US) showed that agents, which adsorb them, diminish the germicidal efficiency of quaternary ammonium compounds (quats). Examples are, filter paper, charcoal, bentonite, and agar. He further showed that fatty surfaces cause quats to orient themselves in a specific direction as they are adsorbed. The hydrophobic end of the molecule is directed toward the fatty material while the germicidal N—OH group faces the aqueous phase (1250).

Emery I. Valko (US) demonstrated that proteins combine with quaternary ammonium compounds, frequently producing a precipitate (1599).

Robert A. Quisno (US) and Milton J. Foter (US) reported that an increase in temperature increases the germicidal efficiency of quaternary ammonium compounds, the temperature coefficient between 20°C and 37°C, being less than 2. They also reported that somewhat larger doses are required to kill gram-negative enterobacteria than streptococci and staphylococci, but rarely more than double the amount. A striking exception is Pseudomonas aeruginosa for which ten to twenty times as much is needed as for staphylococci. Mycobacterium spp. are even more resistant (1244).

 

Octavio de Magalhães (BR) reported much experience with pulmonary geotrichosis (1017).

David T. Smith (US), in 1934, reported five non-fatal infections due to Geotrichum and gave the essential cultural characteristics necessary for identification of the fungus (1456).

Ralph H. Kunstadter (US), Robert C. Pendergrass (US), and Joseph H. Schubert (US) reported a bronchopulmonary infection in humans caused by Geotrichum. sp (905). The etiological agent is the fungus Geotrichum candidum.

 

James Craigie (CA) discovered that typhoid bacilli can be grouped according to sensitivity to certain phages (361).

 

Frank Macfarlane Burnet (AU), and Joyce D. Stone (AU) reported on how Vibrio cholerae damages the epithelial lining of the gastrointestinal tract (230; 231).

 

Robert Joseph Huebner (US), Charles Pomerantz (US), William L. Jellison (US), and Peggy Stamps (US) isolated and named the etiological agent of rickettsialpox, Rickettsia akari, then determined the cycle of infection as mouse-mite-mouse, with man an occasional host (782-784).

 

Sydney Arthur Asdell (US) authored Patterns of Mammalian Reproduction in which he collected data bearing on reproductive behavior of wild as well as domestic mammals (38).

 

William Barry Wood, Jr. (US), Mary Ruth Smith (US), and Barbara Watson (US) studied the lungs of animals infected with encapsulated pneumococci early during the disease before antibody was produced. They discovered surface phagocytosis. On smooth surfaces the phagocytes were unable to engulf bacteria, whereas on rough surfaces they were often able to wedge the slippery bacteria into a corner where they could be phagocytized (1732; 1733).

 

Paul D. MacLean (US), Averill A. Liebow (US), and Arthur A. Rosenberg (US) first described Arcanobacterium hemolyticum infection in U.S. servicemen and peoples of the South Pacific suffering from sore throat (1015). Due to its resemblance to another type of bacteria, Corynebacterium, A. haemolyticum was initially classified as C. pyogenes subspecies hominus. Controversies regarding classification were resolved in 1982 when a new genus, Arcanobacterium (enigmatic bacterium) was created based on its peptidoglycan, fatty acid, and DNA characteristics.

Since its initial description, the spectrum of diseases caused by A. haemolyticum has been expanded to include sepsis and osteomyelitis.

 

Charles E. Dent (GB) was the first to apply the technique of paper chromatography to the isolation and identification of substances in the blood and body fluids of patients (422).

 

Robert Royston Amos Coombs (GB), Arthur Ernest Mourant (GB), and Robert Russell Race (GB) discovered the Kell blood group antigen in man (341).

 

Arthur Ernest Mourant (GB) discovered the Lewis blood group antigen in man. It is named for a Mrs. Lewis in which anti-Le was made (1109).

 

Eric A. Beet (GB), working in Northern Rhodesia, now Zimbabwe, suggested that sickle cell trait is caused by a mutant recessive gene, inherited in a Mendelian pattern (96-99).

James van Gundia Neel (US) proved that from the incidence of sickle cell disease and the trait in American Negro families that it is caused by a mutant recessive gene, inherited in a Mendelian pattern (1131).

Anthony Clifford Allison (GB-KE) performed an epidemiological study from which he concluded that the sickle cell trait protects carriers against malarial infection (22). This balance of advantage and disadvantage helped to explain why the sickle cell allele had been preserved in certain communities rather than being eliminated by natural selection.

Charles C. Macklin (CA) determined that there is no difference at all between positive and negative pressure inflation of the lung, if one is careful to reference airway and vascular pressures to the pleural pressure (1010).

Solbert Permutt (US), Jack B.L. Howell (GB), Donald F. Proctor (US), and Richard L. Riley (US) rediscovered Macklin’s findings (1190). In their companion paper they found that the pulmonary vascular bed could be functionally separated into two parts—alveolar and extra-alveolar vessels— that have opposite responses to lung inflation (775).

 

Ulf Svante Hansson von Euler-Chelpin (SE) and Göran Liljestrand (SE) discovered what is now called the Euler-Liljestrand mechanism. This describes the connection between ventilation and blood circulation (perfusion) of the lung. If the ventilation in a part of the lung decreases, it leads to local hypoxia. The local hypoxia leads to pulmonary vasoconstriction. This adaptive mechanism is beneficial, because it diminishes the amount of blood that passes the lung without being oxygenated (1626).

Robert J. Porcelli (US), Anna T. Viau (US), Margaret Demeny (US), Nosrat E. Naftchi (US) and Edward H. Bergofsky (US) reported that the molecular mechanism seems to be mediated by oxygen-sensitive potassium ion channels in the cell membrane of pulmonary smooth muscle. With a low partial pressure of oxygen, these channels are blocked, leading to the depolarization of the cell membrane. Calcium channels are activated and cause the influx of Ca2+ ions over the membrane and to the release of calcium from the endoplasmic reticulum. The rise of calcium concentration causes contraction of the blood vessels smooth muscle fibers and the resulting vasoconstriction (1222).

 

Kathleen Ethel Boorman (GB), Barbara Edith Dodd (GB), and John Freeman Loutit (GB) demonstrated the presence of autoantibodies on the erythrocytes of patients with acquired hemolytic anemia and the absence of rbc-bound antibodies in patients with congenital hemolytic anemia (165). This test to detect antibodies that had sensitized rbcs in vivo became known as the Direct Antiglobulin Test (DAT). A positive DAT is generally caused by the attachment of immunoglobulin (IgG, IgM, IgA) and / or components of complement (C3d, C3, C4 etc.) to the red cell surface.

 

Dwight Joyce Ingle (US) showed that characteristic damaging effects of stress are produced when adrenal steroids are supplied to adrenalectomized animals at a constant but not excessive rate of administration. He deduced that the role of the adrenal cortex in the stressed state appears to be a subtle “permissive” or supporting role rather than as the primary mediator of the stress reaction (799).

 

Clinton Nathan Woolsey (US), Samuel A. Talbot (US), and John M. Thompson (US) mapped the primary visual area of the rabbit cortex, demonstrated the detailed retinotopic organization, and mapped a second visual area (1750; 1751).

 

Wallace Osgood Fenn (US), Hermann Rahn (DE-US), Arthur B. Otis (US), and Leigh E. Chadwick (US) developed the pressure-volume diagram of the lung and thorax. Hermann Rahn (DE-US) and William Osgood Fenn (US) wrote, A Graphical Analysis of the Respiratory Gas Exchange: The O2-CO2 Diagram in which they were able to represent all variables of the alveolar gas ventilation equations in diagrammatic form. With the O2-CO2 diagram they could represent all possible compositions of alveolar gas and the arterial blood under any specified set of conditions. Although F. Rohrer (?) preceded them on the pressure-volume diagram they conceived it independently, elaborated it further, and distilled into it some ten years of work and thought. It defined the limiting values for muscle forces and the corresponding volumes of gas and blood (539; 1247-1249). This work laid the foundation for respiratory mechanics.

Richard L. Riley (US) and André Frédéric Cournand (US) developed a three-compartment model of pulmonary gas exchange. This model was the standard for assessing ventilation-perfusion inequality in patients with lung disease until the introduction of the multiple inert gas elimination technique (1295; 1296).

Peter D. Wagner (US), Herbert A. Saltzman (US), and John B. West (US) introduced the multiple inert gas elimination technique which allowed VA/Q distributions to be described (1632).

John B. West (US) applied computer analysis to the solution of VA/Q distributions (1678).

 

Charlotte Auerbach (GB), John Michael Robson (GB), and John Gardner (GB) determined that nitrogen mustard gas, the chemical warfare agent, produces a high mutation rate in the fruit fly, Drosophila (46-48).

Louis S. Goodman (US), Maxwell M. Wintrobe (US), William Dameshek (US), Morton J. Goodman (US), Alfred Gilman (US) and Margaret T. McLennan (US) reported on nitrogen mustard therapy. They used methyl-bis(beta-chloroethyl) amine hydrochloride and tris(beta-chloroethyl) amine hydrochloride to treat Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. Then, together with the thoracic surgeon, Gustav Lindskog (US), they injected a less volatile form of mustard gas called mustine (nitrogen mustard) into a patient who had non-Hodgkin's lymphoma. The patients tumor masses were significantly reduced for a few weeks after treatment and although the patient had to return to receive more chemotherapy, this marked the beginning of the use of cytotoxic agents for the treatment of cancer (615). Note: This could be the first phase I/II trial on record.

 

Gunnar Biörck (SE) and Clarence Crafoord (SE), in 1946, repaired an arteriovenous aneurysm on the pulmonary artery simulating patent ductus arteriosus botalli (122).

 

Cecil James Watson (US) and Frederick William Hoffbauer (US) described cholangiolithic cirrhosis. Today it is known as primary biliary cirrhosis (1657).

 

Paul D. Keller (US) described a clinical syndrome following exposure to atomic bomb explosions (848).

 

Paul Divry (BE) and Ludo Van Bogaert (BE) described brothers who presented with epilepsy, pseudobulbar syndrome, extrapyramidal signs, dementia, hemianopsia, and 'marbled skin' resulting from a telangiectatic network. Brain examination showed corticomeningeal angiomatosis and myelination of the white substance of the centrum ovale (Divry-Van Bogaert syndrome) (436).

 

William E. Adams (US), in 1946, performed a lobectomy for carcinoma of the lung on Thomas Mann who authored the tuberculosis saga The Magic Mountain (1124).

 

The Communicable Disease Center was organized in Atlanta, Georgia as a branch of the Public Health Service. In 1970 its name was changed to Center for Disease Control, then in 1981 Center became Centers.

 

Errol Ivor White (GB) discovered a fossil of Jamoytius kerwoodi in deposits of Silurian rock in Scotland. It is probably the most primitive chordate known and may throw some light on the early ancestry of vertebrates (1683).

 

1947

Robert Robinson (GB) was awarded the Nobel Prize in Chemistry for investigations on plant products of biological importance, especially the alkaloids.

 

Carl Ferdinand Cori (CZ-US) and Gerty Theresa Cori, née Radnitz (CZ-US), for their discovery of the course of the catalytic conversion of glycogen, and Bernardo Alberto Houssay (AR), for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar, shared the Nobel Prize in physiology and medicine.

 

Immanuel Broser (DE) and Hartmut Kallman (DE) discovered that certain organic compounds called scintillators fluoresce when exposed to ionizing radiation. Each fluorescence event is proportional to a radioactive decay event, and the frequency of these events is directly proportional to the number of 14C atoms present in the sample (197). This discovery led to the development of liquid scintillation counters.

 

Norbert Weiner (US) conceived and developed a new kind of mathematics that he called cybernetics (negative feedback control). It was originally intended for designing aiming devices for anti-aircraft guns and then later for guided missiles (1692). This concept quickly found acceptance in explaining the control of various biological phenomena. G. Evelyn Hutchinson (US) applied Weiner's cybernetics to Tansley's ecosystem leading to our modern concept of the ecosystem. Endocrinologists gradually realized that the language of feedback control provided an effective way of describing and thinking about endocrine interactions. Biochemists found that many metabolic pathways are controlled by feedback mechanisms.

 

Henry J. Buehler (US), Edward J. Schantz (US), and Carl Lamanna (US) determined the complete amino acid analysis of crystalline botulinus toxin, type A (220).

 

Carl-Bertil Hugo Laurell (SE) and Björn Gunnar Ingelman (SE) described the isolation of the iron-binding protein of swine serum in pure form. Its properties were investigated including molecular weight and isoelectric point (933). Note: This protein was later named transferrin.

 

A. Michael Michelson (GB), James Baddiley (GB), and Alexander Robertus Todd (GB) prepared ribonucleoside-5’-phosphates (AMP, ADP and ATP) (53; 55; 1085; 1086).

A. Michael Michelson (GB), Alexander Robertus Todd (GB), R.H. Hall (GB), and R.F. Webb (GB) were the first to successfully synthesize oligonucleotides as found in DNA—thymidine dinucleotide—thus confirming DNA’s chemical structure (667; 1086).

A. Michael Michelson (GB) and Alexander Robertus Todd (GB) discovered that RNA like DNA has a highly regular backbone of 5’-3’ phosphodiester linkages between nucleotides. ref

 

Herbert E. Carter (US), William J. Haines (US), W.E. Ledyard (US) and William P. Norris (US) proposed the term sphingolipid as a convenient designation for lipids containing sphingosine (cerebrosides, sphingomyelin, gangliosides…) (257).

 

Ronald Scarisbrick (GB) and Robert Hill (GB) discovered cytochrome f (729; 1382).

 

Donald J. Hanahan (US) and Israel Lyon Chaikoff (CA-US) suggested that plant tissues contain an enzyme—later called phospholipase D—which produces phosphatidic acid from various phospholipids (683).

 

Sam G. Wildman (US) and James Bonner (US) isolated fraction I protein from spinach leaves (1698).

Robert W. Dorner (US), Albert Kahn (US), and Sam G. Wildman (US) would declare this fraction I protein to be the enzyme ribulose-1, 5-biphosphate carboxylase-oxygenase (Rubisco), arguably the world’s most abundant and important single species of soluble protein (445). See, Weissbach, 1956.

Melvin Calvin (US), Andrew Alm Benson (US), and associates provided an important clue to the nature of the pathway from CO2 to hexose in photosynthetic organisms. They illuminated green algae in the presence of radioactive carbon dioxide (14CO2) for very short intervals (only a few seconds) and then quickly killed the cells, extracted them, and with the aid of chromatographic methods searched for those metabolites in which the labeled carbon was incorporated earliest. Melvin Calvin (US) and Andrew Alm Benson (US) determined that one of the compounds that became labeled very early in photosynthesis is 3-phosphoglyceric acid, a known intermediate of glycolysis; the carbon isotope was found predominantly in the carboxyl carbon atom. This carbon atom, which corresponds to the carboxyl carbon atom of pyruvate, is not labeled rapidly in animal tissues incubated with radioactive CO2 (110; 247-249).

Melvin Calvin (US) and Peter Massini (US) were the first to postulate that the carboxylation of a molecule of ribulose-1, 5-diphosphate (RuDP) produces two molecules of 3-phosphoglyceric acid (PGA) (250).

Alexander T. Wilson (NZ) and Melvin Calvin (US) gathered evidence that indeed ribulose 1,5-biphosphate is the first substance to react with carbon dioxide in the dark reactions of photosynthesis (246; 1719).

James Al Bassham (US), Andrew Alm Benson (US), Lori D. Kay (US), Anne Z. Harris (US), Alexander T. Wilson (NZ), Martha R. Kirk (US), Melvin Calvin (US), Kazuo Shibata (JP), Kjell Steenberg (NO), and Jean Bourbon (?) proposed, then supported, the concept that the fixation of carbon dioxide is part of a carbon reduction cycle occurring during photosynthesis (now called the Calvin-Benson or C3 cycle) (75-78).

Arthur Weissbach (US), Pauline Z. Smyrniotis (US), and Bernard Leonard Horecker (US) were able to show that with crude extracts from spinach leaves ribose 5-phosphate was a unique substrate for the formation of phosphoglyceric acid, and they purified a kinase from spinach leaves that they used to prepare the barium salt of ribulose 1,5-bisphosphate (RUDP) (1670).

Bernard Leonard Horecker (US), Arthur Weissbach (US), Pauline Z. Smyrniotis (US) and Jerard Hurwitz (US) isolated spinach phosphoribulokinase, performed the enzymatic synthesis of ribulose 1,5-diphosphate, and the enzymatic formation of phosphoglyceric acid from ribulose diphosphate and carbon dioxide (765; 791; 1669). The Weissbach article in 1956 represents the first purification of the enzyme ribulose-1, 5-biphosphate carboxylase-oxygenase (Rubisco), arguably the world’s most abundant and important single species of soluble protein.

William B. Jakoby (US), Dewey O. Brummond (US), and Severo Ochoa (ES-US-ES) showed that 3-phosphoglyceric acid forms as the result of carbon dioxide fixation in spinach leaves (811).

William A. Laing (NZ), William L. Ogren (US), and Richard H. Hageman (US) derived enzyme kinetic equations for a dual substrate enzyme and meticulously showed that the kinetic properties of the isolated Rubisco enzyme could explain the effects of both oxygen and temperature on photosynthesis and photorespiration (914).

Chris R. Somerville (US), Archie R. Portis, Jr. (US), and William L. Ogren (US) while screening Arabidopsis thaliana for photorespiratory mutants discovered Rubisco activase, which releases RuBP and other tight binding inhibitors from Rubisco sites (1477).

 

R. Weismann (CH) reported that H. Speich of Geigy Chemicals observed insect (housefly) resistance to dichloro-diphenyl-trichloro-ethane (DDT) or 2,2-di (4-chlorophenyl)-1,1,1-trichloroethane in northern Sweden—a mere five years after it was first used there (1695).

 

Daniel Bovet (CH-FR-IT), France Depierre (FR), and Yvonne de Lestrange (FR) while searching for a synthetic substitute for curare (a muscle relaxant), discovered gallamine (Flaxedil) and other muscle relaxants (171).

Pierre Huguenard (FR) was the first to use gallamine in clinical trials (788).

 

Emily W. Emmart (US) isolated the antibiotic nocardine from Nocardia coeliaca (517).

 

Robert G. Benedict (US), Asgar F. Langlykke (US), Philip G. Stansly (US), Robert G. Shepherd (US), Harry James White (US), Geoffrey Clough Ainsworth (GB), Annie M. Brown (GB), and George G. Brownlee (GB) isolated the family of antibiotics called polymyxins (aerosporin in England) from Bacillus polymyxa (9; 108; 1514). Renal damage is a serious side effect of their administration to humans.

 

John Ehrlich (US), Quentin R. Bartz (US), Robert M. Smith (US), Dwight A. Joslyn (US), Paul Rufus Burkholder (US), David Gottlieb (US), Lucia E. Anderson (US), and Thomas G. Pridham (US) isolated the antibiotic Chloromycetin (Chloramphenicol) from the actinomycete Streptomyces venezuelae, recovered from soil obtained near Caracas, Venezuela (500; 501). Chloramphenicol blocks the peptidyl transferase reaction on ribosomes of prokaryotes only. To this point in time chemists were convinced that nature could neither chlorinate nor nitrate its products. Chloramphenicol proved them wrong on both counts.

 

Otto Fritz Meyerhof (DE-US) and Peter Oesper (US) provided further proof that during glycolysis a diphosphoglyceric aldehyde intermediate does not exist. They also altered the equation for this step of glycolysis to reflect the fact that the reduction of cozymase is accompanied by the formation of an H+ ion (1080).

 

Theodor Bücher (DE) isolated and crystallized phosphoglycerate kinase (PGK) then demonstrated that it catalyzes the reversible reaction: d-1, 3-diphosphoglyceric acid + adenosinediphosphate ↔️ d-3-phosphoglyceric acid + adenosinetriphosphate (219). Phosphoglycerate kinase or phosphoglycerokinase (PGK) is a metabolic enzyme functioning in the Embden–Meyerhof-Parnas pathway.

Alfred P. Kraus (US), Manly F. Langston, Jr. (US), and Beth L. Lynch (US) reported that PGK-1 deficiency is associated with hemolytic anemia (883).

Shi-Han Chen (US), Laurence A. Malcolm (NZ), Akira Yoshida (US), Eloise R. Giblett (US), John L. VandeBerg (US), Desmond Wishart Cooper (US), and Pierre J. Close (US) noted two functional loci to produce PGK in the mammalian genome. PGK-1 is an X-linked gene expressed constitutively in all somatic cells and premeitotic germ cells. PGK-2 is an autosomal gene expressed in a tissue-specific manner exclusively in the late stages of spermatogenesis (286; 1610).

 

Edgar Stedman (GB), and Ellen Stedman (GB) hypothesized that histones, basic proteins of cell nuclei, may act as regulators of gene activity and exhibit cell specificity (1515; 1516).

James Frederick Bonner (US), Ru-Chih Huang (US), and Nirmala Maheshwari (US) discovered the synthesis of RNA from DNA in plants. They found that RNA transcription is inhibited by histones (162; 780).

Ru-Chih C. Huang (US) and James Frederick Bonner (US) reported that histones influence the ability of DNA to function as primer for RNA synthesis in vitro (779).

James Frederick Bonner (US), Ru-chih C. Huang (US), and Ray Guilden (US) provided experimental evidence that the inhibition of RNA synthesis by histones is specific (161). This was experimental confirmation of the hypothesis by Stedman & Stedman in 1947.

Derek Michael Phillips (GB) discovered that the amino-terminal tails of the four histones (H2A, H2B, H3, and H4) are post-transcriptionally modified by the addition of an acetyl group to the epsilon amino group of specific lysine side chains (1203).

Vincent George Allfrey (US), Robert D. Faulkner (US), and Alfred Ezra Mirsky (US) suggested that such a seemingly minor modification to histones could be involved in the control of gene expression via its “effect on the capacity of the histones to inhibit ribonucleic acid synthesis” (21).

Giorgio Vidali (US), Lidia C. Boffa (US), Vincent George Allfrey (US), Edwin Morton Bradbury (US), and Gloria Lorick Pleger (US), Josephine Bowen Keevert (US), Carol A. Johmann (US), and Martin A. Gorovsky (US) demonstrated a positive correlation between addition of acetyl groups to core histones and transcriptional activity (617; 1616).

James E. Brownell (US), Jianxin Zhou (US), Tamara Ranalli (US), Ryuji Kobayashi (US), Diane G. Edmondson (US), Sharon Y. Roth (US), C. David Allis (US), Jack Taunton (US), Christian A. Hassig (US), and Stuart L. Schreiber (US) showed that histone acetylases and deacetylases are, in fact, transcriptional regulators. These studies provided the first clear connection between histone acetylation and transcriptional regulation (208; 209; 1564).

Stephen Rea (AT), Frank Elsenhaber (AT), Donal O'Carroll (AT), Brian D. Strahl (US), Zu-Wen Sun (US), Manfred Schmid (AT), Susanne Opravil (AT), Karl Mechtler (AT), Chris P. Ponting (GB), C. David Allis (US), and Thomas Jenuwein (AT) provided a functional link between histone methylation and chromatin structure (1270).

 

John Masson Gulland (GB) reported that undegraded calf thymus DNA contains large polynucleotide chains held together by hydrogen bonds (647).

 

André Félix Boivin (FR) and Roger Vendrely (FR) were the first to express, in print, that DNA makes RNA makes protein (158).

 

Michael Doudoroff (RU-US), Horace Albert Barker (US), and William Zev Hassid (RU-GB-US) studied the action of bacterial sucrose phosphorylase in what represents an outstanding early example of the use of radioisotopes for the study of enzyme mechanisms (449).

 

Theodor Bücher (DE) discovered that during glycolysis when glyceraldehyde-3-phosphate is oxidized the immediate product is 1,3-diphosphoglycerate, which donates its phosphoryl group to ADP in the presence of 3-phosphoglycerate kinase (219).

 

Hans Adolf Krebs (DE) announced the steps of the citric acid cycle ("Krebs cycle") (886).

 

Milislav L. Demerec (Yugoslavian -US) explained how bacteria could mutate to resist higher and higher concentrations of an antibiotic. Resistance to penicillin is a step-wise phenomenon due to mutants at three different genes being selected as the concentration of antibiotic rises. The probability of all three mutations appearing in the same cell is 10-7 X 10-7 X 10-7 =10-21. Mutation to various levels of streptomycin resistance occurs even at low levels of the antibiotic.

These discoveries taught lessons for the clinical application of antibiotics such as penicillin and streptomycin. If a patient afflicted with a bacterial infection is to be treated with penicillin, the physician must employ the highest possible concentration of the drug at the very outset; for in that way the chance that all the pathogenic bacteria are killed is maximized, and the chance that high-level resistant mutants are selected is minimized. The avoidance of stepwise mutants is less important in streptomycin treatment, since mutants with high resistance to that drug are selected even in the presence of low concentrations, and little can be done to avoid their appearance. The surest way to avoid the appearance of drug-resistant strains is to administer simultaneously two or more kinds of antibiotics, since the chance that a multiple-resistant mutant will appear is given by the product of the individual mutation rates (397).

 

Joshua Lederberg (US) established the Lac locus in Escherichia coli (937).

 

H. Christine Reilly (US), Dale A. Harris (US), and Selman Abraham Waksman (RU-US) discovered a virus (actinophage) which parasitizes some streptomycetes (1276).

 

Gernot Bergold (DE) demonstrated that many-sided crystalline polyhedra, characteristic of many insect virus diseases called polyhedroses, consist of virus particles (115).

 

John Franklin Enders (US) succeeded in transmitting primary atypical pneumonia to human volunteers by means of filtered secretions from the respiratory tract. This strongly suggested a viral etiology for this disease (519). Note: The etiological agent was later found to be a type of bacterium with no cell wall (mycoplasma).

 

Josephine G. Perlingiero (US) and Paul György (US) recognized a syndrome in infants and young children with the prominent features of chronic eosinophilia, hepatomegaly, liver biopsy findings of eosinophilic infiltrative and granulomatous lesions, a benign course, and occasionally symptoms and signs of transient pneumonitis. Evidence was preponderantly in favor of the etiology in all cases being nematode larvae invasions of the liver and other viscera (1189). Note: This is in a catagory of infestation is referred to as toxocariasis because of the genus Toxocaro.

Helenor Campbell Wilder (US) demonstrated nematode larvae or their residual hyaline capsules demonstrated in serial sections of 24 out of 46 eyes: each eye was obtained from a different patient and almost all from children (1697).

Paul C. Beaver (US), C.H. Snyder (US), Goncalo V.S.M. Garrera (US), Jonathan H. Dent (US), and J.W. Cafferty (US) reported chronic eosinophilia due to visceral larva migrans. They proposed the term visceral larva migrans for this type of parasitism, because it was known in animals but not previously described in humans (91).

 

 John Tyler Bonner (US), and Leonard Jimmie Savage (US) showed that the amoebae of cellular slime molds first undergo growth as separate cells and then aggregate to form cell masses that become differentiated multicellular organisms. This paper gave evidence that aggregation occurred by chemotaxis, and the chemical attractant was given the name acrasin (163).

 

Edgar G. Anderson (US) and William Lacy Brown (US) published landmark monographs on the two ancestral maize types (Southern Dents and Northern Flints) that, when hybridized, gave rise to the North American race (Corn Belt Dent). Corn Belt Dent is the genetic foundation for all hybrid maize of the temperate zones (205-207).

 

Erik Zeuthen (DK) noted that the basic laws of thermodynamics state that metabolic rate must decrease with body size. This counteracted evolution of size in organisms. Cells could not grow larger than present ones and produce sufficient energy. When cells stuck together to form the metazoa, increase in size from that of a cell to that of a 105 X larger metazoan did not result in much decrease in metabolic rate. The surface law was circumvented in this size range and small animals developed elevated rates of heat production per unit of surface. The latter was of no consequence for poikilothermic life but of highest significance for the development of homoiotherms. These organisms reverted to the surface law at larger size than the poikilotherms and met evolutionary requirements for heat preservation and temperature regulation (1762; 1763).

 

Lemuel Roscoe Cleveland (US) gave accounts of how molting in Cryptocercus (a wood cockroach) affected the sexual cycles of its intestinal flagellates (302; 303).

 

Frederick E. J. Fry (CA) developed a model for the way fish respond to their physical and chemical environment. He divided all environmental effects on fish into five classes, controlling, limiting, lethal, masking and directive, increasing understanding of how environmental factors interact to affect performance of individual fish and their populations at any given time (579).

 

Min Chueh Chang (CN-US) disproved the need for large amounts of hyaluronidase at the site of fertilization and the claim that phosphorylated hesperidin, a hyaluronidase inhibitor, had man antifertility action when given orally (277; 278).

 

Robert John Walsh (GB) and Carmel M. Montgomery (GB) discovered the Ss blood group antigen (1651).

 

Thomas Francis, Jr. (US) discovered a non-antibody serum factor, which prevents the agglutination of erythrocytes by myxoviruses. It is referred to as the Francis’ inhibitor (equivalent to alpha-inhibitor) (569).

Chi-Ming Chu (GB) observed a similar factor, now called Chu’s inhibitor (equivalent to beta-inhibitor) (291).

Hiroto Shimojo (JP), Akira Sugiura (JP), Yukihiro Akao (JP), and Chiko Enomoto (JP) discovered gamma inhibitor, which is also a non-antibody serum factor capable of preventing the agglutination of erythrocytes by myxoviruses, specifically the A2 strain of influenza virus (1441).

 

Hurley L. Motley (US), Andre Cournand (US), Lars Werko (US), Aaron Himmelstein (US), and David Dresdale (US) found that short periods of induced anoxia (breathing 10% oxygen) in man rapidly induced pulmonary hypertension in subjects with normal blood pressure. Cardiac output was decreased slightly during anoxia, with a marked decrease in stroke volume. Pulmonary vascular resistance was almost doubled (1108).

 

Tracy Burr Mallory (US) described hemoglobinuric nephrosis following resuscitation from shock. He also saw it following anaphylactic shock, severe streptococcus infection, and infantile gastro-enteritis, and noted that it is possible to recognize many cases in the literature under such titles as interstitial nephritisla and hepato-renal syndrome (1019).

 

Robert B. Howard (US) and Cecil James Watson (US) discovered that patients with evolving cirrhosis of the liver often have an antecedent transient episode of jaundice (774).

 

Aaron Bunsen Lerner (US) and Cecil James Watson (US) discovered cryoglobulins in the sera of some patients with purpura (951).

 

Isaac Berenblum (IL) and Philippe Shubik (GB) discovered that cancer caused by chemicals involves two distinct steps, initiation and promotion. The first step, initiation, was theorized to be a rapid mutational effect on the cellular DNA. The second step, promotion, was believed to be caused by a promoting agent, which altered cellular metabolism, growth, and transport (113; 114).

 

Robert James Morton (US), Malcolm McCallum Hargraves (US), and Helen Robinson (US) discovered a mature neutrophilic polymorphonuclear leukocyte containing the phagocytosed nucleus of another cell and recognized it as a diagnostic aid in acute disseminated lupus erythematosus (685; 1106). The L.E. (lupus erythematosus) cell discovery was the first clear sign that systemic lupus erythematosus could be an autoimmune disease, i.e., Hargraves’ cells.

 

Thomas Holmes Sellers (GB), in 1947, performed the first successful pulmonary valvulotomy. A systemic pulmonary artery shunt was planned on the left side, but the attempt was abandoned in this patient with severe tetralogy of Fallot and advanced bilateral pulmonary tuberculosis. The pericardium was opened. Dr. Sellers could feel the stenotic valve each time it pushed through the pulmonary trunk during ventricular systole. Sellers used a tenotomy knife, which he passed through the right ventricle to perform the valvulotomy. The patient made a good recovery and was markedly improved (1421).

 

Jean-Pierre Soulier (FR) and Jean Gueguen (FR) discovered the anticoagulant phenylidane-dione and the first successful preparation of a therapeutic fraction from blood to treat factor IX and prothrombin complex deficiencies (1491).

 

Ludwig Guttman (DE-GB) established clean, intermittent self-catheterization in the treatment if urinary tract disease (659; 660; 923).

 

Ernest Adolf Spiegel (AT-US), Henry Telesfore (US), Matthew Marks (US), and Arnold Saint-Jacques Lee (US) used a stereotaxic apparatus to perform surgery as a treatment for Parkinson disease. Their goal was to produce discrete lesions in the basal ganglia (1496). Note: This was the first use of stereotaxic devices in surgery upon humans. Lars Leksel (SE) helped develop these devices.

 

Derek Ernest Denny-Brown (NZ-GB-US), E. Harry Botterell (CA), Thomas E. Twitchell (US), Luis Saenz-Arroyo (MX), John S. Meyer (US), Simon Horenstein (US), Betty Q. Banker (US), Geoffrey Rushworth (GB), Sid Gilman (US), Joseph P. van der Meulen (US), Nobuo Yanagisawa (JP), and Edwin J. Kirk (US) between 1947 and 1972, conducted central nervous system (CNS) lesion experiments on about 450 monkeys and made films of the animals post-operatively. The result of this effort is 67,000 m (220,000 ft) of film depicting monkeys with lesions in virtually every major CNS structure (406-416; 420; 421; 609; 862; 1353; 1603; 1618).

 

Alexander Brunschwig (US), in 1946, performed a total pelvic exenteration (surgical removal of the pelvic organs and nearby structures) on a patient with recurrent carcinoma of the cervix (214; 215).

 

Raoul Albert Charles Palmer (FR) used a laparoscope to observe the female genital organs via the transabdominal and transvaginal approach and realized that the former required a controlled pneumoperitoneum during the procedure. In his first report he described his experience with 250 “coelioscopies gynecologiques” using both the transabdominal and the transvaginal approach (1171). Note: In 1961 Palmer was the first to retrieve a human oocyte form a patient via laparoscopy. In 1962 Palmer performed laparoscopic tubal coagulations and other interventions.

 

Joao Cid Dos Santos (PT), in 1946, performed the first successful thromboendarterectomy (endarterectomy) for peripheral occlusive disease and established this procedure as feasible. His first operation was performed on a left femoral artery, his second, on a subclavian artery (446). It was soon accepted as a treatment for aortoiliac atherosclerotic obstructions.

 

Gerhardt von Bonin (US) and Percival Bailey (US) were the first to define with precision the cytoarchitecture of the human brain cortex (58; 1625).

 

Hugh L.C. Wilkerson (US) and Leo P. Krall (US) surveyed for diabetes in a New England town; a study of 3,516 persons in Oxford, Mass. They found 70 cases (1699).

 

Samuel Robert Means Reynolds (US) found that at about mid-pregnancy the enlargement of the human uterus by growth of its parts gives way to enlargement by stretching (1279).

 

Jens Christian Clausen (DK-US), David D. Keck (US), and William M. Heisey (US) used variation in the sticky cinquefoil (Potentilla glandulosa) and the yarrow (Achillea lanulosa) to perform the first documented experimental analysis of genetic differentiation in adjacent populations. During these experiments they introduced transplant experiments as an appropriate technique for distinguishing genetic from environmental effects (300; 301). These experiments clarified for certain species and under certain conditions the question of heredity versus environment.

 

Edward Smith Deevey, Jr. (US) introduced the concept of the life table to ecology (393).

 

Reginald Claude Sprigg (AU) discovered Precambrian metazoan fossils in the Pound Quartzite at Ediacara Hills and in the Flinders Ranges of South Australia (1499; 1500). This represents the dawn of visible life forms.

 

Edwin H. Colbert (US), curator of the American Museum of Natural History, found a massive quarry of Coelophysis dinosaurs in New Mexico and concluded from their skeletons that these Triassic dinosaurs were swift runners with a bird-like posture (316; 317).

 

Alexander S. Watt (GB) related mosaic conditions of plant community growth to dynamic cyclic processes in the environment (1661).

 

The journal Biochimica et Biophysica Acta was founded.

 

English country names and code elements taken from the International Organization for Standardization:

DZ = Algerian; US = American; AR = Argentinian; AU = Australian; AT = Austrian; AT/HU = Austro/Hungarian; BA = Bosnian-Herzegovinian; BE = Belgian; BR = Brazilian; GB = British; BG = Bulgarian; CM = Cameroonian; CA = Canadian; TD = Chadian; CL = Chilean; CN = Chinese; CO = Colombian; CR = Costa Rican; HR = Croatian; CU = Cuban; CY = Cypriot; CZ = Czechoslovakian; DK = Danish; NL = Dutch; EC = Ecuadorian; EG = Egyptian; EE = Estonian; ET = Ethiopian; FI = Finnish; FR = French; DE = German; GR = Greek; GT = Guatemalan; GU = Guamanian; HU = Hungarian; IS = Icelander; IN = Indian; ID = Indonesian; IR = Iranian; IQ = Iraqi; IL = Israeli; IE = Irish; IT = Italian; JP = Japanese; KE = Kenyan; KR = South Korean; KW = Kuwaiti ; LV = Latvian; LB = Lebanese; LT = Lithuanian; LU = Luxembourgian; MK= Macedonian; MG = Malagasy; MT = Maltese; MY = Malaysian; MX = Mexican; NA = Namibian; NZ = New Zealander; NG = Nigerian; NO = Norwegian; PK = Pakistani; PA = Panamanian; PE = Peruvian; PH = Filipino; PL = Polish; PT = Portuguese; PR = Puerto Rican; RO = Romanian; RU = Russian; SA = Saudi Arabian; SN = Senegalese; CS = Serbian-Montenegrin; SK = Slovakian; ZA = South African; ES = Spanish; LK = Sri Lankan; 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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