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DONALD DEXTER VAN SLYKE March 29.1883May 4,1971 BY A. B AIR D H ASTIN GS DONALD DEXTER VAN SLYKE died on May 4, 1971, after a long and productive career that spanned three generations of biochemists and physicians. He left behind not only a bibliog- raphy of 317 journal publications and ~ books, but also more than 100 persons who had worked with him and distinguished themselves in biochemistry and academic medicine. To all who knew him, he was affectionately known as Van, and as Van I shall refer to him in this synoptic account of his life. Van was born in Pike, New York, a small rural community, and he received his early education in the elementary schools and high school of Geneva, New York. His father was the dis- tinguished chemist Lucius L. Van Slyke, who received his Ph.D. at the University of Michigan in 1882 and was on its staff at the time Van was born, on March 29, 1883. His mother, Lucy Dexter Van Slyke, died two years later. In 1890, L. L. Van Slyke became Chief Agricultural Chemist of the New York Agricul- tural Experiment Station, a post that he held until his retire- ment, in 1929. Van and his father and his father's profession were closely intertwined as Van was growing up, which doubt- less made chemistry a natural choice of study for him, though for a time he leaned toward architecture. Van had no chemistry courses in high school, but he used to credit his English teacher, Miss Florence Parker, with the lucidity that later characterized all his scientific publications. 309

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310 BIOGRAPHICAL MEMOIRS Van spent his first college year at Hobart College in Geneva, where he took his first course in chemistry. Since the college had but one chemistry course, he transferred to the University of Michigan, from which he received a B.A. degree in 1905 and a Ph.D. in chemistry in 1907. He once stated: "The chief reason I went there was that Moses Gomberg was there. If there was any outstanding American organic chemist, it was he." In addi- tion to courses in organic, physical, and analytical chemistry, Van also took bacteriology and plant physiology as minor sub- jects. His doctoral thesis, published with Gomberg in the Journal of the American Chemical Society in 1907, was entitled: "The Action of Molecular Silver, of Silver Sulfate and Chloride, and of Sulfuric Acid upon Halogenated Derivatives of Tri- phenyl-Carbinol Chloride." This occurred shortly after Gom- berg's exciting discovery in 1900 of the free radical triphenyl- methyl. Van has delightfully reminisced about his days when he was working in Gomberg's laboratory. One day he needed a two-liter bottle that had once contained metallic sodium under anhydrous ether. Thinking the pieces of sodium in the bottom had long since reacted, he dumped them in the sink with running water. "Flashes went off like cannon firecrackers, and when it stopped, Gomberg looked in through his door and said: 'Now, Van Slyke, you know what metallic sodium and water makes'.... Those were days when your professor was not at a distance." After receiving his Ph.D. and marrying Rena Mosher in the same year, Van became an assistant to Phoebus A. Levene at the newly established Rockefeller Institute for Medical Re- search in New York City. Since this came about somewhat by accident, the circumstances are worth recording. Van had expected to follow in his father's footsteps and become an agricultural chemist. To this end he had taken and passed a civil service examination for a position in the Bureau of Chem- istry. He was scheduled to report right after getting his doctor-

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DONALD DEXTER VAN SLYKE 311 ate. But fate took a hand, and at the spring meeting in 1907 of the American Chemical Society, Van's father chanced to sit next to Levene, who was recruiting for his department at the Institute. Luckily for Van and for the Institute, L. L. Van Slyke mentioned the approaching graduation of his son Donald. The upshot was that Van received an invitation from Dr. Simon Flexner, Director of the Rockefeller Institute, to come to New York for an interview. (In those daysand for many years after Simon Flexner personally interviewed all staff members, no matter how low their rank, before offering them an appoint- ment.) After consultation with his father, Van accepted the offer and thereby began his Rockefeller Institute career as bio- chemist and clinical chemist that was to last forty-one years from 1907 to 1948. THE ROCKEFELLER INSTITUTE, LEVENE PERIOD The first seven years were spent with Levene, which Van has described as a "wonderful time" working on proteins and amino acids. In 1911, Levene arranged for Van to spend a year in Berlin with Emil Fischer, who was then the leading chemist of the scientific world. He even had the privilege of working with Fischer in his private laboratory. Van was particularly impressed by Fischer's performing all laboratory operations quantitatively a procedure Van followed throughout his life. Prior to going to Berlin, Van had published eight papers with Levene and two by himselfone of which concerned his classic nitrous acid method for the quantitative determination of primary aliphatic amino groups. This method, which was in widespread use by chemists and biochemists for many years, depended upon the measurement of the gaseous nitrogen (N~) evolved by the reaction between alpha amino groups and ni- trous acid. It was the first of the many gasometric procedures devised by Van, and made possible the determination of amino acids in small amounts of blood and other biological materials.

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312 BIOGRAPHICAL MEMOIRS Until the development of microbiological and chromatographic procedures, it was the primary method used to study amino acid . . ~ . composltlon ot proteins. Following his return from Berlin, Van continued his study of amino acid composition of proteins with Levene, and began his studies of protein digestion and metabolism. With his col- league G. M. Meyer, he first demonstrated that amino acids, liberated during digestion in the intestine, are absorbed into the bloodstream, that they are removed by the tissues, and that the liver alone possesses the ability to convert the amino acid . nitrogen Into urea. This work led to a study with his assistant, G. E. Cullen, of the enzyme, urease, which decomposes urea to ammonia and carbon dioxide. The quantitative determination of both end products was subsequently the basis of gasometric procedures for measuring urea concentration in blood and urine. From the study of the kinetics of urease action, Van Slyke and Cullen developed equations that depended upon two re- actions: (1) the combination of enzyme and substrate in stoichio- metric proportions and (2) the reaction of the combination into the end products. Publisher! in 1914, this formulation, involving two velocity constants, was similar to that arrived at contempo- raneously by Michaelis and Menten in Germany in 1913. Thus were Van Slyke's activities during his first seven post- doctoral years. They centered around the development of better methodology for protein composition and amino acid metabo- lism. Van was remarkably productive and happy in his work with Levene. As he has stated, work on proteins and amino acids was "his first and enduring love." HOSPITAL OF THE ROCKEFELLER INSTITUTE PERIOD Then in 1914 came an opportunity to become the chief chemist of the newly opened Hospital of the Rockefeller Insti- tute, at the invitation of Dr. Rufus Cole, Director of the

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DONALD DEXTER VAN SLAKE 313 Hospital. Van did not decide to make this change lightly. Years later, he recalled, "I was so distrustful of my ability to develop a department of chemistry in the hospital and so reluctant at leaving Levene, that I made Flexner write me a letter saying that if I didn't like it in the hospital I could go back to Levene." But, he continued, "I began to pick up medicine pretty fast and found it fascinating. So I stayed in the Hospital the rest of the time I was at the Rockefeller." That amounted to thirty-four years. Van once told me that he studied textbooks of physiology and medicine diligently in preparation for his new responsibil- ity. He was fortunate in being able to take Dr. Glenn E. Cullen, his assistant in Levene's laboratory, with him. Cullen, a chemi- cal engineering graduate from the University of Michigan, was mechanically minded, resourceful, and had an outgoing person- ality. He and Van were a harmonious and effective team that developed the chemical laboratory of the hospital into a facility notable for its contributions to the budding science of bio- chemistry and to the yet-to-be-born science of clinical chemistry. Van Slyke also had the good fortune at this time to obtain the services of John Plazin, a young emigre from Latvia, as his personal laboratory assistant. John's ambition was to be the best assistant conceivable for Donald Dexter Van Slyke. This he achieved and maintained until he died forty-seven years later. They worked as one through all those years and their loyalty to and admiration of each other is a tribute to the faithful charac- ter of each man. To John, Van was always "Dr. Van Slyke." Though Van at age thirty entered upon his new responsibili- ties at the Hospital with some trepidation, he found the clinical staff so helpful and friendly that he experienced little difficulty in making the transition from Levene's laboratory to the clin- ically oriented environment. After all, under the directorship of Dr. Rufus Cole, the entire Hospital staff was embarking upon a new undertaking in medical researchthe intensive study of

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314 BIOGRAPHICAL MEMOIRS disease as a scholarly pursuitin patients, in animals, and in the laboratory. "Men who were studying disease clinically had the right to go as deeply into its fundamental nature as their training allowed, and in the Rockefeller Institute's Hospital every man who was caring for patients should also be engaged in more fundamental study," wrote Dr. Cole in 1911. Though commonplace today, this was a revolutionary idea at the time. Van Slyke and Cullen lost no time in applying their sound organic and physical chemical knowledge and technology to the clinical problems under study at the Hospital. The study of diabetes was already under way by Dr. F. M. Allen, the advocate of the "starvation treatment" of diabetics. Though this worked temporarily in some cases, eventual death from acidosis con- tinued to occur. Since acidosis manifested itself in several dif- ferent chemical ways, and no easy, reliable method for its early detection existed, Van Slyke turned his attention to this prob- lem. Characteristically, he went to the heart of the matter directly. He reasoned that if incomplete oxidation of fatty acids in the body led to the accumulation of acetoacetic and ,8-hydroxy- butyric acids in the blood, then a reaction would result between these acids and the bicarbonate ions that would lead to a lower- than-normal bicarbonate concentration in blood plasma. The problem thus became one of devising an analytical method that would permit the quantitative determination of bicarbonate concentration in small amounts of blood plasma. Again Van turned to a gasometric procedure. He ingeniously devised a volumetric glass apparatus that was easy to use and required less than ten minutes for the determination of the total carbon dioxide in one cubic centimeter of plasma and other aqueous solutions. His original method had an accuracy of about 1 percent. After the demonstration of the value of using this procedure in the diagnosis and therapy of patients with diabetes and some other disease states, the method was widely adopted in hospital

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DONALD DEXTER VAN SLYKE 315 and research laboratories. It also was soon found to be an excel- lent apparatus by which to determine blood oxygen concentra- tions, thus leading to measurements of the percentage saturation of blood hemoglobin with oxygen. This found extensive appli- cation in the study of respiratory diseases, such as pneumonia and tuberculosis. It also led to the quantitative study of cyano- sis and a monograph on the subject by C. Lundsgaard and Van Slyke. In all, Van Slyke and his colleagues published twenty-one papers under the general title "Studies of Acidosis," beginning in 1917 and ending in 1934. They included not only chemical manifestations of acidosis, but Van Slyke, in No. 17 of the series (1921), elaborated and expanded the subject to describe in chemical terms the normal and abnormal variations in the acid-base balance of the blood. This was a landmark in under- standing acid-base balance pathology and has not been mate- rially improved for fifty years. Van Slyke and his colleagues, both clinical and chemical, did not confine their interests solely to diabetes and acid-base abnormalities. Van kept work going on proteins and their prod- ucts of hydrolysis and on better methods for blood chlorides, urea, and ketone bodies in blood and urine. Within seven years after Van moved to the Hospital, he had published a total of fifty-three papers, thirty-three of them coauthored with clinical colleagues. Quantitative clinical chemistry was well on its way at the Hospital, and Van Slyke's contribution to it was well established. In 1920, Van Slyke and his colleagues undertook a compre- hensive investigation of gas and electrolyte equilibria in blood. This was not only a logical outgrowth of the ongoing study of the acid-base balance of the blood, but was also encouraged by Franklin C. McLean at the behest of Prof. L. J. Henderson. McLean and Henderson at Harvard had made preliminary studies of blood as a physico-chemical system, but realized that

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316 BIOGRAPHICAL MEMOIRS Van Slyke and his colleagues at the Rockefeller Hospital had superior techniques and the facilities necessary for such an undertaking. A collaboration thereupon began between the two laboratories, which resulted in rapid progress toward an exact physico-chemical description of the role of hemoglobin in the transport of oxygen and carbon dioxide, of the distribution of diffusible ions and water between erythrocytes and plasma, and of factors such as degree of oxygenation of hemoglobin and hydrogen ion concentration that modified these distributions. Publications from the two laboratories were independent and complementary. It was a happy intellectual collaboration. A key development in the progress made was Nlan Slyke's revision of his volumetric gas analysis apparatus into a mano- metric apparatus. Briefly, this amounted to liberating and iso- lating the desired gas contained in a known volume of solution, and recording in millimeters of mercury the pressure of that gas at a known fixed volume. The manometric apparatus proved to give results that were from five to ten times more accurate than the volumetric apparatus, and, in addition, made possible the determination of very small concentrations of gas in solu- tion. A series of papers on the CO2 titration curves of oxy- and deoxyhemoglobin, of oxygenated and reduced whole blood, and of blood subjected to different degrees of oxygenation and on the distribution of diffusible ions in blood resulted. One of these papers was especially notable. In it were developed equations that predicted the change in distribution of water and diffusible ions between blood plasma and blood cells when there was a change in pH of the oxygenated blood. (This work was done in 1923 at the Peking Union Medical Col- lege with F. C. McLean and Hsien Wu.) In a later paper, this was extended to reduced blood as well. A significant contribu- tion of Van Slyke and his colleagues was the application of the Gibbs-Donnan Law to the bloodregarded as a two-phase sys- tem, in which one phase (the erythrocytes) contained a high

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DONALD DEXTER VAN SLYKE 317 concentration of nondiffusible negative ions, i.e., those associ- ated with hemoglobin, and cations, which were not freely ex- changeable between cells and plasma. By changing the pH through varying the CO2 tension, the concentration of negative hemoglobin charges changed in a predictable amount. This, in turn, changed the distribution of diffusible anions such as C1- and HCO3- in order to restore the GibbsDonnan equilibrium. Redistribution of water occurred to restore osmotic equilib- rium. The experimental results confirmed the predictions of the equations. A total of fifteen papers, under the general title "Studies of Gas and Electrolyte Equilibria in Blood," were published between 1922 and 1928. Van regarded this work as among the best of his scientific output. As a spin-off from the physico-chemical study of the blood, Van undertook, in 1922, to put the concept of buffer value of weak electrolytes on a mathematically exact basis. By differen- tiating the mass law equation for weak acids with respect to pH, he arrived at the generalization ~ `1 H 2 3 SKY ~ H+1~2 + tH+] + [OH-~, where ,8 buffer value. This proved to be useful in determin- ing buffer values of mixed, polyvalent, and amphoteric electro- lytes, and put the understanding of buffering on a quantitative basis. It was applied in Van's laboratory to the determination of dissociation constants of polyvalent weak acids such as citric acid, whose three acid groups have overlapping dissociation constants. While this work on blood was going on, Van was preparing to make a detailed and comprehensive study of nephritis and its varied manifestations. In this he had a number of clinical asso- ciates, including Dr. Alma Hiller, who was in charge of his clinical chemical laboratory (1918-1948~. (After Cullen left in

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318 BIOGRAPHICAL MEMOIRS 1921, the basic chemical work of Van's laboratory was succes- sively supervised by A. B. Hastings, 1921-1926 J. Sendroy, Jr., 1926-1937; D. A. MacFadyen, 1937-1940; and R. M. Archibald, 1940-1946.) Van always had a number of problems under investigation at the same time at the Institute, but he never hurried to pub- lish the results. It was customary for him to put each paper through several drafts and revisions. Van had a great capacity to concentrate intensely and effec- tively on the problem at hand, and at the same time keep track of several research problems going on in the laboratory. This is why the publications in any one year often covered a wide range of subjects. For example, during 1928 Van and eight of his associates published twelve papers: one on a gasometric method for sugar determination in blood and urine, another on a new method for hemoglobin determination, three on factors affecting urea excretion in health and disease, and seven additional entries in the series "Studies of Gas and Electrolyte Equilibria in Blood." One of these, "The Solubility of Carbon Dioxide at 38 in Water, Salt Solution, Serum, and Blood Cells," was notable in that the first measurements on the subject were made in 1922, six years prior to publication. Each year the results would be written up for publication and each year Van would say: "We'll take another look at this in the fall, to make sure we can't improve on the accuracy." This was repeated annually until it met Van's standards. It was typical of his publications that one could count on their data and results . . . without question. The period of preoccupation with the study of blood as a physico-chemical system was followed by intensive study of nephritis, undertaken with a number of clinical colleagues. They followed and minutely documented the life history of the disease through its various stages in patients. This resulted in 1930 in a detailed publication by Van Slyke and nine colleagues

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DONALD DEXTER VAN SLYKE 351 With A. S. Alving. The significance of concentration and dilution tests in Bright's disease. l. Clin. Invest., 13:969. With C. P. Rhoads, A. Hiller, and A. S. Alving. The relationship of the urea clearance to the renal blood flow. Am. l. Physiol., 110:387. With C. P. Rhoads, A. Hiller, and A. S. Alving. The effects of novocainization and total section of the nerves of the renal pedicle on renal blood and function. Am. l. Physiol., 110:392. 1935 With I. H. Page, E. Kirk, and L. E. Farr. Nature of nitrogenous constituents in petroleum ether extract of plasma. Proc. Soc. Exp. Biol. Med., 32:837. With I. H. Page, A. Hiller, and E. Kirk. Studies of urea excretion. IX. Comparison of urea clearances calculated from the excre- tion of urea, of urea plus ammonia, and of nitrogen determin- able by hypobromite. J. Clin. Invest., 14:901. With A. Hiller and B. F. Miller. The clearance, extraction per- centage and estimated filtration of sodium ferrocyanide in the mammalian kidney. Comparison with inulin, creatinine and urea. Am. I. Physiol., 113:611. With A. EIiller and B. F. Miller. The distribution of ferrocyanide, inulin, creatinine and urea in the blood and its effect on the significance of their extraction percentages. Am. l. Physiol., 113: 629. With I. H. Page, E. Kirk, W. H. Lewis, fir., and W. R. Thompson. Plasma lipids of normal men at different ages. l. Biol. Chem., 111:613. 1936 The urea clearance as a measure of renal function. American Jour- nal of Medical Technology, 2:42. With R. T. Dillon. Gasometric determination of carboxyl groups in amino acids. Proc. Soc. Exp. Biol. Med., 34:362. With B. F. Miller. A direct microtitration method for blood sugar. J. Biol. Chem., 114: 583. 1937 With A. S. Alving. La cure dietetica del Morbo di Bright. Attualita di terapia medica, 15: 101.

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352 BIOGRAPHICAL MEMOIRS 1938 With R. T. Dillon. Gasometric determination of carboxyl groups in amino acids. Comptes Rendus du Laboratoire, Carlsberg, 22:480. With A. Hiller, R. T. Dillon, and D. MacFadyen. The unidentified base in gelatin. Proc. Soc. Exp. Biol. Med., 38:548. The manometric determination of amino acids. Biochemical iour- nal, 32:1614. With L. E. Farr. Relation between plasma protein level and edema in nephrotic children. Am. l. Dis. Child., 57:306. 1939 With E. F. McCarthy. Diurnal variations of hemoglobin in the blood of normal men. l. Biol. Chem., 128: 567. The development of controlled oxygen therapy. (Willard Gibbs Medal) The Chemical Bulletin, 26: 176. With i. Folch. Preparation of blood lipid extracts free from non- lipid extractives. Proc. Soc. Exp. Biol. Med., 41:514. With i. Folch. Nitrogenous contaminants in petroleum ether ex- tracts of plasma lipids. i. Biol. Chem., 129:539. Determination of solubilities of gases in liquids with use of the Van Slyke-Neill manometric apparatus for both saturation and analysis. l. Biol. Chem., 130: 545. 1940 Renal mechanisms controlling composition of the body fluids. (Willard Gibbs Lecture) Chemical Reviews, 26: 105. With A. Hiller, D. A. MacFadyen, A. B. Hastings, and F. W Klemperer. On hydroxylysine. l. Biol. Chem., 133:xxxiii. With [. Folch. Manometric carbon determination. l. Biol. Chem., 136:509. 1941 . Renal function test. New York Journal of Medicine, 41:825. Renal function tests. Mod. Med., 9:28. Fisiologia de los aminoacidos. Medicas, 2:78. With R. T. Dillon, D. A. MacFadyen, and P. Hamilton. Gasometric

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DONALD DEXTER VAN SLYKE 353 determination of carboxyl groups in free amino acids. J. Biol. Chem., 141:627. With D. A. MacFadyen and P. Hamilton. Determination of free amino acids by titration of the carbon dioxide formed in the reaction with ninhydrin. J. Biol. Chem., 141:671. With A. Hiller and D. A. MacFadyen. The determination of hy- droxylysine in proteins. l. Biol. Chem., 141: 681. 1942 With K. Emerson, in The nephrotic crisis. Journal of the Mount Sinai Hospital, New York, 8:495. With F. l. Kreysa. Microdetermination of calcium by precipitation as picrolonate and estimation of the precipitated carbon by manometric combustion. l. Biol. Chem., 142:765. Physiology of the amino acids. Centennial Address, Univ. of Chi- cago) Science, 95: 259; also in Nature, 149: 342. The kinetics of hydrolytic enzymes and their bearing on method for measuring enzyme activity. Advances in Enzymology, 2:33. With F. W. Klemperer and A. B. Hastings. The dissociation con- stants of hydroxylysine. l. Biol. Chem., 143:433. With R. A. Phillips, P. H. Futcher, P. B. Hamilton, R. M. Archi- bald, and A. Hiller. The source of the ammonia produced in the kidney in acidosis. Fed. Proc., 1:67. (A) With D. A. MacFadyen and P. B. Hamilton. Application of the gaso- metric ninhydrin-CO2 method to determination of amino acids in blood. Fed. Proc., 1:139. (A) With R. M. Archibald. Purification, kinetics and activity measure- ment of liver arginase. Fed. Proc., 1:139. (A) With A. Hiller and R. T. Dillon. Solubilities and compositions of the phospho-12-tungstates of the diamino acids and of praline, glycine and tryptophane. J. Biol. Chem., 146:137. 1943 With D. A. MacFadyen. Note on the use of the o-phenanthroline ferrous complex as an indicator in the ceric sulfate titration of blood sugar. J. Biol. Chem., 149:527. With R. A. Phillips, V. P. Dole, K. Emerson, fir., P. B. Hamilton, and R. M. Archibald, with technical assistance of E. G. Stanley and l. Plazin. The copper sulfate method for measuring specific

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354 BIOGRAPHICAL MEMOIRS gravities of whole blood and plasma. Biomed. Newsl., 1:1; also in Bulletin of the U.S. Army Medical Department, 71:66. With P. B. Hamilton. The gasometric determination of free amino acids in blood filtrates by the ninhydrin-carbon dioxide method. J. Biol. Chem., 150:231. With I). A. MacFadyen and P. B. Hamilton. The gasometric deter- mination of amino acids in urine by the ninhydrin-carbon diox- ide method. l. Biol. Chem., 150:231. With P. B. Hamilton. The synthesis and properties of ninhydrin ureide. l. Biol. Chem., 150:471. With R. A. Phillips, P. B. Hamilton, R. M. Archibald, P. H. Putcher, and A. Hiller. Glutamine as source material of urinary ammonia. l. Biol. Chem., 150: 481. 1944 With R. M. Archibald. Manometric, titrimetric and calorimetric methods for measurement of urease activity. I. Biol. Chem., 154: 623. With W. K. Rieben. Microdetermination of potassium by precipita- tion and titration of the phospho-12-tungstate. i. Biol. Chem., 156:743. With R. A. Phillips, R. M. Archibald, V. P. Dole, and K. Emerson, [r. Effect of shock on the kidney. Trans. Assoc. Am. Physicians, 58:119. 1945 Renal function of dogs given oxyhemoglobin or methemoglobin solutions. Biomed. Newsl., 5:9. 1946 With R. A. Phillips, V. P. Dole, P. B. Hamilton, K. Emerson, [r., and R. M. Archibald. Effects of acute hemorrhagic and trau- matic shock on renal function of dogs. Am. i. Physiol., 145:314. With V. P. Dole, K. Emerson, Jr., R. A. Phillips, and P. B. Hamil- ton. The renal extraction of oxygen in experimental shock. Am. J. Physiol., 145:337. With R. A. Phillips, A. Yeomans, V. P. Dole, and L. E. Farr. Esti- mation of blood volume from change in blood specific gravity following a plasma infusion. J. Clin. Invest., 25:261.

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DONALD DEXTER VAN SLYKE 355 With P. B. Hamilton. The effects of the volatile aldehydes formed on the accuracy of the manometric ninhydrin-carbon dioxide method in analysis of certain a-amino acids. I. Biol. Chem., 164:249. Laboratory Methods of the U.S. Army. Chemical Methods in Medi- cal War Manual TM8-227. Washington, D.C.: U.S. Govt. Print. 0~. Quantitative analysis in biochemistry. Chapter 8 in: Currents in Biochemical Research, ed. by D. E. Green. New York: Inter- science Publishers, Inc. With R. A. Phillips, A. Yeomans, V. P. Dole, and L. E. Farr. Spe- cific gravity estimation of blood volume. Mod. Med., 14:90. With R. M. Archibald. Gasometric and photometric measurement of arginase activity. I. Biol. Chem., 165: 293. With A. Hiller, I. R. Weiliger, and W. O. Cruz. Determination of carbon monoxide in blood and of total and active hemoglobin by carbon monoxide capacity. Inactive hemoglobin and methe- moglobin contents of normal human blood. I. Biol. Chem., 166: 121. 1947 With A. Hiller. Application of Sendroy's iodometric chloride titra- tion to protein-containing fluids. J. Biol. Chem., 167:107. With G. C. Cotzias and G. I. Lavin. Observations on normal and pathologic kidney tissue with ultraviolet photomicrography. Acta Medica Scandinavia, 196: 259. With F. P. Chinard. Comparison of a modified Folin photometric procedure and the ninhydrin manometric method for the deter- mination of amino acid nitrogen in plasma. I. Biol. Chem., 169:571. Studies of normal and pathological physiology of the kidney. (30th Mellon Lecture) Pittsburgh: Univ. of Pittsburgh School of Medicine. The effect of urine volume on urea excretion. l. Clin. Invest., 26: 1159. With P. B. Hamilton, L. E. Farr, and A. Hiller. Preparation of hemoglobin solutions for intravenous infusion. l. Exp. Med., 86:455. With L. E. Farr and A. Hiller. Preparation of dried hemoglobin without loss of activity. I. Exp. Med., 86:465.

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356 BIOGRAPHICAL MEMOIRS With P. B. Hamilton and A. Hiller. Renal effects of hemoglobin infusions in dogs in hemorrhagic shock. I. Exp. Med., 86:477. Nomogram for correction of low urine chloride values determined by the silver iodate reaction. J. Biol. Chem., 171:467. 1948 The effects of shock on the kidney. Ann. Intern. Med., 28:701. Effects of hemorrhage on the kidney. Ann. N.Y. Acad. Sci., 49:593. With H. Eder, F. P. Chinard, R. L. Greif, G. C. Cotzias, A. Hiller, and H. D. Lauson. A study of the changes in plasma volume, renal function and water and salt balance induced by repeated administration of human plasma albumin to patients with the nephrotic syndrome. l. Clin. Invest., 27:532. With A. Hiller and J. Plazin. A study of conditions for Kjeldahl determination of nitrogen in proteins. Description of methods with mercury as catalyst, and titrimetric and gasometric mea- surements of the ammonia formed. i. Biol. Chem., 176:1401. With A. Hiller and l. Plazin. Substitutes for saponin in the deter- mination of oxygen and carbon monoxide of blood. l. Biol. Chem., 176: 1431. 1949 With l. R. Weisiger and K. K. Van Slyke. Photometric measurement of plasma pH. l. Biol. Chem., 179:743. With l. R. Weisiger and K. K. Van Slyke. Photometric measurement of urine pH. l. Biol. Chem., 179:757. With H. A. Eder, F. P. Chinard, H. D. Lauson, R. L. Greif, A. Hiller, and G. C. Cotzias. Studies on the pathogenesis of neph- rotic edema J. Clin. Invest., 28: 779. With V. P. Dole. The significance of the urea clearance. [ournal of Clinical Pathology, 2:273. 1950 With R. A. Phillips, P. B. Hamilton, V. P. Dole, K. Emerson, ir., and R. M. Archibald. Measurement of specific gravities of whole blood and plasma by standard copper sulfate solutions. J. Biol. Chem., 183:305. With A. Hiller. R. A. Phillips, P. B. Hamilton, V. P. Dole, R. M.

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DONALD DEXTER VAN SLYKE 357 Archibald, and H. A. Eder. The estimation of plasma protein concentration from plasma specific gravity. l. Biol. Chem., 183: 331. With R. A. Phillips, N1. P. Dole, P. B. Hamilton, R. M. Archibald, and i. Plazin. Calculation of hemoglobin from blood specific gravities. l. Biol. Chem., 183: 349. 1951 With J. Plazin and J. R. Weisiger. Reagents for the Van Slyke- Folch wet carbon combustion. J. Biol. Chem., 191:299. With R. Steele and J. Plazin. Determination of total carbon and its radioactivity. J. Biol. Chem., 192:769. Studies of normal and pathological physiology of the kidney. Lec- tures on the Scientific Basis of Medicine, 1:143. 1952 With F. M. Sinex. Determination of polyglucose in blood and urine. Proc. Soc. Exp. Biol. Med., 79:163. With R. Steele and I. Plazin. Fate of intravenously administered polyvinylpyrrolidone. Ann. N.Y. Acad. Sci., 55:479. 1953 With l. Sacks. Preparation of serum lipid extracts free of inorganic phosphate. l. Biol. Chem., 200:525. 1954 With F. M. Sinex. Source of the hydroxylysine of collagen. Fed. Proc., 13:297. With H. A. Eder, H. D. Lauson, F. P. Chinard, R. L. Greif, and G. C. Cotzias. A study of the mechanisms of edema formation in patients with the nephrotic syndrome. i. Clin. Invest., 33:636. L'insu~cienza renale tubulare nello shock e Della nefrite. Minerva Medica, Anno 45-Vol. I-N 42. Renal tubular failure of shock and nephritis. (Tohn Phillips Lec- ture) Annals of Internal Medicine, 41:709. Wet carbon combustion and some of its applications. (Fisher Award Lecture) Analytical Chemistry, 26: 1706.

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358 BIOGRAPHICAL MEMOIRS 1955 With F. M. Sinex, i. Plazin, D. Clareus, W. Bernstein, and R. Chase. Determination of total carbon and its radioactivity. II. Reduc- tion of required voltage and other modifications. I. Biol. Chem., 213:673. With F. M. Sinex. The source and state of the Hydroxylysine of collagen. I. Biol. Chem., 216:245. Hydroxylysine. Society of Biological Chemists, India, Souvenir, p. 138. 1957 Hydroxylysine. In: Festschrift Arthur Stoll, pp. 211-19. Basel: Birk- hauser. With F. M. Sinex. The role of Hydroxylysine in the synthesis of collagen. Fed. Proc., 16:~50. The role of oxygen and carbon dioxide in cardiovascular physiology and pathology. Bulletin of the St. Francis Hospital, 14:1. Oxygen physiology, normal and abnormal. (5th Edsel B. Ford Lec- ture) Henry Ford Hospital Medical Bulletin, 5:25. 1958 Alkaline incineration methods for determination of protein-bound iodine in serum. Scandinavian Journal of Clinical- and Labora- tory Investigation, 10(Suppl. 31~: 317. With F. M. Sinex. The course of hydroxylation of lysine to form Hydroxylysine in collagen. J. Biol. Chem., 232:797. Renal tubular function and failure. Proceedings of the Rudolf Vir- chow Medical Society, 17:59. With W. W. Shreeve, L. I. Gidez, H. A. Eder, and A. R. Hennes. Carbon-14 in the study of metabolic processes in man. Second International Conference on Peaceful Uses of Atomic Energy, vol. 25, pt. 2, p. 34. London: Pergamon Press, Ltd. 1959 With F. M. Sinex and D. R. Christman. The source and state of the Hydroxylysine of collagen. II. Failure of free Hydroxylysine to serve as a source of Hydroxylysine or lysine of collagen. J. Biol. Chem., 234:918.

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DONALD DEXTER VAN SLYKE 359 General principles of oxygen transport and transfer. In: Oxygen Supply to the Human Fetus. A Symposium, ed. by J. Walker and A. C. Turnbull. Oxford: Blackwell Scientific Publications. 1960 With i. Plazin. Development of precise methods with a micro form of Van Slyke-Neill manometric apparatus. In: Proceedings of the 4th International Congress on Clinical Chemistry, Edin- burgh, Scotland. Baltimore: Williams & Wilkins Co. With O. P. Foss and L. V. Hankes. A study of the alkaline ashing method for determination of protein-bound iodine in serum. Clin. Chim. Acta, b:301. With I. Plazin. Determination of carbon and its radioactivity. III. Transfer of small samples of CO2 to counting tubes. l. Biol. Ghem., 235:2749. 1961 With i. Plazin. Micromanometric Analyses. Baltimore: Williams & Wilkins Co. 1962 Gasometric methods of analysis. In: International Symposium on Microchemical Techniques, ed. by Nicholas D. Cheronis. Univer- sity Park, Pa. New York: John Wiley & Sons, Inc. With i. Plazin. Determination of carbon and its radioactivity. IV. Transfer of CO2 to counting tubes without use of liquid nitro- gen. l. Biol. Chem., 247: 3296. With E. A. Popenoe. The formation of collagen hydroxylysine. I. Biol. Chem., 237:3491. 1963 With R. B. Aronson and E. A. Popenoe. The formation of collagen hydroxylysine studied with tritiated lysine. Fed. Proc., 22:229. 1964 With P. E. Carson. A simplified technique for determination of small amounts of calcium as oxalate. Clin. Chem., 10:352.

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360 BIOGRAPHICAL MEMOIRS The gases of the blood. (Brookhaven Lecture Series, no. 41) Upton, N.Y.: Brookhaven National Laboratory. 1965 With E. A. Popenoe and R. B. Aronson. The formation of collagen hydroxylysine studied with tritiated lysine. l. Biol. Chem., 240: 3089. With [. Plazin. The preparation of extracts of plasma lipids free from water-soluble contaminants. Clin. Chim. Acta., 12:46. 1966 With E. A. Popenoe and R. B. Aronson. Hydroxylysine formation from lysine during collagen biosynthesis. Proc. Natl. Acad. Sci. USA, 55:393. Reminiscences of life and work with Hastings. Fed. Proc., 25:820. With L. V. Hankes and J. l. Vitols. Photometric determination of pH with a single standard and calculation by nomogram: appli- cation to human plasma pH. Clin. Chem., 12:849. Some points of acid-base history in physiology and medicine. Ann. N.Y. Acad. Sci., 133:~. 1967 With R. B. Aronson, F. M. Sinex, and C. Franzblau. The oxidation of protein-bound hydroxylysine by periodate. l. Biol. Chem., 242:809. 1969 With E. A. Popenoe and R. B. Aronson. The sulfhydryl nature of collagen praline hydroxylase. Archives of Biochemistry and Bio- physics, 133:286. With A. F. LoMonte. Manometric determination of nitrate and nitrite. Microchemical Journal, 14:608. 1971 With R. B. Aronson. Manometric determination of CO2 combined with scintillation counting of C-14. Analytical Biochemistry, 41:173.

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