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Biographical Memoirs: Volume 63 JOHN HOWARD NORTHROP July 5, 1891–May 27, 1987 BY ROGER M. HERRIOTT JOHN HOWARD NORTHROP, trained in chemistry and introduced to general physiology by Jacques Loeb, proved that the enzymes pepsin and trypsin are proteins. The pattern of investigation that he used in this work was followed by his associates in isolating and examining other enzymes. The success of these studies led to the general acceptance of the view that enzymes are proteins. The importance of this work earned Northrop a share in the Nobel Prize in chemistry in 1946. John H. Northrop was an eighth-generation Yankee, a descendant of Joseph Northrop, who arrived in Milford, Connecticut, in 1630. His forebears included men of influence and accomplishment. Three of them were the Reverend Thomas Hooper 1631; the Reverend Jonathan Edwards, president of Princeton College in 1738; and Frederick C. Havemeyer, founder of the American Sugar Refining Company. The Havemeyer family provided Columbia University with a huge chemistry building in his name. John's parents were Alice Rich Northrop and John Isaiah Northrop. His father received a Ph.D. from Columbia's School of Mines in 1888 and was appointed "tutor" in the new Zoology Department under Professor Henry Fairfield

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Biographical Memoirs: Volume 63 Osborne. His mother had been an instructor in the Normal (later Hunter) College of New York City. A tragic explosion and fire in the Zoology Museum took the life of John Isaiah Northrop just two weeks before his son was born in Yonkers, New York. Despite this devastating accident to her husband, Mrs. Northrop maintained a close association with both Columbia's Zoology Department and Hunter College while rearing her son. She was a botanist and naturalist and helped introduce nature studies into the curriculum of the New York City schools. She also prepared most of the manuscript of a book entitled Through Field and Woodland, which was later edited by Oliver P. Medsger and published in 1925 after her untimely death in 1922 when her car was struck by a train. Young John's earliest recollection1 of his mother is of her sitting at her desk correcting proof of "A Naturalist in the Bahamas,"2 a report of a collecting trip his mother and father had made in 1889. With a devoted mother interested in nature, it is not surprising that John was reared with a deep understanding of the natural world. Both John and his mother took long walks, going with ease over rough terrain for long distances. John was educated in the public schools of Yonkers, New York, and recalled excellent teachers of mathematics (Mr. Graves) and chemistry (Dr. Metzger). The latter aroused an interest in chemistry that continued throughout his life. John attended Columbia College, where he was an outstanding member of the championship rifle and revolver team and the intercollegiate championship fencing teams. He received his B.S. in 1912 and proceeded directly to Columbia's graduate program in chemistry, earning a master's degree in 1913. He thought the following were exceptional teachers: F. C. Chandler, J. M. Nelson, and M. T.

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Biographical Memoirs: Volume 63 Bogart in chemistry; T. H. Morgan, E. B. Wilson, and Calkins in zoology; and Carlton Curtiss in botany. Student associates were Michael Heidelberger, George Scatchard, Herman Muller, A. H. Sturtevant, and Calvin Bridges—quite a galaxy of future scientists. John's doctoral studies were supervised by Professor John M. Nelson, a man of broad interests. The subject of John's thesis was "The Essentiality of Phosphorus in Starch." In 1915 the award of his Ph.D. was accompanied by the W. Bayard Cutting Travelling Fellowship, but the turmoil in Europe and Jacques Loeb's acceptance of John to work at the Rockefeller Institute for Medical Research led him to forego the fellowship. This was an important decision because John retained an association with the Rockefeller Institute (later University) for 70 years. On June 26, 1917, John Northrop and Louise Walker were married. Louise was a graduate of Barnard College, where she was elected president of her freshman class. She earned a master's degree in zoology at Columbia University and was working on her doctorate. This work took her to Woods Hole in the summer for studies at the Marine Biological Laboratory. It was there she met John. They lived in Mt. Vernon, New York until about 1925, when John, who strongly disliked commuting into New York City, became interested in offers from other institutions. He was persuaded by W. J. V. Osterhout to try working at the Rockefeller Institute's Animal Pathology Laboratory outside of Princeton, New Jersey, where he could walk to the laboratories. John's Princeton house looked out on Lake Carnegie, a great improvement over conditions in New York. He also became a member of several sporting clubs in New Jersey. Mrs. Northrop gave up her professional studies and de-

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Biographical Memoirs: Volume 63 voted herself to John's interests and the rearing of their two children, Alice Havemeyer and John. She did manage to maintain an interest in music and art in Princeton. During the hot and humid Princeton summers, the family went to Maine and later to their house near Cotuit, Massachusetts. In the latter place, Northrop could maintain laboratory work in nearby Woods Hole and they all could enjoy playing tennis and the cool sea breezes. Alice married Dr. Frederick C. Robbins in 1948. They presently live near Cleveland, Ohio, where Robbins is university professor emeritus of Case Western Reserve University. He has had a most distinguished career. In 1954 he shared with Drs. John F. Enders and Thomas H. Weller of Harvard the 1954 Nobel Prize in physiology and medicine for discovering and developing the growth of the polio virus in tissue culture, which led to the vaccines that have been so effective since 1955. He was elected to the National Academy of Sciences and was president of the Academy's Institute of Medicine from 1981–85. He also was dean of Case Western Medical School from 1966 to 1980. The Robbins have two daughters, Alice Christine Robbins Hamlin and Louise Enders Robbins. Alice's brother John obtained his collegiate education at Princeton and his doctorate at Hawaii and is a program manager at the Naval Ocean Systems Center in San Diego. He married Barbara Mason, and they have three grown children, John H. Northrop II, Geoffrey Mason Northrop, and Helen Haskel Northrop. John H. Northrop II has a daughter, Emma Louise Northrop. Throughout most of his life Northrop was a strong individual physically. Paul de Kruif admired Northrop's ability to pole a canoe up fast-flowing streams to favorite fishing areas in New Brunswick and Newfoundland. He excelled

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Biographical Memoirs: Volume 63 in sailing, hunting, marksmanship, and even horseback riding. He trained bird dogs and loved using them in his fall excursions after pheasants, quail, and partridge, yet he avoided research involving animals for he found that distasteful. A double mastoid operation following an infection during his undergraduate days made Northrop sensitive to certain climatic conditions. He attributed his deafness to exposure to low levels of mustard gas that he worked with during World War II. He avoided scientific meetings in part because of this. Although he devoted virtually his entire career to laboratory research, Northrop had his moments of interest in other endeavors. He so enjoyed hunting and fishing that he sought ventures that would allow him time for these pleasures. In 1913 he and a friend tried farming near Newburgh, New York, which ended when a fire destroyed their buildings. He next turned to prospecting for gold along the Colorado River where today is Lake Mead. World War I put a stop to that. For seven years after moving to Princeton he joined with a plant pathologist in raising seed potatoes, in the summer months in Aroostook County, Maine. His work was selecting varieties or sources of potatoes that were not infected with disease agents, as judged by whether they produced lesions on tobacco plants. This work also allowed him time to fish for salmon in the Miramachi, Tobrique, or Serpentine rivers of New Brunswick. He reported that the Miramachi River drops 2,000 feet in 80 miles and that he and friend Cheney ran the rapids several summers. "It always afforded us plenty of excitement and plenty of salmon." Northrop's influence on his associates was by example or casual comment. He was liberal in his acceptance of manuscripts as long as the evidence warranted the conclu-

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Biographical Memoirs: Volume 63 sions. He was associated with the Journal of General Physiology for nearly 70 years as contributor, editor, and honorary editor. EARLY RESEARCH, 1915-25 Jacques Loeb soon found John Northrop a responsive worker, thoroughly grounded in physical principles and unprejudiced about biological processes. The two quickly developed a strong regard for each other. John recognized and often commented to me later about Loeb's ingenious design of experiments to obtain answers to specific questions. Stimulated by the work on fruit flies of T. H. Morgan at Columbia, Dr. Loeb and John examined some of the effects of environmental factors on heredity. John grew Drosophila aseptically by freeing the eggs of contaminating organisms and cultivating them on a sterile mixture of yeast extract and banana. These may well have been the first animals grown free of microorganisms. With such fruit flies, Loeb and Northrop showed that there was a temperature coefficient for the duration of life and suggested several mechanisms for such control. John undermined the existing theory of life duration being fixed by an energy limit , for he found that carbon dioxide output, a measure of energy expended, was greater at 15°C than at 22°C, yet at 15°C the flies lived longer than at the higher temperature. John also found that inbreeding of aseptic drosophila for 230 generations in the dark had no discernable effect on their life duration, fecundity, or resistance to harmful bacteria. John's work with Loeb was halted by America's entry into World War I in Europe. Many important chemicals were found to be in short supply, and assistance was requested of many laboratories in developing methods of

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Biographical Memoirs: Volume 63 producing these chemicals. John had remembered an acetone odor emanating from flasks containing potato discs. He investigated this with the production of acetone in mind and found an organism that yielded acetone in appreciable quantities. He was commissioned a captain in the U.S. Army Chemical Warfare Service and carried the process through the first stage of plant development for Commercial Solvents Corporation of Terra Haute, Indiana. He succeeded in converting 8 percent of "black strap" sugar to acetone and 22 percent to ethanol. In this connection Northrop recalled that in England the basic explosive "cordite" manufacture depended on the use of acetone, which was in very short supply. Weizman developed an effective means of preparing acetone and saved the day for England. The British government in turn rewarded Weizman by establishing Israel as he wished. After the war Northrop returned to the Rockefeller Institute and studied a variety of phenomena. These included heliotropism in which he and Loeb found that the horseshoe crab Limulus responded to light like a photo cell. Exposed to multiple light sources, the crabs oriented themselves so the product of the intensity of the light, the time of exposure, and the cosine of the angle of incidence at the surface of the photosensitive organ were equal for each light source. In other work he studied Donnan equilibria; the kinetics of osmosis; the swelling of cells; and, with Moses Kunitz, the micellar nature of gelatin. With Paul de Kruif and Jules Freund, he studied the agglutination of bacteria and red cells. Northrop also devoted considerable effort to kinetic studies of the action of pepsin and trypsin and the inhibitor effect of some digestion products. In a paper he published with R. B. Hussey is a comment so characteristic of Northrop's reasoning that I must quote it. In com-

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Biographical Memoirs: Volume 63 menting on the adsorption theories of enzymes held by some European enzymologists, they noted, "In as much as it is possible to account for enzyme reactions on the basis of the laws of general chemistry, there seems to be no theoretical reason to disregard this fact and seek explanations in adsorption theories." Northrop found that "living cells have a peculiar membrane which is very selective about passage of material through it. The selective process is destroyed once the cell is dead. I found that neither pepsin nor trypsin are taken up by living organisms, whereas as soon as the organisms die, the enzyme rapidly digests them. Live fish or worms may live in the presence of pepsin or trypsin strong enough to digest the dead organism in a few hours." Jacques Loeb's sudden death in 1924 brought to a close an important period in Northrop's life. For nearly a decade Northrop had been nurtured by one of the great experimentalists and given the freedom to explore a variety of systems. Promotion of Northrop to member of the Rockefeller Institute soon followed. After his move to the Rockefeller Institute laboratory in Princeton, where the Department of Animal Pathology was directed by Theobald Smith, Northrop gathered a small group beginning with Moses Kunitz, who had been on Loeb's staff and with whom Northrop had collaborated. The respect each member of the group had of the others' qualities led to a highly productive relationship. Mortimer L. Anson joined them and initially developed with Northrop the simple but useful cintered glass disc cell for measuring diffusion constants of substances. In 1929 Albert Krueger, joined the group and studied the bacteriophage infection of Staphylococcus aureus. Krueger's return to California in 1931 left an opening that I was privileged to fill from 1932 to 1948.3

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Biographical Memoirs: Volume 63 PROOF THAT PEPSIN IS A PROTEIN Northrop had isolated swine pepsin in 1920 using a method described earlier by Pekelharing, but when the enzyme failed to crystallize he put the problem to one side. Professor James B. Sumner's success in crystallizing urease in 1926 stimulated Northrop to return to pepsin, especially since the European enzymologists took exception to Sumner's conclusion that urease is a protein. By 1929 Northrop had crystallized swine pepsin from crude commercial preparations, and his paper with the extensive evidence of its protein nature was published a year later. His evidence consisted of a number of attempts to separate the enzymic activity from the protein, all of which failed. He fractionated crystalline pepsin by recrystallization, salt fractionation, pH, heat, or radiation inactivation in which initial and final fractions were assayed for their enzymic activity per milligram of protein. In no case was there a significant change in this measure, a result expected if the enzyme is a protein. The solubility studies that Northrop and Kunitz developed especially to detect inhomogeneity in pepsin were probably his strongest evidence. S. P. L. Sørensen, the Danish chemist who first used the term pH, showed how to measure it, and who had also made earlier solubility studies of crystalline proteins, was unable to find a crystalline protein that was homogeneous by this test. The solubility method is relatively simple and is applicable to any substance. It has a solid theoretical basis in the Gibbs Phase Rule. Briefly, it predicts that the quantity of a pure compound dissolved in a given volume of solvent increases until a saturation concentration is reached. Further addition of the solid compound will not alter the concentration of the dissolved material. When the starting

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Biographical Memoirs: Volume 63 material is made up of two or more substances, the results will deviate from those of an ideal single substance. An early solid phase may persist before saturation is near, or the soluble phase may increase after the quantity of added material is in excess. Northrop made a number of solubility studies of crystalline pepsin, varying the pH and/or the nature of the salt used in the solvent. In general, these solubility curves were close to that of a pure single substance. He also examined all fractions for shifts in enzyme activity per milligram of protein which would indicate the possible separation of the enzyme from the protein. He found no change in this measure in any of the fractions. In his cautious manner he acknowledged that his studies could not rule out the case of pepsin being two closely related proteins but then he noted, "It seems reasonable to conclude from these experiments that the possibility of a mixture must be limited to a mixture of proteins, so that the conclusion seems justified that pepsin itself is a protein." In 1933 workers in two European laboratories reported adsorbing peptic activity onto melon seed proteins. One writer interpreted this as a transfer of the "active group" of pepsin to the seed protein, as expected from their view of enzymes. Although this interpretation was in conflict with his experiments, Northrop recognized that he could not exclude such an interpretation. He therefore carefully repeated their protocols and found that crystals of mellon seed proteins mixed with pepsin under their conditions did bind some peptic activity. However, he carried the study one step further. He dissolved the crystalline seed protein carrying peptic activity in dilute acid. The seed protein was quickly digested by the pepsin, and Northrop crystallized the pepsin out in its usual bipyrimidal form.

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Biographical Memoirs: Volume 63 I am indebted to Mrs. Frederick Robbins and Dr. John Northrop for information about the family. Special thanks go to Dr. John T. Edsall for his careful review and suggestions about the manuscript, which vastly improved it. To Marie King goes my appreciation for volunteering to loan me one of the very few copies of Northrop's unpublished autobiography. NOTES 1.   John H. Northrop, Just for the Fun of It, unpublished autobiography, 1968. 2.   John I. Northrop, A Naturalist in the Bahamas (New York: Columbia Press, 1910). 3.   I worked for my doctorate at Columbia's Chemistry Department under Professor John M. Nelson, as did Dr. Northrop. My thesis dealt with the reversal of denaturation of the enzyme invertase. I was delayed in getting my degree in 1931 by Northrop's publication that spring on the reversal of denaturation of pepsin. Professor Nelson generously wrote Northrop of my interest in working with him, and after he visited us at Columbia an offer was made to me in 1932. 4.   "Moses Kunitz, 1887-1976," In: Biographical Memoirs, vol. 58, (Washington, D.C.: National Academy Press, 1989):304-17. 5.   The discovery in 1982-83, by Thomas Cech and Sidney Altman, that certain RNAs have catalytic properties modifies the generally held belief that all enzymes are proteins. 6.   Material in this talk was expanded and published in the Annual Review of Biochemistry 30(1961):1–10. 7.   George W. Corner, A History of The Rockefeller Institute, 1901-1953 (New York: Rockefeller Institute Press, 1964):331, 454-59.

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Biographical Memoirs: Volume 63 HONORS 1931 The Stevens Prize of the College of Physicians and Surgeons of Columbia 1932 Walter C. Alvarez Lecture, American Society of Gastroenterologists 1934 Election to the National Academy of Sciences 1936 The Charles Frederick Chandler Medal 1936 Honorary Sc.D. degree, Harvard University 1937 Honorary Sc.D. degree, Columbia University 1937 Honorary Sc.D. degree, Yale University 1937 De La Mar Lecture, Johns Hopkins School of Hygiene and Public Health 1938 Jessup Lecture, Columbia University 1939 The Daniel Giraud Elliot Medal of the National Academy of Sciences 1939 The Hitchcock Lectures, University of California (Berkeley) 1939 Honorary LL.D. degree, University of California 1940 Honorary Sc.D. degree, Princeton University 1941 Honorary Sc.D. degree, Rutgers University 1946 Nobel Prize in Chemistry, shared with James B. Sumner and Wendell M. Stanley 1948 The President's Certificate of Merit 1949 Columbia University Lion Award Alumni Club of Essex County 1961 The Alexander Hamilton Award, Columbia University

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Biographical Memoirs: Volume 63 SELECTED BIBLIOGRAPHY 1916 With J. M. Nelson. The phosphoric acid in starch. J. Am. Chem. Soc. 38:472–79. With J. Loeb. Is there a temperature coefficient for the duration of life? Proc. Natl. Acad. Sci. USA 2:456–57. 1917 The role of yeast in the nutrition of an insect (Drosophila). J. Biol. Chem. 30:181–87. With J. Loeb. What determines the duration of life in metazoa? Proc. Natl. Acad. Sci. USA 3:382–86. 1919 The effect of the concentration of enzyme on the rate of digestion of proteins by pepsin. J. Gen. Physiol. 2:471–98. With L. H. Ashe and R. R. Morgan. The fermentation process for the production of acetone and ethyl alcohol. J. Ind. Eng. Chem. 11:723–27. 1920 A device for regulating the temperature of incubators either above or below room temperature. J. Gen. Physiol. 2:309–11. Concerning the hereditary adaptation of organisms to higher temperature. J. Gen. Physiol. 2:313–18. 1921 The mechanism of an enzyme reaction as exemplified by pepsin digestion. Science 53:391–93. 1922 With G. E. Cullen. An apparatus for macroscopic cataphoresis experiments. J. Gen. Physiol. 4:635–38. With P. H. DeKruif. The stability of bacterial suspensions. II. The agglutination of the bacillus of rabbit septicemia and of Bacillus typhosus by electrolytes. J. Gen. Physiol. 4:639–54. With P. H. DeKruif. The stability of bacterial suspension. IV. The combination of antigen and antibody from sensitized organisms. J. Gen. Physiol. 5:127–38.

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Biographical Memoirs: Volume 63 With P. H. DeKruif. The stability of bacterial suspension. V. The removal of antibody from sensitized organisms. J. Gen. Physiol. 5:139–42. The mechanism of the influence of acids and alkalies on the digestion of proteins by pepsin or trypsin. J. Gen. Physiol. 5:263–74. The mechanism of the effect of acids and alkalies on the digestion of proteins by pepsin or trypsin. J. Gen. Physiol. 5:415. 1923 With P. H. DeKruif. The agglutination of bacteria. Science 57:224. With J. Loeb. The photochemical basis of animal heliotropism. J. Gen. Physiol. 5:581–95. The stability of bacterial suspensions. VI. The influence of the concentration of the suspension on the concentration of salt required to cause complete agglutination. J. Gen. Physiol. 5:605–9. 1924 The kinetics of trypsin digestion. II. Conditions under which the reaction is monomolecular. J. Gen. Physiol. 6:417–28. With J. Freund. The agglutination of red blood cells. J. Gen. Physiol. 6:603–13. The kinetics of trypsin digestion. V. Schutz's rule. J. Gen. Physiol. 6:723–29. With M. Kunitz. The combination of salts and proteins. J. Gen. Physiol. 7:25–38. 1925 With M. Kunitz. An improved type of microscopic electrocataphoresis cell. J. Gen. Physiol. 7:729–30. The dynamics of pepsin and trypsin. Harvey Lectures, 1925–26, 21:36–76. With P. K. Olitsky. The inoculation of tomato and tobacco plants with potato mosaic virus. Science 61:544–45. 1926 Carbon dioxide production and duration of life of Drosophila cultures. J. Gen. Physiol. 9:319–24. With M. Kunitz. The combination of salts and proteins. II. A method for the determination of the concentration of combined ions

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Biographical Memoirs: Volume 63 from membrane-potential measurements. J. Gen. Physiol. 9:351–60. The resistance of living organisms to digestion by pepsin or trypsin. J. Gen. Physiol. 9:497–502. A convenient method for the formol titration. J. Gen. Physiol. 9:767–69. 1927 The kinetics of osmosis. J. Gen. Physiol. 10:883–92. With M. Kunitz. The swelling of isoelectric gelatin in water. II. Kinetics. J. Gen. Physiol. 10, 905–26. 1929 With M. L. Anson. A method for the determination of diffusion constants and the calculation of the radius and weight of the hemoglobin molecule. J. Gen. Physiol. 12:543–54. Viscosity. Bull. Natl. Res. Council 69:142–45. Crystalline pepsin. Science 69:580. 1930 Crystalline pepsin. I. Isolation and tests of purity. J. Gen. Physiol. 13:739–66. Crystalline pepsin. II. General properties and experimental methods. J. Gen. Physiol. 13:767–80. With M. Kunitz. Solubility curves of mixtures and solid solutions. J. Gen. Physiol. 13:781–91. With A. P. Krueger. The kinetics of the bacterium-bacteriophage reaction. J. Gen. Physiol. 14:223–54. 1931 Crystalline pepsin. III. Preparation of active crystalline pepsin from inactive denatured pepsin. J. Gen. Physiol. 14:713–24. With M. Kunitz. Isolation of protein crystals possessing tryptic activity. Science 73:262–63. With M. Kunitz. Crystalline trypsin. I. Isolation and tests of purity. J. Gen. Physiol. 16:267–94. With M. Kunitz. Crystalline trypsin. II. General properties. J. Gen. Physiol. 16:295–311.

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Biographical Memoirs: Volume 63 Crystalline trypsin. IV. Reversibility of the inactivation and denaturation of trypsin by heat. J. Gen. Physiol. 16:323–27. 1933 Crystalline pepsin. V. Isolation of crystalline pepsin from bovine gastric juice. J. Gen. Physiol. 16:615–23. Absorption of pepsin by crystalline proteins. J. Gen. Physiol. 17:165–94. With M. Kunitz. Isolation of a crystalline protein from pancreas and its conversion into a new crystalline proteolytic enzyme by trypsin. Science 78:558–59. 1934 Crystalline pepsin. VI. Inactivation by beta and gamma rays from radium and by ultra-violet light. J. Gen. Physiol. 17:359–63. With Roger M. Herriott. Crystalline acetyl derivatives of pepsin. J. Gen. Physiol. 18:35–67. With M. Kunitz. Autocatalytic activation of trypsinogen in the presence of concentrated ammonium or magnesium sulfate. Science 80:190. With M. Kunitz. The isolation of crystalline trypsinogen and its conversion into crystalline trypsin. Science 80:505–6. 1935 With M. Kunitz. Isolation from pancreas of a substance which inhibits trypsin digestion and its effect on the activation of trypsin. Science 81:418. 1936 With M. Kunitz. Isolation from beef pancreas of crystalline trypsinogen, trypsin, a trypsin inhibitor and an inhibitor-trypsin compound. J. Gen. Physiol. 19:991–1007. With R. M. Herriott. Isolation of crystalline pepsinogen from swine gastric mucosae and its autocatalytic conversion into pepsin. Science 83:469–70. Concentration and partial purification of bacteriophage. Science 84:90. With M. L. Anson. The calibration of diffusion membranes and the

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Biographical Memoirs: Volume 63 calculation of molecular volumes from diffusion coefficients. J. Gen. Physiol. 20:575–88. 1937 With M. Kunitz. Solubility of proteins as a test of purity: The solubility of chymo-trypsin and chymotrypsinogen. C. R. Trav. Lab. Carlsberg 22:288–94. Chemical nature and mode of formation of pepsin, trypsin and bacteriophage. Science 86:479–83. 1938 With R. M. Herriott and Q. R. Bartz. Transformation of swine pepsinogen into swine pepsin by chicken pepsin. J. Gen. Physiol. 21:575–82. Concentration and purification of bacteriophage. J. Gen. Physiol. 21:335–66. 1939 The Chemistry of Pepsin, Trypsin and Bacteriophage. In Crystalline Enzymes. Columbia Biological Series, No. 12. New York: Columbia University Press. 1940 With R. M. Herriott and V. Desreux. Fractionation of pepsin. I. Isolation of crystalline pepsin of constant activity and solubility from pepsinogen or commercial pepsin preparations. II. Preparation of a less soluble fraction. II. Solubility curves of mixtures of the soluble and insoluble fractions. IV. Preparation of highly active pepsin from pepsinogen. J. Gen. Physiol. 24:213–46. 1942 Purification and crystallization of diphtheria antitoxin. J. Gen. Physiol. 25:465–85. 1946 "The Quick and the Dead," Radio talk on New York Philharmonic Symphony Program, sponsored by United States Rubber Co.

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Biographical Memoirs: Volume 63 The preparation of pure enzymes and virus proteins. Nobel Lectures, Chemistry 3:124–34. 1947 Plastein from pepsin and trypsin. J. Gen. Physiol. 30:377–78. Detection of mustard gas, Lewisite, ethyldichloroarsine, and phenyldichloroarsine with trained dogs and rats. J. Gen. Physiol. 30:475–78. 1948 Convenient method for potentiometric titration of chloride ions. J. Gen. Physiol. 31:213–15. With M. Kunitz and R. M. Herriott. Crystalline Enzymes, 2nd. ed. New York, Columbia University Press. 1949 With W. F. Goebel. Crystalline pneumococcus antibody. J. Gen. Physiol. 32:705–24. 1951 Growth and phage production of lysogenic B. megatherium. J. Gen. Physiol. 34:715–35. 1952 The effect of various culture media on infection, growth, lysis, and phage production of B. megatherium. J. Gen. Physiol. 35:471–81. 1954 Apparatus for maintaining bacterial cultures in the steady state. J. Gen. Physiol. 38:105–15. 1955 Inactivation and reactivation of Bacillus megatherium phage. J. Gen. Physiol. 39:225–49. 1956 With J. S. Murphy. Appearance of new phage types and new lysogenic strains after adaptation of lysogenic Bacillus megatherium to ammonium sulfate culture medium. J. Gen. Physiol. 39:607–24.

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Biographical Memoirs: Volume 63 Apparatus for microdetermination of physiologically harmful agents in air. U. S. patent no. 2,757,132 to United States by Secretary of War. 1957 The effect of ultraviolet and white light on growth rate, lysis, and phage production of Bacillus megatherium. J. Gen. Physiol. 40:653–61. With M. Kunitz, The proportion of mutants in bacterial cultures. J. Gen. Physiol. 41:119–29. Optically active compounds from racemic mixtures by means of random distribution. Proc. Natl. Acad. Sci. USA 43:304–5. 1958 Concerning the origin of bacterial viruses. Proc. Natl. Acad. Sci. USA 44:229–35. 1960 Studies of the origin of bacterial viruses. VI. Effect of manganese on the proportion of phage-producing, terramycin-resistant, streptomycin-resistant, and phage resistant cells in lysogenic megatherium cultures. J. Gen. Physiol. 43:541–50. Apparatus for the maintenance of bacterial cultures in the steady state. II. Improved turbidity control and culture cells. J. Gen. Physiol. 43:551–54. 1961 Factors controlling the production of lysogenic cultures of B. megatherium. J. Gen. Physiol. 44:859–67. Biochemists, biologists, and William of Occam. Ann. Rev. Biochem. 30:1–10. 1962 Studies of the origin of bacterial viruses. VII. The effect of various mutagens (urethane, ethyl urethane, hydrogen peroxide, desoxycholate, maleic hydrazide, butadiene dioxide, triethylene melamine, versene, and acriflavine) on the proportion of virus-

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Biographical Memoirs: Volume 63 producing and streptomycin-resistant cells in culture of B. megatherium. J. Gen. Physiol. 46:971–81. 1965 Production of a new bacterial virus by prolonged growth of lysogenic E. coli cultures in the presence of triethylene melamine. Proc. Natl. Acad. Sci. USA 54:1632–35. 1966 Increased mutation rate of Escherichia coli K12λ, cultures maintained in continuous logarithmic growth. J. Gen. Physiol. 50:369–77. 1968 Appearance of virulent bacteriophage in lysogenic E. coli cultures after prolonged growth in the presence of triethylene melamine. J. Gen. Physiol. 52:136–43.

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