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Biographical Memoirs: Volume 62

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Biographical Memoirs: Volume 62 WILLIAM SMITH TILLETT July 10, 1892-April 4, 1974 BY H. SHERWOOD LAWRENCE AS HAPPENS SO OFTEN in science, it is one of life's little ironies that William S. Tillett's discovery of the bacterial protein streptokinase and his revolutionary idea of enzymatic therapy of thromboembolic disease had to take so long to reach its full flowering and current successful clinical application in the treatment of coronary thrombosis on a global scale. Yet Tillett never doubted the ultimate outcome or flagged in his pursuit of this idea. He had conceived, explored, and fostered this enzyme's unique thrombolytic applications with the broad vision, gifted intuition, and unerring precision which characterized all of his investigative work. This early major discovery was to become a constant preoccupation and a source of particular pleasure in his mature scientific life, yet he had discovered joy in nature long before. Tillett's love and reverence of nature had its origins in his childhood in Charlotte, North Carolina, where he was born on July 10, 1892. The youngest of four sons, his early years were spent happily midst a warm, devoted, and loving family reinforced by close ties with his older brothers, whom he admired greatly. His father, Charles Walter Tillett, was a successful and highly respected lawyer, and his mother, Carrie Patterson, was a physician's daughter. As a young-

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Biographical Memoirs: Volume 62 ster he used to spend each summer with his three older brothers on his grandfather's farm in North Carolina. Here he savored fully the rich experience of country life, the animals, the garden blooms, and the farm itself. And he cherished the memories of making a country practitioner's rounds in a horse and buggy with his grandfather, Dr. Patterson. His public schooling began in Charlotte, and then he moved on to a private preparatory school, Webb School, in Bell Buckle, Tennessee, for which he continued to have a particular fondness. He remained proud of the fact that at the completion of studies at Webb School students were eligible for admission to any college in America without qualifying examinations. The school was noted for its strict discipline and a curriculum consisting of English grammar, Latin, Greek, history, and mathematics. He was a willing student who enjoyed being taught, yet was most happy when discovering new ideas on his own, a preference which was to characterize his career and persist for a lifetime. Upon graduation from Webb School in 1909, Tillett enrolled at the University of North Carolina, where he excelled as a scholar as well as an athlete; his selection as All-American quarterback earned the high esteem of faculty and classmates alike. More importantly, it was here that Tillett experienced his first exposure to the sciences; from the very outset, the course in biology fascinated him. He was mesmerized by the thrill of watching frog's eggs divide and redivide to finally emerge as tadpoles in his laboratory exercises. This fascination with biology and the orderly, predictable sequence of life unfolding caught his imagination and charted his future course in science and in medicine. Many years later, in his retirement, it would give him the warmest feelings of pleasure to recall anew these still vivid images and recount them with an undiminished awe of the marvelous.

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Biographical Memoirs: Volume 62 Upon graduation from the University of North Carolina in 1913, he entered Johns Hopkins Medical School, which fostered in him a profound and enduring admiration and affection both for the school and for its stellar faculty. As a result of this exposure he emerged strongly attracted to an investigative career in medicine. Tillett's pursuit of these plans after graduating with the M.D. degree in 1917 were put in abeyance with the advent of American participation in World War I. He enlisted promptly, before completing an internship at the Baltimore City Hospital, and was commissioned a first lieutenant in the Army Medical Corps. Upon completion of two years' service as medical officer, much of it in combat with a battalion of engineers in France, he returned to America unscathed and was demobilized with the rank of captain. In 1919, back at his beloved Hopkins, he took up where he had left off, first as an intern and then successively as a house officer and then an assistant in medicine. This experience was capped by a year in Europe visiting medical institutions in London, Vienna, Paris, and Rome to round out his education. Tillett was always a great believer in chance providing the destiny that shaped one's career. Chance frequently smiled on him with coveted job opportunities, as we now learn, as well as in his scientific investigations, as will become evident. Upon his return to New York City from the European grand tour, he invited to dinner an old friend and former classmate from Hopkins who was then chief resident physician at the hospital of the Rockefeller Institute. As the evening waned, this physician invited Tillett back to the hospital to spend the night in the guest bedroom of the residents' quarters. He was delighted to accept the invitation and the opportunity to see the fabled Rockefeller Institute at firsthand. The next morning the chief resident told him of a new clinical department that

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Biographical Memoirs: Volume 62 was being formed for which a resident physician was needed to care for the patients on that service. Would he be interested in the position? Of course he would. And so, as Tillett often recalled in later years, he went to the Rockefeller Hospital to spend the night and remained for eight years. Thus chance and happy circumstance put Tillett, an ideal mind, in the ideal place at the most propitious of times and wound the spring that propelled his scientific career from that moment forward. Coming to the hospital of the Rockefeller Institute as assistant resident physician in September 1922, he was originally assigned to work on the program of viral diseases with Dr. Thomas M. Rivers. This association resulted in his first publications coauthored with Rivers on the transmission of lesions and the immune response of rabbits to varicella infection. Prophetically this work presaged Tillett's lifelong interest not only in the properties, characteristics, and behavior of the specific microbe which caused infection but also in the nature and scope of the host's immune response so critical to a favorable outcome. By 1924 Tillett had moved on to become resident physician on Dr. Rufus Cole's pneumonia service and was assigned to do laboratory research with Dr. O. T. Avery. As he often proudly and affectionately proclaimed in later years, this was the high-water mark of his career. It was at this juncture that he encountered the most propitious chance of all, the golden opportunity and cherished privilege to work and learn with Avery—outstanding scientist and warm human being, revered by his colleagues and affectionately known to all as Fess. Thus it chanced that Tillett entered on the happiest days of his career, enthralled by Avery, whom he held in reverential awe and the warmest affection then and forever after. It was here that Tillett flourished and emerged as an

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Biographical Memoirs: Volume 62 innovative and resourceful scientist under the gentle guidance and inspiration of Avery. And it was here that his lifelong preoccupation with the pneumococcus and the streptococcus was forged. He became intrigued with the behavior and chemical properties of these microbes as critical determinants of the host response to infection and thereby the ultimate outcome of the encounter. In his first work with W. F. Goebel and Avery, he set out to analyze the components of the pneumococcus and in the course of these studies he discovered that in addition to the type-specific polysaccharide, all pneumococci contained a distinctive and unrelated carbohydrate, the somatic C-polysaccharide, dubbed the C-fraction. Tillett, working with Thomas Francis, Jr., then observed that an "antibody" to the C-fraction appeared in the sera of patients with pneumonia during the acute phase of their illness and was not detectable in convalescent sera. This "antibody" became known as the C-reactive protein. Their subsequent studies revealed that the acute-phase sera obtained from patients afflicted with the broad range of infectious diseases as well as noninfectious, inflammatory syndromes had the property of precipitating the C-fraction. These findings resulted in the development and widespread clinical application of the C-reactive protein (CRP) test as an indicator and guide to the presence and course of acute inflammatory disease. The C-reactive protein that is precipitated by the C-fraction is currently still under intensive investigation by immunologists and other students of mechanisms of inflammation and host responses as a potent mediator of the inflammatory cascade. It is now recognized as a unique acute-phase protein which may participate in host defenses concomitant with but independent of the immune response. It was during this period (1922-30) that Tillett accomplished a prodigious volume of work chiefly in collabora-

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Biographical Memoirs: Volume 62 tion with his close friend and esteemed colleague Thomas Francis, Jr., and each of their oeuvres, like that of the C-reactive protein described above, led to new findings of broad significance which proved milestones in the progress of elucidating the repertoire of host responses to infection. Still preoccupied with the properties of the carbohydrates of the pneumococcus as the major determinants of the host response to that infection, Tillett and Francis next turned to studies of the properties of the type-specific polysaccharides. They observed that intradermal injection of such purified protein-free polysaccharide fractions resulted in an immediate wheal and erythematous cutaneous reaction in patients convalescent from pneumonia caused by that specific pneumococcal type. They also observed that purified protein fractions of pneumococci injected intradermally gave rise to a delayed type of cutaneous reaction and that such reactions to this material were not type specific. Further pursuit of these observations in normal individuals revealed that the type-specific polysaccharide was antigenic and resulted in type-specific antipneumococcal antibodies following repeated injection. Such immunized individuals would also respond with the wheal and flare cutaneous reaction when tested intradermally with the related type-specific polysaccharide just as they had observed in the patients convalescent from pneumococcal pneumonia. This intradermal test for type-specific immunity to the pneumococcus later became known as the Tillett-Francis test. Their observations also provided the first demonstration that carbohydrates free of protein contaminants could function as potent antigens. Colin MacLeod, in an appreciation of Dr. Francis1 upon his death, said of this work:

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Biographical Memoirs: Volume 62 On coming to Avery's laboratory, Francis and William Tillett worked together on cutaneous and serological reactions to products of pneumococcus, particularly the specific capsular polysaccharides and the 'C' or somatic carbohydrate, now known to be a constituent of the bacterial cell wall. Over the three-year period of their collaboration two remarkable findings came forth. The first of these was that there occurs in the blood of patients with many acute infections a new substance, not an antibody in the usual sense, which reacts specifically with the 'C' carbohydrate of pneumococcus to give a precipitation reaction. During recovery from the disease the "C-reactive protein," as it came to be known, diminishes in amount and within a few days disappears entirely. This is an enigmatic reaction whose function in man and animals is still unknown but which provides a useful clinical test to measure the activity of a variety of infectious processes, for example the activity of the inflammatory process in rheumatic fever. Francis and Tillett also discovered that minute amounts of specific capsular polysaccharides of pneumococcus injected intracutaneously in man cause the development of specific antibodies and that the antibodies are protective... These seminal observations of Tillett and Francis thus provided the background for the idea of producing a type-specific polysaccharide pneumococcal vaccine which was conceived, initially tested, and proven effective in the prevention of pneumonia in the field by Colin MacLeod and Michael Heidelberger in 1944.2 The vaccine was brought subsequently to its current acceptance and widespread clinical application as a result of the carefully designed and personally monitored trials of its efficacy by Robert Austrian, who had been a research fellow in MacLeod's laboratory at New York University at an earlier time. In 1928, while at the Rockefeller Institute, Tillett met and married Dorothy Stockbridge, who had become and remained forever the brightest light and lodestar of his life. He was then an associate of the Rockefeller Hospital, where he remained until 1930. In that year a daughter, Elizabeth, was born, his and Dorothy's only child, whom

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Biographical Memoirs: Volume 62 he idolized. Then, after eight exciting and productive years spent at the Rockefeller Institute, Tillett was lured back to Johns Hopkins as associate professor of medicine and director of the Biological Division, newly formed in the Department of Medicine by Warfield T. Longcope, who was then chairman of the department. It was here that he continued his studies on acute-phase reactants and shifted attention from the pneumococcus to the streptococcus, and here again that chance intervened to lead his receptive mind to the discovery of enzymatic fibrinolysis, for which he is most acclaimed and renowned. It all developed innocently enough from what seemed to be routine experiments with hemolytic streptococci arising from his earlier observation that the organisms were agglutinated by normal human plasma but not by serum. He deduced that the fibrinogen component present in plasma and absent in serum was the prime candidate for this agglutinating activity. This led Tillett to take oxalated human plasma containing fibrinogen that was unable to clot because of calcium depletion and to add hemolytic streptococci as potential absorbents of the soluble fibrinogen. He wished to observe whether upon the subsequent addition of calcium the anticipated fibrin clot formation would be negated by the binding of fibrinogen to the streptococci. The results of this experiment were uniformly negative; all of the tubes containing plasma clotted following the addition of calcium whether streptococci were present or not. Tillett recalled his disappointment at this result and leaving the test tubes in the rack without even bothering to clean up or discard them. A nagging curiosity about nature's failure to respond to such a good idea led him to examine the tubes again at a later time. To his unbounded amazement and delight, he observed that the clots in those tubes which contained streptococci had lysed and become liq-

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Biographical Memoirs: Volume 62 uid. He repeated this experiment a number of times with the same result and concluded that the hemolytic streptococci elaborated a fibrinolytic principle, streptococcal fibrinolysin, which dissolved fibrin clots. The principle turned out to be an enzyme activator, which was subsequently isolated and identified following Tillett's move to New York University and named streptokinase. Thus, as with his appointment to the Rockefeller Institute, once again chance intervened on Tillett's behalf, but this time the essential ingredient of destiny was the prepared mind. The results of these initial observations were published in 1933, yet Tillett saw the meaning of it all clearly and precisely and conceived the idea of applying this fibrinolytic principle to the dissolution of the tenacious fibrinous clots so devastating to patients with empyema and meningitis. However, the clinical application of his discovery would not be realized until he moved to New York University a few years later. In the interim he continued to study the phenomenon and began analysis of the fibrinolytic principle with characteristic insight and resourcefulness, and by 1934 he and his young colleague, R. L. Garner, had characterized the fibrinolysin further and delineated some aspects of the mechanism of the reaction. In 1937 Tillett was recruited to New York University School of Medicine to become professor and chairman of the Department of Bacteriology by John Wyckoff, its dean. He remained at that post for only one year; when the chair in medicine became vacant in 1938, and he was unanimously selected by the faculty to become professor and chairman of the Department of Medicine and director of the Third (NYU) Medical Division of Bellevue Hospital. It was probably no accident that he was succeeded in the chair of bacteriology in 1938 by his long-time friend and collaborator from the Rockefeller Institute, Thomas

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Biographical Memoirs: Volume 62 Francis, Jr. Happily also for New York University, it evolved that when it came time for Francis to move to his new post as the first dean of the School of Public Health at the University of Michigan in 1941, he was succeeded in turn as chairman of microbiology by Colin MacLeod of the Rockefeller Institute. This felicitous succession of unusually talented and gifted scientists, Tillett, Francis, and MacLeod, were all students and proteges of O. T. Avery, and each enriched and strengthened our faculty at New York University as well as science and the progress of mankind in his uniquely creative ways.3 With respect to the ''Rockefeller connection," it is of interest that one of Tillett's first appointments as chairman of medicine was that of Dr. Maclyn McCarty as a research fellow in 1940. McCarty had been in Tillett's laboratory at New York University for a year when he was awarded a National Research Council fellowship in the medical sciences. With the letter of notification came the suggestion of the chairman of the Medical Fellowship Board that McCarty consider the possibility of working with Colin MacLeod of the Rockefeller Institute to broaden his experience.4 McCarty showed the letter to Tillett, who knew that MacLeod would be leaving Avery's laboratory in July to assume the chairmanship of the Department of Microbiology at New York University. Nothing daunted, Tillett telephoned Avery promptly and recommended that he take on McCarty as a fellow in his laboratory. Avery agreed, and McCarty moved to the Rockefeller Institute, where he began to pursue the course that would lead to his pivotal contributions to the delineation of the biochemical nature and establishment of the pneumococcal transforming principle as DNA. In later years Tillett would recall this incident with great admiration and affection for McCarty, modestly adding that as much as he would have liked McCarty to stay with him,

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Biographical Memoirs: Volume 62 authors, dramatists, and actors, and he had a lively interest in the arts. Most of all, he loved to relax and recharge his spirit with his family in their cottage in Deer Isle on the Maine coast—to plant his garden and watch it grow and to prune and engraft his trees. Tillett's final days were serene and spent with his beloved wife Dorothy in a well-run convalescent home on a pleasant cove in Essex, Connecticut. We who were his close friends still miss him deeply. We miss his humor and gusto, his love of life and nature, his incisive mind, and his great heart. He was a generous and gallant man with a reserved exterior which cloaked a soft heart deeply touched by the plight of the less fortunate brought low by disease. The most prized and fitting memorial in addition to his impressive scientific achievements still stands on a plaque in the corridor of the Tillett Laboratories in Bellevue Hospital, his bequest to the young people of the future which he cherished above all his accomplishments: "These laboratories for Medical Research are named in Honor of William Smith Tillett Professor of Medicine New York University College of Medicine Director Third Medical Division Bellevue Hospital 1938-1958 They are a symbol of his guiding principle that research in the problems of disease is essential to good medical care of patients and proper instruction of students and physicians." Thus we remember him best as he would have wished, not in headstones or mausolea but in the hearts and lives

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Biographical Memoirs: Volume 62 of those he touched and in the scientific achievements of the next generation which meant so much to him. This memoir draws on and expands upon the obituary notice I composed for the Infectious Diseases Society of America (Journal of Infectious Diseases 130( 1974) :311-12) and similar notices prepared by Sol Sherry (Transactions of the Association of American Physicians 88(1975):32-34) and A. McGehee Harvey ( The Interurban Clinical Club (1905-1976)— A Record of Achievement in Clinical Science (New York: Saunders, 1978), pp. 201. Additionally, the materials supplied by the Archives of New York University Medical Center, by Dr. Richard Ross, Dean of Johns Hopkins Medical School, and the office of the Home Secretary of the National Academy of Sciences were most helpful sources of additional biographical information. I am also indebted to the following of Dr. Tillett's colleagues and friends for careful reading of this memoir for accuracy and significant detail: Drs. Maclyn McCarty, Sol Sherry, Saul Farber, Michael Heidelberger, and Herbert Chasis. NOTES 1.   Colin M. MacLeod, "Thomas Francis, Jr., 1900-1969." Archives of Environmental Health 21(1970):226-29. 2.   C. M. MacLeod, R. G. Hodges, M. Heidelberger, and W. G. Bernhard, "Prevention of Pneumococcal Pneumonia by Immunization with Specific Capsular Polysaccharides," Journal of Experimental Medicine 82(1945):445-65. 3.   See also J. R. Paul, "Thomas Francis, Jr.," Biographical Memoirs 44(1974):57-110; W. MacDermott, "Colin M. MacLeod," Biographical Memoirs 54(1982):183-219.

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Biographical Memoirs: Volume 62 4.   Maclyn McCarty, The Transforming Principle (New York and London: W. W. Norton Co., 1985):43-50. 5.   L. R. Christensen and C. M. MacLeod, "Proteolytic Enzyme of Serum: Characterization, Activation, and Reaction with Inhibitor." Journal of General Physiology 28(1945):559-83. 6.   M. McCarty, "Purification and Properties of Desoxyribonuclease Isolated from Beef Pancreas." Journal of General Physiology 29(1946): 123-39. 7.   Gissi, "Effectiveness of Intravenous Thrombolytic Treatment in Acute Myocardial Infarction." Lancet 1 (1986):397-401. 8.   Sol Sherry, "The Fibrinolytic System and Its Pharmacologic Activation for Thrombolysis," Cardiology Clinics 5(1987):1-1 1; "Appraisal of Various Thrombolytic Agents in the Treatment of Myocardial Infarction," American Journal Of Medicine 83(1987):31-46. 9.   S. Sherry, "William Smith Tillett 1982-1974," Transactions of the Association of American Physicians 88 (1975):32-34.

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Biographical Memoirs: Volume 62 SELECTED BIBLIOGRAPHY 1923 With T. M. Rivers. Studies on varicella. The susceptibility of rabbits to the virus of varicella . J. Exp. Med. 38:673-90. 1924 With T. M. Rivers. Atypical distribution of varicella lesions dependent upon a coexistent syphilitic infection. Report of a case. Bull. Johns Hopkins Hosp. 35:137-40. With T. M. Rivers. Further observations on the phenomena encountered in attempting to transmit varicella to rabbits. J. Exp. Med. 39:777-802. With T. M. Rivers. The lesions in rabbits experimentally infected by a virus encountered in the attempted transmissions of varicella. J. Exp. Med. 40:281-87. 1925 With T. M. Rivers. Local passive immunity in the skin of rabbits to infection with (1) a filterable virus, and (2) hemolytic streptococci. J. Exp. Med. 41:185-94. 1927 Studies on immunity to pneumococcus mucosus (Type III). I. Antibody response of rabbits immunized with Type III pneumococcus. J. Exp. Med. 45:713-26. Studies on immunity to pneumococcus mucosus (Type III). II. The infectivity of Type III pneumococcus for rabbits. J. Exp. Med. 45: 1093-1106. Studies on immunity to pneumococcus mucosus (Type III). III. Increased resistance to Type III infection induced in rabbits by immunization with R and S forms of pneumococcus. J. Exp. Med. 46:343-56. 1928 Active and passive immunity to pneumococcus infection induced in rabbits by immunization with R. pneumococci. J. Exp. Med. 48:791-804.

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Biographical Memoirs: Volume 62 1929 With O. T. Avery. Anaphylaxis with the type-specific carbohydrates of pneumococcus. J. Exp. Med. 49:251-66. With T. Francis, Jr. Cutaneous reactions to the polysaccharides and proteins of pneumococcus in lobar pneumonia. J. Exp. Med. 50:687-701. With O. T. Avery and W. F. Goebel. Chemo-immunological studies on conjugated carbohydrate-proteins. III. Active and passive anaphylaxis with synthetic sugar-proteins. J. Exp. Med. 50:551-67. 1930 With T. Francis, Jr. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J. Exp. Med. 52:561-71. With T. Francis, Jr. Cutaneous reactions in pneumonia. The development of antibodies following the intradermal injection of type-specific polysaccharide. J. Exp. Med. 52:573-85. With W. F. Goebel and O. T. Avery. Chemical and immunological properties of a species-specific carbohydrate of pneumococci. J. Exp. Med. 52:895-900. 1931 With T. Francis, Jr. Cutaneous reactions in rabbits to the type-specific capsular polysaccharides of pneumococcus. J. Exp. Med. 54:587-96. 1932 With T. J. Abernethy. Serological reactions with hemolytic streptococci in acute bacterial infections. Bull. Johns Hopkins Hosp. 50: 270-86. 1933 With R. L. Garner. The fibrinolytic activity of hemolytic streptococci. J. Exp. Med. 58:485-502. 1934 With L. B. Edwards and R. L. Garner. Fibrinolytic activity of hemolytic streptococci. The development of resistance to fibrinolysis following acute hemolytic streptococcus infections. J. Clin. Invest. 13:47-78.

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Biographical Memoirs: Volume 62 With R. L. Garner. The agglutination of hemolytic streptococci by plasma and fibrinogen. A comparison of the phenomenon to serological reactions with the same organisms. Bull. Johns Hopkins Hosp. 54:145-56. With R. L. Garner. Biochemical studies on the fibrinolytic activity of hemolytic streptococci. I. Isolation and characterization of fibrinolysin. II. Nature of the reaction. J. Exp. Med. 60:239-67. 1935 The fibrinolytic activity of hemolytic streptococci in relation to the source of strains and to cultural reactions. J. Bacteiol. 29:111-30. The occurrence of antifibrinolytic properties in the blood of patients with acute hemolytic streptococcus infections. J. Clin. Invest. 14:276-84. With T. M. Brown. Epidemic meningococcus meningitis. An analysis of twenty-six cases, twenty-one of which occurred in the spring of 1935. Bull. Johns Hopkins Hosp. 57:297-316. 1937 The bactericidal action of human serum on hemolytic streptococci. I. Observations made with serum from patients with acute infections and from normal individuals. II. Factors which influence the phenomenon in vitro. J. Exp. Med. 65:147-76. The serum treatment of pneumonia. Med. Clin. North Am. 21:148-187. With H. Southworth. Meningococcus meningitis. In International Clinics, ed. L. Hamman, pp. 9-14. Philadelphia: J. B. Lippincott Co. With C. C. Stock. The bactericidal action of human serum on hemolytic streptococci. III. Studies concerning: (1) The significance of hydrogen ion concentration in relation to the streptococcidal action of serum; (2) the effect of reducing agents on the phenomenon. J. Exp. Med. 66:617-36. Hydrogen ion concentration and anticoagulating and fibrinolytic action of cultures of streptococci and pneumococci. Proc. Soc. Exp. Biol. Med. 37:77-82. With C. C. Stock. Bactericidal action of human serum on hemolytic streptococci, active principle obtained by fractionation of sera. Proc. Soc. Exp. Biol. Med. 37:82-87.

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Biographical Memoirs: Volume 62 1938 The fibrinolytic activity of hemolytic streptococci. Bacteriol Rev. 2: 161-216. 1940 A consideration of some of the toxic effects of sulfonamide compounds, particularly sulfapyridine. Bull. N.Y. Acad. Med. 16:217-26. 1941 With M. McCarty. The inactivating effect of sulfapyridine on the leukotoxic action of benzene. J. Exp. Med. 74:531-44. Specific antipneumococcal immunity in relation to the outcome of chemotherapy in pneumonia. Trans. Assoc. Am. Phys. 56:147-50. 1942 With M. J. Cambier and H. Dunn. Specific antipneumococcal immunity in relation to the chemotherapy of pneumonia. J. Clin. Invest. 21:511-25. 1943 With M.J. Cambier and W. H. Harris, Jr. Sulfonamide-fast pneumococci. A clinical report of two cases of pneumonia together with experimental studies on the effectiveness of penicillin and tyrothricin against sulfonamide-resistant strains. J. Clin. Invest. 22: 249-55. 1944 With M. J. Cambier and J. E. McCormack. The treatment of lobar pneumonia and pneumococcal empyema with penicillin. Bull. N.Y. Acad. Med. 20:142-78. The needs for physiological knowledge: Civilian medicine. Fed. Proc. 3:190-91. 1945 With J. E. McCormack and M. J. Cambier. The treatment of lobar pneumonia with penicillin. J. Clin. Invest. 24:589-94. With J. E. McCormack and M. J. Cambier. The use of penicillin in the local treatment of pneumococcal empyema. J. Clin. Invest. 24:595-610.

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Biographical Memoirs: Volume 62 1948 With S. Sherry and L. R. Christensen. Presence and significance of desoxyribose nucleoprotein in the purulent pleural exudates of patients. Proc. Soc. Exp. Biol. Med. 68:179-84. With S. Sherry and L. R. Christensen. Streptococcal desoxyribonuclease: Significance in lysis of purulent exudates and production by strains of hemolytic streptococci. Proc. Soc. Exp. Biol. Med. 68:184-88. The antibiotic age. Am. J. Med. 4:159-62. 1949 With S. Sherry, L. R. Christensen, A. J. Johnson, and G. Hazlehurst. The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal desoxyribose nuclease (streptodornase). Trans. Assoc. Am. Phys. 62:93-97. With S. Sherry. The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal desoxyribonuclease on fibrinous, purulent, and sanguinous pleural exudations. J. Clin. Invest. 28:173-90. With S. Sherry and A. J. Johnson. The action of streptococcal desoxyribose nuclease (streptodornase), in vitro and on purulent pleural exudations of patients. J. Clin. Invest. 28:1094-1104. 1950 With S. Sherry, L. R. Christensen, A. J. Johnson, and G. Hazlehurst. Streptococcal enzymatic debridement. Ann. Surg. 131:12-22. With S. Sherry and C. T. Read. The use of streptokinase- streptodornase in the treatment of hemothorax. J. Thorac. Surg. 20:393-417. With W. N. Hubbard, Jr. Terramycin in the treatment of pneumococcal pneumonia. Ann. N.Y. Acad. Sci. 53:429-32. 1951 With S. Sherry and C. T. Read. The use of streptokinase-streptodornase in the treatment of postpneumonic empyema. J. Thorac. Surg. 21: 275-97. With S. Sherry and C. T. Read. The use of streptokinase-streptodornase in the treatment of chronic empyema. J. Thorac. Surg. 21:325-41. Prevention of rheumatic fever. Am. J. Med. 10:671-72. With S. Sherry and W. R. McCarty. Rationale of therapeutic use of streptokinase-streptodornase in amebic abscess of liver. Arch. Intern. Med. 88:752-59.

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Biographical Memoirs: Volume 62 1952 With S. Sherry. The local use of streptokinase-streptodornase in chronic refractory areas of suppuration with draining sinuses. Ann. Surg. 135:479-88. William de Berniere MacNider. 1881-1951. Trans. Assoc. Am. Phys. 65:28-30. Studies on the enzymatic lysis of fibrin and inflammatory exudates by products of hemolytic streptococci. Harvey Lect. 45:149-210. With W. R. McCarty. Streptokinase-streptodornase in chronic infections of feet involving bones and joints. Surg. Clin. North Am. 32:405-17. With A. J. Johnson. The lysis in rabbits of intravascular blood clots by the streptococcal fibrinolytic system (streptokinase). J. Exp. Med. 95:449-64. 1953 Infectious diseases. Annu. Rev. Med. 4:1-20. 1954 With A. J. Johnson and P. R. Goger. The intravenous injection of bovine crystalline pancreatic desoxyribonuclease into patients. J. Clin. Invest. 33:1670-86. 1955 With A. J. Johnson and W. R. McCarty. The intravenous infusion of the streptococcal fibrinolytic principle (streptokinase) into patients . J. Clin. Invest. 34:169-85. 1957 With A. J. Johnson, A. P. Fletcher, and W. R. McCarty. Effects in patients of intravenous infusions of purified streptokinase preparations. Proc. Soc. Exp. Biol. Med. 94:254-58. With J. H. Ayvazian and A. J. Johnson. The use of parenterally administered pancreatic desoxyribonuclease as an adjunct in the treatment of pulmonary abscesses. Am. Rev. Tuberc. Pulm. Dis. 76:1-21. The principles involved in the topical use of streptokinase-streptodornase. Ann. N.Y. Acad. Sci. 68:151-54. With A. J. Johnson, A. P. Fletcher, and W. R. McCarty. The intravascular use of streptokinase. Ann. N.Y. Acad. Sci. 68:201-206.

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Biographical Memoirs: Volume 62 Presidential address. From where I stand. Trans. Assoc. Am. Phys. 71:1-9. 1959 With A. J. Johnson and J. H. Ayvazian. Crystalline pancreatic desoxyribonuclease as an adjunct in the treatment of pneumococcal meningitis. N. Engl. J. Med. 260:893-900. The changing patterns of disease. Q. Bull. Northwestern Univ. Med. School 33:315-18. 1960 With H. S. Lawrence, F. T. Rapaport, and J. M. Converse. Transfer of delayed hypersensitivity to skin homografts with leukocyte extracts in man. J. Clin. Invest. 39:185-98. With H. S. Lawrence, F. T. Rapaport, and J. M. Converse. The transfer of homograft sensitivity (accelerated rejection) with DNAsetreated leukocyte extracts in man. Ann. N.Y. Acad. Sci. 87:223-30. 1962 With H. S. Lawrence, F. T. Rapaport, and J. M. Converse. Homograft sensitivity in human beings. In CIBA Foundation Symposium on Transplantation, ed. G. E. Wolstenholme and M.P. Cameron, pp. 271-81. Boston: Little Brown. With H. S. Lawrence, F. T. Rapaport, and J. M. Converse. A mechanism of homograft rejection. In Mechanism of Cell and Tissue Damage Produced by Immune Reactions, eds. P. Grabar and P. Miescher, pp. 204-209. Basel/Stuttgart: Benno Schwabe & Co. With F. T. Rapaport, H. S. Lawrence, L. Thomas, J. M. Converse, and J. Mulholland. Cross reactions to skin homografts in man. J. Clin. Invest. 41:2166-72.

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