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Biographical Memoirs: V.47 (1975)

Chapter: 8 Eugene Lindsay Opie

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EUGENE LINDSAY OPIE July 5, 1873-March 12, 1971 BY ESMOND R. LONG EUGENE LINDSAY OPIE, pathologist, distinguished for pioneer and basic studies in many fields of medicine, died in his ninety-eighth year after more than seventy years of research and service in his chosen held. As a medical student at The Johns Hopkins University in the 1890s, he made an important discovery that alone would have made him eminent; namely the close relation of abnormality of the islands or Langerhans of the pancreas to diabetes mellitus. This relationship was his prin- cipal subject of investigation for ten more years. He later went on to studies that had wide influence in malaria, tuberculosis, the fundamentals of immunology, the general principles of in- flammation, medical education and leukemia and cancer. In the late years of his life—his last research paper was published in 1970—he was concerned with factors maintaining the proper water balance in animal tissues. He was almost blind at that time, but retained an astonishing memory of factors that might apply, and a keen sense of touch that gave him knowledge of what he could not see. In the last weeks of his life, marred as they were by blindness and serious loss of hearing, he continued to listen with pleasure to technical discussions by his visitors, even when he had passed the point of understanding them. Impressive as these details are, they still provide but an incomplete list of Opie's services to human health and welfare. 293

294 BIOGRAPHICAL MEMOIRS He held many important administrative positions, which he filled with faithful devotion to detail. He served his country, not only through his influence in teaching and research, but actually in the military activities of two wars—the Spanish- American War and World War I. The Spanish-American War merits more than passing in- terest because Opie's role in it was indicative of his character and receptive mind. In 1898, with William G. MacCallum, an associate at the Johns Hopkins Medical School who also became a distinguished pathologist, he volunteered for medical service. Opie and MacCallum accompanied seriously ill and wounded patients from military institutions in the South to hospitals for continued care in the North. Typhoid fever and malaria were rampant in these camps, and the two young Hopkins interns learned much that they used later in understanding the ravages of these diseases. This is an appropriate place to mention another pioneer investigation in which Opie and MacCallum were engaged as medical students. The eminent pathologist William H. Welch had turned Opie's attention to diabetes. Another Hopkins luminary, internist William Sidney Thayer, drew both men into important studies of lasting value on malaria. In correlated but independent researches, Opie and MacCallum worked out, in meticulous detail, the life cycles of the hematozoon parasite of bird malaria in the sparrows and blackbirds of Baltimore and—in MacCallum's case—in Ontario, Canada. These studies, despite the youth of the investigators, were never considered immature. At the end of their lives, the reports were still con- sidered among the authors' best. Opie was born in Staunton, Virginia, on July 5, 1873. His parents were native Virginians of distinguished ancestry. His father was a surgeon who became one of the founders of the College of Physicians and Surgeons of Maryland (later the Medical College of the University of Maryland). Son Eugene,

EUGENE LINDSAY OPIE 295 who had determined even in childhood to become a physician, matriculated in the school of which his father was dean shortly after he had been graduated with the A.B. degree from The Johns Hopkins University, in 1893. After a year at the medical school of the University of Maryland—already steeped in Johns Hopkins traditions—Opie decided to return to the new medical school at that university. He joined the first class to graduate, completing the medical course in 1897. The unusually active part he took in medical research in his student days is indicated above. Opie was never robust, nor given to strenuous exercise. An anecdote of his Hopkins school days is worth telling. A con- temporary at Hopkins, Lawrason Brown, who became one of America's most noted phthisiologists, took Opie in hand to en- sure a pleasanter life for him in the midst of a grinding cur- riculum. Brown was husky and strong and a leader in sports; Opie was seemingly frail and left out. Brown made the older and bigger boys include Opie in their groups and give him a chance in baseball and other sports. Ironically, after leading immensely useful lives, Brown died of advanced pulmonary tuberculosis at sixty-six, but Opie lived on despite the many infirmities of old age until ninety-seven. Opie remained at Hopkins for seven years after his gradua- tion in medicine, as fellow, assistant, and instructor in bac- teriology under the department head, the celebrated William H. Welch, who had started the younger man on his way to eminence. During the Hopkins years, Opie made a thorough study of lesions of the pancreas. This led, first, to a new outlook on diabetes and eventually to an understanding of the role of the pancreas in furnishing an internally secreted hormone regu- lating carbohydrate metabolism in the body. Other investiga- tions brought out the effect of gallstones impacted at the point of union of the bile and pancreatic ducts—diverting bile to the pancreas and causing the grave lesion hemorrhagic pan-

296 BIOGRAPHICAL MEMOIRS creatitis. This study integrated gross and microscopic study, and produced successful experiments reproducing the disease in animals. These investigations were formative in developing the lasting skill of Opie as an experimental pathologist. In 1904 Opie developed a relationship that lasted all his life, with the newly created Rockefeller Institute for Medical Research (now the Rockefeller University). The Rockefeller Institute was then largely dependent for its leaders on the Johns Hopkins Medical School. The Rockefeller Institute and the Henry Phipps Institute in Philadelphia, as Opie later wrote, ensured the privilege of pursuing research under condi- tions that permitted the results of one study to suggest the next, year after year, with few unwelcome interruptions. One of the most favorable influences at the Rockefeller Institute was daily close association with a score of dedicated investigators who helped make up the backbone of America's early laboratory medical research. Opie's Rockefeller years, from 1904 to 1910, were marked by illuminating studies on proteolytic enzymes and their relation to immunological processes. One of the principal printed sources on Opie's life and work in his forty most active years of research and teaching was his own article, "Peripatetic Education of a Pathologist" (in Med ical Clinics of North A merica, July 1957, pp. 935-952~. Opie always regretted that he did not have a chance to study under the great German leaders in pathology in his formative years, whose printed works he read assiduously. He did travel frequently in later years, and made personal contact with these men and their successors, but he never profited, as he had wished, by their elementary instruction. In his early years, Opie was himself already a leader in the mainstream of medical re- search and teaching and too much in demand in the developing medical schools in his own country to take the necessary time off. In 1910 he accepted appointment as professor of pathology at the School of Medicine at Washington University in St.

EUGENE LINDSAY OPIE 297 Louis, then being reorganized in the light of a now famous report by Abraham Flexner. This report, on medical education in America, was based on a survey by Flexner, sponsored by the Carnegie Foundation for the Advancement of Teaching. One of its first effects was the selection of a few medical schools, not very well off at the time, for development as superior institu- tions for medical teaching and research. These schools were to be developed along the lines followed by the great schools of continental Europe and The Johns Hopkins University in the United States. Pathology was one of the most basic of several fundamental sciences of medicine, and was accorded a high place in the proposed revolution in medical schools. Opie was a promising candidate for a role in the forthcoming develop- ment of a superior department of pathology. In "Peripatetic Education of a Pathologist," he noted a widespread tendency of medical schools to choose pathologists as deans. The medical school of Washington University proved no exception, and Opie soon found himself in that responsible, but not altogether desirable, position. He had been in the top rank as a full mem- ber of the Rockefeller Institute; now he found himself a full professor of pathology in an institution favored for expansion, and its dean as well. The development plan called for integra- tion of the medical school with a hospital—in this case the Barnes Hospital in a medical center for the promotion of realistic clinical teaching. Opie was instrumental in effecting this union; at the same time, he turned out a wealth of research on many topics. In this period, ne Developed hits influential program of studies on tuberculosis, noting the immunologic relations of primary in- fection in childhood to the character of the well-known chronic tuberculosis, or phthisis, in adults. A series of publications, commencing in 1914 and never totally dropped, crystallized his concepts. In simplified form, these held that the pulmonary tuberculosis of adult type is not the continuation of tubercu- losis of childhood, but rather a new exogenous infection ac- · ~ . . . . ..

298 BIOGRAPHICAL MEMOIRS quired in adolescence or adult life—a view that contrasted sharply with that held by many other noted students of the disease. A corollary of Opie's thesis was that the first infection modified the anatomical character of the tuberculosis acquired from contact in later life. Additional studies in the immu- nologicai field, particularly on enzymes, leukocytic and other phagocytic cells, and antigens and antibodies, related immu- nological sequences to the pathology of inflammation. These studies were continued on a wider scale at the Henry Phipps Institute in subsequent years. During Opie's tenure at Washington University (1910- 1923), he served as a medical corps officer in World War I, in grades from captain to colonel in the Hospital Unit formed at Washington University and in special commissions for the study of infectious disease in the Army. Out of his military experi- ence came important studies on pneumonia, influenza, trench fever, and tuberculosis. In 1923 Opie left Washington University to accept appoint- ment as professor of pathology, director of the department of pathology, and director of the laboratories of the Henry Phipps Institute at the University of Pennsylvania. His initial program of research there is best described in his own words taken from "The Peripatetic Education of a Pathologist": "At the Rockefeller Institute I had studied the enzymes concerned with tubercle formation and observed the beneficial effect of injected leukocytes upon the course of experimental tuberculous pleurisy. In the pathological laboratory of Washing- ton University and during my service in the Army I had come to realize how accurately the lesions of tuberculosis are defined by X-ray films of the affected organs after their removal at autopsy.... At the Henry Phipps Institute of the University of Pennsylvania opportunity was offered to continue, under very favorable conditions, study of the spread of tuberculosis and to obtain insight into the pathogenesis and transmission of the disease observed in patients and their families. It was pos-

EUGENE LINDSAY OPIE 299 sible to organize the outpatient department of the Institute so that its routine operation by clinical staff, X-ray department, visiting nurses and laboratory gave accurate and continuous information about the spread of the disease through several generations in whole families, white and colored, living in the district around the institute.... The revealing chest films and ingenious procedures introduced by Maurice McPhedran, my associate in these studies, had an important part in establishing the value of X-ray diagnosis. The frequent occurrence of recog- nizable pulmonary lesions unaccompanied by symptoms became evident for the first time, and the emergence of active disease from those latent, that is asymptomatic lesions, was repeatedly observed.... These studies were guided by parallel investiga- tion of the pathological anatomy, immunology and pathogenesis of the disease.... The relative importance of heredity, nutri- tion and transmission of infection was actively discussed. Studies at the Phipps Institute emphasized the dominant importance of the latter. Transmission of the disease by intimate family contact to both children and adults was clearly shown and marital transmission definitely established. Tuberculosis was found to occur in large part as long-drawn-out family or house- hold epidemics in which it was transmitted from one generation to the next." Opie's studies in Philadelphia were by no means limited to the clinical and visiting nurse services at the Phipps Institute itself. By arrangement with the Philadelphia school system, he carried out careful surveys of similar character on thousands of schoolchildren. At the University of Pennsylvania, he con- ducted investigations of the same character in medical students, whose work with patients in the autopsy room, and at the Philadelphia General Hospital, inevitably involved far more than average exposure to tuberculosis. But this was not enough to satisfy Opie in his examination of every facet of his developing concepts. The relative suscepti- hility of the white and colored races was always an important

300 BIOGRAPHICAL MEMOIRS consideration. He and his Phipps staff collaborated with the International Health Division of the Rockefeller Foundation in a study of the dissemination, transmission and character of tuberculosis in the predominantly black population of Jamaica. For ten years Opie visited the island every year. He found the disease more rapidly progressive in the black population of Jamaica than in either the whites or blacks of Philadelphia. This was particularly true among previously rural families who had moved from the less crowded countryside of Jamaica to the massive contagion of the towns and cities. In all of Opie's studies, the tuberculin test as an indication of the onset of infection was invaluable. The starting dates of childhood infection, in particular, could be determined pre- cisely, and by family X-ray examination the source of the new infection could generally be identified promptly, and protective measures instituted immediately. Long after he left the Phipps Institute, Opie continued with this pattern of study on tuberculosis. In 1939, while on leave of absence from his position at Cornell University (see p. 301), he served as visiting professor of pathology at the Peiping Union Medical College. There he compared the anatomical character of first infection and superinfection in Chinese adults. The crowded urban and less crowded rural environments gave him an unrivalled opportunity to pursue his studies. In effect, these confirmed his previous views on the contagion of the disease. His paper in collaboration with McPhedran on "The Con- tagion of Tuberculosis" in 1926 had already set forth in detail many of the factors concerned in exposure and infection, in- cluding their quantitative and time relations, first infection as compared with reinfection and such considerations as age, sex, and race. There was still controversy regarding the two con- trasting theories of the origin of the common ulcerative pul- monary tuberculosis of adults, i.e., the long-held concept of exogenous spread from old and latent childhood infections and

EUGENE LINDSAY OPIE 301 Opie's concept of new, heavy and continuous infection from another person. In the lone, run, the latter has prevailed in public health practice. Concurrently with his studies of tuberculosis at the Phipps Institute, Opie engaged in two other lines of highly productive research: investigations of the phenomena of immunity and leukemia. The work of Opie and his associate at the Institute, Jacob Furth, cleared up many of the mysteries of the phe- nomenon of anaphylaxis and the allied Arthus phenomenon. With other associates—Stuart Mudd, Joseph Hughes and Daly ~ ~ . . . . . . . Vend—ne related Immunological [actors to surface proper- ties of bacteria and mammalian cells, determined the role of dead tubercle bacilli as an immunizing factor in promoting phagocytosis, and described the fixation of inflammatory ir- ritants at the site of inflammation. Opie's studies in these several fields, carried out in the 1 920s, remain of practical working value today. During Opie's tenure at the Phipps Institute, a generous anonymous donor provided substantial funds for an experi- mental study of leukemia in animals. A program of laboratory investigation outlined by Opie was assigned to his associate, Jacob Furth. Larvae laboratory space was provided, where pro- ductive studies related the leukemias in special strains of labora- tory mice and chickens to heredity and the action of viruses. Opie continued these studies on a larger scale when he left the Phipps Institute in 1931 to assume the position of professor of pathology at the medical college of Cornell University and pathologist of the New York Hospital. The financial Grant that ~ ~ ~ . ~ ~ . A, .. . . .. nick Seen provided In rn~aue~pn~a was transferred to Cornell, and Furth's studies with Opie were expanded on a large scale to include isolation in relatively pure form of leukemia virus and various factors in the induction of leukemia. Opie's ten years at Cornell (1931-1941) were marked by notable contributions to the principles of medical education.

302 BIOGRAPHICAL MEMOIRS Not that this was a new field for him; he had, as noted before, taken an influential part in the modernization of medical teaching as professor and dean at Washington University. At Cornell he was intimately associated with the development of the College of Medicine and the New York Hospital as a medical center, and was indeed an important member of the hospital's Medical Board. One of his biographers, John Kidd, testified to the value of Opie's immense erudition, wisdom, rich experience, long perspective, and uncommon good sense in solving the multiple problems met by the Board. During this period influential immunological studies were also conducted, particularly with Jules Freund, on sensitization and antibody formation, tuberculosis in a variety of aspects, leukemia, and inflammation. Opie's work was not so much a return to these studies as a continuation of researches that had never been dropped. In 1941, at the statutory retirement age of sixty-eight, Opie left the New York Hospital-Cornell Medical Center to move a few hundred yards away and continue research as "guest investi- gator" at the Rockefeller University, where he had been one of the original staff, thirty-seven years earlier. Retirement was a technicality. He was indeed relieved of administrative duties and the multiple harassments and demands on his time that are inevitable in an academic position of daily responsibilities. He could not stop scientific research, however. It had been a part of his life since boyhood and Opie regarded it as enjoyment rather than a series of tasks to be completed. In his own words, "It is a fortunate circumstance that most of those who follow academic careers derive so much satisfaction from the doing of their work that they are unwilling to give it up." He could also reflect quietly on the changing outlook on old age. He recalled, with his gentle and ever present sense of humor, a time when he quizzed a medical student on the time of life when a certain abnormality was likely to occur. "In the later period of life," the student replied, "between forty and fifty years of age."

EUGENE LINDSAY OPIE 303 For nearly thirty years after his technical retirement at sixty- eight, Opie continued scientific research at the Rockefeller Institute. There, incidentally, he occupied laboratory rooms directly across the hall from those of Peyton Rous. The two octogenarians had much in common, and must have enjoyed many reminiscences. Each had been chief editor of the Journal of Experimental Medicine and had watched the march of medicine as reflected in the pages of that distinguished publica- tion. In his period of retirement, Opie, with a few associates, published more than forty medical papers. Careful study of these reveals no decline in their significance and lucidity. The majority of the papers were devoted to carcinogenesis, water exchange, and osmotic pressures in living mammalian tissues. The latter group of studies were physiologic in essence, but had an important bearing on pathologic phenomena, particu- larly those of inflammation. The cancer studies were unique in their exposition of certain dietary factors in relation to the development of experimentally induced tumors. Interest in the problems of previous papers had not abated. Opie brought up to date certain aspects of studies on tuberculosis, leukemia, and bile-induced injury of the pancreas. His final papers (1970) were on arteriosclerosis in the mesenteric arteries of rats, and adoption of standards of the best medical schools of Western Europe by schools in the United States. It must not be forgotten that the later studies were carried out in the face of gathering frailty of age and loss of sight and hearing. Opie retained a good memory, however, and had an extraordinary sense of loca- tion. He negotiated the short distance from his apartment to his office each day on foot and through traffic, and he could tell a visitor exactly where to find a piece of apparatus or a particular book on his laboratory shelves. He emphasized the fact that it was never too late to learn. He looked back frequently to his experience in China in his late sixties, when he observed the unique combination of

304 BIOGRAPHICAL MEMOIRS modern medicine with ancient philosophy, which allowed two systems of the practice of medicine to exist side by side. Speak- ing of his China experience, he said, "Some of my education has come late in life, unfortunately, because I might have profited more if it had come earlier." He reflected frequently on what constituted good teaching in medicine, recalling as formative the close association he had with great men at Johns Hopkins in the correlation of clinical medicine with pathology. He considered the so-called clinical pathological conferences one of the most fruitful practices in developing; an intimate understanding of medicine. Also, as an experienced experimental pathologist himself, he believed that students who might well be engaged in research in later years should not wait until they were faced with investigative prob- lems that might require experimentation, but should learn experimental techniques in their formative days. Accordingly, in his years at Cornell, he offered elective courses in experi- mental pathology, and learned to his joy that the majority of students wished to take them. His method was to assign a problem to groups of four students in various fields in which guidance was at hand in the persons of various members of the faculty of the department of pathology. The method proved remarkably successful. Qualified students went on to research in their postgraduate years, much better prepared than they otherwise would have been. Many undertook fulltime careers in medical teaching and research. Opie discussed the full-time versus the part-time system of teaching and research in medical schools, but without taking a partisan stand. It seemed obvious to him that each system had advantages. Opie always gave great credit to the philanthropic institu- tions and persons who provided financial support for his work. Prominent among these was the International Health Division of the Rockefeller Foundation, which was extremely helpful in his tuberculosis and immunological studies. The National

EUGENE LINDSAY OPIE 305 Tuberculosis Association also aided in Opie's tuberculosis re- search. The leukemia researches were supported by an anony- mous donor that he never identified publicly, and by a trust fund in India established by Sir Dorabji Tata in honor of his wife. A study of arthritis, which Opie largely turned over to his younger associates, was promoted by the Markle Foundation. In general, Opie used this support to secure stipends for the numerous assistants and associates he needed in his many-faceted . . . Investigations. Opie served many scientific societies in his long life. He was elected president of the American Society for Experimental Pathology (1923), the Society for Experimental Biology (1934), the Harvey Society (1936), the American Association of Pa- thologists and Bacteriologists (1918), the National Tuberculosis Association (1929), and the American Association of Immunol- ogists (1929~. He was a member of the Board of Scientific Directors of the International Health Division of the Rocke- feller Foundation (193~1938), and of the Executive Committee of the International Union against Tuberculosis. He was honored many times for his work in special fields. Medals con- ferred upon him included the Trudeau Medal of the National Tuberculosis Association, the medal of the Puerto Rico Society of Phthisiologists, the Gerhard Medal of the Pathological So- ciety of Philadelphia, the Gold Headed Cane of the American Association of Pathologists and Bacteriologists, the Banting Medal of the American Diabetes Association, the gold medal of the New York Academy of Medicine, the T. Duckett tones "VVO-l~ I Lll~ llCICll may VVIllUley rounuarlon, and the Weber- Parkes prize of the Royal College of Physicians of London. He became a member of the National Academy of Sciences in 1923, and was awarded its Kovalenko Medal in 1959. He took all of these distinctions in stride and never capitalized on any of them. Opie was twice married, first to Gertrude Lovat Simpson, on August 6, 1902, and, after her death, to her sister Margaret —Air—~1 fir ~ 1~ ~1~ ~_. ~~71~ ·^ ~ ~ ~ 1 . -

306 BIOGRAPHICAL MEMOIRS Lovat Simpson, on September 16, 1916. There were four children by the first marriage, Thomas Lindsay, Anne Lovat, Helen Lovat and Gertrude Eugenie. The four survived their father. Opie was a gentleman in every sense of the word. He was not expansive in social relations, but was always friendly and always helpful when his advice or assistance was sought. He had a quiet sense of humor that must have helped him many a time in his busy life. He could be firm in defending his opinions in controversy, but always temperately. That wise commentator and warm friend of many years, Peyton Rous, writing of Opie's accomplishments under the in- triguing title, "An inquiry into certain aspects of Eugene L. Opie," at the time of Opie's academic retirement (Archives of Pathology, 1942, 34:1-6) described him as a humanitarian in a telling sense of the word, gifted as a medical teacher, organizer, advisor, and administrator, adventurous in imagination, direct, simple and devout. These were indeed his attributes.

EUGENE LINDSAY OPIE BIBLIOGRAPHY KEY TO ABBREVIATIONS 307 Am. J. Hyg. _.\merican Journal of Hygiene Am. i. Hyg. Monogr. Ser. —American journal of Hygiene Monograph Series Am. I. Med. Sci. American Journal of Medical Sciences Am. I. Pathol. _ American journal of Pathology Am. Rev. Tuberc.—American Review of Tuberculosis Arch. Intern. Med. - Archives of Internal Medicine Arch. Pathol.—Archives of Pathology Arch. Pathol. Lab. Med. Archives of Pathology and Laboratory Medicine Chin. Med. i. - Chinese Medical journal Bull. Johns Hopkins Hosp. - Bulletin of the Johns Hopkins Hospital I. Am. Med. Assoc. - Journal of the American Medical Association J. Exp. Med. Journal of Experimental Medicine I. Immunol. _ journal of Immunology I. Med. Res.—journal of Medical Research i. Tech. Methods— Journal of Technical Methods and Bulletin of the International Association of Medical Museums Proc. Natl. Acad. Sci.—Proceedings of the National Academy of Sciences of the United States of America Traps. Natl. Tuberc. Assoc.— Transactions of the National Tuberculosis · . . Assoclatlon Twentieth Century Pract. Twentieth Century Practice 1898 On the haemocytozoa of birds. i. Exp. Med., 3:79-101. 1899 A case of haemochromatosis. The relation of haemochromatosis to bronzed diabetes. J. Exp. Med., 4:279-306. 1900 Microorganisms (protozoa). In: Twentieth Century Practice of Medicine (An International Encyclopedia of Modern Medical Science by Leading Authorities of Europe and America), ed. by T. L. Stedman, vol. 19, pp. 767-809. New York: William Wood ~ Co. Experimental disseminated fat-necrosis. In: Contributions to the Science of Medicine, dedicated to William Henry Welch, ed. by Simon Flexner. Johns Hopkins Hospital Report, 9:859-76. On the histology of the islands of Langerhans of the pancreas. Bull. Johns Hopkins Hosp., 11:205-9.

308 BIOGRAPHICAL MEMOIRS Pathological changes affecting the islands of Langerhans of the pancreas. journal of the Boston Society of Medical Sciences, 4: 251-60. 1901 The relation of cholelithiasis to disease of the pancreas and to fat necrosis. Am. l. Med. Sci., 121:27~3. On the relation of chronic interstitial pancreatitis to the islands of Langerhans and to diabetes mellitus. I. Exp. Med., 5:397-428. The relation of diabetes mellitus to lesions of the pancreas. Hyaline degeneration of the islands of Langerhans. J. Exp. Med., 5:527- 40. The etiology of acute hemorrhagic pancreatitis. Bull. Johns Hop- kins Hosp., 12:182-88. Typhoid infection without lesion of the intestine a case of haemor- rhagic typhoid fever with atypical intestinal lesions. Bull. Johns Hopkins Hosp., 12:198-203. Filarial lymphatic varix. Am. J. Med. Sci., 122:251-66. 1903 Protozoa. In: Twentieth Century Practice of Medicine, ed. by T. L. Stedman (Supplement). New York: William Wood & Co. Disease of the pancreas. The symptoms and treatment of disease of the pancreas. International Clinics, 16th ser., 2:64-84. The pancreas and pancreatic diseases. The anatomy and histology of the pancreas. Transactions of the Congress of American Physicians and Surgeons, 6: 1-7. Diseases of the Pancreas. Philadelphia: l. B. Lippincott Co. 337 pp. The anatomy of the pancreas. American Medicine, b: 996-98. 1904 The occurrence of cells with eosinophile granulation and their relation to nutrition. Am. J. Med. Sci., 127:217-39. The relation of leucocytes with eosinophile granulation to bacterial infection. Preliminary publication. Bull. Johns Hopkins Hosp., 15:71-72. An experimental study of the relation of cells with eosinophile granulation to infection with an animal parasite (Trichina spiralis). Am. J. Med. Sci., 127:477-93.

EUGENE LINDSAY OPIE 309 Lesions peculiar to the pancreas and their clinical aspect. Medical News, 84:961-67. The relationship of cells with eosinophile granulation to bacterial infection. Am. J. Med. Sci., 127:988-1010. 1905 Enzymes and anti-enzymes of inflammatory exudates. J. Exp. Med., 7:316-34. The presence in the bone-marrow of enzymes resembling those of leucocytes. i. Exp. Med., 7:759-63. 1906 The enzymes in phagocytic cells of inflammatory exudates. I. Exp. Med., 8:410-36. Solution of tissue with abscess. i. Exp. Med., 8:536-41. 1907 With Bertha I. Barker. Leucoprotease and anti-leucoprotease of mammals and of birds. T. Exp. Med., 9:207-21. Opsonins and their relations to the diagnosis and treatment of bacterial infection. Yale Medical journal, 13:301-21. Experimental pleurisy resolutions of a fibrinous exudate. l. Exp. Med., 9:391-413. The transformation of sero-fibrinous into purulent pleurisy. l. Exp. Med., 9:414-27. Opsonins of inflammatory exudates. J. Exp. Med., 9:515-19. 1908 The effect of injected leucocytes upon the development of a tubercu- losis lesion. I. Exp. Med., 10:419-55; Bull. [ohns Hopkins Hosp., 19:115 (A). With Bertha I. Barker. Enzymes of tuberculous tissue. i. Exp. Med., 10: 645-65. 1909 With l. C. Meakins. Data concerning the etiology and pathology of hemorrhagic necrosis of the pancreas Acute hemorrhagic pan- creatitis). l. Exp. Med., 11:561-78.

310 BIOGRAPHICAL MEMOIRS With Bertha I. Barker. Enzymes of tuberculous exudates. l. Exp. Med., 11: 686-94. 1910 Inflammation. (Harvey Lectures, 1910-1911) Arch. Intern. Med., 5:541-68. Diseases of the Pancreas. 2d ed. Philadelphia: I. B. Lippincott Co. 381 pp. On the relation of combined intoxication and bacterial infection to necrosis of the liver, acute yellow atrophy and cirrhosis. J. Exp. Med., 12: 367-86. 1911 With Bertha I. Barker and A. R. Dochez. Changes in the proteolytic enzymes and anti-enzymes of the blood serum produced by sub- stances (chloroform and phosphorus) which cause degenerative changes in the liver. J. Exp. Med., 13: 162-85. 1912 Lymph formation and edema of the liver with experimental nephritis produced by cantharidin. l. Exp. Med., 16:831~9. What is internal secretion? Interstate Medical Journal, 19:415-20. 1913 Human botryomycosis of the liver. Arch. Intern. Med., 11:425-39. Thrombosis and occlusion of lymphatics. i. Med. Res., 29:131~6. 1914 Changes in the incidence and character of tuberculosis produced by preceding infection. California State journal of Medicine (March Supplement). 1915 With Leland B. Alford. The influence of diet upon necrosis caused by hepatic and renal poisons. I. Diet and the hepatic lesions of chloroform, phosphorus, or alcohol. J. Exp. Med., 21:1-20. With Leland B. Alford. The influence of diet upon necrosis caused by hepatic and renal poisons. II. Diet and the nephritis caused by potassium chromate, uranium nitrate, or chloroform. J. Exp. Med., 21:21-37.

EUGENE LINDSAY OPIE 1917 311 Progressive muscular ossification (progressive ossifying myositis); a progressive anomaly of osteogenesis. i. Med. Res., 36:267-75. With Nathaniel Allison. Hypertrophic chondrodystrophy in infancy and adolescence; a progressive anomaly of osteogenesis. l. Med. Res., 36:277-94. The focal pulmonary tuberculosis of children and adults. .T. Exp. Med., 25: 855-76. The relation of apical tuberculosis of adults to the focal tuberculosis of children. l. Exp. Med., 26:263-77. 1919 With Allen W. Freeman, Francis G. Blake, lames C. Small, and Thomas M. Rivers. Pneumonia at Camp Funston. Report to the Surgeon-General. l. Am. Med. Assoc., 72:108-16. With others. Trench Fever, ed. by Richard P. Strong. Report of Commission of Medical Research Committee of American Red Cross. London: Oxford University Press. 446 pp. With Allen W. Freeman, Francis G. Blake, fames C. Small, and Thomas M. Rivers. Pneumonia following influenza (at Camp Pike, Ark.~. l. Am. Med. Assoc., 72:556-65. 1920 With Hans Andersen. First infection with tuberculosis by way of the lungs. Am. Rev. Tuberc., 4: 629-39. First infection with tuberculosis by way of the intestinal tract. Am. Rev. Tuberc., 4:641-48. 1921 The effect of smoke on health. In: Proceedings of the Smoke Preven- tion Association, Fifteenth Annual Convention, St. Louis, pp. 16-19. 1922 Epidemic Respiratory Disease. St. Louis: C:. V. Mosby Co. 402 pp. Phthisiogenesis and latent tuberculous infection. Am. Rev. Tuberc., 6: 525-46. Intracellular digestion; the enzymes and anti-enzymes concerned. Physiological Reviews, 2:552-85.

312 BIOGRAPHICAL MEMOIRS 1923 The relation of antigen to antibody (precipitin) in vitro. J. Im- munol., 8: 19-34. The relation of antigen to antibody (precipitin) in the circulating blood. J. Immunol., 8:~-74. 1924 Inflammatory reaction of the immune animal to antigen (Arthus phenomenon) and its relation to antibodies. l. Immunol., 9: 231-45. Desensitization to local action of antigen (Arthus phenomenon). l. Immunol., 9:247-53. Acute inflammation caused by antibody in an animal previously treated with antigen; the relation of antigen to antibody in the Arthus phenomenon. I. Immunol., 9:255-57. Pathogenesis of the specific inflammatory reaction of immunized animals (Arthus phenomenon); the relation of focal "sensitiza- tion" to immunity. l. Immunol., 9:259-68. The fate of antigen (protein) in an animal immunized against it. J. Exp. Med., 39:659-75. Widespread tuberculous infection of healthy individuals and its significance. Bulletin of the New York Tuberculosis Association, b:1-7. Pathological evidence of first infection in association with active pulmonary tuberculosis. Am. Rev. Tuberc., 10: 249-64. Active and latent tuberculosis in the Negro race. Am. Rev. Tuberc., 10:265-74. 1925 Antibodies and resistance in tuberculosis. Assoc., 21st Annual Meeting, pp. 362-71. Specific inflammatory reactions accompanying (London), pp. 1-7. Pathologic physiology of liver in relation to fection. J. Am. Med. Assoc., 85:1533-37. Trans. Natl. Tuberc. immunity. Tubercle intoxication and in- 1926 With F. Maurice McPhedran. The contagion of tuberculosis. Am. Rev. Tuberc., 14: 347-418.

EUGENE LINDSAY OPIE 313 With i. Furth. Anaphylactic shock caused by antibody in animals sensitized by antigen reversed passive anaphylaxis. J. Exp. Med., 43:469-82. With F. Maurice McPhedran. Spread of tuberculosis within families. I. Am. Med. Assoc., 87: 1549-51. 1927 Infection with tuberculosis in children and in adults, and the re- lation of one to the other. (Mary Scott Newbold Lecture) Transactions of the College of Physicians of Philadelphia, pp. 1-24. With J. D. Aronson. Tubercle bacilli in latent tuberculous lesions and in lung tissue without tuberculous lesions. Arch. Pathol. Lab. Med., 4: 1-21. With Joseph D. Aronson. Human and bovine tubercle bacilli in latent tuberculous lesions. Trans. Natl. Tuberc. Assoc., 23d Annual Meeting, pp. 265-67. Tuberculosis of lungs and bronchial lymph nodes. l. Am. Med. Assoc., 89:1293-96. Latent tuberculosis in children. Am. Rev. Tuberc., 16:468-78. Pathology of the tuberculosis of childhood and its bearing on clinical work. British Medical journal (Dec. 17), pp. 1-15. 1928 Experimental study of the leucemias and lymphomata. Medicine, 7:31-63. The pathologic anatomy of influenza, based chiefly on American and British sources. Arch. Pathol. Lab. Med., 5:285-303. Finding tuberculosis for the good of the public health. American journal of Roentgenology and Radium Therapy, 19:284-86. 1929 Epidemiology and control of tuberculosis. (Address of the President) Am. Rev. Tuberc., 20: 141~9. With H. R. M. Landis, F. Maurice McPhedran, and H. W. Hether- ington. Tuberculosis in public-school children. Am. Rev. Tuberc., 20:413-20. With H. W. Hetherington, F. Maurice McPhedran, and H. R. M. Landis. A survey to determine the prevalence of tuberculous infection in school children. Am. Rev. Tuberc., 20:421-510.

314 BIOGRAPHICAL MEMOIRS Inflammation and immunity. I- Immunol., 17:329-42. 1930 The pathogenesis and transmission of tuberculosis. (Harvey Lec- tures, 1928-1929) Am. J. Med. Sci., 179: 104-19. With E. i. Isaacs. Tuberculosis in Jamaica. Am. .T- Hyg., 12:1-61. The significance of advanced tuberculous infection of school chil- dren. i. Am. iMed. Assoc., 95: 1151-58. The epidemiology of tuberculosis of Negroes. Am. Rev. Tube~rc., 22:603-12. Anatomical characteristics of tuberculosis in Jamaica. Am. Rev. Tuberc., 22:613-25. 1931 With H. W. Hetherington, F. Maurice McPhedran, and H. R. M. Landis. Tuberculosis in medical and college students. Arch. Intern. Med., 48: 734-63. With H. W. Hetherington, F. Maurice McPhedran, and H. R. M. Landis. Tuberculosis in medical students. Transactions of the Association of American Physicians, 46:237-41. 1932 The epidemiology of tuberculosis in relation to the pathological anatomy and pathogenesis of the disease. Libman Anniversary Volumes, 3:901-15. New York: International Press. Cellular reactions of tuberculosis and their relation to immunity and sensitization. Arch. Pathol., 14:706-21. With F. Maurice McPhedran. Exogenous tuberculous infection of adults; marital tuberculosis. Arch. Intern. Med., 50:945-51. 1933 Recognition and control of tuberculosis of childhood. American Journal of Public Health, 23:305-15. With F. Maurice McPhedran. Clinical significance of latent pul- monary tuberculosis. Arch. Intern. Med., 52:137-46.

EUGENE LINDSAY OPIE 1934 315 With H. W. Hetherington, F. M. McPhedran, and H. R. M. Landis. A further study of tuberculosis in public-school children. Am. Rev. Tuberc., 29: 142-68. 1935 With H. W. Hetherington, F. M. McPhedran, and H. R. M. Landis. Further study of tuberculosis among medical and other univer- sity students; occurrence and development of lesions during the medical course. Arch. Intern. Med., 55:709-34. With F. M. McPhedran. The organization of an out-patient tuber- culosis clinic for epidemiological investigation. Am. J. Hyg., 22:539-64. With F. M. McPhedran. The spread of tuberculosis in families. Am. J. Hyg., 22:565-643. With F. M. McPhedran and Persis Putnam. The fate of persons in contact with tuberculosis; the exogenous infection of children and adults. Am. J. Hyg., 22:644-82. Present concepts of tuberculous infection and disease; their prin- ciples and application. Am. Rev. Tuberc., 32:617-30. William Henry Welch. I. Tech. Methods, 14:v-viii. 1936 - With F. M. McPhedran. The spread of tuberculosis in Negro families. Am. J. Hyg., 23:493-514. With F. M. McPhedran and Persis Putnam. The fate of Negro per- sons in contact with tuberculosis. Am. l. Hyg., 23:515-29. With F. M. McPhedran and Persis Putnam. The relative frequency of clinically manifest tuberculosis, open tuberculosis, asympto- matic lesions and deaths in white and Negro persons. Am. T. Hyg., 23:530-38. The significance of allergy in disease. Medicine, 15:489-509. 1937 With Jules Freund. An experimental study of protective inocula- tion with heat killed tubercle bacilli. I. Exp. Med., 66:761-88.

316 BIOGRAPHICAL MEMOIRS 1938 With Jules Freund. Sensitization and antibody formation with in- creased resistance to tuberculous infection induced by heat killed tubercle bacilli. l. Exp. Med., 68:273-98. 1939 With E. W. Flahiff and H. H. Smith. Protective inoculation against human tuberculosis with heat killed tubercle bacilli. Am. J. Hyg., 29: 155-64. Tuberculosis of first infection and of reinfection; their frequency in Chinese people of Peking. Chin. Med. J., 56: 197-215. Tuberculosis of first infection in adults from rural districts of China. Chin. Med. l., 56:216-44. The biology of the tubercle bacillus. Peking Natural History Bulletin (1939-1940), 14:1-3. 1941 With E. Joyce Saward and Persis Putnam. The spread of tubercu- losis in Negro families of Jamaica, B. W. I. Am. J. Hyg. Monogr. Ser.no.16,pp.1-53. With Persis Putnam and E. Joyce Saward. The fate of Negro persons of a tropical country, Jamaica, B. W. I., after contact with tuberculosis. Am. J. Hyg. Monogr. Ser. no. 16, pp. 57-95. The use of x-rays in the post-mortem examination of lungs with reference to tuberculosis. Symposium on the use of x-rays in pathologic investigation and in museum displays. J. Tech. Methods, 21: 1-4. 1942 With Samuel H. Picks. Proteolytic digestion of red and white blood corpuscles in the spleen. Am. I. Pathol., 18~2~:333-41. 1943 The experimental production of leukemia and its significance in relation to the human disease. Proceedings of the Institute of Medicine of Chicago, 14~13~: 382-92. With Eyup H. Canat. Inflammation in embryonic life. I. Changes produced by particulate matter and by a chemical agent. Am. l. Pathol., 19~3~: 371-83.

EUGENE LINDSAY OPIE 317 With Eyup H. Canat. Inflammation in embryonic life. II. Infection of chick embryos with avian tubercle bacilli. Am. I. Pathol., 19~3~:385-94. 1944 The influence of diet on the production of tumors of the liver by butter yellow. J. Exp. Med., 80~3~:219-30. The pathogenesis of tumors of the liver produced by butter yellow. J. Exp. Med., 80~3~:231~6. 1946 Mobilization of basophile substance (ribonucleic acid) in the cyto- plasm of liver cells with the production of tumors by butter yellow. J. Exp. Med., 84~1~:91-106. With G. I. Lavin. Localization of ribonucleic acid in the cytoplasm of liver cells. J. Exp. Med., 84~1~:107-12. Obituary. Simon Flexner, M.D. 1863-1946. Arch. Pathol., 42: 234~. 1947 The influence of diet on the production of hepatic tumors induced by p-dimethylaminobenzene. In: Approaches to Tumor Cherno- therapy' ed. by Forest Ray Moulton, pp. 128-38. AAAS Sym- posium Publication no. 26. Washington: American Association for the Advancement of Science. Normal structure and degenerative changes of the cytoplasm of liver cells and of tumor cells derived from them. i. Exp. Med., 85(4):339-46. Cytochondria of normal cells, of tumor cells, and of cells with various injuries. i. Exp. Med., 86~1~:45-54. 1948 An osmotic system within the cytoplasm of cells. l. Exp. Med., 87~5~:425~4. 1949 The movement of water in tissues removed from the body and its relation to movement of water during life. l. Exp. Med., 89~2~: 185-208.

318 BIOGRAPHICAL MEMOIRS The movement of water in tumor tissues removed from the body. J. Exp. Med., 89~2~:209-22. Osler as a pathologist. Bulletin of the History of Medicine, 23~4~: 321-26. 1950 The effect of injury by toxic agents upon osmotic pressure main- tained by cells of liver and of kidney. J. Exp. Med., 9 1 (3~: 285-94. With Mary B. Rothbard. The movement of water in interstitial tissue and in muscle removed from the body. Arch. Pathol., 50:800-812. 1951 Cancer. In: Nelson Loose-Leaf Medicine, pp. 161-82. New York: Thomas Nelson & Sons. 1953 With Mary B. Rothbard. Osmotic homeostasis maintained by mam- malian liver, kidney, and other tissues. T. Exp. Med., 97~4~: 483-97. With Mary B. Rothbard. Water exchange of collagenous tissues and of gelatin. i. Exp. Med., 97~4~: 499-503. 1954 Osmotic activity of liver cells and melting point of liver. J. Exp. Med., 99(1):29-41. Osmotic activity of tissues during fetal and post-natal growth. T. Exp. Med., 100(4):405-16. Osmotic activity in relation to the movement of water under normal and pathological conditions. (Harvey Lectures, Series I, 1954- 1955) New York: Academic Press, Inc. 1955 Pathogenesis, cellular pathology and the nomenclature of disease illustrated by the hepatic necrosis, lipidosis and cirrhosis that are caused by protein diet deficiency. (The Twenty-first Middle- ton Goldsmith Lecture) Bulletin of the New York Academy of Medicine, 31:279.

EUGENE LINDSAY OPIE 1956 319 Changes in the osmotic activity of liver and of kidney tissue caused by passage of sodium chloride, urea, and some other substances into cells. J. Exp. Med., 103~3~:351-62. Changes caused by injurious agents in the permeability of surviving cells of liver and of kidney. l. Exp. Med., 104~6~:897-919. 1957 The peripatetic education of a pathologist. In: The Medical Clinics of North America, pp. 935-~. Philadelphia: W. B. Saunders Co. Charles Russell Bardeen. In: Addresses Delivered in Honor of Charles R. Bardeen, pp. 6-17. Madison: Univ. of Wisconsin Press. 1958 Osmotic pressure of liver cells. In: Symposium on Liver Function, pp. 141-52. Publication no 4. Washington: American Institute of Biological Sciences. 1959 Isotonicity of liver and of kidney tissue in solutions of electrolytes. J. Exp. Med., 110~1~: 103-11. 1960 The relation of urea to the movement of water in liver tissue. Proc. Natl. Acad. Sci., 46~4~:477-83. With l. D. Broome. The movement of electrolytes and of water in surviving tissue of the liver. I. Exp. Med., 112~3~:491-98. 1961 The relation of oxygen supply to water movement and to urea for- mation in surviving liver tissue. l. Exp. Med., 113:339-~. The effect of varied oxygen supply and of food intake on water movement in surviving liver tissue. l. Exp. Med., 113: 353-57. 1962 On the relation of necrosis and inflammation to denaturation of proteins. l. Exp. Med., 115:597-608.

320 BIOGRAPHICAL MEMOIRS 1963 On the relation of inflammation to the chemical constitution of injurious agents. On the pharmacology of inflammation. J. Exp. Med., 117:425-48. 1964 Inflammation in serous cavities. Arch. Pathol., 78:1-10. 1965 The relation of inflammation to the molecular structure of carbon compounds soluble in the fluids of the body. l. Exp. Med., 121: 487-502. 1966 The normal and pathological movement of water in tissues and its relation to the colligative properties of solutions and to inflam- mation. Proc. Natl. Acad. Sci., 56:426-39. 1968 Relation of visual illusions to memory Diseases of the Nervous System, 29:552-56. 1970 The theory of retrojection of bile into the pancreas. Review of Surgery, 27:1-7. With Clara J. Lynch, M.D., and Marika Tershakovec. Sclerosis of the mesenteric arteries of rats. Its relation to longevity and inheritance. Arch. Pathol., 89:306-13. Adoption of standards of the best medical schools of Western Europe by those of the United States. Perspectives in Biology and Medicine, 13: 309-42.

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Biographic Memoirs Volume 47 contains the biographies of deceased members of the National Academy of Sciences and bibliographies of their published works. Each biographical essay was written by a member of the Academy familiar with the professional career of the deceased. For historical and bibliographical purposes, these volumes are worth returning to time and again.

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