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FRANCIS PEYTON ROUS Octo her 5, ~ 879-February ~ 6, 1970 BY RENATO DULBECCO PEYTON ROUS was awarded the Nobel Prize in 1966, when he was eighty-six years old, for discoveries he had made fifty years before. He was born on the 5th of October 1879 in Balti- more, Maryland, to a family that valued humanistic education. Thus, after the death of his father, when Peyton Rous was a child, his mother rejected the idea of joining her family in Texas and stayed in Baltimore, where excellent education for the children was available. Of the two sisters of Peyton Rous, one became a musicologist, the other a painter; and Peyton himself had a flair for writing. Peyton Rous enrolled in the Medical School of the recently created Johns Hopkins University, which he attended without special distinction. As an undergraduate he showed a naturalist's tendency and published articles about Baltimore's flowers. After graduating in medicine, he went to the University of Michigan, where he began his research career in pathology, which he perfected during a year in Dresden. In 1909 he joined the Rockefeller Institute under Simon Flexner, to engage in cancer research, against the opinion of influential friends who thought it was a hopeless field. There he remained until his death. In 1921 he became co-editor (and later editor) of the Journal for Experimental Medicine. In 1927 he was elected to the National Academy of Sciences. He died in 1970, at the age of ninety, and 275

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276 BIOGRAPHICAL MEMOIRS is survived by his wife, Marion, and three daughters, Marion, Ellen, and Phoebe. In addition to the Nobel Prize, Peyton Rous received many honors and honorary degrees, which are listed at the end of this memoir. The name of Peyton Rous became widely known to biolo- gists in the fifties and sixties for his earlier discovery of a virus causing sarcoma in chickens, which became aptly known as the Rous Sarcoma Virus. At the time he became famous, Peyton Rous appeared as an elderly, highly educated, gentleman with silvery hair. But in his youth he was a very hardworking scientist with a determined, fiery, and highly critical personality. He was a medical man who wished to learn about cancer as a disease and a biologist who did not want to follow the beaten track, and he was willing to hunt for new clues in well-designed but slow experiments. I, like most of my contemporaries, became acquainted with Peyton Rous's fundamental discovery in the early fifties, when Harry Rubin came to my lab to work with the Rous Sarcoma Virus. He started using a focus technique on the chorioallantoic membrane of the chicken embryo, which Rous had invented many years before. Later I had occasion to meet Peyton Rous several times on the platform as a speaker, or across the discus- sion table, or in his laboratory at the (then) Rockefeller Institute. I remember the manrather small in stature with silvery hair and penetrating eyes. I also remember that before our first meet- ing I was inclined to think of him as a figure of the past, but soon changed my mind at that meeting and even more so at subsequent ones. Clearly, he was very much alive until his very last days, with a keen interest in new developments in virology and cancer research. He was able to discuss his past work with equanimity and to accept new interpretations of his data. I re- member I suggested to him an explanation of the clonal charac- teristic of the neoplastic transformation of papillomas in terms

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FRANCIS PEYTON ROUS 277 of somatic cell genetics, a concept that was not part of cancer research in the period of his active work. His interest was im- mediately aroused; he asked me for a thorough clarification of what I meant and then argued, with passion but no animosity. ... ~ ... .. ~ . . . . - rim ~ we parted Able old friends who have found something new to talk about. 4- -' At the time when phage lysogeny was the domain of a very small group of virolo~ists. I suggested to him that it . . might represent a good model for some features of viral cancer. Again his interest was acute, and I had to embark on a detailed discussion of phage integration, immunity, and lysogenic con- version. Peyton Rous discovered the viral etiology of a chicken sar- coma in 1911 through his interest in tumor tr~n~nl~nt~hilirv to 1 , ~ - ~ YE new nosts oy a nitrate. He commented: "The behaviour of the new growth has been throughout that of a true neoplasm, for which reason the fact of its transmission by means of a cell-free filtrate assumes exceptional importance" (191 1~. He fully realized from the outset that this was "a unique and significant finding" (1911~. He also realized that the signifi- cance of the discovery depended on the true nature of the induced growth. As an experienced pathologist he could see that it was a true cancer: "The (pathological) picture (of the growth) does not in the least suggest a granuloma . . . it exhibits to a special degree, not merely a few, but all those features by which the malignant neoplasms are characterized" (191 1~. For about forty years this momentous discovery had little impact, because the minds of scientists were not prepared to think of viruses as agents of cancer. It was expedient to say that the chicken tumor was not a cancer, but some kind of reaction to the virus more akin to inflammation than neoplasia, and perhaps a peculiarity of chicken biology. Peyton Rous soon recognized himself that the tumor would not be accepted as a cancer because it was transmitted by a cell-free extract: "A passing reference should perhaps be made to the ill-defined

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278 BIOGRAPHICAL MEMOIRS group of pathological products called granulomata, with which this neoplasm of the fowl may by some be classed, owing to its transmission by an agent separable from the tissue cells" (191 1~. Many years later he wrote, "This disclosure (that certain chicken tumors were proved due to viruses), which conflicted with the negative findings in mammalian growths, was determined forth- with as erroneous" (1952~. One wonders how firmly in the early years Peyton Rous himself was convinced that he had demonstrated the induction of a cancer by viruses. The statements he made at the time are very cautious and full of qualifications. At first he used to refer to the "agent" that induced the sarcoma; but a year later, after he discovered a new, different tumor transmissible by filtrate, he proposed that the "agent is probably a living virus" (1912~. During the years 1911-1914, Peyton Rous worked hard at disproving the objections on the nature of the induced tumors by isolating other viruses that induced tumors in chickens and by carefully studying their pathology. He could show that the tumors induced by the different viruses were capable of invad- ing neighboring tissues and of metastasizing to distant organs; thus they were true cancers. Moreover, each independently isolated virus caused a tumor of a different kind. These facts should have been convincing evidence that the growths were specific responses of the host, yet this conclusion was not gener- ally accepted. However, these discoveries seem to have been convincing for Rous, who wrote, "The findings with the chicken tumors largely demolish the theoretical basis in which objec- tions to an extrinsic cause for cancer have been built up" (1912~. In order to find more generally acceptable evidence, Peyton Rous attempted to extend his observations "especially through carefully devised experiments with the tumors of other species of animals" (1911~. Evidently for the viral etiology to be ac- cepted, similar findings were needed in mammals. The strategy of Rous's future work was determined at that time. However,

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FRAN CIS PEYTON ROUS 279 the extension to other species came only many years later with Richard Shope's discovery of the rabbit papilloma virus. In the meantime Peyton Rous studied many features of the cell-free transmission of the tumor. Examining the effect of the age of the host, he showed that the virus induces characteristic foci on the chorioallantoic membrane of the chicken embryo. This result supplied an assay for the virus that was universally employed until the fifties, when it was superseded by the focus formation in tissue culture. In this extensive and careful work, Peyton Rous observed the host resistance to the transmission of the tumor, in the form of either absence of growth, slow growth, or normal growth followed by regression. Other experiments showed how essen- tial the conditions of the host are for the development of a tumor after inoculation of the virus. From this observation Peyton Rous began to recognize the existence of limitations to the expression of the oncogenic potential of the virus: "How does it happen that the sarcoma, though ultimately dependent on an extrinsic agent, is dominated in its behaviour by the cells composing it?" (1912~. Perhaps the agent depends "on a special set of conditions in order that it might produce a neoplastic change" ( 1912~. He returned later to this Point on several occasions. . . , After discovering the second chicken tumor agent, Peyton Rous started wondering about the etiology of cancer in general: "The demonstration that extrinsic agents are the cause of two connective-tissue growths of the fowl which are characteristic malignant tumors renders it necessary to suppose either that such tumors of the fowl have an entirely different etiology from mammalian tumors, or else that the latter are of similar origin" (1912~. This point was also developed to a much greater extent later on. As further evidence for a viral nature of the chicken tumors, the resistance of the host to the tumor cells could be separated

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280 BIOGRAPHICAL MEMOIRS from its resistance to the tumor-inducing agent. Moreover, Rous discovered a third chicken tumor, transmissible by filtrate, markedly different in properties from the two previously de- scribed: "The findings with the three tumor-producing agents have a striking similarity and it is difficult to avoid the con- clusion that the three are of one class, whatever that class may be.... It is perhaps not too much to say that their recognition points to the existence of a new group of entities which cause in chickens neoplasms of diverse characters" (1914~. At the beginning of World War I, Peyton Rous, under the pressure of wartime medical needs, gave up his work with chicken tumor viruses. For the following twenty years until 1934, his interest was in the fields of blood transfusion and attending immune reactions, liver and biliary functions, cellu- lar functions, and vascular permeability. I will return to these . . activities ater on. A turning point in Peyton Rous's work on cancer was the discovery of the Shope papilloma. In 1933 Richard Shope re- ported his discovery that a mammalian tumor, the papilloma of cottontail rabbits, was transmitted by a virus-like agent. As in the case of the chicken tumor, Peyton Rous's first concern was whether the papilloma was a true neoplasm. He decided that it was, because, when the papillomas were transplanted deep in- side the body, they developed into carcinomas that grew inva- sively and killed the host. Furthermore, in domestic rabbits the virus-induced papillomas often grew progressively, invading the neighboring tissues and producing metastases, and this malig- nant evolution could be enhanced by exposing the papillomas to various substances, such as Scarlet Red. These findings seem to have been for Rous the decisive argument for the validity of his conclusions concerning the chicken tumors, since in a mammal cancer could also be trans- mitted by a virus. He, therefore, returned to the study of car- cinogenesis using the papilloma virus as a new tool. He focused

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FRANCIS PEYTON ROUS 281 at first on the malignant evolution of the papillomas. By careful observations, following small hints, such as the shape of their growths, color, or the degree of pigmentation, he showed that a few cells in a papilloma became cancerous and generated clones, each with different characteristics. In trying to understand how such evolution to cancer occurs, Peyton Rous studied the effects of tar, as both a carcinogen and tumor promoter. He found that tar not only strongly enhanced the induction of papillomas or carcinomas by the Shope virus in domestic rabbits but by itself elicited similar papillomas. Could tar papillomas also be virus-induced? This new phase of Peyton Rous's work, although a natural development of his earlier work, had more ambitious goals, for it aimed at testing the hypothesis that "this disease (cancer) is an infection.... A main attraction of this hypothesis is its accessibility to test." However, he clearly saw that this hypothe- sis could only be true under certain conditions, one of which is that "a living entity responsible for such growths must require for effectiveness a very special basis of predisposition" (1932~. He sought to possibly disprove the infectious nature of cancer by comparing the frequency of cancer induction by tar in the skin of two groups of mice with different exposure to- the envi- ronment: "The animals of one group have been placed under conditions which would facilitate the entrance into the body of extraneous living agents, whereas those of the others have been sedulously protected" (1932~. The results proved "that the mouse cancer cannot be caused by living entities reaching the body from the surrounding world during adult life" but "fail to exclude the possible activity of entities residing habitually in or upon the body" (1932~. This experiment showed another re- quirement of the hypothesis on the infectious nature of cancer: "The supposition (that tumors in general are due to viruses or other extraneous entities) is tenable only if such entities are widely distributed throughout the animal population, being

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282 BIOGRAPHICAL MEMOIRS constantly present in or upon the body, like the colon bacillus or the staphylococcus; and if their opportunity to cause tumors is restricted by the need for very special conditions.... The more considerable an agent is conditioned in its activity, the more often must it be present if it is to cause disease at all" (1934~. These words were prophetic, as shown by the recent developments in the field; yet they were simply the result of cool, logical assessment of the facts then in hand. However, for Peyton Rous this hypothesis was only a guide for the experiment: "The demonstration of the cause for the generality of tumors, what- ever this is, waits upon the provision by the investigator of the conditions necessary to its effectiveness" (1934~. He tried several new approaches. One of the major tools was still the technique of inducing skin tumors by application of tar. He used it to create favorable cellular conditions for reveal- ing the neoplastic potential of viral agents. Another tool was the immunity of the infected rabbits against the Shope virus. Peyton Rous found no demonstrable antibodies in rabbits with- out papillomas or in those with tar papillomas or Brown-Pierce tumors: these findings "speak decisively against the possibility that these growths are caused by viruses antigenically related to the one causing papillomas. Yet this does not exclude a virus causation for them, since the sera of fowls with Chicken Tumor I and Fujinami Sarcoma respectively, though possessed of neu- tralizing power for the virus causing the growth carried by the host, have no cross-neutralizing effect whatsoever" (1936~. Shortly afterwards, in taking a bird's eye view of his past work and of the cancer problem, he concluded: "How far should one be led by the assumption that certain tumors may be due to viruses? Only so far as to make tests with these growths. The tumor problem has withstood the most corrosive reasoning. Yet since what one thinks determines what one does in cancer research, as in all else, it is as well to think something. And it may prove worthwhile to think that one or more tumors of

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FRAN CIS PEYTON ROUS 283 unknown causes are due to viruses" (1936~. He thus recognized that the problem that he so clearly formulated and actively pursued eluded experimental attack and remained unsolved. In fact he later restated the basic question: "What is the papilloma doing in the cancer, if anything?" (1940~. In a renewed effort to answer this question, Peyton Rous used as a new tool the famous line of transplantable rabbit cancers, derived from a viral papilloma called at first "carcin- oma V2" (1940), and then, after World War II, V X 2 because during the war V2 "came to have another significance" (1952~. This line did not contain infectious papilloma virus, but for many serial transfers in rabbit it continued to elicit the produc- tion of virus-specific antibody. The result suggested that the virus may play a determining role although in "masked or altered form" (1940~. This was a new idea in virology, which had enormous developments many years later. For the next three years, during serial transplanta- tion from one rabbit to another, the V X 2 carcinoma continued to elicit this immune response. However, when it was retested after an interval of one and a half years, four and a half years after its origin, the tumor was found unable to immunize against the papilloma virus; the loss of this property "was not attended by any perceptible change in the V X 2 carcinoma" (1952~. This "wholly unexpected" result must have been quite shattering; and Peyton Rous was led to rethink the role of the virus in the production of the cancer. In this agonizing re- appraisal he proposed that the virus might have undergone "wider variation" (1952~; but he recognized that "at this un- certain point the problem of the cause for the V X 2 carcinoma must perforce be left" (1952~. In this way the work of Peyton Rous went full circle: from complete ignorance on the role of viruses in cancer to definitely establishing such a role through brilliant discoveries, to postulating a wider and possibly general role of viruses in spontaneous cancers, and ending up again in

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284 BIOGRAPHICAL MEMOIRS a condition of uncertainty. I should not say full circle, but rather one turn of the helix, because the uncertainty was now of a different kind. The emphasis of Peyton Rous's work in the forties and fifties shifted from the viruses to chemical carcinogens. Many articles were dedicated to the potentiating effect of tar and other car- cinogens on virus-induced papillomas. During this work it also became clear that tar alone induces papillomas very similar to those induced by the virus on normal skin or on skin pretreated by tar. In all cases the growth showed progression, i.e., remained benign for some time and then developed into carcinomas, which arose in a few isolated cells. However, many observations also showed that the role of the virus and of the chemicals was different: "The generality of the carcinogens bring about tissue conditions out of which tumors may or may not arise for reasons still undetermined. They may' tee fitly called provocative car- cinogens. The viruses, on the other hand, both initiate tumors and determine their character and behaviour. They are actuat- ing carcinogens" (1943~. In a new series of experiments, Peyton Rous convincingly demonstrated that the viral and the chemical agents have a cooperative action, producing in combination cancers at much higher frequency and after shorter time than either agent alone. On the basis of this cooperation, Peyton Rous made three important suggestions. One bears on the mechanism of carcino- genesis. He proposed that in utero or at a young age the human or animal body becomes invaded by viruses that "would give no sign of their presence in most instances.... But if a provoca- tive carcinogen happened to work on the cells with which such a virus was associated . . . it might undergo variation and . . . give rise to a tumor. The new pathogenic variant would not be transmitted to other animals . . . but would be a dead-end virus, though the harmless source virus liable to the same or other variation would be passed on" (1943~. This hypothesis is very

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FRAN CIS PEYTON ROUS 297 The effects of operation, exercise, hot weather, relief of obstruc- tion, intercurrent disease, and other normal pathological influ- ences. J. Exp. Med., 37: 395-420. With G. O. Broun and P. D. McMaster. Studies on the total bile. II. The relation of carbohydrates to the output of bile pigment. l. Exp. Med., 37:421-29. With P. D. McMaster and G. O. Broun. Studies on the total bile. III. On the bile changes caused by a pressure obstacle to secretion; and on hydrohepatosis. i. Exp. Med., 37:685-98. With G. O. Broun and P. D. McMaster. Studies on the total bile. IV. The enterohepatic circulation of bile pigment. I. Exp. Med., 37: 699-710. With P. D. McMaster and D. R. Drury. The genesis of gall stones in the dog. Proc. Soc. Exp. Biol. Med., 20:315-18. With G. O. Broun and P. D. McMaster. Studies on the total bile. V. The relation between blood destruction and output of bile pig- ment. l. Exp. Med., 37:733-57. 1924 With P. D. McMaster and D. R. Drury. Observations on some causes of gall stone formation. I. Experimental cholelithiasis in the absence of stasis, infection, and gall bladder influences. l. Exp. Med., 39:77-96. With I). R. Drury and P. D. McMaster. Observations on some causes of gall stone formation. II. On certain special nuclei of deposi- tion in experimental cholelithiasis. l. Exp. Med., 39:97-116. With D. R. Drury and P. D. McMaster. Observations on some causes of gall stone formation. III. The relation of the reaction of the bile to experimental cholelithiasis. l. Exp. Med., 39:403~5. With P. D. McMaster. The liver requirement of the fasting or- ganism. J. Exp. Med., 39:425-45. The relative reaction of living mammalian tissues. Science, 60:363. 1925 The relative reaction within living mammalian tissues. I. General features of vital staining with litmus. l. Exp. Med., 41:379-97. The relative reaction within living mammalian tissues. II. On the mobilization of acid material within cells, and the reaction as influenced by the cell state. l. Exp. Med., 41 :399-411.

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298 BIOGRAPHICAL MEMOIRS The relative reaction within living mammalian tissues. IlI. Indi- cated differences in the reaction of the blood and tissues on vital staining with phthaleins. T. Exp. Med., 41 :451-70. With D. R. Drury. jaundice as art expression of the physiological wastage of corpuscles. l. Exp. Med., 4 1: 60 1-9. With D. R. Drury. Suppression of bile as a result of impairment of liver function. J. Exp. Med., 41:611-22. The relative reaction within living mammalian tissues. IV. Indi- cated differences in the reaction of the organs on vital staining with phthaleins. l. Exp. Med., 41:739-59. With D. R. Drury. Outlying acidosis. i. Am. Med. Assoc., 85:33-35. The biliary aspects of liver disease. Am. l. Med. Sci., 170:625. 1926 With D. R. Drury. The relative reaction within living mammalian tissues. V. (a) Influence of lymph-soluble tissue materials on the significance of the coloration with some phthalein indicators. V. (b) Influence of lymph-insoluble tissue materials on the signifi- cance of the coloration with some phthalein indicators. J. Exp. Med., 43:669-86, 687-701. The relative reaction within living mammalian tissues. VI. Factors determining the reaction of skin grafts; a study of the indicator method of conditions within an ischemic tissue. l. Exp. Med., 44:815-34. With W. W. Beattie. The relative reaction within living mammalian tissues. VII. The influence of changes in the reaction of the blood upon the reaction of the tissues. l. Exp. Med., 44:835-54. 1927 With D. R. Drury and W. W. Beattie. The relative reaction within living mammalian tissues. VIII. On the course of the tissue aci- dosis secondary to blood acidosis induced with hydrochloric acid. l. Exp. Med., 45:23-39. With D. R. Drury and W. W. Beattie. The relative reaction within living mammalian tissues. IX. On the tissue reaction as influ- enced by inhalations of CO2 and by overbreathing. J. Exp. Med., 45:41-58. Pathology and the glare of the future. Reprinted from Contributions to Medical Science (Dedicated to Aldred Scott Warthin), ed. by Willard J. Stone, pp. 19-22. Ann Arbor, Mich.: George Wahr.

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FRANCIS PEYTON ROUS 1929 299 With D. R. Drury. Outlying acidosis due to functional ischemia. l. Exp. Med., 49:435-60. The Modern Dance of Death. (The Linacre Lecture) London: Cambridge Univ. Press. 51 pp. With H. P. Gilding. The meaning of Bier's spots. Proc. Soc. Exp. Biol. Med., 26:497-98. With H. P. Gilding. Studies of tissue maintenance. I. The changes with diminished blood bulk. J. Exp. Med., 50:189-211. With H. P. Gilding. Studies of tissue maintenance. III. Persisting bloodlessness after functional ischemia. l. Exp. Med., 50:471-87. With H. P. Gilding. The final response of the small cutaneous ves- sels. l. Exp. Med., 50:489-512. 1930 With H. P. Gilding. Is the local vasodilatation after different tissue injuries referable to a single cause? J. Exp. Med., 51:27-39~. With H P. Gilding and F. Smith. The gradient of vascular perme- ability. J. Exp. Med., 51: 807-30. 1931 With F. Smith. The gradient of vascular permeability. II. The con- ditions in frog and chicken muscle, and in the mammalian dia- phragm. J. Exp. Med., 53:195-217. With F. Smith. The gradient of vascular permeability. III. The gradient along the capillaries and venules of frog skin. l. Exp. Med., 53:219-42. With F. Smith. The gradient of vascular permeability. IV. The per- meability of the cutaneous venules and its functional significance. J. Exp. Med., 54:499 514. 1932 With P. D. McMaster and S. S. Hudack. The relation of hydrostatic pressure to the gradient of capillary permeability. l. Exp. Med., 55:203-21. With E. Botsford. The incidence of cancer in tarred and sheltered mice. J. Exp. Med., 55:247-66.

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300 BIOGRAPHICAL MEMOIRS 1933 With P. D. McMaster and S. S. Hudack. The fixation of certain viruses on the cells of susceptible animals and the protection afforded by such cells. Proc. Soc. Exp. Biol. Med., 31:90-91. 1934 Withy. W. Beard. The neoplastic traits of a mammalian growth due to a filterable virus the Shope rabbit papilloma. Science, 79: 437-38. With i. W. Beard. Selection with the magnet and cultivation of reticuloendothelial cells (Kupffer cells). J. Exp. Med., 59:577-91. With i. W. Beard. The characters of Kupffer cells living in vitro. J. Exp. Med., 59~:593-607. With l. W. Beard. A virus-induced mammalian growth with the characters of a tumor (the Shope rabbit papilloma). I. The growth on implantation within favorable hosts. l. Exp. Med., 60:701-22. With I. W. Beard. A virus-induced mammalian growth with the characters of a tumor (the Shope rabbit papilloma). II. Experi- mental alterations of the growth on the skin: morphological considerations: the phenomena of retrogression. J. Exp. Med., 60:723-37. With i. W. Beard. A virus-induced mammalian growth with the characters of a tumor (the Shope rabbit papilloma). III. Further characters of the growth: general discussion. l. Exp. Med., 60: 741-66. 1935 With l. W. Beard. Carcinomatous changes in virus-induced papillo- mas of the skin of the rabbit. Proc. Soc. Exp. Biol. Med., 32: 578-80. With P. D. McMaster and S. S. Hudack. The fixation and protection of viruses by the cells of susceptible animals. i. Exp. Med., 61: 657-88. With i. W. Beard. The progression to carcinoma of virus-induced rabbit papillomas (Shope). J. Exp. Med., 62:523~8. With l. W. Beard. Effectiveness of the Shope papilloma virus in vari- ous American rabbits. Proc. Soc. Exp. Biol. Med., 33:191-93. -

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FRANCIS PEYTON ROUS 301 With John G. Kidd and l. W. Beard. Certain factors determining the course of virus-induced tumors. Proc. Soc. Exp. Biol. Med., 33: 193-95. With J. W. Beard. A comparison of the tar tumors of rabbits and the virus-induced tumors. Proc. Soc. Exp. Biol. Med., 33:358-60. 1936 With l. G. Kidd. The carcinogenic effect of a virus upon tarred skin. Science, 83:468-69. With l. G. Kidd and l. W. Beard. Serological reactions with a virus causing rabbit papillomas which become cancerous. I. Tests of the blood of animals carrying the papilloma. l. Exp. Med., 64: 63-77. Aldred Scott Warthin. In: Dictionary of American Biography, vol. 19, pp. 493-94. New York: Charles Scribner & Sons. With l. G. Kidd and i. W. Beard. Serological reactions with a virus causing rabbit papillomas which become cancerous. II. Tests of the blood of animals carrying various epithelial tumors. J. Exp. Med., 64:79-96. With J. G. Kidd and l. W. Beard. Observations on the relation of the virus causing rabbit papillomas to the cancers deriving therefrom. I. The influence of the host species and of the pathogenic activity and concentration of the virus. J. Exp. Med., 64:385-400. With l. W. Beard and I. G. Kidd. Observations on the relation of the virus causing rabbit papillomas to the cancers deriving therefrom. II. The evidence provided by the tumors; general considerations. J. Exp. Med., 64:401-24. The virus tumors and the tumor problem. (Harvey Lecture) Ameri- can Journal of Cancer, 28:233-71. 1937 With J. G. Kidd. Effect of the papilloma virus (Shope) upon the tar warts of rabbits. Proc. Soc. Exp. Biol. Med., 37: ~ 18-20. 1938 With l. G. Kidd. The carcinogenic effect of a papilloma virus on the tarred skin of rabbits. I. Description of the phenomenon. l. Exp. Med., 67:399~28.

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302 BIOGRAPHICAL MEMOIRS With l. W. Beard. The fate of vaccinia virus on cultivation in vitro with Kupffer cells (reticulo-endothelial cells). J. Exp. Med., 67: 883-910. With l. G. Kidd. The carcinogenic effect of a papilloma virus on the tarred skin of rabbits. II. Major factors determining the phenomenon; the manifold effects of tarring. l. Exp. Med., 68: 529-61. 1939 With l. G. Kidd. A comparison of virus-induced rabbit tumors with the tumors of unknown cause elicited by tarring. i. Exp. Med., 69: 399-424. 1940 With J. G. Kidd. Cancers deriving from the virus papillomas of wild rabbits under natural conditions. l. Exp. Med., 71:469-93. With i. G. Kidd. The activating, transforming, and carcinogenic effects of the rabbit papilloma virus (Shope) upon implanted tar tumors. l. Exp. Med., 7 1: 787-8 1 1 . With J. G. Kidd. A transplantable rabbit carcinoma originating in a virus-induced papilloma and containing the virus in masked or altered form. l. Exp. Med., 71 :813-37. 1941 With J. G. Kidd. Conditional neoplasms and subthreshold neo- plastic states. A study of the tar tumors of rabbits. J. Exp. Med., 73:365-89. With Ian MacKenzie. The experimental disclosure of latent neo- plastic changes in tarred skin. J. Exp. Med., 73:391~15. The conditions determining cancer. (The William Henry Welch Lecture, I) J. Mt. Sinai Hosp., 8:184 - 85. The known causes of cancer. (The William Henry Welch Lecture, II) J. Mt. Sinai Hosp., 8: 186. With W. F. Friedewald. The carginogenic effect of methylcholan threne and of tar on rabbit papillomas due to a virus. Science 94:495-96.

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FRAN CIS PEYTON ROUS 1943 303 Viruses and tumors. In: Virus Diseases, p. 147. Ithaca, N.Y.: Cornell Univ. Press. The nearer causes of cancer. i. Am. Med. Assoc., 122:573-84. 1944 With W. F. Friedewald. The effect of chemical carcinogens on virus- inducedrabbit papillomas. l. Exp. Med., 79:511-37. With W. F. Friedewald. The initiating and promoting elements in tumor production. An analysis of the effects of tar, benzpyrene, and methylcholanthrene on rabbit skin. J. Exp. Med., 80: 101-25. With W. F. Friedewald. The determining influence of tar, benzpy- rene, and methylcholanthrene on the character of the benign tumors induced therewith in rabbit skin. l. Exp. Med., 80: 127~4. lg45 With W. E. Smith. The neoplastic potentialities of mouse embryo tissues. I. The findings with skin of C strain embryos transplanted to adult animals. l. Exp. Med., 81:597-619. The neoplastic potentialities of mouse embryo tissues. II. Contribu- tory experiments; results with skin of C3H and Webster-Swiss embryos; general considerations. J. Exp. Med., 81:621~5. 1946 The activation of skin grafts. l. Exp. Med., 83:383-99. Concerning the cancer problem. American Scientist, 34 (July>:329. Simon Flexner and the Journal of Experimental Medicine. J. Exp. Med., 84(1):i. 1947 Recent advances in cancer research. Bulletin of the New York Academy of Medicine, 23:65-78. The lamentable decline in self-satisfaction. Proceedings of the Cha- raka Club, 11 :7. Karl Landsteiner, 1868-1943. Obit. Not. Fell. R. Soc. Lond., 5:295- 312.

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