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"'D ~ .•,1: FRANK A. HOWARD Chairman Research Consultant, Standard Oil Company (N.J.) EUGENE W. KETTERING Vice Chairman President, Charles F. Kettering Foundation FRANK L. HORSFALL, JR., M.D. President, Sloan-Kettering Institute for Cancer Research EDWARD C. DELAFIELD Secretary Senior Partner, Delafield & Delafield ELLMORE C. PATTERSON Treasurer Senior Vice President, Morgan Guaranty Trust Co. of New York ROGER ADAMS, Ph.D. Research Pro f essor, Department o f Chemistry and Chemical Engineering MARION W. BOYER Vice President and Director, Standard Oil Company (N.J.) DETLEV W. BRONK, Ph.D. President, The Rockefeller Institute REGINALD G. COOMBE Consultant to Laurance S. Rockefeller, Rockefeller Brothers Fund JOSEPH C. HINSEY, Ph.D. Director, The New York Hospital- Cornell 117edical Center B. BREWSTER JENNINGS Chairman, Board of Managers, 1I7em orial Hospital f or Cancer and Allied Diseases DEANE W. MALOTT President, Cornell University W. ALBERT NOYES, JR., Ph.D. Chairman, Department of Chemistry University of Rochester LAURANCE S. ROCKEFELLER Rockefeller Brothers, Inc. ALFRED P. SLOAN, JR. Honorary Chairman of the Board, General Motors Corporation ROBERT M. STECHER, M.D. Director, Artluitis Clinic, Cleveland Metropolitan General Hospital LEWIS L. STRAUSS Former Secretary, United States Department of Commerce ROBERT E. STRAWBRIDGE, JR. Director, Strawbridge & Clothier WARREN WEAVER, Ph.D. Vice President, Alfred P. Sloan Foundation THEODORE P. WRIGHT, D.Sc. Chairman of the Boards of Directors, Cornell Aeronautical Laboratory and Cornell Research Foundation H. LAWRENCE HESS Assistant Secretary LEON W. ZUCKER Assistant Treasurer HARRISON V. SMITH Assistant Trecisurer 01134384

3 ('. V rV " 1- e\ -. 1~~, 1 . 3 G 1. 1 3 7 fT J 1 - ~ '-J' .• ~ . . . ~w . • ` . .. ._ . .. • .. - RO.11:I) OI ~: ;T I1~IC: CC)'\'M "l,"I' PEYTON Rous, M.D. Chairman Member Emeritus, The Rockefeller Institute RICHARD T. ARNOLD, Ph.D. President, Mead Johnson Research Center WILLIAM F. BALE, Ph.D. Professor, Radiation Biology fltomic Energy Project University of Rochester School of Medicine and Dentistry STANLEY E. BRADLEY, M.D. Bard Professor and Chairman, Department of 161edicine Columbia University College of Physicians and Surgeons SEYMOUR S. COHEN, Ph.D. Professor of Biochemistry, University of Pennsylvania School of Medicine WARREN H. COLE, M.D. Professor and I-lead, Department of Surgery University of Illinois College of Illedicine JOHN E. DEITRICK, M.D. Dean, Cornell University Medical College HARRY EAGLE, M.D. Professor and Chairman, Department of Cell Biology Albert Einstein College of Medicine Yeshiva Universit y IRVING M. LONDON, M.D. Professor and Chair•man, Department of Medicine Albert Einstein College of Medicine Yeshiva University RICHARD E. SHOPE, M.D. Professor and 1lleTnber, The Rockefeller Institute HOWARD E. SKIPPER, Ph.D. Assistant Director, Southern Research Institute CHANDLER A. STETSON, JR., M.D. Professor and Chairman. Department of Pathology New York University School of Medicine L' DWARD L. TATUAI, Ph.D. Professor and Member, The Rockefeller Institute J. WALTER WILSON, Ph.D. Frank L. Day Professor of Biology, Brown University ~ 01134385

FRAN K L. HORSFALL, JR., M.D. President and Director LEO WADE, M.D. HENRY T. RANDALL, M.D. Pice President f or Vice President f or Jdministration Clinical Affairs FREDERIC W. NORDSIEK, Ph.D. Chief of Grants and Fellowships BERNARD J. PALL\IBO Fiscal O fficer HENRY E. NIELENEY, JR. .4dntiuistrator VINCENT N. UMLAND fl dministrator Walker Laboratory C. CHESTER STOCK, Ph.D. Vice President for Research Director, Walker Laboratory BERNHARD L. MECKE Vice President f or Business tlffairs JAIIES B. KETCHAM Personnel O f}~ecer ROBERT A. FLECK Jssistant Personnel O f}'icer H. PEYTON MORRIS. JR. Personnel OJficer Walker Laboratory 01134386

6 Since the Sloan-Kettering Institute was founded in i q¢s, it has had one goal--more effective control of cancer in man through cure and eventual prevention. To accomplish this objective, the current research program at the Institute encompasses seven major fields of investigation-chemotherapy, clinical investigation, immunity and virology, chemistry, biophysics, preventive medicine, and pathology. This report is a review of the history of, as well as the work now in progress on, the role viruses may play in cancer. The studies in this area, to some degree, involve many fields of investigation at the Institute. Knowledge is being gathered that is not only vital for potential application in the control of cancer and other related diseases, but which also, may be of great importance in understanding more fully the differences between the living and the non-living-questions man has pondered for centuries. The relation of the findings in this area to those that are already known to play a role in the origin of cancer requires intensive study. It is possible that further progress in viral investigations could en- hance the beneficial effects of chemotherapy and radiation therapy as well as lead to the development of useful procedures for pre- vention. To meet the increasing demands upon its research program, re- lieve the serious overcrowding of its present laboratory facilities and to consolidate related activities, construction of the new research laboratory building on East 68th Street is already underway. This t z-story structure is expected to be in full operation early in i q64. It will provide an additional 8~,ooo square feet of urgently needed laboratory space to meet the requirements of the Institute's broadened research program. The new laboratory building will be directly con- nected with Memorial Sloan-Kettering Cancer Center and the New York Hospital-Cornell Medical Center through tunnels under the streets. 01134387

7 Two new members have been appointed to the Board of Scientific Consultants. They are Dr. Stanley E. Bradley, Chairman, Depart- ment of Medicine, Columbia University College of Physicians and Surgeons, and Dr. Harry Eagle, Professor and Chairman, Depart- ment of Cell Biology, Albert Einstein College of Medicine. Mr. Marion W. Boyer, a vice president and director of Standard Oil Company (New Jersey), was named to the Board of Trustees to fill the vacancy left by the resignation of IDr. Albert Bradley. The Sloan-Kettering Institute's budget for the current year (1962) totals more than $9 million. Among the major sources of support are the National Cancer Institute of the United States Public Health Service, the American Cancer Society, the United States Atomic Energy Commission and the Alfred P. Sloan Foundation. Other sources of major support include the Commonwealth Fund, the Max C. Fleischmann Foundation of Nevada, the Lillia Babbitt Hyde Foundation, the Charles F. Kettering Foundation, the Charles E. Merrill Trust, the Damon Runyon Memorial Fund for Cancer Research, the Andre and Bella Meyer Foundation, the Elsa U. Pardee Foundation, the Fannie E. Rippel Foundation and the Stranahan Foundation. In addition, a large amount of essential support comes from more than two thousand interested individuals and corporations whose contributions range from one dollar to much larger sums. Many of these gifts are presented in memory of friends and loved ones in the hope that others will be spared through the fruits of continuing research. 01134388

Just ioo years ago 7.ouis Pasteur delivered at the Sorbonne his famous lecture on spontaneous generation and so, in the eyes of many medical historians, modern biology came into being, with modern medicine following close behind. Since earliest days, man had paused to ponder from time to time the nature of the difference between the living and the non-living. Aristotle believed simple living things, such as worms, beetles, lice, frogs and salamanders, could originate spontaneously in slime or mud or the morning dew. "Nature proceeds little by little from things lifeless to animal life in such a way that it is impossible to determine the exact line of demarcation nor on which side thereof an inter- mediate form should lie," he concluded, and for centuries thereafter spontaneous generation was considered a normal mode of production of a large number of living things. Paracelsus, van Helmont and other famous physicians reported personal observations on the genesis of frogs and mice and other living creatures from inert raw materials. Such findings failed to surprise a public that was well accustomed to the notion that rodents came from grain, snakes from a woman's hair dropped in rainwater, and plant lice from a dewdrop. Francesco Redi of Tuscany was the first to challenge spontaneous generation by experimental methods. Maggots, he showed, are not 01134389)

9 ,).. ~..J :-l .1 - .... . .., . .. "ei , .''3 J! ! , J f _ . ''; ° ,:~:`4 C ..: .. __ =Y1.: .. formed in decaying meat unless flies have access to the meat and lay their eggs in it. Opposition to Redi soon gained support from an unexpected quarter, however-the early microscopists. Perhaps eels do not come from ooze nor worms from putrefaction, but it is only necessary to put decomposing substances for a short time in a warm place and tiny "live beasts" appear under the lens before one's very eyes, they pointed out. The French biologist Buffon, in the first half of the eighteenth century, formulated a compromise theory: all living material, he proposed, consists of organic molecules that do not change. When a dead organism decomposes, the material of which it is formed recombines, creating new living organisms. The Abbe Spallanzani rejoined with a vitriolic attack on Buffon and his followers. Spallanzani devised careful and elaborate experi- ments to demonstrate that no living "animalcula" ever appeared in a concoction in which they had first been killed by boiling and which were sealed to prevent further entry of microorganisms. These ex- perimental proofs did not win over his determined opponents; ex- cessive heating destroyed the life forces, they argued, and drove from the flasks.the oxygen needed for the formation of life. Further, every gain made by Spallanzani and his followers was at least par- tially offset by experimental defects. In 18 6o, the situation was such that the French Academy of Sciences offered a prize for convincing experiments, one way or the other, on the question of spontaneous generation. Pasteur won this prize for his extremely simple and in- finitely reproducible experiments with the familiar swan-necked flasks. By heating a flask to sterilize its contents and drawing out the neck of the flask to an elongated S, Pasteur was able to show that life developed in any liquid medium only if the medium became infected from the air. The contents of the flasks remained sterile indefinitely until the necks of the flasks were broken, permitting minute organ- isms from the air to settle upon the surface of the medium. Pasteur's experiments came at a time when botanists were mar- velling over the bacteria their microscopes revealed, while physicians, frustrated at the bedsides of their patients, were arguing the nature of contagion. One blaze of new light and the ancient fallacies-the turtle-breeding mud, the miasmas, humours and demons-that had ordered the course of medicine for so many centuries were never seen

10 ~0AM :<_i, .1 !G JR3?U7 _ R again. Pasteur himself predicted that his studies on spontaneous generation and the origin of microbes "would prepare the road for a serious investigation of the origin of various diseases." In truth, they opened wide the avenues to modern medicine, preventive medicine, public health, surgery and chemotherapy. But now science has found itself again at a philosophical cross- roads at which it must pause to ponder the nature of what is meant by "living." This could be only an academic exercise, or, as it was a hundred years ago, perhaps it might be the threshold of a new era of medical advance. The following report on viruses and cancer deals with one aspect of this problem. 01134391

,. r --Yf~~ology~as; from the very beginning, the unwanted child of the bacteriologists. Pasteur postulated the existence of submicroscopic organisms as the cause of rabies but did not stop to demonstrate their existence, and John Buist, who even could see tiny specks in specially prepared specimens from cowpox vesicles (cowpox is one of the largest of the viruses and just on the borderline of visibility with the light microscope), could not grow them by any of the bacteriological techniques and so abandoned the investigation. By and large, how- ever, bacteriology in those early days was so replete with successes that it could well afford to overlook its failures. The crucial experiment was performed in 1897 by a Dutch botanist, Martinus Beijerinck. Beijerinck, a specialist in plant dis- eases, was seeking the cause of tobacco mosaic disease, a common condition that mottles the tobacco leaves and may dwarf the plants. Tobacco mosaic was known to be infectious-juices from an infected leaf would cause the disease in a healthy leaf-but previous sporadic attempts to find the causative organism, including two by Bei j erinck himself, had failed. Beijerinck forced the juice through a fine filter; 01134392

12 C7 .~~-lS;;?l;Tc -07 this was a fairly common procedure by which bacteriologists proved that the infectivity was due to bacteria rather than the fluid that sur- rounded them. This time, however, it was the filtered fluid that in- duced the disease. Furthermore, the juice of the filtrate-infected leaf, in which disease had been caused by the filtrate, could itself yield a filtrate that would induce disease in another healthy plant, ad infini- tum. The filtrate was not merely a toxin or a poison but seemed to have a continuing life of its own. Since Beijerinck could see nothing in the fluid, search as he would, and could cultivate nothing from the fluid, he concluded that it was the fluid itself that produced the infection. Contagium vivum fluidum he called it, and throughout his report he referred to it as a virus, the first use of this now well- known word in this exact context. Beijerinck wrote in 1913, "The existence of these contagia proves that the concept of life-if one considers metabolism and proliferation as its essential characters-is not inseparably linked up with that of structure; the criteria of life . . . are also compatible with the fluid state . . . In its most primitive form life is, therefore, no longer bound to the cell,... In its primitive form life is like fire, like a flame borne by the living substance-like a flame which appears in endless diversity and yet has specificity within it . . . which does not originate by spontaneous generation but is propagated by another flame." Within a year, a disease of animals, foot-and-mouth disease of cattle, was similarly proved to be caused by what became known as filterable viruses (still meaning disease-causing poisons that pass through a filter that holds back bacteria) and in i qo i it was shown that a disease of man, yellow fever, was attributable to a virus. During the thirty years after Beijerinck's discovery, many new viruses were found but little more was learned of the nature of viruses. They were invisible poisons which would induce characteristic dis- eases in a susceptible host and which, as Beijerinck had pointed out, were capable of some form of reproduction. Animals which had been infected with a virus produced equally invisible substances in their blood which could neutralize the virus on future encounters. Ex- posure of an unknown virus to the blood of an animal that had re- 01134393