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JACOB FURTH 179 Roswell Park Memorial Institute, Buffalo-are among the current leaders in cancer research. Gordon Sato was inspired by Jacob to develop completely defined media for cell culture to dissect the endocrine factors in cell growth in vivo being explored by Jacob. He acknowledged his debt by dedicating to Jacob Furth a conference on the "Growth of Cells in Hormonally-Defined Media."7 TWO YEARS IN BUFFALO In 1959, approaching the Harvard retirement age, and with his hitherto cordial relationship with Sidney Farber having become strained, Jacob let it be known that he would like to move and so accepted an invitation from the Roswell Park Memorial Institute in Buffalo. Along with continuing unfinished work begun at Harvard, he was encouraged by Theodore Hauschka to examine chromosomal abnormalities in relation to hormone dependence of neoplasms. In Buffalo a young Japanese pathologist, Kenjiro Yokoro, came to work with Jacob as a visiting scientist. Their association continued through the next seventeen years and included Yokoro's students and colleagues. Their appreciation was demonstrated by cordial receptions accorded Jacob (and Olga) on two lecture tours to Japan, the last one a year before he died. THE FINAL YEARS, COLUMBIA, 1961-79 After two years in Buffalo, Jacob was invited by Alfred Gellhorn, then director of the Institute of Cancer Research, and Donald McKay, chairman of the Pathology Department at Columbia University's College of Physicians and Surgeons, to join the pathology department and to head the pathology department at the Francis Delafield Hospital, Columbia's cancer center. Despite his age of sixty-five,
JACOB FURTH 180 Jacob was warmly welcomed, and with youthful vigor he once again engaged in the broad responsibilities of service and teaching. However, he soon gave these up to concentrate on research and terminated his position at the Delafield Hospital to join the newly formed Institute of Cancer Research, an independent unit of Columbia University, headed by the late Sol Spiegelman. Here Jacob's research focused directly on the induction and properties of endocrine neoplasms, particularly of the thyroid, pituitary, and mammary glands, and on the role of the thymus gland on viral induction of leukemia. During this period, and after his retirement at age seventy, Jacob wrote a number of thoughtful essays on his conceptions of the neoplastic process.3-6 Jacob never really retired. His life was his work, except for several hobbies. In his Cornell years, when he lived in Pelham, he gardened, specializing in dahlias. He was interested in stocks and dabbled in the marketâ always long term; he would never buy and sell for the quick return. He consulted a broker and subscribed to several investment publications but made his own decisions. Overall they were excellent ones and on his death it was his investments, not his retirement pay, that left his wife financially secure. One investment Jacob sold was some General Motors stockâ to buy a farm in Surry, Maine. He thought he would spend the summers there and work at the house or at the Jackson Laboratory in Bar Harbor, about a forty-five- minute drive by car. He never spent more than a few weeks a summer there, often accompanied by colleagues. His children would visit him with their children and what with his frequent moves it became the family home. He called the place ''Jake's folly," but it turned out to be his best investment. He died in Surry on July 23, 1979. The previous day Jacob had attended a meeting at the Jackson Lab, visiting with old friends. This day, as was his
JACOB FURTH 181 custom, he spent the morning working on his latest manuscript. He then went out in the yard to pick up some brush that his son John had scattered about. After about an hour of yardwork he laid down to take a nap, also his custom. He never woke up. The following tribute by Gordon Sato, abridged here, appeared in the proceedings of a 1982 Cold Spring Harbor conference dedicated to Jacob: Great artists and great scientists tend to be identified with more than one masterwork. Furth developed the first experimental leukemia system in mammals. This work involved the derivation of the AKR and RF mouse strains, the unequivocal demonstration that the experimental disease was analogous to human disease, and the transmission of leukemia with a single cell, the first demonstration that neoplasia can be monoclonal in nature. He demonstrated the necessity of the thymus in the genesis of lymphocytic leukemia and also defined the spectrum of neoplasms resulting from a specific virus infection in fowl, the role of genetics in the spectrum, and the incidence of neoplasms in mice following ionizing radiation. He also pioneered in cryopreservation of mammalian cells. Furth's interest in endocrine carcinogenesis was stimulated by the ovarian neoplasms that occurred in his early radiation studies, and this ultimately led to the investigation of radiation and hormone-induced functional pituitary tumors. The concept of conditioned and autonomous neoplasia emerged during these studies, a major insight into the importance of physiological feedback regulation in oncogenesis. Furth employed endocrine neoplasms as indwelling hormone sources in studies of normal and pathological growth, and he gave freely of his unique functional tumor cell lines to others for study in vivo and in culture. Perhaps the most important of his endocrine work was the establishment of the pivotal role of prolactin in mammary growth, differentiation, and neoplasia.7 Perhaps the greatest and most lasting influence of Jacob Furth has been on the crucial role of host factors in the induction and maintenance of tumors. Early on he recognized that the tumor and its host comprise a dynamic duo, in which the host and its regulatory mechanisms are pitted against the unremitting progression of tumors toward au
JACOB FURTH 182 tonomy and invasiveness. Foremost among the host factors are the hormones, and their interplay with each other and the tumor was Jacob's main research interest in the latter part of his career. Several examples from his classical studies with model endocrine systems illustrate how these systems interact. Mammary tumors in rats produced by oral administration of chemical carcinogens, such as 3-methylcholanthrene, are responsive to the presence of the ovary and pituitary gland. Kim and Furth showed that if these organs are removed, the tumors regress, but they can be restored to growth even after months of dormancy by implanting a pituitary tumor secreting a hormone that stimulates mammary growth. If rats are given subcarcinogenic doses of either radiation or methylcholanthrene, or if mice are given a subcarcinogenic injection of milk containing a mammary tumor virus, no tumors occur. However, if the carcinogen is supplemented by mammatrophic growth- stimulating hormone, which is itself noncarcinogenic, mammary tumors arise. This promotional effect of hormones, Jacob concluded, is likely relevant to humans, where we are continuously exposed to small subcarcinogenic doses of multiple carcinogens. Jacob thus amassed an impressive body of evidence for the hypothesis that hormonal imbalances caused by either overproduction of growth-enhancing hormones or underproduction of growth-restraining factors can lead to abnormal cell proliferation. Such growths are generally dependent on or responsive to the hormone that affects its behavior and can regress partially or completely if the imbalance is corrected. However, when to the hormonal imbalance there is added an alteration to the genome that removes intrinsic restraints on proliferation, autonomy ensues, leading to loss of hormone dependency and un
JACOB FURTH 183 controlled cell proliferation. This genomic alteration may occur first, causing the initiation of autonomous tumor development, or may be induced by cellular proliferation, thereby leading to the commonly observed gradual sequential progression resulting in partial and ultimately complete autonomy of growth. Jacob was prominent in a host of professional activities. He was elected to the National Academy of Sciences in 1974 and was a member of its Advisory Committee to the Atomic Bomb Casualty Commission. He was on the Surgeon General's Advisory Committee on Smoking and Health, the Public Health Service's Advisory Committee on Tumor Viruses, and the Committee on Radiation of the Department of Health. He was president of the American Association for Cancer Research and the American Society of Experimental Pathology. He was a fellow of the American Academy of the Arts and Sciences and held honorary memberships in the Endocrinology Society of Chile, the Cancer Society of Peru, and the Pan American Medical Association (diplomate member). Among his awards and honors were the Gold Medal of the American Medical Association, 1932; the Rosenthal Award of the American Association for the Advancement of Science, 1957; the Bertner Foundation Award from M. D. Anderson Hospital and Tumor Institute, 1958; the Robert Roesler de Villiers Award, 1959; the G. H. A. Clowes Award and Lectureship of the American Association for Cancer Research, 1962; the Semmelweiss Medal and Lectureship, 1962; an honorary doctor of science from the University of Pennsylvania, 1968; the Alessandro Pascoli Prize, 1973; and the Rous-Whipple Award of the American Association of Pathologists and Bacteriologists, 1974. Jacob was a thoughtful statesman of science, with extraordinary vision that enabled him to see the process of
JACOB FURTH 184 cancer induction in its formidable complexity. With singular talent, a keen intellect, an inquiring and analytical mind, and experimental skill, he was able to unify otherwise disparate data to explain the development and maintenance of the cellular proliferation of cancer in terms of the operation of extrinsic and intrinsic factors. Our conceptions of cancer induction were broadened greatly in the decade following Jacob's death in 1979 with the discovery of a host of proto- oncogenes whose activation by various mechanisms leads to abnormal cell proliferation. The essential correctness of Jacob's views has been confirmed by the further discovery that the activated oncogenes encode a number of growth- promoting hormones and their cellular receptors. Jacob brought to experimental pathology a high degree of scholarship, an appreciation of the contributions of the basic sciences to the understanding of disease, and an attitude of humility in the face of what still needs to be learned about life's processes. His legacy is captured in the words of Henry Wadsworth Longfellow: When a great man dies, for years beyond our ken, The light he leaves behind him, lies upon the paths of men.
