I. Bernard Weinstein: In Memoriam (1930–2008)
Authors: Scott M. Kahn, Regina M. Santella
Journal: Cancer Research (2009)

On November 3, 2008, we lost a true gentleman and visionary with the passing of Dr. I. Bernard Weinstein. Bernie was a dear friend and distinguished colleague to many in the scientific community. And to those fortunate enough to be included among Bernie's “second family” of students, postdocs, and visiting scientists, he was a beloved mentor. Working for Bernie was like sitting in the midst of a Renaissance master. He inspired with his broad expertise and depth of knowledge in many areas of cancer biology. He excited with his enthusiasm and perceptive understanding of how even the most seemingly diverse concepts could be related, and with his insightful visions for future research. Bernie generously cared for and nurtured his trainees, many of whom have become leaders in their own fields.It is not by coincidence that Bernie's career paralleled many advances in cancer research of the past half century; he was a driving force. His impact extended well beyond his impressive 600+ research publications, and beyond his many internationally recognized areas of expertise, including chemical carcinogenesis, risk assessment, signal transduction, cell cycle control, molecular epidemiology, and chemoprevention, to name a few. Bernie possessed a sharp, creative mind that enabled him to reduce the complexity of cancer into well thought-out theories. He also had a wonderful ability to bring people together from diverse backgrounds through his enthusiasm for research and his optimistic view that cancer is a preventable and treatable disease. Complementing the importance of his own work, Bernie pushed the boundaries of cancer research by stimulating and debating the best of minds. His inspirational presence will be missed at meetings, where Bernie always offered insightful questions and comments, and enjoyed thought-provoking conversations that extended from coffee breaks into the late evening hours.Bernie received both his B.S. and his M.D. from the University of Wisconsin in Madison, his birthplace. He completed his internship and medical residency at Montefiore Hospital in New York followed by research positions at the National Cancer Institute, USPHS in the Department of Bacteriology, Harvard Medical School in the Department of Bacteriology and Immunology, and Massachusetts Institute of Technology in the Department of Biology. He came to Columbia University's College of Physicians and Surgeons in 1961 as an Assistant Professor and remained at Columbia for the rest of his career. During his long career at Columbia, he held many positions, including Chief, Division of Medical Oncology; Director of the Division of Environmental Sciences (now the Department of Environmental Health Sciences); and Director of the Columbia-Presbyterian Comprehensive Cancer Center (now Herbert Irving Comprehensive Cancer Center). At the time of his death, he was Frode Jensen Professor of Medicine, Professor of Environmental Health Sciences; Professor of Genetics and Development; Attending Physician, Presbyterian Hospital; and Director Emeritus, Herbert Irving Comprehensive Cancer Center.Bernie's excellence in research was internationally recognized, resulting in numerous awards, including the Anthony Dipple Carcinogenesis Award, the Charles Heidelberger Award for Cancer Research, and two from the AACR where he served as President from 1990 to 1991, including the Clowes Award and the AACR-American Cancer Society Award for Excellence in Cancer Epidemiology and Prevention. He was a member of the Institute of Medicine, National Academy of Sciences and a Fellow of the Royal Academy of Medicine, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences, and a member of the American Association of Physicians. He served on countless advisory committees and editorial boards where his expertise in a wide area of cancer research was greatly appreciated.To adequately review Bernie's research and its impact would take volumes, so here we provide just a brief summary of some highlights. Bernie's pioneering work in the area of chemical carcinogenesis led to critical information on how the covalent binding of chemicals to DNA leads to conformational changes that can be detected by physical biochemical methods. This initial work was on the DNA adducts formed by model carcinogens, including benzo(a)pyrene (BP) and acetylaminofluorene (AAF), which were found to have very different effects on DNA conformation. Some of these studies used antibodies to the normal nucleosides to probe single-stranded regions of DNA. Bernie astutely recognized that if antibodies could be made against the normal nucleosides, it should also be possible to generate antibodies against carcinogen-DNA adducts. Thus, the first antibodies recognizing the DNA adducts of AAF and BP were developed. Bernie developed the concept of using the antibodies to BP-DNA to quantitate damage levels in humans as a measure of “biologically effective dose” of environmental carcinogens. This was the beginning of his work in molecular epidemiology where he led the first studies monitoring human exposure to polycyclic aromatic hydrocarbons.Although his studies on initiation of cancer through the development of DNA damage helped in our understanding of multistage carcinogenesis, he also carried out extensive studies on tumor promotion using macrocyclic plant diterpene phorbol esters. In a series of articles in the 1970s, he showed that these compounds induce numerous changes that resemble those seen in cells transformed by chemical carcinogens or tumor viruses. He also showed reversible inhibition of terminal differentiation. A model of “two-stage” carcinogenesis included initiating carcinogens that induce stable alterations in the cellular genome but whose effects are not manifested until tumor promoters modulate programs of gene expression and induce the clonal outgrowth of the initiated cell. In the 1980s, Bernie turned to cell culture systems as models for multistage carcinogenesis. Following the discovery of protein kinase C (PKC) as a cellular receptor for phorbol ester tumor promoters, his group participated in the cloning and functional studies of PKC isoforms. Observations that, depending on the context of cells being studied, certain PKC isoforms could exert either positive or negative effects on cell growth, led Bernie to a yin/yang view of how genes may function, and why tumor promoters may exhibit tissue specificity.Bernie began formulating his theory of “oncogene addiction” in the early 1990s. Its inception stemmed from his interest in deregulated cell cycle control as an important driver, and therapeutic target in cancer. Bernie's group showed that esophageal tumors exhibit frequent cyclin D1 gene amplification and overexpression. Subsequently, in a set of esophageal tumors, his group found that cyclin D1 overexpression and diminished RB gene expression were mutually exclusive events, suggesting that multiple genetic lesions could affect the same cell cycle signaling pathway. His view of signaling pathways as integrated circuits was supported by the paradoxical finding that cyclin D1 overexpression in cells is accompanied by increased expression of the p27kip cell cycle inhibitory protein. In its simplest version, Bernie's theory of oncogene addiction suggests that in the midst of its chaotic genetic background, select genetic lesions drive a tumor cell to maintain its homeostatic balance by rewiring circuitries to ensure its survival (e.g., amplified cyclin D1 in esophageal cancer).In 2006, Bernie presented the plenary address at the Fifth International Hormonal Carcinogenesis Symposium in France. He noted that oncogene addiction provides support for the use of western and eastern medicine approaches for the development of new cancer therapies. Whereas a minimalist western approach would target a driving oncogene, the eastern approach would use mixtures of substances, whose active components could target a broad spectrum of altered signaling pathways. The latter approach would especially be useful if cancer cells escape oncogene addiction through their inherent genomic instability. Indeed, Bernie embraced both approaches, especially as they pertained to chemoprevention, maintaining an interest in natural products. One of his most recent 2008 articles was on the mechanism of action of green tea polyphenols investigating their effects on internalization of the epidermal growth factor receptor in human colon cancer cell lines.Bernie also outlined his future perspectives for cancer research in the same address. He noted that we do not yet know all the effects of endogenous and exogenous factors on carcinogenesis, suggesting that answers to the latter might lie in a better understanding of factors suggested by epidemiologic studies. He mentioned that we need a better understanding of the roles of abnormal energy metabolism, inflammation, and infectious agents (he was always partial to the possibility of viral causation of breast cancer). Bernie stressed that systems biology and network theory should be used in conjunction with oncogene addiction to determine those oncogenic targets most suitable for drug therapy. Bernie emphasized the need for studies of tumor stem cells, as these might hold the key for understanding tumor origin, latency, recurrence, and personalizing therapeutic treatments. Bernie closed by calling for a concerted international effort to ensure the future of cancer research by increasing funding for younger scientists. And, with a little grin and smile, he added, “Like me!”.Indeed, many saw Bernie as an eternally youthful scientist, which made the news of his passing so sudden and unexpected. He was fortunate to be able to remain active doing the things he loved until days before his death. Although Bernie left us before completing his role as Editor of the AACR Centennial series of historical articles in cancer research, his Introduction to the series, which was published in the September 1, 2008 issue of Cancer Research, concluded with a tribute to his never-ending confidence in the research community: “Given how far our understanding of cancer at the clinical, tissue, cellular, and molecular levels has come in the past 100 years, it is not overly optimistic to think that well before the next AACR Centennial, the world will be celebrating a major reduction in cancer incidence and mortality. Exciting progress toward that goal is being made every day in our research laboratories and clinics.”As a community, our thoughts go out to Bernie's wife Joan, his daughters, Claudia and Tamara, his son, Matthew, his grandchildren, Max and Noa, and his extended family. It is comforting to know that Bernie leaves a legacy through his work and students that is sure to benefit mankind for generations to come. Above all, perhaps the most important legacy that Bernie leaves is his reminder that one can be both an eminently accomplished scientist and a gentleman. He will be deeply missed.