For over three decades, Harold Varmus has advanced fundamental scientific knowledge at the intersection of virology, oncology, and genetics, both as a researcher and as a science administrator. With his long-time collaborator J. Michael Bishop, Varmus developed a new theory of the origin of cancer, which holds that the disease arises from mutations in certain of our own normal genes. These mutations are triggered by environmental carcinogens or by naturally occurring errors in the course of cell division and DNA replication. The genes that are susceptible to such mutations, Varmus and Bishop found, are closely related to genes in a number of cancer-causing viruses. They have been preserved through over one billion years of evolution and play an important role in controlling cell division and differentiation. Yet, under particular conditions--events during cell division or the reorganization of chromosomes, as well as external influences like particular viruses, cigarette smoke, and radiation--these genes can accumulate mutations that prompt the cell in which they reside to divide indefinitely, the hallmark of cancer.
The surprising discovery that cancer-causing genes, or oncogenes, originate in normal cells and are versions of normal cellular genes altered over time by accreted mutations suggested a common molecular mechanism for the many different types of cancer, explained why cancer is most often a disease of old age, and accounted for individual differences in the response to carcinogens. In his acceptance speech at the Nobel Prize ceremony in December 1989, Varmus, a former graduate student in literature, compared cancer to Grendel in the epic heroic poem Beowulf: "In our adventures, we have . . . seen our monster more clearly and described his scales and fangs in new ways--ways that reveal a cancer cell to be, like Grendel, a distorted version of our normal selves."
Harold Eliot Varmus was born December 18, 1939, in Oceanside, New York, a descendant of Jewish immigrants who had arrived from Poland and Austria at the beginning of the century. His father, Frank, was a general practitioner who also served as medical officer for nearby Jones Beach Park, where Harold and his younger sister, Ellen, spent much or their early summers. His mother, Beatrice Barasch, was a psychiatric social worker active in the civic life of Freeport, New York, where Varmus grew up.
His father urged him to go to medical school, and Varmus obliged by taking premed courses during his undergraduate studies at Amherst College. Nevertheless, he found his first intellectual passion not in medicine, but in English literature and in writing, earning a AB degree magna cum laude in 1961 with a thesis on the novels of Charles Dickens and serving as editor of the campus newspaper. He considered an academic career in literature and even earned an MA degree in English from Harvard University in 1962 with a focus on Anglo-Saxon and metaphysical poetry. However, Amherst friends who had chosen medicine seemed more fulfilled and excited about studying matters with immediate relevance to basic human needs. Varmus came to think that as a professor of literature his students would likely feel relief if he failed to show up for a lecture, whereas as a physician, his patients would be distraught if he cancelled an appointment. He entered the College of Physicians and Surgeons at Columbia University in New York in 1962 (after a rejection from Harvard Medical School), initially with an interest in psychology and later in internal medicine. He received his MD in 1966, which included a three-month internship at a hospital in northern India.
While serving as a medical house officer during his residency at Columbia's Presbyterian Hospital, Varmus felt drawn toward the study of the scientific basis of disease. He applied for a position in the laboratory of Ira Pastan, an endocrinologist at the National Institutes of Health who was then studying the genetics of thyroid function, a subject Varmus considered close enough to his medical training to provide a suitable entry into bench science. However, Pastan, typifying the reorientation of medical research during the 1950s and 60s from examinations of the functioning of whole organs or organisms towards the study of biological processes at the molecular level, decided to change research plans. He took up the investigation of the role signaling molecules--namely the protein cyclic adenosine monophosphate, or AMP--play in regulating gene expression in the intestinal bacterium Escherichia coli. Pastan notified Varmus at Columbia that he would set him to work on this problem, not on thyroid function, which sent Varmus late one night to the hospital's staff library to read Jacques Monod and Francois Jacob's seminal papers on gene control in E. coli. Although his lack of scientific training prevented him from understanding fully what he was reading, he knew then that his future lay in basic research.
After completing his residency in 1968, Varmus joined Pastan at the National Institutes of Health (NIH) in Bethesda, Maryland, as part of a program that taught research methods to physicians who wanted to study basic biomedical science. Like his long-time collaborator Michael Bishop, who had taken part in the same program two years earlier, Varmus set upon a career in research only as he was approaching the age of thirty, unusually late for a biomedical scientist. In his Nobel lecture Varmus described his work with Pastan as "an aesthetic merger of genetics with molecular biology," and an experience that cemented his commitment to basic research.
During a backpacking trip to California in 1969, Varmus visited a small group at the University of California at San Francisco composed of J. Michael Bishop, Leon Levintow, and Warren Levinson, who had begun to study retroviruses to detect cancer-causing genes. It took only a brief conversation to ascertain a compatibility of intellect and temperament with Bishop, whose laboratory Varmus joined in 1970 as a postdoctoral fellow. As Bishop recalled, their relationship evolved rapidly to one of equals, their bond formed not just by a shared fascination with cancer viruses but "by our mutual love of words and language." In a collaboration that was unusual in an era of increasing competition in science, Bishop and Varmus together directed a research group during the 1970s and early 1980s that eventually numbered more than two dozen, and made all of their major discoveries as a team. Varmus rose through the academic ranks at UCSF, starting as Lecturer in the Department of Microbiology and Immunology in 1970 and becoming Professor of microbiology, biochemistry, and biophysics in 1979.
Varmus and Bishop showed that nearly-identical versions of cancer-causing genes (so-called oncogenes) carried by retroviruses, viruses that integrate themselves into the DNA of infected cells, are present in the genome of normal, uninfected cells in a wide range of species, from yeast to fish to humans. Normal cells, the two scientists showed, carried within them the seeds of cancer in the form of genes they called proto-oncogenes. The wide distribution of these genes across species as well as certain features of their molecular structure indicated to Varmus and Bishop that retroviral oncogenes originated as proto-oncogenes in normal cells--that they were not deposited there, but rather were picked up there by retroviruses--and that proto-oncogenes are vital in controlling cell growth and specialization. Only when a proto-oncogene is altered through the rearrangement of the cell's chromosomes or through cumulative mutations--mutations at several different sites in the gene are required--does it trigger uncontrolled cell growth and division. Such mutations can occur through random error during cell division or under the impact of viral infection, environmental carcinogens, and a myriad of other external causes. The genetic mechanism that produces cancer, however, is located deep inside normal cells.
Varmus and Bishop's discovery yielded a better understanding of how retroviruses change the fundamental behavior of cells, and brought scientists closer to a unified theory of cancer. This theory stated that the many different types of cancer in humans and other animals are caused by a similar molecular and genetic mechanism involving the mutation and activation of a proto-oncogene, a process that most often unfolds over the course of many years. Their theory suggested new answers to several questions about cancer that had long puzzled scientists: why there are as many different cancers as there are cell types in the body, why cancer is most often triggered by mutating agents rather than inherited, why some people who are exposed to carcinogens develop cancer while others do not, and why the incidence of cancer rises with age.
In 1989, Varmus and Bishop shared the Nobel Prize in Physiology or Medicine "for their discovery of the cellular origin of retroviral oncogenes."
Varmus continued to search for other proto-oncogenes during the 1980s, but also branched out into new fields, including studies of the replication cycle of hepatitis B viruses. As an expert on retroviruses he soon became involved in research on the retrovirus that was causing the new and frightening epidemic of AIDS. He chaired the scientific advisory committee that in 1986 proposed the name human immunodeficiency virus (HIV) for the etiologic agent of AIDS.
In 1993, President William Jefferson Clinton nominated Varmus as director of the National Institutes of Health, the nation's premier research and funding institution in the biomedical sciences. The first Nobel laureate to head NIH, Varmus strengthened its commitment to basic research while balancing demands from advocacy groups for more targeted research on particular diseases, most notably AIDS. After six years in office, a term he had declared appropriate for the NIH director at the start of his tenure, Varmus left in December 1999 to become president and director of the Memorial Sloan-Kettering Cancer Center in New York.
During his ten years at Memorial Sloan Kettering, Varmus expanded the center's basic research and educational programs, and strengthened connections between laboratory and clinical research staff. He also built stronger collaborative relationships with two neighboring research institutions, Weill-Cornell Medical College and Rockefeller University. In 2010 Varmus returned to NIH, this time as director of the National Cancer Institute (NCI).
At both Memorial Sloan Kettering and NCI, Varmus was able to pursue his cancer research, directing a small laboratory where he and his coworkers devised mouse models of human cancer in order to elucidate the relationship between normal patterns of cell growth and development, and oncogenic events that disturb these patterns. The lab's recent work has focused on mutations in RAS proto-oncogenes, and the roles of certain signaling proteins in cancer growth.
Since 1999, Varmus has been a leading advocate for open-access publishing and archiving of scientific research reports. His first proposal for an open-access system, "E-Biomed," which generated considerable controversy, led to the development PubMed Central, a freely available online archive of scientific journal literature hosted at NIH. Soon afterward, he and several colleagues founded the Public Library of Science (PLoS), a non-profit open-access publishing venture that makes full-text, freely searchable original articles in biomedical science available without cost to readers, and has proved a viable alternative to traditional subscription-based journal models.
Varmus has received many honors for his research in addition to the Nobel Prize, most of them jointly with Bishop. In 1982, he was granted an American Cancer Society Lifetime Research Professorship and, together with Bishop, was named Scientist of the Year by the California Academy of Sciences. The two shared a Lasker Award for Basic Medical Research, also in 1982, the Gairdner Foundation Award in 1983, and the Alfred P. Sloan Prize of the General Motors Cancer Research Foundation in 1984. Varmus was elected to the National Academy of Sciences in 1984, and received the National Medical of Science in 2001. He is the author of more than three hundred scientific papers and five books, including an introduction to the genetics of cancer for a general audience, and his 2009 memoir, The Art and Politics of Science. Varmus has been married to journalist and book critic Constance Casey since 1969. They have two sons, Jacob and Christopher.
Varmus left NCI in March 2015, and returned to New York to become the Lewis Thomas University Professor of Medicine at Weill-Cornell Medical College. He plans to continue his research at the Meyer Cancer Center there, and work with the New York Genome Center.