Harold E. Varmus
Harold E. Varmus is a prominent American physician and Nobel laureate known for his groundbreaking research in the field of oncology and molecular biology. He, along with his colleague J. Michael Bishop, made significant contributions to the understanding of oncogenes—genes that can transform normal cells into cancerous ones. Their work in the 1970s revealed that these oncogenes actually originated from normal cellular genes, which they termed proto-oncogenes, thereby reshaping the scientific view of cancer development.
Varmus’s early life included a diverse educational background, starting with a BA in English before transitioning to medicine, where he earned his medical degree from Columbia University. His academic journey led him to the National Institutes of Health, where he developed an interest in experimental science. Over the years, Varmus has held key leadership roles, including serving as director of the National Institutes of Health and the National Cancer Institute, where he advocated for significant funding and research initiatives in cancer genomics and global health.
Throughout his career, Varmus has received numerous accolades, including the Nobel Prize in Physiology or Medicine, and has contributed over three hundred published articles to the scientific community. He is also a co-founder of the Public Library of Science, promoting open-access to scientific research. His work not only advanced cancer research but also influenced the approach to treating malignancies, emphasizing the importance of understanding the genetic underpinnings of cancer for developing effective therapies.
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Harold E. Varmus
American biologist
- Born: December 18, 1939
- Place of Birth: Oceanside, Long Island, New York
Oncogenes, genetic information associated with the conversion of normal cells into cells that are malignant, were found in viruses during the 1960s and 1970s. In 1975, Varmus and his colleague, J. Michael Bishop, discovered that viral oncogenes actually originated from normal cells, where they played a role in regulating cell division.
Early Life
Harold E. Varmus was the first of two children born to Frank Varmus and Beatrice "Bea" Barasch Varmus. Harold’s parents, the children of Jewish immigrants, were college graduates: his father from Tufts Medical School and his mother from Wellesley College and the New York School of Social Work. Varmus grew up in Freeport, New York, and, following high school, enrolled at Amherst College and graduated with a BA in English in 1961.
Awarded a Woodrow Wilson Fellowship, he enrolled at Harvard University and began his studies in Anglo-Saxon and metaphysical poetry. However, he soon developed an interest in the medical sciences and decided to enter the Columbia College of Physicians and Surgeons to study psychiatry. His studies there eventually drew him into the area of internal medicine, in which he received his medical degree in 1966.
Following a year of internship at Columbia-Presbyterian Hospital, Varmus joined the laboratory of Ira Pastan at the National Institutes of Health (NIH) in Bethesda, Maryland. At the NIH, he encountered his first extensive exposure to experimental science while investigating the role of cyclic nucleotides in gene regulation in bacteria. The work stimulated within Varmus an interest in the newly expanding field of molecular biology, the cutting edge of which was developing in laboratories such as that of J. Michael Bishop at the University of California, San Francisco.
It was during these years that research was focused on the ability of RNA tumor viruses to infect and integrate into cells. The research focused particularly on the possible implications for cancer. Varmus joined Bishop’s laboratory as a postdoctoral fellow in 1969 and was promoted to full professor in the Department of Microbiology and Immunology by 1979.
Life’s Work
While the existence of RNA tumor viruses had been demonstrated as early as the first decade of the twentieth century, albeit with no knowledge of the molecular makeup of these pathogens at the time, the significance of the tumor viruses as a means to induce tumor formation became apparent only in the 1960s. In the early 1960s, Howard Temin suggested that such viruses carry out their infectious cycle using a DNA intermediate. The absence of any known mechanism to copy RNA into DNA resulted in skepticism about Temin’s hypothesis among scientists.
In 1970, Temin and David Baltimore reported the presence of an enzyme, a reverse transcriptase, within the structure of these viruses, which could copy RNA into DNA and thereby provide a means to integrate into the cell chromosome. The presence of genes on these viruses, which could account for the malignant transformation, seemed to provide an explanation for how tumors could be induced. The genes became known as "oncogenes," because of their role in inducing malignancy, and the viruses became known as "retroviruses."
The conventional thinking was that these oncogenes originated with the retroviruses, and following integration after infection, they were instrumental in inducing genetic changes. In the early 1970s, in the process of studying oncogenes, Varmus and Bishop developed a strain of RNA tumor virus called the Rous sarcoma virus (RSV), which lacked the oncogene in its genetic makeup. The altered form was instrumental in addressing an evolutionary question: what was the purpose of the viral oncogene? It seemed to carry out no necessary function in the virus. A possible “generic” function of oncogenes, the oncogene hypothesis, had already been proposed by Robert Huebner.
Huebner and colleague George Todaro put forth the idea that oncogenes were silent pieces of DNA in the cell, activated only by carcinogens. By using the genomes of both the wild-type virus and its altered “relative,” Varmus and Bishop had a genetic probe with which they could investigate the possible presence of oncogenes in cells, answering at least the evolutionary question. They discovered in the mid-1970s that oncogenes similar to that in the tumor virus were already present in normal cells; not only were avian cells infected by RSV but also cells throughout the animal kingdom. In other words, the oncogene did not originate as a viral gene but was a normal cell gene that the virus likely had acquired. The cell version became known as a "proto-oncogene."
The proto-oncogenes were not randomly placed within the cell genome but were found at specific positions. Unlike the form of the gene in the virus, a continuous genetic entity, the proto-oncogene had the characteristic of other eukaryotic genes in being subdivided into separate domains, with each segment separated by stretches of DNA. As more oncogenes were discovered and their functions investigated, it was found that these genetic elements regulate, at various levels, the ability of cells to replicate. Mutations in the genes, or their over-expression, could in some cases account for the malignant transformation of the cell.
In the ensuing years, Varmus and his colleagues demonstrated exactly how some modifications of proto-oncogenes could result in cancers. Some of the gene products were cellular growth factors, inducing the cycle of cell division. Others were receptors for those factors situated on the cell membrane. Still other proto-oncogene products were DNA-binding proteins, which regulated DNA expression and replication.
As well as carrying out research on the role of oncogenes and retroviruses, Varmus and his colleagues collaborated on studies of hormone actions. They also looked into characteristics of hepatitis viruses, studied various forms of blood disorders and mammary tumors, and investigated HIV biochemistry.
As a Nobel laureate in medicine, an honor he shared with Bishop in 1989, Varmus acquired influence among the scientific community and became increasingly involved with policy issues. Returning to the NIH in 1993, Varmus was appointed its director by Secretary of Health and Human Services Donna Shalala. Between 1993 and 1999, he helped double the NIH's five-year budget, implemented improvements to the way the organization conducted its research, and initiated several construction projects for new research facilities.
From 2000 to 2010, Varmus served as the president and chief executive officer of the New York–based Memorial Sloan-Kettering Cancer Center. In May 2010, President Barack Obama selected Varmus to take over the directorship of the NIH's National Cancer Institute (NCI), a position he assumed on July 12, 2011.
During Varmus's tenure as director, the NCI investigated issues in cancer genomics and global health and undertook a "Provocative Questions" Initiative to address oft-overlooked but important areas of cancer prevention, mechanisms, detection and diagnosis, therapies, and clinical efficacy. Other key projects that came together in this period included the National Lung Screening Trial, the Cancer Genome Atlas, and the Transforming the NCI Clinical Trials Enterprise. He served in that role until 2015, when he became the Lewis Thomas University Professor of Medicine at Weill-Cornell Medical College in New York. He also continued his research in genetics at the Meyer Cancer Center and the New York Genome Center.
Varmus received numerous awards in recognition of the significance of his work. The most prestigious award was the Nobel Prize. Among other significant honors were the Albert Lasker Medical Research Award in 1982, the Armand Hammer Cancer Prize in 1984, the Alfred P. Sloan Prize in 1984, the American College of Physicians Award in 1987, and the Vannevar Bush Award and National Medal of Science in 2001. Varmus gained membership in the National Academy of Science, the American Academy of Arts and Sciences, and the Institute of Medicine.
Varmus also chaired or co-chaired a number of scientific advisory bodies, including the Gates Foundation's Scientific Board of the Grand Challenges in Global Health (2003–8), the Institute of Medicine's Committee on the US Commitment to Global Health (2008–9), the Gates Foundation's Global Health Advisory Panel (2008–11), and the President’s Council of Advisors on Science and Technology (2009–10). He was also a commissioner of the World Health Organization's Commission on Macroeconomics and Health (2000–2).
In addition to his research and administrative work, Varmus had a significant impact on scientific publications. He is the author or coauthor of more than three hundred articles and several books, including the cancer genetics introduction Genes and the Biology of Cancer, with Robert Weinberg, and the memoir The Art and Politics of Science (2009). Varmus was instrumental in the NIH establishing the PubMed Central online journal archive and cofounded the Public Library of Science (PLoS), a publisher of open-access biomedical journals, to promote public accessibility to scientific findings and scientists', not editors', control over the publication process for research findings. Moreover, Varmus and Bishop's initial studies on oncogenes inspired a journal of the same name, which was established in 1993 and is devoted exclusively to oncogene–related cancer research. In 2021, Varmus was named chairperson of the newly formed Science Council at the World Health Organization (WHO).
Significance
Oncogenes were first discovered in viruses, but the work of Varmus and his colleagues demonstrated these regions of genetic information had originated as cellular genes, the function of which was to regulate cell division. Cancer is not a single disease but one characteristic of the specific type of malignant cell. However, a common feature among many cancers is that the proliferation and characteristics of such cells is the result of changes or improper regulation among these genes.
Since Varmus and Bishop first demonstrated in the 1970s the origin of a few examples of oncogenes, well over one hundred such genes have been described and located. Understanding the function of oncogenes has helped in the process of learning the origin of a diverse group of malignancies. Knowing these functions also has led to a significant understanding of cell regulation in general. In particular, the role of oncogene products involved in each step leading up to and controlling cell division has resulted in a significant understanding of the process as a whole.
The long-term goal, in relation to cancer, is to develop a means to control or block cell division. For example, the use of the anticancer drug herceptin, used in the treatment of certain forms of breast cancer, is in part based upon a competition with an oncogene product that induces cell division. The ability to block the action of oncogene products may not necessarily result in a cure for the disease, but it could be a means to prevent the further spread of cancer cells and control cancer as a chronic disease.
Bibliography
"Harold Varmus: Biographical Overview." National Cancer Institute. National Institutes of Health, profiles.nlm.nih.gov/spotlight/mv/feature/biographical-overview. Accessed 21 Aug. 2024.
Coffin, John, Stephen Hughes, and Harold Varmus. Retroviruses. Cold Spring Harbor Laboratory P, 1997.
Colome, Jaime S. “Harold E. Varmus.” The Nobel Prize Winners: Physiology or Medicine. Vol. 3. Salem Press, 1991.
Dimmock, N. J., A. J. Easton, and K. N. Leppard. Introduction to Modern Virology. 6th ed. Blackwell, 2007.
Kaiser, Jocelyn. "Varmus's Second Act." Science 25 Oct. 2013: 416–19. PDF file.
Pelengaris, Stella, and Michael Khan, eds. The Molecular Biology of Cancer. 2nd ed. Blackwell, 2013.
"Science Council." World Health Organization, 2024, www.who.int/groups/science-council. Accessed 21 Aug. 2024.
Varmus, Harold. The Art and Politics of Science. Norton, 2009.
Varmus, Harold. Readings in Tumor Virology. Cold Spring Harbor Laboratory P, 1983.
Varmus, Harold. "NIH Cancer Chief Wants More with Less." Interview by Meredith Wadman. Nature, 6 July 2011, www.nature.com/articles/475018a. Accessed 21 Aug. 2024.
Weinberg, Robert. The Biology of Cancer. 2nd ed. Garland Science, 2014.