J. Michael Bishop

• Born: February 22, 1936

• AMERICAN MOLECULAR BIOLOGIST

Oncogenes, genes that, when mutated, transform a normal cell into a malignant one, had been discovered in tumor viruses during the early 1970s. J. Michael Bishop isolated the first known human oncogene and demonstrated its origin in the human genome.

• PRIMARY FIELD: Biology
• SPECIALTIES: Molecular biology; biochemistry; virology

Early Life

John Michael Bishop was born in York, Pennsylvania, then a small town near the Susquehanna River, on February 22, 1936, as one of John and Carrie Bishop’s three children. His father was the Lutheran minister to two local parishes. Bishop’s education during his grade school years occurred in a two-room schoolhouse; four of his school years were spent with a teacher who provided the discipline Bishop would need later in life. Although he received a rigorous education in subjects such as history and penmanship, he noted that the science curriculum was somewhat lacking.

Bishop was valedictorian of his small high school class and earned a varsity letter in track. It was during his high school years that Bishop began to study under Dr. Robert Kough, a local physician who instilled an interest in human biology in his protégé. After graduation, Bishop entered Gettysburg College, a small private college in Gettysburg, Pennsylvania, where he majored in chemistry in preparation for medical school. Bishop graduated with a degree in chemistry in 1957, having been elected to the Phi Beta Kappa honor society. He also met his future wife, Kathryn Putman; they married in 1959 and have two sons.

Bishop was admitted to medical schools at both the University of Pennsylvania and Harvard University and entered the latter in 1957. It was there that Bishop had his first opportunity to participate in scientific research. Two pathologists, Benjamin Castleman and Edgar Taft, allowed him access to their laboratories during his second year, resulting in some expertise in that scientific area. It was during Bishop’s third year in school that he had his first exposure with viral research in animal virology under the auspices of researcher and Harvard professor Elmer Pfefferkorn. Bishop spent his fourth year working with Pfefferkorn outside the classroom and learning early techniques in the nascent field of molecular biology. Bishop graduated with his medical degree in 1962.

Life’s Work

Following two years of clinical training as house physician at Massachusetts General Hospital, Bishop joined the laboratory of Leon Levintow at the National Institutes of Health in Bethesda, Maryland, where he was trained in research in the medical sciences. Levintow’s area of research involved studying the physical and chemical nature of poliovirus genomic ribonucleic acid (RNA) and proteins; Bishop’s research addressed the replication strategy of poliovirus RNA and produced his first professional publications.

Following Levintow’s departure for the University of California, San Francisco (UCSF) in 1967, Bishop joined the laboratory of Gebhard Koch in Hamburg, Germany. Bishop and Koch had collaborated on their polio work at Bethesda; the year overseas significantly expanded Bishop’s world view. Upon returning to the United States in 1968, Bishop received two offers for faculty positions; one with Levintow at the then little-known medical school at UCSF as Assistant Professor of Microbiology and Immunology. He accepted this position and stayed there for the remainder of his academic career.

Bishop had planned on continuing his research into the replication of poliovirus when an element of serendipity entered his career. In the laboratory next to his at UCSF was researcher Warren Levinson, who was studying the growth of Rous sarcoma virus (RSV), which causes some cancers. The virus had been discovered as a filterable agent early in the twentieth century, and had been the subject of significant research for two primary reasons: RSV was capable of transforming normal cells into malignant ones, and it was the first of what were subsequently called retroviruses to be characterized. In 1970 virologists David Baltimore and Howard Temin discovered the presence of an enzyme (reverse transcriptase) in the capsid of these viruses, which could copy the RNA genome into DNA. The DNA would then integrate into the genome of infected cells. The puzzle was to determine the mechanism of cell transformation by the virus.

In 1970, Bishop was joined by postdoctoral fellow Harold Varmus, and the two developed a professional relationship with the goal of studying how RSV transforms cells. By this time, scientists had focused on a specific viral gene, named the src gene for its ability to induce sarcomas. The initial hypothesis among scientists was that expression of the src gene by RSV following infection induced the malignant transformation. Bishop and Varmus discovered it was the opposite situation; the src gene originated within the cell, and was picked up by the virus following integration. The normal cell gene, now referred to as a proto-oncogene, functions to regulate cell division. Only when the gene undergoes a mutation does it result in cell transformation. The src gene was merely the first of the so-called oncogenes to be discovered in the cell. The discovery by Bishop and Varmus subsequently led to the discovery of over one hundred such proto-oncogenes, some by Bishop but most by colleagues entering the field opened by Bishop and Varmus. Bishop’s later research addressed a more in-depth understanding of the roles played by proto-oncogenes in cells from a wide variety of species, ranging from fruit flies to humans. In 1989, Bishop and Varmus were awarded Nobel Prizes in Physiology or Medicine for their discovery.

In 1972, Bishop was promoted to full professor in both the microbiology and immunology departments. He also became a professor in the department of biochemistry and biophysics. He was director of both the G.W. Hooper Research Foundation and the Program in Biological Sciences at UCSF. In 2003, Bishop was awarded the National Medal of Science. In 1998, he was appointed chancellor of UCSF, retiring in 2009. During his period in office, longer than any of the previous seven people in that position, Bishop guided what was at the time the largest academic expansion in the biomedical sciences in the United States.

Impact

Bishop’s discovery and characterization of cellular proto-oncogenes set the stage for an understanding of molecular processes that regulated cell division and also provided an understanding of the role played by mutations in transforming normal cells into malignant cells. The conservation of proto-oncogenes through evolution carried an inherent explanation of their normal function: a critical role in the regulation of cell replication. Once the first proto-oncogene known as src (short for “sarcoma”) was discovered and characterized, it was only a brief period before additional proto-oncogenes were identified, some by Bishop himself. Within twenty years after Bishop’s work with Varmus, over one hundred such genes were identified and characterized. All play some role in initiating or regulating cell division.

Identification of such genes was only the initial step in understanding their role in cell regulation. By studying the effects of mutations in these genes, Bishop was instrumental in the developing story of the role played by gene products in the regulation of cell replication. That role also provided answers to the question of how mutagens, such as chemicals or radiation, transform a cell into one that is malignant. They had discovered that by inducing a mutation in the appropriate proto-oncogene, cell regulation is disrupted.

The significance of Bishop’s discoveries lies in the realization that malignancies are not generally associated with infectious agents such as viruses, which had been the working hypothesis during the 1960s. Rather, the nature of cancer lies within the cell genome itself. In 2020, Bishop was granted the Clark Kerr Award for distinguished leadership in higher education from University of California, Berkeley.

Bibliography

"2020 Clark Kerr Award." UC Berkeley, 2020, academic-senate.berkeley.edu/awards/clark-kerr-award-2020. Accessed 15 Oct. 2024.

Bishop, J. Michael. How to Win the Nobel Prize: An Unexpected Life in Science. Cambridge: Harvard UP, 2003.

Bishop, J. Michael. Interview by Vincent Racaniello. Virology Blog, 13 June 2016, www.virology.ws/2016/06/13/interview-with-j-michael-bishop/. Accessed 15 Oct. 2024.

Bunz, Fred. Principles of Cancer Genetics. New York: Springer, 2008. Print.

"J. Michael Bishop—Biographical." Nobelprize.org, Jan. 2018, www.nobelprize.org/nobel‗prizes/medicine/laureates/1989/bishop-bio.html. Accessed 15 Oct. 2024.

Mukherjee, Siddhartha. The Emperor of All Maladies: A Biography of Cancer. New York: Scribner, 2010. Print.

Pecorino, Lauren. Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics. New York: Oxford UP, 2008.

Weinberg, Robert A. The Biology of Cancer. New York: Garland, 2006. Print.