Harry Rubin, a leader in the search to understand how viruses cause cancer — research that ultimately led to the discovery of cancer-causing genes called oncogenes — died on Sunday, Feb. 2, at the age of 93. Rubin was a professor emeritus of molecular and cell biology at the University of California, Berkeley.
A veterinarian by training, Rubin began investigating in the 1950s how normal cells turn into cancer cells — a process called transformation. This was at a time before genes could be cloned and sequenced, and much of his research relied on manipulating cultured cells in a petri dish.
Many labs were beginning to work with tumor viruses as the only tractable way to understand cancerous transformation, and Rubin chose to focus on a virus known since 1911 to cause cancer in chickens: the Rous sarcoma virus (RSV). RSV is an RNA virus, which means that it carries its genetic instructions in the form of RNA, not DNA. The virus tricks cells into reverse transcribing its RNA into DNA and integrating it into its own genome.
“At that time, there was really no way of studying the molecular or genetic basis of cancer by studying cancer cells, because the genome of the cell is so enormous,” said G. Steven Martin, one of Rubin’s former postdoctoral fellows and a UC Berkeley professor emeritus of molecular and cell biology. “Before the advent of cloning and genetic sequencing, we couldn’t look into the cancer cell and find the genes involved in cancer. Since tumor viruses have such small genomes and carry only a few genes, it was clear that studying tumor viruses would provide an entry point into the basic mechanisms of cancer.”
Between 1953 and 1958, Rubin worked as a postdoctoral fellow and, later, as a research fellow in the lab of virologist Renato Dulbecco at the California Institute of Technology in Pasadena. In 1955, Rubin showed that every cell in an RSV-induced tumor was capable of releasing the virus, implying that RSV was permanently associated with the host cell and suggesting that it plays a direct and continuing role in perpetuating the cell in its malignant state.
Then, working with Caltech graduate student Howard Temin, Rubin developed a way to measure the amount of infectious virus using cultured fibroblast cells from chicken embryos. This opened the way for quantitative studies of the mechanism by which RSV transforms normal cells into cancerous cells.
Dulbecco and Temin, along with David Baltimore, later shared the 1975 Nobel Prize in Physiology or Medicine for their work on tumor-causing viruses.
When Rubin moved to UC Berkeley in 1958 to join the Department of Virology, he continued work on RSV and developed other assays, including one to detect avian leukosis virus in vaccines, such as the measles vaccine, that are produced in chicken cell cultures.
He also showed that one strain of RSV was a replication-defective virus that could transform normal cells into cancer cells, but required a leukosis virus — a “helper virus” — to replicate and spread. In other words, the RSV could transform, but not replicate, itself, while the helper virus could replicate, but not transform.
“This was one of the very first observations to suggest that the virus might carry information about cell transformation and tumorigenesis that was separate from the information needed for the replication cycle of the virus,” Martin said.
Rubin’s work on RSV earned him a prized Lasker Award in 1964.
“The work of Drs. Rubin and Dulbecco proves that cells can carry, for many generations, a foreign nucleic acid, whether RNA or DNA, that is responsible for the malignant properties of these cells,” the Lasker Foundation wrote in giving them the award in clinical research.
Rubin also received the 1961 Eli Lilly Award in Bacteriology and Immunology and the 1963 Merck Research Award for his work on RSV and was elected to the National Academy of Sciences in 1978.
In 1970, a viral gene responsible for cancerous transformation, now known as viral src, or v-src, was identified through genetic and biochemical studies on RSV carried out by Martin, who was then in the Rubin lab, Peter Vogt at the University of Washington in Seattle and Peter Duesberg at UC Berkeley. This allowed Harold Varmus and Michael Bishop of UC San Francisco to identify an analogous gene in the cellular genome — a gene evidently stolen by the Rous sarcoma virus. Called cellular src, or c-src, it was the first known proto-oncogene, that is, a normal gene that, when mutated, can trigger cancer. Many more proto-oncogenes have been discovered since then. The discovery won Bishop and Varmus the 1989 Nobel Prize in Physiology or Medicine.
“The significance of the work on the Rous sarcoma virus is that it led to the work on cellular genes that can cause cancer,” Martin said. “The idea that, by studying the virus, one could get an insight into the cellular and genetic mechanism of carcinogenesis was, in fact, vindicated.”
Although Rubin’s research set the stage for the discovery of oncogenes, by the early 1970s he had switched his focus from viruses to the biology of transformed cells, looking at the mechanisms of growth control and, in particular, the role of inorganic ions in cellular regulation. In later years, he studied the origin of spontaneous transformation of animal cells in culture, using this system as a model for tumor progression.
Chasing cows and horses
Harry Rubin was born in New York City on June 23, 1926, the son of Russian Jewish immigrants. His father ran a grocery store in Manhattan. As a teenager, he worked on farms in upstate New York and at 16 enrolled in the veterinary school at Cornell University. Upon graduation in 1947 with a D.V.M. degree, he went to Mexico to help with an outbreak of hoof-and-mouth disease, then joined the U.S. Public Health Service in Montgomery, Alabama, to work on viral diseases, including rabies and Eastern equine encephalitis. In a 1991 profile in California Monthly magazine, he referred to it as time spent “chasing cows and horses in Mexico and Louisiana.”
Seeking new challenges, he enrolled at New York University and, a year later, in 1952, convinced Nobel Prize winner Wendell Stanley to let him work in his Virus Laboratory at UC Berkeley. Rubin transferred to Caltech in 1953, returning to join the UC Berkeley faculty in 1958, where he eventually occupied Stanley’s old office. He retired as an emeritus professor in 2001.
Rubin is survived by his wife, Dorothy, of Berkeley; three children, Andrew, Janet and Clinton Rubin; six grandchildren; and six great-grandchildren. He and his wife were longtime members of Congregation Beth Israel in Berkeley.