Bishop, Varmus and cellular oncogenes

In the 1960s the word oncogene meant a piece of viral genetic material. A favored theory, the virogene-oncogene hypothesis, held that such viral genes lay dormant in normal cells until a carcinogen woke them. Rous sarcoma virus, the chicken tumor virus first found by Peyton Rous at the Rockefeller Institute, was the model. Steve Martin had isolated a mutant that lost its power to transform cells at a raised temperature, which defined the transforming gene later named src.

Harold Varmus joined Michael Bishop's group at the University of California, San Francisco, as a postdoctoral fellow in 1970. They used reverse transcriptase to copy viral RNA into radioactive DNA probes. In 1971 Peter Vogt had isolated mutants of the virus that multiplied normally but could not transform cells, and their RNA was about 15 percent shorter. By copying DNA from the whole virus and stripping out everything that matched the mutant, the team could make a probe for the missing stretch, known as sarc. Dominique Stehelin produced one that met their standards.

The sarc probe bound extensively to normal chicken DNA, as the old theory predicted. But it also bound to DNA from quail, duck and even the Australian emu, while a probe for the rest of the viral genome bound poorly outside chickens. The gene had been conserved through at least 100 million years of bird evolution. In 1976 Stehelin, Varmus, Bishop and Vogt argued in Nature that the viral gene came from a normal cellular gene, captured in slightly altered form, which probably helped control cell growth or development.

Other laboratories confirmed it. Joan Brugge and Ray Erikson identified the v-src protein, of about 60,000 daltons, and Hermann Oppermann and others found a nearly identical protein in normal cells; it proved to be a kinase that acts on tyrosine. Deborah Spector showed that the probe annealed to DNA of all vertebrates, humans included. By 1989 more than 40 oncogenes were known, among them erbB, found amplified in some glioblastomas. Bishop and Varmus shared the 1989 Nobel Prize in Physiology or Medicine.