Src: The Discovery of the First Proto-Oncogene

In 1951, a young graduate student named Howard Temin arrived at Caltech to pursue a project in fruit fly embryology. However, after only a few months, Temin became bored with fruit flies. He joined a neighboring animal virology lab and shifted his focus to the budding field of cancer biology.

Temin’s new PhD project revolved around a peculiar pathogen known as Rous Sarcoma Virus (RSV). RSV is an RNA oncovirus; upon infecting chickens, it rapidly induces the development of soft tissue tumors. Since the mechanism controlling this transformation was unclear, Temin wanted to narrow RSV’s oncogenic properties down to specific set of genes. An exhaustive series of mutation screens suggested that only a single gene - dubbed v-SRC - was necessary for RSV oncogenesis. RSV remained infectious when this gene was mutated, but lost its characteristic ability to form tumors.

Though the discovery of v-SRC explained what was driving RSV oncogenesis, it did not clarify how this process occurred. Temin, after finding a faculty position in the University of Wisconsin, provided part of the answer. In early 1970s, he conducted a labeling experiment that uncovered a critical component of the RSV life cycle. Following infection, RSV was capable of transiently incorporating its genetic material into a host cell’s genome. Now known as reverse transcription, this process enables RSV to pick up short, random sections of DNA from its host.

After discovering reverse transcription, Temin decided to (once again) switch fields, redirecting his attention towards the newly-minted field of molecular biology. Fortunately, other virologists were eager to his continue his work. In the late 1970s, a NIH researcher named Harold Varmus reviewed Temin’s RSV experiments and attempted to create a DNA probe for the v-SRC sequence. Much to his surprise, his probe not only found v-SRC in cells infected with RSV, but also in uninfected cells. Varmus proposed an elegant explanation after reviewing this result. He argued that v-SRC was a cell proliferation gene that RSV had captured, mutated, and overactivated through reverse-transcription. Though v-SRC is viral, Varmus believed that its less-active cellular progenitor - dubbed c-SRC - should exist as a normal, functional component of the host genome.

This hypothesis was quickly verified by later experiments, which both confirmed the existence of c-SRC and its necessity for cellular growth. c-SRC was not merely similar to v-SRC; the two genes were practically identical. Substituting a single regulatory amino acid effectively transformed healthy c-SRC protein into its hyperactive, oncogenic sibling. Normal, healthy c-SRC was always one or two unlucky mutations away from becoming a proper oncogene, and to acknowledge this fact, Varmus dubbed it proto-oncogene.

Varmus’ proposal led to a paradigm shift in cancer research. Ten years after the publication of his seminal c-SRC paper, laboratories around the world discovered dozens of proto-oncogenes. Much like c-SRC, most of these genes seemed to play two-faced roles: functioning both as central regulators of proliferation and key drivers of oncogenesis. Attention shifted towards characterizing these genes, their associated signaling pathways, and the genetic changes underlying their pathogenic variants. Molecular research began to frame cancer as the now-familiar disease of self: a disorder that arises from our own genome, with an almost inseparable link to growth and development.