The genes that were associated with tumor formation were first found in viruses. So called "tumor viruses" don't kill their hosts directly. Instead they force the cells that they infect to multiply uncontrollably. It turns out that virus-induced cancers are rare, accounting for less than one fifth of all malignancies. Nevertheless, scientists in the 1970's recognized that they might provide clues to the mechanism of carcinogenesis in general. The idea was that if one could understand how a gene in a virus led to cancer then that knowledge could be more widely applied. Ultimately, these studies resulted in the discovery of oncogenes.
Peyton Rous and the Plymouth Rock Hen
The history of the connection between viruses and cancer actually begins in the second decade of the twentieth century. One day a chicken farmer arrived at the Rockefeller Institute in Manhattan bearing a Plymouth Rock hen in her arms. The bird had a large mass (a sarcoma) growing out of its right breast muscle. It isn't clear what the farmer expected from her visit to that venerable institution but she and her bird were shown into Peyton Rous' laboratory. Weinberg writes that Rous "dispatched" the hen but that's not quite correct. Rous etherized the chicken and removed the mass. He sliced it into fragments and injected a few into the chicken's other breast and several into its peritoneal cavity. The hen died a month later. By that time, the cancer had grown in the injected locations and was likely responsible for the fowl's demise. Injections of fragments of the tumor into similar locations in closely related chickens also caused tumors. By continually transferring pieces of tumor from one chicken to another, the cancer could be propagated indefinitely.
These experiments had shown that the agent promoting the cancer was transmissible. Rous wondered what the biochemical nature of the agent was. Could it have been the tumor cells themselves? Or chemicals emanating from the tumor? Could it have been bacteria or something more exotic?
To find out, Rous took a relatively straightforward approach. He took the tumor, ground it up in a weak salt solution, and passed the resulting slurry through a filter. The filter that he used was sufficiently fine that it didn't allow anything bacteria-sized or bigger to pass through. Subsequently, he injected the filtrate (the solution that came through), into the breasts of susceptible chickens. The result: The chickens got tumors! He concluded that the cancer causing agent was smaller than a bacterium and probably a virus (he didn't use the term because it wasn't popular at the time), or, less likely, some chemical given off by the tumor.
The scene not shifts ahead several decades to a laboratory at Cal Tech in Pasadena, California. There two scientists found that Rous' virus, now called RSV (for Rous Sarcoma Virus) could be used to infect chicken cells grown in a Petri dish. The infected cells acted in several ways like they had become cancerous. They didn't stop growing after they covered the entire dish in a single layer. Instead, they piled on top of one another, unlike normal chicken cells. They acquired a distinctive rounded shape that differed from normal cells. And they grew indefinitely. What was it in the virus that caused these dramatic changes?
RSV and similar viruses have a very small genome consisting of less than five genes (RSV is an RNA virus, a retrovirus, that reproduces by making a DNA copy of its genome and integrating it into the chromosome of its host). It seemed to researchers that if a viral gene was responsible for transforming normal cells into cancerous ones, it would be a simple task to identify which viral gene was responsible for the deed. The genes that specify the viral coat were ruled out as were the genes responsible for converting the RNA into DNA and integrating a DNA copy of the virus into the chicken genome. What was left was a gene that researchers called src (pronounced "SARK") for "sarcoma" named for its probable role in cancer formation.
All now seemed clear. The scientists involved reasoned that the virus attaches its DNA to the chicken chromosome, and the newly introduced src gene somehow causes the infected cells to become cancerous. To demonstrate that their reasoning was correct, they infected some chicken cells with the virus and using a well worn molecular technique assayed the cells for the src gene. As expected, they found it. However, as a control, they looked for the src gene in uninfected cells. To their astonishment, it was there too.
What soon became clear was that every animal they looked at harbored a src gene. Mammals, fish, insects, even sponges had it. Or at least a close relative, genes that had almost the same sequence. What was going on? To shorten a long explanation, it appears that the cellular version of the src gene, called c-src to distinguish it from its viral cousin (v-src), is an important gene that regulates cell growth in a great variety of organisms. Somehow the RSV virus had picked up the gene and corrupted (mutated) it, causing it to promote unwarranted proliferation after viral infection. The implications of this interpretation were clear: perhaps some cancers were caused by mutations in the normal c-src gene. Perhaps, by looking in other tumor viruses, other genes could be identified that had cellular counterparts.
And so it was so. The myc gene, a gene present in another avian RNA virus, was found to induce bone marrow cancers in chickens. And in time more than 30 similar genes were found in viruses that infect chickens, mice, cats, and monkeys. The cancer causing genes in these viruses were termed "oncogenes", and their normal equivalents "proto-oncogenes". Scientists predicted that these proto-oncogenes could be converted into oncogenes by mutations.
These observations opened up a key question: How do oncogenes, either of cellular or viral origin, change a cell from normal to malignant? That is the subject of the next post.