Oncogenes are not the end of the story of cancer, however. Simply activating cellu­lar oncogenes does not inevitably lead to cancer. If oncogenes are stepping on the gas in the cellular automobile, are there brakes? Indeed there are. After the break­through in growing tumor cells in culture from a cervical cancer in Henrietta Lacks (20)—the famous HeLa cells—scientists were able to study characteristics of cancer cells more readily. One remarkable experiment was to take cancer cells and fuse them with normal cells, resulting in hybrid cells that would have charac­teristics of both types of cells. The important question was whether the cells would behave like cancer cells or like normal cells. Surprisingly, the hybrid cells were no longer malignant—something in the normal cells was able to override the genetic changes in the cancer cells that made them malignant. The unidentified substance in the normal cells was called a tumor suppressor gene (17), but the tools were not yet ready to discover what it was, though it could be traced to a location on normal human chromosome 13. Whatever it was, it acted like the brakes on the cellular automobile.

In 1969 a geneticist named Alfred Knudson moved to the MD Anderson Cancer Center in Houston, Texas, to study childhood cancer. He became interested in a rare tumor in the retinas of children known as retinoblastoma. Curiously, the tumors most frequently occurred in very young children under age one who are in families with a history of retinoblastoma, but sometimes they occurred in two — to four-year-old children who had no family history of the cancer. Knudson worked out the genetics of the disease and proposed that the infants who had the familial form of retinoblastoma inherited a mutant copy of a gene called Rb. If the infant then got a mutation in the other copy of Rb, it would develop retinoblastoma very early. Older children who got the sporadic form of retinoblastoma did not inherit a mutated copy of Rb so they would have to get two separate mutations in Rb to get the retinoblastoma tumors, which is much less likely (16). The surprise was that a single normal copy of the Rb gene could suppress the tumor, so both copies would have to be deleted or mutated to allow the retinoblastomas to grow.

This Rb gene turned out to be the same type of gene that could suppress the malignant characteristics of the hybrid cultured cells—a tumor suppressor gene. It does this by halting cells in the cell cycle before they enter the synthesis phase where DNA gets replicated, at a location known as a checkpoint. If the DNA of cells is damaged, the normal function of Rb is to block cells at the checkpoint until they can repair the damage. If there is no functional Rb, as in the case of the children with two bad copies of the gene, then the cells proceed through the cell cycle and divide, even though they contain DNA damage.

The retinoblastoma gene turned out to be the tip of the iceberg, as more than 20 tumor suppressor genes are now known (21). These tumor suppressor genes act as anti-oncogenes since they have the capability to halt the hyperactive signaling of the oncogenes. As molecular tools became available to analyze the molecular characteristics of cells from human tumors, it became clear that many different tumors had mutations in the Rb gene. Another tumor suppressor known as p53 became famous as the “guardian of the genome” because of its involvement in halting cell growth in the cell cycle, facilitating repair of DNA damage and induc­ing a form of cell suicide if the damage could not be repaired (22). Mutations in the p53 gene (called TP53) are found in more than half of all human tumors. It became clear that tumor suppressor genes had very powerful influences on whether activated oncogenes could cause a cancer.