The Opposite of Oncogenes

As if oncogenes were not enough, scientists in the early 1980s discovered a second type of gene that can play a role in starting cancer. These genes are the exact opposite of oncogenes: Instead of producing cell growth, their normal job is preventing it. They cause cancer not when they become overactive, as happens with oncogenes, but when they fail to function. Cancer researchers call these genes tumor suppressor genes. Robert Weinberg has often said that active oncogenes are like a stuck accelerator on a car, whereas missing tumor suppressor genes are the equivalent of defective brakes.

Researchers found the first tumor suppressor gene in a rare type of cancer that strikes young children. This cancer, called retinoblas-toma, grows in the eye. When an infant develops retinoblastoma, doctors usually have to remove one or both of the child's eyes in order to save its life.

Physicians had observed that retinoblastoma sometimes ran in families, but in other cases the cancer developed in children who had no relatives with the disease. Living things that reproduce sexually inherit two copies of each gene, one from the father and one from the mother. In 1971, Alfred G. Knudson, Jr., a professor of medical genetics and pediatrics at the Health Science Center in Houston, Texas, proposed that both copies of some gene, then unknown, were defective in retinoblastoma. Children from families in which the disease was common, he theorized, inherited one faulty copy of the gene and later lost the second copy through random mutation, perhaps when eye cells multiplied rapidly after birth. Children from families in which retinoblastoma had been unknown, on the other hand, inherited two normal genes, but mutations made both genes inactive. If both genes were inactivated in even one cell, that cell would begin multiplying uncontrollably and produce a tumor.

But what gene was missing? Jorge Yunis of the University of Minnesota Medical School found a clue in 1980 when he learned that a part of chromosome 13 was absent in all the cells of children with inherited retinoblastoma but only in the tumor cells of those with the noninherited form of the disease. Using techniques similar to those that had helped Bishop and Varmus find the normal form of the src gene, several sets of scientists

Fertilized egg

I Multiple cell f divisions

Retinal (eye) cell lineage

Retinal (eye) cell lineage

Tumor cells

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The damaged genes that result in the eye cancer called retinoblastoma are sometimes inherited and sometimes not. In the example here, a child inherits one damaged gene (vertical bar) from its father. If a mutation damages the healthy gene (inherited from the mother) while eye cells are multiplying before birth, the cell in which the mutation occurs will lose the power to control its growth. It will multiply and form a tumor. A tumor can also result if both copies of the gene are normal when inherited from the parents but become damaged before birth.

began searching chromosome 13 for a gene that suppressed cell growth. Stephen H. Friend, a member of Robert Weinberg's laboratory, finally located the gene in 1986 and named it Rb, for retinoblastoma. The Rb gene has since been found in a variety of tissues, and it has proved to be missing in several different kinds of cancer.

After the discovery of Rb, scientists found a number of other tumor suppressor genes. One such gene, p53, is mutated or absent in a wide variety of cancers, including colon, bladder, and breast cancer. Unlike the case with Rb, even a single defective copy of p53 makes a cell produce a misshaped protein. As with proteins made by oncogenes, those made by tumor suppressor genes are part of complex chains of signals that control a cell's activities. A break or change in any link of one of these chains can keep the whole chain from working properly.

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