Catching a Rogue Gene

By Christine Gorman

Anyone who doubts that the pace of the genetic revolution has accelerated mightily need only consider last week's news about colon cancer. It was just last May that a team of researchers led by Dr. Bert Vogelstein at Johns Hopkins University in Baltimore announced conclusive evidence that a genetic defect causes a hereditary form of colon cancer, accounting for as many as 22,000 cases in the U.S. every year. The next step was to pinpoint the malfunctioning gene, which lurked somewhere on chromosome 2. Back in the 1980s, that search might have taken three years or more. Instead, it took six months: last week two teams of biologists announced that the errant gene had been found and duplicated in the lab.

The discovery does more than satisfy scientific curiosity. It means that researchers will now be able to save lives by developing a diagnostic test for the gene. Perhaps 1 million Americans carry it; if tested, they would be advised to have frequent colon exams. If tumors are discovered early enough, they can often be removed before the cancer spreads and becomes fatal. "This seems likely to be the first DNA test that will find its way into general clinical practice," predicts Dr. Francis Collins, who heads the Human Genome Project that is mapping all 23 pairs of human chromosomes.

The genetic mutation described last week triggers cancer in an indirect way. "Every cell has a genetic blueprint -- its dictionary of genetic instructions," explains Richard Kolodner, a biochemist at the Dana-Farber Cancer Institute in Boston and one of the discoverers of the defective gene. This blueprint must be recopied each time the cell divides. "Some mistakes get made," Kolodner continues. "The ((protein made by the normal gene)) is like the spell-checker on a computer. It helps to scan for errors, detect them and fix them." When the spell-checking gene is damaged in some way, mistakes start piling up in other genes. Eventually some of the genes that keep cells from dividing uncontrollably are affected and cancer arises. It most often strikes the colon, but can also occur in the uterus, ovaries and other organs.

The search for the colon-cancer gene seems likely to go down in history as one of the great races of modern genetics. It was not the odds-on favorite team, led by Vogelstein, that isolated the mutated gene first, but rather a less well-known pair of biochemists from New England -- Boston's Kolodner and Richard Fishel at the University of Vermont.

"When we read about the ((evidence of a colon-cancer gene)) in May, we realized that the genetic instability being describing was identical to one that we already knew about in yeast," Fishel says. So he and Kolodner and their colleagues decided to hunt for a human gene similar to the yeast version. In November they rushed their results to the research journal Cell, which decided to publish the paper on Dec. 3. "We heard from Dr. Vogelstein a couple of hours after our paper was accepted," Kolodner recalls. Vogelstein, realizing he was about to be outpaced, then pulled together the results of his group's ongoing research, which will be published in the journal on Dec. 17. Acting as race stewards, the editors of Cell decided to lift the embargo on the Vogelstein article so that both groups could share the spotlight last week.

Now the competition has started to devise the screening test. It may be available within 12 months -- not a moment too soon for people whose genetic makeup leaves them vulnerable to a killer disease.