In the fall of 1993, Dr. Francis Collins, director of the National Center for Human Genome Research in Bethesda, Md., was contacted by Brad and Vicki Margus of Boca Raton, Fla. The couple had learned that two of their three sons were afflicted with a rare genetic disease, ataxia telangiectasia (A-T). Jarrett and Quinn, then 4 and 2 respectively, were stumbling and bumping into walls, the first symptoms of a neurological breakdown leading to the loss of such vital motor skills as walking, writing and even speaking. In the teen years, A-T victims develop cancers, and most die by their 20s.
By the time Margus, 35, a graduate of Harvard business school and president of a shrimp-processing company, spoke to Collins, he had already raised $600,000 to fund research on the disease's genetic cause. Collins, who had been hunting for the A-T gene as part of a team headed by Dr. Yoshef Shiloh of Tel Aviv University, was inspired to accelerate his efforts. This summer the team announced it had succeeded in isolating the gene that, in a mutated form, causes A-T. Even more significant was the revelation that carriers of the damaged A-T gene, like Brad and Vicki—though suffering none of the neurological problems of the disease's actual victims—appear to be many times more vulnerable to a wide variety of cancers than noncarriers. The A-T gene could become a key to a cure for cancer.
Reared in Staunton, Va., Collins, 45, received his Ph.D. in physical chemistry from Yale and his M.D. from the University of North Carolina. As an assistant professor at the University of Michigan, he pioneered methods of gene detection that, in 1989, resulted in his codiscovery of the gene that causes cystic fibrosis. Collins, a divorced father of two, became head of the Human Genome Project in 1993. (The Project, which so far has mapped 7,000 of the human body's 80,000 genes, expects to complete its work of reading the entire genetic blueprint of the human body by 2003). He discussed the significance of the A-T gene discovery with Chicago bureau chief Giovanna Breu.
What is the connection between A-T and cancer?
Each of the body's genes exists in two copies, one of which we inherit from our mothers, the other from our fathers. The A-T gene is one of about 4,000 located on the 11th chromosome. Each gene can be printed out as a sequence of letters—A, C, G and T, standing for the four chemical compounds that make up DNA. If you printed the A-T gene's sequence, it would run about 100 pages long. The mutation results from a single misspelling somewhere in those 100 pages. If both copies of the gene are misspelled, you get A-T. If only one copy is misspelled, you are an A-T carrier, and you run an abnormally high risk of developing certain cancers.
Women who are A-T carriers may be as much as five times more likely to develop breast cancer than those who are not. Carriers apparently are also more susceptible to cancers of the skin, lung, stomach and pancreas. Overall, a carrier of the A-T gene has a three-to four-fold increased risk of developing some form of cancer over his or her lifetime. Other genetic defects, such as the breast cancer gene called BRCA1, carry an even higher risk of cancer. The significance of the A-T gene is that it is so common.
The mutated form of the gene is carried by one in every 100 people. That's 2.5 million carriers in the U.S.—and the vast majority don't know they have it.
How do you know if you are a carrier—and what do you do if you are?
At present the only way to know if you are a carrier is if you have had a child with A-T. (Even when both parents are carriers, the risk of their child having A-T is only one in four.) We should be able to develop a test for the gene relatively soon—possibly within two or three years. Then, people who know their risk is high might want to alter their diet, their lifestyle, and be checked more often for cancer.
What is the function of the A-T gene?
When cells divide, they usually check themselves beforehand to make sure they're not damaged. Damaged cells usually don't divide. But when the A-T gene contains an error, damaged cells continue to divide when they should have stopped and repaired themselves. An analogy would be a driver who sees the oil-pressure light come on in the car. Most drivers would stop immediately and add oil. A faulty A-T gene is the driver who doesn't stop. He or she keeps on going and destroys the engine.
How was the A-T gene found?
By a very tortuous process of sifting through chromosomes until you hit the right gene—which you can identify because of its misspelling. If you print out the entire genome of a human being, it would fill 23 sets—not volumes, sets—of the Encyclopaedia Britannica with every line of every page filled with strings of A, C, G and T. To find a single gene, first you have to find the right volume, and you have to turn pages, page after page, until you hit on it.
How important is the discovery of the A-T gene in finding a cancer cure?
Cancer is a genetic disease where cells have DNA damage that causes uncontrolled growth. What we learn about A-T will tell us how cells repair themselves and how they go awry.
It should be possible to design a drug that compensates for the effect cancer has on cell checkpoint control. In 10 to 15 years we may know how to fix the problems. Finding the gene isn't a cure, of course. But if you ask Brad Margus, he'd say that now there's hope.
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