Serendipity -- the gift of finding something valuable that had not been sought -- not infrequently plays a part in medical research. From several perspectives, serendipity is in full swing in relation to the discovery of the gene that, when defective, causes the devastating and almost unpronounceable disease ataxia telangiectasia (AT).

AT is a rare inherited disease. It shows up in infants about the time they should start walking. The children move awkwardly, and most are wheelchair-bound by the time they are 10 years old. The immune system of a person with AT cannot successfully fight off infections and cancers. Few people with AT live beyond their late teens or early twenties.

AT is rare -- about 500 children in the United States are known to have it -- and many fewer researchers work on it than work on diseases like breast cancer or the flu. But, as the discoverer of the AT gene, Dr. Yosef Shiloh, said at a press conference on June 22, 1995, "the tragedy for a family (whose child has AT) is 100% for that family, no matter how rare the disorder." Every disease, including the most rare, needs a treatment or a cure.

Shiloh began looking for the gene that causes AT some 18 years ago. That was when he first saw a number of Moroccan Jewish children in southern Israel who were suffering from the disease. Today, he says, he is also studying the disease in a Palestinian Arab village of 5000 people where many of the children have AT.

The defective gene in AT is situated on human chromosome #11. In the 50 patients whose genes have been analyzed so far, Shiloh and his coworkers found 43 different mutations that all caused the disease. The mutations were scattered throughout the AT gene. Dr. Francis Collins, a co-discoverer of the gene, described it this way: "Every (affected) family seems to have a different (gene) misspelling."

The AT gene has turned out to be more than JUST the AT gene, and that is where serendipity first enters the story. The mutated gene on chromosome #11 also seems to predispose its carriers to breast cancer and perhaps other forms of cancer. AT is rare, but breast and other cancers are not. So, dozens of cancer researchers around the world are gearing up to examine the AT-cancer gene from every angle, and this can only prove beneficial for both AT and cancer research and the patients with these diseases.

At the moment, most of the known carriers of the AT gene are the parents of the children who have AT. For a child to develop AT, s/he must have two defective copies of the AT gene, one inherited from each parent. The parents, in contrast, each have one normal gene and one defective one. Their one normal gene makes a product that compensates for the defective product of the AT gene, and this is what keeps them from developing the disease that their children will get.

How many people besides the parents of affected children carry one defective AT gene? Right now, the best guess of researchers is about 1% of the population or, in the United States, some 2.5 million people. With the gene now known and detectable, accurate identification of carriers in the general population can soon be made.

The first benefit from the discovery of the gene will indeed be identification of carriers of the AT gene and follow-up prenatal tests for AT. As researchers got closer to finding the AT gene during the past year, they were able to diagnose AT in a fetus of a pregnant women who already had had a child with the disease. Knowledge of the nature of the gene and other information about how it affects the functioning of the cell should point the way to the development of drugs that can counter the defective gene's devastating effects. Much farther down the road, it may someday be possible to use gene therapy to correct the disease, because, as has been seen with carriers, people who have one normal AT gene do not develop AT.

The AT gene may predispose not only AT patients but also carriers of an AT gene to the development of certain cancers. In the specific case of breast cancer, for example, the best guess now is that, among women with breast cancer, some 8% probably have the AT gene. At first blush, this would suggest that carriers of the gene be monitored closely for tiny tumors. But there's a problem. The diagnostic test for breast cancer -- a mammogram -- may in fact accelerate tumor growth. The cells of children with AT are unusually sensitive to x-rays and other forms of ionizing radiation: when they are placed in a test tube and exposed to radiation, they die rapidly. Cells of normal people are not nearly so susceptible to radiation damage, and the sensitivity of cells of AT carriers falls midway between the two. Whether screening procedures like mammograms or other forms of diagnostic radiation in fact cause or accelerate the problems they are designed to prevent is a puzzle that only time and additional studies can resolve.

The association of a cancer gene with AT is sure to benefit both AT and cancer research. The product of the gene appears to be a large protein that is important in the proper functioning of the normal cell, which means that this research will, serendipitously, also yield important clues to the workings of healthy cells.

Shiloh's findings are published in Science, 1995, 268:1749.