Epstein had first met Chekouras in the spring of 1993, when he visited the Medical College of Wisconsin to give a talk on BCNS. Nancy Esterly, a dermatologist at the college who was treating several BCNS patients, including Jenica, invited two of her families in the region down to hear the talk and meet Epstein. "Not that I had anything much to offer them clinically," says Epstein, "but at least I could tell them about what research was going on. So they had comeI don't know150 miles or something, driving through the mist of early spring in Wisconsin to Milwaukee, and we had a chat. And, of course, they gave us blood as long as they were there.
"We took the blood samples home, and it turned out Jenica had a mutation that was clearly of a type that would disrupt gene function. Her DNA was so abnormal in this gene that there was no question it would be pathogenic. Most importantly, this abnormality was not present in DNA from either of her parents.
"Since her parents had neither the mutation nor the disease, we could say that the mutation arose in the same generation as the disease, which gave us much more confidence that the mutation in patched was really the cause and BCNS the effect. That was the best evidence we had."
Indeed, it was so convincing that Epstein called Chekouras to get a second blood sample from Jenica and her parents just before announcing the discovery of the gene. He wanted to make absolutely sure there was no error. "I was quite surprised to hear his voice," says Jenica. "I'd only met him that once. Now he said, 'I'm sending you these vials by Federal Express and I need you and your parents to give me blood samples and I need them now.' My dad, being an international businessman, was in Italy. So we had to postpone it a
couple days until my dad could get back. Dr. Epstein was not pleased. He wanted my dad home now."
Once Jenica's father returned from Italy, the blood samples were taken and sent off, and they confirmed the early result. That clinched it. Epstein, Scott, and their colleagues published their discovery of the genetic basis of BCNS and basal cell carcinoma in the journal Science on June 14, 1996. On that same day, Allen Bale and an international team of collaborators announced the discovery in the journal Cell. Bale and his coworkers had come to patched in the traditional way, beginning with the key segment of chromosome 9q, where they knew the gene for BCNS must be located, then searching for candidate genes in that region and looking for mutations in patients and families with the syndrome. They were eventually able to identify mutations in the patched gene in six BCNS patients, as well as in two basal cell carcinomas not associated with the inherited disease. The two teams shared credit for the discovery.
Scott's group then went about turning a breakthrough in basic research into an important medical tool. The first step was to create a mouse model that could someday be the testing ground for all treatments of BCNS and basal cell carcinomaa mouse whose patched gene did not function. Mice without any working copy of the gene never survived past the embryo stage, proving that patched was indeed crucial for development, but mice that had one working copy of the gene (as Jenica does) showed symptoms that were very similar to those of BCNS. Some of these mutant mice were abnormally large, some had extra digits on their paws, and many developed a type of brain tumor, known as medulloblastoma, that results in early death. Medulloblastoma is the most common malignant brain tumor in children; the mutant mice provided a new tool for studying this dread disease. The mice also developed basal cell carcinomas when they were exposed to ultraviolet lightand became the first animal models for these common cancers.
Researchers now use mice to analyze how such cancers develop and to test potential therapies. Epstein says he can envision the development of a cream that patients could simply rub on their basal cell carcinomas to make them disappear. Several biotech companies are now working on such a therapy.
There are three reasons to be optimistic, Epstein says. "The first is that unlike most cancers, these hardly ever spread to other parts of the body; they do their damage by local invasion. This means the window of opportunity to treat them is much larger than in something like breast cancer, where you have to treat as soon as possible. Secondly, they are superficial and amenable to repeated therapies; you can get at them readily. And then, third, the cells in these skin cancers are already programmed to die. The function of normal epithelium, especially in epidermis, is for cells to divide, differentiate, and die. So there's a reasonable chance that if you nudge these cells over the precipice, they will do the rest of the killing all by themselves."
No one would welcome such a cream more than Jenica Chekouras. Three years ago she started a new form of therapy, called photodynamic therapy, in which a photosensitive agent is spread over her skin and then irradiated with light, which dries up the cancers and causes them to flake off. While the treatment seems to work better than surgery, it's time-consuming and often leaves Jenica with severe acne, painful boils, and burns. "My original idea was to do the photodynamic therapy until every last cancer was gone," she says. "I'm doing what I said I wanted to do when I was six. I'm burning them off. But it's quite physically trying. I'd love it if there was an easier way."
Gary A. Taubes
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Abnormalities in the first animal model for basal cell carcinomaa mouse with one defective copy of the patched geneinclude extra digits on its paws. Blue areas show where the gene is active.
Photo: Matthew Scott
Jenica leads a normal life but hopes researchers will find better and less painful treatments for her skin cancers.
Photo: Kay Chernush