The Man Who Makes the Pieces of the Puzzle Fit : Medicine: Mark Skolnick’s team discovered the gene that causes inherited breast cancer. He says he empathizes with what the women go through because he has his own genetic disorder.

For most researchers, a major genetic breakthrough is a once-in-a-lifetime experience.

Mark Skolnick has had three, two of them just within the past six months.

He was a key player in the mid 1970s in the development of restriction fragment length polymorphisms (RFLPs), a crucial technology in identifying virtually every disease-causing gene isolated over the last decade.

He headed a team that in April announced the discovery of a tumor-suppressor gene that may be involved in more than half of all cancers.

But his masterpiece achievement, and the one that may bring this University of Utah researcher his first true measure of fame, came last week when Skolnick and his colleagues announced the discovery of the most important gene that causes inherited breast cancer. The gene is carried by an estimated 600,000 U.S. women, 85% of whom will develop the disease by the time they are 65.

Isolation of the gene, scientists predict, will allow identification of women at high risk, allowing them to closely monitor their health to catch the disease at an early stage while it is most curable. The discovery also provides the first firm information about what causes breast cancer, and should thus offer insight into the genesis of non-hereditary breast tumors as well.

“The discovery is an extraordinary advance for cancer research,” said fellow geneticist Bert Vogelstein of Johns Hopkins University.

By the end of the week, Skolnick was hoarse from both a bout with bronchitis and the incessant telephone and television interviews--from local TV to network morning shows. The excitement, he said, “really pleased” his family, which includes two sons, Giancarlo and Joshua Luca, who is named for two of Skolnick’s mentors.

Despite the jubilation about the new finding, celebrations have been low-key. The completion of the paper was marked with low-fat tortilla chips, for example, because Skolnick found out this summer that he suffers from his own genetic problem, a potentially fatal lipid disorder called Syndrome X that leaves him highly susceptible to heart disease. It was identified after doctors found that he had sugar in his urine, a kidney stone and other “annoying” medical problems.

Syndrome X, he said, “kills people in their 40s and 50s.” Skolnick is 48.

Discovery of his own genetic disorder has given him new empathy for women who have inherited the breast cancer gene, he noted in a telephone interview. It has also brought a sharp change in his lifestyle. Although he has always enjoyed trips to the desert and hiking and skiing in the nearby Wasatch Mountains, the pattern has become more regimented, with daily walks with his wife, Angela. He is also on a fat-free diet.

Friends and colleagues who call him an intense and driven researcher in the laboratory now use the same words to describe his efforts to take charge of his health. Skolnick himself noted proudly that he has “lost 19 pounds in the last two months--no, make that 16. I lost three before I started the diet.”

The Utah mountains he now visits regularly were not, however, what lured this self-described “California Jewish boy” to Salt Lake City in 1974 after he completed his education at UC Berkeley and Stanford. Rather, it was the large Mormon population in Utah and the surrounding states.

The Mormons represent a unique population, experts agree. They don’t smoke and they don’t drink. They don’t often move away from the area, and neither do their children. They keep extensive family genealogies.

In short, they are a dream population for an epidemiologist trying to track down genetic diseases. But few geneticists were perceptive enough to recognize their potential, and the population lay fallow until Skolnick’s arrival.

“He was ahead of his time in terms of his insight in starting to use the Mormon pedigrees,” said molecular biologist Andy Futreal of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.

“It was a bold move to leave Berkeley and move out into the desert,” added Roger Wiseman, Futreal’s colleague. “He dedicated many years to collecting the families and setting up the Utah Genealogical Data Base,” which now contains the names of, and critical heath information about, more than 1.3 million people.

Records in the data base can show, for example, how strongly a disease such as cancer clusters in particular families and enable researchers to track it over several generations. Perhaps most importantly, the registry provides a source of blood samples from both affected and unaffected family members that allow researchers to use sophisticated molecular biology techniques to isolate genes.

The data base made the discovery of the breast cancer gene possible.

“I don’t think that it could have been done anywhere else,” said Dr. Randall Burt, a medical geneticist at the University of Utah. “It’s not that it absolutely could not have been done elsewhere. . . . It’s just that it would have been immensely more difficult.”

Lured by the data base, more than 100 geneticists have descended on the previously sleepy Salt Lake City campus, converting it into a hotbed of genetic research that announces genetic discoveries with great regularity. Ironically, one who was attracted was Raymond White, the researcher who identified a major colon cancer gene. White has been more successful than Skolnick at capturing research funds and has a large laboratory in a new building on campus, while Skolnick operates out of a research park half a mile out of town.

White and Skolnick share an intense--and, colleagues say, a sometimes acrimonious--competition. One of Skolnick’s colleagues said his first thought on seeing the paper was, “I’ll bet White is eating his liver.”

“They are two big fish in a relatively small pond,” said geneticist Laurence Meyer of the University of Utah.

White could not be reached for comment, and Skolnick was reluctant to discuss the relationship. But he did say that the competition “is not any different than other relationships, which are either positive or negative, just the way human beings are.”

Skolnick’s team is now pursuing a variety of other genes involved in cancer and heart disease--including one newly added to the list, the gene for Syndrome X. His 3-year-old company, Myriad Genetics Inc., is also working rapidly to develop diagnostic tests for breast cancer and other types of cancer, based on the two discoveries.

Skolnick is the idea man and synthesizer for the group, the person who collects little bits of data produced in the laboratory and puts them together into a coherent picture, analyzing, interpreting and predicting. He does little laboratory work himself. “I spend most of my time on the telephone,” he noted.

Ultimately, said Utah’s Meyer, “We are left with a bright guy who has a good, balanced life. He works hard, he plays hard. He’s been at it a long time, and he has stayed on task. This (the breast cancer gene) is just one of several fruits he’ll be able to pluck.”