Making The Best of a Bad Gene

By LEON JAROFF

Nancy Wexler was 22 when she got the grim news. Arriving home in Los Angeles after studying abroad on a Fulbright scholarship, she learned that her mother, then 53, had been found to have Huntington's disease. Wexler was devastated. The genetic disorder, which afflicts 30,000 Americans, had claimed the lives of her three uncles and her maternal grandfather, and she was only too well aware of what lay ahead for her mother: mental deterioration, uncontrollable movements in all parts of the body and, after a decade or so, death.

Because her mother had Huntington's, Nancy realized that she herself had a 50% risk of carrying the defective gene. And if she had inherited that gene, her fate was sealed; she would eventually come down with the disease, which usually strikes adults between the ages of 30 and 50.

Those dismaying revelations had a profound effect on Wexler, becoming the driving force in her remarkable career and largely shaping her personal life. Today, at 46, she is best known for her work -- which involved tracing the family tree of thousands of Venezuelans -- that led to the development of a highly accurate test for the Huntington's gene. She is president of the Hereditary Disease Foundation and chairs a key advisory group of the $3 billion Human Genome Project, which is attempting to identify all of the more than 100,000 human genes and pinpoint their locations on the 46 chromosomes. As a clinical psychologist at Columbia University, she conducts research and counsels people suffering from Huntington's.

Wexler credits her father, now 83 and still a practicing psychoanalyst in Los Angeles, with motivating her on the day that he told her about her mother's illness and discussed the fact that she was at risk as well. "Practically in the same breath," she recalls, "he said, 'And we're going to fight it.' " He informed Nancy and her sister that he had started a group dedicated to curing Huntington's and had begun organizing workshops at which scientists could plan their attack on the still mysterious cause of the disease. "It was really therapeutic," Nancy says. "It gave us something to hold on to. At the time, we all thought we might find a treatment in time to save my mother. We were pretty naive."

Enrolling in graduate school at the University of Michigan at Ann Arbor, Wexler set her sights on a doctoral degree in clinical psychology, and chose Huntington's disease as her thesis subject. She also set up a Huntington's group in nearby Detroit, working with afflicted families there.

"At first, in Ann Arbor, I didn't tell anyone about being at risk," she says. "I was too stunned, but I was also embarrassed about it, ashamed." In Detroit, however, surrounded by Huntington's families, she freely discussed her risk and her emotions. "So I had this kind of schizophrenic life between my Detroit world and my Ann Arbor world," she recalls. "One was my sick world, and one was my healthy world, and I would commute."

After earning her doctorate in 1974, Wexler set out to look for work, armed with glowing recommendations from her thesis advisers, who by this time had learned of her risk. "I had to ask them to rewrite their letters, to tone them down," she confesses. "While they didn't say I was at risk, they portrayed me as being totally committed to Huntington's research. I was worried that a potential employer might become suspicious that I was at risk and be afraid to hire me."

Wexler did find work: first as a psychology teacher at New York City's New School for Social Research, eventually as a researcher at the National Institutes of Health. Getting that job, says Wexler, "was very healing to me. They knew I was at risk, and they were familiar with Huntington's symptoms. They knew I would become a civil service employee and they would have a hard time getting me out of there if I got sick. Yet they hired me. Finally everything was out in the open."

By this time genetic researchers were devising ingenious ways to isolate and identify disease genes in human DNA, and Wexler recalled a Huntington's meeting she attended in 1972. There a doctor reported the discovery of a group of interrelated Huntington's families, numbering in the thousands, who live along the shores of Venezuela's Lake Maracaibo. "At the time," says Nancy, "we all thought that this extended family was a fantastic resource for genetic research, but nobody knew how to formulate the right research." Wexler decided it was time to act.

In 1979 she led a small expedition to Lake Maracaibo. There she took blood samples from several members of the Huntington's family and sent the samples back to the U.S. for analysis, hoping they might provide a clue to the illness. No luck. Undaunted, she returned to Venezuela in 1981, this time with a larger team and a detailed battle plan. Interviewing hundreds of family members, she began constructing a huge family tree, tracing the transmission of the Huntington's gene from generation to generation. From each person on the chart, she took blood and skin samples.

At first the villagers were suspicious and reluctant to cooperate. Frustrated, Wexler called a town meeting. "We explained that we were trying to find the cause of the disease," she says, "and while it might not help them, it could help their children and grandchildren." She told the villagers that her mother had died of Huntington's and that she might also be stricken. Holding up her right arm, she pointed to a tiny biopsy scar and revealed that she too had contributed a skin sample for analysis. "They really understood that," Nancy says, "and I think they soon realized that we meant them no harm. I became sort of like a family friend, with syringe."

The skin biopsies (soon found to be unnecessary) and blood samples were sent, along with pedigree data, to James Gusella, a young Canadian scientist working at Massachusetts General Hospital. Using a new technique, he was able to locate a DNA marker close to the Huntington's gene. It lay toward the tip of the short arm of chromosome 4. That discovery led to the development of a test, now 96% accurate, that can determine the presence of the errant gene long before any symptoms show up.

But that poses a dilemma typical of the ethical, legal and social issues raised by recent breakthroughs in genetics. Because no cure for Huntington's exists, a positive test result is like a death sentence. Though it cannot foretell when the first symptoms will appear or how long the victim will suffer, the outcome is certain. On the other hand, a negative result can dispel the cloud of anxiety that hangs over every member of a Huntington's family. Before advising people to take the test, Wexler carefully probes each person's attitude and outlook. "Some people can cope very well with a positive result," she says. "Others almost certainly can't."

Has Nancy been tested? "That's a very private matter," she says pleasantly, "and I don't talk about it." Indeed, confidentiality about an individual's genetic makeup ranks high among Wexler's concerns. She is a strong advocate of keeping such information secret from employers, insurance companies, government and any agency that might discriminate against people on the basis of their genes.

Concerned about her own risk, Wexler dated but never married. Then she met -- and now lives in Manhattan with -- Dr. Herbert Pardes, head of the Columbia University medical center. "Around the time we found the marker for Huntington's, I found Herb, and it's been wonderful and fantastic," she says. "I've since realized how wrong it was for me to avoid sharing my life with someone. I held back not only because of doubts about passing the gene on to my children but because it would be unfair for my mate to be burdened, financially and emotionally, with a Huntington's spouse. It would be too much of a sacrifice. But Herb is willing to accept whatever happens."

Returning to Venezuela for six weeks early every spring, Wexler takes more data and blood samples and adds lines and boxes to the growing pedigree chart of her Huntington's family, which now contains the male or female symbols of more than 12,000 people and covers both sides of the corridor wall outside her Columbia office.

Wexler's accomplishments, her life with Pardes and her near celebrity status have largely fulfilled her, but they have not diminished her resolve. "There are two voices in my head," she says. "One is incredulous. It says, 'Can you believe all the good things that have happened to you?'

"But the other says, 'Look here, Wexler, there are still people out there with genetic diseases, out of sight, out of mind, in the hospitals, at home dying. They don't care what you're doing and who you know. You've got to find a cure -- you've got to save them.' "

That voice, says Wexler, "is what makes me tick."