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                                                                                PROFILE, Page 78

Making the Best of a Bad Gene


After discovering that she might fall prey to Huntington's
disease, NANCY WEXLER went on a far-flung quest to help others
at risk

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."