The Pioneers of Molecular
Biology: Nancy Wexler
At
risk for Huntington's disease herself, this scientist has
made
unraveling its mysteries her life's work
By Alice
Park
Posted Sunday, February 9, 2002; 10:31 a.m. EST
To the people living in the tiny communities around Venezuela's Lake
Maracaibo it was el mal, the mysterious affliction that had been
possessing all too many of their friends and loved ones since the 1800s.
You could spot el mal's victims on the street: otherwise healthy men and
women stumbling along, weaving like drunkards. Talk to them and they
would either brush you off rudely or launch into irrational, screaming
tirades.
Nancy Wexler, a neuropsychologist at Columbia University, was also
familiar with el mal. But she called it Huntington's disease, and knew
it as the neurological malady that had stalked her family for
generations, killing her mother, three uncles and a grandfather. She
also knew what the Venezuelans did not: that the disease was passed from
generation to generation through their genes. Because her mother had it
and her father didn't, she and her sister each had a 50% chance of
inheriting it.
Wexler had just begun studying psychology with Anna Freud in London
when she learned of her mother's diagnosis. The year was 1968, when
scientists still knew very little about DNA and even less about
Huntington's. Was one gene or several responsible? Were there different
forms of the disease? What was triggering the motor and cognitive
breakdown in the brain—a rogue enzyme? A protein? A hormone? Some kind
of receptor?
To find out more about Huntington's, researchers needed data not just
from a few isolated families, but from large, extended families, with
good records going back many generations. Molecular biologists, riding
the wave of genetic excitement triggered by Watson and Crick's
discovery, were just developing a new technique that they were eager to
try out on just such a gene hunt. They had identified enzymes that
chopped up the genome at the same place in every person. By comparing
stretches of DNA taken from two family members, one affected by
Huntington's and the other not, scientists could start to narrow down
the location of the gene that caused it.
By 1978, the year Wexler's mother died, only a few such reference
sections of the genome had been mapped out, and the technique had not
yet been used successfully to find a disease gene. But the family was
determined to find the Huntington's gene, and eventually a cure. They
had created a nonprofit foundation to accelerate work on the disease,
and were willing to take a gamble with the new strategy. "It wasn't
like finding a needle in a haystack, it was like finding a specific
piece of hay in a haystack," says Wexler.
By now a Ph.D. on the staff at the National Institute for
Neurological and Communicative Disorders and Stroke, Wexler had embarked
on a hunt of her own. She was looking for large Huntington's families
suitable for a study when she learned about the communities around Lake
Maracaibo. She made her first trip to the region in 1981. Within months,
she had DNA samples and pedigrees of hundreds of Venezuelans, all
members of families stalked by Huntington's. The data proved key to the
gene hunt; just two years later, scientists had narrowed their search to
a region on chromosome 4, and confirmed their findings using DNA samples
from 1,200 Venezuelans.
Ten years later, the researchers reached their next
goal—pinpointing the Huntington's gene. Doctors could now develop a
genetic test to determine whether members of a Huntington's family
carried the disease gene—and thus a certain death sentence.
For the Wexlers, this was good news and bad, for it forced each of
them to make an agonizing decision. "When we couldn't have the
test, we wanted it, we were all set to take it," says Wexler. Now
that the test was available, she wasn't so sure. "Even if you think
you've thought about something inside out and backwards, there is still
something that lets you say that if that you don't know, you're still
somehow protected."
Wexler has never revealed publically whether or not she has been
tested for the Huntington's gene (although, at 58, she is just past the
average age at which symptoms would first appear). But she has decided
that knowing her fate would not change the decisions she made early
on—to not have children and risk passing on the gene, and to continue
the search for a cure.
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