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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