By: Kristin Darwin
One morning in 1968, Dr. Nancy Wexler’s mother, Leonore Wexler, had jury duty in downtown Los Angeles. As Leonore crossed the street on the way to the courthouse, a policeman yelled to her, “How can you be drunk so early in the morning?” Leonore realized that she had been staggering – an obvious sign that something was wrong.
Soon after, Leonore was diagnosed with Huntington disease (HD). Nancy Wexler, who was pursuing a PhD in clinical psychology at the time of her mother’s diagnosis, devoted her life to the study of HD. In 1979, Wexler and her colleagues began a research project in Venezuela to search for the HD gene. They surmised that finding the gene was the most direct route to the development of treatments, even cures! They developed a pedigree of over 18,000 individuals and collected more than 4,000 blood samples from the largest extended family with HD ever to have been discovered. Their data led to the identification of the gene responsible for HD.
Today, Wexler continues her involvement with HD as the Higgins Professor of Neurophysiology at Columbia University, and as President of the Hereditary Disease Foundation. At the November 2011 Huntington Study Group meeting, Wexler told HD Insights about the series of events that led to the discovery of the gene responsible for HD.
Wexler says that her father, Dr. Milton Wexler, was an invaluable contributor to the discovery of the HD gene. She and her father, who was a clinical psychologist and an expert group therapist, began HD workshops the same year her mother was diagnosed. These workshops were the foundation for the Hereditary Disease Foundation that is still active in HD research today. Wexler recalls, “We had a workshop for two days and came up with a research agenda. My dad took what he learned from group therapy, and from creativity, and off-the-wall thinking, and put it into these workshops. And in the 1970s, [the study of] DNA was kind of just being born. So we said, ‘Does that have an answer for us?’”
Wexler collaborated with Dr. David Housman to organize a workshop at the National Institutes of Health to discuss the feasibility of finding DNA markers for the HD gene. “There were very prestigious scientists at the workshop,” Wexler says. It was the early 1970s. A big question was, “How are you going to go from here to the moon if you don’t even know where the moon is, and you have to build your own spacecraft?” Additionally, genetic studies were difficult – all restriction fragment length polymorphisms were hand-crafted. Polymerase chain reaction had not yet been invented. Wexler continues: “At the workshop, there were lots of arguments about how many markers you needed to evenly cover the genome. We had to hand craft each marker and find enough to evenly cover the human genome. And everybody talked about families. The criterion for a family critical for gene mapping was a very large family in which you had both grandparents, both parents, and 10 or 14 kids.” At the time of this workshop, such an HD family was believed not to exist. Some in attendance at the workshop even told Wexler it was unethical to publicly announce that a search had begun for the HD gene.
They estimated a realistic timeframe for HD gene discovery was 50 to 100 years.
In fact, the large HD family Wexler and her colleagues sought had already been discovered by Venezuelan physician Dr. Americo Negrette, who in 1955 practiced in the small Venezuelan town of San Luis, near Lake Maracaibo. According to Wexler, “As he walked around the streets, he thought, ‘These people are drunk all the time! The nursing mothers are drunk, the fathers are drunk, everybody is drunk. What’s the matter with them?’ Finally, a woman pulled him aside, and said, ‘You’re such an arrogant doctor! Have you even looked at these patients? Have you smelled their breath? Nobody’s drinking. They’re not drunk. They’re sick.’”
Negrette realized that the woman was correct. He began to write up cases and make pedigrees of individuals from San Luis and its neighboring villages around Lake Maracaibo. He concluded that the people had HD. Negrette and colleagues made a video of the affected people in the villages and presented it at the 1972 World Federation of Neurology Research Group on Huntington’s Disease. Nancy and her father Milton Wexler were both in the audience.
Negrette’s video presentation and data were central to Nancy Wexler’s determination that she should travel to Venezuela to study HD. With the support and guidance of Negrette, in July 1979, Wexler and colleagues began a search in Venezuela for a person who was an HD homozygote. Her search for a homozygote was inspired by revelations in familial hypercholesterolemia. Wexler explains, “The godsend was that Dr. Michael Brown and Dr. Joseph Goldstein had found the gene causing familial hypercholesterolemia by studying homozygotes for the gene. Without the normal protein, it was more obvious what the abnormal protein was doing.” Wexler and her colleagues began compiling pedigrees and collecting blood samples from HD families. She and colleague Dr. Tom Chase eventually found many children with juvenile HD in a small stilt village in Lake Maracaibo. One two-year-old child had a “giant expansion of 109 CAGs – a very dramatic expansion.” Wexler began to collect blood samples from “all these layers and layers and layers of families, from great-grandchildren all the way up.” Homozygous families and the children with juvenile HD were both essential to finding the HD marker and the gene.
Wexler gave the blood samples she had collected to Dr. James Gusella, Dr. David Housman and Dr. Michael Conneally for benchwork analysis. In 1983, Gusella and Conneally determined that the gene responsible for HD is located at the tip of chromosome four.1 Wexler was working at the National Institute of Neurological Disorders and Stroke (NINDS) when they made their breakthrough. “It was incredible,” she says. “I just started screaming at the top of my lungs: ‘We found the gene!’ I called my dad. I said, ‘Dad, we did it’ and he started crying. I called my sister. It was just euphoric.”
Wexler also understood the larger implications of the discovery of the HD gene. “It meant that our strategy would work not only for HD, but for everything worldwide. At that point, we realized we had the human genome in our hand. We said, ‘Yes, you can do this, you can find new genes.’ We found the marker. That just revolutionized everything.”
Today, nearly two decades after the discovery of the HD gene, a successful disease-modifying treatment for HD has yet to be developed despite efforts from researchers worldwide. However, Wexler remains hopeful. When HD Insights asked what she thought would be the next euphoric moment in HD, Wexler replied, “When we cure it!”
1Gusella JF, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983 306:234-238.