Apoptosis May Provide New Way of Treating Huntington's Disease Michael Purdy ------------------------------ JHMI Office of Public Affairs A built-in cellular "suicide program" vital to early development of the brain and other organs may be called back into action by the effects of Huntington's disease and strokes, according to Hopkins medical researchers. Scientists already know a great deal about this "suicide program," called apoptosis, from research into other disorders. If the new link proves to be true, it will put them tantalizingly close to developing new treatments for Huntington's and strokes. "We already have several compounds that may block this self-destruct process," said Vassilis Koliatsos, an assistant Hopkins professor of pathology, neurology and neuroscience. Examples include interleukin-converting enzyme (ICE) inhibitors, which stop the production of an inflammatory protein that may be involved in apoptosis. Another group of compounds, antioxidants, neutralize damaging chemicals known as oxidants that may help trigger apoptosis. Last year, other researchers at Hopkins linked apoptosis to Parkinson's disease and amyotrophic lateral sclerosis (Lou Gehrig's disease). Koliatsos speculates that apoptosis may be the only way nerve cells know how to die. If so, treatments that can stop apoptosis may also help patients with a wide range of neurological disorders. Using brain tissue from human autopsies and animals with Huntington's disease and strokelike disorders, Koliatsos found that the DNA in dying nerve cells was breaking apart in a pattern characteristic of apoptosis. Apoptosis results from a series of instructions contained in a cell's genes. When "read," these instructions direct the cell to kill itself. Scientists first observed apoptosis in a worm, C. elegans, that regularly directs half its nerve cells to kill themselves. The killing helps the worm maintain its size as it generates new nerve cells. Later experiments showed human immune cells and cancer cells can self-destruct in a similar manner. Researchers previously thought apoptosis only played a role in the nerve cells of higher organisms during the earliest stages of life. "During development, cells compete to accomplish certain goals," Koliatsos said. "For nerve cells, that might be making connections with other nerve cells. "We think a cell that can achieve these goals is rewarded with a protein or chemical that will sustain it," he added. "Cells that can't achieve these goals go into apoptosis and die." But when a national collaborative research group cloned a gene for Huntington's disease, the finding suggested to Koliatsos a link between Huntington's and programmed cell death. Using two different methods, he found clear indications of apoptosis in DNA from Huntington's patients. "My job now is to first test those agents that may block apoptosis in the laboratory, and then to see what can be done to transfer those treatments from the laboratory to animal models and, later, to human patients," Koliatsos said. ----------------------------------------------------------------- Nancy Wexler To Give First Garrett Lecture Nancy S. Wexler, a member of the research group that discovered the genetic marker for Huntington's disease and who is herself at risk for the hereditary disorder, will deliver the inaugural Mary Elizabeth Garrett Lecture at The Johns Hopkins Hospital. Wexler, Higgins Professor of Neuropsychology at the College of Physicians and Surgeons of Columbia University and president of the Hereditary Disease Foundation, will give a talk titled "Variations on a Theme by Huntington" at 4 p.m., June 22, in the hospital's Hurd Hall. The Garrett lectureship, which honors outstanding women in academics, is named for Mary Elizabeth Garrett, who provided financial support that enabled the School of Medicine to open in 1893. Mary Garrett tied her support to the requirement that at least 5 percent of the entering classes be women. "The lectureship is a landmark event," Catherine D. DeAngelis said. DeAngelis is senior associate dean for academic faculty and affairs at the School of Medicine. "It honors not only the woman who made it possible for women to have a real presence here at Hopkins," DeAngelis said, "but also women anywhere who have made valuable contributions to medical science." Wexler, a clinical psychologist by training, was, in 1983, an important member of the research team that discovered a genetic marker, a piece of DNA near a particular gene, for Huntington's disease. This enabled researchers in 1986 to develop a diagnostic test to determine, even decades before symptoms appear, whether a person is affected. The test also gives carriers the choice of whether to have children, who will have a 50 percent chance of inheriting the disease. Researchers discovered the gene itself in 1993 and identified the mutation of the gene. There is no treatment, but researchers continue to study the protein produced by the gene in an effort to stop it from causing the disease. Huntington's disease is a degenerative brain disorder that afflicts one person in 20,000. Symptoms usually do not appear until midlife, with death usually following within 15 years. Wexler's mother, three uncles and maternal grandfather died from Huntington's. The Garrett lectureship is to be an annual event with presenters selected by the Women's Leadership Council at the School of Medicine. All women professors are members of the council, which was formed in 1994 with the goal of advancing women's careers in academic medicine. The School of Medicine admitted three women in its first class in 1893, a revolutionary step in the Victorian era, and last year, for the first time, the freshman class had more women than men. Women comprised 53 percent of the class of 1998, or 63 in a class of 120. -----------------------------------------------------------------