D is for Down's Syndrome

Charles Epstein has been getting "interesting outcomes" for much of his 35-year career. As the co-director of UCSF's Program in Human Genetics and chief of the division of medical genetics, he also directs the genetic counseling clinic. It is there that Epstein, a cellist who also enjoys building dollhouses, first became interested in Down's syndrome, now a major focus of his research.

Down's syndrome, a congenital condition, occurs once in approximately every 800 to 1,000 live births. More than 350,000 people in the US alone have the disorder, which results in lower intelligence, characteristic physical features, Alzheimer's disease and reduced life expectancy. It is diagnosed — often during prenatal testing - using chromosome analysis. In the mid-1900s, scientists discovered that the cells of those born with the syndrome carry an extra complete or partial 21st chromosome. The specific biochemical mechanisms that cause the characteristics of the condition still remain unknown. "It's not treatable in the pharmacological sense," Epstein explains. However, many social and educational advances have been made in the last 30 years. People with the syndrome are no longer institutionalized automatically, for example. "There isn't any specific therapy, but that's the point of digging into it."

This digging process has been aided enormously by the sequencing of the human genome, which offers new hope for a therapy or cure. Says Epstein, "We know that there are roughly 225 genes on chromosome 21. If there is some subset of those genes causing the problem, then maybe you could alter the situation." Targeting that subset has been made easier, thanks in part to a mouse model of the disease, which Epstein and his wife, Lois, a former UCSF professor of pediatrics who spent almost 30 years at the Cancer Research Institute, developed together. The mouse model is trisomic (possessing three instead of two chromosomes) giving it the equivalent of Down's. "We have been trying for years to understand why having that extra chromosome has such a profound impact."

At the same time, the work on Down's syndrome has led Epstein and laboratory colleague Ting-Ting Huang to another area of research: metabolism of oxygen-free radicals. These molecules are thought to cause aging and disease because they damage DNA and cause genetic mutations. Enzymes called superoxide dismutases (SODs) are responsible for the first step in the metabolism of oxygen-free radicals. The gene that codes for copper SOD happens to be on human chromosome 21. Epstein's lab created transgenic mice by inserting human SOD genes into their genomes. "Over the years, we've engineered a series of mice that either lack these enzymes or have extra amounts of these enzymes," Epstein says. Those that lack manganese SOD only survive about three weeks. "We're trying to understand the fundamental processes that control the metabolism of these free radicals." The results may give scientists an idea of how the SODs protect cells - and organisms - from premature death.

It also may lead to an understanding of other diseases and conditions. Why? Oxygen-free radicals are thought to play a role in our response to injury, toxic chemicals and radiation, as well as in the development of heart disease, stroke and cancer.

by Camille Mojica Rey




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