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ita Effros, professor of pathology and laboratory medicine, is attacking the question of aging at the most elemental level: what exactly makes cells grow old.
Married and the mother of two, Effros had been working as a physical therapist in Philadelphia when she decided to return to school. "I found I was just as interested in understanding the disease process of my patients as I was in trying to help them," she recalls. She earned a Ph.D. in immunology from the University of Pennsylvania and, in the bargain, had the opportunity to train under Peter Doherty, who would win the Nobel Prize in Medicine in 1996.
It was Doherty who inspired in Effros an interest in the immune response to viral infection. In 1979 she brought that dedication to UCLA, where she began her postdoctoral work. Eventually, she joined the Department of Pathology and Laboratory Medicine and recently received the UCLAWoman of Science Award, which honors a distinguished female scientist who has made significant achievements in research and teaching.
Effros has focused her work on T-cells, the critical cells of the immune system that help defend the body against viral infection. Like most human cells in tissue culture, T-cells can be induced to divide, divide again, and divide again, generation after generation. But then, after about 25 or 35 generations, they stop dividing. The phenomenon is known as "replicative senescence."
"Anyone who knows old people will observe that they usually recover much more slowly from viral infections," explains Effros. "Some actually die during influenza epidemics." Effros attributes this lack of resistance to senescent immune system cells. As one ages, part of the body's defense system shuts off at the molecular level.
It takes decades for T-cells to reach replicative senescence in the human body. But in order to study the process, Effros had to find a way to speed up T-cell evolution in the laboratory. In the body, T-cells divide when they come in contact with foreign antigen molecules. Effros found that if she repeatedly challenged lab-cultured T-cells with such antigens, the cells divided far more rapidly than they would normally. "We telescope the process that might occur in a real person over many years into a matter of months," she says. "At the beginning, the time between cell divisions in the laboratory is very short: Within a week, they can undergo six cell divisions. After a while, they begin to
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slow down, so you know that the end point is coming. Then they just stop dividing. They don't die. They just sit there. What causes them to stop dividing is one of the major questions in aging research."
Part of the question may have been answered earlier this year by investigators at the Geron Corporation of Menlo Park, CA, and the University of Texas Southwestern Medical Center at Dallas. Using cultures of cells from the human retina and skin, researchers found that replicative senescence could be greatly delayed if they inserted a gene coding for an enzyme called telomerase into these cells. All human chromosomes have telomere structures at their ends. Each time the cell divides, the telomeres get a bit shorter. When they become too short, the cells apparently are prevented from continuing to divide. Telomerase reverses this process, lengthening the telomeres and delaying replicative senescence.
Effros has measured telomeres of human T-cells and observed a similar effect. "We've shown that the telomeres get shorter and shorter as we watch the cells undergo more and more cell divisions," she explains. "They actually reach a certain 'magic' telomere length beyond which they will not divide any further. It will be very interesting to know what will happen to these telo-meres if the telomerase gene can be inserted into T-cells." Effros has received support for her research from various sources, including the University of California AIDSResearch Program, National Institutes of Health, Pfeiffer Foundation and the Seigel Life Project.
Experiments with the telomerase genes have greatly encouraged scientists studying aging. But while the news media have portrayed the results of this work as if the fabled Fountain of Youth had just been discovered, Effros is still cautious in her enthusiasm. Cells that fail to undergo replicative senescence are not necessarily desirable. For example, one of the characteristics of tumor cells is that they never stop dividing, suggesting that manipulation of telomerase requires further research to ensure that the normal cells remain normal.
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