Genetic Fix

Genetic Fix Turning on fetal DNA

Manipulating the body's genes to cure disease has been a long-sought but elusive goal for scientists. The genes, discrete bits of DNA on the chromosomes in each cell, control all body activities by directing the production of essential chemicals. When the genes are intact, they send flawless manufacturing messages, and the body functions normally. But if damaged, they produce garbled instructions and hence disease. In so-called genetic surgery, doctors hope eventually to use recombinant-DNA techniques to cut out "bad"genes and substitute "good" ones. Now, though, there may be a more immediately applicable way to correct genetic defects. In the New England Journal of Medicine, researchers described an alternative method of genetic manipulation that for the first time has been successfully used to treat a serious disease. The solution: employing a drug to reactivate apparently intact genes that had been dormant since birth.

The new method, devised by scientists at the National Heart, Lung and Blood Institute in Bethesda, Md., the University of Illinois College of Medicine in Chicago and Johns Hopkins University in Baltimore, is based on experiments on baboons. It has been used in only a handful of human patients suffering from severe thalassemia or sickle cell anemia. These blood disorders result from defects in the genes that control production of hemoglobin, the substance that carries oxygen in the blood. In essence, thalassemia victims cannot form healthy red blood cells on their own and require periodic transfusions; sickle cell patients are subjected to painful blood vessel blockages.

The drug involved is 5-azacytidine, which until now has been used only to treat cancer. In the most fully described case so far, a 42-year-old man with severe thalassemia, who needed a blood transfusion every two weeks, received a continuous infusion of the drug through a vein in his arm for seven days. At the end of the week, the concentration of healthy red blood cells in his blood had increased by 25%. This beneficial effect persisted for about a month.

"We're not positive of the mechanism involved," say Drs. Arthur Neinhuis and Timothy Ley of the National Institutes of Health's Clinical Hematology Branch. The scientists speculate that, basically, the drug works by stripping genes of chemicals that have repressed their activity, allowing them to switch on again. The genes affected are those that produce hemoglobin for the developing fetus. These fetal genes turn off around birth as other genes take over to produce hemoglobin for human life outside the womb. Scientists still do not know why there are two sets of genes for making hemoglobin.

Despite the initial success, the researchers remain extremely cautious. Though only one patient experienced mild and transient nausea and vomiting, doctors worry about administering a toxic anticancer drug forlong periods. Another concern: What other genes are being altered? A fear is that the drug approach may inadvertently switch on recently discovered cancer genes that apparently lie dormant in most people. Nonetheless, noted Hematologist Edward Benz of Yale University School of Medicine, who wrote an accompanying editorial in the NEJM, "this research represents a major new step in treating disease and demonstrates beyond doubt that genetic manipulation has come to the bedside."

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