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So Far, So Good for 'Immortal' Cells December 29, 1998: Life and death lie nowhere so close together as in the human cell's counting device for limiting how often it can divide. The device is a sort of tally stick that gets shorter at each division. When it runs out, the cell dies. The telomere, as biologists call the device, is overruled in only two kinds of cell and as a result both are immortal, in the sense that they can go on dividing indefinitely with no sign of growing old. One is the cells of the germline, the egg cells and sperm-generating cells, that remain ever youthful from one generation of people to another. The other is tumor cells. Biologists announced last January that they had learned the death-defying secret known to germline and tumor cells, that of how to override the telomere- shortening system. The discovery stirred a euphoric ferment of proposals for immortalizing the various body tissues that are especially prone to give out in old age and disease. But a little knowledge is a dangerous thing. Would the revitalized tissues gain the endurance of germline cells or the lethal exuberance of tumor cells? The two teams of biologists that announced their telomere-override method in January now report in the journal Nature Genetics that their cells are still growing and dividing with no sign of cancerous tendencies. One team, led by Choy-Pik Chiu of Geron Corp., which owns rights to the telomere-override component, says its laboratory cultures of immortalized cells have doubled more than 200 times, with their anti-cancer genes still in good order. This confirms the idea that the cells will "provide therapeutic opportunities for age-related diseases," the Geron scientists assert. Usually cells divide only 50 times or so, depending on their type, before telomere shortening drives them into senescence. The other team, headed by Woodring Wright and Jerry Shay at the University of Texas Southwestern Medical Center in Dallas, said their altered cells had gone through 280 doublings, also without showing any of the wayward behavior typical of cancer cells. Both groups enabled their cells to defeat the telomere-shortening system by activating an enzyme called telomerase, which builds telomeres back up to their normal length. In normal cells an essential component of the enzyme, the template on which it rebuilds the telomeres, is absent because the gene that makes it is switched off. To immortalize their cells, the two groups inserted into them a switched-on form of the human telomerase template gene. Does the new result mean that cells with activated telomerase can be transplanted into patients' bodies without creating an extra risk of cancer? The two experiments mean nothing of the kind, in the view of Robert Weinberg, a leading cancer biologist at the Whitehead Institute in Boston. "They are both kind of nonresults," he said. "Both groups report that putting telomerase into normal cells does not per se create a cancer cell, which is a straw-man issue because no one expected it would. The real problem is whether the telomerase-bearing cells are more predisposed to undergo changes that make them into malignant cells." For a normal cell to become a cancer cell, it must defeat the various safety circuits that protect against runaway growth. Incipient cancer cells are thought to accumulate mutations in the genes that underlie these circuits. Probably four or five separate genes must be knocked out before a normal cell becomes a fully developed tumor cell. One of the cell's safety circuits is the telomere-shortening system. Indeed it may be the cell's last-ditch defense against tumors. An incipient cancer cell that has knocked out all the other genes restraining its growth can divide only so many times before the telomeres drive it into senescence. Perhaps the final hurdle for a successful tumor cell is to activate its telomerase gene. All that the new experiments show, in Weinberg's view, is that the general regulatory circuits of the cell are unaffected by the presence of active telomerase. But a cell with activated telomerase has certainly taken one of the five steps down the road to cancer, in Weinberg's view. "The question is whether you are one big step or one small step nearer, and one can't know that from their experiments," he said. Dr. Calvin Harley, Geron's chief scientific officer, said it was unfair to say that no one had thought telomerase activation would cause cells to become cancerous. Overproduction of telomerase might well have deranged the cells' regulatory mechanisms, an important concern that had now been laid to rest, he said. But the company's plan is not to give patients cells with permanently activated telomerase, if it can avoid doing do. Rather, the hope is to develop drugs that will switch on telomerase temporarily, just long enough for it to rebuild the telomeres back to their youthful length. "The responsible approach in the therapeutic development of telomerase is not to constitutively activate the enzyme but to control its regulation," Harley said. Asked if Geron had yet developed drugs to switch the telomerase gene on and off, Harley said, "We have some data," but he added that the company's research is focused on understanding cells with permanently activated telomerase. By Nicholas Wade The New York Times on the Web janet paterson - 51 now /41 dx /37 onset - almonte/ontario/canada [log in to unmask]