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Turning Back the Strands of Time

Scientists have found a major factor that controls whether a cell dies or thrives
It may not sound as appetizing as aquavit, but telomerase--an enzyme discovered only a decade ago in a single-celled protozoan--may well be the elixir of youth. This chemical acts in immortal cancer cells, sperm and ovum to repair telomeres, the strands of DNA that tie up the ends of chromosomes. And now it seems that activating telomerase in sundry other cells grants them a longer lease on life as well.

The finding, which was published in the January 16 issue of Science, finally proves what was a highly controversial model linking telomeres to cellular aging. More important, it opens up new avenues for research into diseases that occur when cells grow old, including macular degeneration in the eye and atherosclerosis, and those that arise when cells don't age at all, such as cancer.

The connection between telomeres and aging first emerged in 1986, when Howard Cooke of the Medical Research Council in Edinburgh noticed that the telomeres in reproductive cells were longer than those in shorter-lived somatic cells--the sort found in skin, muscle and nerve tissues. Knowing that telomeres shortened each time a cell divided, he speculated that somatic cells might not make telomerase. If somatic cells could not repair telomeres, he reasoned, their telomeres would continually shrink.

In addition, Cooke suggested that ever-shortening telomeres, like sands passing through an hourglass, might count out a cell's days. After a certain number of cell divisions, the telomeres would be so short as to somehow prevent the cell from further proliferation--putting it in a state called senescence. In other words, he proposed that telomere length offered a clock for telling a cell's longevity.

Cell cultures
Image: SOUTHWESTERN MEDICAL CENTER

LIVING PROOF. Cells treated to produce active telomerase continue to divide vigorously (bottom), whereas normal cells of the same age have lost their vigor (top).

The idea got a lot of attention--and attacks. Cooke himself wrote a paper in 1990 showing that mice having extraordinarily long telomeres did not live for an extraordinarily long time. And last year, M. A. Blasco of Cold Spring Harbor Laboratory discovered that even when mice were genetically engineered so that they could not manufacture telomerase, the animals still, on occasion, developed malignancies. Either some other mechanism had protected the telomeres in these murine tumor cells against erosion or shortened telomeres did not suppress tumor growth in mice as it was suspected they did in humans.

Now, it is clear the latter is likely the case. In a salvo of papers published over the past few months, researchers have shown that the telomerase gene can be activated in human cells--and that it does extend cell life. The initial development was a report in the August 15, 1997, issue of Science that a group headed by Nobelist Thomas Cech of the University of Colorado at Boulder and colleagues at Geron Corporation, a biotechnology company specializing in aging research in Menlo Park, Calif., had isolated the human gene for a catalytic protein called telomerase reverse transcriptase (hTRT).

Although the gene for telomerase is present in all cells, hTRT is present only in immortal cells, where it serves to fuse the repeating sequences of DNA to the chromosomes, thereby lengthening the telomeres. Proof that introduction of the hTRT gene into mortal cells would cause them to produce active telomerase was offered in the December 1, 1997, issue of Nature Genetics by the Geron group, this time in a collaboration with researchers from the University of Texas Southwestern Medical Center in Dallas.

But does lengthening the telomeres actually prolong the life of human cells? Groups from Southwestern Medical Center and Geron proved just that in the recent Science article. By introducing the hTRT gene, they caused three different kinds of cells--retinal pigment epithelial cells, foreskin fibroblasts and vascular endothelial cells--to resume telomerase activity.

In all three cell lines, the telomerase knit new DNA onto the ends of chromosomes, artificially elongating the telomeres. And all three lines lived much longer than usual. Whereas unaltered cells in the study reached senescence after a fixed number of divisions, the hTRT-positive cultures had seen 20 population doublings beyond that point at the time the report was published--and they were still going strong. "We have found that cellular aging can be bypassed," said Jerry Shay, who headed the Southwestern Medical Center team with Woodring Wright.

For those who were still unconvinced, a day after the Science paper appeared, another team of investigators published additional proof of the telomere-as-timer model in the Lancet. Robert Wynn and colleagues at the Paterson Institute for Cancer Research in Manchester, England, showed that cells forced to divide at a breakneck pace die sooner.

Shay and Wright
Image: SOUTHWESTERN MEDICAL CENTER

INVESTIGATORS. Jerry Shay and Woodring Wright (right), professors of cell biology and neuroscience at Southwestern Medical Center, working with collaborators at Geron Corp., demonstrated that rebuilding telomeres prolongs cell life.

To demonstrate this point, they looked at 14 cancer patients who had received bone marrow transplants. Chemotherapy normally kills off marrow cells, and transplanted ones must divide rapidly to restore the patient's stock of red blood cells and immune cells.

After 11 months had passed, Wynn and colleagues compared transplanted marrow cells with those from donors and found that the overworked cells had much shorter telomeres. Indeed, as measured by telomere length, the transplanted cells were on average 15 years older than the donor cells. Some had aged by as much as 40 extra years. The lesson, the researchers say, may be transplanting more marrow cells to divvy up the workload and reduce the overall number of necessary cell divisions.

Will techniques for manipulating telomere length go even further to smooth wrinkles and stop cancers in their tracks? Titia de Lange of the Rockefeller University reviewed the possibilities in an accompanying piece to the most recent Science article. As for battling cancer, she notes that tactics for deregulating telomerase or otherwise inhibiting it hold great promise. But deliberately resetting the telomere timer to fight the effects of aging, she adds, may well increase cancer risks. Only time will tell, but one thing is certain: eternal youth will come at a price--Geron Corp. has filed for patents on hTRT.

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