'Immortality Enzyme' Is Studied Appearing forever young like Dick Clark is everybody's dream. But, biologists wonder, what good is immortality if all those extra years are accompanied by cancer? That's the quandary posed by the discovery earlier this year that a body substance called telomerase is an ``immortality enzyme'' that encourages cells to keep dividing indefinitely instead of dying with age. Scientists theorized that telomerase could be used to slow the aging process. At the same time, some feared that the enzyme could cause cancer by allowing cell division to run amok. Now, new experiments by the same University of Texas team of researchers have concluded that such fears are groundless. The researchers watched human cells divide hundreds of times in test tubes and concluded that telomerase does not by itself turn healthy cells into malignant ones. In fact, they said the enzyme may offer promising new ways to treat cancer. ``Telomerase does not cause cancer progression,'' said Woodring Wright of the UT Southwestern Medical Center in Dallas, a co-author of the study, published Tuesday in the January issue of the journal Nature Genetics. ``The abnormalities seen in cancer are due to other mutations.'' Other researchers said the experiment is too limited to exonerate telomerase. They said that while telomerase may not cause cancer by itself, it appears to play a fundamental role in the growth of cancerous cells, even if the cancer itself is triggered by, say, radiation or a virus. ``There is no simple statement that telomerase is irrelevant to cancer,'' said Ronald DiPinho of the Dana Farber Cancer Institute of Harvard University. ``It's a very complex subject.'' Thomas Cech, a 1989 Nobel laureate and biochemistry professor at the University of Colorado, said the Texas researchers looked only at the effects of adding telomerase to a normal cell, not what happens when telomerase is blocked in a cancer cell. A year ago, Wright and colleague Jerry Shay published research demonstrating that telomerase enables cells to keep on dividing and avoid the normal process of aging and death. Normally, human cells divide about 75 times over a lifetime. But each time a cell divides, the telomere, or the protective end of a chromosome, erodes. Eventually, the telomere becomes too short to protect the chromosome. When that happens, the cell can no longer divide and eventually dies. By the time a person is an adult, most of their healthy cells no longer contain any telomerase. But 90 percent of cancer cells have been found to have telomerase, raising suspicions that telomerase is linked to cancer. In test-tube experiments, Wright and Shay showed that normal cell death can be avoided by inserting a gene that instructs the cell to produce telomerase. As of late December, the cells had divided as many as 220 times beyond their typical lifespan, and none exhibited cancerous traits such as abnormalities in chromosomes, the researchers said. At least a dozen pharmaceutical companies are in the early stages of developing drugs that would shut down telomerase and starve cancer of the tumor growth substance critical to its survival. Telomerase also is being considered for use in unclogging blood vessels, restoring circulation involved in some forms of blindness, and accelerating the healing of skin grafts. Geron Announces First In Vivo Data Indicating Telomerase Expression in Normal Human Cells Extends Their Replicative Lifespan Without Oncogenic Transformation MENLO PARK, Calif.--(BW HealthWire)--Dec. 28, 1998--Geron Corporation (Nasdaq:GERN) and the University of Texas Southwestern Medical Center at Dallas announced today the publication of two papers in the Jan. 1, 1999, issue of Nature Genetics demonstrating that telomerase expression in normal cells confers an infinite replicative capacity, but does not result in cellular changes associated with cancer. These findings have important implications for scientific research as well as pharmaceutical drug discovery and product development. Telomerase is an "immortalizing" enzyme that imparts infinite replicative capacity to reproductive and cancer cells. Conversely, normal somatic cells that do not express telomerase have a finite replicative capacity and eventually senesce. Senescent cells can damage surrounding tissues, contributing to age-related pathologies. For example, senescent skin fibroblasts can contribute to slower healing and wrinkling. Similarly, senescent retinal pigment epithelial cells can contribute to age-related macular degeneration. Research published Jan. 16, 1998, in Science (by the same two research teams making today's announcement) demonstrated that the introduction of telomerase into normal cells resulted in the extension of their replicative lifespan. The two papers announced today provide new in vitro and the first in vivo data demonstrating that telomerase expression in normal cells results in cellular immortality but does not induce cancer-associated physical and biochemical characteristics. Specifically, the Geron researchers report that human skin fibroblasts and retinal pigment epithelial cells transfected with telomerase over a year ago have been continually dividing and can therefore now be considered immortal. Moreover, these same cells retain normal growth control and do not form tumors in vivo, even after twice the normal maximum number of population doublings. The University of Texas Southwestern Medical Center researchers report that the expression of telomerase in human fibroblasts is sufficient in vitro to extend their replicative capacity three times beyond when they would normally senesce without malignant transformation. According to Dr. Calvin Harley, Geron's chief scientific officer, "These findings and similar results from others to whom we have given the telomerase gene, increase our confidence that `telomerizing' normal human cells will prove useful in research, genetic engineering, drug discovery, and treating disease". Geron believes that being able to generate an essentially unlimited supply of normal human cells will create new opportunities to study basic mechanisms of cell growth and differentiation, and as a result provide a reproducible source of young normal cells for both drug screening and testing as well as cell and gene therapy. For example, telomerase could be used to extend the limited lifespan of blood vessel forming cells, the shortage of which has prevented their widespread use for discovery of new treatments for hypertension and other cardiovascular diseases. The ability to increase and potentially regulate the lifespan of normal cells should also help overcome a major hurdle in genetic engineering and cell and gene therapies. For example, it is now known that the isolation, expansion, and manipulation of cells outside the body for reimplantation into patients causes accelerated aging of the cells. The use of `telomerized' cells with an extended lifespan should enable the cells to survive longer in the body. Finally, for therapeutic applications, Geron will seek to use regulated telomerase expression to postpone or reverse senescence and age-related pathologies such as macular degeneration, skin atrophy, and atherosclerosis. Telomerase is actually a complex of at least two distinct molecules, one made of RNA and another made of protein. These two molecules are necessary for making active telomerase. Geron owns or co-owns issued patents with claims on both these molecules as well as their use in research, diagnostics and therapeutics. Senior author of the Geron Nature Genetics paper, "Telomerase Expression in Human Somatic Cells does not Induce Changes Associated with a Transformed Phenotype," is Dr. Choy-Pik Chiu at Geron. Co-authors at Geron include Xu-Rong Jiang, Edwin Chang, Maria Frolkis, Brenda Kusler and Andrea Bodnar. The work reported in this paper was done in collaboration with Dr. Geoffrey M. Wahl at the Salk Institute and Dr. Thea Tlsty at the University of California, San Francisco. Geron Corporation is a biopharmaceutical company focusing on discovering and developing therapeutic and diagnostic products based upon the company's understanding of human embryonic stem cells, and of telomeres and telomerase in cells -- fundamental biological platforms underlying cancer and other age- related degenerative diseases. The company desires to take advantage of the "safe harbor" provision of the Private Securities Litigation Reform Act of 1995. Specifically, the company wishes to alert readers that the matters discussed in this press release may constitute forward-looking statements that are subject to certain risks and uncertainties. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect the company's results is included in the company's quarterly report on Form 10-Q for the quarter ended September 30, 1998. To receive an index and copies of recent press releases, call Geron's News On Demand toll-free fax service, 1-800-782-3279. Additional information about the company can be obtained at www.geron.com. CONTACT: Geron Corporation Nancy Robinson, 650-473-7765 (Investor & Media Relations) or CLM Communications Mike Jackman, 415/388-3216 (Media) or Burns McClellan Lisa Burns or John Nugent, 212/213-0006 (IR)
