Geron: Telomerase 'Immortalizes' Cells Without Oncogenic Transformation

Biotech 1999 will begin with a bang, with two peer-reviewed reports from Geron Corp. (Menlo Park, CA) and the University of Texas Southwest Medical Center, showing that telomerase expression in normal cells confers infinite replicative capacity without making the cells cancerous. The two papers will appear in the Jan. 1 issue of Nature Genetics.

If these findings hold up to scrutiny by both friendly and unfriendly telomere/telomerase researchers they could end perhaps the most significant scientific controversy of the past five years. Introducing telomerase into diseased somatic (non-germline) cells could point the way to curing or significantly delaying a wide range of degenerative, age-related diseases such as arthritis, atherosclerosis, Alzheimer's disease and organ failure.

Telomerase is an "immortalizing" enzyme that imparts infinite replicative capacity to reproductive and cancer cells. Just about every cancer studied expresses the enzyme, whereas normal skin, muscle, nerve and bone cells do not. Telomerase maintains the lengths of telomeres—repeat TTAGGG units at the ends of all chromosomes. Normal somatic cells that do not express telomerase have a finite replicative capacity and eventually senesce, or "get old," stop replicating, and die. 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 contributing to this announcement) demonstrated that the introduction of telomerase into normal cells resulted in the extension of their replicative lifespan. This earlier work, however, left many biologists with strong suspicions that telomerase-transformed cells would eventually become cancerous. The two Jan. 1 papers provide new in vitro—and the first in vivo data—showing that telomerase expression in normal cells 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 U. Texas researchers report that the expression of telomerase in human fibroblasts is sufficient to extend their in vitro 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 generating 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.

Telomeres and Telomerase

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.

This work, on immortalizing normal somatic cells, represents just half of the telomerase story. The other has to do with cancer.

Normal cells lose pieces from the ends of their telomeres with each replication. After a point the telomeres become too short, leading to chromosome instability and cell death. For this reason telomeres are thought to be a type of biological "clock" that ticks with each cellular replication. The so-called "Hayflick limit" tells us that human cells reproduce between 50 and 100 times before too much telomere is lost and the cells senesce. In cancer cells telomeres never reach this critical shortness and just keep on reproducing. The reason, according to Geron and leading academic researchers, is that cancer cells (unlike normal cells) express telomerase, which maintains telomere length. Think of telomerase as a perverse "fountain of youth" for deadly cancer cells.

Geron and other firms are searching for telomerase inhibitors as general cancer therapeutics. The idea is that since telomeres are already quite short in cancer cells compared with normal cells, a telomerase inhibitor—if applied long enough—will cause tumors to die on their own. The details of proposed "telomere-based" therapy will be quite complex since each cell division brings the tumor closer to its natural end, but also makes the patient sicker.

For more information: Nancy Robinson, Director of Investor Relations, Geron Corp., 230 Constitution Drive, Menlo Park, CA 94025. Tel: 650-473-7765. Fax: 650-473-7750.