Telomerase Gene Clone Sets Stage for Drug Development

MENLO PARK, Calif—Researchers have cloned a critical component of the human telomerase gene—the catalytic protein subunit. Some scientists view the finding as the “holy grail” of cell aging research.

The discovery of the protein, named hTRT (human telomerase reverse transcriptase), is the result of a collaboration between scientists from Geron Corporation and the laboratory of Nobel Laureate Dr. Thomas R. Cech at the University of Colorado, Boulder.

Previously, scientists working with Geron had cloned the RNA component of the human telomerase gene (named human telomerase RNA, or hTR). Now, with the cloning of the active center of the gene, the stage may be set for the development of telomerase-based cancer diagnostics and therapeutics.

Telomerase has been called an immortalizing enzyme because its presence in cells allows them to reproduce without the constraints of the “molecular clock,” ie, the repeated shortening of the telomeres (the ends of the chromosomes) with each cell division until, after 50 to 100 divisions, cells senesce and die.

Telomerase, which synthesizes telomeres, is found in human embryonic cells, allowing the repair of developing cells, and in germ-line cells, but is generally absent in normal human somatic tissues and cells. However, it is abnormally activated in up to 90% of cancers, conferring “immortality” on the tumor cells and allowing their rapid multiplication.

The researchers first identified a version of the new gene in the fission yeast Schizosaccharomyces pombe and found that its disruption led to telomere shortening and senescence. They then sequenced a nearly identical human version and assessed the expression of mRNA from this gene (hTRT mRNA) in telomerase-positive immortal and telomerase-negative mortal cell lines.

They found that levels of hTRT mRNA correlated with telomerase activity in these cell lines. “The steady-state level of hTRT mRNA was higher in immortal cell lines with active telomerase than in any of the telomerase-negative cell strains tested,” Dr. Cech said.

Furthermore, telomerase activity was more strongly correlated with the abundance of hTRT mRNA than with that of telomerase RNA (hTR).

Sequence comparisons placed both of these human telomerase proteins in the reverse transcriptase family, where they form a discrete subgroup. This suggests that the telomerase reverse transcriptase genes “are an ancient group, perhaps originating with the first eukaryote,” Dr. Cech commented.

Clinical Implications

With an essential protein component of telomerase now in hand, Dr. Cech said, “the stage is set for more detailed investigation of fundamental and applied aspects of this ribonucleoprotein enzyme.”

The findings may be used in drug screening to discover telomerase inhibitors (to halt the growth of cancer cells) or possibly telomerase activators (to reverse conditions of aging by reactivating the enzyme and extending the cells’ replicative lifespan).

Telomerase may be a unique target for cancer therapeutics due to its near universality in cancer and its specificity to cancer cells.

According to Geron, it is present in all of the major types of human cancers studied by the company to date. Therefore, a telomerase inhibitor should be active against all cancers that express telomerase. No other known cancer target has this universality, the company said.

The specificity of telomerase for cancer cells should mean that telomerase inhibitors should have few if any adverse effects on normal cells. Also, since cancer cells lack growth control, they keep dividing even when their telomeres are critically short, which would lead to cell death following telomerase inhibition. Normal cells, on the other hand, even those few that express telomerase, stop dividing when their telomeres reach a critically short length, so telomerase inhibition therapy should, in theory, have no negative impact on normal cells.

Promise in Cancer Diagnosis

Dr. Cech pointed out that the correlation between hTRT mRNA levels and human telomerase activity shown in the study indicates that hTRT also has promise for use in cancer diagnosis. Geron said it has developed antibodies to hTRT that can detect the hTRT protein. A product based on this technology could play a role in the diagnosis, prognosis, and monitoring of cancer patients.

Dr. Cech was the lead author of the article on the discovery of hTRT, published in Science (277:955-959, 1997). His colleagues from the Howard Hughes Medical Institute at the University of Colorado include Toru M. Nakamura and Dr. Joachim Lingner. Co-authors from Geron are Drs. Gregg B. Morin, Karen B. Chapman, Scott L. Weinrich, William H. Andrews, and Calvin B. Harley.

A second group of researchers, working independently of Geron and Dr. Cech’s group, reported similar findings in an issue of Cell published a week later. These scientists were from the Whitehead Institute for Biomedical Research, Cambridge, Mass; Massachusetts General Hospital; Merck Research Laboratories, West Point, Penn; and McMaster University, Ontario.