Welcome to the research area of the Shay / Wright Laboratory. Information about Dr. Shay and Dr. Wright's research into telomeres and telomerase is contained here. For a more general overview of what telomeres and telomerase are, go to the Basic Introduction to Telomeres and Telomerase area of the site.
Telomeres are composed of repetitive DNA sequences at the end of linear chromosomes. In humans there are 46 chromosomes and thus 92 telomeres (one at each end). Human telomeres contain thousands of repeats of the six nucleotide sequence, TTAGGG. The telomere-telomerase hypothesis of aging and cancer is based on the findings that most human tumors have telomerase activity while most normal human somatic cells do not. Telomere length is maintained by a balance between processes that lengthen telomeres [telomerase] and processes that shorten telomeres [the end-replication problem]. Telomerase (TEE-LēM-ER-ACE) is a ribonucleoprotein enzyme complex (a cellular reverse transcriptase) that has been referred to as a cellular immortalizing enzyme. It stabilizes telomere length by adding hexameric (TTAGGG) repeats onto the telomeric ends of the chromosomes, thus compensating for the erosion of telomeres that occurs in its absence. The enzyme is expressed in adult reproductive cells, but is undetectable in normal somatic cells except for proliferative cells of renewal tissues (e.g. bone marrow cells, basal cells of the epidermis, proliferative endometrium, and intestinal crypt cells). In all non-reproductive cells progressive telomere shortening is observed, eventually leading to greatly shortened telomeres and to a limited ability to continue to divide. It has been proposed that telomere shortening may be a molecular clock mechanism that counts the number of times a cell has divided and when telomeres are short, cellular senescence (growth arrest) occurs. It is believed that shortened telomeres in mitotic (dividing) cells may be responsible for some of the changes we associate with normal aging.
Cellular senescence may have evolved, in part, to protect long-lived organisms, such as humans, against the early development of cancer. It takes many divisions to accumulate all of the mutations (alterations) needed to become a cancer cell. Cells that use up their replicative life span and become senescent while accumulating a few of these mutations, remain pre-malignant and do not progress to cancer. It has been proposed that up-regulation or re-expression of telomerase may be a critical event responsible for continuous tumor cell growth. In contrast to normal cells, tumor cells show no net loss of average telomere length with cell division, suggesting that telomere stability may be required for cells to escape from replicative senescence and proliferate indefinitely. Most, but not necessarily all, malignant tumors may need telomerase to sustain their growth. Immortalization may occur through a mutation of a gene in the telomerase repression pathway. Thus, up-regulation or reactivation of telomerase activity may be a rate-limiting step required for the continuing proliferation of advanced cancers. There is experimental evidence from hundreds of independent laboratories that telomerase activity is present in almost all human tumors but not in tissues adjacent to the tumors. Thus, clinical telomerase research is currently focused on the development of methods for the accurate diagnosis of cancer and on novel anti-telomerase cancer therapeutics.
In addition to the accumulation of several mutations in oncogenes and tumor suppressor genes, almost all cancer cells are immortal and, thus, have overcome the normal cellular signals that prevent continued division. Young normal cells can divide many times, but these cells are not cancer cells since they have not accumulated all the other changes needed to make a cell malignant. In most instances a cell becomes senescent before it can become a cancer cell. Therefore, aging and cancer are two ends of the same spectrum. The key issue is to find out how to make our cancer cells mortal and our healthy cells immortal, or at least longer-lasting. Inhibition of telomerase in cancer cells may be a viable target for anti-cancer therapeutics while expression of telomerase in normal cells may have important bio-pharmaceutical and medical applications in cell and tissue engineering. In summary, telomerase is both an important target for cancer and for the treatment of age-related disease.
In contrast to tumor cells, which can divide forever (are "immortal"), normal somatic human cells have a limited capacity to proliferate (are "mortal"). Telomeres are thought to be the "clock" that regulates how many times an individual cell can divide. Telomeric sequences shorten each time the DNA replicates. When at least some of the telomeres reach a critically short length, the cell stops dividing (is senescent), which may cause or contribute to some age-related diseases. Introduction of the telomerase catalytic protein component into normal human cells without detectable telomerase results in telomerase activity and an extension of life span. The cells with introduced telomerase maintain a normal chromosome complement and continue to grow in a normal manner. The development of better cellular models of human disease and production of human products are among the immediate applications of this new advance. This technology has the potential to produce unlimited quantities of normal human cells of virtually any tissue type. In the future, it may be possible to take a person's own cells, manipulate and rejuvenate them without using up their life span and then give them back to the patient. The manipulation of telomere length for cell and tissue engineering offers many biomedical opportunities. In collaboration with Brian Pilcher and Michael White, our laboratory is pursuing studies on the factors regulating the rate of telomere shortening in different cell types, the structure of telomeres, factors that interact with telomerase and regulate its action on telomeres, and the application of the ability to immortalize cells for the treatment of human diseases, such as muscular dystrophy and chronic ulcers.
In cancer, a special cellular reverse transcriptase, telomerase, is reactivated and maintains the length of telomeres, allowing tumor cells to continue to proliferate. Therefore, detection of telomerase may have utility in cancer diagnostics, as a prognostic indicator of outcome, and as a marker of minimal residual disease after standard cancer therapy. Since cancer cells must maintain their telomeres, any treatment that prevents telomere maintenance is potentially an important anti-cancer therapeutic. For example, preventing precancerous cells from immortalizing may be a potent chemopreventive strategy. Another strategy is to inhibit the activity of telomerase, forcing immortal cells into a normal pattern of permanent growth arrest (senescence) or death (apoptosis). Recent experiments have shown that antisense oligonucleotides (peptide nucleic acids and 2'-O-methyl-RNAs) directed towards binding the template region of telomerase RNA are highly effective in repressing telomerase activity in cancer cells. In collaboration with David Corey, our laboratory is conducting xenograph testing of our antisense telomerase inhibitors (by putting human tumors in immunodeficient mice). If we can inhibit human tumors in mice this would be an important precursor to human clinical trials. In addition to approaches directed at telomerase RNA, other strategies include targeting the catalytic reverse transcriptase subunit or telomerase as well as its associated proteins. Identification of the cellular genes that regulate the telomerase repression pathway offers an independent tactic for developing telomerase antitumor drugs. In this regard there is substantial evidence that a gene on chromosome 3p contains a telomerase repressor.
Kim, N-W., Piatyszek, M. A., Prowse, K. R., Harley, C. B., West, M. D., Ho, P. L. C., Coviello, G. M., Wright, W. E., Weinrich, S. L., and Shay J. W. Specific association of human telomerase activity with immortal cells and cancer. Science, 266:2011-2015, 1994.
Weinrich, S.L., Pruzan, R., Ma, L., Ouelette, M., Tesmer, V. M., Holt, S. E., Bodnar, A., Lichsteiner, S., Trager, J., Taylor, R. D., Carlos, R., Andrews, W. H., Wright, W. E., Shay, J. W., Harley, C. B., Morin, G. B. Reconstitution of telomerase with the catalytic protein subunit hTERT. Nature Gen., 17:498-502, 1997.
Bodnar, A. G., Ouellete, M., Frolkis, M., Holt, S. E., Chiu, C-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., and Wright, W. E. Extension of life span by introduction of telomerase in normal human cells. Science 279:349-352, 1998.
Shay, J. W. Telomerase in cancer: Diagnostic, prognostic and therapeutic implications. Cancer J. Scientific Amer., 4:26-34, 1998.
Morales, C. P., Holt, S. E., Ouellette, M., Kaur, K. J., Ying, Y., Wilson, K. S., White, M. A., Wright, W. E. and Shay, J. W. Lack of cancer-associated changes in human fibroblasts after immortalization with telomerase. Nature Gen., 21:115-118, 1999.
Shay, J. W. Toward identifying a cellular determinant of telomerase repression. J. Natl. Cancer Inst., 91: 4-6, 1999.
Herbert, B-S, Pitts, A. E., Baker, S. I., Hamilton, S. E., Wright, W. E., Shay, J. W., Corey, D. R. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Nat. Acad. Sci., 96:14276-14281, 1999.
Shay, J. W. and Wright W. E. The use of "telomerized" cells for tissue engineering. Nature Biotech, 18:22-23, 2000.