Telomere Biology

CELLULAR CLOCK: From left, University of Texas Southwestern Medical Center at Dallas investigators Michel Ouellette, Woodring Wright, Jerry Shay, and Shawn Holt continue to investigate how telomerase regulates human cell division. S.E. Holt, W.E. Wright, J.W. Shay, "Regulation of telomerase activity in immortal cell lines," Molecular and Cellular Biology, 16:2932-9, 1996. (Cited in more than 70 publications to date) Comments by Jerry W. Shay and Woodring E. Wright, department of cell biology and neuroscience, University of Texas Southwestern Medical Center at Dallas Telomeres--the ends of chromosomes--shorten during each round of cell replication, suggesting that they dictate the number of times a cell can divide before it reaches senescence. Almost all cancer cells and other immortalized cells thwart that stop mechanism by expressing telomerase, an enzyme that, in effect, rebuilds the chromosomal tips. In an earlier Hot Paper feature (The Scientist, 10[11]:14, May 27, 1996), Jerry W. Shay, a professor of cell biology and neuroscience at the University of Texas (UT) Southwestern Medical Center at Dallas, described a polymerase chain reaction-based telomerase assay (N.W. Kim et al., Science, 266:2011-5, 1994). Shay notes that the relative ease of using that assay may have focused attention on the 1994 paper. Even after the paper by Kim and colleagues--which has been cited more than 500 times--scientists knew little about the relationship of telomerase to stages of cell development. In this 1996 article, Shay and his UT-Southwestern colleagues Woodring E. Wright, a professor of cell biology and neuroscience, and Shawn E. Holt, a research fellow in cell biology and neuroscience, attempted to explore those relationships by asking, "Is telomerase cell-cycle regulated?" To determine the answer, they isolated immortalized cells at various stages in the cell cycle and measured telomerase. Their assays showed that telomerase activity remained constant through all stages of the cell cycle. They also examined mouse and human cells, noting that telomerase activity declines when cells differentiate or become quiescent. The difference between the immortal growing cells and the immortal quiescent cells provided the answer to the group's initial question. "Although the pathway silencing telomerase may have mutations in tumor cells, there is clearly another intact pathway for repressing telomerase when cancer cells become quiescent," Wright concludes. Still, some questions about the relationship remain--especially regarding regulatory mechanisms. "We really don't know why telomerase goes down when cells exit the cell cycle," Shay adds. In a more recent paper, Shay and colleagues described their efforts to add the protein component of the telomerase enzyme to human skin and retinal cells devoid of it (A.G. Bodnar et al., Science, 279:349-52, 1998). "We found that telomerase could be turned back on," Shay says. The cells with the introduced telomerase continued to divide long after the control cells stopped. "They just kept growing and growing and growing," he notes. Both the 1996 article and the 1998 paper suggest some interesting applications for telomerase, which may explain the attention given to this research. The most immediately viable lies in diagnostics, Shay notes. Telomerase tests could be especially useful for forms of cancers in which current diagnostics lack specificity and sensitivity--requiring painful, invasive clinical tests such as cystoscopy, which patients being examined for bladder cancer must endure. Telomerase tests, perhaps in combination with other diagnostic markers, could reduce the use of that procedure. Telomerase tests also could indicate the success of tumor removal, since residual cancer cells sometimes evade destruction from surgery and chemotherapy. "If you have residual telomerase, you might want to go back in and do a second surgery or try another therapy," Shay suggests. A more distant application may be to use telomerase therapeutically for diseases such as muscular dystrophy, in which muscle cells eventually stop growing. Since the defective dystrophin gene results in muscle degeneration, eventually most of the stem cells that give rise to new muscle cells age and can no longer replace the damaged muscle. "The hope is that we might be able to take a patient's muscle stem cells, introduce telomerase to give the cells extended proliferative capacity, then replace the defective dystrophin gene with a healthy one and give the cells back to the patient," notes Wright. However, that approach is years from being clinically viable. Shay adds that the field of telomerase research suggests that the gene for the enzyme is a target for both cancer and age-related diseases. "The telomerase gene will likely have many applications in the future of medicine and cell engineering," he concludes.

Telomere Biology

The Scientist Staff

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