In 1961 Leonard Hayflick discovered the limit that bears his name: normal cells can divide only so many times–roughly fifty–before running out of steam. At #3 is a paper, from Serge Lichtsteiner of the Geron Corporation and Woodring Wright of University of Texas Southwestern Medical Center at Dallas, and their colleagues, proving that telomerase, an enzyme, underpins the Hayflick Limit.
The key question was whether telomeres had anything to do with cell aging. The telomere is a repetitive stretch of DNA found at each end of a chromosome. In 1986, Howard Cooke, of the Medical Research Council's Human Genetics Unit in Edinburgh, Scotland, noticed that the telomeres capping sex chromosomes were much longer when those chromosomes came from a germline cell than when they came from a normal body cell. Because of the way DNA replicates, telomeres are shortened each time a cell divides. An enzyme, telomerase, which extends the telomere, had been discovered just before, and Cooke wondered whether it might be inactive in normal human cells. The progressive shortening of the telomere would then impose the Hayflick Limit on the cell's ability to divide.
The analogy is with a shoestring–more specifically, the little plastic bit at each end. I don't know who first came up with it, but it is a striking analogy. Just as the little plastic bit (it couldn't possibly have a name, could it?) stops the lace fraying and makes it possible to thread the lace through the eyelets, so the telomere stops the end of the chromosome fraying. And just as one might have to abandon a perfectly good shoelace, just because it has become unlaced after the little plastic bit has been destroyed by wear and tear, so the cell sometimes has to abandon a perfectly good chromosome (and die in the process) just because the telomere has been destroyed. Telomerase, then, is the little bit of Scotch tape that gives new life to a frayed shoelace.
Cooke's theory gained support from a great deal of evidence. Crucially, telomerase is present, but inactive, in most normal cells. And it is active in tumor cells, which do not grow old and know no reproductive limit. But the evidence was circumstantial or correlative. The Bodnar et al. paper at #3 offers the first definitive proof that shortened telomeres cause cell senescence. The paper does so by activating telomerase in normal cells–producing, as the authors proclaim, an "extension of life span."
The approach depended on two previous discoveries that were hot papers in their time. First, the isolation by Thomas Cech and his colleagues of TRT, the reverse transcriptase subunit of telomerase, the bit that actually adds the repetitive TTAGGG sequence that characterizes telomeres. That sequence, taken from a protozoan, was then used to fish for hTRT, the human version, allowing Wright's group to insert hTRT into normal human cells.
"The results," as one commentator put it, "were strikingly unequivocal." The telomeres in cells with hTRT lengthened, and the cells themselves kept on multiplying, through the Hayflick limit and well beyond. At the time the paper was submitted they had made 20 or more "extra" divisions, yet they looked young, vigorous, and essentially normal.
Immediately after publication there was interest in blocking telomerase to treat cancers, which skeptics criticized because the telomeres would take too long to shorten. According to Jerry Shay, a member of the team at UTSMC, that's a straw man: no one would consider anti-telomerase as a front-line therapy. "Realistically," Shay tells Science Watch, "I believe telomerase inhibitors will be used after surgery and perhaps in combination with chemotherapy or radiotherapy in a clinical setting of minimal residual disease." The hope is that with the main tumor under control anti-telomerase might target small hidden metastases, shortening their telomeres enough to prevent or delay cancer relapse.
Equally exciting is the possibility that telomerase could act as a marker for cancers that are otherwise difficult to detect. Early detection improves clinical outcome enormously, but many cancers, for example bladder cancer, are hard to detect early. A kit targetting telomerase–and Geron has licensed the technology to Roche–would enable routine screening of urine samples in high-risk patients. Shay tells Science Watch that in many cancers the expression of telomerase is a good indication of prognosis, and there are now opportunities for measuring telomerase. "This knowledge," he says, "may help oncologists decide when additional surgery or therapy is needed."