Telomeres and the Nobel Prize

A scientist can make no greater contribution than launching an entirely new field, and that is what this year's Nobel laureates in medicine did. But in the 29 years since the first discovery that has earned Elizabeth Blackburn of UC San Francisco, Carol Greider of Johns Hopkins, and Jack Szostak of Harvard Medical School this year's Nobel, even their seminal insight into how cells work has failed to bring real progress in treating disease—a testament to the frustrating and tragic difficulty of translating basic science into medical progress.

The trio "solved a major problem in biology: how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation," as the Nobel announcement put it. That solution was telomeres: molecular caps at the end of chromosomes that protect DNA from degradation. Blackburn and Szostak discovered telomeres (the key papers were in 1980 and 1982; the Nobel committee tends to take its time in these things); in 1984 Blackburn and Greider, her grad student, discovered telomerase, the enzyme that builds telomeres.

By "launching a new field," I mean that telomeres have, for more than a quarter century, been shedding light on aging and cancer, and Blackburn, Greider, and Szostak have been leading the research since the beginning If telomeres are shortened, cells age. Because aging is such a multifactorial process, however, targeting telomeres to slow aging is not in the cards, despite early optimism that the fountain of youth might be that simple. For instance, a paper this August by Blackburn and her colleagues tested the idea that elderly people with shorter telomeres (as measured in white blood cells) are destined for a shorter life span and fewer years of healthy life. But they found that telomere length "was not [my emphasis] associated with overall survival ... or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases." Telomere length was, however, linked to more healthy years: the longer your telomeres, the longer you can go without succumbing to the diseases of old age. Telomere length, then, "may not be a strong biomarker of survival in older individuals," Blackburn's team concluded, "but it may be an informative biomarker of healthy aging." Translating even that more-limited insight into something that helps people, however, remains elusive.

The application of telomeres to cancer is even less straightforward. The basic idea is that if cells have high levels of telomerase activity, telomeres retain their length, and cells stay alive—the crucial (and, ironically, deadly) characteristic of cancer cells. They divide and divide—something that should degrade telomeres—and yet their telomeres never shrink, allowing the cells to divide some more. The reason is increased telomerase activity.

Not surprisingly, this led to the hope that cancer might be treated by eradicating telomerase. Geron has worked on one such vaccine, and Merck is taking it into late-stage clinical trials. With cancer, as we have seen time and again, unfortunately, nothing is straightforward; the most likely use of a telomerase vaccine would be in follow-up therapy after initial surgery and/or chemotherapy , probably for some forms of leukemia, melanoma, and lung and prostate cancers.

Telomeres might prove more useful as an early warning sign, but here, too, the line from lab to clinic has not been exactly straight. From Blackburn's initial work, it seemed that long telomeres—conferring cellular immortality—should increase the risk of cancer. But it turns out, as a new paper finds, among premenopausal women the risk of breast cancer is 60 percent or 70 percent higher with the shortest telomere lengths. "Carrying shorter telomeres, as compared with the longest, was associated with significantly increased breast cancer risk," they found. That was not some out-of-the-blue finding: a 2007 study also found that "shortened telomere length may be associated with breast cancer risk."

The Nobel Prizes have long since strayed from Alfred Nobel's original wish, expressed in his will, that they reward work that "shall have conferred the greatest benefit on mankind." The work of this year's laureates elucidated some of the deepest mysteries of the cell, surely a benefit. As Jeremy Berg, director of NIH's National Institute of General Medical Sciences, said when the same trio won the 2006 Lasker Award for basic medical research, "This research on a basic biological process, which at the time had no known application to human health, has proven to be an important breakthrough in understanding the mechanisms of diseases such as cancer. It clearly shows the value of basic research in helping to establish the causes and cures for certain diseases"—and the immense difficulty of translating even such a fundamental insight into something that helps patients.

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