Aging, Cancer and Stress

Elizabeth Blackburn's work on telomeres led to new research and discoveries

With their molecule in hand, Blackburn and others could start to tease out how telomerase works in the cell. From work in the 1960s it was known that human cells grown outside the body, unlike the ceils of single-celled organisms, have a limited life span. After some twenty to fifty divisions (a number thought to be highly dependent on cell type), human cells stop dividing and enter a static phase known as senescence. Could telomeres be functioning as a clock that tells cells when they have reached the end of their line?

Greider left Blackburn's laboratory in Berkeley in 1988, for a postdoctoral fellowship at Cold Spring Harbor Laboratory, in Long Island, New York. There she discovered that the telomeres in laboratory-grown human skin cells get shorter with every cell division. The idea took hold that shortened telomeres could be a signal to the cell that its genetic material is getting old and is at risk of losing its integrity--in short, the shortened telomeres become the canaries in the coal mine that tell a cell it is dangerous to continue dividing.

Greider's finding led to speculation that the telomerase gene is turned off in normal cells; that telomerase remains active only in other actively dividing cells, such as immune cells and germ cells. "We know now that there's a smidgen of telomerase in just about all cells, and that it is protecting telomeres," says Blackburn. "But there's not enough telomerase to keep up with the shortening. With time, she adds, "the telomeres will gradually run down."

Intriguingly, human telomeres vary in length from individual to individual. Telomeres in centenarians, for instance, are longer than one would expect. Could longer telomeres be protecting longlived people? After all, centenarians live longer in part because they don't die from the diseases that kill most of their age cohorts. Perhaps robust telomeres and extra telomerase are helping protect them against heart disease and other diseases.

An important link between telomerase, disease, and aging was identified in 2001, with the discovery of a genetic mutation responsible for a rare disease called dyskeratosis congenita. People with the condition are born with only one functioning gene for telomerase, and as a result, their telomeres shorten rapidly. They show some signs of premature aging, such as gray hair in their teenage years, but the most dire effect is that they usually die in early adulthood or middle age from bone marrow failure and a resulting inability to fight infections. "It's a striking reminder that we need a lot of self-renewal and telomerase in immune cells," says Blackburn. Immune cells have to multiply rapidly when they meet an antigen. Without sufficient telomerase, those cells cannot survive enough cell divisions to overcome the invader.

Once it became clear that telomere shortening might have a role in cell aging and, conversely, that long telomeres might somehow contribute to human longevity, Blackburn's colleagues began to take notice. The once-quiet field exploded, and the cumulative citations for "telomerase" in medical and biological journals skyrocketed. As others began working on telomeres and telomerase, new insights into disease and aging have come to light. With them has come the potential for developing new treatments against some of humanity's most intractable killers.

One recent discovery is that shortened telomeres do not necessarily spell imminent cell death, or even loss of vitality; the more important factor is whether enough telomerase is available in the cell nucleus to rescue and protect the remaining telomere ends. Remarkably, available telomerase turns out to be at least one key to the ability of cancer cells to circumvent the genetic safeguards of normal cell senescence.

In a malignant tumor, cancer cells divide and multiply indefinitely, becoming immortal, runaway tissue that consumes all the resources that would otherwise go to healthy tissue. In the early 1990s Greider and others found that the telomerase concentration in cancer cells is 100 times higher than it is in normal cells. The elevated telomerase occurs both in cancer-cell lines grown in the laboratory and in ovarian tumors growing in the body.