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Medicine | IN THE LAB

At DNA's ends, the clues begin

An enzyme found on the edges of the double helix may help unravel the mysteries of aging and cancer. A biologist continues the intriguing research she began 30 years ago.

June 23, 2003|Linda Marsa | Special to The Times

Elizabeth Blackburn didn't think the peculiar genetic structures she discovered as a young scientist would consume her career. But the 54-year-old molecular biologist's research on telomeres -- the ends of a chromosome -- is yielding promising clues in the fight against cancer and increasing our knowledge of the aging process.

Telomeres are known to prevent the ends of DNA from fraying, like the plastic ends on shoelaces. Blackburn's experiments revealed that telomeres do more than just protect DNA; they also control the lifespan of a cell and enable deadly cancer cells to grow indefinitely. "Like Jekyll and Hyde, depending on the context," says the Australian-born scientist, who now heads a 12-person laboratory at UC San Francisco.

Of course, Blackburn had no inkling of this in the early 1970s, when she mapped out the genetic structure of the telomeres that she found in protozoan ciliates, single-celled organisms that float on the surface of ponds. "Sometimes the DNA sequence was growing, and sometimes it was shrinking, which was very strange," says Blackburn. "This behavior indicated there had to be an enzyme that created or preserved telomeres."

In 1984, she and a research colleague named Carol Greider identified the enzyme, now called a telomerase. Their discovery brought this research into the scientific mainstream because some researchers believed the enzyme might play a crucial role in human aging and could yield clues in the fight against cancer.

Scientists have known since the 1960s that living cells stop dividing after about 50 generations. Researchers soon noticed that each time the double strands of DNA, which are coiled inside of each cell, unravel and split apart to form a new cell, the telomeres shorten. As the cells multiplied, and the telomeres were reduced to a tiny nub, the cells would die.

That finding suggested the telomeres somehow regulated our biological clocks. "The idea [that] this had to do with aging came quite quickly from these observations," says Blackburn.

Subsequent research has confirmed that telomere shortening is a fundamental process of aging, making people more vulnerable to age-related diseases. Scientists at the University of Utah reported earlier this year that people with shorter telomeres, on average, died four to five years sooner than people with longer telomeres. They also were three times more likely to die of heart disease, and more than eight times more likely to die from an infectious disease.

Since the enzyme telomerase preserves or even lengthens telomeres, it is possible it could retard the aging process.

Though research is still in its early stages, says Blackburn, "we do know that if you want to keep cells from dying off in the test tube, a little jolt of telomerase does the trick."

On the other hand, telomerase inhibitors may combat the growth of cancerous tumors. More than 80% of cancers, including some of the most common forms such as cancers of the breast, bladder, ovaries, prostate and lungs, continuously activate telomerase. Consequently, these cancers' telomeres remain long, which allows them to reproduce indefinitely.

"Cancer cells love their telomerase; they're absolutely addicted to it," says Blackburn. "Take it away, and they die quickly, which surprised us because we thought these cancer cells were hard-bitten warriors."

Human tests should begin soon on a telomerase blocker to treat cancer. And Blackburn's team is searching for mutant telomerase that would cause cancer cells to die.

It's all been great fun, Blackburn says of her 30 years tracking telomeres, "but I never thought it would grow into this huge field."



Tests on cancer

Since 1995, researchers from New York's Memorial Sloan-Kettering Cancer Center, the National Cancer Institute in Bethesda, Md., and Geron Corp. in Menlo Park, Calif., have collaborated on tests of a telomerase inhibitor to combat 13 types of cancers, including myeloma, lymphoma and cancers of the breast, pancreas, kidney, cervix, brain, lung, prostate and ovary.

In laboratory tests and testing using animals, the compound has proved to be effective at killing off tumor cells without the toxicity of chemotherapy. The compound, known as GRN163, is scheduled for use in human clinical trials later this year to test its effectiveness at treating brain cancer.

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