Sometimes stories that start with pond scum can have good endings. In the case of the single-celled organism called Tetrahymena thermophila, important bits of DNA at the ends of its chromosomes led to a Nobel prize for three scientists.
Elizabeth Blackburn, Carol Greider and Jack Szostak will share the Nobel Prize in physiology or medicine for discovering telomeres, the caps on the end of chromosomes, and telomerase, the enzyme that tacks those caps on, Sweden’s Nobel Foundation announced October 5.
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Telomeres, repeated sequences of DNA at the end of chromosomes, prevent degradation of genetic material. The discoveries of the sequences and the enzyme adds or elongates them solved a long-standing biological mystery: How do cells replicate chromosomes without losing any genetic information? Telomeres have broad implications for medicine, and may be especially important for cancer, certain inherited diseases and aging.
Once DNA replication was understood, it became obvious that the ends of chromosomes presented a problem, says Titia de Lange, a cell biologist at The Rockefeller University in New York City.
“It’s like painting a floor. You can’t paint directly under your feet,” she says. Without some mechanism for copying the ends of chromosomes, the strands of DNA would get shorter and shorter each time a cell divides and replicates its genetic material. “Before you know it, your whole chromosome is gone,” de Lange says. “This is a problem.”
Bacteria solve the problem by making circular chromosomes with no ends. But humans and many other organisms have long, linear chromosomes.
Blackburn, currently at the University of California, San Francisco, had a hand in both discoveries in the late 1970s and early ’80s. She first identified the repeated sequences capping the ends of chromosomes in Tetrahymena, a single-celled organism that lives in freshwater lakes, ponds and streams. At the time, the purpose of the sequences was unclear.
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Tetrahymena has hundreds of small linear chromosomes, making it the perfect organism for finding telomeres and telomerase, says Jeremy Berg, director of the National Institute of General Medical Sciences in Bethesda, Md.
About the same time, Szostak, now a Howard Hughes Medical Institute investigator at Massachusetts General Hospital and Harvard Medical School in Boston, was attempting to make minichromosomes in yeast. Those chromosomes kept getting degraded or made into circular bits of DNA instead of remaining long, linear pieces of DNA — the normal state of yeast cell chromosomes. Blackburn and Szostak teamed up and found that the capping sequences from Tetrahymena chromosomes could keep the yeast chromosomes intact. Some experiments by Blackburn and Szostak also led them to predict the existence of an enzyme for lengthening telomeres.
Greider, now at Johns Hopkins University in Baltimore, worked as a graduate student with Blackburn to find that enzyme, telomerase. Greider first saw evidence that she had isolated the enzyme on Christmas day, 1984.
“It was quite courageous for a graduate student to take on a project that daunting, where so little was known,” Berg says. But Greider is “a ball of enthusiasm and energy” with passion for science. “Even in a crowd of type A people, she stood out,” he says.
The award “is really a tribute to basic, curiosity-driven science,” Greider said in a news conference. “We didn’t know at the time that there were any particular disease implications.”
Other scientists discovered that telomeres are important in human diseases of aging, some rare genetic diseases and in cancer. Most mature human cells turn off telomerase, de Lange says. After about 50 divisions, chromosomes are eaten away enough to stop cells from dividing or to trigger cell suicide. In stem cells, the enzyme remains active, and about 85 percent of cancers reactivate the enzyme, she says.
When active, the enzyme allows cells to keep dividing indefinitely. Cancer cells have shorter telomeres than normal cells, Greider says, so telomerase-inhibiting drugs would probably kill the cancer cells before much damage is done to normal cells. Clinical trials are underway to test whether interfering with telomerase will kill cancer cells, Berg says.
Blackburn and Greider continue to investigate the formation of telomeres and their role in maintaining the integrity of chromosomes. “It seems there are more questions now than when we started,” Greider says. Among the remaining mysteries is how cells keep telomeres from getting too short or too long.
Szostak’s research now focuses on trying to discover the biochemical origins of life. “It’s really exciting, bold stuff — life in a test tube that might actually happen,” Berg says. “It’s really cool, but a little bit scary.”