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Carol Greider: Fundamental Science Fuels Practical Applications

SAN DIEGO—At the end of every human chromosome, a short string of repetitive genetic code called a telomere keeps the chromosome from unraveling or clinging to its companions. Not much more than a tiny stutter of DNA, the telomere nonetheless tells an eloquent story about the importance of basic research, Carol W. Greider said at the 2010 AAAS Annual Meeting.

Researchers now know that telomeres play a critical role in aging and diseases such as cancer, but these implications were far from Greider's mind when she began the studies that would lead to her 2009 Nobel Prize in Physiology or Medicine.

Telomere research is "the perfect example of bridging science and society," she said in her 19 February plenary speech. "It's fundamental knowledge that fuels practical implications."

Greider is the Daniel Nathans Professor and Director of the Department of Molecular Biology and Genetics and a professor of oncology at Johns Hopkins University School of Medicine. She shared the 2009 Nobel Prize for telomere studies with Elizabeth Blackburn of the University of California, San Francisco, and Jack Szostak of Harvard Medical School.

It took many kinds of basic science, she recalled, just to solve an essential mystery: Telomeres lose a little bit of themselves each time a cell divides, but they never disappear entirely. Why?

To answer the question, Greider, then a 22-year old graduate student, and Blackburn turned to a single-cell organism bristling with hundreds of arms--and 40,000 chromosomes. Their biochemical studies eventually led to the discovery of  telomerase, an enzyme that balances the perpetual pruning of telomeres by repairing and rebuilding their genetic sequence.

As often happens in science, the finding raised another set of questions. What kinds of cells need telomerase repair, and what happens when the repairs stop?

After completing her Ph.D. at the University of California Berkeley and establishing her own research group at Cold Spring Harbor Laboratory, Greider embarked on research showing that that telomerase "was essential for all cells that need to divide many times." Cancer cells and cells that rebuild normal body tissues, she said, are some of the most intriguing cells in this category, hinting at the possibility of telomerase as a therapeutic target.

The researchers also discovered that telomerase's protective powers eventually wear out, and telomeres get shorter as a part of normal human aging. At a certain point, Greider said, so much of the telomere is lost that the stubby end looks like a lesion of "damaged DNA, and then you have cell death."

With these facts in hand, Greider's lab was ready when clinicians at Johns Hopkins approached them with a rare genetic disease called dyskeratosis congenita. The condition affects tissues such as skin and bone marrow that are frequently renewed by dividing cells. The lab researchers now think that abnormally short telomeres may lie at the heart of the disorder.

Rare diseases like dyskeratosis can be a model for understanding more common disorders that affect the immune system and organs that constantly replace tissues as we age, said Greider.

She hopes to clarify the link between aging and telomere length, although she cautioned that aging probably has multiple causes. Other studies in her lab that look at telomerase in cancer cells and failing stem cells may someday have clinical applications, but she hasn't forgotten her roots in basic science.

"Understanding the telomeres came from simple curiosity about the chromosomes," she said. "but we've learned so much along the way that is really pertinent to human disease."