3 Americans share Nobel in medicine

Three Americans - two of them women - won the 2009 Nobel Prize in medicine for work that used simple pond organisms to uncover a key part of the aging process in our own cells.

It was the first time that the prize for medicine went to two women - Elizabeth Blackburn of the University of California San Francisco and Carol Greider of Johns Hopkins University. The other winner, Jack Szostak, is a biologist at Massachusetts General Hospital.

Their work in the early 1980s clarified the nature of molecular-scale structures called telomeres - sometimes likened to the caps at the ends of shoelaces because they keep our genetic material from fraying. As we age, our telomeres inexorably shrink, causing the death of our cells and, eventually, us.

The study of telomeres has since opened up vast avenues of research not only in aging but in cancer and other diseases. "Those of us in the field have been asking, 'When in the world is the Nobel committee going to get around to this?' " said Joseph Gall, a biologist at the Carnegie Institution in Baltimore.

In cancer, tumor cells often manage to turn off the telomere aging clock - allowing more rapid, uncontrolled division, and researchers are experimenting with drugs to turn the clock back on.

Others have found that in healthy people, exercise can keep telomeres long while certain kinds of stress can shorten them. NASA is investigating how telomeres are affected by long-duration space flight.

Greider, 48, of Johns Hopkins, said she was folding laundry when she got the early-morning call yesterday from the Nobel committee. She normally attends a spinning class but had missed it yesterday. Greider made her contribution to the Nobel-winning research while working as a graduate student in the UC Berkeley lab of the other female winner, Elizabeth Blackburn, 60.

Back in the early 1980s, scientists knew that when cells divide, the resulting cells lose a little DNA on the ends of each chromosome. In theory, our genetic material should waste away before we're even born because the cells divide so rapidly during development. DNA codiscoverer James Watson recognized this as the "end problem."

In the 1970s, Blackburn thought she might get some insight by working with a single-celled pond organism called tetrahymena. "We were working on something most people would have considered amusing or interesting but not directly related to aging or cancer," said Carnegie's Gall, who was then Blackburn's senior colleague at Yale University.

The pond organisms were interesting because they had hundreds of chromosomes - as opposed to 46 in human cells - and that meant there were lots of these mysterious ends.

"When Liz came to our lab, I said it would be interesting to look at the ends to know what they are like," Gall said. Blackburn had come to Gall's lab as a postdoctoral fellow with knowledge about sequencing genetic material - and she used that knowledge to decipher the genetic code of the tetrahymena's many ends. What she found was that the sequence GGGGTT repeated hundreds of times.

This repetitive stuff became known as the telomere.

Szostak, meanwhile, now 56, was investigating the "end problem" using both tetrahymena and yeast - inserting telomeres from one organism into the other. Working together, Blackburn and Szostak were the first to show that in these organisms, the telomeres were sometimes getting longer.

"They thought, 'There must be a machine in there that is doing this,' " said Thomas Cech, a biochemist and telomere researcher at the University of Colorado and winner of the 1989 Nobel Prize for Chemistry. (Cech's Nobel also used tetrahymena, making this year's prize the second to involve this pond organism.)

In the early 1980s, Blackburn, then at UC Berkeley, assigned the task of finding this machine to her new graduate student, Carol Greider. "This is a pretty scary project for a beginning doctoral student," Cech said. "To prove something exists that maybe doesn't exist."

Greider took apart the pond creatures and looked for internal parts that could add length to stretches of DNA. Greider was so excited about the project that she came to the lab on Christmas Day in 1984 and saw the first signs that an enzyme isolated from the cells was building up new DNA.

They called the enzyme telomerase.

Szostak, meanwhile, showed that without the ability to add new length to the telomeres, they keep shrinking and cells eventually stop dividing and die.

Colorado's Cech likens telomerase to a sewing machine, replacing stitches that get pulled out when a cell divides and DNA copies itself.

Today, Szostak has moved on to studying other issues including the origin of life. Blackburn and Greider have continued as leaders in telomere research.

At the Wistar Institute in Philadelphia, Emmanuel Skordalakes is following the trail by investigating the way telomerase misbehaves in cancer. While it's essential for allowing cells to divide during development, adult cells no longer use telomerase, for the most part. That's one reason we age.

But telomerase is active in about 90 percent of human cancers, Skordalakes said.

That suggests that drugs designed to attack or shut off telomerase won't affect healthy cells and therefore should have few side effects, he said.

On the flip side, he said, telomerase looks as if it could stave off aging. In one experiment, he said, researchers used it to extend the lives of mice by about 30 percent, but they also had to do various other manipulations to keep them from getting cancer.

Telomerase is a dangerous fountain of youth, said Cech. So maybe it's not so bad that most of our cells no longer make it. We humans are relatively lucky our telomeres start out with about 6,000 elements of genetic code - more than most creatures get.

"They last a pretty long time," he said.

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