Carol Grieder, a professor and the director of the Department of Molecular Biology and Genetics at Hopkins, was awarded the Nobel Prize for Physiology or Medicine on Monday.
She shares the prize with her former mentor, Elizabeth Blackburn, of the University of California, San Francisco, and Jack Szostak of Harvard Medical School.
The Nobel Prize committee chose these three scientists for their discovery of telomerase and telomeres, molecules that protect genes near the ends of chromosomes from eventual deletion as a result of repeated cell replication.
The discovery for which Greider earned this award was made on Christmas in 1984. Then a graduate student in Blackburn's lab at the University of California, Berkeley, Grieder was only 23 years old when she detected an enzyme in a cell extract, naming it telomerase.
Together, Greider, Blackburn and Szostak solved a major problem that had been puzzling biologists since the 1950s, when the molecular mechanisms behind DNA replication were discovered.
"There is an 'end replication problem' inherent in the structure of the DNA molecule and the mechanism used by cells to create duplicates," said Forrest Spencer, professor of the McKusick- Nathans Institute of Genetic Medicine at Hopkins.
When DNA undergoes replication, the double-stranded helix "unzips" down the middle, creating two single, unpaired strands. These strands act as templates onto which new DNA bases are added, creating two identical sets of DNA.
The molecules that add these new bases, known as DNA polymerase enzymes, can only travel in one direction along the template DNA, based on the strand's orientation. But since the two template strands always run in opposite directions, only one of them can have bases added continuously in the direction of replication. Polymerases on the other strand add bases discontinuously in short fragments, starting the fragment closer to the end of the DNA and backtracking toward the beginning until it runs into the last fragment.
However, the replication machinery encounters a problem when the discontinuously-synthesized strand reaches the end of the DNA. Polymerases are unable to bind at the very end of the strand to create the final fragment, so every time the DNA is replicated, one would expect the polymerases to leave a few bases uncopied.
Over time, this could significantly shorten the DNA and possibly end up deleting genes near the end of the chromosome. "If there was no mechanism to correct for this, our chromosomes would be losing bits of genetic information and with each cell generation [become] shorter, bringing genetic instability and finally death," said Evangelos Moudrianakis, a professor in the Hopkins Departments of Biology and Biophysics and a close colleague of Greider's.
To resolve the problem, the cell adds extra sequences of DNA to the ends of the template strand to extend it, so the replication molecules can bind to and copy the entire chromosome without missing the ends. These protective repeating sequences, known as telomeric DNA, were discovered by Szostak and Blackburn.
"Those add-on extensions do not code for any genes," Moudrianakis said. "They simply function as protective caps for the ends of chromosomes, protecting them from 'erosion' of their innate genetic information."
The question of how those telomeres were formed and preserved was answered by Greider and Blackburn. They were the first to purify the enzyme, now known as telomerase, which adds repeating sequences of nucleotides, battling the chromosome shortening that results from every round of replication.
Our understanding of telomeres and telomerase today has allowed researchers to go far beyond the basics of this molecular safeguard and investigate the implications in cellular aging and disease.
"There are more implications in disease today than when we started 25 years ago," Greider said in a press conference at Hopkins on Monday. "Being at Hopkins changed my research to a more clinical direction."
All three of the Nobel Laureates showed that the chromosomes of mutant organisms that did not possess telomerase eventually shortened until the cells were no longer able to divide.
"After multiple generations and significant loss of telomeric repeats, the "capping" function of telomeres eventually disintegrates, causing severe consequences for the genome, the cell and potentially the organism," said David Zappulla, a professor in the Hopkins Biology Department and an expert in telomerase.
At the other end of the spectrum, cancer cells are capable of dividing uncontrollably and rapidly, without their telomeres ever shortening.
"This length [of the telomere] appears to be the result of a delicate balance between spontaneous shortening and the continuous rebuilding 'efforts' of the telomerase," Moudrianakis said. "It is this 'correct' balance between the two processes that yields a healthy state."
Researchers have linked elevated levels of telomerase activity to cancer cells, which may eventually lead to a treatment for the disease that targets this mechanism.?
Furthermore, according to Spencer, the function of telomeres extends beyond the protection of chromosome ends. Telomeres have been implicated in affecting gene expression, chromosome movement in meiosis and DNA repair.
However, there is still much to learn about the biochemistry and regulation of telomerase.
"The coming years of further telomerase and telomere research will shed more light on many important issues," Zappulla said. "It seems clear that telomere and telomerase regulation have direct roles in aging and many diseases even in addition to cancer."
At the time, Greider did not expect her discovery to have such a far-reaching impact in the field of medicine.
"What happened today is really a tribute to curiosity-driven basic science," Greider said. "We didn't know at the time that there were any particular disease implications. We were just interested in the fundamental questions of cell biology."
While the Prize recognizes one of the most important discoveries of the century in cellular biology, the Prize in itself is history-making as well.
"Drs. Greider and Blackburn are the ninth and 10th women to receive Nobel prizes in medicine and the first women to be co-awardees," Zappulla said.
At Hopkins, Greider is the third woman to win a Nobel, and the first woman to receive it in the category of physiology or medicine.
She will share the 10 million Swedish kronor prize ?- slightly under $1.5 million U.S. - equally with Blackburn and Szostak. The three also shared the Albert Lasker Award for Basic Medical Research, often described as "America's Nobels," in 2006.
"This is an exciting award for Johns Hopkins and also wonderful recognition for basic research everywhere," Spencer said.?"The collaborative and collective work of these three people exemplifies the importance of publicly-funded basic research and its promise for medicine."
