Scientist honored for role in discovering telomerase
Nobel Prize winner continues to probe the role of telomeres in human disease
Carol Greider, PhD, had heard rumors that her contribiition to the discovery of telomerase might someday be considered for a Nobel Prize, but she shrugged them off. “As a scientist, I don't really pay attention to rumors,” she says with a laugh.
Last fall, however, that rumor became a reality when Dr. Greider was awarded the 2009 Nobel Prize in Physiology or Medicine by the Royal Swedish Academy of Sciences. She was recognized for her 1984 discovery of the enzyme telomerase, which maintains the length and integrity of chromosome ends as well as the health and survival of living cells and organisms.
Dr. Greider, the Daniel Nathans professor and director of molecular biology and genetics at the Johns Hopkins Institute for Basic Biomedical Sciences in Baltimore, Maryland, shared the prize with Elizabeth Blackburn, PhD, professor of biochemistry and biophysics at the University of California at San Francisco, and Jack Szostak, PhD, professor of genetics at Harvard Medical School in Boston, Massachusetts. The trio's work led to future studies linking both telomeres and telomerase to cancer and age-related conditions.
“Not only did their discoveries propel cancer science forward on a grand scale, it also is changing the way we explore how to treat other types of disease and how to potentially prolong cell life,” says Margaret Foti, PhD, MD, chief executive officer of the American Association of Cancer Research, in a news release congratulating the 3 clinicians.
Carol Greider, PhD, shared the 2009 Nobel Prize in Physiology or Medicine with Elizabeth Blackburn, PhD, and Jack Szostak, PhD.
She was honored for her 1984 discovery of the enzyme telomerase.
She later found that human cancer cells escape mortality and continue to divide by activating telomerase, which enables the cells to maintain the length of their chromosome ends.
Further studies demonstrated that if telomerase can be inhibited long enough to eliminate the telomeres in malignant cells, the cancer cells would no longer be able to replicate themselves.
She also is studying the role ottelomeres in age-related degenerative diseases.
An Award Years in the Making
Dr. Greider is grateful for the opportunity winning the Nobel Prize has provided her to tell her story and illustrate “the importance of curiosity-driven research—fundamental discoveries that later on have implications in the clinic,” she says. One reason awards for fundamental discoveries such as hers often occur 25 years after the fact is because many additional experiments need to be conducted to demonstrate the clinical applications of the discoveries, Dr. Greider notes.
When Drs. Blackburn, Szostak, and Greider were performing their pioneering research in the 1970s and 1980s, they were not specifically trying to determine how telomeres affect human cancer. Rather, they were questioning how the lengths of chromosomes can be maintained when they get shorter and shorter every time a cell divides. Dr. Blackburn discovered that telomeres, which reside on the end of chromosomes, comprise simple, repeating DNA building blocks that are found in all organisms. Telomeres often are compared with the plastic tips at the end of shoelaces that stop them from unraveling. Drs. Blackburn and Szostak also demonstrated that these repeated DNA sequences stabilize the chromosomes and prevent them from becoming damaged.
Fascinated by Dr. Blackburn's work, Dr. Greider joined her as a graduate student in her laboratory at the University of California at Berkeley. Dr. Greider tracked down the enzyme telomerase and determined that each organism's telomerase contains an RNA component that serves as a template for a creature's specific telomere DNA repeat sequence.
Dr. Greider conducted her research in a single-celled, pond-dwelling organism called Tetrahyrnena because it contains some 40,000 chromosomes, compared with the 23 pairs in humans.
“It was 4 or 5 years later that it was shown that telomerase plays a role in the growth of human cancer cells,” Dr. Greider notes. “At the time, the DNA seqtience of telomeres wasnt identified in humans —we didn't know what it looked like.”
In 1988, Dr. Greider moved on to Cold Spring Harbor Laboratory in Cold Spring Harbor, NewYork, where scientists at an early Human Genome Project meeting described the human telomere DNA sequence. This led her to begin experiments in human cells. She and Calvin B. Harley, PhD, who was, at the time, assistant professor of biochemistry at McMaster University in Hamilton, Ontario, Canada, found that human cancer cells escape mortality and continue to divide by activating telomerase, which enables the cells to maintain the length of their chromosome ends. They also demonstrated that telomere length was related to cellular aging.
She and Dr Harley pursued the idea that if telomerase could be inhibited long enough to eliminate the telomeres in malignant cells, the cancer cells would no longer be able to replicate themselves. They went on to prove this theory by developing a knockout mouse that lacked telomerase and crossing it with a variety of tumor-prone mouse models.
“Many of these studies showed that when telomeres become short, this triggers apoptosis, which limits the growth of cancer cells,” Dr. Greider says. “It's not universal in all cancers, but it works in some.”
Through multiple clinical trials in patients with solid tumors, chronic lymphoproliferative disease, multiple myeloma, and lung and breast cancers, Geron Corporation, based in Menlo Park, California, has developed an anticancer drug and cancer vaccine that targets telomerase as a single agent or in combination with standard treatments. Phase 1 and 2 trials are currently ongoing.
Telomeres also play a role in age-related degenerative diseases because their length limits the renewal capacity of cells. For example, Dr. Greider and colleagues recently developed a mouse model for dyskeratosis congenita, a rare, inherited disorder that leads to bone marrow failure caused by mutations in telomerase. Another example, previously known as idiopathic pulmonary fibrosis (because physicians did not know the cause), was also recently shown to be related to insufficient telomerase. “We're just beginning to see the tip of the iceberg in understanding how the shortening of telomeres may limit cells' renewal capacity,” Dr Greider notes.
She currently is working on new mouse models that will help scientists further understand how telomerase affects both cancer and degenerative diseases. Ever curious, she continues to delve deeper into the mysteries of human genetics. For example, she wants to learn more regarding how telomere-length equilibrium is maintained, noting that various components likely contribute. “The questions we have now are greater than the ones we had before;” she says. “There is still so much that's unanswered.”