Cells, aging, and disease: Nobel winner paves way for treatment researchApril 1, 2010
Nobel Prize winner Dr. Carol W. Greider didn’t set out to find the secrets of healthy aging or a cure for cancer and other serious diseases. But her basic research of the past 25 years, focusing on the structure and function of telomeres and telomerase, has helped point many other researchers toward those goals. Telomeres are repetitive DNA sequences on the ends of chromosomes that appear to help regulate cellular replication; telomerase is an enzyme involved in cell replication and maintenance.
“I like to follow the next, most interesting thing that’s there,” says Dr. Greider, on a video produced by Johns Hopkins University School of Medicine in Baltimore, where she is a professor and director of the Department of Molecular Biology and Genetics. Dr. Greider, a longtime NIA grantee who describes her research as “driven by pure curiosity,” was awarded the 2009 Nobel Prize in Physiology or Medicine in December 2009 in Stockholm, along with fellow Americans Drs. Elizabeth H. Blackburn and Jack W. Szostak.
The $1.4 million, three-way prize was given for “the discovery of how chromosomes are protected by telomeres and the enzyme telomerase,” the award announcement states. The three scientists solved “a major problem in biology” in the late 1970s and ‘80s when they discovered how chromosomes are copied completely during cell division and protected against degradation, according to the Nobel Assembly at Sweden’s Karolinska Institutet.
“The work of the three Nobel Prize winners on telomeres has critical implications for the study of aging at the cellular level and has provided key avenues for investigators to pursue,” says NIA Director Dr. Richard J. Hodes. The NIA has extensively funded Dr. Greider’s work since 1991.
Telomeres, telomerase, and aging cells
Dr. Greider started her investigations with a basic question: How do chromosomes maintain themselves as cells divide? Previous research by Dr. Blackburn and others had revealed the existence of telomeres and their unique DNA sequence, which is found in most plants and animals, including humans.
Scientists recognized that telomeres somehow protect chromosomes as cells replicate, but they didn’t understand exactly how or why. In 1984, Dr. Greider, then a graduate student in Dr. Blackburn’s lab at the University of California, Berkeley, found that the protective effect came from an enzyme now known as telomerase.
As cells divide over and over—a process essential to an organism’s preservation—telomeres get shorter and shorter. Over time, this shortening triggers chromosome instability and a cell’s aging and even death. But some cells escape this aging process, called senescence, thanks to telomerase. The enzyme adds the repetitive telomere sequences to the ends of chromosomes to overcome shortening. As a result, the cell remains intact as it replicates.
“Telomerase is important in cells that divide for a living, such as white blood cells and muscle satellite cells,” says Dr. Anna M. McCormick, chief of the Genetics and Cell Biology Branch of NIA’s Division of Aging Biology. However, many human cells do not divide frequently, so they do not need to express high levels of telomerase, she adds.
Maintaining telomere length can be beneficial, especially during human development, when it’s important for cells to keep dividing. But it can also be harmful, as in the growth of a cancerous tumor. “You need telomerase, but having it active in every cell when you’re an adult isn’t necessarily a good thing because of the cancer potential,” Dr. McCormick says.
The key to healthy cells is the length of the telomere. “There’s a happy medium at which the telomere length has to be maintained,” Dr. Greider says, “and there’s a wide distribution of telomere lengths that are normal.” Telomeres that are too short increase susceptibility to age-related diseases, while telomeres that are maintained by telomerase allow cells to grow indefinitely, she explains.
A piece of the aging puzzle
Dr. Greider, who joined the Hopkins faculty 12 years ago, has studied the link between telomerase and aging with more than $7 million in NIA support. The NIA has funded many of Dr. Greider’s studies since her initial grant in 1991. “She’s my favorite kind of scientist,” adds Dr. McCormick. “She’s well trained, she’s smart, and she follows her curiosity.” Dr. Greider is also a grantee of the National Institute of General Medical Sciences, another part of the National Institutes of Health.
Her early studies of a single-celled organism called Tetrahymena have evolved into research that encompasses the roles of telomeres and telomerase in the biology of human aging. The tantalizing question of whether telomere maintenance might promote healthy aging remains unanswered. “Telomeres and telomerase are one piece of the aging puzzle. It’s a very complex process,” Dr. McCormick says.
As it turned out, Tetrahymena was not a good model for human aging because its cells have much more telomerase than human cells do. Dr. Greider turned to developing mouse models to help explore the telomerase-aging link more thoroughly.
These models knock out certain genetic components of telomerase to cancel its activity, allowing scientists to gauge the impact of telomeres getting shorter over several generations of mice. “The result is a mouse whose telomeres are more like human telomeres,” Dr. McCormick says. “The models have been used to find that some rare degenerative diseases are caused by telomerase defects.”
Looking to the future
Scientists have begun to delve into the details of how shortened telomeres and telomerase defects affect, and perhaps predict, the development of cancer and rare disorders such as an inherited form of pulmonary fibrosis and congential aplastic anemia, a severe form of anemia. “In the clinical arena, we’re just starting to understand the mechanisms of telomerase,” Dr. Greider says. Any translation of basic research into new treatments is years away, but “one of the applications will definitely be in cancer,” Dr. McCormick adds.
In cancer cells, telomerase maintains telomere length, enabling the cells to grow indefinitely. The goal is to find a telomerase inhibitor that can remove telomeres in malignant cells, effectively shutting them down and preventing them from replicating.
Studies in genetically engineered mice and cultured human cells have confirmed that telomerase inhibition can limit cancer cell division and tumor production. Early-stage clinical trials in humans are underway to test potential treatments based on the properties of telomerase.
Stem cells, which help repair damaged cells, are another potentially rich area of research, as their failure may play a part in aging. Dr. Greider is currently looking to see if short telomeres and/or telomerase defects cause stem cell loss and, by extension, tissue damage and aging-related disease. Dr. Greider will also continue to examine the biochemistry of telomerase, looking at details of the molecular process of telomere length maintenance and cell equilibrium.
You can download and view Dr. Greider’s 50-minute Nobel Lecture, delivered December 7 at the Karolinska Institutet in Stockholm.
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