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Laskers for Telomerase

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Elizabeth H. Blackburn, Ph.D., has been awarded the highly prestigious Albert Lasker Basic Medical Research Award for her pioneering work on telomeres, the structures that protect chromosome ends, the Albert and Mary Lasker Foundation announced recently.
Blackburn, a professor at the University of California in San Francisco and a nonresident fellow at the Salk Institute for Biological Studies, shares the 2006 Lasker with Carol W. Greider, Ph.D., a professor at Johns Hopkins University School of Medicine and Howard Hughes Medical Investigator Jack W. Szostak, Ph.D., a professor at Harvard Medical School. The honored trio is being recognized for the discovery of telomerase, which maintains the ends of chromosomes, and the demonstration that unlimited cell division relies on telomerase.
Telomerase activity is now known to be the main mechanism by which human tumor cells achieve immortal growth. Cancer cells are “addicted to telomerase”, as Blackburn likes to put it, and reducing the quantity of telomerase will halt the division of cancer cells in their tracks. Not surprisingly, telomerase has become a prime target for novel therapeutic cancer intervention, and several clinical trials for telomerase based cancer therapy are already underway.
The Lasker Awards, first presented in 1946, are considered the nation’s highest recognition for basic medical research and are widely regarded as a strong predictor of future Nobel Prize winners. The awards will be presented at a luncheon ceremony, September 29, at the Pierre Hotel in New York City.
Blackburn, Greider and Szostak provided the solution for a long-standing biological puzzle better known as the “end replication problem”: Each time a cell divides it has to faithfully duplicate all its chromosomal DNA so that each daughter cell receives a complete set. The problem with this crucial process is that the replication machinery cannot copy linear chromosomes all the way to the tip. This led to the prediction, more than 30 years ago, that without some additional mechanism to continually replenish the very tips of chromosomes, the ends would slowly whittle away, and the cells left to perish.
Even as early as the 1930s and 1940s, scientists had suggested that chromosome ends were capped by special structures, so-called “telomeres” from the Greek for “end” (telos) and “part” (meros) that would protect these fragile ends. But it was not until 1978, when Blackburn – with the help of the tiny pond-dwelling ciliate Tetrahymena - discoveredthat telomeres consist of a short, simple DNA motif repeated over and over again, that the precise makeup of telomeres was determined. Blackburn made this key initial discovery while a postdoctoral fellow in the laboratory of Joe Gall, Ph.D., a professor at the Carnegie Institution of Washington in Baltimore, who is also being recognized with the 2006 Albert Lasker Special Achievement Award in Medical Research, for his life- long contributions to cell biology.
The mechanism by which these sequence repeats were added to the ends of telomeres, however, was still left to speculation. Although most researchers thought that recombination was responsible, a collaborative set of two studies between Blackburn and Szostak in 1982 and 1983 led them to predict the existence of an as-yet-unknown enzyme that would perform this task. Determined to pin down the enzyme behind the observed telomere-lengthening activity, the two labs set out independently, pursuing different strategies to reach their goal.
Blackburn, in collaboration with Greider, who joined Blackburn’s lab as a graduate student in 1984, once again banked on the ciliate Tetrahymena to provide the solution: During a certain period of its life cycle, the ciliate has to rebuild a million new telomeres, which made it an ideal source to fish for the hypothesized activity.
Within months, Greider and Blackburn hit paydirt. They identified an enzyme that was capable of adding telomeric repeats, one by one, onto the end of an artificial telomere and which they dubbed “telomerase”. In a surprising departure from the behavior of other DNA polymerases, telomerase seemed to know exactly which sequence motif to attach at chromosome ends. The reason behind this unexpected behavior turned out to be a single essential molecule of RNA buried deep within telomerase. It serves as a template and dictates the sequence of the added telomeric repeats.
Meanwhile, Szostak and Vicki Lundblad, Ph.D, then a post-doctoral researcher in his lab and now a professor in the Molecular and Cell Biology Laboratory at the Salk, relied on baker’s yeast, a long-trusted tool of cell biologists, to identify telomerase. They reasoned that the normally immortal growth of yeast cells should be reversed, if they could isolate a mutant version of yeast that no longer expressed telomerase.
In 1984, undeterred by the amount of work ahead of her, Lundblad started to sift through 7,000 mutagenized yeast colonies until she found a single strain of yeast that displayed the predicted Est or “ever-shortening telomeres”- phenotype. Unlike wild type yeast, in which telomeres are maintained at a constant length, the tips of chromosomes in the est1-1 strain slowly whittled away until the strain stopped growing. Stostak and Lundblad had demonstrated that the long-ago prediction – that fully maintained telomeres are they key to replicative immortality of cells – was indeed correct. They then went on to clone the gene that was altered in the est1-1 strain, making it the first known protein subunit of telomerase.
In her own laboratory, first at Baylor College of Medicine in Houston and now here at the Salk, Lundblad has continued the search for additional subunits of telomerase and has identified the long-sought-after catalytic subunit of the enzyme. This subunit is expressed at high levels in most human cancers, allowing them to grow indefinitely by replenishing shortened telomeres, and explaining their “telomerase addiction”. Lundblad’s laboratory at the Salk is currently studying a new set of factors associated with chromosome ends that are required for normal telomere function in both baker’s yeast and human cells, and also appear to be expressed at high levels in cancer cells.

About Elizabeth W. Blackburn

A native of Tasmania, Australia, Blackburn studied biochemistry at the University of Melbourne and received her doctorate in molecular biology from Cambridge, England. After finishing her postdoctoral studies at Yale University, she moved to the West Coast, joining the Department of Molecular Biology at the University of California in San Francisco in 1993.
Throughout her career, Blackburn has been honored by her peers as the recipient of many prestigious awards. These include the Eli Lilly Research Award for Microbiology and Immunology (1988), the National Academy of Science Award in Molecular Biology (1990), and an Honorary Doctorate of Science from Yale University (1991). She was a Harvey Society Lecturer at the Harvey Society in New York (1990), and the recipient of the UCSF Women's Faculty Association Award (1995). Most recently, she was awarded the Australia Prize (1998), the Harvey Prize (1999), the Keio Prize (1999), the American Association for Cancer Research-G.H.A. Clowes Memorial Award (2000), the American Cancer Society Medal of Honor (2000), the AACR-Pezcoller Foundation International Award for Cancer Research (2001), the General Motors Cancer Research Foundation Alfred P. Sloan Award (2001), the E.B.Wilson Award of the American Society for Cell Biology (2001), the 26th Annual Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research (2003), and the Dr. A.H. Heineken Prize for Medicine (2004).
She was named California Scientist of the Year in 1999, elected President of the American Society for Cell Biology for the year 1998, and served as a Board member of the Genetics Society of America (2000-2002). Blackburn is an elected Fellow of the American Academy of Arts and Sciences (1991), the Royal Society of London (1992), the American Academy of Microbiology (1993), and the American Association for the Advancement of Science (2000). She was elected Foreign Associate of the National Academy of Sciences in 1993, and was elected as a Member of the Institute of Medicine in 2000.

About Salk Nonresident Fellows

Salk Nonresident Fellows serve as members of the faculty for renewable six-year terms. Nominated by the president and faculty, these individuals come from academic organizations around the world and have achieved high levels of success in the research areas at the Institute. They visit the Salk yearly to help benchmark the Institute by advising on the scientific progress of its faculty and on the effectiveness of its existing and proposed scientific programs.

About the Salk Institute

Internationally renowned for its groundbreaking basic research in the biological sciences, the Salk Institute was founded in 1960 by Dr. Jonas Salk, five years after he developed the first safe and effective vaccine against polio. The Institute’s 59 faculty members are scientific leaders in the fields of molecular biology, neurosciences and plant biology.

This is an open-access article

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