The Nobel Prize in Physiology or Medicine 2009
"how chromosomes are protected by telomeres and the enzyme telomerase"
Summary
This year's Nobel Prize in Physiology or Medicine is awarded to three scientists who have solved a major problem in biology: how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. The Nobel Laureates have shown that the solution is to be found in the ends of the chromosomes – the telomeres – and in an enzyme that forms them – telomerase.
The long, thread-like DNA molecules that carry our genes are packed into chromosomes, the telomeres being the caps on their ends. Elizabeth Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects the chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase.
If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life. Certain inherited diseases, in contrast, are characterized by a defective telomerase, resulting in damaged cells. The award of the Nobel Prize recognizes the discovery of a fundamental mechanism in the cell, a discovery that has stimulated the development of new therapeutic strategies.
Telomeres delay ageing of the cell
Scientists now began to investigate what roles the telomere might play in the cell. Szostak's group identified yeast cells with mutations that led to a gradual shortening of the telomeres. Such cells grew poorly and eventually stopped dividing. Blackburn and her co-workers made mutations in the RNA of the telomerase and observed similar effects in Tetrahymena. In both cases, this led to premature cellular ageing – senescence. In contrast, functional telomeres instead prevent chromosomal damage and delay cellular senescence. Later on, Greider's group showed that the senescence of human cells is also delayed by telomerase. Research in this area has been intense and it is now known that the DNA sequence in the telomere attracts proteins that form a protective cap around the fragile ends of the DNA strands.
An important piece in the puzzle – human ageing, cancer, and stem cells
These discoveries had a major impact within the scientific community. Many scientists speculated that telomere shortening could be the reason for ageing, not only in the individual cells but also in the organism as a whole. But the ageing process has turned out to be complex and it is now thought to depend on several different factors, the telomere being one of them. Research in this area remains intense.
Most normal cells do not divide frequently, therefore their chromosomes are not at risk of shortening and they do not require high telomerase activity. In contrast, cancer cells have the ability to divide infinitely and yet preserve their telomeres. How do they escape cellular senescence? One explanation became apparent with the finding that cancer cells often have increased telomerase activity. It was therefore proposed that cancer might be treated by eradicating telomerase. Several studies are underway in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity.
Some inherited diseases are now known to be caused by telomerase defects, including certain forms of congenital aplastic anemia, in which insufficient cell divisions in the stem cells of the bone marrow lead to severe anemia. Certain inherited diseases of the skin and the lungs are also caused by telomerase defects.
Some inherited diseases are now known to be caused by telomerase defects, including certain forms of congenital aplastic anemia, in which insufficient cell divisions in the stem cells of the bone marrow lead to severe anemia. Certain inherited diseases of the skin and the lungs are also caused by telomerase defects.
In conclusion, the discoveries by Blackburn, Greider and Szostak have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies.
Elizabeth H. Blackburn has US and Australian citizenship. She was born in 1948 in Hobart, Tasmania, Australia. After undergraduate studies at the University of Melbourne, she received her PhD in 1975 from the University of Cambridge, England, and was a postdoctoral researcher at Yale University, New Haven, USA. She was on the faculty at the University of California, Berkeley, and since 1990 has been professor of biology and physiology at the University of California, San Francisco.
Carol W. Greider is a US citizen and was born in 1961 in San Diego, California, USA. She studied at the University of California in Santa Barbara and in Berkeley, where she obtained her PhD in 1987 with Blackburn as her supervisor. After postdoctoral research at Cold Spring Harbor Laboratory, she was appointed professor in the department of molecular biology and genetics at Johns Hopkins University School of Medicine in Baltimore in 1997.
Jack W. Szostak is a US citizen. He was born in 1952 in London, UK and grew up in Canada. He studied at McGill University in Montreal and at Cornell University in Ithaca, New York, where he received his PhD in 1977. He has been at Harvard Medical School since 1979 and is currently professor of genetics at Massachusetts General Hospital in Boston. He is also affiliated with the Howard Hughes Medical Institute.
