The 2009 Nobel Prize in Physiology or Medicine was announced earlier this week. The prize was awarded to three U.S. scientists for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.
Two women, Elizabeth H. Blackburn, age 61, at the University of California in San Francisco, and Carol W. Greider, age 48, at Johns Hopkins University School of Medicine in Baltimore along with one man, Jack W. Szostak, age 57, at Harvard Medical School, will share the $1.4 million prize.
Telomeres are regions of repeating DNA sequence at the ends of chromosomes (picture the aglets, or plastic sleeves, at the ends of a shoelace). These unique sequences serve to protect the chromosomes from being degraded as cells divide. The enzyme that forms telomeres is called telomerase. If the telomeres are shortened, cells age. In contrast, if telomerase activity is high, telomere length is maintained and cellular senescence (meaning the processes of deterioration) is delayed.
Increased telomerase activity is observed in cancer cells. Modestly reduced telomerase activity is implicated in bone marrow failure and pulmonary fibrosis [1]. Accelerated shortening of telomeres in peripheral blood lymphocytes, including T cells, has been observed in a number of diseases, including Down syndrome, rheumatoid arthritis and cardiovascular disease [2-4]. Research also suggests that telomere shortening occurs in mood disorders [5].
A brief history of telomere and telomerase research
Elizabeth Blackburn was studying a unicellular organism called Tetrahymena in the early 1980s and observed that a DNA sequence was repeated several times at the ends of chromosomes. At the same time, Jack Szostak had observed that a linear DNA molecule, a type of minichromosome, was rapidly degraded when introduced in yeast cells. Blackburn and Szostak collaborated to couple the repeated Tetrahymena DNA sequence to the minichromosome. Surprisingly, the repeated DNA sequence — now recognized as a telomere — protected the minichromosome from degradation [6]. Szostak went on to identify mutations in yeast that led to a progressive decrease in telomere length and increased frequency of chromosome loss [7]. In subsequent years with further research, it became clear that telomeres, with its characteristic repeated DNA sequence, is present in most plants and animals.
Carol Greider was a graduate student of Blackburn, who in 1984 provided evidence for an enzyme that could form telomere DNA. Greider and Blackburn purified the enzyme and called it telomerase. They showed that telomerase extends telomere DNA necessary for the replication of chromosome ends [8-9].
NIH Director Francis S. Collins, M.D., Ph.D., said [10]:
The question of how cellular aging relates to abnormal cell division, such as cancer, and the aging of organisms continues to be the focus of rigorous study, thanks to the insights of Drs. Greider, Blackburn and Szostak. These NIH grantees’ discoveries offer a classic example of how basic science research driven by investigators’ curiosity can illuminate our understanding of health and disease.
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References
- Lansdorp PM. Telomeres and disease. EMBO J. 2009 Sep 2;28(17):2532-40. Epub 2009 Jul 23.
View abstract - Vaziri et al. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet. 1993 Apr;52(4):661-7.
View abstract - Koetz et al. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9203-8.
View abstract - Fuster and Andres. Telomere biology and cardiovascular disease. Circ Res. 2006 Nov 24;99(11):1167-80.
View abstract - Simon et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry. 2006 Sep 1;60(5):432-5. Epub 2006 Apr 11.
View abstract - Szostak and Blackburn. Cloning yeast telomeres on linear plasmid vectors. Cell. 1982 May;29(1):245-55.
View abstract - Lundblad and Szostak. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell. 1989 May 19;57(4):633-43.
View abstract - Greider and Blackburn. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985 Dec;43(2 Pt 1):405-13.
View abstract - Greider and Blackburn. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell. 1987 Dec 24;51(6):887-98.
View abstract - NIH Grantees Win 2009 Nobel Prize in Physiology or Medicine for Telomere Research. NIH News. 2009 Oct 6.
Dr. Blackburn will be working with researchers involved in the Kaiser Permanente/UCSF genotyping project to measure telomeric DNA among 100,000 patient samples as part of a study that will look at gene-environment interactions as determinants of health, disease, and longevity. Also described here.