Monday, October 5, 2009

Medicine Nobel

The 2009 Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak, for their unraveling the special role of the ends of chromosomes, and how they are maintained. The tips of the chromosomes, called telomeres, help ensure the eventual senescence of cells--a process that breaks down in cancers.

In the early days of DNA, as scientists clarified the molecular mechanisms of its replication, they realized that the ordinary step-by-step copying process would not function all the way to the end of the chain. Over time, it seemed, the DNA would get shorter and shorter, progressively infringing on coding sequences near the end of the chain. Szostak and Blackburn discovered that the ends contained a repeated six-base sequence, CCCCAA. A cap of proteins bind to this sequence and protects the tips--Blackburn has likened them to the plastic tips that keep the ends of shoelaces from fraying. Blackburn and her then student Greider discovered the enzyme, telomerase, that recognizes and extends this sequence to prevent continued erosion of the genetic information during division.

Only a few cells normally produce telomerase, however. It had been discovered by Leonard Hayflick that many cells, grown in culture, only divide a fixed number of times--now known as the "Hayflick limit," after which they enter an extended period of senescence. This observation suggested a built-in program for aging that might limit longevity even in multicellular organisms. Researchers quickly realized that the shortening of the telomere during DNA replication provided a natural mechanism for this limit to the number of cell divisions.

Some ordinary cells, like those that lead to sperm and eggs, naturally make the telomerase that restores the telomeres. The enzyme is also produced by many cancer cells, which is one of the reasons that they are able to evade the usual limitations on cell division.

The role of telomerase in preventing cellular senescence suggested to many researchers that the enzyme might also arrest aging in complex creatures like ourselves. The biotech company, Geron, for example, was founded in 1992 in the hopes of exploiting telomerase against aging. Of course one of the dangers of such an approach would be that it might remove protections against cancers. On the other hand, researchers have sought drugs that suppress telomerase as potential anti-cancer agents.

The reality of aging is, not surprisingly, more complicated, and telomerase has not proven to act like the mythical fountain of youth. Geron has moved on to other pursuits, notably stem cells. The current wave of excitement about anti-aging centers on completely different drugs aimed at activating the same molecular pathways as severe caloric restriction, which has long been known to extend life even in mammals.

Even though telomeres and telomerase have not released us from aging, however, their discovery has clarified important aspects of cellular division and programmed senescence, and stimulated new approaches to drug development.

A very good book that discusses the Hayflick limit, telomeres, Geron, caloric restriction and much more is Stephen S. Hall's 2003 Merchants of Immortality.

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