This article was contributed by Carrie L. Lucas
On Monday, October 5th, 2009, the Nobel Prize in Physiology or Medicine was awarded to three scientists for their work decades ago on understanding how integrity of the genetic code at the ends of the chromosomes is maintained as cells divide. Drs. Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak shared this most prestigious prize for work they did in the 70’s and 80’s on the “caps” at the ends of chromosomes. These “caps” are called telomeres (‘telos’ meaning ‘end’ and ‘meros’ meaning ‘part’ in Greek) and are added by an enzyme called telomerase. So why is understanding telomeres important? In order to appreciate their role, we need some background on chromosomes.
Putting chromosomes in perspective
Organisms are made up of many, many cells (around 100 trillion cells in an adult human) that all have specialized roles in the body to maintain health. Within each cell there are roughly 1 billion protein molecules, which are like miniature machines that perform the tasks essential for cell and organism survival. But how are all these proteins made in the right cells at the right time? This is where the genetic code and chromosomes come in. Genes are sequences of DNA that encode the instructions for making proteins, but these instructions are only used when signals in the cell direct the genes to turn on. Although only some of all possible proteins are present in each cell at any given time, the DNA encoding all proteins is present in all cells all the time (with a few exceptions such as eggs and sperm). All this DNA is housed within a compartment of the cell called the nucleus. In order to fit the massive amount of DNA in the human genome into the nucleus, it must be condensed into a compact structure. This has been achieved evolutionarily by compact nuclear structures called chromosomes. Human cells have 46 chromosomes, 23 inherited from mom and 23 from dad. Each chromosome is a tightly coiled, rod-like structure consisting of one linear, double-stranded molecule of DNA with many genes (ranging from 80 genes on the tiny Y chromosome to 4,220 genes on chromosome 1). Every time a cell divides, all chromosomes need to be replicated so that both the parent cell and the daughter cell have the proper 46 chromosomes with all their genes intact and capable of providing instructions for making the essential protein ‘machines’.
What are telomeres?
During cell division, the DNA that is packed into the chromosomal structures must be duplicated, so that each cell gets a copy of the instructions after division. During this process, the double-stranded DNA structure is unzipped so that each strand can be used as a template for enzymes called polymerases to read as they make the extra copy of DNA. A long standing conundrum before the work of this year’s Nobel winners was how the genes at the very end of the chromosomes can be copied. This was puzzling because it was known that one of the two DNA strands is copied in a manner that requires the polymerase to latch on to the template strand beyond the end of the last gene at the most extreme end of the chromosome. How could the genetic material remain intact if there was no sequence to latch onto? In other words, what is preventing genomic DNA at the very end of the chromosome from being lost? A discovery in the 70’s began to shed light on this question. Elizabeth Blackburn found a DNA sequence that was repeated multiple times within the telomere “caps” at the ends of chromosomes and, together with Jack Szostak, found that these evolutionarily conserved sequences are sufficient to prevent degradation of linear chromosomes. But exactly how does this work?
The repeating DNA sequence (in humans, 5’-TTAGGG-3’) that makes up telomeres is present in hundreds to thousands of copies at the end of the linear chromosome. This sequence solves the puzzle by providing ‘extra’ non-essential DNA that the polymerase can bind to replicate the genome in its entirety. In fact, with each cell division, 50-100 of the building blocks (called nucleotides) that make up the ‘extra’ repeated DNA sequence in the telomere are lost. Without the telomere DNA, the lost sequence would be from genomic DNA at the end of the chromosome, and dramatic mutations would occur with every cell division.
Since the repeat DNA sequence starts off as a finite length, won’t genomic DNA eventually be lost if enough cell divisions, each with 50-100 building blocks removed from the telomere sequence, occur? In fact, this very phenomenon is thought to provide the cell with a way to “count” the number of cell divisions it has been through so it “knows” when to stop dividing or, in other words, when to become “senescent”. However, cellular senescence is delayed in cells that must divide regularly by the action of an enzyme named ‘telomerase’, discovered by Carol Greider in the laboratory of Elizabeth Blackburn. Telomerase carries with it a template for the DNA repeats within telomeres and allows new repeats to be added. The telomerase enzyme is highly active in embryonic stem cells and rapidly dividing cells of the immune system so that they can continue to divide to do their job. Most other cells, however, have very little active telomerase. Thus, telomerase plays a key role in controlling which cells in our bodies are allowed to continue to divide and which are limited.
Telomeres in disease
Part of the reason these and related discoveries about the biology of telomeres and telomerase are worthy of the Nobel Prize is that they have tangible implications and, indeed, proven links to diseases. Telomeres are now known to be critical for keeping chromosomes from attaching to one another and for regulating the aging process. Moreover, telomerase activity has been shown to be aberrantly re-activated in cancer, allowing cancer cells to avoid becoming senescent. The tantalizing possibilities of inhibiting the loss of telomeres to prevent senescence in order to slow aging and of blocking the activity of telomerase in cancer cells in order to induce their senescence are currently areas of active investigation within the scientific community.
These discoveries provide yet another example of how basic science research can unexpectedly have a profound impact on our understanding of disease and our future therapeutic approaches. The 2009 Nobel Prize in Physiology or Medicine is also the first time two women have shared the Prize in the same year. Advances on both these fronts are encouraging, and provide us with an important reminder that pursuing answers to curiosity-driven questions, no matter how seemingly esoteric, really can contribute to improving the human condition.
For more information, please see:
Nobel Prize press release: http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html
Nicholas Wade. “Three Americans Share Nobel for Medicine.” NY Times. Oct 5, 2009. http://www.nytimes.com/2009/10/06/science/06nobel.html
Primary research referenced in this article:
Carol Greider and Elizabeth Blackburn. “Telomeres, Telomerase, and Cancer.” Scientific American. Reprint of Feb. 1996 article. http://www.scientificamerican.com/article.cfm?id=telomeres-telomerase-and
Szostak JW, Blackburn EH. Cloning yeast telomeres on linear plasmid vectors. Cell 1982; 29:245-255.
Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985; 43:405-13.
Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 1989; 337:331-7.