Most denizens of the interwebs (at least of this corner of the interwebs) will have heard the announcement that the 2009 Nobel Prize in Physiology or Medicine will be given to Elizabeth Blackburn, Carol Greider and Jack Szostak for their work on telomeres – the structures found at the ends of human chromosomes. You may already have read a little about the research behind it (if not, the NobelPrize.org press release is a very good place to start) so I’ll try to keep the background as short as possible. What I would like to do here is to explain the assertions that “cancer research has also benefited from the Nobel-winning trio’s work”.
Telomeres are necessary for several reasons, among them to act as ‘padding’ during cell duplication. Every time a linear DNA molecule is replicated it loses a few base pairs from the ends (the reason why is quite interesting, see this description of the end replication problem). The telomeric sequence is simply “TTAGGG” (in vertebrates) repeated several thousand times so it doesn’t matter when some sequence is deleted. But, I hear you cry, how is this important for cancer?
Most cells in the body do not replicate. A typical tissue, such as skin, has a thin layer of stem cells that divide to produce more stem cells, as well as cells that will differentiate into skin cells. These cells divide a few more times until they are ‘terminally differentiated’. In the case of skin that means that they are filled with keratin and die, and when they reach the surface they are sloughed off. In other tissues the non-replicating terminally differentiated cells have different functions, for example as nerve cells or muscle cells. Thus the only cells that need to replicate infinitely are stem cells (and germ line cells, the cells that become sperm and eggs), so they express a protein called telomerase which adds extra copies of the repetitive sequences to the ends of chromosomes.
Those of you who’ve read my first ‘Understanding Cancer’ post – and anyone who knows a little bit about cancer biology – will see why this system is a major inhibitor of carcinogenesis: when a cell starts to over-proliferate it can only divide a certain number of times before the telomeres are fully eroded. In order to continue dividing it has to accumulate further mutations that render it immortal. These mutations have to be very specific, making them rarer: there are thousands of ways to make a cell grow faster, but only very few ways to lengthen its telomeres. Around 90% of cancers (remember: a cancer is, by definition, a collection of cells that have jumped this hurdle) have mutations that cause them to produce telomerase. Most of the remaining cases of cancer have recruited a normal DNA repair mechanism to lengthen the chromosomes by a process called ALT (Alternative Lengthening of Telomeres).
On a short side note: when telomeres were first elucidated it was thought by some that we’d found the key to aging. Unfortunately upregulating telomerase in an attempt to stay young only leads to more cancer, because you’ve removed one of the hurdles that a nascent tumour has to surmount.
Does anyone see the further significance here? All cancers have to overcome a certain problem, and most of them do it in exactly the same way. This makes telomerase a very attractive target for new chemotherapeutic drugs or other types of intervention, and the field is bustling with new ideas. A few clinical trials are showing progress, using gene therapy and small molecule inhibitors (a.k.a. drugs): for a fuller account read this nice open-access review. The approach that strikes me as the most fascinating – and promising – is the idea of vaccinating against telomerase. Almost all cells in the body constantly chew up a sample of their own proteins and display them to the cells of the immune system as a defence against viruses. If you can tell the immune system to attack cells that express telomerase (not quite as straightforward as one might think) it will specifically attack cancer cells. This should be more specific (read: cause less side effects) than most anti-cancer therapies because most drugs attack all rapidly-replicating cells, whereas this would only target immortal cells, and just like you may have learnt from comic books: immortality is a very rare privilege.
Shay, J., & Keith, W. (2008). Targeting telomerase for cancer therapeutics British Journal of Cancer, 98 (4), 677-683 DOI: 10.1038/sj.bjc.6604209