(Oct. 5th, 2009) The news from Stockholm wasn’t too surprising: For their work on telomeres and telomerase Blackburn, Greider and Szostak (see photo, from left to right) are awarded the Nobel Prize for Physiology or Medicine. Karin Hollricher reports.
Once again, the Lasker Foundation jurors seem to have had a nose for scientific excellence. Three years ago, Blackburn, Greider and Szostak were honoured for the “prediction and discovery of telomerase, a remarkable RNA-containing enzyme that synthesises the ends of chromosomes, protecting them and maintaining the integrity of the genome”. Now, the Nobel follows “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”.
In the 1930s, Barbara McClintock and Hermann Muller observed the very special features of chromosomal ends. Muller described how they do not fuse with each other as other artificial chromosomal pieces do. He named the ends telomeres, derived from the Greek words 'telos' (ends) and 'meros' (part). McClintock showed that chromosomal pieces can be replicated and survive in maize cells if they fuse with telomeres.
Later, in 1972, James Watson hypothesised that cells must have a special strategy to maintain the ends of chromosomes because the DNA-polymerase cannot replicate the very 3'-ends of linear DNA strands.
However, the scientific community had no solution to that problem until the late 1980s, when Elizabeth Blackburn, then working in Joseph Gall’s lab, identified the sequences of mini-chromosome ends of Tetrahymena thermophila to be repeats of CCCCAA. Together with the yeast geneticist Jack Szostak, Blackburn fused theses repeats to artificial linear yeast chromosomes. Until then, Szostak had tried, unsuccessfully, to develop such molecules as vectors but the generated chromosomes were unstable and did not replicate. Adding the Tetrahymena ends provided the solution: those molecules were stable. Szostak and Blackburn found out that the ends of these chromosomes not only contained the added Tetrahymena repeats but also sequences that turned out to be yeast-specific chromosome ends. The scientists concluded that this elongation was due to an unknown enzyme.
This theory was absolutely new and contradictory to all theories at that time.
Together with the graduate student, Carol Greider, Blackburn started searching for the enzyme. At Christmas 1984, they finally found the molecule and named it telomerase.
Many scientists are now working on various aspects of telomeres and telomerase. The data supports a theory that goes back to the Russian scientist Alexey Olovnikov. He postulated in the 1970s that telomeres are a kind of cellular clock showing the age of a cell. That idea turned out to be true – but as is the case so often in nature, biology is rather complicated. We know today, that in yeast, telomerase is regulated by 150 genes. In an interview at the genetics congress in Berlin last year Blackburn told LabTimes, “That's a very complex regulation, similar to the regulation of cholesteron levels. It's interesting now to see how telomeres and telomerase work in humans. Telomeres for example are indicators for the status of health and disease in quite a striking way.” Indeed, it has been shown that long telomeres correlate with healthy ageing. Greider said in an interview with the Nobel Foundation, “It's really what we've been able to show is that what really matters is the telomere length. So, when a telomere gets shorter, that's when either senescence or apoptosis is triggered. So, short telomeres are the things that are really critical and will cause disease as well as problems with tissue turnover. The telomerase just needs to maintain the telomere length equilibrium, as I said, to be able to keep the telomeres from getting short.”
Telomerase also plays a pivotal role in the development of cancer. Up to 80 percent of tumours have very high telomerase activity, making them immortal. Shutting down telomerase in melanomas in mice inhibits their growth and replication. Perhaps, speculated Blackburn, one can develop new therapies based on telomerase inactivation.
Today, the Nobel Foundation awarded two women who have not only performed excellent science but also actively promote women in science. Carol Greider told the Nobel Foundation, “I think actively promoting women in science is very important because the data has certainly shown that there has been an under-representation and I think that the things that contribute to that are very many social ... subtle, social kinds of things. So, yes, I think that one should definitely be cognizant of that and be aware of it.” Blackburn would certainly agree. In 2008, she received one of the L'Oreal-UNESCO Women in Science Laureates. She told LabTimes, “It's wonderful that UNESCO and L'Oreal are supporting women in science. When I was a young scientist, I often felt so uncertain and I see younger colleagues are still feeling so. We have to change that, we have to more talk about that issue.” Now she and Greider are certainly in a position to do so.
(Fotos: Elisabeth Blackburn by Karin Hollricher, Jack Szostack via KNAW Amsterdam, Carol Greider via Gerbil.)