Wednesday, October 07, 2009

2009 Nobel for telomeres and ribosomes: answering basic questions in life

It’s fair to say that there were few surprises when the Nobel prizes in Medicine and Chemistry were announced. Chemists might again quibble, since the prize again went to biophysicists/biochemists for their work on a biological problem, but other than that, the prizes deservedly recognize magnificent work in two areas of basic biology that reveal very important ways by which life, literally, goes on.

Also, for the first time, there are three women scientists winning the prize in the sciences. While the prizes themselves are “gender neutral”, it remains a fact that (at least until recently), women have been massively underrepresented in the sciences, and only a handful of women have won Nobel prizes (a reflection of that underrepresentation). If not anything else, these prizes will at least inspire many more women scientists (and the winners have all been great role models, not just for women but all scientists).

Now to the prizes themselves.

The medicine prize went for discovering how one of biology’s most important processes is enabled by a quirky unit called a telomere. People realized early that DNA, which encodes all our genetic information, was packaged into chromosomes inside cells. Later, proteins called DNA polymerases were discovered, and these proteins were responsible for making copies of DNA, which would allow the DNA to replicate and be propagated. Scientists observed very early that there would be trouble with this copying process, cine the polymerase would leave tails of DNA at the ends, and that chromosomes would slowly shorten. But if that happened, how could all the genetic information be passed on correctly over generations? And then, was there a relationship between this chromosome shortening and the lifespan of the organism? Over the years, the winners of the medicine prize, Elizabeth Blackburn, Jack Szostak and Carol Greider went on to show how all of this was made possible by telomeres, the capped ends of chromosomes. Telomeres were shown to stabilize the ends of chromosomes, and proteins called telomerases synthesize chromosome ends inside the cell. The Nobel website has an excellent short summary on the discoveries.

Here are two general comments. The first is that all these discoveries were made in two organisms that seem as different from humans as possible; the humble yeast, and a common fresh water microscopic protozoa called tetrahymena. Though some people often question the purpose or use of studying these organisms, basic biological processes (like chromosome maintenance and telomere function) are perfectly conserved across evolution, from these simple bugs through humans. So the findings that came out of these organisms were directly relevant to human and mammalian cell function. Model organisms have taught us a tremendous amount of biology that has been directly applicable to humans.

The second general comment is that when Blackburn, Szostak or Greider started working on these organisms, there was no “application” for their research. At the time, telomeres weren’t known to cause any disease, nor could any “product” be made from studying them. The work was done in tetrahymena and yeast, and there was no “utility” in studying them. But the researchers followed their noses, pursuing questions in basic biology. Now their discoveries might play key roles in developing new therapeutics for cancer, ageing or hereditary diseases. When chromosomes shorten too much (and the telomeres shorten beyond a point), the cell stops dividing and goes into senescence. Normal cells don’t divide too much, so don’t need too much telomerase activity. Yet cancer cells divide incessantly. But they still preserve their telomeres, and don’t go into senescence. It has now been observed that cancer cells have high telomerase activity, and people now believe cancer can be treated by removing telomerases from cancer cells (and thus forcing the cells to go into senescence). There is a ton of work being done now to develop therapeutics against cancer targeting telomerases. Yet when this process was being studied, none of this was apparent.

The chemistry Nobels have gone to Venki Ramakrishnan, Tom Steitz and Ada Yonath for their pioneering work revealing the structures of yet another of the fundamental enabling units of life, the ribosome. This prize also recognizes the third act by which the process of how DNA encodes the units of life is completed. All three discoveries were seen at the level of the chemical atom using the same technique, called X-ray crystallography. Something that can only be described as an atomic photographic snapshot of biological molecules can be obtained using this technique. In the first Nobel Prize awarded way back when to Watson and Crick, X-ray crystallography revealed the famous double helical structure of DNA, which showed how DNA could be easily copied and replicated. Crick was later able to devise the triplet code, which allowed us to understand how DNA, with just combinations of four nucleic acids, could encode all the information for proteins, the building blocks of all life. This DNA was faithfully copied out to another form of nucleic acid, called (messenger) RNA. mRNA is made by a complex of proteins which form the RNA polymerase units, and the precise molecular details of this process were also largely revealed by X-ray crystallography. This work was recognized in the 2006 Nobel to Roger Kornberg. But there remains the third step, the extremely complex process by which this RNA is made into the actual functional units, the proteins of the cell. This work is done by the massive RNA-protein complex within the cell, called the ribosome. Primarily using X-ray crystallography (with other structural and biophysical methods) Ramakrishnan, Steitz and Yonath revealed the structures of the ribosome, first with different sub-units of the complex, and later with the structures of the entire complex itself. The Nobel website has a good, simple summary of the process here. It is a pity that only three Nobel prizes are awarded at a time for a discovery, because Harry Noller has made just as many pioneering contributions to ribosome structure and function. It is too bad that he missed out (and it must have been a close call between Ramakrishnan and Noller).

Most of the work on ribosomes was also done on the most obscure of organisms, mostly microbes that live in harsh environments, like Geobacillus stearothermophilus or Haloarcula marismortui (which lives in the Dead Sea) or Thermus thermophilus. Much of the basic mechanisms of ribosome function are conserved right from bacteria through eukaryotes (of which humans are also a part of). Yet, there are also many differences between bacteria and eukaryotes (and the microbial yeast, a eukaryote, has ribosomes more similar to humans than to bacteria, a fellow microbe). Yonath, Steitz and Ramakrishnan soon had structures of ribosomes with various antibiotics bound to them, showing how these antibiotics could block the ribosome and hence kill bacteria. Their work now gives us a fantastic snapshot to ribosome function, and provides a platform for chemists to come in and make new antibiotics against harmful bacteria.

All in all, the prizes have gone to recipients without any major surprises, and their work has tremendous impact, and is a celebration of research in basic, fundamental biology.

I’ll leave you with this video of the ribosome from Tom Steitz’s lab. I never thought the ribosome looked like a death star, but with the music playing I see it in a different light.

8 comments:

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Nagesh.MVS said...

Nice post.
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theusualblabber said...

nice post and an amazing video.. :)
i wish the granting agencies read ur post and realized the importance of supporting basic research and not just the translational medicine stuff.. we are all suffering because of this neglect which seems to be increasing day-by-day.. :(

Anonymous said...

Very informative post--

Aniket said...

Hi Sunil,

Very nice-- a great piece.

It might help to have occasional articles on people inducted into the National Academies for very significant work.

Are you a member of the National Association of Science Writers? If yes, what has your experience been like?

Thanks,

Aniket

krishna said...

Sunil,

Nice post. To the best of my knowledge, Peter Moore also probably deserved a share. He was one of the first to work on this problem when it was not fashionable, and has done a lot of the early structural work (and also is a co author on the structures published with steitz, with some of the other authors being joint postdocs with him and steitz). There were essentially 5 serious candidates, which shows how silly the prize is becoming.

Sunil said...

Aniket......for articles on people inducted into the NAS, there is this nice series in PNAS which does exactly that. But it is a good idea, since I'm really interested in the history (recent and older) of science and scientific breakthroughs. Nope...not a member of the National association of science writers.

Krishna......yup, Moore could also consider himself unlucky. But I don't think the Nobel's are silly. The rule says 3 people, so they have to pick 3 tops. So there will be some near misses. But there are few (if any) prizes in the sciences where you go "oh, he/she shouldn't have gotten the prize", and you usually go "oh, he/she should also have received it". That's different.

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