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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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October 7, 2009

A Nobel for Ribosome Structure

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Posted by Derek

This was another Biology-for-Chemistry year for the Nobel Committee. Venkatraman Ramakrishnan (Cambridge), Thomas Steitz (Yale) and Ada Yonath (Weizmann Inst.) have won for X-ray crystallographic studies of the ribosome.

Ribosomes are indeed significant, to put it lightly. For those outside the field, these are the complex machines that ratchet along a strand of messenger RNA, reading off its three-letter codons, matching these with the appropriate transfer RNA that's bringing in an amino acid, then attaching that amino acid to the growing protein chain that emerges from the other side. This is where the cell biology rubber hits the road, where the process moves from nucleic acids (DNA going to RNA) and into the world of proteins, the fundamental working units of a day-to-day living cell.

The ribosome has a lot of work to do, and it does it spectacularly quickly and well. It's been obvious for decades that there was a lot of finely balanced stuff going on there. Some of the three-letter codons (and some of the tRNAs) look very much like some of the others, so the accuracy of the whole process is very impressive. If more proofs were needed, it turned out that several antibiotics worked by disrupting the process in bacteria, which showed that a relatively small molecule could throw a wrench into this much larger machinery.

Ribosomes are made out of smaller subunits. A huge amount of work in the earlier days of molecular biology showed that the smaller subunit (known as 30S for how it spun down in a centrifuge tube) seemed to be involved in reading the mRNA, and the larger subunit (50S) was where the protein synthesis was taking place. Most of this work was done on bacterial ribosomes, which are relatively easy to get ahold of. They work in the same fashion as those in higher organisms, but have enough key differences to make them of interest by themselves (see below).

During the 1980s and early 1990s, Yonath and her collaborators turned out the first X-ray structures of any of the ribosomal subunits. Fuzzy and primitive by today's standards, those first data sets got better year by year, thanks in part to techniques that her group worked out first. (The use of CCD detectors for X-ray crystallography, a technology that was behind part of Tuesday's Nobel in Physics, was another big help, as was the development of much brighter and more focused X-ray sources). Later in the 1990s, Steitz and Ramakrishnan both led teams that produced much higher-resolution structures of various ribosomal subunits, and solved what's known as the "phase problem" for these. That's a key to really reconstructing the structure of a complex molecule from X-ray data, and it is very much nontrivial as you start heading into territory like this. (If you want more on the phase problem, here's a thorough and comprehensive teaching site on X-ray crystallography from Cambridge itself).
Ribosomal%20structures.jpg
By the early 2000s, all three groups were turning out ever-sharper X-ray structures of different ribosomal subunits from various organisms. The illustration above, courtesy of the Nobel folks, shows the 50S subunit at 9-angstrom (1998), 5-angstrom (1999) and 2.4-angstrom (2000) resolution, and shows you how quickly this field was advancing. Ramakrishnan's group teased out many of the fine details of codon recognition, and showed how some antibiotics known to cause the ribosome to start bungling the process were able to to work. It turned out that the opening and closing behavior of the 30S piece was a key for this whole process, with error-inducing antibiotics causing it to go out of synch. And here's a place where the differences between bacterial ribosomes and eukaryotic ones really show up. The same antibiotics can't quite bind to mammalian ribosomes, fortunately. Having the protein synthesis machinery jerkily crank out garbled products is just what you'd wish for the bacteria that are infecting you, but isn't something that you'd want happening in your own cells.

At the same time, Steitz's group was turning out better and better structures of the 50S subunit, and helping to explain how it worked. One surprise was that there was a highly ordered set of water molecules and hydrogen bonds involved - in fact, protein synthesis seems to be driven (energetically) almost entirely by changes in entropy, rather than enthalpy. Both his group and Ramakrishnan's have been actively turning out structures of the ribosome subunits in complex with various proteins that are known to be key parts of the process, and those mechanisms of action are still being unraveled as we speak.

The Nobel citation makes reference to the implications of all this for drug design. I'm of two minds on that. It's certainly true that many important antibiotics work at the ribosomal level, and understanding how they do that has been a major advance. But we're not quite to the point where we can design new drugs to slide right in there and do what we want. I personally don't think we're really at that stage with most drug targets of any type, and trying to do it against structures with a lot of nucleic acid character is particularly hard. The computational methods for those are at an earlier stage than the ones we have for proteins.

One other note: every time a Nobel is awarded, the thoughts go to the people who worked in the same area, but missed out on the citation. The three-recipients-max stipulation makes this a perpetual problem. This is outside my area of specialization, but if I had to list some people that just missed out here, I'd have to cite Harry Noller of UC-Santa Cruz and Marina Rodnina of Göttingen. Update: add Peter Moore of Yale as well. All of them work in this exact same area, and have made many real contributions to it - and I'm sure that there are others who could go on this list as well.

One last note: five Chemistry awards out of the last seven, by my count, have gone to fundamental discoveries in cell or protein biology. That's probably a reasonable reflection of the real world, but it does rather cut down on the number of chemists who can expect to have their accomplishments recognized. The arguing about this issue is not be expected to cease any time soon.

Comments (59) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Current Events | Infectious Diseases


COMMENTS

1. Anonymous on October 7, 2009 9:38 AM writes...

Rib-x Pharmaceuticals has clinical candidates (and both Steitz and Ramakrishnan (and Peter Moore, another person who clearly missed out) are scientific advisors). I would say they are doing a decent job of finding drug that target the ribosome.

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2. T on October 7, 2009 9:47 AM writes...

Having spent a number of years working in the field of biological crystallisation I know just how difficult and elegent this type of work is. However, with my chemists hat on, this clearly not a nobel prize in chemistry. It is biology through and through

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3. D. on October 7, 2009 10:04 AM writes...

Derek, slight error: it's Weizmann rather than Weitzman.

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4. philip on October 7, 2009 10:08 AM writes...

I think they should have a Nobel prize for crystallography, so that some of the scientist who aren't crystallographers could get a chance to win on occasion. If you go back and count, since the Bragg's in 1915, a bunch in physics and about half of the prizes in chemistry and medicine have gone to crystallographers.

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5. RB Woodweird on October 7, 2009 10:14 AM writes...

From the Nobel website

http://nobelprize.org/prize_awarders/chemistry/committee.html

the list of the committee:

Gunnar von Heijne (Chairman)
Professor of Theoretical Chemistry

Astrid Gräslund (Secretary)
Professor of Biophysics

MÃ¥ns Ehrenberg (Member)
Professor of Molecular Biology

Sven Lidin (Member)
Professor of Inorganic Chemistry

Lars Thelander (Member)
Professor of Physiological Chemistry

Håkan Wennerström (Member)
Professor of Theoretical Physical Chemistry

Yeah, see any organic chemistry represented? Face it, synthetic chemists have a better chance to get the IgNobel.

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6. Rajesh on October 7, 2009 10:26 AM writes...

To my mind, this is actually an achievement which required a strong understanding of physics (x-ray production, detection and interpretation), chemistry (the nature of the interactions between proteins and substrates) and biology (knowledge of the function and production/purification of the protein). Chemists may feel cheated that they are missing out and the continuum of physics-chemistry-biology is a little blurry, but I feel this achievement does fall significantly under the chemistry umbrella.

As for the first comment, I would strongly question any assertion that the advisor's contribution has helped them make significant leaps in rational drug design, which I believe, was to what DL was referring. Sure, Rib-X have had some 'success' and the advisors have probably helped move things forward, but I doubt we are talking about 1 in 10 as opposed to 1 in 10,000. If anyone knows otherwise, I'd be keen to hear about it.

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7. HappyDog on October 7, 2009 10:31 AM writes...

Derek, your observations about who gets the credit from the Nobel Prize committee are quite correct, but I'm glad that Ada Yonath at least got to share in the glory. When I was in grad school, my advisor was collaborating with a group working on the structure of the ribosome using cryo-EM approaches. He said that Ada had been working on the ribosome structure since the late 70's. At the time, there was an unspoken rule among crystallographers that you don't work on someone else's project, but by the 1990's when there was still no crystal structure of the ribosome, some researchers at meetings in the field were questioning whether the project was just too difficult for her and maybe some other groups should solve the structure. Clearly, she worked on the problem much longer than anyone else and her contributions were crucial to the eventual solution of the atomic resolution x-ray structure. Kudos to all three!

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8. Tim on October 7, 2009 10:33 AM writes...

Just the fact that they are toting this as an 'important target for drug design' should push this into Medicine-prize area. I'm not saying this wasn't great research, i'm just saying that the nobel prize for medicine was already given out two days ago. I thought for sure after GFP won last year they would feel guilty enough to give the chemistry prize for pure chemistry research, but no. Cellular biology FTW. All the cool stuff with nano-(insert anything here) gets the bump. Maybe once the nano-stuff starts kicking ass and taking names in the human body chemists can start stealing the prize for medicine!

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9. XIMIK on October 7, 2009 10:40 AM writes...

In an instance, Rib-X got two Nobel laureates (Steitz and Ramakrishnan) and two should-have-also-been Nobel laureates (Moore and Noller) on its SAB. Not bad for a small company. ;-)

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10. wood on October 7, 2009 11:06 AM writes...

Outstanding biochemists having long been awarded the Nobel prizes in both medicine and chemistry. Biochemistry deals with questions that relate to human health and often attempt to provide mechanistic answers on the molecular level. Protein structure determination is the perhaps the purest form of this. Having said this, I don't see any more x-tal structures being awarded Nobel's anytime soon. The big ones have been awarded - Membrane proteins, RNA Polymerase and Ribosome structures are all recent winners. They were are very difficult structures to determine and provided answers to paramount biological questions.

Unfortunately, chemists will not be getting a break anytime soon. The Chemistry Nobel prizes will start to go to engineers who reprogram organism into green chemistry machines. This has already been accomplished to produce the anti malaria drug Artemisinin. Nanochemistry/technology is also a field whose application is dominated by bio-engineers who could see their share Nobel prizes in the future.

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11. MedChem on October 7, 2009 11:58 AM writes...

This work is NOT chemistry!

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12. umesh on October 7, 2009 12:42 PM writes...

Though I share my concern with many chemists, the contribution the trio have done is remarkable. Let us congratulate them for this achievement with the hope that in future the Nobel Committee, will do something...

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13. Anne on October 7, 2009 1:31 PM writes...

Someone help out a budding scientist - why isn't there a biology Nobel? I assume it has something to do with how they were started, but I'd be interested in the story, and why hasn't it been changed?

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14. befuddled on October 7, 2009 2:36 PM writes...

I'd always thought that the ribosome structure would *not* get a Nobel, simply because too many people had made crucial contributions. And I'm particularly surprised to see Noller left out, though of course the contributions of Steitz, Yonath, and Ramakrishnan are as important.

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15. RM on October 7, 2009 3:26 PM writes...

@Anne - The Nobel prize categories were set out in Alfred Nobel's will. It's probably worth remembering that the Nobels were effectively established in 1895-96 when Nobel wrote his will. Biology back then isn't what it is now, and consisted primarily of anatomy, taxonomy, and animal husbandry. Advances in anatomy slot neatly into the "physiology and medicine" bracket, and I doubt that taxonomy would be considered by anyone to "... have conferred the greatest benefit on mankind" (the criteria stated in the will for awarding the prize). Animal husbandry is a bit of a blind spot, but so is engineering, mathematics, ecology ... The Nobel committee is very reluctant to expand the prize to categories outside of the ones stated in the will - going so far as to stress that the Economics prize is a "Memorial" prize, and not a full Nobel prize.

@MedChem - You've got to remember that what constitutes "chemistry" has changed over the years. Remember that back in 1895-96 we didn't really know about subatomic particles yet - J.J. Thompson's work wasn't published until 1897 or so. However, the theory of vitalism was well and truly invalidated by 1895. The basic thrust of chemistry - what sort of substances are things made of, and how do they react with each other - can be applied to biological molecules too. In this sense the composition, structure and reaction of a biology-derived ribosome is as "chemistry" (in the 1895 sense) as is the composition, structure and reaction of a coal-tar-derived heterocycle. It's only recently that we've carved out the fields of biochemistry/chemical biology/biophysics/molecular biology and considered them "distinct" from chemistry.

The granting of chemistry prizes for "biological" developments has a long history. The seventh prize was granted to Eduard Buchner "for his biochemical researches and his discovery of cell-free fermentation"

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16. SP on October 7, 2009 3:28 PM writes...

One of the key discoveries from this work was very chemical- the fact that the catalytic active site reside for peptide bond formation was in fact from the RNA, not the protein, portion of the ribosome (an A residue if I recall correctly,) proving that RNA catalysis isn't just some fluke of maturation in a few viruses but is the foundation of all of life.

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17. FME on October 7, 2009 3:28 PM writes...

I think this is extremely crazy and the situation as such is very unsatisfactory. Hats off, however, to the three scientists who obtained the Nobel prize for "Chemistry" - except for it is NOT Chemistry, but Biology. So if the Nobel committee is of the opinion that the field of Chemistry does not cut it anymore, then they should cancel it altogether, substituting it with the field of Biology.

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18. Lucifer on October 7, 2009 3:44 PM writes...

Government Orders Columbia to Tell Patients 'True Nature' of Drug Study

http://www.huffingtonpost.com/2009/10/07/government-orders-columbi_n_312536.html

...The study, conducted between December 1999 and February 2001 in the famed heart surgery unit at what is now called New York-Presbyterian Hospital/Columbia University Medical Center, involved four blood expanders approved by the U.S. Food and Drug Administration. The fluids are generally administered by anesthesiologists and combat medics when patients or soldiers have lost significant quantities of blood...

...In the consent form used in the study, patients were told that they would receive one of four fluids approved by the FDA and routinely "used to replace blood and fluid lost during surgery." The consent form stated that the researchers would extract a few tablespoons of blood from the patient to test a machine that monitors clotting. Patients were not told that they could be given high doses of the fluids or that they faced a risk of serious bleeding, according to a copy of the consent form obtained by the Investigative Fund.
Documents later filed in court show that about half of the 215 people who agreed to participate were given hetastarch, and some received up to three times the level recommended by the manufacturers. Some of the subjects were Spanish-speaking patients who lived in low-income neighborhoods near the hospital and were admitted through the emergency room, according to people who worked at the hospital at the time. The names of the patients and details about their cases have not been made public because of medical privacy rules...

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19. Charlie on October 7, 2009 3:50 PM writes...

If chemists really don't think that crystallography is chemistry, then I'm sure that molecular biology departments will be glad to continue taking faculty appointments, and put the crystallographers to excellent use!

Science continually changes; if you do not welcome the big discoveries that come from your field and instead dismiss them as being part of a different field, then your field is dying will not remain as a science for long. The existing body of knowledge will persist as engineering knowledge, but you have eliminated the pursuit of fundamentally new knowledge as "not my field."

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20. RKN on October 7, 2009 4:21 PM writes...

I have a dream.

That one day the Nobel committee will rise up and award the prize in biology to a bioinformatician.

I have a dream today!

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21. cookingwithsolvents on October 7, 2009 4:33 PM writes...

RM said what I wanted to say about bio vs chem for nobel prizes. I DO wonder if the committee will establish a biology prize in the next 10-15 years. . . if the backlash continues to grow they may, but who knows.

RE: this years prize
Part of the reason a large # of biochem prizes are being awarded is that the 1970-2000 was really when a LOT of modern tools of molecular biology were being discovered and developed (with this years prize a fantastic example). Moving crystallography from film to CCD, utilizing focused sources, and cryogenic temperatures are all HUGE advances in crystallography which have benefited small molecule people immensely, too. Solving "the phase problem" might sound ambiguous but just having a "named problem" might give you and idea about just how hard it was.

I believe that there will be a coming era where the Nobel prize will be dominated by the individuals that solve the outstanding chemical problems in "energy" (cheap PV's, chemical storage of e-'s, driving uphill reactions with light, multielectron catalysis like CO2 fixation and H2O splitting, etc). Of course, that's IF we solve them.....

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22. MedChem on October 7, 2009 5:41 PM writes...

15. RM:

I respectively disagree, even though I appreciate what you're saying, to a degree. Spin it however you want, crystallography is not chemistry. If you don't believe me, just ask any crystallographers themselves. I think some of them will be offended to be called a stinky chemist :) By your logic, anything could be called "chemistry" because it inevitably deals with chemical matter.

Maybe the field of classical chemistry has reached a point where it ceases to contribute significantly to the betterment of mankind. If so, stop giving Nobel Prize in Chemistry in that given year untill something worthy comes along. Just don't insult the chemists by awarding the Prize to some Non-chemists.

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23. Sili on October 7, 2009 5:54 PM writes...

I feel like such a waste of space for only having done (being able to do?) run-of-the-mill small molecule crystallography. And I'm not gonna get a job doing that.

This is a welldeserved prize, and I think people who whine about it not being chemistry should go ahead and invent a timemachine and go back and convince Alfred of that. After all that's how physiology got a special mention. And, hey!, that way you'll set yourself up for the physics prize, yourself! (Just be prepared to defend yourself for being too much engineering and not enough physics.)

I saw an excellent talk on ribosome structures at the BCA Spring Meeting some years ago, but I'll be damned if I can remember who gave it.

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24. Polymer Bound on October 7, 2009 6:06 PM writes...

Ugh... again with the structural biology. This seems too applied to me.

Not to diminish their achievement, but are there not more important chemistry contributions that need to be acknowledged before their innovators die off? I would argue (and would win the argument) that particular metal catalyzed carbon-carbon bond forming reactions have had a larger impact on human health than a structure of the ribosome. Is having this picture really game changing? Huge accomplishment, sure... but so was the synthesis of Palytoxin. Neither, as far as I know, have drastically altered the trajectory of science like, say, GFP, PCR, or catalytic asymmetric reactions.

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25. Hap on October 7, 2009 6:19 PM writes...

It's important, but why not Medicine? It seems like ribosome biochemistry is important enough to displace chemists from the Chemistry award, but not enough to displace biologists/doctors from Medicine. Kind of like how things are always cheap with someone else's money.

If the lack of a Nobel for Biology is a problem based on Nobel's will, then how is giving a Biology prize and calling it Chemistry consistent with the will? - the choice excludes the originally designated targets for the prize and replaces them with ones the will didn't intend to reward. In addition, the mismatch between sciences and the topics the Nobel rewards is asymmetrically applied - chemists are not going to be seeing Nobels for drug design. Alternatively, if there isn't enough chemistry worthy of a Nobel to give one, then why do so?

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26. Jim Hu on October 7, 2009 6:26 PM writes...

Spin it however you want, crystallography is not chemistry. If you don't believe me, just ask any crystallographers themselves.
Try asking them to make the choice between being called chemists or being called physiologists or doctors. ;)

I strongly suspect that there are also those in Biology departments who think that the structure of the ribosome at atomic level, or any of the more biological Chemistry prizes, isn't "real biology". When they start giving Chemistry prizes for work in ecology and evolution, I'll pay more attention to this kind of complaint.

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27. Curious Wavefunction on October 7, 2009 7:01 PM writes...

I think the awarding of this prize and the protests it caused simply underscore the vast and remarkably diverse landscape of chemistry, from solar cells to ribosomes. No other science can boast such variety.

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28. Old Pharma Guy on October 7, 2009 8:42 PM writes...

The physics awards seem to be more a reward for engineering and materials science than physics.

I guess the committee has a flexible interpretation of what a field is.

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29. Anne on October 8, 2009 1:21 AM writes...

@RM Thanks for the clarification.

Why does it matter what a certain kind of work is labeled? It's just words. I find it petty and counterproductive to bicker about what should be "called" chemistry or biology or what have you. Who says crystallography can't be its own "field"? We're all scientists here, all (supposedly) working to expand the knowledge and capabilities of humankind... it's just rather sad to see the acknowledgment of such important work devolve into sniping and complaining about labels.

I do agree that there should be more Nobel categories - it's such a prestigious prize, and to limit it so drastically is a little unfair, given how many deeply important advances deserve it. But to complain about deserving work that gets put into a category that it maybe doesn't fit *exactly* seems to be missing the point.

My $0.02. *shrug*

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30. XIMIK on October 8, 2009 3:02 AM writes...

Encyclopedia Britannica:
Chemistry - Science that deals with the properties, composition, and structure of substances (elements and compounds), the reactions and transformations they undergo, and the energy released or absorbed during those processes.

Now, can somebody explain to me why figuring out structure,chemical mechanism, and regulation of a molecular machine performing one of the most important chemical reactions (at least on this planet) is NOT chemistry???

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31. XIMIK on October 8, 2009 3:06 AM writes...

I actually like Wikipedia's definition of chemistry much better (http://en.wikipedia.org/wiki/Chemistry), but some might argue that it does not qualify as encyclopedia...

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32. Morten G on October 8, 2009 4:03 AM writes...

Re: One last note

3 of those 7 prizes have covered the central theorem. There's only one central theorem so there should be some lightening of the molecular biology load on the chemistry prize now (no it's not biology! Biochem or molecular biology). And half the worlds crystallography groups are placed in chemistry departments. And 30 years ago it was pretty much all of them.

Besides Marina and Noller, Joakim Frank should be mentioned as well.

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33. anonymous on October 8, 2009 6:19 AM writes...

Hopefully, the Nobel committee will redeem themselves next year when Al Gore wins the Nobel in Chemistry.

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34. Hap on October 8, 2009 9:08 AM writes...

1) If everything is chemistry, then nothing is chemistry - the designator becomes meaningless.

2) Lots of interesting phenomena require chemistry, but the chemistry in them is not what is important. Will the techniques used to ferret out the structure and activity of the ribosome be useful to anyone in the chemical field (will they be able to use those techniques to do neat things), or was their development at its core a chemical one? Both of the answers would probably be "no" - the ribosome and its activity are really interesting, but primarily to biologists and doctors, and we probably can't use what the winners did to do other useful things.

It just seems that biology prizes invariably go to Chemistry, which means that discoveries that affect what chemists do and are important to the practice of chemistry are not going to be rewarded - instead things interesting to other people get Chemistry prizes (on top of getting Medicine ones). It seems unjust, although I guess it's better than C60 - at least the ribosome discoveries are useful to someone now and not in an (imaginary) future.

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35. MedChem on October 8, 2009 9:26 AM writes...

34 Hap:

Both are excellent points!

And have we really run out of excellent chemists to acknowldge? I can think of a few just in organic chemistry.

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36. DC on October 8, 2009 10:12 AM writes...

Everyone knows that ribosomes are made of atoms, which is, of course, a chemistry topic.

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37. befuddled on October 8, 2009 2:49 PM writes...

It's not just the Chemistry prize that gets awarded for work that is, arguably, in another field. One could argue that Lauterbur and Mansfield's prize in 2003 could have been in physics.

One could also argue that von Frisch, Lorenz, and Tinbergen's prize (1973) was for work that was neither physiology nor medicine.

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38. malar on October 8, 2009 4:05 PM writes...

Certainly, this is not good, giving chemistry noble prize to biologists.

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39. Econ on October 13, 2009 12:09 AM writes...

Economists are more enraged about their own prize here consider real scientists to be more mature about it:
http://www.econjobrumors.com/topic.php?id=5151

(100+ posts in 3 hours, 300 posts in 18 hours)

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40. srp on October 15, 2009 3:58 AM writes...

Actually, most active economists were quite pleased with this year's Nobel (Memorial) Prize. Read Paul Romer's comments about Ostrom, for example, or the bloggers at Marginal Revolution or Organizations and Markets and the roundups of reaction there. The website listed by Econ is an anonymous gossip site frequented by a subset of doctoral students--hardly a representative indicator of professional sentiment.

The reason why almost nobody important was upset about Ostrom, a political scientist, sharing the prize is that her work is clearly economic in both subject and method. The same was true for Kahneman, a psychologist, who received the prize a few years ago and had tons of econ citations. Economists are far less guild-obsessed than natural scientists--they may have strong opinions about what kind of work qualifies as economics (and they have huge stratification in the labor market according to degree-granting institution), but they don't care that much about degrees per se. Ronald Coase doesn't even have a Ph.D, if I recall.

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49. fdpod on October 29, 2014 7:23 AM writes...

When I initially commented I appear to have clicked on the -Notify me when new comments are added- checkbox and now whenever a comment is added I get four emails with the same comment. Perhaps there is a means you are able to remove me from that service? Thank you!

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