Last week in Stockholm (and Oslo), the 2009 Nobel Prize winners were gloriously hosted while giving their lectures and receiving their medals and diplomas. In Chemistry this year, the Nobel was shared by Venkatraman Ramakrishnan, Thomas A Steitz, and Ada E Yonath for their studies on the structure and function of the ribosome, a remarkable nucleoprotein complex that catalyzes the rapid, coordinated formation of peptide bonds as instructed by messenger RNA. My post on the day of the announcement in October was designed to counter the inevitable (and now realized) criticisms that the prize was not for "real" chemistry.
Only ten days later, we in the NC Research Triangle area were very fortunate to host Dr Yonath at the North Carolina Biotechnology Center for the Symposium on RNA Biology VIII, sponsored by The RNA Society of North Carolina.
Among the many noteworthy speakers was Dr Greg Hannon from Cold Spring Harbor Laboratory, a scientist who some feel was overlooked for the 2006 Nobel Prize in Medicine or Physiology, one where Andrew Fire and Craig Mello were recognized for RNA interference and gene silencing.
NC Biotech's Senior Director of Corporate Communication, Robin Deacle, kindly invited me to an audience with Dr Yonath and two science reporters following Dr Yonath's lecture. As you might suspect, I was quite honored to visit for awhile with the woman who defied the naysayers and successfully crystallized a bacterial ribosome, then used X-ray crystallography to determine its structure below three angstroms resolution. The fact that she also used natural product antibiotics to stabilize ribosomal structure added to my magnitude of admiration.
(The photos here were provided for you by Steven R McCaw, Image Associates. McCaw is also a photographer and videographer with the National Institute of Environmental Health Sciences (NIEHS))
Dr Yonath started our discussion by sharing with us her tricks for fighting jet lag: no medications and do not sleep until bedtime local time. She said she'd get to test this many more times over the next few months as the inevitable speaking engagements came through.
"No one wanted to believe it because they didn't do it first"
One of the most challenging issues in generating crystals of ribosomes is that the RNA-protein complexes are huge by molecular standards (~2.5 megadaltons), lack the symmetry of other large particles such as viral capsids, and can exist in more conformations than a typical enzyme.
While recovering from a bicycle accident, Yonath read an article and seized upon an observation that the ribosomes of polar bears begin to associate just prior to hibernation to protect them from degradation so that protein synthesis can resume upon their reawakening. Yonath therefore felt that conditions could indeed be recreated for an orderly assembly of ribosomes that would be consistent with crystallization. She was very much criticized at the time for being a dreamer of something that would be impossible but she joked that perhaps the concussion she suffered from the bicycle crash made her think it was possible to solve the structure.
Her next choice was the use of ribosomes from microorganisms called extremophiles: those that live at life's extremes, such as hot springs (thermophiles) and bodies of water with high salinity (halophiles). Since they operate at extremes, she reasoned that they might crystallize more easily under "normal" conditions as opposed to, say, human ribosomes which operate at 37°. Growing up in Israel particularly made her aware of halophiles from them being one of the very few forms of life in The Dead Sea. At the time (the late 70s and early 80s), Yonath was told she was crazy to work with these organisms but they became all the rage over the next ten years, especially for polymerase chain reaction (PCR).
As an aside, Yonath was humorously exasperated when telling us of the kinds of questions she had gotten in the 10 days since the award. When one reporter asked what it was like growing up in Israel she answered, "Compared to what? How should I know? Israel was the only place I grew up."
But back to the science. Despite the heterogeneity, Yonath's group demonstrated that the core of the ribosome, the peptidyl transferase center (PTC) tunnel is highly symmetrical and allows for a 180-degree repositioning of the aminoacyl-tRNAs as amino acids are transferred from the tRNA to the growing peptide strand.
Few believed the overall structure was real and even fewer believed that the central aspect of the ribosome was so symmetrical. "No one wanted to believe it because they didn't do it first," she said. It has since become known that there is extremely high conservation, "98% from bacteria to elephant," Yonath says, that is highly resistant to any environmental attempts at mutagenesis.
This fact has led those in the field to agree that the PTC tunnel is the center of the proto-ribosome that existed long, long ago in the prebiotic RNA world. Three Science papers in 2000 from the Steitz and Strobel groups at Yale confirmed that the ribosome is a ribozyme; that is, while amino acids assist in the positioning of peptide and tRNA, the catalytic activity is due to ribosomal RNA.
Is it really chemistry?
When speaking of the proto-ribosome in her talk, Yonath referred us to a recent 2009 commentary by Jack Szostak (incidentally one of the 2009 Nobelists in Physiology or Medicine) entitled, "Origins of life: Systems chemistry on early Earth," which began with the sentence:
Understanding how life emerged on Earth is one of the greatest challenges facing modern chemistry.
So, we chatted a bit about the criticism that her work and that of her two fellow laureates was not chemistry. She responded that she was a very good chemistry student - "the best chemistry student" in her class - and worked for weeks to synthesize a peptide bond - "a hundred degrees, all kinds of acids," and finally created a covalent peptide bond in the laboratory.
The ribosome catalyzes 10 peptide bonds per second.
The Awesome Power of Natural Products
One of the key features in her subsequent series of crystallizations was the availability of the natural product antibiotic, spasmomycin. You've never heard of it before because it binds at the highly conserved tunnel of the ribosome. Discovered in 1962 and demonstrated as a protein synthesis inhibitor by Harvard's Dr Irving Goldberg in 1966, sparsomycin lacks selectivity between mammals and infectious microorganisms because it binds to this very highly-conserved region of the tunnel.
However, Yonath's group and others have shown where other antibiotics bind to more unique areas of bacterial ribosomes: erythromycin, clindamycin, chloramphenicol - and in subsequent work are trying to investigate new compounds.
She is concerned, however, that attempts to develop antibiotics to overcome resistance to previous ones runs the risk of having less selectivity. But Yonath is also enthusiastic about antibiotic synergy whereby weakly acting drugs have far more than additive effects when combined because of their blockade of the tunnel at different sites. One of these drug combinations has already been marketed since 1999, Synercid, a combination of quinupristin and dalfopristin.
For this reason, Yonath told me that her laboratory will take any antibiotic that any drug companies might have - "we take all their garbage" - because some may be great tools and others may be quite useful clinically if combined with others that spatially attack the ribosome in a synergistic manner.
We finished talking about the relative underemphasis of antibiotic development efforts in pharma despite to increasing emergence of drug resistant infectious organisms. Yonath holds that companies had better be interested in concentration on antibiotic drugs so that people live long enough to have a need for their blockbuster drugs such as cholesterol-lowering agents.
Her Nobel lecture this past week reflected the convergence of life's treasures on her work and was entitled, "Polar bears, unpaved roads, Everest climbing, and ribosomes in action." The video runs 43 min and is available here at Nobelprize.org. In launching the talk and explaining basic crystals before going on to the challenges of ribosomes, she showed how some basic proteins can be crystallized such as lysozyme, a process so easy that it can be done by a 6th grader (in this case, her granddaughter Noa Yonath Comarov). Therein you will see photographs of Yonath at the cyclotron in Grenoble, France, and a more lengthy discussion of the early RNA world and the proto-ribosome.
Women as Science & Medicine Nobelists
Our blog and those of several of our colleagues at ScienceBlogs and elsewhere spend a lot of time emphasizing special issues of women and other underrepresented groups in science and medicine. This year's prizes were particularly notable in that Yonath was the first Chemistry laureate in 45 years and only one of four ever (the others were Madame Marie Curie (1911), her daughter Irene Joilot-Curie (1935), another X-ray crystallographer, Dorothy Hodgkin (1964)). Two other women, Elizabeth Blackburn and Carol Greider, won the 2009 Nobel Prize in Physiology or Medicine with Jack Szostak. This Washington Post interview with Greider by Liza Mundy nicely addresses some of the issues of women in the academy.
I had anticipated Yonath would have something to say about being a woman in science, or at least that one of the other two women reporters would ask such a question. However, I had a discussion before the interview with Nobelprize.org editor, Simon Frantz, who pointed me to this passage from Adam Smith's telephone interview with Yonath immediately following the prize announcement:
Smith: And perhaps particularly special to be a woman who receives it?
Yonath: I'm sorry that I can't, I can't think this is because of my gender. And, I don't think that I did something that is specially for women, or the opposite. During my time I had some very difficult years and I had very pronounced competition, all by men. But I don't think that this is because I was a woman. I'm pretty sure that if I was a man too they would compete, if the men would get to where I was at that time. I think that it doesn't help to be a woman in science. Maybe now, but not when I was progressing. But I don't think that it disturbs, in my opinion. I may be wrong. I may be wrong: women try to explain me all types of things. And I think that women can make ... women need, actually, they're fortunate because if they don't want to do science they can say, "I want to be with my kids." And this is understandable, whereas a man cannot do this. So if we look at it from the other point, but this means also stopping science.
In an LA Times blogpost last month, Batsheva Sobelman discussed that some in the feminist community were not happy with Yonath for taking a more vocal stand on the challenges for women in science (although most of the post was about Yonath being outspoken about the release of Palestinian prisoners; she is well-known to be a critic of continued Israeli settlement of the West Bank.)
Professor Esther Hertzog, an anthropologist and coordinator of the Women's Parliament, was upset by Yonath for different reasons. Yonath, only the fourth woman to have won a Nobel Prize in chemistry since 1901, had brushed aside the gender issue, as had male colleagues like professor Aaron Ciechanover, who won the chemistry award in 2004. "I don't walk into the lab in the morning thinking, 'I am a woman and I will carry out an experiment that will conquer the world.' I am a scientist, not male or female. A scientist," she said. Hertzog regretted Yonath's approach and that often women who do succeed attribute this to their skill and perseverance alone and overlook the contribution of decades of feminist struggle for women's right to education and equality. This is what allowed women to succeed in the 21st century, she wrote, albeit with a price.
I now wish that I had asked Dr Yonath about this issue in greater detail. Why did she not use the platform of the Nobel Prize to more aggressively discuss the issues of women in science? Indeed, she is from a different generation than Blackburn and Greider but certainly one that would have faced even more challenges than the younger laureates. Or is there something cultural about Israeli science that was more accepting to women scientists - I think here in the States of Hunter College in New York City, a school that has historically cultivated Jewish women in the sciences.
But, I wouldn't say that she was entirely quiet on the subject, as in this widely distributed AFP article by Ron Buosso:
"Women make up half the population," she says. "I think the population is losing half of the human brain power by not encouraging women to go into the sciences. Women can do great things if they are encouraged to do so."
"I would like women to have the opportunity to do what is interesting to them, to go after their curiosity. And I would like the world to be open to that. I know in many places there is opposition to that."
Regardless, it was a remarkable honor and pleasure to visit with this tremendously accomplished scientist. Our discussion is one that I shall remember for the rest of my career.
For further reading intended for general audiences, this PDF produced by the Royal Swedish Academy of Sciences is excellent. One could even use it as the basis for discussion in an entry-level course in biology.
Many thanks to Robin Deacle at the North Carolina Biotechnology Center for inviting us to this standing-room-only symposium and the special audience with Dr. Yonath. The photographs shown here are used with the permission of Steven R McCaw - Image Associates.