Thomas Steitz, Sterling Professor of Molecular Biophysics and Biochemistry and Professor of Chemistry at Yale University and Howard Hughes Medical Institute Investigator, receives one-third of this year's Nobel Prize in Chemistry for elucidating the structure and function of the ribosome, the protein-making factory of the cell. Joining him are Venkatraman Ramakrishnan of the MRC Laboratory of Molecular Biology in Cambridge, England, and Ada Yonath at the Weizmann Institute of Science in Rehovot, Israel, who also worked on the problem.
The Nobel not only recognizes 69-year-old Steitz for his seminal work on the ribosome, but also for his work's ramifications, including the promise in bettering the next generation of antibiotics. The award comes after numerous plaudits, including the 2007 Gairdner Foundation International Award, the same won the previous year by his wife Joan, a fellow Yale biochemist. Steitz's other honors include the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Sciences and the American Association for the Advancement of Science Newcomb Cleveland Prize, both in 2001.
We asked Steitz about his studies of the ribosome and its implications,
You mapped each of the ribosome's 100,000 atoms, using synchrotron-generated x-rays, which scattered off the atoms in the ribosome and hence revealed their locations. What were some of the challenges you faced in conducting such x-ray crystallography on ribosomes?
One of the problems with the ribosome is that it’s big, and so whereas a mercury bound to a small molecule like myoglobin gives a big signal, mercury bound to the ribosome does not. [Adding metals such as mercury boosts the scattering and hence the signal strength.]
So we used a heavy atom cluster containing 18 tungsten atoms bound to each other, so they’re very close to each other. At low resolution they scatter essentially as one atom. That gave a strong signal, which got us started.
During the cell's protein-making process, ribosomes recognize the genetic code as relayed by messenger RNA and then, with the help of transfer RNA, assemble amino acids into a protein—a process called translation. What particular ribosome question were you looking to answer when you began your research in the mid-1990s?
We were trying to understand the structural basis of the mechanism whereby the ribosome can recognize [the genetic code] and the transfer RNA and match it with the messenger RNA. Such recognition is done in a small ribosomal subunit.
The other question was how does the ribosome catalyze the formation of the chemical bonds between amino acids attached to the transfer RNA. … That’s done on a large subunit.
What we found was this catalysis is done entirely by RNA, which is consistent with the hypothesis that the original ribosome was all RNA, which makes sense if you realize the-chicken-and-the-egg nature of the problem. You can’t make proteins starting with a protein if the first protein is the enzyme that does it, so instead you use RNA.
You are in New Haven and your Nobel counterparts are in the U.K. and Israel. Was the geography relevant for some reason or was it simply your individual preeminence in the field that caused you to work on the same problem?
We were independently working on the problem. Ramakrishnan started working on the small subunit one when he was on the faculty at the University of Utah and then he moved to Cambridge. Ada Yonath’s been in Israel and also at the Max Planckin Berlin for many, many years. And I’ve been here for a long time.
This all started independently, and we really worked independently as well.We paid attention to publications, but otherwise there wasn’t any collaborative communication.
But you all worked on this same project.
Same, but there are different aspects. Yonath was working on both the large and small subunit. Ramakrishan was working on the small subunit. We [at Yale] were working on the large subunit.
You began your work in 1995 and published the results in 2000. What occurred in the intervening five years?
Five years was quite fast given the scale of the problem and the technical developments required. In 1995-2000 the computation and x-ray data collection tools were largely developed, but numerous changes in data collection technology in the late '90s helped a lot.
Patrick Sung, chair of the Yale department of molecular biophysics and biochemistry, was quoted as saying your work will be put to practical use because "bacteria cannot survive without a functional ribosome" and your "studies will likely lead to more efficacious treatment of bacterial infections via the design of new antibiotics that target the ribosome." And you established a large biopharmaceutical firm, Rib-X (pronounced "rye-bex") here in New Haven that seeks to develop new antibiotics. Why are the results of your research exciting to someone at one of the pharmaceutical companies seeking to craft new antibiotics?
It looks to me that the ones Rib-X is designing by piecing together portions of existing compounds work very effectively, but it's hard to know what one should call "new." It's a new compound in the sense that it hasn't been used before. And they have different properties.
Bacteria evolve, and so they become resistant to existing drugs. Sometimes they revert, depending on how damaging the mutation is to the life cycle of the bacteria. Mutations that give rise to resistance against particular compounds do increase and that is why you constantly have to have new ones.
Would you compare the discovery of ribosome structure to something as lofty as say, the discovery of DNA's double helix?
I don't think it will have as wide an impact. What was important about that discovery is not the structure, so to speak—the pitch and rise per residue and all that—as interesting as all that is. What was important is the base pairing, which then gives you immediately the answers to how you copy the DNA and go on to the next generation. That had major impact, it seems to me.
That leads to your own work and your great achievement. Is there some aspect of your ribosome work that you hope will resonate most with humanity, long after we're both gone?
You don't have to answer it.
It depends. If you're talking about biological scientists, and people trying to understand structure and function and perhaps designing new molecules, it can be useful, but I doubt it will have the same resonance as the double helix. That's a hard one to compete with.