This week (and possibly a bit beyond), Nobel Intent will be bringing you coverage of a rather exceptional event, the Lindau Nobel Laureates Meeting, being held in Germany. It's an annual meeting that brings together scientists in their formative stages—undergrads, grad students, and post-docs—and a collection of researchers who have won Nobel Prizes in the sciences for a series of lectures, discussions, and informal chats. The students, who come from around the globe, are chosen through a competitive process based on indications of their scientific potential; the speakers are chosen using much simpler criteria, and most years come from a single subject area: chemistry, physics, or physiology and medicine.

The event was started as an attempt to re-establish a scientific community in Germany following World War II, which had caused many of its best minds to flee, and left the remainder isolated. This year is the 60th anniversary of the first meeting, and features laureates from all three subject areas. I'll be attending many of the talks thanks to a travel fellowship sponsored by Lindau and the US' National Association of Science Writers. The talks will cover the history of what won the researcher a given Nobel Prize, interesting questions in that field today, and whatever happens to have caught the Laureate's interest since then.

This morning's first talk, from Ada Yonath, was a mix of the three. Yonath talked about the ribosome, which makes the cell's proteins and has remained the subject of her work, even as progress on understanding it has allowed her to focus in on new questions.

The ribosome is a huge complex of proteins and RNA that has a seemingly simple job: to take the messenger RNAs that are transcribed from the DNA of genes, and translate them into a protein. Yonath got her Nobel for work on understanding the structure and catalytic activities that drive the translation reaction, and spent a portion of her talk describing the basics of ribosome activity, presumably for the benefit of the physicists in the audience. Using cartoons from a children's book, she described how a messenger RNA sequence is matched to a series of transfer RNAs (tRNAs), each of which adds a single amino acid to a growing protein.

Yonath spent a few moments describing the ribosome's staggering efficiency: a chemist might take a day and carefully controlled conditions to make a single peptide bond between amino acids in the lab. A ribosome can catalyze 20 of these reactions a second, and does so with an accuracy of about 99.99999 percent (humans make mistakes quite a bit more often).

As we've figured out the structure of different pieces of the ribosome, the importance of the RNA it contains has become increasingly obvious. Many proteins reside in the ribosome, and others shuffle in and out to push the complex between specific states. But two-thirds of the mass of a ribosome comes from RNA—many of the key reactions are now known to be catalyzed by this RNA, and two key sites within it are comprised of RNA that binds tRNAs by standard base pairing.

Knowing more about the structure has allowed Yonath to start thinking more about two otherwise unrelated issues: antibiotics and the origin of life. Based on Yonath's numbers, it appears that over a quarter of our current antibiotics act by interfering with the ribosome; most of these act by binding to essential sites. The problem is that evolution has ensured that these essential sites are nearly identical, meaning that differences between human and bacterial sequences are very small—at least some of the mutations that produce drug resistance involve changes that place a human-specific amino acid into the bacterial context.

Bypassing bacterial drug resistance



How do we possibly work around this? Yonath described two ways that would make it harder for bacteria to evolve resistance. One involves designing drugs where most of the specificity of binding to the ribosome comes from conserved sequences. Although these drugs will stick to both human and bacterial ribosomes, the overall environment provided by the bacterial ribosome induces a conformation change in the drug, causing it to clog up its machinery. In humans, it remains pinned to the ribosome surface, harmlessly out of the way.

Option number two is to actually use two drugs that can interact with each other. This allows each drug to have a weak specificity for the bacterial ribosome, one that's harder to eliminate by mutation. The mutual affinity between the two components ensures that the overall interaction is much stronger than its individual parts.

Yonath is also using the ribosome's structure to look for what she called molecular fossils of the origin of life, left over in the structure of the ribosomal RNA. Right now, several of the key catalytic sites are generated by the careful folding of a single large RNA, but you can split things up into a couple of smaller RNAs that are still functional. She breezed past this very quickly, though, so it's not clear how far her group has gotten on this problem. Anyone interested in the origin of life should check back later to hear about the talk from Jack Szostak.

Hibernating ribosomes

Yonath wrapped up with a bit of personal perspective on her work. The huge size of the ribosome had limited attempts to perform structural work on it, since it's difficult to get something that big to form the ordered crystals necessary to decipher structures. But Yonath heard that bears pack up and store their ribosomes during hibernation, so she knew it was possible.

Ultimately, getting the crystals she needed required the discovery of a bacteria in the Dead Sea that survives while dried out on salt deposits, meaning that it had pretty robust ribosomes.

After years of work, her group got the crystals and took them to a synchrotron light source. The particle accelerator produced such intense X-rays that her imaging took less than a second. "The machine was more important than I was," she joked.

She also noted how international her science has been. Although she's based in Israel, she's also worked at Germany's Max Planck Institute, and received funding from the US National Institutes of Health. She has also managed to maintain a rich family life (illustrated by photos of her children and a drawing by a grandkid) while being a successful scientist, and she said the students present (especially the women) should never feel that they need to choose between science and family.

Listing image by Los Alamos National Laboratory