A Nobel for deciphering the ribosome’s subunit

A few minutes before noon on October 7, Thomas A. Steitz, Ph.D., Sterling Professor of Molecular Biophysics and Biochemistry and professor of chemistry, walked into the President’s Room at Woolsey Hall to sustained applause. Amid the cheering crowd were his colleagues on the Yale faculty, students and postdocs in his lab, the staff of his biotech company, Rib-X Pharmaceuticals, and news reporters and photographers.

A few minutes later Yale President Richard C. Levin warmly greeted Steitz and his wife, Joan A. Steitz, Ph.D., Sterling Professor of Molecular Biophysics and Biochemistry. Then Levin took his place at a lectern in front of a Yale-blue backdrop to say, “It is with the greatest pride and enthusiasm that I am here to introduce you to Tom Steitz, the winner of the 2009 Nobel Prize in Chemistry.” The news had arrived at 5:30 that morning in a phone call to Steitz from Stockholm.

Steitz, a Howard Hughes Medical Institute (HHMI) investigator, was one of three scientists recognized by the Royal Swedish Academy of Sciences for their work on the ribosome, a complex of RNA and protein found in all cells. The Academy noted in its statement that this year’s chemistry prize honors “studies of one of life’s core processes: the ribosome’s translation of DNA information into life.”

“It is an amazing piece of work,” Levin said. “It is fundamental, sweat-it-out, figure-it-out science. It is like solving a gigantic jigsaw puzzle. This is the factory that makes the proteins that are the source of life.”

The other scientists honored were Venkatraman Ramakrishnan, Ph.D., FW ’82, of the Medical Research Council (MRC) Laboratory of Molecular Biology in England, and Ada E. Yonath, Ph.D., of the Weizmann Institute of Science in Israel. Ramakrishnan studied the smaller of the ribosome’s two subunits, while Yonath began making crystals of the ribosome in 1980, and Steitz concentrated on the ribosome’s larger subunit starting in 1995. Although the three teams tackled parallel problems related to the ribosome, Steitz said, they worked separately. “We communicated via papers and meetings.”

Steitz offered thanks for the supportive environment at Yale and in particular to Peter B. Moore, Ph.D., Sterling Professor of Chemistry and professor of molecular biophysics and biochemistry, who worked with him on the ribosome project. “He has been a friend and colleague and co-worker and collaborator for many years. I very much appreciate his company and his work and his participation,” Steitz said. (Ramakrishnan was a postdoctoral fellow with Moore and Donald M. Engelman, Ph.D., Eugene Higgins Professor of Molecular Biophysics and Biochemistry, from 1978 to 1982.)

The Steitzes came to Yale in 1970 after three years as fellows at the MRC, where Francis Crick and James Watson had elucidated the double-helix structure of DNA in 1953. As Levin noted, “Tom Steitz has a rare family. His wife Joan is one of the leading scientists at Yale as well. She is someone we hope will some day get the same recognition Tom received today.” (Their son, Jonathan G. Steitz, J.D. ’07, was drafted from Yale in 2001 by the Milwaukee Brewers as a right-handed pitcher, but tendonitis in his right shoulder ended his baseball career. He is now a consultant in San Francisco.)

Since the late 1970s Steitz has been exploring how DNA is copied into DNA and then into RNA at the molecular level and how RNA makes proteins. In those early days, however, the National Institutes of Health offered little support for structural biology, he said. Then HHMI stepped in during the 1980s. “HHMI funded five or six structural biology labs in the country. That helped the whole field because they set the agenda,” Steitz said.

By 1995 Steitz had turned to what Levin called “one of the most challenging and difficult problems in molecular science,” namely the structure of the ribosome’s large subunit. Steitz’s tool was X-ray crystallography, but in the early stages of the research, it was hard to form a high-quality crystal of the ribosome. Once a suitable crystal was achieved, the next step was to beam X-rays through it to plot a diffraction pattern that would reveal the ribosome’s atomic structure. In 2000 Steitz and his team used a 2.5 billion electron volt X-ray beam at Brookhaven National Laboratory’s National Synchrotron Light Source.

“It was the most exhilarating moment I have had in science, to peer into the inner workings of the ribosome and think about how it works,” Steitz said. “It was like trying to climb Mount Everest. We knew it was doable in principle but we didn’t know if we would ever get there.”

Although the prizewinning research began as a quest to find out how a complex molecular structure works, it has since yielded clinical applications. By blocking ribosomal activity in bacteria, many antibiotics cure diseases caused by bacterial infection. No organism can live, Steitz said, “without a machine that makes proteins.”

The company that Steitz co-founded in 2001, Rib-X Pharmaceuticals, has applied the insights obtained from the ribosome-antibiotic structures to develop new antibiotics that can be used to treat such multi-antibiotic resistant infections as MRSA. The company is developing both oral and intravenous drugs for treating skin infections, pneumonia, bronchitis, and soft tissue infections. One compound developed by the company has successfully completed phase 2 clinical trials.