Ronald Breaker says riboswitches are strong proof of the RNA World hypothesis—and they make great targets for new antibiotics.

Research spearheaded by Breaker has opened a window back in time, offering a tantalizing glimpse at just how RNA organisms may have achieved such complex environmental surveillance. He has found sequences of RNA that control gene expression by binding vital nutrients and switching on or off genes involved in producing or transporting those nutrients.

Following a tradition that molecules involving RNA begin with the word ribo—as in ribosome—Breaker dubbed these RNA sequences riboswitches. "The name didn't impress one of the reviewers of our first paper," Breaker laughs. "He said it sounded like something that came from the back of a cereal box." But the name stuck and these snippets of antiquity have proven useful to scientists exploring evolution.

Breaker, however, is most recently interested in targeting certain riboswitches in the modern world to develop new types of antibiotics against bacterial scourges like salmonella and anthrax.

To hear Breaker tell it, the entire field of riboswitches began with an intellectual exercise. He decided to engineer RNA sensors in the lab to demonstrate that components of the RNA World could monitor RNA's environment. As a chemist, he wanted to understand the chemical limitations of RNA, figuring it must be capable of doing more than simply folding and catalyzing the cleavage reactions that Yale University's Sidney Altman and University of Colorado researcher (and now HHMI president) Thomas R. Cech described in winning the 1989 Nobel Prize in Chemistry.

"I wanted to test the RNA World hypothesis in a small way," Breaker says. "If we had failed to create RNA sensors, that would have struck a significant blow against the RNA World hypothesis."

He built on the work of HHMI investigator Jack W. Szostak, at the Massachusetts General Hospital, and Larry Gold, at the University of Colorado, who independently discovered that short RNAs could form structures capable of binding molecules such as vitamins and amino acids. Szostak dubbed these RNAs "aptamers," and he and others subjected them to evolution in a test tube by selecting only those RNAs that were exceptionally good at binding a target molecule.

Breaker engineered his RNA sensors to include an aptamer that bound a target molecule, like a vitamin or drug, followed by sequences of RNA that folded into a structure capable of cleaving the RNA strand at a specific location. The cleavage structure formed only if the aptamer section bound the target molecule. Once the metabolite was bound, Breaker could watch the RNA cut itself in two: the RNA truly sensed its environment and took action as a result.

Photo: Michelle McLaughlin / AP, © HHMI

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