PAGE 5 OF 6
The application of riboswitches to human health does not necessarily depend on whether humans have them. More than a dozen bacteria that are dangerous to humans rely on riboswitches, which offers "a real opportunity to specifically target bacterial processes," Breaker says.
He believes the capacity of riboswitches to control gene expression by monitoring nutrient availability could provide desperately needed targets for developing antibiotics. Although bacteria have a prodigious talent for replicating themselves, they still struggle to survive in a nutrient-poor environment. Drugs that mimic vital metabolites could take advantage of that fact. Breaker has cofounded a company called BioRelix to pursue this technology.
"Drugs targeted at unique and essential riboswitches could trick microorganisms into believing that they are swimming in nutrients when they are actually starving for them," says Breaker, who described in the January 2007 issue of Nature Chemical Biology that several antibacterial compounds, which never became drugs for humans, appear to target lysine riboswitches in anthrax and other bacteria. He also believes that designing metabolite mimics that target only riboswitches presents an opportunity to ameliorate adverse drug interactions.
Breaker speculates that, if bacteria were to develop resistance to the metabolite mimics, they wouldn't have much of a survival advantage because they would continue to produce unnecessary proteins, exhausting resources. For example, Tina Henkin at Ohio State University discovered a mutation that deregulates the riboswitch-regulated SAM synthetase gene, leaving Bacillus subtilis struggling to grow in laboratory growth media.
Still unclear is whether riboswitches are actual relics of the RNA World. To date, the closest living descendant of that world is the ribosome—a protein-enrobed RNA machine that translates mRNA into protein. Scientists speculate that the ribosome marks the place where RNA ceded its supremacy to more stable and efficient molecules. Riboswitches could be one step further back in evolution.
"It is very tempting to speculate that at least some riboswitches are ancient relics from the RNA World," Breaker says. "Some riboswitch classes sense metabolites that certainly were present in the last common ancestor of all modern cells, and these riboswitches are preserved with very little variation in most bacteria."
Gelfand, who is using riboswitches to study evolution, agrees noting that "the riboswitches that are present in diverse bacteria are likely very old." That's not to say that all riboswitches are ancient. Gelfand and Breaker posit that a number of riboswitches may have emerged much later than the RNA World. "This doesn't contradict the hypothesis of ancient origin of some riboswitches," Gelfand says. "Rather it demonstrates that the process of their creation continues."
From his vantage point in the modern world, Breaker sees riboswitches as good proof of the RNA World hypothesis. Even though a self-replicating RNA would offer ultimate proof of the RNA World, Breaker notes, "All you have to do is crack open a modern cell and see how common these RNA elements are and everything screams RNA World."