At C&E News, Lisa Jarvis has an excellent writeup on Warp Drive Bio and the whole idea of "cryptic natural products" (last blogged on here). As the piece makes clear, not everyone even is buying into the idea that there's a lot of useful-but-little-expressed natural product chemical matter out there, but since there could be, I'm glad that someone's looking.
Yet not everyone looked at the abundant gene clusters and saw a sea of drug candidates. The biosynthetic pathways defined by these genes are turned off most of the time. That inactivity caused skeptics to wonder how genome miners could be so sure they carried the recipes for medicinally important molecules.
Researchers pursuing genomics-based natural products say the answer lies in evolution and the environment. “These pathways are huge,” says Gregory L. Challis, a professor of chemical biology at the University of Warwick, in Coventry, England. With secondary metabolites encoded by as many as 150 kilobases of DNA, a bacterium would have to expend enormous amounts of energy to make each one.
Because they use so much energy, these pathways are turned on only when absolutely necessary. Traditional “grind and find” natural products discovery means taking bacteria out of their natural habitat—the complex communities where they communicate and compete for resources—and growing each strain in isolation. In this artificial setting, bacteria have no reason to expend energy to make anything other than what they need to survive.
“I absolutely, firmly believe that these compounds have a strong role to play in the environment in which these organisms live,” says Challis, who also continues to pursue traditional approaches to natural products. “Of course, not all bioactivities will be relevant to human medicine and agriculture, but many of them will be.”
The article also mentions that Novartis is working in this area, which I hadn't realized, as well as a couple of nonprofit groups. If there's something there, at any kind of reasonable hit rate, presumably one of these teams will find it?