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More on Warp Drive Bio and Cryptic Natural Products

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?

7 comments on “More on Warp Drive Bio and Cryptic Natural Products”

  1. Helical Investor says:

    Cryptic Natural Products?
    So now big pharma will start searching for bigfoot and the Loch Ness monster?

  2. JoJo says:

    This has been a focus of academic researchers, like Jon Clardy, for some time, so this is not new. To be successful, a start-up would need a specific strategy to identify actives. If it is just HTS coupled with some technology to produce the cryptics, it seems a long shot to have success. Seems like a lot of attention is being brought to this venture, perhaps more than promise or accomplishment merits at this point.

  3. Vaudaux says:

    Also looking for cryptic natural products is Novobiotic Pharmaceuticals, started by Kim Lewis and Slava Epstein. They are specifically interested in finding novel antibacterial agents. The approach is not genomic – rather they screen environmental samples for antibacterial activity against a reporter strain (could be staph, E coli, etc). The idea is to keep potential producers of antibacterial compounds in the same environment in which they would normally produce those compounds. I remember some interesting early data from several years ago, suggesting that they were indeed detecting active compounds produced by previously uncultivated organisms. Haven’t heard much recently, but the company is still around.

  4. paperclip says:

    I doubt anyone, if given a random list of active genes and cryptic genes, could distinguish which ones are switched on and which ones are turned off in a laboratory organism. There doesn’t seem to be any fundamental quality about the “off” genes that distinguish them from the “on” genes. I won’t bet my bank account that these ventures will succeed, but given the good track record of the “on” genes leading to bioactive compounds (and the recent track record of researchers demonstrating bioactivity in the “we managed to switch them on” genes), I certainly won’t bet my bank account that they will fail.

  5. insilicoconsulting says:

    We did this kind of work on unculturable bacteria around the late 1990’s to early 2000. We also compares 16s rDna of soil bacteria and found many unknowns. These were then cultured using very unconventional microbiological methods and their sexreted products were screened for cancer etc. We had some limited success, but ran out of funding as india was a backwater for this kind of research.

  6. clockwork says:

    For me, the most interesting part of the article was the reality check being written by a warp drive board member:
    ‘Those watching the field might wonder if the research community’s enthusiasm is grounded in reality. Whenever Verdine waxes too rhapsodically about the science his company is pursuing, he’s brought back to Earth by one of Warp Drive’s board members, Greylock venture capitalist Bill Helman. According to Verdine, he likes to ask, “Yeah, Greg, but where are the drugs?’

  7. Dr. Manhattan says:

    Another approach to this area was SelectX, a novel antimicrobial company in Worcester, Ma. They had probes for known bioactives (macrolides, aminoglycosides, carbapenems) and recovered DNA from the soil, used oligonucleotide probes to know genes in the pathways, and fished out genes coding for new variants of these compounds. These were then cloned into Streptomyces vectors, transformed into Streptomyces and screened for expression activity. The did find novel variants of compounds, but not different enough to interest Big Pharma. So, I would agree that this is not totally virgin territory; the approach might be somewhat different, but it has been tried in the past.

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