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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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July 11, 2013

More From Warp Drive Bio (And Less From Aileron?)

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Posted by Derek

There hasn't been much news about Warp Drive Bio since their founding. And that founding was a bit of an unusual event all by itself, since the company was born with a Sanofi deal already in place (and an agreement for them to buy the company if targets were met). But now things seem to be happening. Greg Verdine, a founder, has announced that he's taking a three-year leave of absence from Harvard to become the company's CEO. They've also brought in some other big names, such as Julian Adams (Millennium/Infinity) to be on the board of directors.

The company has a very interesting research program: they're hoping to coax out cryptic natural products from bacteria and the like, molecules that aren't being found in regular screening efforts because the genes used in their biosynthetic pathways are rarely activated. Warp Drive's plan is to sequence heaps of prokaryotes, identify the biosynthesis genes, and activate them to produce rare and unusual natural products as drug candidates. (I'm reminded of this recent work on forcing fungi to produce odd products by messing with their epigenetic enzymes, although I'm not sure if that's what Warp Drive has in mind specifically). And the first part of that plan is what the company has been occupying itself with over the last few months:

“These are probably really just better molecules, and always were better,” he says. “The problems were that they took too long to discover and that one was often rediscovering the same things over and over again.”

Verdine explains the reason this happened is because many of the novel genes in the bacteria aren’t expressed, and remain “dark,” or turned off, and thus can’t be seen. By sequencing the microbes’ genetic material, however, Warp Drive can illuminate them, and find the roadmap needed to make a number of drugs.

“They’re there, hiding in plain sight,” Verdine says.

Over the past year and a half, Warp Drive has sequenced the entire genomes of more than 50,000 bacteria, most of which come from dirt. That library represents the largest collection of such data in existence, according to Verdine.

The entire genomes of 50,000 bacteria? I can well believe that this is the record. That is a lot of data, even considering that bacterial genomes don't run that large. My guess is that the rate-limiting step in all this is going to be a haystack problem. There are just so many things that one could potentially work on - how do you sort them out? Masses of funky natural product pathways (whose workings may not be transparent), producing masses of funky natural products, of unknown function: there's a lot to keep people busy here. But if there really is a dark-matter universe of natural products, it really could be worth exploring - the usual one certainly has been a good thing over the years, although (as noted above) it's been suffering from diminishing returns for a while.

But there's something else I wondered about when Warp Drive was founded: Verdine himself has been involved in founding several other companies, and there's another one going right here in Cambridge: Aileron Therapeutics, the flagship of the stapled-peptide business (an interesting and sometimes controversial field). How are they doing? They recently got their first compound through Phase I, after raising more money for that effort last year.

The thing is, I've heard from more than one person recently that all isn't well over there, that they're cutting back research. I don't know if that's the circle-the-wagons phase that many small companies go through when they're trying to take their first compound through the clinic, or a sign of something deeper. Anyone with knowledge, feel free to add it in the comments section. . .

Update: Prof. Verdine emails me to note that he's officially parted ways with Aileron since 2010, to avoid conflicts of interest with his other venture capital work. His lab has continued to investigate stapled peptides on their own, though.

Comments (14) + TrackBacks (0) | Category: Biological News | Business and Markets | Natural Products


1. JAB on July 11, 2013 8:20 AM writes...

Yeah, they've got a lot of sequence and can find the biosynthetic genes, perhaps even predict what they might make, and weed out known compound genes. Now, how are they going to get a large fraction of what's left to express, and THEN what are they going to screen the product against? Seems like a really long shot bet to me.

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2. jrftzgb on July 11, 2013 8:58 AM writes...

I agree with #1, but I'd add how are they going to get enough of the funky natural product produced. Getting enough natural product from a fermentation to screen a compound can be a heck of a chore as well.

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3. Hap on July 11, 2013 9:15 AM writes...

It seems interesting, but I wonder if there's a reason why those biosynthetic pathways aren't normally expressed - if it's just because the conditions under which their expression makes sense aren't in place, if they are rough drafts of previous NPs that don't work as well as the expressed ones (or which aren't as stable, or something else) and whose genes haven't been discarded, or if there's some other reason.

I'm glad someone's working on NPs and perhaps finding some interesting new ones. Perhaps this is the kind of long shot pharma should be taking. It does look like a really long shot, though.

What do you do if your advisor goes away for three years? Even (potentially) worse, what if you went there to work for him only to find out he's not there (UIUC with Hartwig, MIT with Jacobsen and Nocera, etc., etc.)? I'm sure if he had some inkling, he might have not encouraged people to come if they wanted to work for him, but that's not a guarantee.

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4. Anon on July 11, 2013 9:31 AM writes...

What is the difference between a known protein [produced by bacteria], a known protein that you have modified 50,000 ways (making the naive assumption that them sequencing 50,000 bacteria will yield them 50,000 new candidates), and the proteins that this company plans to find?
Is that difference worth 500 million $ (or whatever they are hoping to get out of this)?

Even if I ran a 10billion$ R&D unit somewhere, I would be very skeptical of paying a significant amount of money to access their new library.

On a separate note, what is the best way to deliver protein therapeutics?

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5. barry on July 11, 2013 9:38 AM writes...

Depressingly, it would scarcely be news were Aileron cutting back research now that one cmpd is in Phase One. To many on the business side, this is an expression of faith in that one compound, that it will get all the way through Clinicals and FDA approval and produce revenue on the market. That's the sort of gamble that doesn't appeal to scientists. But Businessfolk do it again and again.

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6. Hernán Cortés, Ph.D. on July 11, 2013 10:00 AM writes...

@5: That's right, to show 'em who's boss, let's burn the ships!

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7. Hap on July 11, 2013 10:01 AM writes...

Why stop gambling other people's money when it keeps working for management and the companies selling the stock and running the mergers and liquidation - their investors and employees get hosed, but you need to break some eggs to make other people's omelettes. The fact that their faith is verifiably blind (based on the conversion of P1 candidates to marketable drugs) is irrelevant. Until they stop making money for the people in charge, the gambles will continue to be made.

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8. Ros on July 11, 2013 10:09 AM writes...

4. Anon: They are not claiming to modify one protein 50,000 ways, they are claiming to have 50,000 bacterial species that may only expressed under particular conditions other than vegetative growth. 1 bacterial species can have as few as 1000 or as many as 10,000 *known* proteins; Warp Drive is claiming there are likely several per bacterial species they've collected which are not currently known. That's why the exhaustive sequencing, because you wouldn't find them with the usual proteomics stuff.

How many modifications you can make to a single protein depends on how large that protein is. Take Cry from B. thuringiensis--1,178 aas, each of which can be modified 20+ (23 if you include the Se-containing aas) ways can easily be modified 2.6 x 10^61 ways. 50,000 modifications wouldn't come close to being useful information. And they aren't trying to mutate the native proteins at this point, they are more like going on a fishing expedition with a trawler.

There's no point in trying to make, say, a cytochrome into an exotoxin or a chaperone into a ferritin, which is what you are describing.

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9. littlegreenpills on July 11, 2013 10:11 AM writes...

I believe their research plan is actually a fairly well established branch of natural products chemistry. They will most likely be looking for NRPS and PKS gene clusters, with plans to place the interesting ones in E. coli for heterologous expression. The gene clusters can be compared to known ones to determine how closely related they are and thus if they are interesting. In some cases, knowledge of the sequence can even predict the final compound.

The theory usually given for why the compounds are not normally produced in culture is that microbes do not normally grown in culture. They will likely face some issues in obtaining useful levels from the heterologous expression system, but that can usually be fixed.

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10. hn on July 12, 2013 2:06 PM writes...

It's funny how you can't get grant funding to go on a fishing expedition but you can get big VC/pharma money.

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11. anoninboston on July 12, 2013 4:21 PM writes...

Regarding Aileron--yes, they recently went through cutbacks--about 50% of the staff were thrown off the back of the sleigh (that's about 15 people).

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12. lynn on July 12, 2013 11:02 PM writes...

#4 and #8 - They are not going after proteins, they are going after small molecule natural products produced by sets of genes [usually linked in operons].

Similar approaches have been undertaken - to little avail. I think the concept that these dark operons are not expressed under "standard" conditions has not been proven. In classical NP fermentation, isolates were grown under many conditions, media, time, temp, starvation, addition of inducers, etc - and there might be only one condition that worked. Have all these been tried with the 50,000 sequenced isolates? Several companies tried cloning operons from "soil DNA" into suitable hosts, but the outcome was an unacceptably low yield. I worry more about the questions #1 and #2 have brought up - how do they plan to express these operons after they've selected them [in some way]? En masse? One-by-one? And how will they be screened? I love natural products - but I favor the use of better screens to find novelty...since I'm a screener.

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13. Dr. Manhattan on July 13, 2013 4:48 PM writes...

"Similar approaches have been undertaken - to little avail. I think the concept that these dark operons are not expressed under "standard" conditions has not been proven."

Totally agree with the above (and Lynn should know from her time at Merck!). One such company several years ago was SelectX, which took the strategy of cloning DNA from the soil into Streptomyces expression vectors. Some interesting compounds emerged, but not enough to keep the company afloat.

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14. eswar on July 25, 2013 8:50 AM writes...

Since there is so much discussion about PKS and NRPS biosynthetic gene clusters in heterologous hosts I thought I should bring to the attention of this group, the exact way it is done. The vector of choice for heterologous expression of PKS/NRPS small molecules is the pESAC shuttle vector (developed by Naicons, Italy) which allows construction of a BAC library containing thousands of clones, with insert sizes in each clone ranging from 100-150 kb (enough to cover an entire biosynthetic gene cluster) in E.coli. The expression of individual BAC clones is done in a good expression strain of Streptomyces.

Please read this paper by Mervyn Bibb published on July 11, 2013 as to how it is done.

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