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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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: derekb.lowe@gmail.com Twitter: Dereklowe

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April 22, 2004

The Vapor Trail I Referred To

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Posted by Derek

I mentioned the other day that not everything in that Stuart Schreiber interview sounded sane to me, (although more of it does than I'd expected). The interviewer, Joanna Owens, asks him to expand on a statement he made about ten years ago: famously (in some circles, at any rate) Schreiber said that he wanted to - and thought that eventually he could - produce a small-molecule partner for every human gene.

A worthy goal, to be sure, but a honking big one, too. To his credit, though, Schreiber isn't making light of it:

". . .that challenge understates what we really want to do, which is to use small molecules to modulate the individual function(s) of multifunctional proteins, activating or inactivating individual functions as necessary. This is one of the differences between small molecules, for example, and the knockout of knowckdown technologies, where you inactivate everything to do with the protein of interest."

Note how things have appropriately expanded. There are a lot more proteins than there are genes (a lot more, given the surprisingly lowball figure for the total size of the human genome), and the number of protein activities is several times larger than that. He's absolutely right that this figure is the real bottom line. But here comes that Muhammed Ali side of his personality:

"Small molecules allow you to gain control rapidly, and can be delivered simply but, most importantly, we've shown that we can discover molecules that only modulate one of several functions of a single protein. . .(the scientific community has) identified 5000 out of the required 500,000 small molecules, which is similar to where the Human Genome Project was in year two of its 12-year journey. That might be a useful calibration - optimistically, we're ten years away."

Midway through that paragraph is where I start pulling back on a set of imaginary reins. Whoa up, there, Schreibster! Let's take the assumptions in order:

Small molecules allow you to gain control rapidly. . . Compared to transcription-level technology, this is largely correct. But the effects of small-molecule treatment often take a while to make themselves known, for a variety of reasons that we don't fully understand. The problem's particularly acute in larger systems - look at how long it takes for many CNS drugs to have any meaningful clinical effect. And these complex systems have other weird aspects, which make the phrase "gain control" seem a bit too confident. U-shaped dose-response relationships are common. Look at what you find in toxicology, where you see threshold effects and even hormesis, with large and small doses of the same substance showing opposite effects.

. . .and can be delivered simply. . . Well, when they can be delivered at all, I guess. But there more of them that come bouncing back at us than we'd like. In every drug research program I've been involved with, there are plenty of reasonable-looking compounds that hit the molecular target hard, but then don't perform in the cellular assay. You can come up with a lot of hand-waving rationales: perhaps the main series of compounds is riding in on some sort of active transport and these outliers can't, or they're getting actively pumped back out of the cell, or they hit some other sinkhole binding site that the others escape, and so on. Figuring out what's going on is an entire research project in itself, and rarely undertaken. Every time someone tells me that drug delivery is simple, I can feel my hair begin to frizz.

. . .we've shown that we can discover molecules that only modulate one of several functions of a single protein. . . True enough, and a very interesting accomplishment. But the generality of it is, to put the matter gently, unproven. It would not surprise me at all if there turn out to be many proteins whose functions can't be independently inhibited. The act of binding a small molecule to alter one of the functions would cause the other ones to change. And a bigger problem will be distinguishing these effects from the consequences of actually taking out that first function cleanly: how will you know when you've altered the system?

. . .which is similar to where the Human Genome Project was in year two. . . True, but that and forty dollars will get you an Aldrich Chemical can opener. The comparison isn't just optimistic - it's crazy. The problems that the genome sequencers faced were engineering problems - difficult, tricky, infuriating ones, but with solutions that were absolutely within the realm of possibility. Faster machines were made, with more computing power, and new techniques were applied to make use of them.

But as I've been saying, I'm not sure that the Maximum Inhibitor Library that Schreiber's talking about is even possible at all. Don't get me wrong - I hope that it is. We'll learn so much biochemistry that our heads will hurt. But its feasibility is very much open to question, to many questions, and we won't even begin to know the answers until we've put in a lot more work.

Comments (5) + TrackBacks (0) | Category: Biological News | Drug Assays | Drug Development


COMMENTS

1. zp2k on April 23, 2004 1:03 AM writes...

While it's hard to defend Schreiberian hyperbole too vigorously, the first two of the points you object to are probably referring mainly to the use of small molecules in cultured cells.

Cockroaches and zebrafish notwithstanding, the majority of the work that's been done in the Schreiber lab and at ICG (and its earlier incarnation, the Institute for Chemistry and Cell Biology) has been in tissue culture and yeast, where the technical advantages he names are self-evident. This difference was essential to one of the arguments used early in the history of ICCB, which was that big pharma was presumed to have troves of stillbirthed drugs that remain hidden for IP reasons but would be very useful to cell biologists, who don't care about things like hepatic toxicity or pharmacokinetics.

I'm pretty sure this difference underlies the thought that you cited earlier about using screening to 'interrogate biology' rather than for direct drug discovery.

On the other hand, you didn't even mention the questions raised by the use on his webpage of a black and white portrait in three-quarters profile...

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2. Derek Lowe on April 23, 2004 7:26 AM writes...

I'll take the point for my first objection, although odd dose-response relationships happen in cell culture too. Since I use some in vivo examples making this objection, I should have made clear that I switched gears for the next one.

Because as for my drug-delivery point, I actually had cultured cells in mind; those are the cellular assays I referred to. They're the ones that show all sorts of weird behavior, with very similar compounds getting in or seemingly bouncing right back out. The PK problems are smaller, but they're real. In vivo drug delivery is, of course, even crazier.

The idea that there are a lot of useful compounds at that level, though, which never make it far in vivo is certainly correct. We just shipped one from my lab off to an academic collaborator the other day.

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3. zp2k on April 23, 2004 9:58 AM writes...

Sorry, I guess you did refer to cellular assays very clearly.

My response would be that this is why there's a large emphasis on cell-based primary screening at ICCB et al. While it's not clear that this model works so well in the absence of efficient target ID strategies, it's a direct response to the bottlenecks that arise when in vitro primary assays feed cell-based secondary assays.

Your point about weird dose-response in tissue culture is of course true, although it's not clear whether this is a statement about specificity, interesting partial penetrance behavior, or the fact that drug inhibition is really more analogous to overexpression of a dominant negative construct than to genetic deletion.

But I can cite a complementary set of problems inherent to genetic perturbations. We're never going to be able to modulate a given protein activities just by turning a knob, and I don't think that's the standard that the "gain control" language was intended to suggest.

Again, I'm not really sure why I'm defending any thoughts expressed in the same breath as a claim that we're ten years away from anything...

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4. William Knight on April 23, 2004 12:15 PM writes...

Well, they said the Genome Project was a crazy idea too, at first.

While I think your skepticism and specific objections are well-founded, it could turn out to be easier than we think because the early information from a project like this could help to control and untangle the weird and unknown stuff.

In other words, the project might have a kind of positive feedback where the identificaton of more small molecule controls just makes it easier and easier to design assays to disentangle the remaining small molecule - protein interactions.

I don't know how likely it is that things will turn out that way, but maybe Schrieber is counting on something like that to happen.

Permalink to Comment

5. Charlie Murtaugh on April 23, 2004 10:13 PM writes...

Ah, Derek, I clearly haven't been checking your blog regularly enough, because this one almost flew under my radar. Keep it up, man! I'm almost ready to come out of the closet on this issue myself -- just six months or so 'til I'm out of swatting range, career-wise...

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