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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: Twitter: Dereklowe

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August 12, 2004

A Week in the Life

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Posted by Derek

I have a weird job. I feel safe in saying that, not least because I'm supposed to discover a drug that can be sold to sick customers, and I haven't even come close to doing that in fifteen years of work. (No, it's not just me.) Another thing that makes me sure that my line of work is abnormal is that nothing I've ever worked on has ever quite gone the way I thought it was going to.

For instance: we make a compound, and it works in the first assay - it binds tightly to the protein target. Then it works in living cells, so we make more of it and we put it into mice. And it works there - not wonderfully, not really good enough yet, but enough to show that we're on the right track. So we go back and start changing the structure of the compound and making new analogs, which is the whole point of a medicinal chemist's job. You try to find something better.

Change a group over on this side of the molecule: dead. OK, be that way, we'll change it the other way around. . .well, the activity is back to where we started, but no better. Hmm - try this part over on the other side of the ring. Hey, it works! Ten times as active as the first compound! Let's put it into cells! And. . .nothing. Dead. Corn starch would be more active. No way to find out why. Back to the drawing board.

OK, let's try doing this change at the same time as we switch this part over here (keep in mind, this stuff doesn't happen instantaneously, these are days or weeks spent the lab for each of these bolts of inspiration). . .hey! Back to great activity! Time for the cell assay again. . .this time it works. Make more of it, put it into that mouse assay, and - nothing. Nothing at all. Exactly the same as giving them club soda. Now what?

I'm not exaggerating. I fully expect some of my med-chem colleagues from around the industry to back me up in the comments section below: this is what our days and weeks look like around here. This is why I roll my eyes when I come across moonbat conspiracy theories about how the drug companies have all these secret cures that we're sitting on, see. . .hah. Secret cures, my colon. Some days we go home unsure if we're capable of boiling an egg.

Comments (6) + TrackBacks (0) | Category: Life in the Drug Labs


1. William Knight on August 13, 2004 2:21 AM writes...

Maybe you are at a particularly discouraging point right now, but it makes me wonder, if things are really that bad, perhaps the drug development industry should pull back some and focus more on research and fundamentals.

I'm not suggesting that you duplicate the pure research of academia, but maybe you and others in the field should have the freedom and resources to set up longer-term experiments and analyses to understand why these approaches didn't work.

Of course, you could spend 15 more years trying to understand why one particular approach did or did not work, but if it led to significant new insights into what's really going on in the cell, maybe that's better than 15 more years of frustrating trial and error.

Anyhow, I wish you luck.

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2. Derek Lowe on August 13, 2004 9:25 AM writes...

You know, reading over my post, it sounds like I'm really ticked off and discouraged, but that's not how I meant it to sound. That's just how things work in research - this isn't any kind of particular difficult stretch or anything, just the normal run of events.

Some of the long-term research you mention does go on in the industry, because we'd like to smooth things out as much as possible. But we're far from being able to solve most of what slows us down.

So far, basic research into these things has, with great effort and expenditure, peeled back a layer of onionskin to expose a further layer of complexity. One way of looking at it is that this state of affairs sure keeps me gainfully employed!

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3. The Novice Chemist on August 13, 2004 10:06 AM writes...

Does anyone know if the "success rate" of medicinal chemists has gone up, down or stayed the same over time? It would seem like there is SO many more tools now, but of course, there are so many more hoops (scientific and regulatory), too.

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4. Linkmeister on August 13, 2004 3:04 PM writes...

I don't know if you've ever tried computer programming, but you've described the process I used to go through when getting paid to do that pretty well, particularly this sentence:

"Change a group over on this side of the molecule: dead. OK, be that way, we'll change it the other way around. . .well, the activity is back to where we started, but no better."

Substitute "this section of code" for "group."

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5. Maynard Handley on August 14, 2004 10:12 PM writes...

So Derek, how far are we from doing at least a substantial fraction of this stuff in silico? I've read that some amazing computational models of full cells now exist, but even so, this author didn't expect that drugs could be usefully tested computationally until 2030 which seems awfully far out.
(Note that I'm not assuming that computing replaces human testing, simply that it weeds out losers ASAP.)

Does this match your experience? Is the holdup that we simply don't know enough to do this yet, or is it based on a simple Moore's law attraction --- to do this we need x Zettaflops, and that will be available on this date? Both ways, making this sort of prediction out to 25 yrs seems awfully foolhardy, but is that simply shorthand for saying "Yeah, I can't think of a reason why this wouldn't work, but it's so far from where we are now that it's not even worth thinking about"?

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6. BJK on August 21, 2004 2:45 PM writes...

Despite your sense of frustration, the thing that you can cite with pride is the fact that you are fully engaged in the chemistry of your lab on a daily basis, that you regard basic research as fundamentally important. I wonder what it means for the long-term success of drug discovery when companies reward lab heads not for original, novel research, but for, say, finding loopholes in patents that would (legally) permit a group to simply copy some other firm's work. (I've heard that this is actually occurring in companies with research budgets of hundreds of millions of dollars). I also wonder whether the industry is effectively employing their most valuable resource (the enormous combined knowledge capital of their staff) by encouraging scientists, who have trained years in the most prestigeous research groups, to leave lab work behind, in some cases only three years into a research "career". I wonder what effect that kind of environment has on promoting a research culture of original work and risk-taking? Maybe this is what accounts for big-pharma's 'research strategy' of seeking out small biotech firms in the hope of benefitting from their novel programs through co-licensing agreements; it is an admission that despite great resources, their own programs have failed.

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