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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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July 16, 2006

The Future is Unwritten

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Posted by Derek

What I would miss, if I had to go into another line of work besides research, would be the surprises. I'd miss other things, but that might be one of the first. At this point, I don't know what I'd do with a job where I always knew what was coming. I should clarify that - I'm well aware that if, say, I was the head chef in a restaurant, that I wouldn't know what order was coming in next, or how many we were going to be hit with at once. But people would mostly order things that were on the menu, wouldn't they? No one would come in and demand stir-fried sargasso on a bed of wood chips or a coelocanth en croute.

But that level of craziness can be achieved in a good research project. What I enjoy is the occasional result that just makes no sense at all, that reminds us that we really don't know what we're doing. This happens all the time in chemistry - it's a very inexperienced organic chemist who thinks that everything's under control. There's no reaction so reliable that it can't turn on you under the right (wrong) conditions, and as the process chemists know, there aren't many that can't be tamed if you're willing to spend enough time and money. To partially make up for those, there are also times when something works wonderfully even though you gave it almost no chance.

If the chemistry has random elements, then you can imagine how things start to act once you move toward living systems. The dosing behavior of a new compound is, almost without fail, impossible to predict, and a stone solid fortune is waiting for anyone who can say different and prove it. Tiny changes to a molecule's structure will suddenly make its blood levels soar (or flatline completely), and if we knew that that was going to happen, we wouldn't have run the experiments, would we?

Toxicology is, without question, the poster child for unexpected results. As I've said before, if you don't hold your breath when your drug goes in for tox testing, you haven't been doing this very long. I had a project once where adding a single methyl group to the a molecule changed it from being an infallible overnight rodent-killer to something that could be given for two weeks straight at ten times the normal dose. Clearly we managed to slip out of whatever protein target it was dealing death, but these things can't be modeled or predicted.

What would I do with myself if I knew how these things were going to come out? What scientist could stand it? I can picture a nightmare world of time-to-make-the-donuts folks in lab coats, shuffling in to press the buttons and turn the cranks to produce yet another winner. It'd be like watching a baseball game where every batter hit a home run. Medicinal chemistry's not going to get there in my lifetime, but if it ever threatened to, I'd pack up and move off to the frontier, wherever in the scientific world that might be by then, to the place where I could once again look at my results and say "Well, why the @#$! did that happen"?

Comments (12) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Cryptic Ned on July 16, 2006 10:24 PM writes...

This post has somewhat inspired me; as a beginning graduate student who's spent 14 months in a lab where things just keep making less and less sense, it's nice to know that that happens everywhere. If only now I could imagine a way that things would start making sense.

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2. Abel Pharmboy on July 17, 2006 2:55 AM writes...

In trying to describe to colleagues why I have a BS in toxicology and a PhD in pharmacology, the tox part gets blown-off by most folks as "just the high dose range of pharmacology." I'd argue that toxicology is far more mysterious and less predictive - and those who are working on tools to take the mystery out of pharmaceutical toxicology have my admiration as a working pharmacologist.

Good luck - and be sure to breathe whenever possible.

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3. Peter Ellis on July 17, 2006 3:43 AM writes...

I had a project once where adding a single methyl group to the a molecule changed it from being an infallible overnight rodent-killer to something that could be given for two weeks straight at ten times the normal dose.

... which raises the worry that, oooh, maybe the death target is a normal polymorphism that'll be present at substantial levels in the population.

Nothing like a drug candidate that *might* unpredictably kill 5% of the users, eh?

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4. Kay on July 17, 2006 5:16 AM writes...

Thank you for the honesty. I don't find very many tox or ADME folks who are willing to be so candid regarding their work, however.

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5. Still Scared of Dinosaurs on July 17, 2006 5:57 AM writes...

Isaac Asimov dealt with this in the essay "The Eureka Effect" going so far as to say that listening to your results when they don't make sense is the essence of scientific discovery. Or something like that.
One suspects that checking that you really did everything correctly and replicating the results plays a part also.
Per a post here some months back, the trick is making the right decision as to whether the odd results are pointing to a discovery worth making.

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6. tom bartlett on July 17, 2006 7:55 AM writes...

My thrill is looking at an SAR table, thinking til the smoke comes out of my ears and deciding exactly what the most logical next-analog-to make is. And sometimes being right....

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7. Grubbs the cat on July 17, 2006 8:09 AM writes...

Derek, does the management of your company share your passion for the unexpected and serendipity (by the way: this keeps me going as well)? Or would it much rather make everybody believe that drug discovery is totaly predictable, plannable and under control (a phenomenon which I am sure is most common in a lot of pharma companies)? I sometimes miss the commitment to scientific crazyness in a world of project managers, deadlines and bureaucrats...

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8. RKN on July 17, 2006 8:30 AM writes...

Just a point: bafflement at outcome is not unique to pharmaceutical research or even research in general. There are a number of professional fields where the results of your work might keep you satisfyingly stymied.

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9. John Johnson on July 17, 2006 10:44 AM writes...

Grubbs,

It's my guess that the management of the Wonder Drug Factory will file this under "risk management" and assume that the average over all the individual events will result in something profitable.

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10. chemdork123 on July 17, 2006 11:47 AM writes...

"The most exciting phrase to hear in science, the one that heralds new discoveries, is not 'Eureka! I found it!,' but rather 'hmmm... that's funny...'" - Issac Asimov

SSOD, I think that might be the quote you were referring to. I don't remember where I got that from, but I definitely agree.

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11. Pharmachick on July 18, 2006 9:59 PM writes...

Where Pharm meets Tox - I love it.

I like to think of myself as DM/PK but 1/2 the scientists I know think I'm a toxicologist errmm...EC50 yes, therapeutic index check, NOAEL ????

In terms of "hmmm, thats funny" ha ha: try allosteric co-operativity in enzyme action or trying to build a predictive PBPK model, or even, dare I say it; something as "simple" as allosteric scaling (ummm anyone up for a 2/3 or 3/4 argument?)

Nope, we have no idea what we're doing but it sure is cool when it works.

Permalink to Comment

12. Pharmachick on July 18, 2006 10:04 PM writes...

Errm thats alloMETRIC scaling - time to go home!

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