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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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May 12, 2008

Explaining It All

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Posted by Derek

One of the reasons I starting this blog was that many people I met were interested in my job. Very few of them had ever talked to someone who discovered new medicines for a living, and a surprising number of them (well, surprising to me) had no idea of where medicines came from in the first place.

Talking to such folks (interested, but with no particular training in science) gave me some good practice in explaining the work. It helps that the kind of work I do is actually fairly easy to explain. There are a lot of details – as with any branch of science, the closer you look, the more you see – but I haven’t run across any key concepts that can’t be communicated in plain language. (It also helps that medicinal chemistry, as it’s actually practiced, uses an embarrassingly small amount of actual mathematics).

The toughest things to deal with are the parts of the field that actually touch on physics and math. My vote for the hardest everyday phenomenon to explain at anything past a superficial level is magnetism. So that means that explaining how an NMR machine works is not trivial. At least, explaining it in a way that a listener has a chance of understanding you isn’t – a while ago, I took up the challenge to try to explain it here in lay terms, and I haven’t done it yet, for good reason.

Explaining statistical significance is doable, but going much past that (principal components, the difference between Bayesian and frequentist approaches) takes some real care. And, of course, when you open the hood on chemical reactivity, the mechanisms of bond-forming and bond-breaking, you quickly find yourself in physics up to your armpits. It’s easier to stipulate, openly or by assumption, that there are such thing as chemical bonds, and that some of them are stronger than others. You don’t want to start answering a question about why one group falls off your drug molecule easier than another one does, only to find yourself fifteen minutes later trying to explain the Pauli exclusion principle. Counterproductive.

But the basics of medicinal chemistry can be sketched out pretty quickly, which makes some of the more curious listeners wonder, after a while, why we aren’t better at it. The best example I can give them is to advance a quick, hand-waving explanation of, for example, how compounds get into cells. Then I point out that that explanation is unnervingly close to the best understanding we have of how compounds get into cells. The same holds for a number of other important processes, way too many of them.

And that's why drug discovery is simultaneously frustrating and fascinating. We know huge numbers of things, great masses of detail that can take years to piece together. And it's not enough. Some of the most important puzzle pieces are still weirdly ill-defined, and there are probably others whose existence we haven't even realized yet. I'd be willing to bet that if you scanned the whole history of pharmaceutical discovery, you'd find people at every point thinking "You know, in any thirty years they should have all this figured out". But the years go by, and they - we - don't. Give it another thirty years, you think?

Comments (13) + TrackBacks (0) | Category: Blog Housekeeping | Life in the Drug Labs


1. S on May 12, 2008 8:51 AM writes...

Touche, Derek. But that being true, there is something so different about being an organic/medicinal chemist; I have often heard colleagues telling people in other fields that " chemists can pick up any new thing, but it is more challenging to teach someone else organic chemistry..". The NMR issue.....totally true!

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2. HelicalZz on May 12, 2008 9:51 AM writes...


You undersell your ability to communicate through writing. It isn't a simple skill and often underappreciated. Should you ever contemplate the thankless and financially disappointing effort to write a book on the topic, I'd buy it.

As for drug discovery / development it will indeed look different 30 years hence, but I don't doubt there will still be substantial challenges. One prediction - it won't be any cheaper.

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3. Daveh on May 12, 2008 10:52 AM writes...

Speaking of explaining and magnetism:

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4. anon on May 12, 2008 11:21 AM writes...

Have a look at, you need to scroll down:-

"54 The Birth of Stochastic Science: Rewriting the History of Medicine

Amioun – Controlled experiment can easily show absence of design in medical research: you compare the results of top-down directed research to randomly generated discoveries. Well, the U.S. government provides us with the perfect experiment for that: the National Cancer Institute that came out of the Nixon “war on cancer” in the early 1970s.

“Despite the Herculean effort and enormous expense, only a few drugs for the treatment of cancer were found through NCI’s centrally directed, targeted program. Over a twenty-year period of screening more than 144,000 plant extracts, representing about 15,000 species, not a single plant-based anticancer drug reached approved status. This failure stands in stark contrast to the discovery in the late 1950s of a major group of plant-derived cancer drugs, the Vinca Alcaloids –a discovery that came about by chance, not through directed research.”

From Happy Accidents: Serendipity in Modern Medical Breakthroughs, by Morton Meyers, a book that just came out. It is a MUST read. Please go buy it. Read it twice, not once. Although the author does not take my drastic “stochastic tinkering” approach, he provides all kind of empirical evidence against the role of design. He does not directly discuss the narrative fallacy(q.v.) and the retrospective distortion (q.v.) but he certainly allows us to rewrite the history of medicine.

We did not realize that cures for cancer had been coming from other brands of research. You search for noncancer drugs and find something you were not looking for (and vice versa). But the interesting constant:

a- The discoverer is almost always treated like an idiot by his colleagues. Meyers describes the vicious side effect of “peer reviewing”.

b- Often people see the result but cannot connect the dots (researchers are autistic in their own way).

c- The members of the guild gives the researcher a hard time for not coming from their union. Pasteur was a chemist not a doctor/biologist. The establishment kept asking him “where is your M.D., monsieur”. Luckily Pasteur had too much confidence to be deterred.

d- Many of the results are initially discovered by an academic researchers who neglects the consequences because it is not his job --he has a script to follow. Or he cannot connect the dots because he is a nerd. Meyers uses Darwin as the ultimate model: the independent gentleman scholar who does not need anyone and can follow a lead when he sees it.

e- It seems to me that discoverers are usually nonnerds. Egomaniacs, perhaps, but certainly of the nonnerd category.

Now it is depressing to have to review the works of the late Roy Porter, a man with remarkable curiosity and a refined intellect, who wrote many charming books on the history of medicine. Does the narrative fallacy cancels everything he did? I hope not. But we urgently need to rewrite the history of medicine without the ex post explanations. Meyers started the process: he provides data for modern medicine since, say, Pasteur. I am more interested in the genesis of the field before the Galenic nerdification."

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5. Rich Apodaca on May 12, 2008 12:58 PM writes...

There certainly are a lot of unconnected dots in drug discovery. You might think that the pharmaceutical industry's understandable emphasis on intellectual property security would be responsible, and it partly is.

But even within individual companies, I suspect that a staggering number of connectable dots go unconnected. Building tools that enable companies to connect those dots could be incredibly revealing - and useful.

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6. Joel on May 12, 2008 2:24 PM writes...

It's always weird for me to discover what of my research (inorganic nanomaterials) makes sense to non-scientists and what doesn't. Even though *I think* most people can understand intuitively the main concepts, they always always always screw up something frustratingly simple- it's silicon, not siliconE, dammit!

There's something also to be said for being able to clearly explain science in plain language without dumbing it down. Non-scientists are actually quite bright, and are usually a lot better at seeing through BS that I give them credit for.

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7. CMC guy on May 12, 2008 2:52 PM writes...

Derek I enjoy your blog and envy your ability to express complex concepts in less technical terms so keep it up..

#4 anon in regards to NCI effort we could (hopefully) be in the 2nd "30 year" window Derek suggests as it helped establish many tools, methods and procedures that are the foundation of majority of current efforts targeting cancers today. This includes awareness that approaches to cancer not a "one size fits all" and need for precise targets/treatments some of which are being now realized. BTW wasn't paclitaxel discovered during this program (and would negate no approval statement)?

Likewise although agree researchers can often get myopic, particularly academic ones, drug discovery and development takes many diverse skills/disciplines to make the connections in order to get to safe and effective drugs. Design is difficult and bringing together right people at right time then providing right resources to execute is critical and rare. Luck can play a role but Pasteur's quote "Chance favors the prepared mind" is very apropos in drug discovery research.

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8. Nil Hinckle on May 12, 2008 3:12 PM writes...

You could tell them that finding a drug to treat a specific disease is like finding which ice cream flavor served in Reno will lower the Treasury rate.

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9. Nick K on May 12, 2008 4:02 PM writes...

It would be most interesting to plot the productivity per scientist in pharma R&D against the size of the company. I suspect the correlation would be strong - and negative.

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10. srp on May 12, 2008 8:28 PM writes...

It seems like a really important point that there is little useful theory--i.e., predictive equations or algorithms--that can cope with all the nonlinear interacting feedbacks of the body and all the diverse parallel pathways. Derek's prior dismissive remarks about mathematical models of pharmacokinetics are really telling. If you can't predict from first principles how fast or completely a molecule is going to get taken up by the cells, it's hard to see how you can predict in advance much of anything about what it will do once it gets there.

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11. mersault on May 13, 2008 3:13 AM writes...

I find that as soon as I mention that I am a chemist the lights go out in the individual I am talking to. I have better joy when I say "I am in cancer research". I have managed to explain a few things in the past, one triumph was a lay description of TLC and following that column chromatography to a friend of a friend who had no scientific background.

Nick K - I work in a small biotech, it's not as clear cut as you think. Thanks to the 'efforts' of some of my colleagues, your plot would be seriously skewed...

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12. Jonadab the Unsightly One on May 26, 2008 8:01 AM writes...

I had a college prof -- a brilliant man by the name of Donald DeYoung -- who had the uncanny ability to explain virtually anything clearly and in layman's terms. It was amazing. I didn't notice so much in the physics course, because everybody in there was a math or science major anyhow, but in the gen-ed science class I had him for ("Science and Society") it was really something to behold. He'd be explaining how temperature is really a measure of kinetic energy, or somesuch, and the communications and music and art majors and so on would actually be *getting* it. It was cool.

He also writes children's books. Non-fiction children's books about science.

I did, however, also have a class with him that he was unable to make easy: DiffEQ. However, in fairness, the bookstore completely and repeatedly flubbed the textbook order, leaving us with no text for the course for over half the semester, and I'm sure that didn't help.

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13. Jonadab the Unsightly One on May 26, 2008 9:12 AM writes...

OBTW, Derek, this would be a good time to mention that, as an educated non-chemist, I enjoy your blog. Most of the time it's very much clear enough that I can follow it. There are times that I have to look things up (e.g., I remember having to look up what TLC stands for at one point), but we're talking less than once per article, which is really no big deal. Indeed, sometimes I have to do that when I'm reading in my major field (math) or my career field (network administration).

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