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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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November 16, 2005

What Sort of Training?

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Posted by Derek

I had some email from an undergraduate chemistry major who's interested in doing drug discovery work eventually. He was wondering if organic synthesis was still the way to go in graduate school, and my answer is "definitely." I've warned people away from too much of a medicinal chemistry focus in their graduate work before, and I'll be glad to do it again.

Let me be clear, though, that I'm talking about academic medicinal chemistry programs as they've usually been run. What you often end up doing in these is learning a fair amount about each of the major areas of drug discovery, but you generally don't get really good at any of them. And since there's no market for a one-man drug company, you're left in a bad situation. We don't need fair-to-middling chemists who are also fair-to-middling pharmacologists. Perhaps there are other ways to run a med-chem department at a university that won't lead to this problem, but the only one I can think of is to run it like a little drug company, which I don't think is going to work out very well.

The reason we like for people to do lots of organic chemistry before they join the drug industry is that we (the medicinal chemists) are the only ones who understand that stuff. Other departments have members (sometimes) with a reasonable knowledge of the main points of organic synthesis, but it's only the chemists who can really dive into it. Someone has to, and by golly, it's us. So we need people who really know what they're doing: people who can use the fastest and cleanest routes to making the most diverse analogs, who can think up structures that no one else has ever made and reduce them to practice, and who can find the cheapest, most reliable ways to scale up a synthesis for real world use. The wider the range of serious organic synthesis experience you have, the more we'd like to talk to you.

This might eventually become a problem for us in industry, as the field of organic synthesis continues to mature. Already, I think we have a bit less emphasis on people who've done total synthesis of natural products, because fewer groups are doing that these days. (And some of the groups who are, aren't doing it in a way that everyone in the group gets the kind of training we need - the "team of lab Sherpas" approach damages as many people as it improves, as far as I'm concerned).

But total synthesis, done right, is still the perfect sort of training for our needs, even though we don't do thirty-two step reaction sequences. It sends you all over the state of the synthetic art, gives you a varied problem-solving workout, and trains you to always look for alternatives to the chemistry you're doing. We couldn't ask for more. I find this state of affairs a bit irritating, though, since I think that total synthesis is a slowly dying art form, and rightfully so. There's less and less need, in my opinion, for those thirty-two step routes. I can almost imagine keeping it all going just to provide the drug industry with the kind of people it likes to hire, though. In fact, I can almost imagine that this is already happening right in front of us. . .

One of the major alternatives to total synthesis is working on new synthetic methods, which is a valuable service to the science. But while that can train people very well for drug research, it can also leave them partially crippled. It depends on how broad their experience of different reactions has been, and how general their approach to problem solving has had to be. If you come out of graduate school as the world's best set of hands for one particular reaction, my advice is to go do a completely different sort of post-doc, to prove that you have the hands to do something else. And that's because "do something else" is pretty much the job description of a working medicinal chemist.

Comments (13) + TrackBacks (0) | Category: How To Get a Pharma Job


COMMENTS

1. Grubbs the cat on November 17, 2005 6:11 AM writes...

"...since I think that total synthesis is a slowly dying art form, and rightfully so. There's less and less need, in my opinion, for those thirty-two step routes..."

I agree that total synthesis is one of the training areas that prepares you best for a MedChem job. And there are more reasons for keeping this discipline alive for as long as possible.

Who else is going to prove or disprove an absolute configuration that cannot be determined otherwise?
Who else is going to prove a structure of a complicated natural product beyond any doubt (see diazonamide...)?
Who else is going to produce synthetic papers that are REALLY fun to read? (for me, this is where the art-form comes into play - and I am not talking about the uninspiring 32 step routes that certain 50-people-groups provide)

I see that more and more people are having difficulty getting funding doing total synthesis without any accompanying methodology. This trend can be argued although it probably prevents a lot of people who have a good idea for a key disconnection for a natural product out of their research area to pursue it further.

The days where applied total synthesis produced the Woodward-Hoffmann rules are probably over - but it should not die. If it does, not "rightfully so".

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2. Kay on November 17, 2005 7:56 AM writes...

I agree. Synthetic chemistry has such a solid foundation. If a solidly-trained student is then asked to participate in voodoo (Lipinski's rules; in silico predictions with no basis; in vivo and in vitro studies that aren't relevant to the paying species), then at least they have good fundamentals to fall back on. Further, they can move to other industries with less voodoo.

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3. Drew on November 17, 2005 11:26 AM writes...

Yup. A good synthetic chemist can always absorb med chem on the job; the converse in certainly not true.

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4. PS on November 17, 2005 3:13 PM writes...

Derek,

I agree with some of the stuff you said but there are some of us who graduated from Med Chem departments and consider ourselves as pretty good synthetic chemists (and have the publication record to back it up). It just seems that some people from certain synthetic labs would have you believe that only they are capable of making natural products and that is certainly not the case. I have seen many graduate students from chemistry departments who are as clueless about synthesis as graduate students from a med chem department.

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5. PS on November 17, 2005 3:22 PM writes...

Drew said "Yup. A good synthetic chemist can always absorb med chem on the job; the converse in certainly not true".

I dont know what evidence you have to make the above statement. You just sound like the arrogant, conceited chemist' who seem to be on the hiring board for most big pharmas and make hiring decisions to cover their own asses.

Milo, I am sorry to say that pyrazoles, pyridines.....are just not going to fly if you are going to start looking for a job (for reasons, see Derek's post).

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6. Derek Lowe on November 17, 2005 4:10 PM writes...

Actually, pyridine/pyrazole stuff is just fine, as long as that's not all you can do. A good varied background in heterocyclic chemistry will serve you as well as anything in the drug industry.

And as for synthetic chemists picking up the med chem/biology and vice versa, the point is directed at people who don't have a strong synthetic chemistry background and have to acquire one. It's hard to do that without time and experience, and the best place for that is grad school.

It's better to have already acquired it when you get to industry, because the first thing you're expected to do is make compounds. Being able to talk with and understand the biologists is a good thing, but it comes second, because it doesn't help you much when it's time to make compounds. Your colleagues can steer you away from egregious med-chem mistakes while you learn the ropes.

I take PS's point about there being some very good synthetic chemists in med-chem departments. It all depends on how the department is set up - some of them have people who could just as easily slot into any organic chemistry faculty slot.

But the academic side of medicinal chemistry is just not something that comes up much for a working medicinal chemist, in my experience. I used to hear some of these faculty guys setting out to Explain Medicinal Chemistry, and before long they were off to two-compartment models and all the rest of it. I've never had to use a single equation for my work in the last sixteen years.

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7. milo on November 17, 2005 4:14 PM writes...

PS... I had interpretted Derek's post as saying that the industry is looking for people who can design and manipulate molecules, that they (industry) would rather have a person who has a lot of synthesis experience rather than someone who has a little synthesis, a little biology, a little blah blah blah. Drew seemed to back this up by saying that a good synthetic person can pick up the med chem on the job.


Am I aiming too high? Is my career goal a "pie in the sky"? Maybe.

I do think that those folks who have done the ugly 38 step synthesis of Taxol probably have good hands in the lab. I also think that it is a shame that natural product synthesis is on the decline. But I find it difficult to believe that they are the only ones that pharma looks at.

Then again, I could be wrong.

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8. PS on November 17, 2005 5:50 PM writes...

"Yup. A good synthetic chemist can always absorb med chem on the job; the converse in certainly not true."

I still take an exception to the latter part of the above statement. I also dont understand what academic medicinal chemists you guys are talking about. My dissertation project (in a med chem department) was total synthesis of a natural product. But I had colleagues who worked on more traditional medicinal chemistry projects that involved designing and making molecules. The biological evaluation was carried out by other group members or by some one in pharmacology.

I agree that some Medicinal Chemistry departments may have a diverse faculty profile which includes professors whose focus is more Pharmaceutics than Medicnal Chemistry. And usually students comming out of such labs find good employment opportunites in a Pharmaceutics, PK/PD type settings (and not as synthetic chemists).

But I dont like chemistry folks contantly beating on people from medicinal chemistry departments and pretenting that they alone have the license and skills to be good synthetic chemists.

Sorry Milo, dont mean to be an ass - but having good chemistry skills is not enough. The question always comes down to - who did you work with and what sort of connections/reputation your boss has.

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9. Drew on November 17, 2005 7:42 PM writes...

PS- the comment was not meant to be offensive. As a chemist beginning in pharma, you are getting paid to make analogues, end stop. The more experience you have making diverse structures, the ability to sieve the literature, and experience/intuition with lots and lots of different chemistry, (old school name reactions, organometallics, cutting edge Buchwald-Fu-Hartwig systems, etc, etc) the more succesful you will be. Med chem knowledge is basically irrelevent. The "big dogs" make the med chem decisions; it certainly helps to understand it, but that part of the process is out of your hands for a good decade or so...

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10. Steve on November 18, 2005 9:07 AM writes...

Thanks for getting this message out there! I earned my Ph.D. in one of 'those' group where I spent about half my time making compounds and half designing assays and running them. I went through a few 8-10 step synthetic schemes and developed some nice transcriptional assays all the while encouraged by my supervisor who was saying that big pharma "really does want people with broad backgrounds and who can do more than just make compounds". At that time I was naive enough to believe it. Needless to say, despite several fairly high profile publications, I had a very difficult time getting interviews for synthetic chemistry jobs. Anyway, I encourage everyone here to keep getting this message out there for students heading off to grad school to really think about how the group they are joining will greatly effect the job they end up with.

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11. Mark McPhee on November 18, 2005 10:22 AM writes...

PS

You said everything I wanted to yesterday but didnt have the time to. I am pretty fed up with the med chem bashing. Who cares if Big Pharma has a bias toward PhD Medicinal Chemists?

I am a damn good synthetic chemist and a proud holder of a PhD in Medicinal Chemistry. 90% of my time in grad school was spent doing the exact same things Derek did. Only we called it total synthesis of "unnatural products". However, I have extensive, additional training in pharmacology, medicinal chemistry and biochemistry.

This broad training has given me tremendous job flexibility to continue to feed myself, my wife and our 3 kids during and after a difficult lay-off period.

I think Derek's point is that training in synthetic chemistry is pivotal to sucess as an industrial med chemist--I dont dispute that.

Clearly, not all medicinal chemistry programs provide the relevant caliber of synthetic training. But I can think of more than a handful who produce synthetic chemists on par with any total synthesis program.

Another point is that Derek's post seemed to inadvertantly denigrate the mechanistic folks out there who are also damn good synthesis folks (and yes, some end up doing discovery vs process).

Let's start evaluating talent based on abilities vs pedigrees alone, shall we?

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12. Derek Lowe on November 18, 2005 11:15 AM writes...

No question that mechanistic people can have good synthetic hands. Sometimes, though, if they've been working intensively in one area, they may have trouble convincing people that they're good outside it, too. That's where a year of postdoc work would come in handy.

And I certainly don't want to be seen as coming out in favor of "pedigree", if by that you mean "from the right group". I don't have much time for that kind of hiring.

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13. RB on November 18, 2005 1:41 PM writes...

Coming from a similar background as PS and Mark I agree with their views, and I appreciate that Derek doesn't give much credence to pedigree based hiring, (is that the general view at your shop or are you in the minority?).

I must admit that I came out of the academia with some inferiority complex as I hadn't practiced the holy art of NPS, however over the past 5 years having worked with numerous people with classical NPS training and having interviewed countless more, I am confident that I can stand toe to toe with the best of them. I agree that I was exposed to a lot less peripheral chemisty than say if I had been in a 40 people synthetic lab, however the availability of Scifinder and beilstein have helped me narrow this exposure gap quite rapidly.

I am glad my resume was routed to "junk-Pile" as soon as it hit the pharma recruiting desk because that opened the door to smaller "biotech" companies for me. I sincerely believe this is a much more rewarding environment, you get exposed to all aspects of the business and learn a lot, plus if you have the drive, desire and smarts you can grow in responsibility a lot faster than in any big pharma setting. I am not just a "chemist" that can be readily replaced by the next young hot "chem-jock" from the big name lab.

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