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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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October 24, 2012

Chem Coach Carnival: A Few Questions

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Posted by Derek

Over at Just Like Cooking, See Arr Oh has been organizing a "Chem Coach Carnival". He's asking chemists (blogging and otherwise) some questions about their work, especially for the benefit of people who don't do it (or not yet), and I'm glad to throw an entry into the pile:

Describe your current job
My current job is titled "Research Fellow", but titles like this are notoriously slippery in biotech/pharma. What I really do is work in very early-stage research, pretty much the earliest that a medicinal chemist can get involved in. I help to think up new targets and work with the biologists to get them screened, then work to evaluate what comes out of the screening. Is it real? Is it useful? Can it be advanced? If not, what other options do we have to find chemical matter for the target?

What do you do in a standard "work day?"
My work day divides between my office and my lab. In the office, I'm digging around in the new literature for interesting things that my company might be able to use (new targets, new chemistry, new technologies). And I'm also searching for more information on the early projects that we're prosecuting now: has anyone else reported work on these, or something like them? And there are the actual compound series that we're working on - what's known about things of those types (if anything?) Have they ever been reported as hits for other targets? Any interesting reactions known for them that we could tap into? There are broad project-specific issues to research as well - let's say that we're hoping to pick up some activity or selectivity in a current series by targeting a particular region of our target protein. So, how well has that worked out for other proteins with similar binding pockets? What sorts of structures have tended to hit?

In the lab, I actually make some of the new compounds for testing on these ongoing projects. At this stage in my career (I've been in the industry since 1989), my main purpose is not cranking out compounds at the bench. But I can certainly contribute, and I've always enjoyed the physical experience of making new compounds and trying new reactions. It's a good break from the office, and the office is a good break from the lab when I have a run of discovering new ways to produce sticky maroon gunk. (Happens to everyone).

This being industry, there are also meetings. But I try to keep those down to a minimum - when my calendar shows a day full of them, I despair a bit. Most of the time, my feelings when leaving a meeting are those of Samuel Johnson on Paradise Lost: "None ever wished it longer".

Note: I've already described what happens downstream of me - here's one overview.

What kind of schooling / training / experience helped you get there?
I have a B.A. and a Ph.D., along with a post-doc. But by now, those are getting alarmingly far back in the past. What really counts these days is my industrial experience, which is now up to 23 years, at several different companies. Over that time, I don't think I've missed out on a single large therapeutic area or class of targets. And I've seen projects fail in all sorts of ways (and succeed in a few as well) - my worth largely depends on what I've learned from all of them, and applying it to the new stuff that's coming down the chute.

That can be tricky. The failings of inexperience are well known, but experience has its problems, too. There can be a tendency to assume that you really have seen everything before, and that you know how things are going to turn out. This isn't true. You can help to avoid some of the pitfalls you've tumbled into in the past, but drug research is big enough and varied enough that new ones are always out there. And things can work out, too, for reasons that are not clear and not predictable. My experience is worth a lot - it had better be - but that value has limits, and I need to be the first person to keep that in mind.

How does chemistry inform your work?
It's the absolute foundation of it. I approach biology thinking like a chemist; I approach physics thinking like a chemist. One trait that's very strong in my research personality is empiricism: I am congenitally suspicious of model systems, and I'd far rather have the data from the real experiment. And those real experiments need to be as real as possible, too. If you say enzyme assay, I'll ask for cells. If you have cell data, I'll ask about mice. Mice lead to dogs, and dogs lead to humans, and there's where we really find out if we have a drug, and not one minute before.

In general, if you say that something's not going to work, I'll ask if you've tried it. Not every experiment is feasible, or even wise, but a surprising amount of data gets left, ungathered, because someone didn't bother to check. Never talk yourself out of an easy experiment.

Finally, a unique, interesting, or funny anecdote about your career
People who know me, from my wife and kids to my labmates, will now groan and roll their eyes, because I am a walking collection of such things. Part of it's my Southern heritage; we love a good story well told. I think I'll go back to grad school for this one; I'm not sure if I've ever told it here on the blog:

When I first got to Duke, I was planning on working for Prof. Bert Fraser-Reid, who was doing chiral synthesis of natural products using carbohydrate starting materials. In most graduate departments, there's a period where the new students attend presentations by faculty members and then associate themselves with someone that they'd like to work for. During this process, I wanted to set up an interview with Fraser-Reid, so I left a note for him to that effect, with my phone number. His grad students told me, though, that he was out of town (which was not hard to believe; he traveled a great deal).

That night I was back in my ratty shared house off of Duke's East Campus, which my housemates and I were soon to find out we could not afford to actually heat for the winter (save for a coal stove in the front room). And at 9 PM, I was expecting a call from a friend of mine at Vanderbilt, a chemistry=major classmate of mine from my undergraduate school (Hendrix) who knew that I was trying to sign up with Fraser-Reid's group. So at 9 PM sharp, the phone rings, and I pick it up to hear my friend's voice, as if through a towel held over the phone, saying that he was Dr. Fraser-Reid, at Duke.

Hah! Nice try. "You fool, he's out of town!" I said gleefully. There was a pause at the other end of the line. "Ah, is this Derek Lowe? This is Dr. Fraser-Reid, at Duke." And that's when it dawned on me: this was Dr. Fraser-Reid. At Duke. One of my housemates was in the room while this was going on, and he told me that he'd thought until then that watching someone go suddenly pale was just a figure of speech. The blood drained from my brain as I stammered out something to the effect that, whoops, uh, sorry, I thought that he was someone else, arrgh, expecting another call, ho-ho, and so on. We did set up an appointment, and I actually ended up in his group, although he should have known better after that auspicious start. This particular mistake I have not repeated, I should add. Ever restless and exploring, I have moved on to other mistakes since then.

Comments (7) + TrackBacks (0) | Category: General Scientific News | Graduate School | Life in the Drug Labs


COMMENTS

1. CMCguy on October 24, 2012 10:24 AM writes...

Derek thanks for sharing all this as even though knew most of this already from reading your blog it is nice to see collected together.

I do especially appreciate your comments on "experience" as is true not enough (of the right kind) can be problematic yet on the other side over reliance on it can be damaging as well. The best places have combination of both that if they work together get a balanced approach.

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2. milkshake on October 24, 2012 1:49 PM writes...

A day without a meeting is like a ballroom without women...

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3. MLBpitcher and Medicinal Chemist on October 24, 2012 4:55 PM writes...

I thought you were a baseball player. Don't you throw some bullpen sessions?

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4. milkshake on October 24, 2012 6:15 PM writes...

so basically you volunteered yourself for doing the levoglucosane vacuum pyrolysis-based caramel chemistry - it was not assigned to you as a form of humbling punishment

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5. Derek Lowe on October 24, 2012 9:32 PM writes...

Yep, the project needed levoglucosan as starting material, so I had to crank out batches of it. And you're right, caramel is what it smelled like (burnt caramel). I had my own workup for it - take the syrup up in some water, add a bit of bicarb for the acids, then liquid-liquid extraction for two or three days with EtOAc to get out a lot of brown smelly stuff. Run the aqueous over ion-exchange resin (can't remember which one I used; I'd have to check my dissertation), and voila: pale yellow aqueous layer that crystallized as it evaporated. The resin was a goner, though - turned black and couldn't be regenerated (or at least I never found out how). I'd get about a 5% yield, 50g from a kilo of Argo corn starch.

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6. newnickname on October 25, 2012 6:37 AM writes...

How did levoglucosan enter this discussion? I needed levoglucosenone, also from pyrolysis of cellulose, as a starting material for a synthesis project. (Shafizadeh; Witzcak; et al) The sustainability folks are still pounding away at these processes. Maybe you should go back and compare your method to the current "best" methods. Of course, if you didn't use an ionic liquid, scCO2, dendrimer or nanoparticle your chances of publishing are substantially reduced.

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7. Network Pharmacology Blog on October 26, 2012 8:41 AM writes...

An interesting insight. Of particular interest is your description 'think up new targets and work with the biologists to get them screened'.

This potentially presses some frustration buttons. A chemist of your obvious experience and talent should have those skills channeled to maximum effect. Having talked to pharmaceutical company chemists who predated the high throughput era they indicated they felt the process at that was more iterative with biology allowing greater adaptation of chemistry based on biology results feedback and more productive as a consequence.

In complex disease and complex biological systems then heuristic observation or pathway analysis is statistically very unlikely to result in an effective mode of action. As such single 'targets' are unlikely to effective according to the rules established by complex systems science.

The obvious question is therefore how do you think up new targets? Have you encountered network pharmacology as an approach toward multi-target proteins based on analysis of proteomic systems?

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