About this Author
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
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September 22, 2008
Posted by Derek
Science is taking a look at the 1991 members of Yale’s Molecular Biology and Biophysics PhD program. The ostensible focus of the article is to see what the effect of flat federal research funding has been on young potential faculty members, but there’s a lot more to pick up on than that.
The first thing to note is that out of 26 PhDs from that year’s class, only one of them currently has a tenured position in academia. Five others are doing science in some sort of academic setting, but only one of those is tenure-track. And you can tell that for at least a few observers, the response to those numbers is “What went wrong?”
Well, nothing did. As it turned out, the students didn’t necessarily come out of the program on a mission to go out and get tenure. But there was no particular way to blame the research funding environment for the numbers, because almost no one that Science interviewed mentioned that as a factor at all. Instead, many of them decided that there might be something more (or at least something else) to life than going from being a grad student and post-doc directly to. . .supervising more grad students and post-docs:
For some MB&Bers, academia was never really an option. "Even as an undergraduate in college, I never bought into the concept of being a professor," says Deborah Kinch, associate director for regulatory affairs at Biogen Idec in Cambridge. "Being a grad student is the last bastion of indentured servitude, and being a faculty member is pretty much the same thing, at least until you get tenure. Earning the same low salary and fighting for every grant--that was the last thing I wanted to do. . .
. . . Midway through their graduate training, a few MB&Bers hatched the idea of a seminar series to hear from former graduates working outside the academic fold. (Athena) Nagi said the group wrestled with the definition of an alternative career and decided that the answer was, in essence, "anything that didn't involve teaching at a major research university”. . .what (Tammy) Spain remembers most were their reasons for branching out. "They all said they didn't want to go into academia. None of them said, 'I failed.' None had even tried to find an academic job. It was the first time I got the sense that there was no shame in not going into academia."
That heightened sense of empowerment reinforced what some class members were already feeling. "At first, you think that academia makes sense," says Nagi. "But by your 3rd or 4th year, you start to get the lay of the land and look at the options. You realize that a postdoc isn't just for 1 year and that there are multiple postdocs."
I particularly like the way that a third-year graduate student had never realized until then that there was no shame in not going into academia. This is a major problem in academic science – the amount of this attitude varies from department to department, but there’s always some of it floating around. It’s no wonder that some of these people were baffled by the prospect of what they were going to do with their lives, because a large, important range of choices was being minimized or ignored.
But I have no room to talk – by that point in my graduate career, I wasn’t clear about what I was going to do, either. I was getting pretty sure, though, that going off and fighting for tenure at a major university was not in the running. I’d seen what the younger faculty put up with in my department, and it didn’t look much better than the life I was leading as a grad student. In many ways, actually, it was worse. Why would I want to do that?
As it turns out, a good number of the 1991 Yale people ended up at various small biotech companies. Some of them have made a success of it, and naturally enough, some of them are out of science altogether. But the rarest, least likely thing for them to do was to get tenure – or even to try. When I think back on the folks I went to grad school with in the mid-1980s, the picture is very similar. You just wish that there were a way to make this sorting-out process less painful. . .
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School
July 18, 2008
Posted by Derek
Here’s an appropriate topic for a Friday, although at first many of you may think I’ve lost my mind. What would happen if you combed the full text of the experimental sections of the chemistry journals, looking for how long people ran their reactions?
I’m pretty sure that I know what you’d see: there would be a lot of scatter in the short time periods, with some peaks at the various half-hour and hour marks just for convenience. But as you went out into the multiple-hour procedures, I feel sure that you’d see pronounced spikes in the data at around sixteen to twenty hours and again at around 72 hours.
Some readers have doubtless started nodding their heads, having done the math. Those times correspond to "overnight" and "over the weekend", and I'm willing to bet that they're over-represented (and how) in the data set. I'll go on to predict scarce examples in, say, the 14-hour or 38-hour ranges - there's not much way to run a reaction for those intervals and not be in the lab too early in the morning or too late at night.
A second-order prediction is that when such reactions are found, that their origins will skew heavily toward academia rather than industry. And I'm also willing to bet that patent procedures will tend to follow the working-day timelines more than the general literature, for the same reasons. My last higher-order prediction is that the reaction times would not, in fact, obey Benford's Law, as many other data sets of this kind do.
As far as I know, no one's ever done this sort of analysis, but I suppose it would be possible, especially for someone at Chemical Abstracts or at one of the scientific publishers. If someone wants to try it, please let me know what comes out. And if the results follow my predictions, please feel free to refer to the title of this post or something similar. I won't object.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs | The Scientific Literature
March 25, 2008
Posted by Derek
There’s an interesting article in Angewandte Chemie by Richard Silverman of Northwestern, on the discovery of Lyrica (pregabalin). It’s a rare example of a compound that came right out of academia to become a drug, but the rest of its story is both unusual and (in an odd way) typical.
The drug is a very close analog of the neurotransmitter GABA. Silverman’s lab made a series of compounds in the 1980s to try to inhibit the aminotransferase enzyme (GABA-AT) that breaks GABA down in the brain, as a means of increasing its levels to prevent epileptic seizures. They gradually realized, though, that their compounds were also hitting another enzyme, glutamic acid decarboxylase (GAD), which actually synthesizes GABA. Shutting down the neurotransmitter’s breakdown was a good idea, but shutting down its production at the same time clearly wasn’t going to work out.
So in 1988 a visiting Polish post-doc (Ryszard Andruszkiewicz) made a series of 3-alkyl GABA and glutamate analogs as another crack at a selective compound. None of them were particularly good inhibitors – in fact, most of them were substrates for GABA-AT, although not very good ones. But (most weirdly) they actually turned out to activate GAD, which would also work just fine to raise GABA levels. Northwestern shopped the compounds around because of this profile, and Parke-Davis took them up on it. One enantiomer of the 3-isobutyl GABA analog turned out to be a star performer in the company’s rodent assay for seizure prevention, and attempts to find an even better compound were fruitless. The next few years were spent on toxicity testing and optimizing the synthetic route.
The IND paperwork to go into humans was filed in 1995, and clinical trials continued until 2003. The FDA approved the drug in 2004, and no, that’s not an unusual timeline for drug development, especially for a CNS compound. And there you’d think the story ends – basic science from the university is translated into a big-selling drug, with the unusual feature of an actual compound from the academic labs going all the way. Since I’ve spent a good amount of time here claiming that Big Pharma doesn’t just rip off NIH-funded research, you’d think that this would be a good counterexample.
But, as Silverman makes clear, there’s a lot more to the story. As it turned out, the drug’s efficacy had nothing to do with its GABA-AT substrate behavior. But further investigation showed that it’s not even correlated with its activation of the other enzyme, GAD. None of the reasons behind the compound’s sale to Parke-Davis held up, except the biggest one: it worked well in the company’s animal models.
The biologists at P-D eventually figured out what was going on, up to a point. The compound also binds to a particular site on voltage-gated calcium channels. That turns out to block the release of glutamate, whose actions would be opposed to those of GABA. So they ended up in the same place (potentiation of GABA effects) but through a mechanism that no one suspected until after the compound had been recommended for human trials! There were more lucky surprises: Lyrica has excellent blood levels and penetration into the brain, while none of the other analogs came close. As it happened, and as the Parke-Davis folks figured out, the compound was taken up by active transport into the brain (via the System L transporter), which also helps account for its activity.
And Silverman goes on to show that while the compound was originally designed as a GABA analog, it doesn’t even perform that function. It has no binding to any GABA receptor, and doesn’t affect GABA levels in any way. As far as I can see, a really thorough, careful pharmacological analysis before going into animals would probably have killed the compound before it was even tested, which goes to show how easy it is to overthink a black-box area like CNS.
So on one level, this is indeed an academic compound that went to industry and became a drug. But looked at from another perspective, it was an extremely lucky shot indeed, for several unrelated reasons, and the underlying biology was only worked out once the compound went into industrial development. And from any angle, it’s an object lesson in how little we know, and how many surprises are waiting for us. (Silverman himself, among other things, is still in there pitching, looking for a good inhibitor of GABA aminotransferase. One such drug, a compound going back to 1977 called vigabatrin, has made it to market for epilepsy in a few countries, but has never been approved in the US because of retinal toxicity).
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | Pharmacokinetics | The Central Nervous System
December 19, 2007
Posted by Derek
There is a pecking order in chemistry. That’s because there’s one everywhere. If it’s a human endeavor, staffed by humans, you’re going to have hierarchies, real and perceived - who you did a post-doc with, what huge company you're a big wheel in. But that doesn’t mean that we have to bow down to them, and it doesn’t excuse this sort of thing, from The Chem Blog:
” Waaaaaayyy back at the ACS in San Fran at the poster session, we were walking around and introduced ourselves to this guy standing in front of his poster. Now… old boy (a graduate student) engaged us in some dialog about his poster and we were getting along famously, my friend asking most of the intelligent questions (I was still recovering from giving blood a few hours before and drinking multiple beers immediately after.) As conversations normally flow, he asked us where we were from. I told him my fine institution and my buddy told him his. I assume he wasn’t put off my by school, but the look on his face when my buddy told him where he was from was at first a “are you serious” chuckle, which melted into one of those “do they have a department” and finally to a resound(ing), “I’m done with you.”
I stood there and watched it the whole time. So, my buddy being naive to the ways of the world, kept asking questions but the answers weren’t forthcoming any more. In fact, in the midst of a question my buddy was asking, the guy actually walked away from his poster and started talking to his friends. . .”
Read the rest of the post for the rest of the story, which goes off in a different (and still interesting) direction. But as for this behavior, there’s just no call for it. As far as I’m concerned, if a person is asking intelligent questions, they’ve already provided all the credentials they need to show. Likewise, I reserve the right to discriminate against time-wasting bozos (just as I reserve the right to define that class, although I’ll bet that most of my picks would easily pass a show of hands). But if you’re presenting a poster, you have, whether you realize it or not, entered into an agreement to take on the broad unwashed masses.
Tactfully dealing with the clueless is a learned skill, but no such skill seems to have been called on here. This is tactfully dealing with the intelligent and informed, and if you can’t do that, you have some serious problems. It takes an awful lot of red-hot results to make up for a really obnoxious attitude, and a degree from Big Name U is only partially going to offset one as thick as this. Now, it's true that there are certainly some pretty abrasive folks from BNU, but the ones with the proven big-time track records can at least get away with it. Too many other morons take the shortcut, deciding that the nasty attitude is some sort of essential first step – in some cases, deciding that it and the Big Name is all they need.
Out here in the real world, where Poster Boy has yet to tread, it becomes clear that the wonderfulness of a marquee school background eventually goes stale. There are places in the drug industry where working for particular academic bosses will give you a leg up – for a while. It’s a real advantage to be able to get in the door that way, no doubt, but once you’re through the door you generally have to produce something. (And it’s good to keep in mind that even these advantages don’t necessarily last forever. A rollicking management purge can destabilize an old-boy network very quickly).
No, doing lots of work and doing it really well is a better long-term strategy. (Another part of that strategy is to make sure that people know who’s doing it, but that's a topic for another day). And having a personality that makes people grit their teeth and wait for you to leave is not such a good long-term plan. I wish Poster Boy well, but I hope that he has a lot to talk about. This isn't one of those businesses where you can get by on looks.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School | Life in the Drug Labs
September 18, 2007
Posted by Derek
 I also mentioned recently that I’d come across a good example of an academic compound with interesting activity but no chance of being a drug. Try this one out, from Organic Letters. Yes, there aren’t many other compounds that do what this one does (inhibit the production of TNF-alpha). And no, it’s not going to be a drug – well, at least the odds are very, very long against it.
Why so negative? Several reasons. For one thing, this molecule is extremely greasy. This is not a killer in and of itself, but it’s inviting trouble, for the reasons noted here. The second problem is that this thing looks like it’s going to have some trouble dissolving. That’s trouble both from both the thermodynamic (eventual amount in solution) and kinetic (speed of dissolution) senses. That greasiness will be the problem with the former, since a lot of this molecule’s surface area gives water molecules no incentives to join in on anything. And all those aryl rings (along with the symmetric structure) are asking for trouble with the latter. Those features make the structure look like it’ll form a very good, very happy crystal, with its aromatic rings stacked onto each other like ornamental bricks. “Brick” is the very word that comes to mind, actually.
But solubility is only the beginning. The real problem is that catechol functionality in the center of the molecule, which is just waiting to turn into a quinone. In medicinal chemistry, no one wants quinones; no one likes them. They’re just too reactive. It would not surprise me for a minute to learn that this group, though, is the reason for the compound’s activity. It’s probably reacting with some functional group on the surface of the target protein and gumming up the works that way. It’ll do that to others, too, if it gets the chance. There are all sorts of weird little quinones in the literature that hit proteins that nothing else will touch, but none of them are going anywhere.
No, it’s safe to say that any experienced drug-company chemist would draw a red X through this one on sight. Plenty of reasonable-looking compounds turn up with unanticipated problems, so we don’t need to go looking for trouble. That’s not to say that it can’t be a research tool (although I’d be careful interpreting the data from complex systems – there’s no telling how many other things that quinone is going to react with).
But all this brings up another thing that we were talking about around here – how much do drug companies owe academia for working out fundamental biochemistry and molecular biology? What if someone uses this very compound, for example, as a research tool and discovers something about its target that could be used to develop an actual drug? What do we call that?
Well, we call that “science”, as far as I can see. Everything is built on top of something else. In a case like this, the discoverers of this current compound, even if they’ve patented it, do not have a claim on what discoveries might come from it later on. An even stronger case was decided in that direction – the University of Rochester’s discovery of the COX-2 enzyme, the patent for which led to their attempt to claim revenue from Celebrex. The judge ruled, absolutely correctly in my opinion, that the discovery of a drug target is not the discovery of a drug, and that the effort and inventiveness needed for that second step is more than enough for it to stand on its own.
There’s a “research exemption” for patents, giving legal room to use the disclosed inventions and compounds to make further inventions. I think that’s an extremely important concept. It lets academic labs study patented industrial compounds for their own purposes, and it even lets companies do that to each other. How would we compare our internal compounds to the competing ones if we couldn’t use them? (There’s more than one research exemption, though, and the traditional common-law one took a big hit a few years ago in Madey v. Duke, which worries me).
I strongly oppose broad patent claims for uses and pathways, because I think that these cut into legitimate research. Patents should cover things that are novel and useful. They should completely disclose the substance of their invention. And in return for the period of exclusive rights, anyone else who wants to should be able to get to work on what will replace them. A patent is not a license to kick back; it’s a reminder to keep moving.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | Patents and IP
September 12, 2007
Posted by Derek
The mention of tropical diseases here the other day turns out to be timely, since the latest Nature has several articles on various ways for industry and academia to partner on attacking these. Some adjustments are needed every time you try this sort of thing, naturally. I particularly enjoyed this article. Here’s a sample:
“. . .translational research requires skills and a culture that universities typically lack, says Victoria Hale, chief executive of the non-profit drug company the Institute for OneWorld Health in San Francisco, California, which is developing drugs for visceral leishmaniasis, malaria and Chagas' disease. Academic institutions are often naive about what it takes to develop a drug, she says, and much basic research is therefore unusable. That's because few universities are willing to support the medicinal chemistry research needed to verify from the outset that a compound will not be a dead end in terms of drug development.
Academics will currently publish, say, a chemical scaffold, which they bill as a potential new target for parasites. "But had a medicinal chemist looked at it, he might immediately see that it will never work as a drug, because it has an inappropriate solubility or toxicological profile," says Els Torreele, a product manager at the DNDi. "Having a chemical structure that kills your parasite is only one of many aspects of what makes a drug a drug”.
Ted Bianco, director of technology transfer at the Wellcome Trust in London, agrees. "It's fine if a researcher is just using a compound as a ligand to probe a biological process," he says, "but don't kid yourself it's a drug unless you ask whether it has druggable properties." What's needed, says Hale, is a 'target product profile', which sets out the appropriate drug chemistry properties. "Getting a drug through regulatory processes is not just about how good your science is and how great your trials are; it is much more complex," says Hale. "And academics don't have the experience — they need to hire people from the drug industry."
This would make particularly interesting reading for the NIH-funding-discovers-all-the-new-drugs crowd. That idea seems pretty indestructible, although you’d think it would at least be dented by talking to the people who actually try to develop drugs (like me, or many readers of this blog), or to the people who are actually partnering with academia (see above).
I first came across this whole debate a few years ago, not having even realized that it was a debate at all. Even now, when I tell co-workers in the industry that there are people who believe that pretty much all drugs come right out of from publicly funded research, the usual result is an incredulous stare and a burst of laughter. That’s often followed by a question like “So what is it that I’m doing all day, then?”
Unfortunately, there really are occasional examples of companies scooping things up and making a killing on them – an example will follow in a coming blog post. And on the flip side, I have a recent example coming up of an academic compound which may well do exciting things in a dish, but has as much chance of becoming a drug as I do of becoming an Olympic pole-vault champion. And it’s not that I’m not reasonably aerodynamic – it’s just that there’s more to the pole vault than that, and there’s more to making a drug than working in vitro.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development
April 17, 2007
Posted by Derek
The doctorate-or-not discussion is roaring along in the comments to the last post, and they're well worth reading. I have a few more thoughts on the subject myself, but I'm going to turn off comments to this post and ask people to continue to add to the previous ones.
One thing that seems clear to a lot of people is that too many chemists get PhD degrees. I'm not talking about the effect of this on the job market (more on that in a bit) so much as its effect on what a PhD is supposed to represent. So, here's my take on what a PhD scientist is supposed to be, and what it actually is in the real world. I'm going to be speaking from an industrial perspective here, rather than an academic one, although many of the points are the same.
Ideally, someone with a doctorate in chemistry is supposed to be able to do competent independent research, with enough discipline, motivation, and creativity to see such projects through. In an industrial applied-research setting, a PhD may initiate fewer projects strictly from their own ideas, but they should (1) always be on the lookout for the chance to do so, (2) be willing and able to when the opportunity arises, and (3) add substantial value even to those projects that they themselves didn't start.
That value is both creative and managerial - they're supposed to provide ideas and insights, and they're supposed to be able to use and build on those of others. They should be able to converse productively with their colleagues from other disciplines, which means both understanding what they're talking about and being able to communicate their own issues to them. Many of these qualities are shared with higher-performing associate researchers, who will typically have a more limited scope of action but can (and should) be creative in their own areas. Every research program is full of problems, and every scientist involved should take on the ones appropriate to their abilities.
So much for the ideal. In reality, many PhD degrees are (as a comment to the previous post said) a reward for perseverence. If you hang around most chemistry departments long enough as a graduate student, you will eventually be given a PhD and moved out the door. I've seen this happen in front of my eyes, and I've seen (and worked with) some of the end results of the system. The quality of the people that emerge is highly variable, consistent with the variation in the quality of the departments and the professors. Unfortunately, it's also consistent with the quality of the students. But it shouldn't be. The range of that variable shouldn't be as wide as it is.
There are huge numbers of chemistry PhDs who really don't meet the qualifications of the degree. Everyone with any experience in the field knows this, from personal observation. You will, I think, find proportionally more of these people coming out of the lower-quality departments, but a degree from a big-name one is still far from a guarantee. The lesser PhD candidates should have been encouraged to go forth and get a Master's, or simply to go forth and do something else with their lives. They aren't, though. They're turned loose on the job market, where many of them gradually and painfully find that they've been swindled.
Over time, the lowest end of the PhD cohort tends to wash out of the field entirely. There are, to be sure, many holders of doctoral degrees in chemistry who go into other areas because of their own interests and abilities. But there are also many jobs that make an outside observer wonder why someone with a PhD is doing them, and that's where many people end up who shouldn't have a doctorate in the first place. Others, somewhat more competent, hold on to positions because they're able to do enough to survive in them, if no more. While there are plenty of bad or irrelevent reasons for people not to be promoted over the years, some cases aren't so hard to figure out.
Those, then, are my thoughts on the doctoral degree. What can be done about this situation, if anything, will be the subject of a future post. I have another set of opinions on the Master's degree and its holders, which I'll unburden myself of a bit later on. Comments, as mentioned, should go into the discussion here.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School | Life in the Drug Labs | Who Discovers and Why
March 23, 2007
Posted by Derek
There's an unusual article in Nature that several folks have e-mailed me about. It's unusual for several reasons. For one thing, it's synthetic organic chemistry, and there's not much of that in Nature at all - it's an interesting choice of journal on the part of the authors, Phil Baran of Scripps and two of his students, Thomas Maimone and Jeremy Richter. The title also gives away the other odd feature (as a title should): "Total Synthesis of Marine Natural Products Without Using Protecting Groups".
I was talking about protecting groups here just a couple of months ago. In synthesizing complex molecules, they're often necessary, because there will often be several similarly reactive groups exposed at the same time, and you need to be able to distinguish them. Or you'll need to do something severe to another end of the molecule-in-progress, which an amine or alcohol somewhere either won't let you do or won't survive if you try.
The trouble, as any synthetic chemist can tell you, is that protecting groups introduce their own complexities. Ideally, you want to be able to put them on and remove them with no loss of material, but that's impossible. Ideally, you'd want each one to be removable under conditions that won't disturb any of the others, or anything else in your molecule, but that can be a tall order too as they start to add up. And ideally, you'd want all of them to be able to stand up to anything else you'd like to do, until it's time for them to leave, but that's not available in the real world, either. Sometimes a big part of the work (mental and physical) that goes into a total synthesis is figuring out how to manage all the protecting groups.
Baran makes the case that this has gone too far. He's made several complex molecules without protecting anything at all. There's a price to be paid, of course - some of the steps along the way have not-so-impressive yields because of the bareback conditions. But the counterargument is that the overall yield of the synthesis is often higher in spite of this, because there are so fewer steps, and the cost and complexity are cut similarly.
Of course, you can't do this by just plowing ahead with the same reactions that a protecting-group-laden synthesis would use. They're on there for a reason, and that method would send you right into the ditch. Baran tries instead to mimic the biochemical synthesis of these molecules as much as possible, since after all, cells don't use protecting group chemistry, either.
This is an idea with a long and honorable history in organic chemistry, starting with Sir Robert Robinson's startling one-pot synthesis of tropinone back in the 1917. That one is usually taken as the father of all biomimetic syntheses, although it's been pointed out (by no less an authority than Arthur Birch) that this is partly a legend. But it's a legend that has performed function of its reality, leading to a whole series of biologically-inspired syntheses. This latest paper is a call to make biomimetic synthesis the centerpiece of the field again.
I'm sympathetic to that view, but it's not going to be easy. Read closely, the paper shows that this kind of work can be very difficult indeed, even when the biogenic pathways to your target molecules have been studied (which isn't always the case). There are a lot of steps here that required careful coaxing to work in reasonable yields, or at all - no one should confuse the lack of protecting groups with a savings in time. And these difficulties also undermine the claim of reduced cost and complexity a bit, since they represent plenty of time and effort - and if they aren't synonymous with cost and complexity, I don't know what is. Academia may obscure this a bit, since we're only talking graduate student labor here, but it's a real issue.
Where I see this making an impact industrially is in process chemistry. Many times companies work out several parallel routes to an important drug substance, looking for the lowest overall cost. That's where attention to no-protecting-group methods could pay off. Process groups already try to avoid these steps anyway, for the same reasons.
But for the most part, drug substances aren't so complex that they need lots of protecting group manipulation. We could always try to get into more complicated structures through these routes, but this leads to a chicken-and-egg problem. The medicinal chemists generally don't have the time to investigate the picky conditions needed to make no-protection chemistry work, so they're not going to have access to the shorter, higher-yielding syntheses needed to do analoging work. (And there's the real problem that these analogs might need complete re-optimization of the trickier steps each time, which would be a real nightmare). The process chemists would have the time and mandate to work out the no-protection stuff, on the other hand, but if med-chem can't deliver a good drug candidate, then they have nothing to optimize.
The Nature link above is subscriber-only, but you can read the supporting information with all its synthetic details here if you like. It's a pretty big PDF file, though, so be warned. I'd be interested to hear what readers, both academic and industrial, think about this one.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | General Scientific News
January 28, 2007
Posted by Derek
So, as reader CalProf asked in a comment the other day, what should academic scientists who want to help discover drugs be doing?
As a first approximation, I'd say not drug discovery. That sounds a bit strange, I know, but there are some good reasons behind it. Modern drug discovery takes a lot of resources, from several rather widely separated fields, and it's not easy to bring all the necessary people together in an academic environment. You need med-chemists to make the compounds, pharmacologists and molecular biologiss to develop and run the primary and secondary assays, in vivo people to dose and evaluate effects in the animal models (which they'll also need to develop, in many cases), toxicologists, formulation chemists, computer modelers, scale-up chemists. . .and it's a great help to have people in each of these departments who've done this kind of thing many times and know all the obvious pitfalls. It's a lot easier to organize this as a company where everyone is hired to do their specialty, rather than try to run it with whatever post-docs and grad students you have handy.
But that doesn't mean that academia can't play a big role. They already do, of course, in doing much of the basic biochemical research that leads to new drug targets. Unraveling which protein interacts with which in some important cellular process is as basic as it comes, and most of the time that won't lead to drug one - but once in a while those experiments will set the entire industry off on a chase.
Another place where some academic thinking could come in very useful would be in attacking the important pharmaceutical processes that we don't understand: things like pharmacokinetics, oral availability, human versus animal toxicology, and (lots of) better disease models. The inefficiencies in these areas caused by our lack of knowledge are costing everyone billions of dollars - any improvement at all would be good news. Of course, it's not like the industry hasn't taken a crack at them, too (after all, there are those billions of dollars out there to be rescued from the bonfire). But we really need every approach we can get, and some fresh thinking would be welcome.
Want some more in that vein? Better ways to dose large proteins. New formulations, so that insoluble gunk like Taxol could be given in a dosing vehicle that doesn't occasionally give people anaphylactic shock. Some hope of predicting blood-brain barrier penetration. More understanding of active transport of drug-size molecules, and how it varies between species and among different cell types. Make no mistake, these are hard problems. But whoever can make real progress on them will get plenty of recognition, plenty of funding, and will be a flat-out benefactor of humanity to boot.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development
January 14, 2007
Posted by Derek
I had some e-mail from a graduate student in a good lab the other day, and I thought the questions raised were worth a blog post. He wrote:
One thing which stands out to me is your enthusiasm for chemistry,
after having been in pharma for a while. This is something which I am
afraid I might lose getting out of academics. I actually was strongly
leaning academically until recently. It just seems the chemical problems you
would be presented in industry are very vanilla....the problem is I
really don't have a good grasp on what these are (especially in drug
discovery).
Then I imagined in drug discovery, you can use any chemistry you want,
so the "cutting edge" (i.e. new organometallic transformations with way
too much expensive catalyst) is still very relevant. I guess I'm just
curious how you stay as passionate about the science as you are. Do you
see this/has this changed since you started in industry? As you move up
the ranks and further from the bench does chemistry get less and less
important?
These are definitely worth asking. My reply was:
?As for the enthusiasm part, I may be a little bit odd, but not all that much. There are still plenty of people who enjoy what they're doing.
But part of it is realizing that chemistry is a means to an end in the drug business, not an end in itself. People are enthusiastic about finding something that works as a drug - that's why we don't mind mundane reactions as much, because those give you a lot more shots at making a drug than something that needs 2 days to set up. Of course, if you do nothing but (say) make sulfonamides all day, every day, you'll go nuts. But things vary too much for that to be a problem (most of the time). There's always another new structure idea that you have to figure out how to realize, another new core to work on, etc.
And the chemistry problems are just as knotty as you'd get in academia - how do I set these stereocenters, how do I do this reaction selectively so I can avoid a protecting group, etc. Sometimes they're on a different wavelength as well: How can I make this stuff in fewer steps? How can I avoid that evil mercury reagent? How do I get this stuff to form the right polymorph? How can I get to an intermediate that'll let me sit back and crank out a few analogs, instead of making everything from the ground up?
But, as I said, chemistry is means to an end. And the non-chemical problems are a lot harder: how do I get these compounds to have higher blood levels? (Next question - why are they so low now? Do they not get in through the gut, or are they getting whacked by the liver, or are they partitioning into some other tissue, or getting hosed out extra fast by the kidneys?) Why does this compound work, but the one without a methyl group kill the rats? (I've had that exact situation - truth be told, we never did completely figure out what was going on. . .) Why does this thing work so much better in mice than rats, and which one is going to be more predictive of humans - if either? And so on.
So, in a way, the chemistry problems take up less of your time the further on you go. Biology and development problems pick up the slack, and then some."
I'd be interested in hearing other takes on these, and I'm sure my correspondent would, too. Any industrial readers care to add some details?
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs
June 8, 2006
Posted by Derek
There's an article in Wednesday's Wall Street Journal (subscriber-only link here) (Update: also available freely here - thanks to Kyle of The Chemblog for finding this) on Merck's head of research, Peter Kim. It's well-written, in the sense that depending on how you come to it, you could come away with very different conclusions. If you're a fan of Kim and his approach since he took his current job, then you may well see a portrait of a driven, hard-working scientist struggling to change an insular, arrogant research culture and drag it into the real world. But if you're not so sure about Kim's managerial virtues, you can find evidence that he's in well over his head.
As the article notes, one of the big changes he's made is the number of deals that Merck has been signing. To be fair, the company was probably going to pick up the pace on outside collaborations anyway when its late-stage pipeline took so many hits, but maybe not to this extent. Much is made of a "charm school" operation where Merck's people were supposedly told not to be so haughty with potential small-company partners. I find it hard to imagine that this made a huge difference, though. Merck most certainly does have an attitude, even now, but I have to think that small company pitchmen are used to getting the same stuff everywhere they go.
Everyone knows the score at these presentations. The people from the smaller outfit are saying "We have something that you don't. Even though you're big and have more money than we do, believe us, you want this." And their counterparts on the other side of the table are saying "Prove it. We know that you think we're a big piggy bank to be turned over and shaken, but no nickels are coming out until you show us something more than snappy PowerPoints". The glad-handing approach that the article portrays Kim as using sounds to me like a recipe for overpaying for deals.
But my favorite part is on the various departures that have taken place:
Soon after he arrived, he angered Emilio Emini, Merck's senior vice president of vaccine research. During his 20 years at the company, Dr. Emini had done some seminal AIDS work. Dr. Kim wanted to hire another accomplished but controversial AIDS researcher, David Ho, to oversee him. Dr. Emini strongly objected. . .(and) left Merck in early 2004. He now works for rival Wyeth. . .
Vetern Merck research managers such as Kathrin Jansen, who was instrumental in the devleopment of (cervical cancer vaccine) Gardasil, and Scott Reines, a top researcher in psychiatric diseases, also took jobs at other pharmaceutical companies. . .Dr. Kim hired other academic scientists who enjoyed good reputations but, like hiim, had never developed a drug. . ."
Not having developed a drug is no particular shame - all of us in the industry start out never having done that. The thing is, we also start out knowing that everyone else in the place knows more than we do about it. High-level academia transplants have a poor track record in the drug industry - if you'd like some more evidence, you can ask some people with a few years of experience at Bristol-Meyers Squibb. Kim is probably correct when he says that Merck had too much of a "That's not how we do things here" attitude, but people sometimes forget that academia has no immunity to that disease, either.
Update: I also recommend checking out the take at Health Care Renewal, from an ex-Merck employee.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Industry History
December 4, 2005
Posted by Derek
I mentioned phosphatase inhibitors while talking about okadaic acid the other day, and that brings me to a paper from the journal ChemBioChem (6, 1749) that I was recently reading. It's a collaboration from six German academic groups, led by one at the Max Planck Institute for Molecular Physiology in Dortmund. And there are some things about it that just don't seem to make much sense.
On the surface, everything's fine. They're investigating some cyclic peptide derviatives called stevastelins, which are microbial natural products known to show some phosphatase inhibitor activity. They produced some synthetic analogs of the natural products and ran them against several phosphatases of interest. They then turned around and did the same thing with some analogs of two more phosphatase-inhibiting natural products, roseophilin and prodigiosin. (For those of you who've done some bacteriology, that first compound is responsible for the red color of Serratia marcesens colonies).
Then the paper makes a sharp turn, as they move on to a 20,000 compound library that's been assembled by a German academic team. They screened this against their panel of phosphatase enzymes, and came up with 8 or 10 pyrrolobenzoic acid structures that showed some inhibitory activity. End of paper.
Well, the way I've presented this, it sounds like a fairly reasonable paper, if a bit of a hodgepodge. But it's the way everything's presented that makes me wonder. For example, their first group of stevastelin analogs is (for the most part) inactive against the five phosphatases they assayed. One of them hits the Cdc25a enzyme, one of them hits PTP1B, and one of them is active against MptpA, all of which are legitimate drug targets. But these compounds are all around 10 to 15 micromolar, which potency doesn't exactly make me leap up out of my chair.
But the authors refer to this as "pronounced selectivity for individual phosphatases". If you read the fine print, the "not active" values are compounds that were 30 micromolar and worse, so we could easily be looking at just two- or three-fold selectivity here. That is not my definition of "pronounced". Add that to the very weak potency, and you have results that I would toss if I saw them come out of a screening run. As a medicinal chemist, I'd start to get really interested at about a hundred times the potency of these compounds, and I'd be willing to bet that by that time the selectivity, if it's really there, would be long gone.
Their other natural product analogs are similar - one's as good as 3 micromolar against PTP1B, but others start to hit the 30 micromolar ceiling of the assay again. Even the active compound has a very unappealing chemical structure, which would only be developed by a desperate drug company indeed. (I particularly enjoy one of them that's reported against MptpA as "28.7 +/- 9.7" micromolar).
What's also irritating is the statement the authors make to justify all this: "We have previously forwarded the notion that biologically active natural products should be regarded as evolutionarily selected and biologically prevalidated starting points for inhibitor development." I'm glad they brought that up, since drug development from natural products has only been a popular technique for a century or so. The problem, as they're demonstrating here, is that if these compounds really are evolutionarily selected as phosphatase inhibitors, and the last hundred million years have only given you micromolar potency, then the odds of being able to push that lower by making half a dozen analogs are rather slim.
And that brings us to their screening efforts. Their compound library is "selected due to their diverse representation of reportedly bioactive scaffold elements". But 20,000 small molecules, however carefully selected, is not a very large collection. And when you get down to it, our compound collections in the drug industry are also supposed to represent a lot of reportedly bioactive scaffolds, and most of them are a couple of orders of magnitude larger.
The compounds from the screen are all micromolar. One of them looks a bit interesting, and possibly selective between the two kinases they ran it against. (What happened to the other enzymes by this point in the paper, I wonder?) I wouldn't want to try to develop these guys, but with the application of a lot of time, money, and effort, you might be able to get somewhere. Or you might wipe out within six months, which is how a lot of projects go, even the ones with better starting points than this, which is most of them.
Ah, but the authors are more optimistic than I am, because (I suspect) they haven't actually tried to do any drug development. "Further application of medicinal chemistry methodologies should allow for the development of more potent inhibitors for subsequent biological investigations in iterative cycles", they say. Oh, yes. Shouldn't it always?
Why am I going on at this length? Because I think that this paper illustrates a general problem: many academic labs do not understand what drug discovery entails, and (worse) they don't realize that they don't understand. The attitude shown here - presenting a few micromolar compounds as fine lead compounds and saying that med-chem should be able to sort things out - would actually be a good way to get fired at most companies. If this paper's data were somehow presented to me as a rationale for starting a project, I would create a distraction and dive for the door. No, there's still a long way to go.
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November 8, 2005
Posted by Derek
There's an interesting letter to Science in the latest issue (Nov. 4, #5749, p. 777), in response to their special section on drug discovery in the July 29th issue. Adrian Ivinson, a former editor of Nature Medicine and now head of a new research center at Harvard Medical School, writes that the section:
". . .did not recognize an increasingly relevant but underappreciated and underutilized role for academic research in drug discovery.
Universities invest may millions in basic research that exposes disease mechanisms and therefore unearths new targets. Yet few have invested in the relatively modest infrastructure required to put their discoveries to the test. As a result, many promising targets gather dust on the university shelf. . ."
Really? Send 'em over here. I've spent a lot of time defending the way the drug industry takes basic research from academia and turns it into applications. (See the September 9th, 2004 post here and work up from there if you're interested). The usual complaint is that that's all we ever do, so it's refreshing, in a weird way, to hear a complaint that we're not taking enough. But if these targets are being published somewhere even semi-reputable, believe me, we're seeing them.
And as for the "relatively modest infrastructure", that depends on what you mean by modest. For example, the research site I work at does no manufacturing, no human trials, no large animal toxicology studies, and very little scale-up chemistry (just enough to get through two-week rodent runs). But we have hundreds of people working here, in several rather large and expensive buildings crammed full of expensive stuff. Now, it's true that we're working on a number of projects simultaneously - just how many, I'm most certainly not going to say. But you'd need a lot of this stuff around no matter how few projects you were developing.
Dr. Ivinson goes on to say that assay development and validation, compound screening, medicinal chemistry and preliminary animal tests are functions "well suited" to academia. Perhaps, perhaps. But it should be noted that there are some well-known people (such as Stuart Schreiber) with experience in both academic and industrial research who worry about academia's ability to do this sort of thing. He also says:
"Demonstrating a credible mechanism and target, proprietary lead compounds, and preliminary in vivo efficacy will be enough to bring some of our industry colleagues back to the table."
That it will! Be prepared, though, to drop more than a good-sized grant application's worth of money to do that, though. It's harder than it looks to get that far. And those proprietary compounds might scare away as many companies as they attract, by the way. Proprietary means, of course, that you guys own them, and that means that we have to buy them. We'd naturally much rather have our own compounds. That would mean demonstrating proof of concept with something that's not patentable, but there are worse things. We can always screen, and believe me, we have a lot more things in our screening files than you do.
As I've said, I think that Dr. Ivinson is underestimating the difficulty of drug discovery, but at least he realizes that it's worth doing. The letter finishes with a sentiment that I can only applaud:
"But this will only happen when academics stop treating drug discovery as the intellectually inferior domain of the commercial sector and start seeing it as the natural development of their research."
Yes, indeed!
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October 6, 2005
Posted by Derek
A reader at a large research university sends this along for comment:
"My advisor is a staunch skeptic of the value of "big pharma". He recently made a comment in a group meeting that "Merck has not discovered anything in 25 years. They don't do research, they acquire it. In fact, I don't know why they even have chemists and biologists, maybe they feel they have to..."
Well. I realize that there's a lot of good-natured sniping between industry and academia, but that kind of crosses the line, doesn't it? The first thing that I feel like saying to this professor is that Merck, which is indeed one of those Big Companies That Makes Money, presumably doesn't employ an army of expensive chemists and biologists for cosmetic reasons. So if you can't figure out why they've kept such people around for decades, perhaps there could be valid reasons that you haven't fully appreciated. It's a hypothesis worth considering, and that would be a higher-percentage move than assuming that the company must be so thickheaded that it hasn't yet figured out that it could fire everyone. That's an interesting approach to the data, sort of like trash-canning any experiment that didn't fit your original assumptions. You don't do that, though, right?
This is an especially rich comment when applied to Merck, which does as much (or more) fundamental research as anyone in the industry. If you want to talk about just going out and buying your stuff, snipe at Pfizer. But Merck is famous for digging into its own projects for years and years until they get them to work. Perhaps a look at a search for "Merck" in PubMed would illustrate the point?
Maybe the problem is that phrase "discovered anything." I've found that some university-based scientists actually take that to mean "discovered anything that would make a neat article in Cell". In the drug industry, our definition is more like "discovered something useful that no one else has done before". And "something useful" means "something that improves a person's health enough that they're willing to pay us money for it". I realize that I've introduced the monetary snake into the Garden of Pure Research, but ah, what choice do we have? They don't give out grants big enough to pay for what we do.
I'm willing to bet that you're thinking about the case of the COX-2 inhibitors. As many people have heard, Merck made quite a bit of money until recently selling one of those. The University of Rochester had a patent on the enzyme and its use as a screening tool, and sued Searle (now Pfizer). But they were trying to reach through and claim a share of the profits for the drugs found through this method (while not, last I heard, offering to soak up any of the recent losses). This suit failed, and it's worth remembering why:
As one of my readers put it, Rochester discovered a new shovel, and laid claim to any gold that might be dug up with it. That's an excellent metaphor, and I'd extend it to say that they were laying claim not just to the raw gold, but to the finished jewelry. The gap between a basic discovery and a drug is much, much wider than even well-educated people seem to realize.
I could go on, and have. But I think I'll close with an item from this morning's news wires. Merck has announced that they have successfully tested a vaccine that will likely prevent the vast majority of cervical cancers. That must have been accomplished by their idle scientists in those brief intervals between cackling with glee while they threw stacks of hundred dollar bills into the air, but I'm glad they took the time to do it. Does this, I'd very much like to know, count as a discovery? After all, vaccines have been known for a long time. Heck, cervical cancer isn't a new disease either, nor is its association with the HPV viruses. I'll bet Merck couldn't get this study published in Cell, or even PNAS. They'll have to settle for the front pages of virtually every newspaper in the world. Time to kick back for another twenty-five years!
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August 22, 2005
Posted by Derek
I'm not saying these are all true, or true all the time. But here are three things that industrial pharma researchers tend to believe about academic ones:
1. They talk too darn much. Don't even think about sharing any proprietary material with them, because it'll show up in a PowerPoint show at their next Gordon conference. How'd that get in there?
2. They wouldn't know a real deadline if it crawled up their trouser legs. Just a few weeks, just a few months, just a couple of years more and they'll have it all figured out. Trust 'em.
3. They have no idea of how hard it is to develop a new compound. First compound they make that's under a micromolar IC50, and they think they've just discovered Wonder Drug.
And (fair's fair), here are three things that academic researchers tend to believe about industrial ones:
1. They have so much money that they don't know what to do with it. They waste it in every direction, because they've never had to fight for funding. If they had to write grant applications, they'd faint.
2. They wouldn't know basic research if it bonked them on the head. They think everything has to have a payoff in (at most) six months, so they only discover things that are in front of their noses.
3. They're obsessed with secrecy, which is a convenient way to avoid ever having to write up anything for publication. They seem to think patent applications count for something, when any fool can send one in. Try telling Nature that you're sending in a "provisional publication", details to come later, and see how far that gets you.
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August 9, 2005
Posted by Derek
You hear an awful lot about teamwork when you're in industry. (Personally, my fist clenches up whenever I here the phrase "team player", but perhaps that's just me.) But there's a bit of truth in all this talk, and it's something that you generally don't encounter during graduate training.
As a chemistry grad student, you're imbedded in a chemistry department, and most outside groups will either be irrelevant or there to service things for you. Getting along with people outside your immediate sphere is useful, but not so useful that everyone makes the effort. But pharmaceutical companies have a lot of different departments, and they're all pretty much equal, and they are all supposed to get along. You've got your med-chem, your pharmacology, the in vivo group (or groups, who may be stepping on each other's toes), metabolism, PK, toxicology, formulations. . .as a project matures, everybody gets dragged in.
These other folks do not see themselves, to put it mildly, as being put on earth to service the medicinal chemistry group. They are very good at detecting the scent of that attitude, and will adjust theirs accordingly. (Some of them already have filed chemists in the "necessary evil" category.) For the most part, no one is supposed to be able to pull rank on anyone else, so in order to get things done, you'll have to play nicely with others.
Not everyone figures this out. I watched someone once whose technique of speeding up the assay results for his compounds was to march down to the screening lab and demand to know where his procreating numbers were, already. No doubt he thought of himself as a hard-hitting, take-charge kind of guy, but the biologists thought of him, unsurprisingly, as a self-propelled cloaca. His assay submissions automatically got moved to the "think about it until next Tuesday" pile, naturally.
Earlier entries in the series can be found here.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs
April 20, 2005
Posted by Derek
There was a good question asked in the comments to the previous post on first job interviews: what do you talk about when you work at one company and you're interviewing at another?
Well, I've done that myself, more than once (note to my current co-workers: not in the last few years, folks.) And it can be tricky. But there are some rules that people follow, and if you stay within their bounds you won't cause any trouble. That's not to say that my managers wouldn't have had a cow if they'd seen my old interview slides at the time, but I was at least in the clear legally. Here's how you make sure of that:
First off, it would be best if you could confine your interview talk to work that's been published in the open literature. That stuff is, by definition, completely sterilized from an intellectual property standpoint, and you can yammer on about it all day if you want. The downside is that published work tends to be pretty ancient stuff by the time it shows up in a journal, and you've may have done a lot more interesting things since then. (The other downside is that published projects are almost always failed projects.) Work that's appeared in issued patents is also bulletproof, of course, but it suffers from the same time-lag disadvantages.
Second best is work that's appeared in patent applications. This stuff hasn't been blessed by the patent office yet, so things could always change, but it's at least been disclosed. When you talk about it, you're not giving away anything that couldn't have already been downloaded and read. (Of course, you do have to resist the temptation to add lots of interesting details that don't appear in the application.)
If you've at least filed the applications, then you can still be sort of OK, since they're going to publish in a few months, anyway. This is a case-by-case thing. If the company you're interviewing at is competing with you in that very field, you'd better not give them a head start. But if you're talking antivirals at a company that does nothing but cardiovascular and cancer, you should be able to get away with it. It would be best if you didn't disclose full structures - leave parts of the molecules cut off as big "R" groups and just talk about the parts that make you look like the dynamic medicinal chemist you are.
The worst case is "none of the above." No published work worth talking about, no patent applications, no nothing. I actually did go out and give an interview seminar under those conditions once, and it was an unpleasant experience. I had to talk about ancient stuff from my post-doc, and it was a real challenge convincing people that I knew what was going on in a drug company. I don't recommend trying it.
But I don't recommend spilling the beans in that situation, either. I've seen a job interview talk where it became clear that the speaker was telling us more than he really should have, and we all thought the same thing: he'll do the same thing to us if he gets a job here. No offer.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | How To Get a Pharma Job | Life in the Drug Labs
April 19, 2005
Posted by Derek
I've been seeing quite a few candidate seminars recently, so allow me to pass on some advice to those of you out on the first-job-in-the-drug-industry trail.
First off, some presentation tips: Speak up, if possible. I hear ten too-soft seminars for every too-loud one. Don't give your talk to the screen - either the one on your laptop or the one on the wall. Give it to the people in the room. Look up, turn around, do what you need to do to give them the sense that you're passing information on to them. Find a way to sound somewhere between the extremes of here-is-my-script and gosh-I-don't-remember-this-slide.
As for that information, slides in a scientific presentation should have a medium amount of information on them. A whole slide with one big reaction on it is OK during the introduction, but you'd better fill things out a bit as you move on in the talk. Your audience can tell if you're padding things out.
But don't make the opposite error, putting all your information on one slide in One Big Table. You might think it looks more impressive that way, but it's just irritatingly illegible and uninterpretable. Spread those big data heaps out a bit into coherent piles - put all the aliphatic examples on a slide, followed by the aromatic ones, and so on. You'll find more things to talk about that way, too.
Be honest. If you have to come in with a thin talk, for whatever reason, admit it to yourself and be prepared to admit it in some fashion to your audience. Find some ways to show them that you know more than your slides can illustrate. And don't try to pretend that your results are groundbreaking and exciting, unless they really, really are. Exciting results usually speak for themselves, and your audience will know 'em when they see 'em.
Be prepared for the obvious. If you put a weird reaction up on the screen, someone is going to ask you about the mechanism. If you have some unusual results in a series, someone's going to ask you why you think they came out that way. Be ready with some ideas - it can be fine to not know the answer yet, as long as you've shown that you've thought about what the answer might be. Looking unprepared for down-the-middle pitchs like these will get you crossed off the list very quickly.
And look as if you can learn. No one comes into the drug industry knowing what they really need to know. It comes with experience, and you need to make it clear that you're the sort of person that experience is not wasted on.
That should help. I'll settle for a fee of 10% of your first year's salary, OK?
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+ TrackBacks (0) | Category: Academia (vs. Industry) | How To Get a Pharma Job
March 30, 2005
Posted by Derek
I thought I'd briefly explain one of my "Ten Questions" from the other day. The old-fashioned qualitative organic tests that I mentioned in #4 are things that were used in the 1960s and before to identify classes of compounds. Various brews can give you color indicators for the presence of double bonds, methyl ketones, aldehydes and the like. Some of them are quite dramatic - Tollens reagent, for example, suddenly deposits a silver mirror layer (scroll down on that link to see it) on the inside of the flask when it goes right.
But no one uses this stuff any more. No one at all, at least not if they can help it. Modern methods like NMR and routine HPLC/mass spectrometry have completely destroyed the usefulness of the old chemical tests, because you can now find out far more about your compound with little or no destruction of the sample.
Some undergraduate courses apparently still have these reactions in their curricula, and the only reason I can see is inertia. I've heard rationalizations about using them to teach reaction mechanisms and so on, but you can do that just as easily with reactions that real chemists actually run in the real world. And why wouldn't you? If you're a student that's been asked to run a battery of qualitative organic tests, you should ask for a refund of your tuition. You're being had.
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February 24, 2005
Posted by Derek
Being a harmless science blogger, I've stayed out of the whole Harvard/Summers/women-versus-men tar pit. (Proof that I don't spend all my time fishing for traffic, as if posts on patent law weren't enough evidence already.) If you want, you can find more discussion of that controversy than you could want on any of the current-affairs blogs. But, still, I was struck by a comment from Virginia Postrel. She's discussing what might be done to increase the female presence in the sciences, given that biological clocks for reproduction work very differently for women and men (i.e., fathering a child at 45 is a lot easier than getting pregnant at that age. Neither Virginia nor I make any claims about the wisdom of doing either one; we're just talking biological feasibility):
"If, however, you spend six years in grad school and another two as a postdoc, you'll be 30 when you get your first tenure-track post--and that's assuming you don't work between college and grad school. I don't have the numbers, but science training is notorious for stretching out the doctoral/postdoc process, in part because the researchers heading labs benefit from having all that cheap, talented help. Female scientists who want kids are in trouble, even assuming they have husbands who'll take on the bulk of family responsibilities."
Fortunately, that long a stint in academia is unusual by chemistry standards, but molecular biology is notorious in just the way she's talking about. I've seen biology postdoctoral positions break up marriages, because the other partner eventually just wanted to finally, finally move on with life. Her suggested remedies?
"So, if a university like Harvard wants to foster the careers of female scientists, this is my advice: Speed up the training process so people get their first professorial jobs as early as possible--ideally, by 25 or 26. Accelerate undergraduate and graduate education; summer breaks are great for students who want to travel or take professional internships, but maybe science students should spend them in school. Penalize senior researchers whose grad students take forever to finish their Ph.D.s. Spend more of those huge endowments on reducing (or eliminating) teaching assistant loads and other distractions from a grad student's own research and training."
I got my first real PhD-level job at 27, after a year's post-doc, but that's a year or so younger than average for organic chemistry. I spent my undergraduate summer breaks doing research internships (of greater and lesser value), but I should make clear to those outside the field that graduate students in the sciences already work all through the summer. When I was in grad school, we watched the law students across the street pack up and leave in the spring while we cranked away in the lab days, nights, weekends, and holidays. I treasure a memo in my files from the chemistry department head, pointing out that the university vacation calendar did not apply to grad students - and he wasn't just talking about summers, of course. Do not, the memo warned, attempt to take all these holidays, things with names like "spring break", even though you may hear people talking about them.
As for Virginia's other prescriptions, I think penalizing slowpoke professors is a great idea. I know that some schools talk about doing this, but I've never seen any of them follow through. I think that the inverse idea, rewarding those research groups with a high percentage of students finishing on time, would be worth looking into as well. There are plenty of groups that could use a better work ethic - not in terms of the number of hours put in, but in terms of making sure that everything the students do is devoted to the great and holy cause of getting the hell out of graduate school. That's something you should do on general principles, man or woman, whether you plan to start a family or not. Grad school is for getting through, not for lingering.
Reducing TA assignments would also help. I know that many professors, if they have enough grant money, try to get their students out of teaching assistant positions as early as the university will let them (I did one year of it, the minimum.) But if you work for someone without as much of the ready cash, you can be TA-ing until your last year, and in an increasingly bitter mood about it, too.
Speeding up graduate education can be done. You don't want to turn out a bunch of unprepared losers, but as far as I can see, the system we have now does that anyway, but often too slowly. It's true that real research projects take time - you're never going to get well-trained chemistry PhDs out the door in two and a half years. But you shouldn't be expecting five and six years out of people as the norm.
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February 10, 2005
Posted by Derek
These two posts (here and here) over at Uncertain Principles are well worth reading if you like discussions of the divide between people who understand science and people who don't. Chad Orzel, being a physicist, instantly translates "doesn't understand science" to "doesn't understand math", which is fair enough, especially for physics. His analogy to the language of critical theory, as found in English literature classes and the like, has threatened to turn the comments threads for both posts into debates about that instead, but Chad's doing a good job of trying to keep things on topic.
What he's wondering about, from his academic perspective, is how to teach people about science if they're not scientists. Can it be really done without math? He's right that a fear of mathematics isn't seen as nearly as much of a handicap as it really is, and he's also right that physics (especially) can't truly be taught without it. But I have to say that I think that a lot of biology (and a good swath of chemistry) can.
Or can they? Perhaps I'm not thinking this through. It's true that subjects like organic chemistry and molecular biology are notably non-mathematical. You can go through entire advanced courses in either field without seeing a single equation on a blackboard. But note that I said "advanced". I can go for months in my work without overtly using mathematics, but my understanding of what I'm doing is built on an understanding of math and its uses. It's just become such a part of my thinking that I don't notice it any more.
Here are some examples from the past couple of weeks: a colleague of mine spoke about a reaction that goes through a reactive intermediate, an electrically charged species which is in equilibrium with a far less reactive one (which doesn't do much at all.) That equilibrium is hugely shifted toward the inert one, but pretty much all the product is found to have gone through the path that involves the minor species. That might seem odd, but it's not surprising at all to someone who knows organic chemistry well. A less reactive species is, other things being equal, usually more energetically stable than a more reactive one, and the more stable one is (fittingly) present in greater amount. But since the two can interconvert, when the more reactive one goes on to the product, it drains off the less reactive one like opening a tap. There's a good way to sketch this out on a napkin, where the energy of the system is the Y coordinate of a graph - anyone who's taken physical chemistry will have done just that, and plenty of times.
Here's another: a fellow down the hall was telling us about a reaction that gave a wide range of products. Every time he ran one of these, he'd get a mix, and bery minor changes in the structure of the starting material would give you very different ratios of the final compounds. That's not too uncommon, but it only happens in a particular situation, when the energetic pathways a reaction can take are all pretty close to each other. The picture that came to my mind instantly was of the energy surface of the reaction system. Now, that's not a real object, but in my mental picture it was a kind of lumpy, rubbery sheet with gentle hills and curving valleys running between them. Rolling a ball across this landscape could send it down any of several paths, many of them taking it to a completely different resting place. Small adjustments from underneath the sheet (changing the height and position of the starting point, or the curvature of the hills) would alter the landscape completely. Those are your changes in the starting material structure, altering the energy profile of all the chemical species. A handful of balls, dropped one after the other, would pile up in completely different patterns at the end after such changes - and there are your product ratios.
Well, as you can see, I can explain these things in words, but it takes a few paragraphs. But there's a level of mathematical facility that makes it much easier to work with. For example, without a grounding in basic mathematics, I don't think that that picture of an energy surface would even occur to a person. I believe that a good grasp of the graphical representation of data is essential even for seemingly nonmathematical sciences like mine. If you have that, you've also earned a familiarity with things like exponential growth and decay, asymptotes, superposition of curves, comparison of the areas under curves and other foundations of basic mathematical understanding. These are constant themes in the natural world, and unless they're your old friends, you're going to have a hard time doing science.
That said, I can also see the point of one of his commentators that for many people, it would be a step up to be told that mathematics really is the underpinning of the natural world, even if some of the details have to be glossed over. Even if some of them don't hit you completely without the math, a quick exposure to, say, atomic theory, Newtonian mechanics, the laws of thermodynamics, simple molecular biology and the evidence for evolution would do a lot of folks good, particularly those who would style themselves well-educated.
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January 17, 2005
Posted by Derek
Over at Sean Carroll's "Preposterous Universe", there's a post on a physicist's advice to students who want to become scientists. Don't even try, he tells them. No jobs, no money, no thrill, no hope. It's depressing stuff. Carroll is a physicist himself, so he has quite a bit to say on the topic. (Link found via yet another physicist.)
Reading the whole thing, though, I was struck by how far from my own experience it is. The drug industry's going through a rough patch, for sure, but there are companies still hiring. And although we've had some layoffs, and more are in the offing, there are still thousands upon thousands of us out here. We're gainfully employed, working on very difficult and challenging problems with large real-world implications. (And hey, we're getting paid an honest wage while we're doing it, too.)
That's when it hit me: the article that Carroll's referring to isn't warning people away from becoming scientists. It's warning them away from becoming physics professors. Very different! Those categories intersect, all right, but they're not identical. There are other sciences besides physics (no matter what Rutherford said), and in many of them, there's this other world called industry. (The original article doesn't even mention it, and Carroll disposes of in his first paragraph.)
Some of this is (doubtless unconscious) snobbery - academic science is pure science, after all, while industry is mostly full of projects on how to keep cat litter from clumping up in the bag or finding new preservatives for canned ravioli. Right? And some of it reflects the real differences between physics and chemistry. To pick a big one, research (and funding) in physics has been dominated for a long time by some Really Big Problems. The situation's exacerbated by the way that many of these big problems are of intense theoretical but hazy practical interest.
I am not knocking them for that, either, and I'll enter my recent effusions about the weather on Titan as evidence. I'd love to hear that, say, an empirically testable theory of quantum gravity has made the cut. But that kind of work is going to be the domain of academia. I think that it's a sign of an advanced civilization to work on problems like that, but advanced civilization or not, it's not likely to be a profit center. Meanwhile, chemistry doesn't have any Huge Questions at the moment, but what it has are many more immediately applicable areas of research. Naturally, there are a lot more chemists employed in industry (working on a much wider range of applications.)
Many of the other differences between the fields stem from that basic one. Chemistry has a larger cohort of the industrially employed, so the academic end of the business, while not a jolly sight, isn't the war of all against all that you find in physics, astronomy, or (the worst possible example) the humanities. The American Chemical Society's idea of worrisome unemployment among its members would be clear evidence of divine intervention in many other fields. So those of us who get paid, get paid pretty well. And we don't do three, four, five-year post-docs, either, which is something you find more of in fields where there aren't enough places for everyone to sit down. Two years, maximum, or people will think that there's something wrong with you.
All of this places us, on the average, in a sunnier mood than the physics prof who started this whole discussion (whose article, to be sure, was written four or five years ago.) I was rather surly during grad school, but for the most part I'm happy as the proverbial clam. As I've said, if someone had come to me when I was seven years old and shown me the work I do now, I would have been overjoyed. Who can complain?
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January 5, 2005
Posted by Derek
You know what I don't miss about chemistry after years in the drug industry? Big, long, multi-step syntheses. Oh, we'll gear up to do eight- and ten- and thirteen-steppers here, even though some of those steps are just things like hydrolyzing methyl esters, stuff that blindfolded grannies should be able to do. But what I'm happy to leave the mighty academic natural product synthetic schemes behind, the ones where step fourteen finds you just getting warmed up.
As I've mentioned here before, I did that kind of thing in graduate school, and I swear it's scarred me for life. I pulled the plug on my total synthesis at step 27, about six steps short of the end (this is, if everything had worked perfectly, obese chance.) I've never regretted it. The benefits of getting out of grad school are huge, spacious, and well-appointed compared to the benefits of being able to say that I finished my natural product. Any of my readers in grad school, take note.
Long linear sequences are a slog. You have to start them in the largest buckets you can find, because you're never, ever going to have enough material. Now, we do large scale work in the drug industry, yes indeed, but that's because we intend to finish on large scale. If you're going to do six-week toxicity testing, you'd better have a fine keg of material on hand before you start. But those academic syntheses need huge amounts at the beginning in order to have anything at all by the time they finish. You work until you can't handle or characterize the stuff any more, then you trudge back down the mountain and start porting the loads back up the trail.
An example: I got to the point where I needed to take an optical rotation on the material from about step 25 or so. For those outside the field, this is an analytical technique that involves shining polarized light through a solution of your compound. If it's not an even mix of left-handed and right-handed isomers, that is to say, if there's some chiral character to the sample, the light will rotate. The degree of rotation can be used as an indicator of compound purity - I'm tempted to add "if you're a fool." They're not the most reliable numbers in the world, because some things just don't make the light twist much. And in those cases, a small amount of an impurity that rotates light like crazy will throw everything off. It's happened more than once.
Well, in my case, I loaded a half milligram or so of my precious stuff into the smallest polarimeter tube we had and jammed it into the machine. Hmm, I thought, a rotation of 0.00 degrees. A singular result, since I knew for certain that the molecule had six pure chiral centers. So I went back upstairs and loaded the whole batch into the tube, walking very carefully down the hall with this investment of several months of my life held in both sweaty hands. This time I got a specific rotation of about 1.2 degrees, which means that all those chiral carbons were roughly canceling each other out. Did I believe that number? Not at all! Did I put it in my dissertation? You bet! Gotta have a number, you know.
And that's how you work - purifying things through increasingly tinier columns, collecting them in slowly shrinking vials, running all the instruments for longer and longer with the gain turned up higher and higher, trying to prove that it's really still in there and really still what it's supposed to be. Then it's back to the buckets. Never again!
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November 9, 2004
Posted by Derek
The October 29th issue of Science has an interesting article from a team at Stanford on a possible approach for Alzheimer's therapy. The dominant Alzheimer's hypothesis, as everyone will probably have heard, is that the aggregation of amyloid protein into plaques in the brain is the driving force of the disease. There's some well-thought-out dissent from that view, but there's a lot of evidence on its side, too.
So you'd figure that keeping the amyloid from clumping up would be a good way to treat Alzheimer's, and in theory you'd be correct. In practice, though, amyloid is extremely prone to aggregation - you could pick a lot of easier protein-protein interactions to try to disrupt, for sure. And protein-protein targets are tough ones to work on in general, because it's so hard to find a reasonable-sized molecule that can disrupt them. It's been done, in a few well-publicized cases, but it's still a long shot. Proteins are just too big, and in most cases so are the surfaces that they're interacting with.
The Stanford team tried a useful bounce-shot approach. Instead of keeping the amyloid strands off each other directly, they found a molecule that will cause another unrelated protein to stick to them. This damps down the te |
