About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
September 30, 2010
Several people have brought this editorial (PDF) to my attention: "Where is the Passion?" It's from a professor at the Sidney Kimmel Center at Johns Hopkins, and its substance will be familiar to many people who've been in graduate school. Actually, the author's case can be summed up in a sentence: he walks the halls on nights and weekends; there aren't enough people in the labs. Maybe "kids these days!" would do the job even faster.
I'm not completely unsympathetic to this argument - but at the same time, I'm not completely unsympathetic to the people who've expressed a desire to punch the guy, either. The editorial goes on for quite a bit longer than it needs to to make its point, and I speak as someone who gets paid by the word for printed opinion pieces. It's written in what is probably a deliberately irritating style. But one of the lessons of the world is that annoying people whom you don't like are not necessarily wrong. What about this one?
One of the arguments here could be summed up as "Look, you people are trying to cure cancer here - don't you owe it to the patients (and the people who provided the money) to be up here working as hard as possible?" There's no way to argue with that, on its face - that's probably correct. But now we move on to the definition of "as hard as possible".
He's using hours worked as a proxy for scientific passion - an imperfect measure, to be sure. At the two extremes, there are people who are not in the lab who are thinking hard about their work, and there are people in the lab who are just hamster-wheeling and doing everything in the most brutal and stupid ways possible. But there is a correlation, especially in academia. (In many industrial settings, people are actively discouraged from doing too much lab work when they might be alone). If you're excited about your work, you're more likely to do more of it.
Unfortunately, it's hard to instill scientific excitement. And if anyone's going to do it at all, you'd think it would be the PIs of all these grad students. What surprises me is that more of them aren't falling back on the traditional grad-school substitute for passion, which is fear. The author does mention a few labs at his institute that have the all-the-time work ethic, and I'm willing to bet that good ol' anxiety and pressure have as much or more to do with their habits. And a little of that mixture is fine, actually, as long as you don't lay it on with a trowel.
So yes, I wish that there were more excited, passionate researchers around. But where I part company with this editorial is when it goes into get-off-my-lawn mode. The "You have to earn your way to a life outside the lab" attitude has always rubbed me the wrong way, and I've always thought that it probably demotivates ten people for every one that it manages to encourage. The author also spends too much time talking about the Good Old Days when people worked hard, with lousy equipment. In the dark! In the snow! And without all these newfangled kits and time-saving reagents! That makes me worry that he's confusing some issues. An idiot frantically digging a ditch with a spoon looks like a more passionate worker than someone who came through with a backhoe three hours ago, and is now doing something else.
Still, the point of all those time-saving kits is indeed to keep moving and do something else. Are people doing that? I'd rather judge the Sidney Kimmel Center by what comes out of it, rather than how late the lights burn at night. Is that the real "elephant in the room" that the editorial winds up invoking? That what the patients and donors would really be upset about is that not enough is coming out the other end of the chute? Now that's another problem entirely. . .
Update: Chemjobber has some questions.
+ TrackBacks (0) | Category: Graduate School | Who Discovers and Why
September 28, 2010
I'm out of touch at a meeting all day today, so I thought I'd put up a request thread. What topics would people like to see covered here in the coming days and weeks? I have some chemical biology posts queued up, and current events will always intervene, but if you have any other topics for a medium-to-long horizon, feel free to suggest 'em. Thanks!
+ TrackBacks (0) | Category: Blog Housekeeping
You don't see an awful lot of chemistry publications from Vietnam. So in a way, I'm reluctant to call attention to this one, in the way that I'm about to. But it's in the preprint section of Bioorganic and Medicinal Chemistry Letters, and some of my far-flung correspondents have already picked up on it. So it's a bit too late to let it pass, I suppose.
The authors isolate a number of natural products from Wisteria (yep, the flowering woody vine one), and most of them are perfectly fine, if unremarkable. But their compound 1 (wisterone) is something else again.
Man, is that thing strained. Nothing with that carbon skeleton has ever been reported before (I just checked), outside of things that you can draw as part of the walls of fullerenes. I have a lot of trouble believing that this compound exists as shown - and if it does, then it deserves a lot more publicity than being tossed into a list inside a BOMCL paper - even though that journal is now getting a reputation for. . .interesting structural assignments.
This thing could get you into Angewandte Chemie or JACS, no problem. But the authors don't make much of it, just calling it a new compound, and presenting mass spec and NMR evidence for it. The 13C spectrum is perfectly reasonable for some sort of para-substituted aryl ring, but this compound would not give a perfectly reasonable spectrum, I would think. Surely all that strain would show up in some funny chemical shifts? Another oddity must be a misprint - they have the carbon shift of the carbonyl as 190.8, which is OK, I suppose, but they assign the methylenes as 190.8, which can't be right. (The protons come at 4.48).
No, I really think something is wrong here. I don't have a structure to propose, off the top of my head (not without resolving that weirdo methylene carbon shift), but I don't think it's this. Anyone?
Update: just noticed that this is said to be a crystalline compound, melting point of 226-228. I find it hard to imagine any structure like this taking that much heat, but. . .it's a crystal! Get an X-ray structure. No one's going to believe it without one, and BOMCL should never have let this paper through without someone asking for at least that. . .
+ TrackBacks (0) | Category: Analytical Chemistry | Chemical News
As we head towards October, the thoughts of a very select group of scientists may be turning to their chances of winning a Nobel Prize - and the thoughts of the rest of us turn to laying odds on the winners. I've handicapped the race here before (here's the 2009 version), and that's one place to start a list. Another excellent roundup can be found over at Chembark, and another well-annotated one at the Curious Wavefunction. Meanwhile, Thomson/Reuters sent me their citation-voodoo list the other day, but to my eyes, they're always a bit off the mark.
So who are the favorites? Last year I mentioned Zare, Bard, and Moerner for single-atom spectroscopy, and I think that after a run of biology-laced prizes that a swing back over to nearly-physics is pretty plausible. If the committee is going to stick with nearly-biology, then perhaps humanized antibodies, microarrays, or chaperone proteins will make it in, but I really don't think that this is the year (in the Chemistry prize, anyway). On the chemistry/medicine interface, there's always the chance that the committee could turn around and honor Carl Djerassi after all these years, but that's the only med-chem themed prize I can see. I think the chances of a pure organic synthesis prize are very low indeed - and that includes palladium-catalyzed couplings, too, unfortunately. There are too many people deserving of credit there, "too many" meaning "more than three" for Nobel purposes, and not all of them are still alive.
The more I think about it, the more skeptical I am of a Nobel for dye-based solar cells (Grätzel et al.) or any form of asymmetric catalysis this year. If anything, the committee waits too long before recognizing things, and it's just too early for these (and some other ideas floating around out there). The Thomson/Reuters list seems to be very big on metal-organic framework materials, for example, and I just don't see it. Waiting too long is a problem, but giving trendy things out too soon can be an even bigger one.
On the other end of the scale, I used to confidently predict a Nobel for RNA interference (in one field or another), and they finally took care of that one. The only Nobel I feel similarly sure of is in Physics, for the "dark energy" finding that the expansion of the universe is accelerating. At some point that one's going to win - maybe when there's more of an explanation for it, although that could be a bit of a wait. This is an area where I and the Thomson/Reuters people agree (and a lot of physicists seem to go along, too).
Want to make your own odds? This Chembark post is a fine overview of the factors involved. Suggestions welcome in the comments from anyone who feels as if their psychic powers are tuned up. . .
+ TrackBacks (0) | Category: Chemical News | General Scientific News
September 27, 2010
Readers may remember the case of Ronald Daigle, who died of exposure to TMS diazomethane a couple of years ago in Nova Scotia.
Sepracor, the company who owned the facility at the time, has now pleaded not guilty to five charges related to this accident. (Many more details at C&E News). This case appears (slowly) to be going to trial, so it'll be something to keep an eye on. . .
+ TrackBacks (0) | Category: Safety Warnings
A group at GSK has published a paper in Angewandte Chemie on the kinds of reactions that medicinal chemists use, and why they use them. The conclusions will come as no surprise to anyone practicing in the field. The workhorse reactions were condensations (amides, etc.), palladium-catalyzed couplings, and alkylations. And if you look at the reactions used to generate arrays (small libraries) of compounds simultaneously, those reactions almost take over the list.
Why is that? Well, for one thing, because those reactions tend to work. You'll almost always get product out of them - no small thing. You really, really don't want to spend time tweaking a reaction just to make it produce something, not when the odds of any individual product working are still small. And you can also get a good amount of structural diversity off-the-shelf, by using the huge numbers of commercial amines, acids, aryl boronic acids, and so on. They're also fast reactions, for the most part: set 'em up one day, work 'em up the next, and on to the next analogs.
The authors list some criteria that new reactions would need to order to make the list: not fussy about conditions (temperature, time, order of addition, atmosphere, etc.), compatible with polar solvents, tolerant of a wide range of functional groups, easy to dispense, easy to clean up, and so on. They mention that there's been funding in the UK over the last few years (as there has been here) for discovery of new chemistries that would meet this standards, but (reading between the lines) it doesn't seem as if anything major has made it up the charts yet.
Their other take-home is that people who specialize in running arrays can usually do them more efficiently than those who set them up just once in a while. They suggest that it takes a slightly different sort of person to be good at this:
. . . Owing to their focus on and expertise with arrays, we have found that the array chemists can make, purify, analyze, and register array compounds more efficiently than the program medicinal chemists. They are frequently also more effective in delivering a higher percentage of products from the array in greater yield and purity.
The team has a unique skill set and mindset. We have found that an array chemist should be highly organized, show attention to detail, be manually dexterous, be comfortable with repeatedly delivering to deadlines, and have an ability to work with often introverted and occasionally obstreperous program chemists ! This combination of characteristics is uncommon amongst chemists.
As an obstreperous program chemist myself, I should resent that remark. But you know, they're probably right. . .
+ TrackBacks (0) | Category: Life in the Drug Labs
September 24, 2010
I came across this book the other day, and bought it on sight: Happy Accidents: Serendipity in Modern Medical Breakthroughs. From what I've read of it so far, it's a fine one-stop-reference for all sorts of medical discoveries where fortune favored the prepared mind (as Pasteur put it). There are drug discovery tales, surgical procedures, medical devices, and more.
Even the stories I thought I knew well turn out to have more details. Albert Hoffman's famous discovery of LSD, for example - what I hadn't known was that some of his colleagues didn't believe him when he said he'd taken only 0.25mg of a compound and hallucinated violently for hours. (From what we now know, that was actually a heck of a dose!) So Ernst Rothlin, Sandoz's head of pharmacology, and two others tried it themselves. "Rothlin believed it then", Hoffman noted. Those days will never come again!
+ TrackBacks (0) | Category: Book Recommendations | Drug Industry History
So now Avandia (rosiglitazone) looks to be withdrawn from the market in Europe, and heavily restricted here in the US. This isn't much of a surprise, given all the cardiovascular worries about it in recent years, but hindsight. Oh, hindsight: all that time and effort put into PPAR ligands, back when rosi- and pioglitazone were still in development or in their first few years on the market. Everyone who worked on metabolic diseases took a swing at this area, it seems - I spent a few years on it myself.
And to what end? Only a few drugs in this class have ever made it to market, and all of them were developed before we even knew they they hit the PPAR receptors at all. The only two that are left are Actos (pioglitazone) and fenofibrate, which is a PPAR-alpha compound for lack of any other place to put it. Everything else: a sunk cost.
Allow me to rant for a bit, because I saw yet another argument the other day that the big drug companies don't do any research, no, it's all done at universities with public funds, at which point Big Pharma just swoops in and makes off with the swag. You know the stuff. Well, I would absolutely love to have the people who hold that view explain the PPAR story to me. I really would. The drug industry poured a huge amount of time and money into both basic and applied research in that area, and they did it for years. No one has to take my word for it - ask any of the academic leaders in the field if GSK or Merck, to name just two companies, managed to make any contributions.
We did it, naturally, because we expected to make a profit out of it in the end. The whole PPAR story looked like a great way to affect metabolic disorders and plenty of other diseases as well: cancer, inflammation, cardiovascular. That is, if we could just manage to understand what was going on. But we didn't. Once we all figured out that nuclear receptors were involved and got busy on drug discovery on that basis, we didn't help anyone with any diseases, and we didn't make any profits. Big piles of money actually disappeared during the process, never to be seen again. You could ask Merck about that, or GSK (post-rosiglitazone), or Lilly, or BMS, or Bayer, and plenty of other players large and small.
No one hears about these things. We're understandably reluctant to go on about our failures in this industry, but the side effect is that people who aren't paying attention end up thinking that we don't have any. Nothing could be more mistaken. And they aren't failures to come up with a catchy slogan or to find a good color scheme for the packaging - they're failures back at the actual science, where reality meets our ideas about it, and likely as not beats them down to the floor.
Honestly, I don't understand where these they-don't-do-any-research folks get off. Look at the patent filings. Look at the open literature. Where on earth do you think all those molecules come from, all those research programs to fill up all those servers? There are whole scientific journals that wouldn't exist if it weren't for a steady stream of failed research projects. Where's it all coming from?
Note: previous posts about PPAR drug discovery can be found here, here, and here. Previous posts (and rants) about research in the drug industry (and academia, and the price of it all) can be found here, here, here, here, here, here, here, here, and here.
+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History | Regulatory Affairs | Why Everyone Loves Us
September 23, 2010
And I now present today's winner of the Ugliest Molecule To Actually Show In Vivo Efficacy. Here, just in time for lunch, is Torin-1, a selective mTOR inhibitor. Yowza.
+ TrackBacks (0) | Category: Chemical News
I agree with many of the commenters around here that one of the most interesting and productive research frontiers in organic chemistry is where it runs into molecular biology. There are so many extraordinary tools that have been left lying around for us by billions of years of evolution; not picking them up and using them would be crazy.
Naturally enough, the first uses have been direct biological applications - mutating genes and their associated proteins (and then splicing them into living systems), techniques for purification, detection, and amplification of biomolecules. That's what these tools do, anyway, so applying them like this isn't much of a shift (which is one reason why so many of these have been able to work so well). But there's no reason not to push things further and find our own uses for the machinery.
Chemists have been working on that for quite a while. We look at enzymes and realize that these are the catalysts that we really want: fast, efficient, selective, working at room temperature under benign conditions. If you want molecular-level nanotechnology (not quite down to atomic!), then enzymes are it. The ways that they manipulate their substrates are the stuff of synthetic organic daydreams: hold down the damn molecule so it stays in one spot, activate that one functional group because you know right where it is and make it do what you want.
All sorts of synthetic enzyme attempts have been made over the years, with varying degrees of success. None of them have really approached the biological ideals, though. And in the "if you can't beat 'em, join 'em" category, a lot of work has gone into modifying existing enzymes to change their substrate preferences, product distributions, robustness, and turnover. This isn't easy. We know the broad features that make enzymes so powerful - or we think we do - but the real details of how they work, the whole story, often isn't easy to grasp. Right, that oxyanion hole is important: but just exactly how does it change the energy profile of the reaction? How much of the rate enhancement is due to entropic factors, and how much to enthalpic ones? Is lowering the energy of the transition state the key, or is it also a subtle raising of the energy of the starting material? What energetic prices are paid (and earned back) by the conformational changes the protein goes through during the catalytic cycle? There's a lot going on in there, and each enzyme avails itself of these effects differently. If it weren't such a versatile toolbox, the tools themselves wouldn't come out being so darn versatile.
There's a very interesting paper that's recently come on on this sort of thing, to which I'll devote a post by itself. But there are other biological frontiers beside enzymes. The machinery to manipulate DNA is exquisite stuff, for example. For quite a while, it wasn't clear how we organic chemists could hijack it for our own uses - after all, we don't spend a heck of a lot of time making DNA. But over the years, the technique of adding DNA segments onto small molecules and thus getting access to tools like PCR has been refined. There are a number of applications here, and I'd like to highlight some of those as well.
Then you have things like aptamers and other recognition technologies. These are, at heart, ways to try to recapitulate the selective binding that antibodies are capable of. All sorts of synthetic-antibody schemes have been proposed - from manipulating the native immune processes themselves, to making huge random libraries of biomolecules and zeroing in on the potent ones (aptamers) to completely synthetic polymer creations. There's a lot happening in this field, too, and the applications to analytical chemistry and purification technology are clear. This stuff starts to merge with the synthetic enzyme field after a point, too, and as we understand more about enzyme mechanisms that process looks to continue.
So those are three big areas where molecular biology and synthetic chemistry are starting to merge. There are others - I haven't even touched here on in vivo reactions and activity-based proteomics, for example, which is great stuff. I want to highlight these things in some upcoming posts, both because the research itself is fascinating, and because it helps to show that our field is nowhere near played out. There's a lot to know; there's a lot to do.
+ TrackBacks (0) | Category: Analytical Chemistry | Biological News | Chemical News | General Scientific News | Life As We (Don't) Know It
September 22, 2010
In the wake of yesterday's revelation about the latest breakthrough in amide formation, one point that's come up is whether we getting into the era of diminishing returns in finding new synthetic methods.
My opinion? We may well - but we shouldn't have to be. It is true that we know how to do an awful lot of transformations. And I'd also subscribe to the view that we can, given no constraints of time, money, or heartbreak, synthesize basically any stable organic molecule that anyone can think up. In what we're pleased to call the real world, though, constraints of money and time (related by a similar equation to Einstein's mass-energy one) are always with us. (Heartbreak, well, that seems to be in constant supply).
So even though we can do so many things, everyone realizes that we need to be able to do them better. That applies even to amide formation. There are eleventy-dozen ways to form amides in the literature. But as some of the comments to yesterday's post show, sometimes you have to go pretty far down the list to get one that meets your needs. There is no set of conditions that is simultaneously easy, fast, cheap, nonracemizing, nontoxic, tolerant of all other functional groups, and generates a benign waste stream. Finding such a universal reaction is a fearsome goal, especially considering the number of alternatives that have already been tried.
This is why stoichiometric samarium metal is such a ridiculous idea. There are a lot of good ways to form amides. And there are a lot of lesser-known ways that might save you in tough