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: email@example.com
August 31, 2007
Stability is a relative concept in chemistry. In the lab, we tend to use the term a bit loosely, and we mix up with “reactivity”. But those are two axes of an x-y graph, and there are chemicals in all four quadrants. Stable and non-reactive? Sure, for whatever value of “non-reactive” you choose. Stable and reactive: how about acid chlorides? You can keep many of them happily for years away from water, amines, etc., but open the flask and they’ll be ready to party. Unstable and non-reactive? An odd category, but I’d say that something like a polyazide or polynitro compound would fit. It doesn’t do much with other chemicals; it just falls apart on its own, and how. And unstable and reactive? Oh, yeah, we have those, all right.
In the lab, there’s a large middle ground of things that sort of gradually deteriorate on you, but not so quickly as to be a nuisance. Solutions that used to be clear pick up a yellowish cast, crystals get cloudy. This is the sort of stability that people are used to seeing with newsprint paper and household chemicals like bleach – they’re good for a while, but you can’t expect them to hang around forever. In research, you deal with this by either buying new stuff (the industrial way!) or re-purifying the old bottle by distilling or recrystallizing it (the academic way, by necessity).
After these compounds, though, you come to the ones that can give you trouble. There are a lot of compounds that are only stable on a time scale of days, hours, or minutes, and you’ve got to keep an eye on these guys. Often the rate of decomposition is very dependent on how pure the stuff was at the beginning. Trace amounts of water, oxygen, or other such rare substances can start one of these down the slope.
The dangerous ones are the compounds whose decay begets their own decay. These will run away on you, and if there’s enough compound in the flask where heat transfer is a problem, the process can turn violent. At this point, we’re shading over from “troublesome decomposition” to “explosive hazard”. Things like this are best kept as cold as possible, and in dilute solution. Concentrating them or warming them is a deliberately provocative act for which payment will be due.
Even without explosions, this sort of thing can be alarming. I’ve heard of intermediates that were so lively that initial clearish substances in a round bottom flask turned brown and began to fume as the person walked down the hall holding the stuff. Generally, that only happens once, the first time you make one of these beasts. After that, you take appropriate precautions (like having the next reaction step set up right next to this one, ready to go). Or, of course, you just decide that you can live without that one, and never make the darn stuff again.
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August 30, 2007
I hope that in decades to come that our current drugs look as crude as I think they will. For all of our knowledge and all our equipment, we still don't have much of an idea of what we're doing around this industry, not compared to the sum of what there is to know.
Most of our drugs (by "most", I mean way over 95%) bind to proteins. And that's fine, as far as it goes, because proteins sure are important things. We love them because many of them have pockets and cavities that fit small molecules, of course, giving us a tremendous leg up. But it's not that we've figured out how to attack them reliably, though, when you consider that there are many entire classes that have never been successfully targeted (phosphatases, to pick an outstanding example).
Once you get out of the small-molecule-binding zone, you're out in the wild, wide open prairie of protein-protein interactions. So far, we can't really affect those with small molecules, not worth squat. It's a shame, because the number of potential targets goes up by orders of magnitude when you take these interactions into account - well, assuming that we figure out what these zillions of interactions are actually doing, which is quite another problem in itself. But they're doing something, that's for sure, and we'd love to be able to step in for our own purposes.
But protein-protein interactions are only the beginning. If you want to go upstream and alter protein production at the source, then you're going to be targeting protein-DNA and protein-RNA) interactions. The list of known drug-like molecules which can do that is pretty short, and the success rate has been pretty small (more on the reasons for that in another post). And this is another area where only small regions of interaction space have been mapped out and understood, so there's room to work in - if you can find a way to make things work.
Don't stop there, though. We really don't pay enough attention to carbohydrates in all their forms, but they've got some crucial roles, too. Contacts involving complex polysaccharides are key to immune function, and small molecules that can affect them are rare indeed. A whole landscape of inflammation targets is waiting for someone who can get a handle on this stuff. And I haven't even talked about lipids, because frankly, we don't understand a lot of what they're doing. Protein-lipid interactions have been targeted, but can be a hard row to hoe, since the small molecules that work tend to look awfully greasy themselves. But there may also be lipid-lipid interactions that no one has ever noticed, and how you'd target those therapeutically is a real stumper.
There are even more exotic combinations, but you get the idea. When you look at the whole medicinally active universe, it's clear that we've only done successful work in a few small parts of it. An interesting and rewarding time awaits those who can extend those holdings. . .
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August 28, 2007
There are a lot of drug development issues that people outside the field (and beginning medicinal chemists) don't think about. A significant one that sounds trivial is how often your wonder drug is going to be taken.
Once a day is the standard, and it's generally what we shoot for unless there's some reason to associate the drug with meals, sleep/wake cycles, or the like. People can remember to take something once a day - well, they remember it better than most of the other dosing schedules, anyway. That's why you actually want your compounds to be metabolized and cleared - everything has to be ready for the next dose tomorrow.
If your compound has a long half-life in the body after dosing, you'll step on the tail end of the last dose and you can see gradual accumulation of the drug in plasma or other tissues. And that's almost always a bad thing, because eventually every drug in the world is going to do something that you don't want. All you have to do is get the concentration up too high for too long (and figuring out what's too high and what's too long is the one-sentence job description of a toxicologist). If you stairstep your way up with accumulating doses, you'll get there in the end.
Ah, you might say, then just take the drug every other day. Simple! Sorry. Every other day (or every three, or four) is a complete nightmare for patient compliance. People lose track, and doctors know it. You'd better have a really compelling reason to go ahead with a weird regiment like that, and if you do, someone's going to seize the chance to come into your market with a once-a-day as soon as they can find one. (The exceptions to this are drugs given in a clinic, like many courses of chemotherapy - but in those cases, someone else is keeping track).
How about more often than once a day (q.d., in the Latin lingo). Well, twice a day (b.i.d. can work if it's morning/night. Three times a day can go with meals, presumably, but people are going to get tired of seeing your pills. More than three times a day? There'd better be a reason, and it had better be good.
So don't be scared as you watch your compounds disappear after giving them to the animals. You want that. Just not too quickly, and not too slowly, either.
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August 27, 2007
I hope that this is still the silly season for merger speculation. Right after the run of dimwitted Novartis-buys-Bayer/Schering rumors, we now have the even more spectacularly slackjawed Pfizer-should-buy-Wyeth ones. I first came across this at Invivoblog, and could hardly believe my eyes.
Wyeth's not a bad company, although they've had their problems over the years. They've put a lot of money into some difficult areas, such as vaccines and Alzheimer's, and I have to give them credit for that. But Pfizer isn't interested in most of these things, because they can't start paying off in time to to sheild them from the Big Lipitor Sales Slaughter in a few years. Pfizer needs big sales, real soon.
But doesn't Pfizer have enough on its plate without going through yet another massive acquisition? And weren't its two previous whoppers designed to get their hands on specific huge-selling drugs? Where's Wyeth's? And isn't Pfizer big enough (and isn't its research productivity bad enough) already? Wouldn't some of the company's biggest shareholders likely throw a rug-biting fit? I could fill the rest of this post with such questions.
Others are already asking them, as it turns out. Here's hoping that this is just investment-bank noise, trying to scare up some action for the fall dealmaking season so that everyone can rake in a good bonus this year. No, you have to go all the way to Peter Rost to find someone who likes this idea - and for all I know, he's probably urging it on in the hopes that it'll bring down the roof on his former company.
Nominations are open for the most idiotic drug company merger combination you can think up. But you have to beat this one to win, and good luck.
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August 26, 2007
This is the first post from the new Blogging Room of Stately Lowe Manor here in Massachusetts. The internet is hooked up, the lights are on, and I'm surrounded by boxes no matter where I turn.
I had a few requests to do more posts on graduate school and what goes on there. Problem is, it's becoming an increasingly distant event for me (which in most other ways is not much of a problem at all!) There's one immediate thing I can think of to say to people who are still in the middle of it, though: Don't worry. You're not going to be stuck like this forever.
I'm thinking of what a generally foul mood I was in throughout my PhD work, compared to my overall sunnier disposition since. I didn't like having to work on the exact same molecule for years, and I didn't like having to do it days, nights, weekends, and holidays. I especially didn't like that little voice in the back of my head that took up residence there, telling me - every moment that I wasn't in front of my fume hood - that I should stop goofing off and get back to work.
And I wondered if the experience had permanently damaged me. I really worried about that. When you're younger, these thoughts occur to you if you've got any introspective tendencies at all, and my working hours gave me plenty of time for thinking about such things. Was I ever going to wake up and feel enthusiastic about going to work in the lab? If not - and there seemed a real chance that the answer was, in fact, "Never again" - how was I going to make any sort of worthwhile life for myself? After all, here I was committing a good slice of my 20s to getting an advanced degree in a field whose same advanced degree might be ruining my chances of ever using it.
No wonder I was surly. I wasn't sure I was doing the right thing, and I wasn't sure what shape I'd be in if I stopped or if I kept going. Admittedly, I never seriously considered the first option. The going didn't get really rough until I was in far enough that the shortest way out was at the other end. I knew that I could hang in long enough to get the degree; what I didn't know was what kind of shape I'd be in after I got it.
Well, as it turned out, I was fine. My worries, though real, were overblown. It took a while on my post-doc in Germany, but my brain proved to be more resilient than I'd feared, and it soon bent back to its usual shape. I stopped feeling as if the dogs were chasing me when I wasn't in the lab on, say, Sunday nights or the day after Christmas. And I started enjoying the times that I did go in. Not being up to my elbows in lab work all the time made it fun when I did it out of choice. No permanent damage seemed to have occurred.
Actually, I came out of the experience stronger than when I went in, for having gone through it without breaking. So, if you're trying to finish up your last year or two of a degree, and you feel as if it's never going to end, take it from me: it does. And if you think that you can't stand the time remaining, prepare to surprise yourself, because odds are very good that you can. And no, you won't always feel like you do on your worst days in your grad school lab. That's not the real world; it's just pretending to be.
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August 23, 2007
The FASEB folks have collected a large amount of data on training and employment in the life sciences (start here), and see the discussions over here at the AAAS).
Many of the conclusions are not going to surprise people, but it's good to have some data to back up everyone's impressions. I can sum the whole presentation up in a sentence: academic life science is a hard place to make a living, and getting harder every year. For example, the average age of first-time R01 grantees has been going up for the past thirty-seven years. And over the past twenty years, the number of doctorates awarded has roughly doubled, while the number of people employed in tenured (or tenure-track) positions has stayed exactly the same.
So where is everyone going? Well, down the hall from me - industry is where the job growth is. I know that my pharma/biotech readers might be startled by that statement, but compared to academia, we're a boom town. (I mean, look at it, no head count increase since 1987?) The problem is, as far as I can see, many PhD candidates and post-docs have been trained in environments where an tenure-track academic position is seen as the natural and desirable goal, and industry is just the fallback for the also-rans. If this ever was congruent with reality, it isn't now. As a commentary in the latest Nature put it:
More effort is needed to ensure that recruitment interviews include realistic assessments of prospective students' expectations and potential in the academic workplace. And training should address broader career options from day one rather than focusing unrealistically on jobs that don't exist.
Chemistry doesn't have this mindset problem to the same extent. There do seem to be some research groups who don't so much look down on industry as over-exalt academia, but there are plenty of strong people from the top-ranking groups all over the pharma landscape. But the hiring problems, well, I'm sure those track pretty close to the FASEB story.
And that gets us back to the ever-popular topics of medicinal chemistry employment, outsourcing, restructuring, and so on. For now, I'll reiterate my strongest opinion on these subjects, which is that this is not a good time to be an ordinary medicinal chemist in the US. You need skills, you need to keep them sharp, and you need to be ready and able to move into new research areas as they get interesting. It's not easy. But at least it's easier than trying to make it as a professor. . .
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August 21, 2007
We're in the final stages of moving into the newest version of Stately Lowe Manor. And that means, among many other more useful things, that I'll soon see my literature files for the first time in a few months. I've missed them.
Of course, paper files are slowly turning anachronistic, in the same way that paper libraries of the scientific literature are. (I've mused on their disappearance before). I now accumulate piles of PDF files and the like, scattered among folders on my hard drive(s). How to organize them?
That's what I'd like to ask people. I've come across reviews of various programs that are supposed to help with this kind of thing, but there are surely others that I don't know about. What I need is something that will cross-reference papers and graphics (in any format) as well as things like Excel files and such, and allow me to draw and return to connections between them. (At this point, I'm being paid for ideas as much as for anything else, and this is how I seem to generate them). There are several tools that can be made to do this work, with varying degrees of ease and efficiency, but I'm looking for something that's built specifically for the purpose.
One possibility is Yojimbo, which I haven't tried out yet. The ability to write down notes and ideas, with the relevant papers appended to them, is appealing. Does anyone out there have experience with this one, or with its competition? (And for that matter, if there are other ways that people find useful for generating interesting ideas, I'd be glad to hear about those, too. . .)
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There were rumors late last week that Novartis was thinking of buying Bayer(-Schering). Wherever these came from, they're apparently back, sending the company's stock on some rather uncharacteristic one-day rides.
But this deal makes little or no sense. Bayer and Schering AG are still in the throes of merging their organizations, so things are presumably still a mess. No one has a good picture of how effective the new company is going to be. One of their most promising clinical candidates (a Factor Xa inhibitor against blood clotting) is already tied up with Johnson & Johnson here in the US. And the company's stock was a lot cheaper earlier this year, anyway: why would anyone wait until now to start eyeing them?
This also doesn't sound like a Novartis-y thing to do. They've swallowed up some companies in the past, certainly, but nothing on this scale. And they don't seem like a company that needs a lot more Euro-pharma exposure. (Roche, their fellow Swiss behemoth, has long been a rumored (and out of reach) target of theirs, but at least they have a much larger US and worldwide research footprint). It's also not like they're in any sort of desperate need to merge with someone.
So I'll be very surprised indeed if this rumor has anything behind it. Surprised and disappointed in Novartis, a company that I've mostly thought better of. . .
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August 20, 2007
As I've mentioned before, advances in molecular biology have continued to make all sorts of brute-force approachs possible - things that would have been laughed at (or, more likely, not even proposed at all) a few years ago.
Another recent example of this is a paper earlier this year in Nature from the group of Michael White at UT-Southwestern. The authors selected a lung cancer cell line that's know to be very sensitive to Taxol (paclitaxel), and looked for possible targets that might increase the drug's effectiveness. (It's a good compound to pick for a study like this, since it's simultaneously quite effective and quite toxic).
So, how do you go fishing for such combinations? These days, you set up 21,127 experimental wells, each one contained some cells and some silencing RNA molecules targeting, one at a time, 21,127 different human genes. And you look to see if knocking down expression of any of those genes increased the potency of a normally ineffective dose of the drug. (There were four different siRNAs per gene, actually, and each one was run in triplicate with and without Taxol, leading to a Whole Lotta 96-well plates. I'm glad I'm not paying for all the pipet tips, I can tell you that for sure.)
As you'd imagine, working up the data from this kind of thing takes as long, or longer, than setting one up. After comparing everything to the control wells and to each other several different ways, they ended up with 87 candidate genes whose knockdown seems to make the drug more effective. Gratifyingly, many of these make one kind of sense or another - there are several genes, for example, that are known to be involved in spindle formation, which is the target of paclitaxel itself.
Even more interestingly, not all the hits were obvioius. Another group of genes code for parts of the proteasome. That part of the cell is targeted by Millennium's Velcade (bortezomib), and it's recently been reported that the combination of Velcade and paclitaxel is more effective than expected. And there's another combination that seemingly hasn't been tried at all: the experiment suggests that inhibitors of vacuolar ATP-ase should synergize with Taxol, and (as it happens) a compound called salicylihalamide A has been looked at for just that target. They tried this experimental combination out on the cells, and it seems to work well - so, in humans?
As a commentary in the New England Journal of Medicine on this work dryly put it, "This hypothesis should be tested." And so it should. I've always had doubts about how far one can extrapolate cell data in cancer studies, but this kind of thing will tell us for sure. If something hits from this work, more such studies will come pouring out - they're getting easier to do all the time, you know. . .
+ TrackBacks (0) | Category: Cancer | Drug Assays
August 17, 2007
Having had the chance recently to see a number of interview seminars (other than my own, for once!), I have a few more thoughts for aspiring job seekers. It turns out that many of these are things that high school speech teachers have been telling their students for decades, but you know, there's only so much new information in this world.
Know your audience. In this case, your audience is pretty well-informed about synthetic chemistry, since they've been putting food on the table by practicing it. To pick one example, there's no point in stepping through detailed reaction mechanism slides for reactions that people already know. A surprising number of people seem to do this, perhaps thinking that it'll demonstrate that they know their stuff, but it tends to have the opposite effect. If you want to put one of these up, don't leave it up there for long. Just hit the highlights (you know, like you're familiar with it) and keep going. And that brings up another key point. . .
Keep moving. I'm not saying that you should fly through your slides, although I've never in my life seen a job candidate who did. I'm saying that you shouldn't linger on them. Figure out what you're trying to say with each slide, say it, and move on. Not to be too cynical about it, but the longer your slide sits up there, the greater the chances of bad things happening: either you say something unhelpful because you feel you should be saying something, or people start fiinding the mistakes in your slide, or people start looking out the window. You don't want any of these. I can't count the number of times I've watched a job candidate while silently imploring them to hit a button and go to the next slide already. It's easier to keep moving if you remember that. . .
Your slides should tell a story. Maybe you have two stories, or even three, if you've had to break things up and talk about more than one project. That's OK. But what you should never, ever do is put up a bunch of unrelated stuff in no particular order. Once in a while I've seen this kind of talk, but I have never, ever seen one lead to a job offer.
Don't ask for questions until the end. This may also sound a bit cynical, but trust me on it. At many companies, they'll interrupt you if they really want to ask questions; you don't have to invite them. If the culture is to wait until the end, then it's in your best interest to go along with that. I say these because many people sink their chances by the way they handle questions from the audience. You want to have some questions, of course (no questions at all is a bad sign), but you want them to be the ones you're prepared for. Give people those good answers you've worked up and move on. The more opportunities you give people to grill you, the better the chances of them finding gaps in your knowledge. But that said. . .
Don't be afraid to say "I don't know" (or its equivalent). Some of those equivalents are "You know, we wanted to investigate that, but weren't able do during the project" or "That's a good question, and we'd like to know the answer to that one, too". Now, you don't want to use these when someone asks you why you used lithium aluminum hydride or something - those are the kinds of questions you have to be ready for. But if someone asks you a question that you really, really don't know the answer to, punt. It's better than trying to whip something up on the spot. But remember. . .
Put your work in context. It's very important that you show that you know why you were doing something, and how it fit into the larger scheme. You're always going to be working inside a larger context if you're in industry, since chemistry is just a means to an end. A classic interview-killer is to say that you did something because that's what someone told you to do. If you don't have some broader reasons than that - or if it's never occurred to you that you might need some - your chances of being hired at a drug company are very slim. And finally. . .
Remember what your talk is supposed to do. Many of the points above boil down to this one. You are not giving an informational talk, you're giving a persuasive one, but a shocking number of candidates don't seem to realize this. As mentioned above, you may not be able to tell your drug-company audience much that they don't already know. But you can persuade them that you know the stuff well, that you did a good job with it, and can do the same for them. Everything you're presenting should be aimed at demonstrating those points.
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August 14, 2007
A co-worker put me on to an interesting paper earlier this year by Harvard's George Whitesides (with a co-author credit going to a well-known chem-blogger). Whitesides, a perennial favorite in Nobel betting, does a lot of absolutely first-tier physical organic chemistry, an area that I love to read about (and one that I'd probably be an awful practitioner of).
Almost all drugs bind to sites on proteins. Some proteins have only one site (that we know of) that a small molecule will fit into, while others have several. There have been a lot of attempts over the years to go after the latter group by hitting more than one site at the same time - but with only one drug. Imagine two different drug molecules, each fitting into a different site on a single (multi-sited) protein. Now imagine combining them into one compound, by attaching some sort of linking chain between them, and you've got one (larger) molecule that can reach around and fill two binding sites.
This has worked in some cases, at least on a research level (I'm not aware of any drugs that have yet made it to market by taking advantage of this effect, though). (Update: there is a marketed protein, bivalirudin, that binds to two sites on thrombin, but I'm still not aware of any small molecule drugs in this category). You can pick up huge amounts of affinity by this trick, though, to the point that neither of the original "business ends" of the molecule need to be particularly good binders on their own. And since we in the industry are distressingly good at producing molecules that don't bind to things very well, the idea of combining some of these into multivalent wonders is appealing.
But there are a lot of unknowns. Figuring out how to modify the original structures in order to tie them together is, as they say, non-trivial. (If you hang around scientists and engineers much, you know to head for cover when you hear that expression). And what kind of chain should you use, anyway? How long does it have to be, and what happens if it's too long or too short? And what's the linking chain doing, anyway - sticking to the surface of the protein, waving around by itself, or what?
Whitesides and his people have used carbonic anhydrase as a model system, which is an enzyme whose structure and behavior is as well known as these things get. They find, not unreasonably, that when the linking chain is too short the activity of your wonder molecule just gets killed: you're stuck with one end bound to the protein, and a big tail flopping around uselessly, unable to reach the next binding site. The "just-right" chain length is the best, naturally. But (interestingly) you don't pay much of a penalty for being longer than necessary, even several times longer. Apparently the chain will coil around and find something to do with itself as long as the two ends are bound.
And while it's doing this, it doesn't appear to be contacting the protein in any meaningful way. This took a lot of careful experimental thermodynamics to check, but there's no extra binding energy involved with any of the common chains. So if you're going to try this trick, Whitesides's advice is not to worry about what chain to use. Stick with a plain-vanilla linker, as flexible as possible, make it a bit longer (at least at first) than you think you'll need, and you've improved your chances right there. And he has the numbers to back this up, which is what physical organic chemistry is all about: opinions made solid by data. It's good stuff.
+ TrackBacks (0) | Category: Drug Development | General Scientific News
August 13, 2007
One of the comments to my brief post earlier today brought back some memories. Back in graduate school, we were a comparatively well-off group. That is, we graduate students lived off grant money after our first year - no more teaching assistant duties. Compared to some of the other professors, whose students were TAing in their fourth years and beyond, this was luxury.
But luxury went only so far. We still had to watch our expenditures in the lab, and ordering of reagents and supplies was kept under tight control. We didn't go as far as recycling our wash acetone (well, most of us didn't - see here for what happened to the fellow who did), but If you wanted a fresh bottle of something, you had to justify it: what's wrong with the one we've got, heh?
I was pushing a big pile of material through the early stages of a long synthesis, so I (and the people like me) needed larger amounts of things. I remember getting in a fresh 800 mL bottle of borane/THF, of which I was going to use about 700 mL in one big ol' hydroboration reaction. Ready to go! Got my starting material on the pump, got my freshly distilled solvent, got my untouched bottle of. . .wait a minute. That's not on the shelf where I left it. And it's. . .it's. . .
What it was, was about half empty. Yes, one day in the lab was all it took for my pristine stockpile of borane to be raided. To add that extra emotional touch, when I unscrewed the cap and looked at the seal, the person who'd pirated the stuff had apparently used something the size of a knitting needle to remove it. The "Sure-Seal" was surely hollowed out, to the point that I could see the borane solution sloshing down there in the distance.
I didn't take it well - it was grad school, so I didn't anything too well. I went stomping through the labs, beard bristling out, hands making involuntary strangling motions in the air, asking who, just who, had helped themselves to half a liter of borane/THF in the last day? Eh? Well, as you'd guess, no one had. Nope, nobody at all had used that there borane, no-sir-ree, didn't even know it was there. Some of my colleagues assured me that they'd never used borane in their lives, and a couple of them seemed surprised to find that there was a chemical with such an odd and catchy name. What you say, boh-rain?
I never did find the culprit. Most of the time, you never do. I gritted my teeth, used some more foul language, ordered another bottle of reagent - and used it right out of the box this time, trailing little flecks of vermiculite packing material behind me.
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August 12, 2007
1. A testy e-mail from the one of the analytical chemists, saying that the open-access walk-up LC/MS machine was clogged - again - and reminding everyone, in a tone both exasperated and resigned, that the machine is not there for everyone just to come and inject their dark orange cloudy stuff into.
2. Lab bench drawers that have accumulated a low-energy high-entropy slough of weird-sized adapters, unusable syringes, metal fittings to machines that aren't even being used any more, and strangely shaped plastic pieces that look as if they must be the vital inner workings of something - but what?
3. A testy note on the common fridge, stating that anything that's left in there by Friday at 3 PM is going to be thrown out, and reminding the reader that this means you. The note is written in faded black Sharpie marker, and the edges of the paper are frayed.
4. A radio, off in the distance in some other lab, playing AC/DC's "Back in Black". What lab radios played before this was recorded, I'm not sure.
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August 9, 2007
I didn't note it at the time, but Amgen just recently finished buying a smaller company, Alantos. That cost them about $300 million, and for that money they got a diabetes drug in the clinic and a program generating compounds for arthritis and other diseases.
Sound OK, eh? That's the one-line executive summary right there, but look closer: the diabetes drug is a DPP-IV inhibitor. There's nothing wrong with that, except that this one is going to be what, if it makes it to market - fourth in line? Fifth? I've lost count. The Alantos compound may be a good one (Amgen certainly thinks so), but it's a crowded space, for sure.
And the arthritis drugs? Matrix metalloproteinase inhibitors. No, no, it really is 2007, not 1995. MMPs have been the subject of a big old pile of drug development over the years, all of which (to my knowledge) has come to grief. Again, there may be something particularly good about these (Amgen certainly thinks so), but it's a well-trodden space, for sure.
This deal makes me wonder a bit about Amgen's small-molecule pipeline. They don't talk much about it, although they have a lot of people doing traditional med-chem these days. No one seems to know what they're up to, though, and the inlicensing of drugs from such well-known therapeutic classes - ones that have not been particularly difficult to find lead compounds for, yet - is food for thought.
(As a sideline, Alantos, at least in its early days, was a champion of relatively exotic approaches like dynamic combinatorial chemistry, which I'll have to write a post on some day. Anyone know if these compounds came from that kind of work, or is this another case where the neat stuff never generated any drugs?)
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August 8, 2007
The latest issue of Nature has an article (subscriber-only) on Steve Ley's long-anticipated total synthesis of azadirachtin, which can be read, again subscriber-only, here and here at Angewandte Chemie. (For a open-source look at the synthesis, try Totally Synthetic). I'm quoted in the piece expressing numerous doubts about the merits of total synthesis, most of which made it into print.
I also expressed quite a bit of admiration for Steve Ley's work, most of which didn't make it into the article, so I wanted to get that on record over here. The reason I can hold both those opinions is, of course, that Ley has done a lot more over the years than just make azadirachtin. As I told Nature, if he'd been running one of the make-it-or-die total synthesis factories, he'd have no doubt been finished well before now. But he's introduced reagents and experimented with many new ideas and techniques, and those have (in my view) a greater chance of having an impact on the world than natural product synthesis does.
A lot of what goes on in that field seems to me to have about as much relevence and utility as do chess problems. It's to Ley's credit that he's made a molecule of this complexity while avoiding the large pitfalls in that part of chemistry - some of which are marked with names like "If You're Not First, You're Nothing", "You Worry About the Reactions and I'll Worry About the Yields" and "If You Can't Get This Coupling To Go, I'll Find A Post-Doc Who Will".
Back when I was finishing up graduate school in 1988, I had to put together a research proposal. I chose, like a fool, the polycyclic core of azadirachtin, and I cranked out a paper synthesis plan for it. Would it have worked? Not a chance in hell. Looking back, I can see that I was already falling out of love with total synthesis even back then, and time has not healed the rift. Steve Ley never lost the faith, but (to his credit) he hasn't let it define him, either.
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You know, you can run the biggest marketing behemoth the drug industry has ever seen - but if people really aren't interested in buying your product (and if insurance companies really aren't interested in paying for it), that's not enough.
The evidence? Pfizer's Exubera, the inhaled insulin that for years was thought by some to be one of the Next Big Things. Earlier this year, a "relaunch" of the product was announced, but that doesn't seem to have helped much. Pharmalot passes on the news that one of Pfizer's main suppliers is cutting back production.
This comes after the drug ran up only $4 million in sales in the second quarter, relaunch be damned. And I mean that "only" - compared to what Pfizer and its partner Nektar spent on developing Exubera, a few million dollars is nothing at all. You'd think that if we in the industry were as powerful and as evilly resourceful as our worst critics have us, we'd be able to keep things like this from happening - wouldn't we?
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August 7, 2007
When I mentioned that I was moving to a company in the Boston area, I had a number of responses from readers of the site about meeting up in person. Now that I'm (sort of!) settled in, I wanted to see if there was still some interest in that idea. It's an odd thought for me, I have to say, but this is the first time I've lived in an area with enough readership density to make such an idea practical. Being recognized at several recent gatherings has brought home to me (in a way that Sitemeter can't quite manage) that a lot of people drop by here.
Lunch would probably be easiest, and I can get to most of the locations that people would think of in the Cambridge research zone. Those who are interested can leave suggestions for a venue in the comments. I've only lived here a month, so I'll defer to the people who know the area better. As for food, I'll eat most things that were once alive, so that won't be a problem on my end.
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August 6, 2007
As I mentioned the other day, drug companies manage the shift from med-chem to process in a lot of different ways. (For those outside the industry, the medicinal chemists are focused on making relatively small amounts of a lot of different compounds, while the process labs concentrate on making large amounts of a few). Some places allow the med-chem labs to use whatever wild chemistry they can think up, on the theory that if a compound is really interesting the process labs will find a way to make it on scale. Others strongly discourage some kinds of chemistry (particularly nasty solvents and reagents), since real problems can occur if a lead compound comes from that sort of background.
I incline more to the latter. Perhaps it's just a dislike of leaving messes for other people to clean up. But I'm not as pure as I might sound, because I have done some ugly reactions (mercury, organoazides, etc) in my med-chem analoging, and these were real possibilities for trouble if the compounds had ever taken off (they didn't). In these cases, the unappealing reactions were by far the fastest way into the compounds I wanted, and I figured that I'd take a quick look and see if they were any good. (The same reasoning, I'm sure, had led to most of nightmares that process groups find themselves in).
Other things being equal, though, I'd rather approach my drug analogs using something that isn't demonstrably foul. I suppose that's as good a middle ground as any - try not to use hideous reagents, but if they're the quick way into a series, go ahead - but be mindful of the tradeoff you're making. If you go the next step, where the ugly stuff is (as far as you can tell) the only way into a series, then you're taking a real risk and should only do it with a reasonable expectation that it'll be worth it. It's very hard to have reasonable expectations of that kind in medicinal chemistry, though - which is why this sort of thing shouldn't become a habit.
The comments that came in to my recent post on this topic were all over the place - I wouldn't mind seeing an informal head count of how various departments feel on this issue. If we get a decent sample, I'll post on the results.
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August 5, 2007
Over at Life Sciences Daily, Ogan Gurel has a post on the recent FDA Avandia vote that's worth reading. That's not so much for the Avandia news, which we all know about now - the main focus of the piece is on the Center for Medicine in the Public Interest (CMPI) and their blog, Drugwonks.
I don't have a permalink up to Drugwonks, partly for the reasons that Gurel goes into. I should disclose, though, that I've met the people behind CMPI (Robert Goldberg and Peter Pitts), and have accepted their hospitality while attending a CMPI-sponsored conference last spring. I got along with both of them just fine. But that said, I don't think that their web site is as effective as it could be.
I think that whoever writes the posts there is trying for a lively, irreverent tone, but (as Gurel goes into a great amount of detail to show), a lot of the entries slide over into ad hominem invective. Now, I'm no stranger to that form of argument myself - any of my pieces on Kevin Trudeau would furnish a number of examples, and I enjoyed writing every one of them. (In fact, I reserve to right to back up and insult him again, when the opportunity arises).
But the weapon should fit the offense. There's almost nothing too nasty to say about Kevin Trudeau, but Steve Nissen (the cardiologist who's raised the alarm on Avandia and several other drugs) is no Kevin Trudeau. He's a very competent guy, with a set of strongly held opinions which he backs up with publications in high-ranking journals. Agree with him or not (and I've come down both ways in the past myself), he's a serious person making serious arguments. And they deserve serious responses, not the sort of raspberries and hoots coming from some of the Drugwonks posts.
And the thing is, I assume that the whole purpose of a think tank (like CMPI) is to influence debate. The tone of their blog, though, suffers from the same defects that make most political blogs (left or right) nearly unreadable to me. Conclusions are assumed without argument, choirs are preached to, poses struck - if you didn't agree with the point of view before you started, there's nothing there to convince you. Actually, if you didn't agree with the point of view before, you probably didn't even look at the site at all.
I've never felt the need to hang around sites where people do little more than cheer each other on about the rightness of their cause. I'd rather someone tell me something I didn't know, or show me a new way to think about an issue and why it might be correct. Perhaps that's the scientist in me. Are there other people who are more convinced by this sort of thing, from either end of the debate?
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August 3, 2007
My travel schedule has left me little time for blogging this morning, so I wanted just to report that I'll be revisiting some of the recent topics around here. My post on virtual companies led to a number of examples being sent to me - I want to look them over and report back. It's my guess that many of these deal with generic drugs or abandoned products, but we'll see. I still don't see how this model would work on a large scale (Pfizer, anyone?), but perhaps there's room for it on a smaller one.
And my post on abandoning the likes of tin, HMPA, and other nasties in med-chem research bought in quite a few counterexamples. I put a note up on that entry to direct new readers of it to the comments, so as not to miss them. I think that different companies treat these issues differently - in some shops, the med chem labs are encouraged to do whatever it takes to make the compounds, with the expectations that process chemistry will straighten out the kinks. Other companies, though, frown on that as irresponsibly throwing the problem over the wall to the next group, and want their med-chem people to forestall such problems if they can. I'll do a whole post on that subject next week, if possible, and we'll take an informal head count.
These bring up a general thought: as with any blog, this one is a reflection of my own experience and biases. (That's the whole point of a blog, eh?) I like the fact, though, that there are so many readers around the industry to confirm or disprove things as they come up. It's my hope that the non-industry audience finds the back and forth on these topics worth reading - I have a mixed crowd around here, and I try to keep things readable for anyone interested who happens by.
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August 1, 2007
You know that I’m on a long airline flight when I start blogging about something I’ve read in an in-flight magazine. I’m somewhere over the Great Plains as I write this, and American Airlines is telling me that drug companies need anthropologists to help them manage their scientists.
If they’d left it at that, I probably would have nodded my head. If you can do field work with savage Amazon tribes, you could probably feel right at home observing some lab corridors I've worked in. But no, since this was (like most airline magazine pieces) geared to the needs of middle managers, we get a brief case history:
A new CEO at Pfizer Pharmaceutical (sic, and boy, that narrows it down, doesn’t it?) wanted company scientists to operate differently, but they balked. Anthropologist Marsha Shenk asked them what they’d define as a more effective operation. The scientists realized that ever since they were grad students, they’d been in business to keep their projects funded for as long as possible – because in science, funding is a status symbol. But in business, it’s more efficient to kill projects that don’t show potential for big financial payoffs. About-face! They moved from judging themselves by how long they could string a project along to how quickly they could quash it.
Well, all right, then! We should be seeing some results from that innovative Pfizer approach real soon now, don’t you think? Honestly, though, this passage makes me want to bury my head in my hands. Where to begin?
Let’s see. . .how about we start by pointing out that grad students generally don’t worry much about keeping their projects funded, once the grant application is approved, which is mostly the boss's problem. Grants are written for entire programs of research, and a large graduate group will have several going on simultaneously. The folks working on one project aren’t competing with the ones working on a different one, since they’re funded through different means.
Now let’s try that “funding is a status symbol” line out. I can see how this was an anthropologist’s work, but we’re not talking about feather headdresses (or fancy cars). Funding is indeed a status symbol for professors, but for their students? Their status tracks with the name of their professor, the department they’re in, the perceived hotness of the project they’re working on, and so on. And what does this have to do with industrial drug discovery? Most lab heads and bench scientists don’t spend much time on budgets for individual projects. The money’s there. The company knows about how many programs it can run, with a reasonable number of people on each one. You're working on one of them, or another one of them, and when you're through you'll work on yet another.
Now, I’m not saying that there’s no competition to keep your program alive. That’s the main way that this whole anthropological excursion makes sense. But project leaders want to keep their teams going because they want to deliver, not just for the sheer sake of keeping things going. (You come across people once in a while who have their priorities confused on this, but that tends to get straightened out after it gets noticed by higher management). There's always a case to keep going. Hope does little more than spring eternal, and I’ve never seen a drug discovery program that didn’t think it could solve its problems if it just had a little more time. That’s the thing that spins projects out – they all have problems, and they’re all trying to solve them.
Ah, now we get to the "big financial payoff" part. So, it’s more efficient to kill the losers off, is it? Who knew? You’d think that companies would think about the financial prospects for a drug before they even started a project. . .and you know, here outside the pages of in-flight magazines, that’s just what they do. The projects that don’t look like they could pay off don’t get started in the first place, so you’re left with a bunch of projects, all of which could be profitable if they’d just work. Now perhaps a team of anthropologists can come in and tell us which ones will.
And as quickly quashing . .well, just as there's always a reason to keep going, there are always plenty of reasons to stop. Every single major drug I've ever heard of has been near death more than once. If you make killing things your priority in drug discovery, you risk killing off everything. Remember, the overwhelming majority of drug projects die at one point or another as it is.
But we’re supposed to think that this strategy hit the Pfizer scientists like a hot sizzling bolt of truth. They fell to their knees, confessed their project management sins, and resolved to lead new lives. Anyone at Pfizer want to bear witness for us unenlightened types?
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