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
October 30, 2009
Here's a most interesting graph from the latest issue of Nature Reviews Drug Discovery. It's from an article on trying to discern trends from broad-scale literature analysis, and it's worth a separate blog post of its own (coming shortly). But after yesterday's discussion of whether there are too many graduates in science and engineering, this looked useful.
Note, for example, the ramp up in NIH funding in the late 1950s/ early 1960s (a very large change in percentage terms), which was followed by a similar surge in doctorates granted. The late-1990s funding increases seem to be having a similar effect near the end of the chart.
Note also the well-publicized drug drought - but the historical perspective is interesting. We've clearly fallen off the 1970-2000 trend line of increasing drug approvals, but we seem to be stabilizing at roughly a 1980s level. The argument is whether that's where we should be or not. We have all these new tools, but all these new worries. Lots of new targets, but fewer good ones like the old days. Many new tools, but plenty of difficult-to-interpret data generated from them. And so on. But 1985 is apparently about where the balance of all these things is putting us.
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October 29, 2009
Here's one to get your attention: there's been a lot of arguing (on this blog and others) about the continual talk of shortages of scientists and engineers. That's a little hard to take for the number of people who've been laid off from this industry over the last two or three years and who often are having trouble finding a new position.
A study from Rutgers and Georgetown now says, though, that there is no such shortage. Here's the PDF, so you can check it out for yourself. The intro:
A decline in both the quantity and quality of students pursuing careers in science, technology, engineering, and mathematics (STEM) is widely noted in policy reports, the popular press, and by policymakers. Fears of increasing global competition compound the perception that there has been a drop in the supply of high-quality students moving up through the STEM pipeline in the United States. Yet, is there evidence of a long-term decline in the proportion of American students with the relevant training and qualifications to pursue STEM jobs?
In a previous paper, we found that universities in the United States actually graduate many more STEM students than are hired each year, and produce large numbers of top- performing science and math students. In this paper, we explore three major questions: (1) What is the “flow” or attrition rate of STEM students along the high school to career pathway? (2) How does this flow and this attrition rate change from earlier cohorts to current cohorts? (3) What are the changes in quality of STEM students who persist through the STEM pathway?
What they're finding is (again) that there's no shortage of graduates - in fact, quite th opposite, unfortunately for wages and employment. One worrisome thing, though, is that at some point in the mid-to-late 1990s the top-performing students at both the high school and college level began to jump ship from the science/engineering fields. There are several possible explanations, but the one that comes to mind is that students are looking ahead a bit and don't like the prospects that they see and/or are lured by other fields that seem more attractive.
More on this later - for now, here's some commentary over at Science which shows that the arguing has already begun.
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Here are a few more of those questions that medicinal chemists have to deal with from time to time. Most of these have no definitive answers (which is why they keep coming up!)
1. You're making a compound that looks to be important in the project - maybe even the clinical candidate, if things go right. But there's a step in the synthesis which - while it does work - is clearly not something that's going to scale up too well. You need more compound right now, and you can push things through. But you're eventually going to have to ditch that step (unless this compound gets overtaken by another one), so. . .when's the right time to worry about that?
2. Your compound series is in a pretty crowded patent landscape. In fact, another application has just published that really looks to be breathing down your neck. Of course, that means the work in it was done a year and a half ago (or more). Can you assume that Company X has followed the same course that you have, and has already investigated the series you're working on? Should you drop them, or go in in the chances that six months from now another application will drop that covers you like a tarp?
3. You're finally writing up one of your old projects for publication. But it's been a while, and the details of what happened are not as sharp as they were when thing were going on. What's more, on looking the work over, you realize that there are some obvious gaps in it, stuff that didn't look that way at the time, but sure does so now. You can write things up to make it look more coherent, but only by rearranging the way it really happened. Where do you draw the line?
4. Your lead compound is ready to go into toxicology testing, the last big step before declaring victory and naming it as the development candidate. Trouble is, there's something funny about it in rats. They just don't get the blood levels that mice and dogs do, and your tox people would really, really rather run the tox study in rats (since that's the standard, and what they have the most comparison data for). Update: I mistakenly switched rodents mentally this morning on the train, now they're switched back to what they should be). You can get the blood levels up to where they need to be - but only by using a dosing vehicle that might have problems of its own, and that the toxicologists haven't had much experience with either. What to do?
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October 28, 2009
Now here's a completely weird idea: a group in Korea has encapsulated individual living yeast cells in silica. They start out by coating the cells with some charged polymers that are known to serve as a good substrate for silication, and then expose the yeast to silicic acid solution. They end up with hard-shell yeast, sort of halfway to being a bizarre sort of diatom.
The encapsulated cells behave rather differently, as no doubt would we all under such conditions. After thirty days in the cold with no nutrients, the silica-coated yeast is at least three times more viable than wild-type cells (as determined by fluorescent staining). On the other hand, when exposed to a warm nutrient broth, the silica-coated yeast does not divide, as opposed to wild-type yeast, which of course takes off like a rocket under such conditions. They're still alive, but just sitting around - which makes you wonder what signals, exactly, are interrupting mitosis.
The authors tried the same trick on E. coli bacteria, but found that the initial polymer coating step killed them off. That's disappointing, but not surprising, given that disruption of the bacterial membrane with charged species is the mode of action of several broad-spectrum antibiotics.
"Hmmm. . .so what?" might be one reaction to this work. But stop and think about it for a minute. This provides a new means to an biological/inorganic interface, a way to stich cell biology and chemical nanotechnology together. If you can layer yeast cells with silica and they survive (and are, in fact, fairly robust), you can imagine gaining more control over the process and extending it to other substances. A layer that could at least partially conduct electricity would be very interesting, as would layers with various-sized pores built into them. The surfaces could be further functionalized with all sorts of other molecules as well for more elaborate experiments. No, this could keep a lot of people busy for a long time, and I suspect it will.
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Johnson & Johnson's CEO has given an interview to the Financial Times explaining his company's strategy with acquisitions. And right now, that strategy is. . .not to make acquisitions. They see partnerships as making a lot more sense:
“The cost of developing compounds has become so high and become so risky that we are looking to share the risks and opportunities and find more and more partnerships.”
J&J has been putting this into practice recently, taking equity stakes in several different companies. In the case of Elan and Crucell, interestingly, the company has agreed to standstill provisions, in order to make it clear that they're not just on the first step to an outright acquisition any time soon. It's interesting that this would be coming from Johnson & Johnson, since in many cases they've been one of the less destructive acquirers in the business already. (Well, with some exceptions, like when they took over Scios).
The temptation to compare this policy with Pfizer's is almost overwhelming, but the two companies are in very different positions. For one thing, J&J has their medical devices and diagnostics businesses, which are both profitable and run on different rhythms than their pharma side. Even more importantly, they also aren't locked into a grow-or-die situation, needing larger and larger infusions of revenue to meet the expenses which get larger every time they go out and buy those revenue streams, which mean that they need to go buy some more and then. . .
The article says that J&J has no deals under consideration right now, but that this style of deal-making is definitely how the company plans to operate. There's definitely enough risk to be spread around - I just hope that there's enough reward for everyone, too.
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October 27, 2009
I've been occupied all morning with voodoo. Well, the technical name for it is catalytic hydrogenation, but let's call it for what it is: witchcraft. It's a widely used reaction in organic chemistry, and you can use it to reduce all kinds of different functional groups on your molecules. But once you get off the well-traveled roads, it's all jungle drums at midnight.
One reason we chemists like this reaction so much is that it's simple. You add some dark insoluble powder to your compound - which is some metal like palladium, platinum, nickel or the like, adsorbed onto carbon black or another solid. Then you add solvent and put the whole thing under an atmosphere of hydrogen gas. That soaks into the metal particles, your compound sits on them and gets magically reduced, and after a while you filter everything off and there's your clean, transformed product.
Most of the time. You'll note that I've skipped over a lot of variables there. For one thing, there's the choice of metal catalysts. Pt and Pd get the most use, but they come on a variety of solid supports. Carbon, alumina, barium sulfate, calcium carbonate. . .they all act differently. And don't stop with those guys: nickel's not to be ignored, then rhodium's available, and even ruthenium if you want to crank up the pressure. The pressure of all that hydrogen, there's another variable. Just a balloon on top, atmospheric pressure? Or put in a thick glass bottle on a shaker and turn it up to 50 pounds per square inch? Higher, in a metal apparatus? And what temperature did you have in mind? Ambient, or would you like to heat things up? Remember, as the pressure goes up, so does the temperature you can run the solvents up to.
Ah yes, the solvents. A lot of the time you see this work done in methanol or ethanol, but the reactions will often go quite differently in ethyl acetate or even something less polar. I've even seen some done in dichloromethane, although that somehow just seems wrong. Acids often have a profound effect on things, particularly if there's a basic amine in your compound.
And I haven't mentioned poisoned catalysts yet, have I? A bit of lead, or the addition of (non-protonated) amines or sulfur-containing compounds can dial down the reactivity of a lot of these metals - often down to zero, but sometimes to a useful level that you can't reach any other way. And then there's transfer hydrogenation, where you don't use the gas itself, but let some other compound give up hydrogen inside the reaction and transfer it over to your substrate. Paraformaldehyde, formic acid, phosphites, cyclohexene - all of those will work, and they can all work differently.
So. . .how many variations are we up to? Do you want to use 5% palladium on carbon in methanol, room temperature at 50 psi? Or platinum oxide in acetic acid at 50 degrees? Rhodium on alumina, ethanol, 100 psi at 100 C? Or wet 10% platinum catalyst with formic acid? That should get you started on this simple, well-known reaction. I've run 22 of them in the last two days, with the assistance of the H-Cube reactor, and I have to say: I'm about hydrogenated out.
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October 26, 2009
I wrote about this topic a few years ago, and thought I'd update it. Many chemists find themselves looking at a periodic table and wondering "How many of these things have I personally handled?" My list is up to nearly 45 elements (there are a couple that I've got to think about, one-off catalyst reactions from twenty-two years ago and the like). And there are at least 29 that I hope to never use at all, since they're radioactive and I'm generally not in the mood for that. So what does that leave me?
Well, I've never used beryllium, although it's not that I'm tapping my foot waiting for any. It's pretty toxic stuff, for the most part, and there are hardly any organic chemistry reactions that get near it. That means that I can't even think what I might use it for, and I could easily go my whole career without seeing any.
The next lowest molecule weight element I haven't messed with (excluding unreactive neon, which you at least get to see in its excited state) is probably scandium. That whole first column of transition metals is pretty useless for organic chemists, to be honest (Yttrium? Lanthanum?), and I've never seen any reactions that leapt out at me as things I had to try. No, if the answer is scandium, it must have been a pretty odd question.
Next up, I haven't used either of the G twins, gallium and germanium. They're not too well studied compared to their family members above and below: aluminum and even indium are more widely used than gallium, and silicon and tin show up in organic labs a million times more often than germanium. But with those relatives, you'd have to think that there's something interesting that can be done with these, so it depends on whether anyone finds out what that might be during the rest of my chemistry career.
And right next to these is arsenic, which I've also managed to avoid. It's famously poisonous, although it's really not worse than a lot of other things that get used much more often. But again, there's not a lot of compelling chemistry to be done with the stuff, not that I know of, anyway, and there are always those unfortunate nomenclature problems to be dealt with, especially if you have a British accent.
Krypton I've never had a use for, and I'd have to rate the chances as very low indeed. In the next row, I've handled strontium chloride, but only to make red-colored flames for a school demonstration show. I have yet to touch yttrium, as mentioned above, and I've managed to miss zirconium so far as well. There are actually a number of organometallic reactions that use that one, so it's at least a real possibility. Niobium I have yet to encounter, and at the rate it's used, I probably never will. Cadmium's another toxic beast - there are some old reactions that use organocadmiums, but I can't think when I saw a modern reference that used any of them, and I don't see this one in my future, either. Antimony I might use if I never need some horrible superacid. Tellurium, well. . .there would have to be a pretty good reason, given its reeking, nose-wrinkling sulfur and selenium relatives, but someone might yet come up with one. Can't rule that one out, unfortunately.
Now we're getting into the heavy metals, and a lot of gaps start to appear. Has anyone in an organic chemistry lab ever used hafnium or tantalum? Didn't think so. The best candidate for "something I could use, but haven't" in this bunch is osmium. The tetroxide is a very useful reagent that I just haven't had the need for. It wouldn't surprise me if that's the next addition to my list. I've no desire whatsoever to use thallium. It's part of a short run of nasties that you hit right after the jewelry metals - you have your platinum, then gold, and you think you're in the high-rent district, and suddenly it's mercury, thallium, and lead right in a row. Reminds me of the way towns were stuck next to each other in New Jersey.
And as far as the lanthanides, well, I've used cerium as a TLC stain, and once I used samarium iodide - which, true to its reputation, didn't work. None of the others have I touched, and unless I need some funky NMR shift reagent, which fewer and fewer people do these days, I don't see it happening. There are a lot of funny rare earths down there, but little reason for an organic chemist to go digging around among them.
Weirdest element I actually have handled? Xenon would have to be the winner - I've used the difluoride, and yes, that was the recourse of a desperate chemist. But it did work to turn a silyl enol ether into an alpha-fluoro ketone, so I can't say anything bad about it, other than its rather penetrating smell, which I probably should have taken more care not to experience. . .
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October 23, 2009
Organometallic reagentss come from large tribes, and there are always wild cousins up in the hills. A good place to look for the livelier ones is in the simplest alkyl derivatives, and you should go all the way down to the methyls if you want to know their real character. Ignore the halides. Methylmagnesium bromide you can get in multiliter kegs; they might as well sell it in Pottery Barn.
Dimethylmagnesium, though, is not an article of commerce. I've made it myself. So although it's definitely something you want to keep an eye on, I can't very well say that I won't work with it. And the other metals? Dimethyl mercury I will not get within yards of, for very well-founded reasons. Trimethylaluminum is a flamethrower extraordinaire, with a solid reputation among pyromaniacs. I've used the stuff, although I wasn't whistling while I was syringing it out. Handling it in solution, as I did, is less stressful than using the pure stuff - I'd definitely want to sit down and think about that one.
But neat dimethyl zinc. . .no, I don't think so. A colleague of mine made some in graduate school, and came down the hall to us looking rather pale. He'd disconnected a length of rubber tubing from his distillation apparatus and seen it go up in immediate, vigorous flames. "This stuff makes t-butyllithium look like dishwater" is the statement I remember from that evening. You can buy the pure stuff from Alfa, if you're inclined to run a head-to-head comparison. Do make sure to post the video on YouTube; that's as close as I want to get.
One problem is that it's a pretty volatile compound, boiling at 46C, so there's plenty of vapor around to start a party. The diethyl analog is a bit better, but it's nearly as pyrophoric. The Library of Congress discovered this in the 1980s and 1990s, during a long-running project to deacidify old documents. The diethyl zinc reacts with the acid in aged wood-pulp papers, neutralizing it, lightening the color, and stiffening the paper, so you'd think it would be ideal. Well, except for the instant-bursting-into-ravenous-flames part. Making sure that all the reagent was gone before opening the hatch, that was rather important. The pilot plant for this process suffered from some regrettable explosive bonfires before the whole idea was abandoned. Interestingly, one of the biggest problems seems to have been that the treated books were (at least at first) rather odorous, and some colored book covers were initially affected. You can sense a certain testiness about these issues in the Library's final report on the subject:
It has also been established that tight or loose packing of books; the amount of alkaline reserve; reactions of DEZ with degradation products, unknown paper chemicals and adhesives; phases of the moon and the positions of various planets and constellations do not have any influence on the observed adverse effects of DEZ treatment.
You'll notice that the LOC didn't even bother with the dimethyl compound, and I think I'll take a tip from them.
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October 22, 2009
Xconomy has a useful two-part interview with Christopher Henney, who helped to found Icos, Dendreon, and Immunex. The part I found most interesting, naturally, was the section entitled "Five Red Flags of Biotech". (Note to the Xconony folks - the article actually has six of them). Here are his warning signs if you're thinking of investing in (or, I should add, working for!) a new company and you're checking them out. Beware of. . .
1. Top management without a scientific background. If the CEO isn't a scientist, Henney says, there had better be some good ones very close to him, and he's not talking about the scientific advisory board, either.
2. Saying that they have no worries. Any small company in this game has plenty to worry about - heck, the huge companies have plenty to worry about. So if they try to tell you otherwise, then you're the one who should be worrying.
3. Hard-to-understand science. Henney says to look out if they can only tell you that it's really hard to explain. I'd agree with that, but I'd also add that you can go too far in the other direction. If they spout a bunch of advertising copy under the impression that they're giving you the science, then you should also flee. (That might be a consequence of Red Flag #1). I honestly think that any concept in this industry can be explained to any reasonably intelligent person. So if someone tells you that they can't do that, you have to worry that they don't understand it very well themselves.
4. Geographic remoteness. This is an interesting one, because ideas can come from all over. But for a viable company, Henney maintains, you need to be somewhere that you can recruit talented and experienced people. That doesn't mean that every company has to be in Cambridge or South San Francisco, because there are plenty of other possibilities. But trying to get a great biotech idea off the ground will definitely be a lot harder in Winnipeg, El Paso, Chattanooga, or Scranton. There are smart people there, but most of the ones who know this business or have a real interest in it will have gone somewhere else. And it'll be tougher to persuade others to move somewhere that could leave them without options if the company doesn't work out.
5. Too many VCs. This goes for just about any industry. A board that's full of venture capital people shows a lack of imagination at the very least, and it makes you wonder why the VCs will even stick around when all they see are their own kind.
6. Family members in key roles. My take is that you can get away with one sibling or the like, preferably as long as they're not like a CEO and CFO team or something. But I agree with Henney's take that if you see a board dominated by a family, you should hit the exits. This stuff hasn't been around long enough to be a family tradition.
I would add a couple of others to be wary of:
7. Breathless hype. Sure, all press releases have some of this. But if a small company is unable to speak in any other terms than "breakthrough, unprecedented, game-changing paradigm shifts" or the like, you should be worried. Either they don't really believe this stuff (in which case they may not be very trustworthy), or they do (in which case they may be delusional). Real breakthroughs in this business don't need all the glitter and spray paint.
8. Too much emphasis on the SAB. Henney addresses this partly in Red Flag #1. But it's worth remembering that a wonderful blue-ribbon scientific advisory board stacked with Nobel Prize winners is also stacked with very busy people who will only be able to give this little company a small portion of their time. These aren't the folks who will be driving the projects forward. If a small company relentlessly promotes the big-name advisors they've signed up, you have to wonder if there's anything else to promote.
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October 21, 2009
I just wanted to note that the entire BioCentury "Back to School" issue mentioned in the post below can now be read for free (PDF). Thanks to the folks over there for doing this! The original post has been updated as well.
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I wanted to highlight a comment that showed up recently in the latest Pfizer post:
I would just like to point out that there is often mention of Pfizer as being a poorly productive R&D outfit on this blog, but there is rarely any mention of the scientists themselves. Having worked as a chemist at both Merck and also at Pfizer, I would just like to point out that in my experience, the chemists at both are highly productive, extremely hardworking, and passionate individuals. It's a shame that the discussions here do not distinguish between those carrying out the research and the direction of the company overall.
That's true, and although I've put in disclaimers like that in the past, I haven't recently. There should be some sort of default blanket statement for cases like this. I know a lot of people at Pfizer, and they know their stuff. Pfizer's problems are not due to a shortage of smart, competent, hardworking people. Everyone in the industry is having a hard time keeping a good pipeline of drug candidates going these days, no matter how good they are.
But I think that the course that Pfizer has put itself on is making its problems worse, and doing damage to the entire industry at the same time. That actually makes it even more of a tragedy, the fact that they have so many good people there trying to make things work.
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Steve Usdin at BioCentury sent along a reprint of the newsletter's annual "Back to School" issue from last month (available for open access here) in response to my note about "micropharma" the other day. And it's clear that he's been thinking along the same lines. Whether or not this model is going to work is another question, but that looks like something that we're going to be finding out.
As the issue notes, in a pithy quote from Mike Powell of Sofinnova, the key problem is "how to restructure an industry where it costs $100 million to answer a question but people are only willing to pay you $50 million for the answer." Since the amount of money being handed out is probably not going to increase any time soon, the only way out of that dilemma is to find some way for that first figure to go down.
One of the groups that won't be happy about that process are academic centers that are used to seeing their intellectual property as a potentially lucrative source of funds. The strike-it-rich days do not look to be coming back any time soon. Instead, BioCentury advises universities to get ready to adopt a "non-ROI" approach to developing their ideas, by use of grants, public-private consortia, and help from foundations and other nonprofits. (Perhaps a name like "delayed ROI" or, if you're being especially weasely about it, "enhanced ROI", might help that concept go down a bit smoother).
CRO firms are almost certainly going to have to be part of that process, since there are plenty of skills needed to push a drug target or molecule along that are not found in most universities. That, to me, would indicate a real market for a low-cost CRO outfit targeting academia. I'm not sure if anyone is serving that market, or trying to, but it would seem to have some potential in it. Anyone who can help to run should-we-kill-this experiments, without spending too much money getting the answer, will have something that looks to be in demand.
In general, this landscape would mean that ideas will go longer before companies are formed around them, with the idea that they can be tested out a bit without having to build new corporations to do it. (As another quote from the article had it, "The unmet need in the industry is drugs, not companies".) Payoffs will be slower, and they won't be as large when they come, either. Venture capital investors will be asked to have more patience under this model, and that's not something that they're necessarily noted for. And someone's going to have to have the money (and nerve) to form mid-sized organizations that will pick up the best of the things coming out of academia, since many of them still won't be quite ready to go right into a big organization. The non-humungous companies that have survived to this point might step up and fill this role, and BioCentury also suggests that Japanese and Indian companies might fill this space as well.
The big question is: will people be able to put up with this, or not? After all, no one's envisioning failure rates going down, they're just hoping that the failures will happen sooner and cost less money. Will they? It's not like "fail quickly" hasn't been a goal of companies in the business for years now. But sometimes it's hard to fail any other way than slowly (and expensively).
Well, the common theme to all this (and to most of the other crystal-ball reading going on these days) is that the industry isn't going to be able to go on in the way it's been accustomed to. If you ask a hundred people in this business what it's going to look like ten or fifteen years from now, the only thing you could probably get them to agree on is "Not like it does today". We'll just have to wait to see if they're all playing "Cheat the Prophet" or not. . .
+ TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History
October 20, 2009
The Wall Street Journal's Health Blog got a chance to ask the higher-ups at Pfizer what their R&D will look like a year from now. Their (understandably) not too-in-depth answers are here: Decentralized research units, with some functions run company-wide, and this quote: "There are elements of drug discovery and development where you just need scale".
Well played! I wouldn't expect anything less. But are there elements of drug discovery and development where scale - massive, ponderous, hundreds-of-vice-presidents scale - actually hurts? I don't think you're going to hear that topic brought up very much at Pfizer, at least not out in the open. And let's not lump those two functions together: drug development benefits from a company's size a lot more than drug discovery does. Once you've gotten to a critical-mass level, sheer size (as far as I can see) does nothing to help productivity in drug discovery, and actually seems to damage it. As evidence for that statement, let me point to Pfizer's internal research record, as opposed to the stuff they've gone out and bought.
And what might be refreshing is an admission that big mergers - drag-on-for-months am-I-going-to-still-be-here mergers - come with an acute productivity penalty no matter what. I may have missed it, but I don't recall hearing anyone from Pfizer say anything like "Although we know that this is going to be a huge disruption, we think that in the end it'll be worth it". No, it always seems to be the Day One, hit-the-ground-running, now-the-synergy-starts stuff, which is just not in sync with reality.
Well, we can come back in a year and see what Pfizer's R&D operation really looks like. But I'll venture a guess: huge. Unwieldy. Not as productive as you'd think it should be. Still rearranging and getting smaller as the company tries to figure out how to make it all work. And looking over its shoulder for the next big acquisition. Anyone want to bet against any of those?
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October 19, 2009
(1) Bnet Pharma on "How Not to Write a Pharma Press Release". Privately held Epeius is sending out bulletins loaded with phrases like "more stunning results" and "Epeius Biotechnologies draws the sword of targeted gene delivery from the stone of chemistry and physics". If they were publicly traded, this would be fun to watch. . .
(2) The rise of Micropharma? We'll come back to this subject:
The drug discovery pipelines of the major pharmaceutical companies have become shockingly depleted, foreshadowing a potential crisis in the ability of Big Pharma to meet the pharmaceutical demands created by the ever-changing spectrum of human disease. However, from this major crisis is emerging a major opportunity, namely micropharma – academia-originated biotech start-up companies that are efficient, innovative, product-focused, and small. In this Feature, we discuss a “new ecosystem” for drug development, with high-risk innovation in micropharma leading to Big Pharma clinical trials. . .
(3) Cleaving amyloid precursor protein into beta-amyloid has long been thought (by many) to be the key pathological event in Alzheimer's. But what about the piece of APP that's left inside the cell?
(4) A favorite post around here for some time has been "Sand Won't Save You This Time", about the wonderfulness of chlorine trifluoride. Well, here's a method to produce very interesting-looking compounds that uses. . .bromine trifluoride. How much do you want these products, that's what you have to ask yourself. To be sure, the authors do mention that "Although commercial, bromine trifluoride is not a common reagent in every organic laboratory, and many chemists do not feel at ease with it because of its high reactivity. . .". You have to go to the Supporting Information file before you start hearing about freshly preparing the stuff from elemental fluorine.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease | Business and Markets
October 16, 2009
I've heard from several sources that today is what they're calling "Day One" at Pfizer. The merger with Wyeth is now official, and word is going to start going out on which sites will stay, which will close, and who will be moved or let go during the entire process.
Problem is, I'm also hearing that (for research, anyway) it could take as long as another sixty days for all the news to come out. We'll see what the real timetable is, but that's enough to make me wonder if there's any way they could have found to make the whole business more excruciating.
But it's a sad day. I think the Pfizer-Wyeth merger is a bad idea which will do bad things. I wish it hadn't happened, just like I wish many of the other mergers on this scale had not happened, and I wish that I could have some hope that this sort of thing won't happen again. But the lessons are taking a long time to be learned.
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There have been several reports over the years of people engineering receptor proteins to make them do defined tasks. They've generally been using the bacterial periplasmic binding proteins (PBPs) as a starting point, attaching some sort of fluorescent group onto one end, so that when a desired ligand binds, the protein folds in on itself in a way to set off a fluorescent resonance energy transfer (FRET). That's a commonly used technique to see if two proteins are in close proximity to each other; it's robust enough to be used in many high-throughput screening assays.
So the readout isn't the problem. But something else certainly is. In a new PNAS paper, a group at the Max Planck Institute in Tübingen has gone back and taken a look at these receptors, which are reported to bind a number of interesting ligands such as serotonin, lactate, and even TNT and a model for nerve gas agents. You can see the forensic applications for those latter two if the technique worked well, and the press releases were rather breathless, as they tend to be. But not only did these workers claim a very interesting sensor system, but they also went out of their way to emphasize that they arrived at these results computationally:
Computational design offers enormous generality for engineering protein structure and function. Here we present a structure-based computational method that can drastically redesign protein ligand-binding specificities. This method was used to construct soluble receptors that bind trinitrotoluene, l-lactate or serotonin with high selectivity and affinity. These engineered receptors can function as biosensors for their new ligands; we also incorporated them into synthetic bacterial signal transduction pathways, regulating gene expression in response to extracellular trinitrotoluene or l-lactate. The use of various ligands and proteins shows that a high degree of control over biomolecular recognition has been established computationally.
The Max Planck group would like to disagree with that. Their PNAS paper is entitled "Computational Design of Ligand Binding is Not a Solved Problem". They were able to get crystals of the serotonin-binding protein, but could not get any X-ray structures that showed any serotonin binding in the putative ligand pocket. They then turned to a well-known suite of techniques to characterize ligand binding. One of these is thermal stability: when a protein is binding a high-affinity ligand, it tends to show a higher melting point, since its structure is often more settled-down than the open form. None of the reported receptors showed any such behavior, and all of them were substantially less thermally stable than the wild-type proteins. Strike one.
They then tried ITC, a calorimetry measurement to look for heat of binding. A favorable binding event releases heat - it's a lower-energy state - but none of the engineered receptors showed any changes at all when their supposed ligands were introduced. Strike two. And finally, they turned to NMR experiments, which are widely used to determine protein structure and characterize binding of small molecules. WIld-type proteins of this sort showed exactly what they should have: big conformational changes when their ligands were present. But the engineered proteins showed almost no changes at all. Strike three, and as far as I'm concerned, these pieces of evidence absolutely close the case. These so-called receptors aren't binding anything.
So why do they show FRET signals? The authors suggest that this is some sort of artifact, not related to real receptor binding and note dryly that "Our analysis shows the importance of experimental and structural validation to improve computational design methodologies".
I should also note a very interesting sidelight: the same original research group also published a paper in Science on turning these computationally engineered PBPs into a functional enzyme. Unfortunately, this was retracted last year, when it turned out that the work could not be reproduced. Some wild-type enzyme was still present as an impurity, and when the engineered protein was rigorously purified, the activity went away. (Update: more on this retraction here, and there is indeed more to it). It appears that some other results from this work may be going away now, too. . .
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October 15, 2009
A couple of articles have come together and gotten me to thinking. Back during the summer, long-time medicinal chemist Mark Murcko published a short editorial in Drug Discovery Today comemmerating the Apollo 11 moon landing's 40th anniversary:
"People like me, who are old enough to actually remember the events of July 1969, are instantly assailed with powerful and reflexive emotions when we think back to the effect Apollo had on us: the excitement, awe and wonder. My family, like so many others, was obsessed with space exploration. The walls of our den were covered with NASA photos, diagrams and technical bulletins – anything we could get them to send us. Models of rockets hung from the ceiling by fishing line. . .We soaked it all in, and the events of that day remain a seminal memory of my childhood. It was glorious; nothing could possibly be more exhilarating.
And yet...there are some interesting parallels to what all of us, engaged in the roiling tumult of biomedical research, do here and now. Our mission – to invent new therapies that transform human health and alleviate suffering – captures the imagination as profoundly as did Apollo. Our efforts once were regarded with the same admiration as the NASA breakthroughs (and while public perceptions may be different today, our mission has not wavered). We are attempting, one could argue, even more complex technical achievements. . . ."
And just the other day I came across this piece in The New Atlantis entitled "The Lost Prestige of Nuclear Physics". (Via Arts and Letters Daily). Its thesis, which I think is accurate:
"The story of nuclear physics is one of the mos