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Home > Weblog Columns > In the PipelineWeblog columns [select a blog][Corante Blog]BETWEENLAWYERS: technology + culture + lawBRAINWAVES:neurons, bits & genesCOPYFIGHT: thepolitics of intellectual propertyGOYAMI: search engine marketingIDEAFLOW:creativity+ innovationIN THEPIPELINE: drugdiscoveryMANY-TO-MANY: socialsoftwareREBUILDINGMEDIA: the economics of mediaSTRANGE ATTRACTOR:social mediaTOTALEXPERIENCE: experience designAbout this Author Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.comChemistry and Pharma Blogs:PharmalotOrg Prep DailyOn PharmaOne in Ten ThousandAway From the BenchQDIS BlogChemical MusingsIn Vivo BlogThe ChemblogMolecule of the DayKinase ProDrugs and PoisonsJungfreudlichChembarkSocial DetritusPharmagossipWhistling in the WindOrganometallic CurrentGreat Molecular CrapshootPost Doc Ergo Propter DocA Chemist's Lab NotebookThe Curious Wavefunction
July 18, 2008Lowe's Law of Diurnal Distribution Posted by DerekHere’s an appropriate topic for a Friday, although at first many of you may think I’ve lost my mind. What would happen if you combed the full text of the experimental sections of the chemistry journals, looking for how long people ran their reactions?I’m pretty sure that I know what you’d see: there would be a lot of scatter in the short time periods, with some peaks at the various half-hour and hour marks just for convenience. But as you went out into the multiple-hour procedures, I feel sure that you’d see pronounced spikes in the data at around sixteen to twenty hours and again at around 72 hours.Some readers have doubtless started nodding their heads, having done the math. Those times correspond to "overnight" and "over the weekend", and I'm willing to bet that they're over-represented (and how) in the data set. I'll go on to predict scarce examples in, say, the 14-hour or 38-hour ranges - there's not much way to run a reaction for those intervals and not be in the lab too early in the morning or too late at night.A second-order prediction is that when such reactions are found, that their origins will skew heavily toward academia rather than industry. And I'm also willing to bet that patent procedures will tend to follow the working-day timelines more than the general literature, for the same reasons. My last higher-order prediction is that the reaction times would not, in fact, obey Benford's Law, as many other data sets of this kind do.As far as I know, no one's ever done this sort of analysis, but I suppose it would be possible, especially for someone at Chemical Abstracts or at one of the scientific publishers. If someone wants to try it, please let me know what comes out. And if the results follow my predictions, please feel free to refer to the title of this post or something similar. I won't object.Comments (24) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs | The Scientific Literature July 16, 2008Receptors: Can't Live With 'Em, Can't Understand 'EmPosted by DerekAt various points in my drug discovery career, I’ve worked on G-protein-coupled receptor (GPCR) targets. Most everyone in the drug industry has at some point – a significant fraction of the known drugs work through them, even though we have a heck of a time knowing what their structures are like.For those outside the field, GPCRs are a ubiquitous mode of signaling between the interior of a cell and what’s going on outside it, which accounts for the hundreds of different types of the things. They’re all large proteins that sit in the cell membrane, looped around so that some of their surfaces are on the outside and some poke through to the inside. The outside folds have a defined binding site for some particular ligand - a small molecule or protein – and the inside surfaces interact with a variety of other signaling proteins, first among them being the G-proteins of the name. When a receptor’s ligand binds from the outside, that sets off some sort of big shape change. The protein’s coils slide and shift around in response, which changes its exposed surfaces and binding patterns on the inside face. Suddenly different proteins are bound and released there, which sets off the various chemical signaling cascades inside the cell.The reason we like GPCRs is that many of them have binding sites for small molecules, like the neurotransmitters. Dopamine, serotonin, acetylcholine – these are molecules that medicinal chemists can really get their hands around. The receptors that bind whole other proteins as external ligands are definitely a tougher bunch to work with, but we’ve still found many small molecules that will interact with some of them. Naturally, there are at least two modes of signaling a GPCR can engage in: on and off. A ligand that comes in and sets off the intracellular signaling is called an agonist, and one that binds but doesn’t set off those signals is called an antagonist. Antagonist molecules will also gum up the works and block agonists from doing their things. We have an easier time making those, naturally, since there are dozens of ways to mess up a process compared to the ways there are of running it correctly!Now, when I was first working in the GPCR field almost twenty years ago, it was reasonably straightforward. You had your agonists and you had your antagonists – well, OK, there were those irritating partial agonists, true. Those things set off the desired cellular signal, but never at the levels that a full agonist would, for some reason. And there were a lot of odd behaviors that no one quite knew how to explain, but we tried to not let those bother us.These days, it’s become clear that GPCRs are not so simple. There appear to be some, for example, whose default setting is “on”, with no agonist needed. People are still arguing about how many receptors do this in the wild, but there seems little doubt that it does go on. These constituitively active receptors can be turned off, though, by the binding of some ligands, which are known as inverse agonists, and there are others, good old antagonists, that can block the action of the inverse agonists. Figuring out which receptors do this sort of thing - and which drugs - is a full time job for a lot of people.It’s also been appreciated in recent years that GPCRs don’t just float around by themselves on the cell surface. Many of them interact with other nearby receptors, binding side-by-side with them, and their activities can vary depending on the environment they’re in. The search is on for compounds that will recognize receptor dimers over the good ol’ monomeric forms, and the search is also on for figuring out what those will do once we have them. To add to the fun, these various dimers can be with other receptors of their own kind (homodimers) or with totally different ones, some from different families entirely (heterodimers). This area of research is definitely heating up.And recently, I came across a paper which looked at how a standard GPCR can respond differently to an agonist depending on where it's located in the membrane. We're starting to understand how heterogeneous the lipids in that membrane are, and that receptors can move from one domain to another depending on what's binding to them (either on their outside or inside faces). The techniques to study this kind of thing are not trivial, to put it mildly, and we're only just getting started on figuring out what's going on out there in the real world in real time. Doubtless many bizarre surprises await.So, once again, the "nothing is simple" rule prevails. This kind of thing is why I can't completely succumb to the gloom that sometimes spreads over the industry. There's just so much that we don't know, and so much to work on, and so many people that need what we're trying to discover, that I can't believe that the whole enterprise is in as much trouble as (sometimes) it seems. . .Comments (19) + TrackBacks (0) | Category: Biological News | Drug Assays July 15, 2008Metabolic Hope Springs EternalPosted by DerekNow, if I were still doing metabolic disease work, I'd be all over this target: CAMKK2, which is mercifully short for "Ca2+/calmodulin-dependent protein kinase kinase 2". (Kinase nomenclature has been out of hand for years, in case you're wondering).CAMKK2 is right in the middle of a lot of pathways that are known to be important for regulation of appetite and glucose levels, namely ghrelin, AMPK, and NPY. These have been rather hard to approach directly with small molecules, or (in the case of NPY) hitting them hasn't been enough by itself. That's the problem with a lot of potential therapies for obesity, as I've mentioned here before. As a behavior, eating is full of overlapping backup redundant pathways, since we're all descendants of creatures that ate whatever they could, whenever they could. The ones whose feeding could be easily shut down or interrupted didn't make it this far.So even though the field is littered with things that haven't worked out, perhaps a target like this, which seems to be more upstream, might have a better chance of success. We're definitely going to find out. Given the number of companies interested in this area, and the number with kinase expertise, someone's going to be able to take a good swing at this one. The benefits might go beyond weight loss - animals given a known inhibitor (STO-609, a Sumitomo compound) were also resistant to the bad effects of a high-fat diet, putting on less weight than controls and showing better glucose control.Of course, the fact that Sumitomo had a compound years ago that hits this target so well makes you wonder what ever happened to it. I can't find much about why it didn't progress, but you can be sure that other people are asking that same question right now. . .Update: see this comment for more on this topic. . .Comments (11) + TrackBacks (0) | Category: Diabetes and Obesity July 14, 2008Things I Won't Work With: Cyanogen AzidePosted by DerekCyanogen bromide is not a nice reagent. It’s not quite on my list of things that I refuse to use, but it’s definitely well up on the list of the ones I’d rather find an alternative to. The stuff is very toxic and very volatile, and reactive as can be.But it’s not the worst thing in its family. A good candidate for that would be cyanogen azide, which you get by reacting the bromide with good old sodium azide. Good old sodium azide, which is no mean poison itself, will do that with just about any bromide that’s capable of being displaced at all. Azide is one of the Nucleophiles of the Gods, like thiolate anions – if your leaving group doesn’t leave when those things barge in, you need to adjust your thoughts about it. Cyanogen bromide (or chloride) doesn't stand a chance.Cyanogen azide is trouble right from its empirical formula: CN4, not one hydrogen atom to its name. A molecular weight of 68 means that you’re dealing with a small, lively compound, but when the stuff is 82 per cent nitrogen, you can be sure that it’s yearning to be smaller and livelier still. That’s a common theme in explosives, this longing to return to the gaseous state, and nitrogen-nitrogen bonds are especially known for that spiritual tendency.There were scattered reports of the compound in the older German and French literature, but since these referred to the isolation of crystalline compounds which did not necessarily blow the lab windows out, they were clearly mistaken. F. D. Marsh at DuPont made the real thing in the 1960s (first report here, follow-up after eight no-doubt-exciting years here). It's a clear oil, not that many people have seen it that state, or at least not for long. Marsh's papers are, most appropriately, well marbled with warnings about how to handle the stuff. It's described as "a colorless oil which detonates with great violence when subjected to mild mechanical, thermal, or electrical shock", and apologies are made for the fact that most of its properties have been determined in dilute solution. For example, its boiling point, the 1972 paper notes dryly, has not been determined. (The person who determined it would have to communicate the data from the afterworld, for one thing).The experimental section notes several things that the careless researcher might not have thought about. For one thing, you don't want to make more than a 5% solution in nonpolar solvents. Anything higher and you run the risk of having the pure stuff suddenly come out of solution and oil out on the bottom of the flask, and you certainly don't want that. You also don't want to make a solution in anything that's significantly more volatile than the azide, because then the solvent can evaporate on you, making a more concentrated stock below, and you don't want that, either. Finally, you don't want to put any of these solutions in the freezer - a particularly timely warning, since that's one of the first things many people might be tempted to do - because that'll also concentrate the azide as the solvent freezes. And you don't want that. Do you?Actually, the careless researcher shouldn't even work with cyanogen azide, or anything like it, but you never can tell what fools will get up to. The compound has around a hundred references in the literature, a good percentage of which are theoretical and computational. Most of the others are physical chemistry, studying its decomposition and reactive properties. You do run into a few papers that actually use it as a reagent in synthesis, but I believe that those can be counted on the fingers, which is a good opportunity to remind oneself why they're all still attached.  In fact, the reason I got to thinking about this wonderful little reagent was a recent paper in Angewandte Chemie, which details the preparation of horrible compounds like the one shown. But what does the experimental section spend the most time warning you about? The cyanogen azide used to make them. Enough said.Comments (25) + TrackBacks (0) | Category: Things I Won't Work With July 11, 2008Sharing the EnlightenmentPosted by DerekHere's an interesting idea: Merck, Lilly, and Pfizer are bankrolling a startup company to look for new technologies for drug development. Enlight Biosciences will focus on the biggest bottlenecks and risk points in the process, including new imaging techniques for preclinical and clinical evaluation of drug candidates, predictive toxicology and pharmacokinetics, clinical biomarkers, new models of disease, delivery methods for protein- and nucleic acid-based therapies, and so on.It's safe to say that if any real advances are made in any of these, the venture will have to be classed as a success. These are hard problems, and it's not like there's been no financial incentive to solve any of them. (On the contrary - billions of dollars are out there waiting for anyone who can truly do a better job at these things). I wish these people a lot of luck, and I'm glad to see them doing what they're doing, but I do wish that there were more details available on how they plan to go about things. The opening press release leaves a lot of things unspoken, no doubt by design. (For instance, where are the labs going to be? What's the hoped-for balance of industry types to academics? How many people do they plan to have working on these things, and how will the companies involved plan to share the resulting technologies?)Enlight is a creation of Puretech Ventures, a Boston VC firm that's been targeting early-stage ideas in these areas. Getting buy-in from the three companies above will definitely help, but their commitment isn't too clear at present. For now, it looks like they're getting to take a fresh look at some areas of great interest, without necessarily having to spend a lot of their own money. The press release says that Enlight will "direct up to $39 million" toward the areas listed on their web site, but those problems will eat thirty-nine million dollars without even reaching for the salt. Further funding is no doubt in the works, with the Merck/Pfizer/Lilly names as a guarantee of seriousness, and if any of these projects pan out, the money will arrive with alacrity.Comments (11) + TrackBacks (0) | Category: Business and Markets | Drug Assays | Drug Development July 10, 2008More on OutsourcingPosted by DerekIn the wake of continued expansion of medicinal chemistry efforts in China, a discussion between me and some of my colleagues at work had me sticking to my positions: (1) Scientific outsourcing is not going to go away, although it may move from country to country as costs change. (2) If you’re going to stay employed as a medicinal chemist in a high-wage area like the US, you have to bring something that can’t be purchased so easily overseas.We got to discussing what that something is. One position was that it could be fast in-house turnaround time, but while true, that one makes me uneasy. It is easier to run a fast-moving project with in-house chemistry, because you can react more quickly to changes. The cycle time for stuff that’s being done in India and China is always going to be longer. But I expect that the outsourcing outfits are working on that problem, too, in order to bring in more business. So if you’re going to compete with them just on the basis of turnaround, you’re saying that you’ll always be able to make the compounds quickly enough to justify your higher salary. Not, I think, necessarily a safe bet.I’d rather not try to outdo the low-margin people at their own game. I held out for the high-wage advantages being things like idea generation, the ability to take on harder chemistry that doesn’t lend itself as well to making libraries of compounds, and the advantages of real-time interaction with the biologists, PK, and formulations people. You’ll note that all of these are harder than cranking out methyl-ethyl-butyl-futile analog lists. That’s outsourcing in a nutshell: the easy stuff can be done more cheaply somewhere else, so the hard stuff is going to be left for us. We’d better get used to it, and fast. (Some of that hard stuff will eventually be done offshore as well, but it’ll be more expensive to do, intrinsically, and offshore wages in general will have risen by then. The big cost savings will be at the margin, for the routine work, and I expect other countries to rise up and take business away from India and China as their economies improve).A few more points: I get a fairly constant stream of complaints about the whole business of outsourcing, but I have to say that I don’t see the point of many of them. I mean, I understand why people are upset, but I don’t see what complaining about it is supposed to lead to. What are we going to do, lobby for a law that forbids any aspect of drug discovery to take place outside our borders? Whether you think that’s a good idea or not, it’s not going to happen, any more than we’re going to do the same thing for clothing, cars, or candy bars. If it’s feasible and effective to do something more cheaply, companies will do it more cheaply. ‘Twas ever thus.It’s true that there’s room to argue about how appropriate all the chemistry outsourcing is. Some of it is surely being misused, and there are surely some companies that are (or will try) outsourcing too much of their expertise, then ending up less effective than they would have been. Trends are taken to extremes, before things settle back. But things are never going to settle back to the pre-outsourcing employment situation for chemists. For better or worse – and I still think that overall, it’s for better – industrial science can now be found (and contracted for) around the globe. Comments (36) + TrackBacks (0) | Category: Business and Markets July 9, 2008How's The New Boss Doing?Posted by DerekHere’s a question that came up in a discussion at work the other day: when a new head of research comes in, how long should you give them before judging how they’re doing?That’s a tough one to answer, I think, because there are a lot of variables. First is the size of the outfit, coupled with the scope of the position. A really big organization is a very, very hard thing to change, no matter how powerful the new person might be. I’m not at all sure how possible it is to change a company’s culture, but I’m pretty sure that it requires major shock therapy to do it. (If any of you have read C. N. Parkinson on what he calls “injelititis”, you’ll know the sort of thing I have in mind).And different levels of authority affect processes with different timelines. A head of chemistry will be able to show results in less time than a head of research, who will need less time than a head of total R&D, because that person has to wait for the clinical results. As I’ve mentioned before, that seems to me to be one of the biggest challenges in this industry – the way that big changes can take years to work their way through to the results stage. It’s hard to steer intelligently if the front tires respond ten miles after you cut the wheel over hard.You also have to ask what the new person is being asked to do. Steer the course on something that already seems to be working? Or shake the place up and make things happen (for once)? Expand the workforce, contract it, spend money or save it, stick with the existing therapeutic areas or branch into new ones? The job descriptions on these things are pretty wide-ranging, so the evaluations have to be, too. Without a clear idea of what the new boss is trying to do, it’s impossible to say how well it’s being done. You could wind up giving bozos credit for something that had nothing to do with them, or blame excellent managers for things that were completely out of their abilities to control. (I know, I know, that kind of thing happens all the time, but you don’t have to add to it if you can help it).So, how long for an evaluation, then? One to three years for head of chemistry, five or six for head of research, up to ten for head of R&D (if they last that long?) I'd be interested in hearing other estimates. . .Comments (15) + TrackBacks (0) | Category: Life in the Drug Labs July 8, 2008Glaxo Asks the EurocratsPosted by DerekThere was a story yesterday about GlaxoSmithKline taking what’s being called an unusual step to prioritize their clinical candidates. According to the Wall Street Journal, they invited officials from the national health care plans of several European countries to a presentation on the company’s pipeline and asked them which ones they’d be more likely to pay for (and what they’d need to see in the clinic to convince them to do that).Actually, I think the unusual thing here is that they made a formal meeting out of the whole process. I believe that this sort of thing goes on already – after all, drug companies spend a lot of time trying to figure out the size of potential markets and what the eventual purchasers will be willing to pay. In Europe, those are the national health care systems, and if they’re not willing to pay, your drug will go nowhere. In the US, you’re going to want to sound out the big health insurance companies for the same kind of reality check.And I don’t see how GSK showed these officials anything that you wouldn’t see (or haven’t seen) at an investor’s conference – otherwise, we’d have seen some Regulation FD disclosures, since the company’s stock is listed on the NYSE. This seems to have been a one-stop rundown of what’s already been disclosed about the whole pipeline, but with opinions specifically solicited along the way– and the company’s not obliged to say what those opinions were or what they’re doing in response to them. GSK got a lot more previously unavailable information out of this process than the health care officials did.How much, though, will this help? For one thing, I suspect that the officials didn’t say much that GSK didn’t know about what everyone wants for a new drug. They want it to work better than anything that’s currently on the market, with fewer side effects, and for less money. (There, that was easy). And predicting the future doesn’t always work too well. The medical landscape could always change by the time the drugs make it up to the regulatory stage. There will also be a lot more information (good and bad) about the compounds themselves by that time, much of which could make these earlier discussions moot. “Remember that oncology drug we were developing? Well, turns out that it doesn’t work against quite as many different tumors as we were hoping, but. . .” or “Remember that CNS drug we were telling you about back in ’08? Well, turns out that it also has this little cardiovascular thing going, too, and. . .” In the end, the drugs will do what they will in the clinic, and the company will have to bring what it has, not what the regulators asked for.And even though companies are already supposed to be doing this kind of legwork, there are still some spectacular disconnects. Sanofi-Aventis, for example, did manage to get Acomplia (rimonabant) on the market in Europe (which is more than they ever managed in the US), but they didn’t get the national health care to pay for it. More recently, as in "yesterday", the UK's health care system just told Glaxo itself that they're not going to pay for Tykerb/Tyverb (lapatinib), because they don't see the benefit for the price. And when we’re talking about totally mistaken ideas about market size and acceptance, how can we not mention Pfizer’s Exubera?Comments (9) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Regulatory Affairs July 7, 2008Pfizer's Prospects: Just DuckyPosted by DerekI thought I’d start out the week by opening the mailbag for a recent reply to my posts about Pfizer’s research cutbacks. Here’s a perspective that you won’t get from me, at any rate:You never surprise me of your uncanny ability to cast good news in a negative light. Pfizer has been a bloated company following its acquisitions of Warner Lambert and Pharmacia & Upjohn. The company should have rationalized its workforce, including sales, marketing, and most especially R&D, a long time ago. So, hopefully, you are correct and there will be massive layoffs in R&D soon. Why should Pfizer spend all that money on high risk, low probability of success R&D projects? Pfizer's belated cost-cutting will make it a leaner and more focused company. All the bad news is out there. Pfizer generates over $7 billion in free cash flow annually and pays a 7.4% dividend. Projected 2012 earnings per share (without Lipitor) are $2.05. So the stock is trading today fully discounting Lipitor and any possible good news the next 5 years. Does that really make sense to you? So keep up your trash talk, so to speak. Pfizer today is money in the bank. The lower you can drive the stock price, the greater the future return. I just love folks like you who help to create great buying opportunities. Are you certain you're not buying Pfizer as you trash talk??My response? Well, I can reply on several levels. I’m actually going to skip the outraged how-dare-you stuff about what a great thing it is that all those research people are losing their jobs, though. Let’s just take that as having been delivered, because I think a lot of good invective would just be wasted, anyway. We’ll keep this on a strictly business level, since my correspondent is nothing if not all business.And from a business perspective, he has the beginning of a point. As many readers can attest, Pfizer’s in-house research productivity has not been good – at least, nowhere near as good as it’s had to be to sustain a company as huge as Pfizer. (There’s the problem, actually – as I’ve said before, the one thing that certainly doesn’t scale when a company gets larger is research productivity). So from my correspondent’s perspective, what do you do with the underperforming units of a company? You lop ‘em off, like pruning a shrub to get rid of unsightly branches.Of course, one branch of a bush is pretty much like another as far as the survival of the whole plant goes, but cutting the R&D out of an R&D organization is not without risks. A Pfizer investor might be excused for forgetting that, since most of the company’s money has been made off the research of other labs, but the Lipitors do have to come from somewhere, eventually. And try as I might, I just can’t see Pfizer buying its way out of its current troubles. So, why should Pfizer spend its money on those "high risk, low probability of success R&D projects"? Because that's the only kind of R&D projects there are.Now, as to whether all the bad news is already out there, I won't speculate. But I do know that if I had a dollar for every time someone proclaimed that all the bad news was already in some company's stock, I wouldn't have to work for a living. I invite my correspondent, though, to take a look at the company's history before sitting back and trusting those EPS numbers from the past. Let's take a trip down memory lane, back to the days of 2002, when the analysts said that it was going to earn about $1.60 per share for that year, $1.84 in 2003, and $2.14 per share in 2004. Watch it go! And after that, hey, who knew. . .well, reality intervened on those forecasts, but by 2005, now, double-digit growth was on the way.Let's take a look at the company's actual financials and stock price over that period. It isn't inspiring. Click around on that chart: if you'd bought Pfizer ten years ago, you would have been flat with the index until early 2004, but since then it's been a disaster. Now, like my correspondent, you may be able to look at this and figure that hey, what could go wrong, and that all the bad news just has to be in by now, and that those earnings forecasts will finally start working out. Or. . .So let's file that statement away for future reference: "Pfizer today is money in the bank". That's July of 2008, folks, and if you'd like to put some of your cash down on that statement, PFE is available during normal trading hours. I'll sit this one out.Comments (37) + TrackBacks (0) | Category: Business and Markets | Drug Industry History July 4, 2008Happy Fourth of JulyPosted by DerekThis, at least, I have observed in forty-five years: that there are men who search for it [truth], whatever it is, wherever it may lie, patiently, honestly, with due humility, and that there are other men who battle endlessly to put it down, even though they don't know what it is. To the first class belong the scientists, the experimenters, the men of curiosity. To the second belong politicians, bishops, professors, mullahs, tin pot messiahs, frauds and exploiters of all sorts - in brief, the men of authority. . .All I find there is a vast enmity to the free functioning of the spirit of man. There may be, for all I know, some truth there, but it is truth made into whips, rolled into bitter pills. . .I find myself out of sympathy with such men. I shall keep on challenging them until the last galoot's ashore. - H. L. Mencken, "Off the Grand Banks", 1925Comments (7) + TrackBacks (0) | Category: Blog Housekeeping July 3, 2008I Can Has Ugly Molecules?Posted by DerekA colleague and I were talking the other day about some of the molecules that turn up when you dig through a company's internal database. This was a favorite sport of mine during slow afternoons at the Wonder Drug Factory - I would put in a query for bizarre or unlikely chemical groups and see what fell out. I was rarely disappointed - eventually I assembled a folder of the most hideous examples, which never failed to astound.The compound collection at my current employer isn't nearly so weird, fortunately. But every drug company has large lists of compounds that aren't so attractive as leads, because they were made in the last stages of previous projects. This is a well-known problem, often referred to as a gap between "drug-likeness" and "lead-likeness". For the most part, the compounds you start a project with don't get smaller - they get bigger, as people hang more things off of them to get more potency, selectivity, or what have you. So you're better off starting as small as you feasibly can, giving you room for this to occur without taking you off into the territory of too-huge-to-ever-work. (That's one of the fundamental ideas behind the vogue for fragment-based drug discovery, for example)."Too-huge-to-work" is a real category, as my industry readers will gladly verify. I think that the "Rule of Five" cutoffs have been sometimes applied a little too mindlessly, but there's no getting around the fact that if your latest molecule weighs 750 and has thirteen nitrogen atoms in it, the odds of it being a drug are rather slim. As my colleague put it, when you make something like that and send it in for testing, what you're saying is "I know that almost every molecule that looks like this fails. But I'm different. I feel lucky". And that's no way to run a research program. Given finite time and finite money, you're better off prospecting in chemical areas with better chances.So what to do? We kicked around the idea of setting up some filters in the compound registration system itself - if someone tries to send in some horrible battle cruiser of a molecule, the system would make a puking noise or something and refuse to register the compound at all. There would have to be be some sort of override (perhaps for a higher-level manager to authorize) for those times when you actually have evidence that the ugly molecule works, but maybe the "You Lose: Make Something Else" screen would focus attention on the properties of what's being made. Of course, if anyone ever implemented this, the arguing would begin about where to draw the line (maybe there'd be a yellow "warning zone" in between), but I think that everyone agrees that at some point a line should be drawn.So, for my readers around the industry - do you have such a cutoff? Can you register any crazy compound that crosses your bench, or does your company's software fight back? If so, what's the feedback - beep, e-mail warning, electric shock? Inquiring minds want to know.Comments (25) + TrackBacks (0) | Category: Life in the Drug Labs July 2, 2008More Pfizer Layoffs?Posted by DerekUnfortunately, I’m getting reports of significant chemistry layoffs coming this fall at Pfizer’s Groton facility. Rumors of all sorts seem to be going around: one indication is that this is going to hit both PhD and associate chemists, as opposed to some earlier reorganizations there which mostly seemed to let lab heads go. The timing is also uncertain, but September/October seems to be the average of what I’m hearing. I assume that biology and other areas will feel the tremors, too, but I have no information about them. There's nothing on the news wires about any of this, so it's not at the official announcement stage, but people seem to be getting braced.I’m not happy to hear about this kind of thing, but I can’t say that it’s a surprise, either. Pfizer is going to be having a rough time of it for years to come, what with the Lipitor patent expiration coming closer. And as fate would have it, the company will get to feel that one about as hard as possible, because the various things that were going to cushion the blow haven’t worked out so well.Think about it – Celebrex was the whole driving force for the Pharmacia/Upjohn acquisition, and just look at it now. Compared to what it was supposed to be by 2008, it’s in terrible shape. Then you have the gigantic failure of torcetrapib, the CETP inhibitor that was going to extend the Lipitor franchise and make it even bigger. That was in late 2006, and the echos have not died away even now. And then there’s the ruinous failure of Exubera, the inhaled insulin that was going to be a runaway best seller all its own. (Oh, it really was, although it’s hard to remember that - a reader sent me a 2006 analyst report (Hambrecht) which is just giddy with expectations – Pfizer’s 1.2 billion sales projection is clearly way too low, you see, and the brokerage’s own 2.5 billion might be conservative. Heck, 5 billion in sales is “very achievable” by 2010, so you’d better load up now, because the ship is sailing, the train’s leaving the station, and so on. . .ah, Wall Street.)So, Pfizer’s buffers are exhausted, but the big beaker of fuming nitric acid is still going to unload on schedule. It’s going to be a tough place to work, and it’s going to be a tough stock to own. If you have a chance to do anything about either of those situations, I’d look into it.Comments (39) + TrackBacks (0) | Category: Current Events July 1, 2008Leaving Comments: A FixPosted by DerekI know that a lot of people have been having trouble leaving comments here over the past few weeks, with plenty of "Too Many Comments" error messages coming up. I see from today's comment thread that there's a brute-force fix for this - deleting the cookie that this site leaves. In Firefox, you can do that by going to Preferences, then Privacy, then Show Cookies. Find the "Corante.com" one and kill it - here's hoping that fixes the problem and that it doesn't show up again!Comments (7) + TrackBacks (0) | Category: Blog Housekeeping The Gates Foundation: Dissatisfied With Results?Posted by DerekWell, since last week around here we were talking about how (and how not to) fund research, I should mention that Bill Gates is currently having some of the same discussions. He’s doing it with real money, though, and plenty of it.The Bill and Melinda Gates Foundation definitely has that – the question has been how best to spend it. They started out by handing out money to the top academic research organizations in the field, just to prime the pump. Then a few years ago, the focus turned to a set of “Grand Challenges”, fourteen of the biggest public health problems, and the foundation began distributing grant money to fight them. But according to this article, from a fellow who’s writing a book on the topic, Gates hasn’t necessarily been pleased with the results so far: ”. . .Gates expected breakthroughs as he handed out 43 such grants in 2005. He had practically engineered a new stage in the evolution of scientific progress, assembling the best minds in science, equipped with technology of unprecedented power, and working toward starkly-defined objectives on a schedule.But the breakthroughs are stubbornly failing to appear. More recently, a worried Gates has hedged his bets, not only against his own Grand Challenge projects but against how science has been conducted in health research for much of the last century.”My first impulse on hearing this news is not, unfortunately, an honorable one. To illustrate: I remember a research program I worked on at the Wonder Drug Factory, one that started with a series of odd little five-membered-ring molecules. Everyone who looked them over had lots of ideas about what should be done with them, and lots of ideas about how to make them. The problem was, the latter set of ideas almost invariably failed to work.This was a terribly frustrating situation for the chemists on the project, because we kept presenting our progress to various roomfuls of people, and the same questions kept coming up, albeit in increasingly irritated tones. “Why don’t you just. . .” We tried that. “Well, it seems like you could just. . .” It seemed like that to us, too, six months ago. “Haven’t you been able to. . .” No, that doesn’t work, either. I know it looks like it should. But it doesn’t. Progress was slow, and new people kept joining the effort to try to get things moving. They’d come in, rolling up their sleeves and heading for the fume hood, muttering “Geez, do I have to do everything myself?”, and a few weeks later you’d find them frowning at ugly NMR spectra next to flasks of brown gunk, shaking their heads and talking to themselves.I’d gone through the same stage myself, earlier, so my feelings about the troubles of the later entrants to our wonderful project devolved to schadenfreude which, as mentioned, is not the most honorable of emotions. I have to resist the same tendency when reading about the Gates Foundation – sitting back and saying “Hah! Told you this stuff was hard! Didn’t believe it, did you?” isn’t much help to anyone, satisfying though it might be on one level. I’m cutting Bill Gates more slack than I did Andy Grove of Intel, though, since Gates seems to have taken a longer look at the medical research field before deciding that there’s something wrong with it. I note, though, that we now have well-financed representatives of both the hardware and software industries wondering why their well-honed techniques don’t seem to produce breakthroughs when applied to health care.Now the Gates people are trying a new tactic. The “Explorations” program, announced a few months ago, is deliberately trying to fund people outside the main track of research in its main areas of focus (infectious disease) in an effort to bring in some new thinking. I’ll let Tadataka Yamata of the Gates Foundation sum it up, from the NEJM earlier this year:”New ideas should not have to battle so hard for oxygen. Unfortunately, they must often do so. Even if we recognize the need to embrace new thinking — because one never knows when a totally radical idea can help us tackle a problem from a completely different angle — it takes humility to let go of old concepts and familiar methods. We have seemed to lack such humility in the field of global health, where the projects related to diseases, such as HIV, malaria, and tuberculosis, that get the most funding tend to reflect consensus views, avoid controversy, and have a high probability of success, if "success" is defined as the production of a meaningful but limited increase in knowledge. As a result, we gamble that a relatively small number of ideas will solve the world's greatest global health challenges. That's not a bet we can afford to continue making for much longer.”What’s interesting about this is that the old-fashioned funding that Yamata is talking about is well exemplified by the previous Gates Foundation grants. After last week’s discussion here about “deliverables” in grant awards, it’s interesting to look back at the reaction to the 2003-2005 round of “Grand Challenges” funding:”Researchers applying for grants had to spell out specific milestones, and they will not receive full funding unless they meet them. "We had lots of pushback from the scientific community, saying you can't have milestones," says Klausner. "We kept saying try it, try it, try it." Applicants also had to develop a "global access plan" that explained how poor countries could afford whatever they developed.Nobel laureate David Baltimore, who won a $13.9 million award to engineer adult stem cells that produce HIV antibodies not found naturally, was one of the scientists who pushed back. "At first, I thought it was overly bureaucratic and unnecessary," said Baltimore, president of the California Institute of Technology in Pasadena. "But as a discipline, to make sure we knew what we were talking about, it turned out to be interesting. In no other grant do you so precisely lay out what you expect to happen."I have to think, then, that in no other grant are the chances of any breakthrough result so slim. It would be interesting to know what the Gates people think, behind closed doors, of the return they’ve gotten on the first round of grant money, but perhaps the advent of the Explorations program is already comment enough. (One round of Explorations funding has already taken place, but a second round is coming up this fall. You can start your application process here).The next question is, naturally, how well the Explorations program might work – but that’s a big enough topic for a post of its own. . .Comments (27) + TrackBacks (0) | Category: General Scientific News | Who Discovers and Why June 30, 2008Another Alzheimer's Compound Goes DownPosted by DerekI was mentioning the gamma secretase enzyme around here just the other day as a longstanding target for Alzheimer's therapy. I remember the periodduring the 1990s when the enzyme hadn't been identified yet, and frankly, it was a lot easier to get excited about it then. That's because when it was finally worked out, the protease turned out to be a big multifunctional multiprotein complex, and among its many functions was affecting Notch signaling.That's worrisome, because a lot of important cellular development pathways go through the Notch receptor, and these are things that you'd really rather not mess with. (Just run the word "notch" through PubMed to see what I mean). Indeed, some of the toxic effects of the earlier gamma secretase inhibitors seem to have been mediated through just those side effects. So for some years now in the gamma secretase field, the hunt has been on for compounds that will shut down beta-amyloid production without messing with the other functions of the enzyme complex.Myriad Genetics took such a compound of theirs, Flurizan, into the clinic, after licensing it out to the Danish CNS drug company Lundbeck. They claim that these aren't straight inhibitors, but rather change the activity of the protease in some way that relatively less amyloid is produced. The drug showed some effects in Phase II studies - nothing to jump up and down about, but enough for Lundbeck to pony up for Phase III.They wish now that they hadn't. As of this morning, the drug appears to have missed all its clinical endpoints in the Phase III trial: no improvement in cognition, no improvement in quality of life. There's no way to spin this kind of result, and the company announced at the same time that they're discontinuing any further work on the compound. (Interestingly, this news seems to have actually made some of its investors happier). It's Lundbeck, though, that seems to be left holding the bag, and their stock is getting hammered to multiyear lows. They have a monstrous patent expiration coming up in 2012 (Lexapro, by far their biggest drug ever), which might explain why they took a flier on the Myriad compound in the first place. The whole effort looks like something of a Hail Mary throw on their part - and most of those go down as incomplete. . .Comments (9) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials June 27, 2008Unknown - But You Can Buy ItPosted by DerekI sketched out a rather small molecule the other day, a perfectly reasonable looking thing, which nonetheless had absolutely no references in Chemical Abstracts. (I’d certainly like to be able to put up a drawing of the structure, but it’s something that I have a work-related interest in, so it has to stay under wraps). But it’s something with only a dozen or so heavy atoms, most of them flat and aromatic – you’d certainly expect something to have been made like it, but apparently not.This has happened to me many times over the years. Now, you can obviously get into unknown territory immediately if you start looking for bizarre compounds: I don’t happen to have SciFinder access here on the train this morning, but I’m willing to bet that (for example) three-membered rings with one carbon, one boron, and one silicon are pretty wide open for some brave weirdo to explore. Enjoy!But you don’t have to go that crazy to leave the paved roads behind. Many reasonable low-molecular-weight areas are only very lightly explored. You can get out of the universe of known compounds very quickly, for example, by searching for spirocycles, particularly with an oxygen or nitrogen or two scattered into the rings. Most of these would surely be interesting scaffolds for drug discovery libraries, if there were reasonable chemistry to explore them with. Even some perfectly normal looking substitution patterns of monocyclic compounds haven’t been looked into – I dreamed up a series of oxazole derivatives not long ago that no one’s ever made, and there’s nothing odd about them at all.As you’d expect, there’s a commercial niche here. Novelty is a key requirement for patentability, so seeing no references turn up around your interesting structure is good news from an IP standpoint. (It may be bad news from a laboratory standpoint, though, because sometimes these things are unknown for a reason). But not always: there are companies that pride themselves on being able to supply such unknown scaffolds and libraries.  The perfectly reasonable-looking diazabicyclo compound shown here, for example, has no references in SciFinder, but can be purchased on a multigram scale. (There are about fifty derivatives of that bare scaffold known in the literature, which makes it pretty much uncleared ground compared to the absolutely pulverized IP landscape around, say, piperazine). Next time you're searching for such things, refine your answer set to give only those compounds with no references, and take a look at how many of them are commercially available anyway. . .Comments (9) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature June 26, 2008Funding in the EU: The Simple WayPosted by DerekToday I have the second part of the guest commentary from Zurich's Dr. Theo Wallimann on research funding in Europe. Today he advances his proposal for a new way of funding young scientists:The definite proof that European Research Programs (such as the FP-6 and FP-7 Framework Programs) are not the sort that basic scientists regard as most useful is the fact that one has to indicate and list so-called "Deliverables". These are research results or products that one wants to or should achieve in the given time period, e.g. being able to express a protein at high levels in bacteria, (Deliverable 1), to purify it to high purity (Deliverable 2) to characterize it by biochemical and biophysical methods (Deliverable 3) and then try to crystallize this protein in order to produce X-ray compatible protein crystals (Deliverable 4).One then has to provide yearly reports and let the reviewers know whether the goals set were achieved and met in time and whether one could "deliver" as predicted. If one meets one's own prognosis, one is considered a very good scientist who is able to meet one’s Deliverables. In other words, being able to deliver exactly what was predicted is considered good science, at least by the bureaucrats.But anyone working in the fields of protein crystallization and X-ray crystal structure solving, for example, knows very well that protein crystallization is still an art which often needs a stroke of luck to get good crystals for X-ray studies. This can literally take years, guided first by brute force screening approaches, and if this does not work by intuition and perseverance. All of a sudden, out of the blue, one may be able to grow crystals once, but they sometimes never come again, even if you repeat the experiment under the very same conditions. In those cases you may find out that something subtle has changed, e.g. the battery of the distilled water apparatus was changed and the water quality was thus somewhat different, etc.I know of an incident where a long, flexible protein should have been crystallized, but many doctoral students and post-docs could not manage to get crystals. After a year or so, a new post-doc came to the lab and started the project from scratch. However, he realized that his predecessors had left many crystallization trials in multi-well plates in the cold room. They must have stayed there for years, some were murky, even greenish and bacteria or algae must have grown in them. The new post-doc could have gotten rid of these murky old plates, but he was smart and clever enough to take his time to look at them.Lo and behold, he saw crystals in some of them. He opened the micro-chambers with crystals in them, but saved the mother liquor and the buffer drop in which the crystals had grown. Be honest now, how many of you would have done such a thing? But this turned out to be absolutely crucial, for the bacteria or algae that grew in the protein solution drop and mother liquor produced a protease enzyme, which cut the long protein strand somewhere at its most flexible site. The rest of the protein then crystallized. Although this was a somewhat truncated form of the protein in question, the structure of this core could be solved and years later it was the basis for solving the whole protein structure. Why was it so important to save the supernatant and mother liquor? The post-doc cultivated the bacteria or algae, I don't remember exactly, and purified from them the very protease that was cutting the protein at the specific site, such that it then crystallized.With this tool (the peculiar protease) at hand, he could reproduce what he had seen at first, and was rewarded with protein crystals which otherwise would not have seen at all. I think this is a very nice example of a) serendipity but also of b) a smart experimenter who reacted very cleverly and used foresight in formulating hypothesis that he then could prove to be true.Would you ever state in a EU funding proposal that you plan to grow protein crystals by letting a protein solution stand around in a messy cold room, in hopes that the right bacteria would grow and nibble the protein’s flexible loop off so that the rest of the protein would crystallize? You would blatantly be considered as totally crazy, I would predict. But this episode took place in the 1980s, not back in Marie Curie’s or Pasteur's time, and similar events can and will happen today.But such considerations are not a concern of the EU functionaries. They want to see the crystals, especially if you told them you would deliver them in a year or two. This is science on deliverables, as one may call it. But it has nothing to do with daily work in a laboratory. Therefore, as some have pointed out, the administrators should be educated scientist themselves, ones who have worked for a few years in a real laboratory environment. I think this would improve things quite a lot.My proposition for EU research funding would therefore be: give young PhD investigators (after their post-doctoral training and after meeting various quality standards) no-strings-attached research support for 5 years. In this way they can demonstrate their talent and independence by doing what they like to do, as best they can. If after this time their work stands out, support is then generously extended for another 3-5 years.After that, the tenure decision has to be made, and those not fulfilling the criteria (to be determined) will leave academia. This would give young people an excellent start-up chance – perhaps then there would be fewer people accumulating in academia who were promised promotions that might be delayed and postponed. (In many of these cases, all of a sudden these researchers are then considered "too old" and fall out of the system completely).This generous scheme is of course risky, for some money will not be spent the best way it could have been. But on the other hand this will allow the really talented young researchers to thrive and take off for their Nobel PriZe ambitions. So, let’s simplify the granting bureaucracy by being much more generous, while trusting in peoples’ ability to self-organize to meet their challenges and perform. In the end it is not bookkeeping that will count, but the really great and innovative research results that bring humanity a step further along. Why shouldn’t we be prepared to take this risk? I am afraid, though, that my scheme would leave thousands and thousands of desktop offenders unemployed. . .Comments (10) + TrackBacks (0) | Category: Who Discovers and Why June 25, 2008(No) Anarchy in the EU: A Report From InsidePosted by DerekMy post a few days ago on research in the EU, quoting a letter to Nature from Dr. Theo Wallimann in Zurich, started off a long comment thread. And now I've heard from Dr. Wallimann himself, who has a wealth of personal experience with research funding, with the EU, and with large consortia of academic groups.He's sent along a very interesting commentary, which I'm going to post in two parts. Today is on what EU research funding is like, and tomorrow it'll be on what it could (or should) be. So here's Dr. Wallimann with a report from the field:I did by no means intend to say that important findings can only be made by lone wolf scientists, but wanted to say that if (and I am talking here about basic science, not industrial applied science), small groups are left to work independently, with passion, in the realm of those things that interest them from the inside of their spirit and heart, then the chances of making an unexpected finding are statistically much higher - compared to a granting agency telling you what topics should be worked on in order to qualify for funding.Once an important finding in basic science has been made, it is relatively easy to find partners and to build up from the bottom a collaborative interdisciplinary team, even up to Manhattan Project-like applications. The latter step is mostly a matter of finances, for one knows what has to be done, since the basic findings and ground-work has been done by the basic scientists.It is fact that the EU agencies (and probably most of the research funding agencies) want to see such interdisciplinary research networks even before any novel findings have been made. They tend to focus on relevant societal problems, like cancer, obesity, climate change, etc. And this is bloody ridiculous, for this encompasses only (or mostl) those scientists who just happen to work in these areas and who may happen to be excellent or mediocre. But it excludes other groups, mostly younger ones, who may not directly work on such a topic, but whose findings may turn out to be most important for them in the future.What I would like to stress fervently is that true science is not predictable. If you already know what you want to find out it is no longer truly innovative science: this is exactly what Albert Einstein meant (and explicitly said), and what Albert Szent-Gyorgyi, the archetype of a "Free Radical", said as well. The latter Nobelist (for Vitamin C and on muscle contraction) never received substantial research money from NIH, for he refused to write a 50 page grant proposal exactly delineating and spelling out what he wanted to do during the next 3-5 years. He said, "How can I say what I am going to do in the laboratory in 3-5 years, if I don't even know today what I shall do there tomorrow".I have been working in an "enforced" consortium of a EU program with a total of 26 laboratories Europe-wide. The sheer size of the consortium, with all of its members focusing on different aspects of the same global question, apparently seems to have been the most convincing argument for the EU administrators The program was substantially funded and we all profited indeed from this financial support, although the administration and book-keeping and report-writing efforts were horrendous. However, as it turned out, when the members met and got acquainted and divided into sub-groups (so-called “work-packages”), one had to realize relatively quickly that one was sitting on a table with competitors who worked on the very same problems as oneself. And example would be wanting to grow crystals of an important enzyme to solve its X-ray structure and from there, to design inhibitors or activators for pharmacological intervention.So my question now is: how are you going to communicate in such a group? Which of your secrets that would give an advantage to the competitors are you going to spell out? Which hints does your neighbor disclose to you? And so on. This fact led to some rather awkward situations where people were sort of lingering around the real questions and problems and all tried to talk about those results that had just been accepted in a publication and were to be in press very soon. So here is the situation, we were forced to officially "collaborate" by the EU program, in order to get at the EU research financial honey-pot. But once we had the money, we would rather have preferred to work independently again and not share bench data with competitors.By contrast, if the EU would foster independent smaller groups and if one then made an important finding, they themselves could go out and look for ideal collaboration partners on the spot without any granting agency telling them what to do and whom to consider. This gives a project a real kick-off, since such partners can be specifically selected for mutual compatibility and collaboration. Certainly, they would have to be as passionate as the original about the new finding and call in some other colleagues who would complete a strong team. Finally, such self-organization leads to true potentiation, but desktop planners can definitely not enforce this, I am convinced.I was participating yet in another consortium program that was overshadowed by its own so-called steering committee. They felt responsible for the success of this program, so they started to strongly interfere and prescribe to us what to do, out of anxiousness that something unpredictable could happen. This simply shut down any possible creative outcome for this program.As mentioned above, if a basic science program is successful in finding something really novel and important, only then can a "Manhattan Project"-like application of the basic research lead to an applied mega-project.Many of the commenters here seem to have a misconception about the difference between basic science versus a Manhattan Project. I hope that this helps to clarify some of these issues, and I wish that you could come to work in a basic research laboratory for at least 10 years. You could easily grasp then what I mean to say here, I think. Thanks for your consideration and patience.Comments (13) + TrackBacks (0) | Category: Who Discovers and Why June 24, 2008Prasugrel: Come Back This FallPosted by DerekThis week was supposed to reveal the FDA's decision on Dai-Ichii Sankyo and Eli Lilly's anticlotting drug prasugrel. That one's in the same chemical class as Plavix (clopidogrel), and works by the same mechanism. Since Plavix did about eight billion dollars of business last year, and the anticlotting area seems to be a limitlessly huge market in general, you can understand why another drug is entering the space.Both clopidogrel and pasugrel are prodrugs - their structures, as they come out of the bottle, are inactive. But they're converted by cytochrome P450 enzymes in the liver to their active forms, which bind irreversibly to the P2Y12 purinergic receptor on platelets. The clopidogrel link above shows the active form - that thiophene ring gets broken open, and a reactive SH is exposed. The P2Y12 receptor mediates platelet aggregation, so shutting it down extends clotting time.A few points: for one, you'll note that the structures of the two drugs are very similar indeed. Is pasugrel just a "me-too", then? Well, it certainly is trying to do the same thing by the same mechanism, but as I've said here many times, it's hard to sell a drug unless you can point to some difference. The advantage that prasugrel has is that its metabolic activation takes place through a broader number of liver enzymes, so more of the active metabolite is produced across a wider patient population. And it is indeed about ten times more potent in humans - which may, though, prove to be its downfall.In the clinic, the large TRITON-TIMI trial ran the two drugs head to head in over 13,000 patients, which is certainly the expensive (and definitive) way to go. The end result was that the prasugrel-treated group had fewer cardiovascular problems of all kinds (good!), but more episodes of severe bleeding (bad!). Overall mortality was the same between the two groups, and that's where the arguing has started. There's a lot of room to break down the numbers more thoroughly to see if there's some real benefit to the drug (or alternatively, to show that it really isn't any more useful than Plavix).Of course, this is the job of the FDA. And now it seems that they've chosen to punt, delaying their decision by three months. Since the companies don't seem to have been asked to submit any more data, this seems to be an internal wrangle at the agency. I'm not sure what they're going to accomplish by holding their heads and moaning for another quarter, unless the hope is that the numbers can be crunched in some direction which will offer enough of a fingerhold to justify a decision. This is a very, very close call.If I had to predict - and hey, I write this blog, so I've got a license to do that sort of thing - I'd say that the agency will ultimately approve the drug, but with label restrictions. In the end, they'll turf the problem over to the cardiologists, but with enough warning language on it that no one should be surprised if patients bleed out on occasion. The best outcome would be for some sort of clinical sign to indicate which patients should avoid the drug. The FDA will probably head in that direction, since it appears that the majority of bleeding problems occurred in the oldest and/or lowest-body-weight groups in the trial.Update: but is that the case? Looking at the NEJM paper, it appears that patients not in these groups did have better efficacy with prasugrel, which improves the numbers. But the hazard ratio for major bleeding was 1.42 in the risky patients (>75 years old, or body weight < 60 kilos, or history of stroke/TIA), but still 1.24 in the ones outside these groups. So it's not at all fair to say that most of the bleeding events were in the risky patients - frankly, it looks like everyone bled, but the healthier cohort just responded better to the drug at the same time. That complicates my guess in the above paragraph, and raises the worst-case chance that the FDA might want to wait until the current trial comes in. What a mess. . .There's another 10,000 patient study underway which might clarify the situation, or might just emphasize what a tied-up tangle it all is. In the end, I think that the FDA will let the drug be sold until that one finishes up, with the option to revise its opinion when the data come in. The three-month delay will serve to show how seriously they're taking all the safety issues - a big political consideration these days - and to work up the most bulletproof labeling they can come up with.Comments (9) + TrackBacks (0) | Category: Cardiovascular Disease June 23, 2008Auroral ActivityPosted by DerekIf you go to the med-chem or pharmacology literature databases and type "Aurora kinase", you'd better stand back. A geyser of publications will come spraying out, most of them having to do with Aurora A and/or Aurora B as possible targets for cancer therapy. These enzymes are involved in different phases of cell division, among other things, and a lot of evidence points to them as key players in several cancer lines. There are a number of inhibitors compounds known for them as well, in various stages of development, some of which are selective and some of which hit both to different degrees. Attempts to unravel all the functions of the kinases through these compounds, and through various loss/gain of function mutations in cells, have been. . .well, "complex" is a judicious term to use. The functions of the two enzymes may well be tied to each other, so getting a clear look has been hard.There's a new paper that illustrates just why it hasn't been easy. This one looks at an AstraZeneca compound, ZM447439, which inhibits both Aurora A and Aurora B in enzyme assays, but in cells seems to be the closest match to a clear knockout of B. The authors started with a well-known cancer cell line (HCT-116), and picked out mutants that had acquired resistance to the drug. They turned out, indeed, to have mutated forms of Aurora B in them, and when they introduced those mutant forms into other cells, they also became able to grow in the presence of ZM447439. That's about as good a test of mechanism as you're going to get in the oncology field, and as the commentary on the paper says, "Even had the authors stopped at this point, it would have been an important contribution."But they kept on digging, and good for them - perhaps they were (rightly) suspicious that everything was working out a bit too neatly. They then chose two other Aurora inhibitors, VX-680 (which hits both forms) and MLN8054, which is known to be selective for Aurora A. When the cells with mutant forms of Aurora B were exposed to the VX compound, they grew anyway - which makes sense from the Aurora B side of things, since they could well have mutated the efficacy away from this compound, in the same way they got away from the AstraZeneca one. But VX-680 definitely seems to hit Aurora A, too - so is that pathway not doing anything at all for efficacy?Well, when they treated the Aurora B mutant lines with the Aurora-A-selective MLNM compound, they died off, implying that Aurora A inhibition can do the job all by itself, so there's a pretty blatant contradiction here. The authors advance the two hypotheses that have to be looked at: either Aurora A is a good target and the VX compound isn't doing as much against it as everyone thought, or Aurora A inhibition is largely useless (at least in HCT-116 cells!), and the MLNM compound has another target that no one's realized yet. (It's important to realize that this situation could vary from tumor to tumor - here's a suggestion that Aurora A might be the way to go for pancreatic cancer, for example).And there's another, rather troubling take-home lesson, having to do with the alacrity with which these cells mutated away from sensitivity to the Aurora inhibitors. As the authors put it:"The rather surprising picture emerging from our studies and from previous studies on Abl and other tyrosine kinases is that the kinase scaffold is very tolerant of mutations in the hinge loop that lines the ATP-binding site. A discouraging consequence of this fact is that these mutations are likely to affect a wide range of ATP-competitive inhibitors—even ones from distinct chemical classes—as most ATP competitors are sensitive to the active site's architecture, to which the mutated residues contribute considerably."Put simply, the kinases we're targeting have more room to maneuver than we do as medicinal chemists. They can mutate quite a bit and still function, shedding the key binding motifs that our drugs are targeting along the way. We're going to have to work a lot harder to come up with effective combinations.Comments (12) + TrackBacks (0) | Category: Cancer June 19, 2008Anarchy in the EUPosted by DerekThere’s been a lot of arguing – has been for many years – about research funding over in the EU. This is above and beyond the usual “not enough” protests, which are the way with funding of pretty much everything, pretty much everywhere, pretty much all the time.A word on that: in my last 25 years of hearing academic researchers talk about grant money, never once have I heard that the situation is good. It’s always bad, worse, getting worse, tight, terrible, year in and year out. That’s not to say that sometimes those adjectives haven’t been accurate, but it’s hard to imagine that they’ve applied without letup. Some years ago, I realized that asking a professor about research grants is exactly like asking a farmer about rain. I did grow up on the Mississippi Delta, which actually comes in handy once in a while.But the latest EU discussion is only partially about the amount of money involved; it’s also about how it’s to be used. There was an editorial in Nature not long ago from a fellow who wanted to make sure that it was spent wisely. “Wisely”, in his view, was to make sure that it goes to “problems society recognizes as central”, and the way to do this, naturally, was to have large research collaborations and consortia. These would presumably be put together by committees, commissions, and various far-seeing agencies staffed by the sorts of experts who spring up whenever the money starts to sprinkle down. I can just hear the Third Organization Meeting of the Steering Committee starting up right now, the chairman reminding everyone that they have a very full schedule today, please take your seats for our first speaker on "The Challenges and Opportunities of Interdisciplinary Research Management in a Multipolar World". . .I grit my teeth when I think about this sort of thing; it's enough to make a man wish he'd gone to truck-driving school instead. So I particularly enjoyed a letter that the journal printed in response, from Theo Wallimann at the ETH in Zurich. He points out that nearly every single significant discovery in the history of science has come outside the framework of such top-down research consortia. Single researchers or small groups pursuing their own ideas have been the source of the good stuff, and half the time these breakthroughs haven’t even been what people were looking for in the first place. Says Wallimann about the big multicenter operations: “. . . These mostly involve laboratories that have already established their name and fame, and are now often comfortably operating on well-worn tracks or working opportunistically on headline-grabbing problems or fashionable topics.Science and innovation are chaotic, stochastic processes that cannot be governed and controlled by desk-bound planners and politicians, whatever their intentions. Good scientists are by definition anarchists,”I can only cheer him on, because I couldn’t do a better job of summing up what I believe about science myself. In tribute, I’m going to go out to my lab and try something anarchic: an experiment that’s very interesting, but has very little chance of succeeding. If the EU really wants to tell its scientists what to do, they would be better off mandating six months of the same.Comments (46) + TrackBacks (0) | Category: Who Discovers and Why June 18, 2008All The Fat Cells You'll Ever Have - Sort OfPosted by DerekI’ve done a fair amount of work against drug targets for metabolic disorders, so a recent letter in Nature caught my eye. The authors have used an ingenious technique to determine the number and age of the adipocytes (fat cells) that an individual has, and have tracked that cell population year by year.One thing that comes out is confirmation of the fact that people basically set their number of fat cells during childhood and/or adolescence, and that number is then constant through their adult life. Several subjects in this study put on or took off weight during it, but that made no real difference to their number of adipocytes. And though liposuction does reduce the number of fat cells (by brute force!), they’re back to their original count after three years or so. So weight changes, as other studies have also indicated, are almost entirely due to individual fat cells becoming larger and smaller. But that doesn’t mean that you’ve got the same fat cells all the way through. Most interestingly, this study found that about 8% of the adipocyte population turns over every year, which is a higher fraction than anyone realized. Half the fat cells in the body, then, have been replaced after about eight years have gone by. That also means that the stable total number results from a balance between adipocyte death and new cell formation, and it would certainly be interesting to know how these are tied together so well. The authors suggest that this relatively high turnover could be a potential target for weight loss drugs. If we could figure out how, say, to keep the fat cell population from being renewed so exactly, their numbers might naturally decrease. (On the other hand, perhaps the rate at which they die would drop to keep the balance – no one knows yet).So, how do you tell how old a fat cell is, anyway? That’s the ingenious part I mentioned above, and it involves the same sort of techniques used in radiocarbon dating. The amount of carbon-14 in the atmosphere is relatively constant, with a few minor variations over the last fifty thousand years or so. Well, relatively constant except for the 1950s and 1960s, when we as a species reset the counter but good by atmospheric testing of atomic and nuclear weapons. Those tests released a much larger than usual amount of 14C into the world - in 1963 the count had doubled over normal background - and that's since cycled into the biosphere through uptake by plants and other living creatures.That process has sent the atmospheric levels of radioactive carbon down steeply over the years, but there’s plenty of signal to detect, and we know just how much it’s gone down every year. In effect, every year of the last 50 or 60 has an anomalous carbon-14 reading, and each one is unique and vintage-dated. We take up the carbon through our food, and as a cell is formed, the particular carbon isotope signature of your body at the time is in all its parts. Many of these are recycled constantly – but the DNA isn’t. Extracting the DNA from cells and looking at the carbon-14 levels through mass spectrometry gives you a “production date” stamp for when that cell was born. (See here for a longer discussion of carbon isotope mass spectrometry as it relates to detection of banned steroid hormone use, specifically in the Floyd Landis case. That post, by the way, led to the longest comment thread ever seen on this blog). The same technique is being used for other cell populations as well.The confirmation that the number of fat cells seems to be set before adulthood also ties in with the obesity trends seen in the general population. The great majority of obese adults were also obese as children, and the great majority of non-obese children do not become obese as adults. What factors set this adipocyte count in a person’s early life, and how many of them are environmental and could be modified, will be very useful to know. . .Comments (7) + TrackBacks (0) | Category: Diabetes and Obesity June 17, 2008Protecting Amyloid's Parent?Posted by DerekLet’s start from first principles: most drugs mess something up. More elegantly, most drugs inhibit some enzyme’s activity or block some receptor’s binding site. Proteins are generally pretty well optimized at what they do, so it’s a lot easier to block their activities than it is to speed them up. (There are rare exceptions).And if you’re going to target an enzyme with a small molecule inhibitor, you’ll do just that – find a small molecule that fits into the active site of the enzyme and gums up the works. In a few cases, we know of drugs that bind to other sites on the protein and mess up the active site indirectly, by altering the whole conformation of the protein, but most inhibitors are in or near the site where the natural substrates bind.This background is what makes a paper in the latest Nature so odd. A large multicenter academic team has been studying inhibition of beta-amyloid formation by some known anti-inflammatory drugs. Beta-amyloid is cleaved out of a larger protein called APP, and the proteases that do the chopping have long been drug discovery targets. (Mind you, when I was working on Alzheimer’s disease in the early 1990s, we still didn’t know which enzymes those were, which made things rather difficult).The key enzymes in that process are known as beta-secretase (or BACE) and gamma-secretase. The effect of the various known drugs has seemed to be more tied to the latter, although no one’s been sure just what the mechanism is, since none of them seem to be actual gamma-secretase inhibitors when you study them in isolated systems. The current work has turned some of these drugs into photoaffinity probes to try to find out what they’re really targeting.(For those outside the field, photoaffinity probes are derivatives of some compound of interest, where some special UV-light-absorbing group has been attached off the back end. These photoaffinity groups are innocuous under normal conditions, but they turn into crazily reactive intermediates when they’re irradiated, and will then form a bond with the first thing they see. The idea is that you let your photoaffinity-modified compound find its usual protein targets, then you turn on the ultraviolet lamp. The reactive group does its werewolf thing and forms a permanent bond to the protein its next to. You can then search for the strangely labeled proteins, and you’ve found what the drug of interest was binding to. When it works, it works, although it’s a lot harder than I’ve made it sound).When they labeled various gamma-secretase systems, all the way up to whole cell extracts, they found that the anti-inflammatories did not actually seem to bind to gamma-secretase at all: it wasn’t labeled. Based on earlier enzyme studies, that’s probably what they expected. But what was labeled was a real surprise: the APP protein, the substrate of the enzyme. Looking more closely, it appears that the compounds bind right to the part of APP that gets cleaved into beta-amyloid, and inhibit the enzyme’s action that way.That, as far as I know, is pretty much a first. Update: the closest thing might be the mechanism of the antibiotic vancomycin, which binds to the weird D-Ala-D-Ala section of two of the components of the gram-positive bacterial cell wall and prevents them from being used.). This isn’t something that most drug discovery programs would try a priori, that’s for sure. For one thing, we have a hard time getting small molecule to bind to protein surfaces. Active sites inside proteins are our usual speed, because those are more defined cavities which are optimized to hold reasonably small substrates. But sticking to some outer part of a protein, while it does happen, is very hard to do in a targeted fashion. (We’d love to learn the trick, if there’s a trick to be learned – inhibiting protein-protein interactions with small molecules would open up a whole new world of drug targets).Another reason that no one targets substrates instead of enzymes is that there’s generally a whole lot more substrate floating around than there is enzyme. Imagine someone throwing a hungry piranha into a pond full of goldfish. Which is the more efficient way to defuse the situation - armoring each goldfish, or disabling the piranha? That metaphor just occurred to me, and while a bit weird, it’s actually reasonably close to the situation you have with a protease enzyme and its substrates - if you want to get fancy, you can imagine that the piranha only likes certain types of goldfish, and only bites them in select spots.But on the other side, there's also a reason why protecting the substrate might actually help out in some situations. Proteases tend to have multiple targets, so inhibiting them can also disrupt pathways that you didn't want to touch. Binding to the one substrate you care about might give you a much cleaner profile, compared to shutting down everything.So you have to wonder what this result means. Have we been missing a whole range of potential enzyme inhibitors by ignoring things that bind to the substrates? I'm not convinced of that yet, but I am interested. I still have a hard time believing that we can do a good job targeting particular protein surfaces, at least at present, and I can't help wondering if there's something odd about that beta-amyloid sequence that makes it more likely to pick up small molecule interactions. (It certainly excels at picking up interactions with itself if it gets a chance, which is the whole problem). It's still going to be a lot easier to inhibit enzymes directly rather than bind to their targets, but it's worth exploring. We need all the ideas we can get.Comments (7) + TrackBacks (0) | Category: Alzheimer's Disease June 16, 2008Alli: "Underwhelming"Posted by DerekAbout a year ago, I wrote about GSK's attempt to sell the lipase inhibitor orlistat over the counter as Alli:"So my forecast for Alli is strong sales - for a while. Then it takes a dive, never to scale those heights again, as the word gets out. And the demand continues to grow for a weight-loss drug that works. . ."Thanks to Pharmalot, this week we find this AP story which seems to confirm that suspicion. Sales for Alli aren't up to GSK's hopes, and the company is declining to say how much repeat business there is after people have tried it out, which says all that needs to be said. And this after one of their biggest marketing campaigns ever.What still throws me is that an analyst quoted in the piece still talks about it as a drug that should, in theory, be a big seller. As that post from last summer makes clear, I've never once understood that, since Roche never could make it a huge seller as Xenical. You'll never be able to get around the unpleasant side effects of a pancreatic lipase inhibitor, as far as I can see, and you'll never be able to advertise one without mentioning them.I think that the new, slimmed-down GSK organization is wasting money on this whole idea. But hey, Marketing thinks it's a great opportunity. . .Comments (12) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity June 13, 2008Elan Tries AgainPosted by DerekThe long-running saga of Elan's attempt to come up with a vaccine for Alzheimer's disease continues. There have been bold attempts, setbacks, rethinks, more setbacks, and now they're starting up again. Dosing of the latest version of their vaccine against the beta-amyloid protein, known as ACC-001, was suddenly halted in April when one patient came down with a skin lesion which was thought to be possibly autoimmune-linked vasculitis.Biopsy results didn't confirm that, though, and the Elan/Wyeth partnership is resuming clinical studies. I'm not sure what that couple of months has done to their trial design; I assume that they've just started enrolling new patients and will continue with them, while continuing to monitor the former dosage groups. Maybe, though, there's a way to continue with some of those people and not lose all the time, effort, and data.The idea of an amyloid vaccine has always excited and alarmed me in equal measure. But that's how I feel about the immune system in general, come to think of it. We have enough cellular firepower to completely destroy ourselves from the inside out - keeping that on a leash to where it (mostly) only goes after what it's supposed to is extremely impressive.Now, I think that the usual sorts of vaccines are one of the great public health advances of civilization, but they work so well because they're targeted to outside agents (viral coat proteins and the like). Even so, there's a disturbingly large part of the population that remain suspicious of all vaccinations - I say "disturbing" not least because if that population gets too large, the efficacy of vaccination in general could be crippled. But what will these people think about a vaccine that's targeted to an endogenous protein? My immunology may need brushing up, but I can't think of any other example of such.One thing that may keep this from becoming a huge issue, though, is that an amyloid vaccine, if it succeeds, will be targeted at the elderly rather than at children. And it'll be something that will have an effect against a disease that everyone can see right in front of them, rather than preventing diseases that most people have only read about in books. We'll be back at the situation that prevailed when the polio vaccine was introduced: no one had much doubt that the vaccine was better than the disease.But even a vaccine fan like me still has room to admire, from a distance, the nerve of this approach. The brain is a special case, immunologically, and letting slip the dogs of war in there is not an intrinsically safe idea. But Alzheimer's is an intrinsically nasty disease. . .Comments (2) + TrackBacks (0) | Category: Alzheimer's Disease June 12, 2008Suits vs. Lab Coats?Posted by DerekWell, this is turning into GlaxoSmithKline week around here, but with good reason. I’ve had a lot of mail from people who have been affected by this week’s cutbacks, and others who left the company before the latest round. And that leads to these thoughts for today:1. The company is being rather coy when they describe the current layoffs as only involving 2% of the work force. The recent cuts were focused on the Centers for Excellence in Drug Discovery (CEDDS), which is where the great bulk of discovery medicinal chemists are. To be more specific, this one seems to have hit the Metabolic Pathways group especially hard, and there’s thought that the other CEDDS will be going through similar contractions.And there have been other cutbacks over the last few months, though, and there are surely more to come. With such a smaller head count in the CEDDS, everyone seems to be expecting the related groups to be next in line – IT, chemical development, more of the in-house biology, and so on. If the company is doing more research on the outside, then some of these folks will presumably not be needed. GSK looks to be shrinking for many months to come.That makes a person wonder about whether these cutbacks are meant to send some big signal to the investors or not. You'd think that you'd make a bigger deal out of them if that were the case, rather than minimizing them for the public, as the company seems to be doing.2. It’s going to be interesting to watch to see if the new style the company is trying will work. They’re breaking down the CEDDS into even smaller teams, from what I hear, turning the discovery organization into who-knows-how-many smaller competing units. It’s been described as the “if only we were a bunch of startups” philosophy, and there are several points to consider about that.For one thing, startups may not be as wonderful as they appear statistically, because of survivorship bias: a number of them disappear with people having hardly been aware that they were around in the first place. Even if that’s a desirable state of affairs, will a large company be able to replicate it in-house? And even if it can be done, will it happen in this case, or will the teams be either too large to be nimble or too small to work? I’ve no idea. Neither does anyone else, and it'll be years before we know.3. There have been a lot of comments, both here and at other news sites, about how this is another evil deed of the MBA folks, and if they’d only turn things over to the scientists and get back to the science, the company wouldn’t be in this position. Hmmm.What I'm about to say feels strange to me, because I’m a scientist through-and-through, and I’ve done my share of complaining about ridiculous business attitudes. For that matter, I've found myself laid off though what I thought was a mistaken site closure. But all that said, there’s a case to be made that GSK partly got themselves into this fix by letting the scientists free to do science. That’s how I see, for example, the huge effort the company had for years in nuclear receptors. A massive amount of fundamental work was done, but (because it’s such a horrendously difficult area) little or nothing ever came out the far end to make anyone any money. I'm willing to be corrected on those points, but that's how I see it now.And it’s not like the company’s productivity has been one of the wonders of the world overall. One correspondent, an ex-GSK researcher, pointed out to me in an e-mail that one of the sites hit hard this week had taken one drug to market in twenty-five years. Some of that is surely bad luck, but that explanation can only take you so far.It’s interesting to hear people talk about the good old days in the industry. The other day I saw a comment about getting things back to the good productive days of the mid-to-late 1990s, which (I can tell you) didn’t seem to flippin’ productive at the time. But there are stories beyond counting of the days when Company XYZ Really Had Their Act Together, when the scientists were happy and management was wise and stayed out of their way, and the clinical candidates flowed like a free bar at an ACS meeting.I used to feel bad, hearing these tales, sorry that I’d missed such days. But then I noted their similarity to the myths of Golden Ages that you see everywhere, and began to wonder. The drug industry was definitely a different place back when. Screening cascades weren’t so rigorous, animal models ruled the day (and actually, in some cases, steered projects right more quickly than their replacements), and there were more good targets that hadn’t been exploited yet. I’m willing to stipulate all that; it was a different world.But most of us, I think, date the Real Good Old Days of the industry to a period before we joined – no matter when that was. Listening to people talk about when things were good is like listening to the guys down at the lake tell you that you should have been around last week when the fish were biting. There were any number of severe problems back in any Golden Era, but those sort of disappear into the glowing mist.4. So GSK’s upper management is doing what upper management does: they’re trying to get a better return on their money – for which, read “the money of the shareholders”. Looking over the last ten years or so, they’ve decided that what the company has been doing has not been working. The loss of Avandia (whose discovery goes back further than that period) made the problems unignorable. So they’re trying something different. It’s hard to make the case that something different wasn’t needed. We can all argue about whether this particular something is the right idea, or whether it’s being implemented in the right way. But no one should be surprised that a company with GSK’s current issues and cost structure is being shaken up. These cutbacks may be the work of people who are mistaken; they may even be the work of fools. But it's not the work of greedy sociopaths bent on destroying the drug industry. I’d give up on that line of thought and switch to something more useful.Comments (36) + TrackBacks (0) | Category: Business and Markets June 11, 2008More On the GSK LayoffsPosted by DerekThoughts on the GSK cutbacks, whose size, interestingly, is reported by Reuters this morning as (only) 350 jobs (i.e. 2%) worldwide, a figure which does not jibe with what I've been hearing from various people on the ground:1. If the company seriously expects external collaborations to run at the same level of detail and efficiency as their internal research, they’re kidding themselves. I think – or hope – that they’re smarter than that, and that they’re planning to mostly just buy these things outright, as with Sirtris, rather than strike collaborative deals for them. Of course, they now have fewer people to prosecute the fruits of those acquisitions, but someone appears to think the numbers add up.2. Doesn’t a statement that you’re going to emphasize external research rather than internal stand as an indictment of upper management? After all, who set the priorities and funded the programs? They surely won’t let individual project leaders or area heads explain lack of progress as “just one of those things, you know how it goes”, so how to explain what is apparently a catastrophic lack of progress across the board? And what does this say about the whole “Centers of Excellence” framework for drug discovery, erected some years ago at great cost of time and money?3. Still, if you’re going to do such as thing as cut half your research staff, it’s probably better to go ahead and do it the way that GSK did. Update: see the comments. This has actually dragged on for a while, and productivity appears to have gone where it goes in the sentence after next. Get it over with in one day rather than spread it out over time, department by department. The latter method sends productivity straight to hell. The death-of-a-thousand-cuts routine tends to terrify and dismay everyone, even in areas that are left untouched, and it sends a lot of good people out the door on their own. 4. But it’s not that productivity is going to be anything wonderful at GSK now. The people that are left will feel (will have felt?) a brief interval of relief that they still have jobs. But that’s followed by the employment equivalent of survivor guilt as they watch longtime colleagues go out the door, and on the heels of that comes the realization that nothing in particular holds the company back from doing the same thing to them, whenever it sees fit. That brings on (rightly) a feeling that you owe your company exactly as much loyalty as it seems to owe you. Many good people will be looking for the door themselves, and will be gone as soon as an opportunity presents itself.Comments (43) + TrackBacks (0) | Category: Business and Markets June 10, 2008GSK: Money-Green Outside, Pink-Slip InsidePosted by DerekUpdate: GSK is indeed wielding the ax today and tomorrow. I'm hearing that that the smallest cuts are around 40% of the entire research staff at the various sites. This is big, and it's bad. . .GlaxoSmithKline has been going through some sort of mid-life crisis recently. Their chairman, Jean-Pierre Garnier, just retired amidst the mutter of angry shareholders, for one thing. And the company has been splashing out on some very flashy acquisitions, such as the Sirtris deal which has just now completed. This is all going on against the backdrop of the Avandia disaster, and a perceived drought of current clinical successes. Now the company is cutting their own head count in research, to what sounds like a pretty serious degree. There have been substantial cuts at their sites in Italy and the UK, and the Research Triangle and Pennsylvania sites are getting it even harder, from what I'm hearing. Some chemistry areas are losing more than half their people. I believe that today is the day that a lot of people are hearing whether they stay or go, and I feel bad just hearing it from a distance, having seen that stuff close up a few times myself. The proximate cause of all this turmoil is probably the loss of all that Avandia revenue, although that may have just advanced the timetable on some decisions that the eompany was going to make eventually no matter what. Many GSK scientists are (understandably) feeling as if they’re being ditched in favor of a bunch of people whose main advantage is that upper management isn’t so familiar with them yet.Whether that’s true or not, it’s a tough one to refute. There is a persistent “grass is greener” mentality in the drug industry. Perhaps that’s partly because, on an individual basis, the grass really is often greener. The best way to work your way up in the industry, for the majority of scientists, is to jump ship once in a while, which keeps you from being pigeonholed or taken for granted in your current company. (A less charitable view, accurate in a few cases, is that it’s in some people’s best interest to leave before everyone else catches on to them).And on a company-wide level, it’s hard not to think of everyone else as being at least a little more competent than your own shop is. That’s because you see the inevitable bozo mistakes of your own workplace up close, whereas you don’t get such good seats for the ones happening elsewhere. And the side that all drug companies show to their competition is a bristling pile of patents and confident press releases about their mighty drug pipelines. You know, looking at your own company’s public face, how much of it is real and how much is bravado or wishful thinking. But it’s hard to keep in mind that the same goes for everyone else, too.I don’t know how much this effect is contributing to what’s going on at GSK. After all, some of the deals that the company’s making are for specific development compounds that they didn’t have in house. But I’m pretty sure that there are researchers over there who are thinking about whether they could have gotten a sirtuin program off the ground a few years ago, like the one they just bought. Or what would have happened to them if they'd tried. . .Comments (41) + TrackBacks (0) | Category: Business and Markets June 9, 2008An Impressive Nanolist of NanocitationsPosted by DerekTime for just a brief piece this morning, about a topic I've mentioned before which is getting more noticeable all the time. If you follow the papers coming out in the Journal of the American Chemical Society (known as "Jay-ay-cee-ess" or just plain "Jacks" to the working chemist), you've been seeing an awful lot of nano-scale work. Nanorods, nanoprisms, nanoarrays of nanocrystals. The percentage of these things has, to my eye, just been rising steadily. Try the ASAP section and see what you think.And what's interesting about these papers, completely apart from their subject matter, is that they're surely headed for obscurity in almost every case. That's not because nanoscience is going nowhere (quite the contrary, I think). It's because things are in such an early stage still. There are so many small steps to be made, many of which will turn out to have been in the wrong direction. Even the work that leads to something will be cited for its historical interest (". . .the first report of nanoscale battleaxes, now a crucial part of the world economy, came as early as 2008. . .").This is the era when this work can be published. Much earlier and we wouldn't have been able to characterize these structures, and much later it'll seem trivial. (I know, some of it seems trivial on arrival - there are still a lot of chemists who roll their eyes and groan when they see this stuff). And boy, are people taking advantage of this window of opportunity. It has to be a good thing, in general, that there's so much work going on in so many different directions. I'm just glad that I don't have to figure out which of these seeds are going to bloom. . .Comments (9) + TrackBacks (0) | Category: Chemical News June 6, 2008Resveratrol in MicePosted by DerekSince it’s a favorite topic of mine, I really have to point out this study in PLoS ONE on resveratrol. A large collaboration looked at the gene transcription effects of dosing the compound in mice, compared to a normal diet and to a calorie-restricted one. I can’t do better than the first paragraph of the paper does at setting the scene:” Caloric restriction (CR) retards several aspects of the aging process in mammals, including age-related mortality, tumorigenesis, physiological decline and the establishment of age-related transcriptional profiles. The wide scope of these actions, and the profound metabolic and hormonal shifts induced by CR has led to efforts at identifying natural or synthetic compounds that mimic the effects of CR in the absence of overt metabolic and endocrine disturbances or reduced caloric intake. Because most age-related diseases are likely to be secondary to the aging process itself, the discovery of such compounds could have a profound public health impact by reducing disease incidence and possibly extending the quality and length of the human lifespan.”That’s a fine list of things that everyone would like to avoid: cancer, decline, and death. And the last sentence makes a key point, that the age-related diseases are not inevitable, but can be attacked as a group by attacking aging itself. A few years back, that statement might not have made it into a scientific paper at this level, but it can now.This study had three groups of male mice (in a hybrid strain derived from C57 black): a control group getting 84 kcal/mouse/week of food, a calorie-restricted group getting 25% less chow, and a group getting the first diet plus 4.9 mg/kg of resveratrol, both experimental diets starting at mouse middle age (14 months). This same group had already reported that starting CR at that point in that mouse strain leads to about a 13% increase in lifespan.As a baseline, they checked the transcriptional changes in young versus old mice on the control diet. There were, for example, about a thousand genes in heart tissue (out of twenty thousand checked) with a highly significant change in their profile. Comparing old heart tissue from the controls to the old tissue from the CR group, 536 genes showed a highly significant difference due to caloric restriction. The resveratrol-treated group, meanwhile, showed the same level of change in 522 genes, from basically the same list.They also looked at skeletal muscle and brain | |
