Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: firstname.lastname@example.org
The NBER (National Bureau of Economic Research) has been looking at the patterns of scientific publication and grant awards in the US, and has noticed some interesting trends. According to Inside Higher Ed, the study found (first off) that scientific publications are increasing at about 5.5% a year, and the report suggests that this might mean that any individual who reads at the same rate is seeing their own current knowledge decrease by the same amount.
I'm not so sure about that. While there are indeed more papers every year, the marginal utility of each new paper isn't necessarily very high - if I can switch into econ-speak myself. That's especially true if increased numbers of articles are due to new journals that end up (directly or indirectly) pulling things into the literature that wouldn't have even been published otherwise, simply because journals need to fill their pages. That said, the volume of interesting science done (and to be read about) each year is still increasing - I certainly can't deny that - but it would be a mistake to assume that "Scientific Journal Publications" are some sort of homogeneous good that can be measured as such.
Two other trends that were spotted make more sense to me: one is that the average number of co-authors is rising steadily. You wonder if that last part is just due to those physics papers that have six hundred people on them, but it seems to be the case across all disciplines. There are fewer and fewer solo scientific publications than there used to be, which confirms my own experience looking across the the chemistry literature.
Another trend is that fewer highly-cited big-news papers are coming from the younger end of the age distribution. The report says that "Peak productivity has increased by about 8 years, with the effect coming entirely from a collapse in productivity at young ages." The average ages for discoveries that later went on to win Nobels has been going up, as has the average age at which a scientist appears on their first patent. And that's worth thinking about - is it that our educational setup in the sciences sends people out into the fray at later and later ages? Or that the disciplines themselves have gotten more complicated, requiring a longer period before a substantial contribution can be made?
I think that a big factor is that younger scientists probably feel insecure working on high-risk high-reward projects. In academia, they're fighting for grant money and tenure, and I think that many people in that situation are careful about balancing "exciting and groundbreaking" against "likely to produce solid, publishable results". And industrial scientists tend to need more experience before they can make a big discovery as well, since the more applied fields have a larger body of specific knowledge built up.
The report contrasts these trends against the long-held image of the brave young researcher pushing toward a big discovery. I'd argue that the Nobel itself suffers from this problem, with its strict three-names-only rule. It's my impression that the committees that decide the prize have been having a harder and harder time of it over the years trying to find a way to stick to that. It has (inevitably) led to a number of deserving people getting left out - as well as a number of deserving discoveries that couldn't be narrowed down well enough. (Organic chemistry has the metal-catalyzed couplings as an example).
Finding ways to recognize large (often interdisciplinary) teams would be one step. Another change that might need to be made could include easing up a bit on the younger grant recipients, realizing that it's going to be increasingly difficult for them to hit things out of the park at that point in their careers. Could that also allow some of the better ones to work in tougher areas, with less fear of the consequences of failure?
Pfizer was able to announce some good news today - their trial of Inspra (eplerenone) for patients with a particular combination of heart failure symptoms. The trial was halted early, but (for once) because the endpoints were reached so early that it would have been unethical to continue the placebo arm. It's always nice to hear about one of those; we don't get them that often.
The drug is an aldosterone antagonist which had already been approved several years ago for heart failure and hypertension, so it's not really a surprise that it worked in this population. But you never know, and Pfizer wanted to be able to get specifically recommended for patients of this type. And that they will.
For once, I'm going to farm out a "Things I Won't Work With" post to someone else. For those who missed it in the comments, here's the link to the PDF of Max Gergel's extraordinary memoir "Excuse Me Sir, Would You Like to Buy a Kilo of Isopropyl Bromide?" Gergel founded Columbia Organic Chemicals, and if you want to see how it was done in the Old Days, this is the place to go. A sample:
". . .As we chatted, as if the thought had struck him for the first time, the old rogue said, "You know Gergel, I have a prep you could run for us which would make you a lot of money." Now this was the con working on the con. When my mother told me that a gentleman had called from town asking to visit Dr. Gergel there was no one at the plant except the two of us; when Parry, whom I already knew by reputation, sauntered in disguised as a simple country bumpkin I knew he was the director of research for Naval Research Labs, and his mission was to find someone foolhardy enough to make pentaborane. News travels. I met him at the door and told him that I was simply a lab flunky but would fetch Mr. Gergel, that my boss was extremely smart but had been prevented by the war effort (in which he had served valiantly and with distinction) from getting a PhD; that right now Mr. Gergel was extremely busy with priority reaction but would be able to see him in ten minutes—which gave me time to change my clothes and wash my face. He never realized that we were the same person. Parry chatted with me in the breezy, confidential voice that has been used by every con man since Judas Iscariot and told me that the only reason that the Navy was willing to farm out this fascinating project was simply luck of qualified personnel. That my splendid contribution to Manhattan District was well known by the military, that people spoke of me as a true Southern prodigy. (The old devil was so good that I listened with gradually increasing preparedness to make pentaborane, although I had been forewarned that it was dog with a capital "D". . .
I came across the book in Duke's chemistry library in 1984, a few years after its publication, and read it straight through with my hair gradually rising upwards. Book 2 is especially full of alarming chemical stories. I suspect that some of the anecdotes have been polished up a bit over the years, but as Samuel Johnson once said, a man is not under oath in such matters. But when Gergel says that he made methyl iodide in an un-air-conditioned building in the summertime in South Carolina, and describes in vivid detail the symptoms of being poisoned by it, I believe every word. He must have added a pound to his weight in sheer methyl groups.
By modern standards, another shocking feature of the book is the treatment of chemical waste. Readers will not be surprised to learn that several former Columbia Organic sites feature prominently in the EPA's Superfund cleanup list, but they certainly aren't alone from that era.
Remember Pfizer's "golden age of drug discovery", the one that it was entering back in April? News comes now that Martin Mackay, the company exec who gave Bloomberg News that quote, has left for AstraZeneca.
Mackay had been head of Pfizer's research for the last three years, and will be head of R&D in his new position. The news story linked to has various analysts talking about Pfizer's recent problems, and Mackay's effect on them, but I think that sort of thing is unfair. Three years (in most cases) is nowhere near enough time to say whether a head of research is making an impact on the drug pipeline. That's one of the biggest problems with managing in this industry - the long lead times before you get the real answers about anything.
At any rate, I wish good luck to Mackay in his new position, and the same to his successor at Pfizer, Wyeth's Mikael Dolsten. They, like all of us, need all the luck that they can get, golden age or no.
". . .As part of its strategy to increase global competitiveness and remain diligent in managing its costs, the company is also implementing significant cost reduction activities at its operations in the US. . .AMRI is reducing its US workforce by approximately 10%, or an estimated 80 jobs. This includes currently open positions that the company is not filling at this time.. . .Further, the company is suspending operations at one of its research laboratory facilities in Rensselaer, New York. Employees and equipment will be consolidated into nearby AMRI locations.
. . .These actions reflect the focus by our customers on cost of services amid a highly competitive environment coming primarily from Asia. This has led to a continued shift in demand for AMRI's services from the US to lower cost resources in Asia and Europe. While we remain cautiously optimistic about a return in demand for contract research outsourcing by the biopharmaceutical industry, softness in the US market has extended beyond our expectations. . .
AMRI's whole reason for starting was to save other companies money on chemical services. Given that, it's no surprise that they've been feeling the pressure in recent years, and the economic conditions out there must really be cranking things up. I hope that they're right about a return in demand - but I'm not so sure that there's going to be much of a return in demand at the prices that they used to get.
The Boston Globe has an interview with James Foster, the CEO of Charles River Labs, about their acquisition of WuXi. It's an overview of the whole outsourcing/consolidation story in the industry, which will be familiar to readers here. But an e-mail pointed me to one particular quote:
“For some period of time, there’ll be a wage benefit to using Chinese labor,’’ Foster said. “The labor is plentiful, cheaper, and better educated than in the States. It pains me to say so, but it’s true.’’
I assume that it doesn't pain him so much to say that the labor is plentiful and cheaper - rather, it's the "better educated" part. And that pains me, too, to be honest. Is it true? I'm sure that opinions are going to vary widely on that question - I've sent an e-mail to the people at Charles River asking if Foster's willing to go into more detail.
Update: I've heard back from them; through a spokesperson, Foster declines to comment further, citing the demands on his time during the WuXi merger. Good thing the Globe was able to talk to him, I guess!
R. A. Mashelkar of India's National Chemical Laboratory has a provocative opinion piece in Science on the research culture of his country. And it brings up a point that I don't think anyone could deny: that the attitudes of a society can affect (for better or worse) its ability to participate in scientific research:
Nobel Laureate Richard Feynman believed that creative pursuit in science requires irreverence. Sadly, this spirit is missing from Indian science today. As other nations pursue more innovative approaches to solving problems, India must free itself from a traditional attitude that condemns irreverence, so that it too can address local and global challenges and nurture future leaders in science. But how can the spirit of adventurism come to Indian science?
The situation has deep roots in Indian culture and tradition. The ancient Sanskrit saying "baba vakyam pramanam" means "the words of the elders are the ultimate truth," thus condemning the type of irreverence inspired by the persistent questioning that is necessary for science. The Indian educational system, which is textbook-centered rather than student-centered, discourages inquisitive attitudes at an early age. Rigid unimaginative curricula and examinations based on single correct answers further cement intolerance for creativity. And the bureaucracy inherited from the time of British rule over-rides meritocracy.
He points out that India's greatest scientific names (and there are some heavy hitters) got there in spite of such pressures, not because of them. It's not like this issue hasn't been aired out in India before; I've had Indian colleagues say much the same things to me. And these attitudes can be found in many countries, of course - you can find them here in the US. Mediocre researchers the world over keep their heads down, avoid projects that make their bosses (or themselves) nervous, and keep within the bounds of the literature.
The key, though, is to make sure that people who want to try risky ideas are able to do it. If they're inhibited by pressure from their bosses or their peers, the productivity of a whole country's science can suffer. Not everyone is capable (or willing) to go out on the edge, but it's crucial that the people who can and will are able to do so. That's where we've excelled in the US, where we have an entire infrastructure (the venture capital system) for funding things that are probably not going to work. It's not like we're perfect at this process, but we're better than many others.
But India appears to be moving in the right direction - Mashelkar goes into some details on the way that scientific education is changing. The next step will be to give risk-tolerant investors ways to back the good ideas that emerge. That's a tough one, and a lot of countries have been unable to quite get there. Sometimes the needed investors aren't there, or aren't quite well-capitalized (or willing) enough, or there aren't enough good ideas floating around, or there are no good ways to get the ideas and the money together. Personally, I think India's going to get there, and that it'll be a good thing for the country, and for the rest of the world.
Today's entry on an embarrassingly wrong structure in Bioorganic and Medicinal Chemistry Letters has a number of people in the comments talking about experiences they've had reviewing for the journal. I've done reviews for them myself, naturally, as well as for other journals. I have too few examples to judge from, but (so far) I have managed to kill off papers at other journals, but I have never managed to kill off a manuscript at BOMCL. I have - apparently like some other people - recommended in the past that a paper be published (if at all) only with major revisions, only to see it sail through basically untouched.
I hope I'm not being unfair here, because there are a lot of hard-working people at the journal. And similar stories can, I'm sure, be told about every other journal (in every other discipline). But I think that BOMCL gets so many manuscripts that their workload is very high. Unfortunately, the journal also publishes a great deal of what it gets. We're unlikely to see the real figures any time soon, but I'd have to guess that the percentage of papers rejected is definitely lower than average.
I also realize that I'm open to accusations of conflict of interest here, since I'm on the editorial board of a competing journal, ACS Medicinal Chemistry Letters. What I can promise is that I will, in fact, work to keep any papers that I consider inadequate out of those pages (and, at the same time, to encourage good work to go there). I've tried to do that with BOMCL, too, in my capacity as reviewer, but it just hasn't always worked out.
But perhaps this is something I can do for them: to point out, publicly, that their credibility as a venue for medicinal chemistry results has suffered recently. When people get the impression that work is being sloppily reviewed at a given journal, they wonder how much they should trust the other papers that get published. Bioorganic and Medicinal Chemistry Letters has been around for twenty years now, and has published some very useful stuff over the years. There's a real place for it in the publishing world. But it's been better than it has been recently, and it should be better than it is. I hate to say this. But someone should.
There are probably some other reactions of the same order as this one - but does anyone know a higher one? I'm talking about this four-component condensation reaction, reported from a lab in Iran, which actually makes semi-useful looking oxadiazoles. Anyone know of a five-component condensation? A real one, I mean, that makes a real product, as opposed to dark gooey stuff. Those, I can imagine.
Something definitely went wrong with this paper: check out the thiophenes, which look through the whole paper just like they do in that abstract. It's another who-let-that-through moment for Bioorganic and Medicinal Chemistry Letters. Perhaps it's all a plot, to get you to read every paper in the hopes that something bizarre will turn up. . .
I note with sadness that Martin Gardner died this weekend at the age of 95.. Many will know him from his longtime "Mathematical Games" column in Scientific American (where I first encountered him while I was growing up in the 1970s). In recent years, he devoted a lot of time to speaking up for skeptical causes and against all sorts of quackery, a cause I respect very much (although I sometimes wonder how much good it does).
I'm going to be off helping out with my daughter's field trip today, so it's not like there are going to be a lot of posts around here. But I did want to mention this book, "The Elements", by Theodore Gray.
That's this guy, Theodore Gray of Wolfram Research and of Wooden Periodic Table fame. He's clearly a wild man for chemical elements, and good for him. Now what someone needs to do is a coffee-table book on photogenic chemical compounds - dissolving potassium permanganate, crystals of chromium (III) chloride, hunks of copper (II) sulfate. It would (as those examples suggest) be mostly inorganic chemistry, but what the hey. . .
As had been widely expected, Craig Venter's team has announced the production of an organism with a synthetic genome. All the DNA in these new mycoplasma cells was made first on synthesizer machines (in roughly 6 KB stretches), then assembled first enzymatically and finally in yeast into working chromosomes.
And we know that they work, because they then transplanted them into mycoplasma and ended up with a new species. The cells grow normally, with the same morphology as wild-type, and sequencing them shows only the synthetic genome - which, interestingly, has several "watermark" sequences imbedded in it, a practice that this team strongly recommends future researchers in this area follow. In this case, there's a coded version of the names of the team members, a URL, and an e-mail address if you manage to decipher things.
Nothing about this process was trivial - the team apparently worked for months on just the last genomic transplantation step until things finally lined up right. But there's been a lot learned by this effort, and the next ones will be easier. I'm not sure if I call this a synthetic organism or not, since the cytoplasm (and all its machinery) was already there. But whatever it is, it sure has a synthetic genome, designed on a screen and built by machine. And it works, and more will surely follow. Will 2010, looking back, be the year that things changed?
This post from 2006 on the science behind Floyd Landis's suspicious steroid blood tests set my blog record for comments - the debate went on and on about Landis, about the lab that reported the results, about how the samples were handled, etc.
Well, Landis has now admitted using performance-enhancing drugs for most of his career. Widely, expensively, and thoroughly did he use them. The blood test was correct. Carbon isotopes don't lie.
The fine people at Angewandte Chemie's English edition, who continue to have way too much time on their hands, appear to have declared this 70s and 80s music month. So far I've spotted The Beach Boys, Toni Basil (a particularly strained one), and Elvis Costello.
There are movies, too here's another James Bond reference - but if anyone can tell me where the "Beverley Hills" part comes into this one, other than the desire to reach for a joke, I'd be grateful.
Finally, I have proof that at least one of their English-speaking editors is not only American, but specifically from Baltimore. Number of non-English speakers who will get that reference? To be counted on the fingers of the hands. . .
Update: I get the reference to the movie "Beverley Hills Cop II", but I just don't understand reaching for that reference - other than, of course, to show that you can. And as for the Baltimore one, I hadn't noticed that the authors are from Johns Hopkins, so we have to presume that they're to blame - and that the editors at the journal let that one through, too. . .
Well, here's an advantage of writing a blog: I can go with items like these. A source I have no reason to doubt has heard that high-level people at OSI are saying that the Astellas deal is not exactly going like the Takeda/Millennium deal, at least so far. In Takeda's case, they came in with assurances that they wanted to keep Millennium, that there would be retention bonuses for its people, and so on. Nothing like this has been brought up by Astellas.
In fact, the impression that I'm getting is that no one knows what's going to happen at all. Nothing seems to be known about the fate of OSI's site or its staff - and given that Astellas spent some time pursuing them, you'd think that they'd be more prepared (one way or another) to say what's going on.
This isn't to say that the worst is going to happen - I don't know that at all. It's just that in the absence of any concrete information from the acquiring company, people who have just been acquired are free to assume all kinds of things, which doesn't make for much of a constructive work environment, does it? If and when anyone hears differently, please let me know, and I'll be glad to update things. But for now, I'm sticking with what I've heard: that no one has heard a thing, including some people who really think that they should have by now.
Here's a quick warning for the bench chemists in the crowd: look out if you're making pyridines and using dichloromethane as solvent. This paper reports that the two can react, forming bis-pyridinium compounds - which isn't too surprising, in theory. What's alarming is that this happens at an appreciable rate at room temperature, which is something that I don't think a lot of people knew. I didn't.
As you'd imagine, electron-rich pyridines are the worst offenders. So keep an eye on these guys. . .
I don't cover the sales-force side of the drug industry very much - there's always CafePharma, you know, assuming that your company's firewall lets you visit the site. (As far as I know, this one gets in everywhere, in case anyone's wondering).
But this headline is an eyebrow-raiser: AstraZeneca seems to have been replacing most (perhaps all) of its sales-rep activity for Nexium to. . .call centers. And it seems to have worked. (The sales reps themselves were redeployed to other medications).
They're looking at trying this for other "mature" drug brands that already have years of sales push behind them - and considering the cost-cutting environment that we're in these days, I would guess that other companies are watching this experiment with great interest.
Via Avik Roy at Forbes, there's news of a deal between Pfizer and Washington University at St. Louis. The company is giving the university "unprecedented access" to what they say is a list of more than 500 drugs and failed drug candidates, and letting them tear into them in an effort to find out what new uses there might be for both current and failed compounds.
“There are two realities in drug discovery,” explains Don Frail, chief scientific officer of Pfizer’s Indications Discovery Unit. “The majority of candidates tested in development do not give the desired result, yet those drugs that do succeed typically have multiple uses. By harnessing the scientific expertise at this leading academic medical center, the collaboration seeks to discover entirely new uses for these compounds in areas of high patient need that might otherwise be left undiscovered.”
Pfizer's paying Wash. U. $22.5 million as well, which will be well worth it if a single good repurposing idea comes out of the collaboration. Pfizer (or any large drug company) can run through twenty million dollars of expenses on its own without a qualm, so this deal should be no problem. These compounds seem to already have had a lot of work done on them, and will thus have a shorter path through development if something turns up.
I've no idea what the chances of that are, of course - probably not all that great, but it's impossible to be sure about that. I do like the idea of letting a completely different set of eyes go over things, though. One of the biggest problems in a large organization is group-think. People get convinced that something is a hot area because other people seem convinced that it's a hot area, and the same holds true for getting convinced that something's not worth working on.
Look at the way Pfizer convinced itself that Exubera (inhaled insulin) was going to be a huge success, when it was actually a major disaster. On a smaller scale, that sort of thing happens all the time, all over the industry. Projects and ideas rise and fall only partly on their scientific merit - the drug labs are still staffed by human beings, and we're susceptible to all the biases and errors that everyone else is. And it's not like the Washington U people won't have their own biases, but theirs will at least be different.
That brings me back to one of the many reasons that I don't like giant drug company mergers. I think that we need as many different sets of eyes looking at our problems as we can get. The more shots get taken, from all sorts of angles, the better the chance of hitting something. And a huge company, while it does have room for some differences inside it, tends to homogenize viewpoints. The One Big Project with its One Big Compound will get the resources for a given area in the end. It's like when a multiplex theater opens in a smaller town - they tell everyone that with 16 screens they'll be able to bring in movies that otherwise never would play there. But come July, all sixteen screens are probably showing Revenge of the MegaSequel Part II, just to make sure that one's starting every twenty minutes.
This post drew a lot of comments here about how the big companies are going after follow-on biologic drugs. As a late-2008 article put it:
Merck already has one FOB in clinical development: a pegylated erythropoietin for anemia similar to Amgen's Aranesp (darbapoetin alfa) called MK-2578, which is being developed using a sugar-modification technology the pharma obtained via its 2006 purchase of GlycoFi. The company hopes to launch its EPO product in dialysis and pre-dialysis patients with chronic kidney disease in 2012.
Clyburn declined to offer any sales projections for that product or the MBV unit in general, nor would he identify any of the other products or therapeutic areas Merck will attempt to develop. He said MBV will identify product candidates by looking at their value in the marketplace.
Good move to decline those speculations, because Merck just announced recently that they're discontinuing that whole Aranesp-oid project. The FDA made it clear that they'd expect a full human cardiovascular safety workup before approval, which appears to have thrown Merck's numbers off severely, as you might imagine.
So Astellas and OSI have finally come to terms. OSI's stock was at about $37 back in early March, and now the acquisition will go off at $57.50/share. That's an increase from the earlier $52 per share that Astellas offered, and comes after a month or two of wrangling - and, one would assume, attempts by OSI to see if another buyer might materialize. And we still don't know about that part, actually:
Astellas said in a statement the revised offer price is based on its review of OSI's non-public information since late April and its consideration of the U.S. company's medium- and long-term corporate value. After extending its tender offer on April 23, Astellas has been reviewing OSI's confidential information on the condition that it wouldn't attempt to buy any OSI shares through May 15. Astellas President Masafumi Nogimori said in a news conference the newly offered price is "very reasonable," but he declined to comment on whether there were rival bids his company had to beat.
It's hard to take that explanation for the raised bid at face value - "Gosh, now that we look at you more closely, you're worth even more than we thought. Have some more money!". My guess is that OSI's board - which resisted the deal up until now - told the company's institutional investors to sit tight, confident that they could work out a higher price (either from Astellas or from someone else). And that strategy appears to have worked, at least to the extent of $5/share. Update: here's the web site that Astellas used as a press-release vehicle to make their case for the buyout.
Of course, that makes the acquisition that much more expensive for Astellas, who will then have to find a way to make up those costs. That's what happened when Bayer merged with/bought Schering AG in 2006 - Merck (Darmstadt) stepped into the process by buying up enough Schering on the open market to force Bayer to buy their stake at a premium, which I'm sure made the eventual merger a more constrained affair.
It'll be interesting to watch how Astellas treats OSI once the deal goes through (which I assume it will). When Takeda bought out Millennium in a similar deal, they made a point of leaving MLNM alone, and tried to keep its people from leaving. (From what I can see, that non-interference policy continues). Has Astellas said anything similar, or anything about its plans at all?
I've been meaning to write about this paper from a recent issue of Science. They've been studying the differences between young (3-month) mice and old (16-month) mice - their ability to learn, and to remember. Markers of neuronal plasticity and the like are pretty similar between the groups, although the older mice definitely show some impairments in spatial learning and recall. Looking down at the genetic level, for effects on chromatin handling, didn't seem to show much, either - the young and old mice have similar levels of histone deacetylase and histone acyltransferase enzymes.
But a look at the real levels of acetylated histones showed something different: the older mice seemed to be deficient in one particular type of acetylation, H4K12. That particular lysine residue was acetylated much more readily in the younger animals in response to a fearful event, but the older animals didn't upregulate the process. A broad-based search using microarrays showed that a wide range of genes were regulated by the young mice when learning to avoid a fear stimulus, but were not altered to nearly the same degree in the older ones. And as it turns out, the H4K12 acetylation looks to be one of the common factors in the regulation of these genes.
The authors went so far as to use Vorinostat (SAHA), a marketed histone deacetylase inhibitor, to test this hypothesis. Administering that to the older mice (directly into the brain; it doesn't really cross on its own) led to both H4K12 effects and to beneficial effects on learning.
This is a long way from being a therapy, but it's a very interesting lead towards one. The effects of messing around with histone acylation states could be profound (both in the sense of "profoundly good" as well as "profoundly bad"), so it's going to be quite a while before the dust settles enough for us to know what to do. But I'm encouraged to see things like this coming up. Given that I'm 48, we're going to have to keep moving right along in order to have something ready by the time I'm going to need it!
I'll have the opportunity to sit in on a few talks during a conference on free energy calculations in drug design. Since I'm not a computational guy myself, I'll be picking my sessions carefully, but I am interested in hearing what the state of the art is.
If we could just walk right up and calculate the free energies of binding events reliably, that would mean that the era of high throughput screening would begin to come to its end - well, in the physical world, anyway. Depending on how lengthy the computations needed to be, we could (in theory) just sit back and let the hardware hum while it ran through all the compounds we could think up - then we'd come back in on Monday and see who the winners were. Despite what some of you outside the field of medicinal chemistry might have read, we are not exactly to this point yet. That phrase "in theory" covers an awful lot of ground. But progress is apparently being made (here's a recent paper (PDF) with background).
So here's a question for the readership: what would you most want such calculations to be able to do for you? What would convince you that they're actually believable? And how close to you think that we actually are to that? Your comments will go directly to the ears of a roomful of high-powered modelers, so feel free to unload.
That thought of a roomful of computational chemists, though, reminds me inexorably of a story about Robert Oppenheimer that Freeman Dyson retells here. At a theoretical physics conference in Vancouver, the attendees were on a boat ride among the islands when the weather turned impenetrably foggy. Someone asked what the consequences for physics would be if the boat sank, and Oppenheimer instantly said "It wouldn't do any permanent good". There, that should ensure me a warm welcome at the meeting!
For Friday lunchtime, I have a brief but alarming video clip from a 2007 incident in Dallas, where a fire started at a company supplying industrial gases to welding shops and the like. The incident was heralded, like so many others, by the simple but meaningful phrase "I hooked up something wrong". This as smoke began to emerge from the bed of a delivery truck full of aceylene cylinders.
If there's one thing to be learned from the whole "How Not to Do It" category on this blog, it is to treat pressurized gas containers with respect. Roasting them over an open fire does not qualify.
In early 2007 there was quite a stir caused by reports of dichloroacetate (DCA) salts as possible cancer therapies. I didn't cover it as well as I should have here, partly because I was in the final stages of getting laid off from my previous job at the time, but here's a good roundup from Orac while the story was going on. It appeared that dichloroacetate was quite active in a number of cancer cell lines, where it worked by some sort of metabolic disruption pathway, quite possibly involving the Warburg effect through inhibition of mitochondrial PDHK. In short form, what that means is that some of these tumors stop using glucose exclusively as an energy source, and divert more of it into other pathways where it's used as a feedstock for the synthesis of other biomolecules. That allows the cells to get by on less oxygen (since the traditional glucose pathways use up a fair amount), which is particularly important in a solid tumor. This is also tied with with a resistance to apoptosis (programmed cell death), so it makes a pretty good package, if you're a tumor cell. But it does leave them metabolically vulnerable, and there have been attempts over the years to target this. (The latest idea in the area is a kinase called PKM2, a good candidate for the key switch that turns on the whole Warburg effect).
The news sent a lot of people searching for their own sources of dichloroacetic acid, and also was the occasion for a lot of "Unpatentable Cancer Wonder Drug Ignored By Big Pharma" commentary, which is always enjoyable. A new paper is now out in Science Translational Medicine looking at DCA in glioblastoma. That's a good place to look, because aggressive solid tumors of that sort are probably the most vulnerable to a Warburg-effect strategy. The authors found that mitochondia from glioblastoma tissue isolated from a number of patients do indeed show the signs of altered metabolism, which DCA reversed in cell culture. And they present the results of treating 5 patients over a period of months with oral DCA therapy.
How'd it work? They were able to compare pre- and post-therapy tissue samples in only three of the patients, but all three showed signs that more cells were undergoing apoptosis, slowing the growth of the tumors. So this wasn't an amazing cancer-disappears result, but it definitely keeps the story going. Three patients is not enough to draw robust conclusions from, of course, and they did see some (reversible) neuropathy as a side effect, but I'd say that DCA is still worth looking into on a larger scale.
Should cancer patients just up and take it themselves? It's really hard to recommend that, since we still don't know a lot about what's going on with the stuff. But it's also hard to tell someone with a refractory solid tumor not to try whatever they can get their hands on.
Update: more from Orac, including details of all five patients treated in this study.
When I wrote here about unknown compounds, using aza-steroids as examples, I apparently wasn't thinking far enough afield. I noticed this new paper on a new class of tellura-steroids. I've no doubt that they're new; probably no one has ever thought to make anything that looks quite like this before (there's one other report of a tellura-steroid from 1990). Tellurium remains an element I've never used, but after that barrage of reports from fans of hafnium the other day, I'm sort of afraid to ask what people have used this one for. . .
Takeda has announced cutbacks, and from what I'm seeing, the most concentrated of these are in the Chicago area. 28% of the 1300 jobs at the Deerfield headquarters are going, as are about 20% of the 840 jobs at the Lake Forest R&D center. Nothing at Takeda-San Diego or at Millennium in Cambridge, from what I've heard. The rest of the announced job losses (the majority, in fact) appear to be coming from the sales force.
Some recent conversations about China and chemistry outsourcing prompt this morning's observations. Every major drug company is working with Chinese contractors and/or setting up their own operation there. This is partly (in some cases, almost entirely) driven by the low cost of scientific labor there compared to North America and Europe.
But that cost is going up. Everyone keeps mentioning that "China isn't as cheap as it used to be". And that's going to continue, I think - I'm not expecting them to reach US/EU cost levels any time soon, but the bottom-line advantages of doing contract work there, which a few years ago were immediately apparent, are starting to become more of a matter for thought. There are problems with doing things that way, you know - the time difference, the at-a-distance decision-making problems that any far-flung effort suffers from, the worries (sometimes founded, sometimes not) about intellectual property leakage. When the cost was so dramatically lower, these factors weren't enough to slow things down, but as time goes on, they could be.
As an aside, I'm happy to see costs going up in China (and in India, too). As a free-trade sort of guy, I think that's exactly what's supposed to happen. The high-cost country gets goods and services at a better price, and the low-cost country improves its economy and its standards of living. But then some other low-cost country has an opportunity to get into the game - and who's that going to be? Someone's going to give it a try within the next few years.
This also makes a person wonder about the big operations that Novartis and others have been setting up in China. Are these things going to really hit their stride just as the costs of doing business there come within range of the parent company's? One answer is that these branches aren't completely about cutting costs. They're an entry into the Chinese market. Everyone looks at the Chinese economy, and has the same thought that foreign businesses have always had: "If we could just sell one of our widgets to every tenth household here. . .every hundredth, every thousandth, then holy cow. . ." And there's a lot to that.
But the feeling is that the best way to get entry to that gigantic market is to show that you're a big, friendly business partner. China (the government and the population, who are not always completely on the same page of the sheet music) is worth taking seriously, and they most definitely want to be taken seriously as a world power. It's safe to assume that the regulatory authorities there will look more kindly on drugs developed with a lot of local participation, and that doesn't mean just shipping them in at the last minute for the last step or two. (A lot of that gets done in reverse in the US and Europe, by the way, if you didn't know that). The best treatment, I think, will be given those drugs that had the highest amount of value-added work done in China.
The logical extension of that is a local all-Chinese drug discovery company, which we haven't quite seen yet. A lot of people had WuXi picked as a good candidate for that, until the recent Charles River deal - I have to think that this announcement was probably a disappointment to many people inside China itself. But as a colleague of mine was pointing out to me recently, the people who founded WuXi are still around, and after a year or two helping to run the new company, they just might use their unmatched connections and local business sense to start up what they'll hope turns into Chinese equivalent of Novartis, Merck, Pfizer, or GSK. Worth watching for.
As a brief followup to my "Elements I Have Yet to Use" post, I note this new paper on cleavage of molecular nitrogen by a hafnium complex. And to get right down to organic synthesis, here's a paper from last year that used hafnium triflate as a Lewis acid.
OK, here goes: has anyone out there ever used hafnium for anything? Anything at all? I sure haven't. (N.b. - ordering some on purpose to raise your desktop monitor or prop the door open does not count).
Well, you have to go back to the early days of this blog to find it, but I wrote here about insulin degrading enzyme. The name tells you some of what you need to know about it, for sure - it degrades insulin, so if you could stop that, insulin would probably hang around longer in the bloodstream. There's more to it - it's also been thought to be a way that insulin might be broken up inside cells as well, for one thing - but that's the elevator pitch for it.
And it has indeed been a diabetes target through the years. No one's come up with any really good inhibitors of it, although in vitro studies have been done with things like bacitracin and thioesters. Now a large multicenter academic team, led by the Mayo people from Florida, report some compounds that seem quite potent. (It's worth noting that these inhibitors are somewhat old news if you follow the patent literature).
The structures are not lovely, but there are a lot worse compounds in the protease inhibitor world. One thing that every experienced medicinal chemist will quickly notice about these is that they're hydroxamic acids. Those are compounds with a very spotty past in the business (although there is vorinostat (SAHA) out there on the market). Hydroxamates can be very potent inhibitors of metalloenzymes, and every time you target one they're always out there as a temptation, but the ugly clinical failures in that structural class tend to give people pause. Or was it just the targets (chiefly matrix metalloproteases) that the hydroxamates were aimed it? Have they been unfairly maligned? The arguments continue, and these compounds are unlikely to settle them.
Unless, of course, they go to the clinic and make a big success. I wonder if that's going to happen, though - the "go to the clinic" part, that is. This new paper is an interesting piece of work, and has a lot to say about the strange workings of IDE (which go a ways to explaining why there hasn't been much success targeting it - I was once involved briefly in the area myself). But it has nothing to say about whether these compounds have any exposure in any sort of animal, and that's the beginning of the really tricky part. These new compounds, in addition to be hydroxamic acids, are retro-inverso peptides. That's an old trick in the protease inhibitor world where you flip a natural sequence around and use the unnatural (D) amino acids to build it as well. Off the top of my head, I don't know of any retro-inverso compounds that have actually made it to market, although I'd be glad to be corrected on this.
The other complication will be IDE itself. One reason that no company has made a massive push on the target is that the enzyme is known to be multifunctional, as in "doing totally unrelated things all over the darn place", which makes one nervous about an inhibitor. Foremost among the off-target effects would be the beta-amyloid story (which is what led me to write about the enzyme back in 2003). IDE looks as if it could be one clearance mechanism for beta-amyloid (and perhaps for other easily-aggregating peptides), which has prompted people to think of actually trying to enhance its activity as an Alzheimer's therapy. One group that's tried this is, in fact, the same team that's now reporting the inhibitors (see this paper from 2009).
So I think these compounds will prove useful to figure out what IDE is doing, and that's a worthwhile goal. But I don't see them as drugs, no matter what the press release might say.
I was looking at the list the other day of the 2009 drug approvals from the FDA. Here's a breakdown from Nature Reviews Drug Discovery - 25 total, 16 small molecules and 9 biologics. And here, from the same journal, is a look at approvals in Europe. There were 29 - but the weird thing is that only five entries overlap on the two lists. The authors of this latest article suggest that this raises questions about global strategy.
Does it? Let's break that down. Here are the small molecules approved by the FDA in 2009 that were not approved in the EU:
Milnacipran: was already on the market in Europe for depression, approved in the US for fibromyalgia. Febuxostat: approved by the EU in late 2008, by the FDA in early 2009. Artemether–lumefantrine: approved by the EU back in 2001. Benzyl alcohol (Ulesfia), of all things, for head lice: not yet approved in the EU. Iloperidone: approved (most unexpectedly) in the US, not even submitted yet in Europe, as far as I know. May never be. Besifloxacin (opthalmic): not approved in the EU yet. Prasugrel: apparently didn't make the list because the CHMP in Europe approved it in December 2008. Pitavastatin: expected to be approved in the EU this year, and has been in Japan since 2003. Asenapine: still under review in the EU. Vigabatrin: approved for infantile spasms in the US, but has been approved as an antiepileptic in Europe since 1989 and in the US since 1997. Bepotastine: not approved in the EU yet, although I think that's underway. Telavancin: has had a complicated past in the EU - basically, they have approval against hospital-acquired pneumonia as part of the EU application, while in the US it's part of a separate add-on. Pralatrexate: approved for lymphoma in the US, and under review in the EU. Pazopanib: under review in the EU. Romidepsin: under review in the EU as well.
So overall, it's not as much of a split as it looks. Several compounds are just missing showing up in the same calendar year, and if you did this analysis using a two-year window, I think the overlap would be much greater. Admittedly, for some drug launches every day counts, so ideally you'd want approval for both the US and EU to come soon and simultaneously, but mostly, things are reasonably close. The next thing to do will be to look at the compounds on the EU approval list and see how they stand in the US - no time for me to do that today, but shortly.
Here's a new paper from the folks at the Burnham Institute and UCSD on a new target for vaccinia virus. They're going after a virulence factor (N1L) through computational screening, which is a challenge, since this is a protein-protein interaction.
They pulled out a number of structures, which have some modest activity in cell infection assays. In addition, they showed through calorimetry that the compounds do appear to be affecting the target protein, specifically its equilibrium between monomeric and oligomeric forms. But the structures of their best hits. . .well, here's the table. You can ignore compounds 6 and 8; they show up as cytotoxic. But the whole list is pretty ghastly, at least to my eyes.
These sorts of highly aromatic polyphenol structures have two long traditions in medicinal chemistry: showing activity in assays, for the first part, and not being realizable as actual drugs, for the second. There's no doubt that they can do a lot of things; it's just that getting them to do them in a real-world situation is not trivial. Part of the problem is specificity (and associated toxicity) and part of it is pharmacokinetics. As you'd imagine, these compounds can have rather funky clearance behavior, what with all those phenols.
So I'd regard these as proof-of-concept compounds that validate N1L as a target. I think that we'll need to wait for someone to format up an assay for high-throughput (non-virtual) screening to see if something more tractable comes up. Either that, or rework the virtual screens on the basis that we've seen enough polyphenols come up on this target already. . .
Note: readers of the paper will note that our old friend resveratrol turns up as an active compound as well. It's very much in the polyphenol tradition; make of that what you will.
My take on the recent news that Bill Gates has invested ten million dollars in the computational drug design company Schrödinger is here at Nature News. (They've recently made all their stories open-access, by the way, so you don't need a subscription to get the full stories).
In short, I think that patient billionaire money is just the sort of thing the field needs, because anyone with a short timeline and a need for a good return is going to have a rough time of it. . .
The folks at the New Yorker sent along this link to a new article by Malcolm Gladwell about Synta and their attempts to get elesclomol (STA-4783) to work as a melanoma therapy. (If you don't know how this one turns out, you might want to read the article before clicking on that second link).
Update: didn't realize that the full article was subscriber-only at the New Yorker site. Not sure if there's anything to be done about that, but I've dropped them a line. . .
Gladwell (an occasional reader of this blog) often takes some hits from experts in the fields he writes about, but after reading the article this morning, I think he's done a fine job of showing what drug discovery is like. His division between screening and rational drug design is a bit too sharply defined, to my eyes, but he gets all the important stuff right - namely, just how hard a business this is, how much luck is involved, and how much we don't know. Those are messages that a lot of people need to hear, and I hope that this piece helps get them out to a wide audience.
I find the President's Cancer Panel report -at least, the general tone of it - hard to believe. Most of the headlines yesterday focused on the "grievous harm", "bombarding", and "grossly underestimated" statements, and suggested that there was an epidemic of environmentally-caused cancer. Since most age-adjusted cancer incidence rates have, in fact, been dropping, I find this a bit hard to believe.
Here's the whole report (whopping PDF). Update: that link may be bad - try here. It actually does mention that cancer rate data, but (as far as I can see) just sort of blows right past it. And while I take the point that endocrine disruptors and the like need to be watched (and that we really do need to study these things more), I don't see why the alarm bells need to be rung quite this loudly.
I see that the American Cancer Society seems to agree. My own views are closer to those of Bruce Ames (PDF) than to the President's panel. We should always be alert to possible environmental causes of cancer, but we should also realize that (as far as we can tell) they seem to be relatively minor.
Everyone's heard of cyanide, whether they've spent any time in a chemistry classroom or not. And if you form a covalent bond to the carbon of that CN group, you've got a nitrile, and those are familiar compounds to any organic chemist. But what if you flip the group around and bond it via the nitrogen? That gives you a weird situation, where the nitrogen has a formal positive charge and the carbon is left with a formal negative one, which looks somehow unnatural. But that's an isonitrile (isocyanide) for you.
They're actually quite useful, although I'd guess that the majority of chemists have never encountered one. But if they have, they've remembered it, because isonitriles are not shy about announcing their alien character. Our noses can immediately tell the difference between garden variety nitriles and their evil twins. The former often have no smell at all, or run to a faint spicyness. The latter smell like. . . like. . .well, I've never actually been downwind of the Abominable Snowman's armpit or been had my eyeglasses fogged up by a Komodo dragon with stomach trouble, but those are the examples that come to mind.
Fragrance expert Luca Turin has described isonitriles as "the Godzilla of scent", and that's accurate, if you also try to imagine Godzilla's gym socks. "Penetrating" and "repulsive" are good words to describe your typical isocyanide. It feels like the odor is aggressively storming your nasal passages, and it really makes you want to be somewhere else very quickly. This abstract gets the point across well. Problem is, it can be one of those smells that stays with you ("I like it in here. Stop bothering me."), so going somewhere else - although a recommended first step - is not always enough to do the trick. As a paper on the synthesis of these fine compounds puts it:
It should also be noticed that due to the extremely distressing odour of isocyanides the application of the usual techniques of purification is especially difficult since the exposure to isocyanide vapours, even at very low levels, must be rigorously avoided.
Good advice! But hard to put into practice if you use the things at all, since it doesn't take much. Even the not-so-volatile isonitriles get up on the table and shout at you, but the low-molecular-weight ones are truly hard to take. And the pride of that bunch seems to be the n-butyl, which should come as no surprise. Straight-chain butyl compounds are well known to be just a poor match for human sensibilities. Butyl alcohol is stinky, butylamine foul, butyraldehyde reeks, butyric acid is famously disgusting, and butyl mercaptan is a standout even in the vile crowd of thiols.
So butyl isocyanide is, well, something to experience. I've never had the pleasure, and will take pains not to. I can do no better than to quote the 1937 observations of one of the first groups to figure out how to prepare this noble reagent in quantity:
Butyl isocyanide proved to be so disagreeable to manipulate that none of its physical constants except boiling point were determined. Even when a hood with an extra forced draft was used, the odor pervaded the laboratory and adjoining rooms, deadening the sense of smell and producing in the operator, and in others, severe headaches and nausea which usually persisted for several days.
Sounds great. Many of you may have had similar experiences at some point, but it usually takes more than just spilling a drop of stuff on the floor to bring them on. Here's the whole thing, in a bottle! Available wherever fine chemicals are sold, actually. Don't just live an average, boring life: go wild - go isocyanide!
I came across an article from 2007 that I'd missed, and I'm willing to bet others have, too. It's on the sometimes perverse incentives in developing oncology drugs (although the points in it apply to many other fields as well. The author (Tony Fiorino) is an investor, not a researcher, and seems to be an exceptionally clear-headed one.
He notes that larger profitable companies have more of an incentive to be careful about what drug candidates they take into the clinic, since they're spending their own profits when they do so. Start-up companies, on the other hand, tend to get valued according to how many clinical candidates they have going, so their incentive is to push things along rather more. . .briskly. This will be a familiar phenomenon to many readers here - the topic has come up whenever we talk about some compound wiping out in Phase III after what looked like promising data:
"This factor often leads development-stage companies to make very poor assessments with their own product candidates and to radically misjudge their likelihood of success. Indeed, if the fortunes of the entire company depend on the fate of a single phase II compound, and the interests of those deciding whether or not to enter phase III are tied entirely to the ongoing viability of the company, it would hardly seem surprising that companies push forward with the development of drugs when to objective outside observers further development seems futile. Indeed the market is likely to punish correct decision making by development-stage biotechnology companies. Given a set of questionable phase II data, the stock price of a company would suffer far more if management concluded it would be improper to expend shareholder capital on a phase III program likely to fail than if management decided to forge ahead into phase III on the basis of some dubious, post hoc subgroup analyses."
Of course, when this article was written, the funding environment was more permissive than it is today - but it will surely go that way again, and anyway, when the money is tight, the pressures to fight for it are even stronger.
"Thus, market forces do not produce efficient drug development; at least for the biotechnology industry, they may actually hinder it. This is particularly true in oncology drug development, where a set of unique circumstances conspire to make drug development more difficult and increase the likelihood that drug candidates are advanced too quickly. Zia et al1 documented a high rate of phase III failures in oncology, even when the phase III protocol uses a regimen identical to what was used in phase II. In particular, the lack of reliable surrogate markers and the common practice of looking for response rates in single arm trials make phase II oncology trials unreliable.
Most troubling, in my view (which is admittedly the view of a battle-scarred skeptic), oncology clinical development programs often appear to be designed specifically not to provide insight into the likelihood of success in phase III. . ."
Remind you of any events of the last few years? Fiorino's only answer to these problems is to call for the oncology clinical community to be more skeptical when it comes to enrolling patients in Phase III trials. And that might help a bit, but in a better world, we'd be running better Phase IIs.
If you're looking for some ammunition in a creationist argument, evolutionary biologist John Avise of UC-Irvine has provided plenty in a new PNAS article entitled "Footprints of Nonsentient Design Inside the Human Genome". He goes over a number of not-too-intelligent-looking kinks in our genes.
This same point has occurred to many other people before, of course (I went on about it a few years ago here), but Avise has done a real service by collecting the arguments in one place in a clear and concise way. Exons and introns, spliceosomes, disorders of gene transcription and regulation, the unreliability of mitochondrial DNA, duplicons, pseudogenes, mobile DNA elements - they're all here, and all (to my eyes) much better explained by random, nonsentient tinkering than by thoughtful design.
Avise tries at the end to propose evolution as a helpful adjunct to religon, but I don't think his argument is going to fly with the people who might be most in need of it:
Evolution by natural causes in effect emancipates religion from the shackles of theodicy. No longer need we agonize about why a Creator God is the world’s leading abortionist and mass murderer. No longer need we query a Creator God’s motives for debilitating countless innocents with horriﬁc genetic conditions. No longer must we anguish about the interventionist motives of a supreme intelligence that permits gross evil and suffering in the world. No longer need we be tempted to blaspheme an omnipotent Deity by charging Him directly responsible for human frailties and physical shortcomings (including those that we now understand to be commonplace at molecular and biochemical levels). No longer need we blame a Creator God’s direct hand for any of these disturbing empirical facts. Instead, we can put the blame squarely on the agency of insentient natural evolutionary causation. From this perspective, the evolutionary sciences can become a welcome partner (rather than the conventionally perceived adversary) of mainstream religion
No, we're not going to get rid of theodicy that easily. The people whose beliefs most draw them to creationist and ID arguments tend, I'd say, to see life (and most especially intelligent human life) as one of the most important parts of Creation. Humans are, according to the Bible, the absolute peak of the entire process, and are thus the deserving subjects of continuous special attention from the Deity. Very few people with these foundations to their beliefs are willing to allow random evolution to share the stage.
Back in March, Intermune's stock saw a sudden jump on news that an FDA advisory committee treated their drug pirfenidone more positively than expected. But the agency is in no way committed to following these recommendations, and yesterday they turned down the drug, sending Intermune stock right back down into the basement again.
Pirfenidone was, even after the advisory committee, an iffy proposition. It made it through one Phase III trial, but missed its endpoints on another. And even though there's no current treatment for idiopathic pulmonary fibrosis, there's no use in telling people that there is one (and asking their insurance companies to pay for it) if there really isn't. The company isn't saying much, but all indications are the the FDA is concerned about efficacy: they aren't convinced that the drug really works, and will want fresh clinical trial data before reconsidering approval.
Whether Intermune can raise the cash to do that is in doubt. If they can't convince the FDA that they have something worthwhile, they'll likely have trouble persuading investors.
You don't often get to see so direct an exchange of blows as this: Steve Nissen, of cardiology and drug-safety fame, published an editorial about GlaxoSmithKline and Avandia (rosiglitazone) earlier this year in the European Heart Journal. And GSK took exception to it - enough so that that the company's head of R&D, Moncef Slaoui, wrote to the editors with a request:
". . .(the editorial) is rife with inaccurate representations and speculation that fall well outside the realm of accepted scientiﬁc debate. We strongly disagree with several key points within the editorial, most importantly those which imply misconduct on the part of GSK and have identiﬁed some of these issues below. On this basis, GSK believes that it is necessary for the journal to withdraw this editorial from the website and refrain from publishing it in hard copy, until the journal has investigated these inaccuracies and unsubstantiated allegations.
Instead of doing that the EHJ invited Nissen to rebut GSK's views, and ended up publishing both Slaoui's letter and Nissen's reply, while leaving the original editorial up as well. (Links are PDFs, and are courtesy of Pharmalot). Looking over the exchange, I think each of the parties score some points - but I have to give the decision to Nissen, because the parts that he wins are, to my mind, more important - both for a discussion of Avandia's safety and of GSK's conduct.
For example, Slaoui disagreed strongly with Nissen's characterization of the company's relations with a coauthor of his, Dr. John Buse. Nissen referred to him as a prominent diabetes expert who had been pressured into signing an agreement barring him from publicly expressing his safety concerns, but Slaoui countered by saying:
The document that Dr Buse signed was not an agreement barring him from speaking but was a factual correction regarding data, which did not bar him from speaking at all. In fact, Dr Buse subsequently communicated his views regarding the safety of rosiglitazone to FDA.
Nissen's reply is considerably more detailed:
The intimidation of Dr John Buse by GSK was fully described in a report issued by US Senate Committee on Finance.3 The Senate Report quotes an e-mail message from Dr Buse to me dated 23 October 2005 following publication of our manuscript describing the risks of the diabetes drug muraglitazar. In that e-mail, Buse stated: ‘Steve: Wow! Great job on the muraglitazar article. I did a similar analysis of the data at rosiglitazone’s initial FDA approval based on the slides that were presented at the FDA hearings and found a similar association of increased severe CVD events. I presented it at the Endocrine Society and ADA meetings that summer. Immediately the company’s leadership contact (sic) my chairman and a short and ugly set of interchanges occurred over a period of about a week ending in my having to sign some legal document in which I agreed not to discuss this issue further in public. I was certainly intimidated by them but frankly did not have the granularity of data that you had and decided that it was not worth it’. In an e-mail to GSK, Dr Buse wrote: ‘Please call off the dogs. I cannot remain civilized much longer under this kind of heat’
This, to me, looks like a contrast between legal language and reality, and in this case, I'd say reality wins. The same sort of thing occurs when the discussion turns to the incident where a copy of Nissen's original meta-analysis of Avandia trials was faxed to GSK while it was under review at the NEJM. Nissen characterizes this as GSK subverting the editorial process by stealing a copy of the manuscript, and Slaoui strongly disagrees, pointing out that the reviewer faxed it to them on his own. And that appears to be true - but how far does that go? GSK knew immediately, of course, that this was a manuscript that they weren't supposed to have, but it was then circulated to at least forty people at the company, where it was used to prepare the public relations strategy for the eventual NEJM publication. I don't think that GSK committed the initial act of removing the manuscript from the journal's editorial process - but once it had been, they took it and ran with it, which doesn't give them much ethical high ground on which to stand.
Many other issues between the two letters are matters of opinion. Did enough attention get paid to the LDL changes seen in Avandia patients? Did the lack of hepatotoxicity (as seen in the withdrawn first drug in this class) keep people from looking closely enough at cardiac effects? Those questions can be argued endlessly. But some of GSK's conduct during this whole affair is (unfortunately for them) probably beyond argument.
I've heard rumblings from more than one source that Merck may be close to making good on those hefty job cuts that are surely coming as a consequence of the Schering-Plough merger. Anyone have anything to add? No specifics here, but several bits and pieces that all point in the same direction. . .
I was talking with a colleague yesterday, and I suddenly had an insight into an opportunity in scientific publishing. We were discussing the various computational/modeling papers that you see out in the literature. Some of them are quite interesting, many are worth looking at if it's your particular field - but many others are, well, not so great. I should mention up front that the same objections apply - and how - to the non-computational literature, of course. But there are a number of second-tier (and lower) journals to soak up those sorts of papers in the other disciplines.
What surprises me is that there's no Computational Chemistry Letters or some such. Communications in Computational Chemistry? CADD Comm? This would be the dumping ground for the piles of unconvincing computer-driven stuff that gets sent around by people who have paid a bit too much attention to the sales brochures that came with their software packages.
The barriers for entry to such things have been getting lower and lower, while the real state of the art has been getting more and more complicated. That's created a gap into which too much stuff falls. Who will speak for the bottom-dwelling "We modeled it, therefore it's real" constituency? The advent of systems biology has created more opportunities than ever for these folks. Isn't it time that there was an expensive, low-impact, completely disregardable journal for them, too?
A comment to this post on the Sirtris compound saga just had me checking Clinicaltrials.gov. And indeed the commenter is correct: a trial against myeloma of a combination of Velcade (bortezomib) and SRT501, which I believe is reformulated resveratrol itself, was suspended as of April 22 for "unexpected safety concerns".
There's no way of knowing what those are, and it's worth keeping in mind that a number of other studies have been completed with SRT501. But since there's been (as far as I can tell) no mention of this trial's halt anywhere, I thought it worth noting.
The answer he arrived at was that (these societies) hadn’t collapsed despite their cultural sophistication, they’d collapsed because of it. Subject to violent compression, Tainter’s story goes like this: a group of people, through a combination of social organization and environmental luck, finds itself with a surplus of resources. Managing this surplus makes society more complex—agriculture rewards mathematical skill, granaries require new forms of construction, and so on.
Early on, the marginal value of this complexity is positive—each additional bit of complexity more than pays for itself in improved output—but over time, the law of diminishing returns reduces the marginal value, until it disappears completely. At this point, any additional complexity is pure cost.
Tainter’s thesis is that when society’s elite members add one layer of bureaucracy or demand one tribute too many, they end up extracting all the value from their environment it is possible to extract and then some.
Readers who work in the industry - particularly those at the larger companies - will probably have just shivered a bit. To my mind, that's an eerily precise summation of what's gone wrong in some R&D organizations. Shirky talks about internet hosting companies and the current dilemmas of the large media organizations, but there's plenty of room to include the drug industry in there, too. Look at the way research has been conducted over the past thirty years or so: we keep adding layers of complexity, basically because we have to - more and more assays and screens. It used to be (so I hear) all about dosing animals. Then you had cell cultures, then cloned receptors and enzymes came along (we're heading out of the 1970s and well into the 1980s now, if you're keeping score at home). Outside of target assays, the Ames test came along in the 1970s, and there were liver microsomes and isolated P450 enzymes for stability, Caco-2 cells for permeability, hERG assays to look out for cardiac tox, et cetera. You can do the same thing for the development of animal models - normal rodents, then natural inbred mutations, then knockouts, humanized transgenics. . .you get the picture.
As I say, we have very little choice but to get more complicated, because our knowledge of biology keeps expanding. But while this is going on, everyone keeps thinking that all this new knowledge is (at some point) going to start making things easier - a future era known, informally, as "when we really start figuring all this stuff out". It hasn't happened yet. If you're someone like Ray Kurzweil, you expect this pretty soon. I don't, although I hold out eventual long-term hope.
Shirky's message for the media companies is that their high-value-added lifestyles are being fatally undermined. We're not facing the same situation in this industry - there's no equivalent of free YouTube stuff eating our lunch, and I'm not expecting anything in that line for a long time, if ever. But the complexity-piling-on-complexity problem is real for us, nonetheless. If the burden gets too heavy, we could be in trouble even without someone coming along to push us over.