About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
April 17, 2014
Here's a suggestion for a total reform of the graduate student/postdoc system of scientific labor and training. It's from a distinguished list of authors, and appears in a high-profile journal, and it says without any equivocation that the system we have is in major trouble:
In the context of such progress, it is remarkable that even the most successful scientists and most promising trainees are increasingly pessimistic about the future of their chosen career. Based on extensive observations and discussions, we believe that these concerns are justified and that the biomedical research enterprise in the United States is on an unsustainable path. . .We believe that the root cause of the widespread malaise is a longstanding assumption that the biomedical research system in the United States will expand indefinitely at a substantial rate. We are now faced with the stark realization that this is not the case. Over the last decade, the expansion has stalled and even reversed.
They trace the problem back to the post-World War II funding boom (Vannevar Bush's "Endless Frontier"). I have to say, the paper gives the impression (no doubt for lack of space) that the progress of funding in the biomedical sciences was smoothly upwards up until about 1990 or so, but as I understand it, the real kick was the post-Sputnik expansion. The 1960s were the real golden years for federal science and education spending, I think, as witness the profusion of buildings from that era to be found at many public universities. You can spot them from a hundred yards away, and boy, are there are lot of them. The authors lump that era in with the 1970s, but that latter decade, at least post-1973 or so, was hardly a period of a "vibrant US economy", as stated.
The doubling of the NIH's budget is also dealt with like a matador deals with a bull - a flick of the cape. But there's no doubt that the situation now isn't good:
However, eventually, beginning around 1990 and worsening after 2003, when a rapid doubling of the NIH budget ended, the demands for research dollars grew much faster than the supply. The demands were fueled in large part by incentives for institutional expansion, by the rapid growth of the scientific workforce, and by rising costs of research. Further slowdowns in federal funding, caused by the Great Recession of 2008 and by the budget sequestration that followed in 2013, have significantly exacerbated the problem. (Today, the resources available to the NIH are estimated to be at least 25% less in constant dollars than they were in 2003.)
The problem has been the same one faced by highway engineers: double the lanes on the highway, and new traffic fills up it again. Extra NIH money has been soaked up, and more, by an expansion in the customers for it. Even if their history is a bit off, the authors' analysis of the current situation seems to me to be right on target. :
The mismatch between supply and demand can be partly laid at the feet of the discipline’s Malthusian traditions. The great majority of biomedical research is conducted by aspiring trainees: by graduate students and postdoctoral fellows. As a result, most successful biomedical scientists train far more scientists than are needed to replace him- or herself; in the aggregate, the training pipeline produces more scientists than relevant positions in academia, government, and the private sector are capable of absorbing.
The result, they say, has also been Malthusian: an increasingly nasty competition for resources, which is taking up more and more of everyone's time. It's creating selection pressure favoring the most ruthless elbow-throwers and body-slammers in the bunch, and at the same time making them scientifically timid, because the chances of getting something unusual funded are too low. (Paula Stephan's thoughts on all this are referenced, as well they should be). You may now see the birth of the "translational research" bandwagon:
One manifestation of this shift to short-term thinking is the inflated value that is now accorded to studies that claim a close link to medical practice. Human biology has always been a central part of the US biomedical effort. However, only recently has the term “translational research” been widely, if un- officially, used as a criterion for evaluation. Overvaluing translational research is detracting from an equivalent appreciation of fundamental research of broad applicability, without obvious connections to medicine.
I'm not quite so sure about the evocations of the golden age, when great scientists were happy to serve on grant review committees and there was plenty of time for scientific reflection and long-term thinking. I would place those further back in history than the authors seem to, if they existed at all. But there's no need to compare things today to some sort of ideal past - they're crappy on the absolute scale, prima facie.
From the early 1990s, every labor economist who has studied the pipeline for the biomedical workforce has proclaimed it to be broken. However, little has been done to reform the system, primarily because it continues to benefit more established and hence more influential scientists and because it has undoubtedly produced great science. Economists point out that many labor markets experience expansions and contractions, but biomedical science does not respond to classic market forces. As the demographer Michael Teitelbaum has observed, lower employment prospects for future scientists would normally be expected to lead to a de- cline in graduate school applicants, as well as to a contraction in the system.
In biomedical research, this does not happen, in part because of a large influx of foreign applicants for whom the prospects in the United States are more attractive than what they face in their own countries, but also because the opportunities for discovering new knowledge and improving human health are inherently so appealing.
Too many players have an incentive to act as if things are supposed to go on the way that they have - universities get overhead out of grant money, so why not hire as many grant-bringers as possible? And pay salaries, as much as possible, out of those grants instead of from university funds? Why not take in as many graduate students as the labs can hold? The Devil is (as usual) on hand to take the hindmost.
The rest of the paper is an outline of what might be done about all this. The authors propose that these steps be phased in over a multiyear period, with a goal of making funding more sensible (and predictable), and altering the way that the academic research workforce is recruited and handled. Here are the steps, in order:
1. Require longer-term budgeting for federal research funding.
2. Gradually reduce the number of PhD students in the biomedical sciences. Support them on training grants and fellowships rather than out of research grants. The rules barring the funding of non-US citizens through these routes need to be changed, because these should become the only routes.
3. Make more funding opportunities available between science career paths and allied fields, so that there are more possible off-ramps for people with science training.
4. Gradually increase the salaries offered federally-funded post-docs, so the system doesn't overload with cheap labor. Limit the number of years that any postdoctoral fellow can be supported by federal research grants, and require salaries to be at staff scientist level if the person continues after this point.
5. Increase the proportion of staff scientists. Universities and granting institutions need to be given incentives to value these positions more.
6. Change at least some of the NIH granting mechanism to a system more like the Howard Hughes fellowships - that is, award longer-term money to outstanding people and labs, rather than to individual proposals. There should be several separate programs like this for different career stages.
7. Set aside a higher proportion of grants for "high-risk, high-reward" ideas.
8. At the same time, consider capping the total amount of money going to any one group, because of the diminishing-returns problem that seems to set in past a certain level.
9. Make grant evaluations less quantitative (number of publication, impact factors) and more qualitative. Novelty and long-term objectives should count more than technical details.
10. Broaden the reviewing groups (in age, geographical representation, and fields of expertise) to keep things from getting too inbred.
11. Start revising the whole "indirect cost recovery" system for grants, which has provided perverse incentives for institutions, with special attention to paying faculty salaries out of grant money.
The authors note that all these changes will tend to increase the unit cost of academic research and shrink research group sizes, but they regard these costs as worthwhile, because (1) the current system is artificially propped up in both regards, and (2) the changes should lead to higher-quality research overall. A lot of these idea seem sound to me, but then, I've never had to deal with the academic research environment. There will, I'm sure, be many people who look on one or more of these proposals with dismay, for various reasons. It will be quite interesting to see if this gets any traction. . .
+ TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School
January 10, 2014
One of the authors of a paper I commented on has shown up in the comments section to that post, and I wanted to highlight his reply out here on the front page of the blog. Here's J. R. Brender, from the Michigan side of the authorship:
Hi. I appreciate the comments the given about the paper. As one of the authors of the paper (with Ramamoorthy on the NMR part), I would like to clear a few things as time permits.
@ Derek An uncharitable view would be that they have also taken aim at the year 1995, which is about when all three of these ideas were also being worked on for AD.
All three are still be working on and are in (mostly mixed or unsuccessful) clinical trials. Vitamin E in particular went through a phase III clinical trial for mild to moderate Alzheimer's with mixed results http://www.alzforum.org/news/research-news/trial-suggests-vitamin-e-protects-function-mild-alzheimers
To be fair, none of the other hypotheses have much support either.
@19 from Bob "The paper only uses the word drug once, in the context of including "drug-likeness" as a designed property, and therapeutics once in the conclusion."
Correct. I wasn't aware that at any point we claimed that this was a therapeutic or even a lead compound for a therapeutic. The discussion about drug discovery in academia vs. industry, while interesting, is in my opinion somewhat off-topic. A more relevant question is whether it is worth investigating one compound with a detailed approach (which you are going to have do if you want in any kind of mechanism based inhibitor) or try a high-throughput non-mechanistic approach phenotypic screening. I'm agonist on this point and i think both are viable (or a maybe both non-viable options). Large scale phenotypic screening for Alzheimer's is going to exceed the resources of academic lab. Based on the amount of money spent on pharma and the current success rate, I suspect its been tried on some level and failed at relatively early stage.
@21 from JSR "If the end result of months or years of work by 14 authors and almost as many sources of funding...
The non mass spec work (the bulk of the paper) was supported by a single R21 and a private foundation grant of which this paper is a small part.
@21 from JSR "not ready to publish, especially not in the once hallowed pages of JACS."
"MedChem journals likely would have asked that more work be done to answer some of the same questions Derek raised."
@35 "I’d add ‘who partners with someone who knows how to build / run relevant screening assays"
There are no relevant high-throughput screening assays for amyloid inhibition in common use. This point in particular I would like to stress and is the reason (as one of the commenters guessed) we left some of the expected the out of the paper. A very high percentage of the papers in JACS and J. Med. Chem on amyloid inhibitors consist of a set of compounds with only three sets of data. A high-throughput thioflavin T assay to measure amyloid inhibition, a set of EM images to show amyloid disappearing, and an MTT assay. There is very rarely any kind of pharmokinetics often not even to the extant of calculating drug-likedness (if you don't believe me look up amyloid inhibitor on basically any journal including the med chem ones). Though usually not acknowledged, ThT assay has a very high false positive rate since ThT generally binds at the same site as the inhibitor. Although not in the paper, we have shown this is true for the compound in the paper and many others. EM images suffer from multiple issues due to bias in binding to the grid, selection bias in sampling etc. The MTT assay has a sensitivity problem as suggested, and is not ideal for amyloid for a variety of other reasons.
The conformational antibodies sometimes used are also pretty non-specific, although this is only occasionally acknowledged in the literature. The end result is a lot of compounds with apparently quantifiable information that really isn't. There is no information on where the compound binds and what it binds to (amyloid beta is a mixture of many different, rapidly equilibrating species even when it is claimed to be in a single form).
If you have experience in high-throughput screening, I urge you to team up with an amyloid person (there are many amyloid specific factors that need to be considered). The field desperately needs you. Also, if you know of compounds for which reliable PK data has been obtained let me know (jbrender at umich.edu). I am compiling a database of amyloid inhibitors and an discouraged at what I am finding.
Our goal in the Ramamoorthy NMR lab in particular was to take a single compound and analyze its binding on low MW and fibrillar Abeta , using a labor intensive approach with the aim of developing a future high throughput fluorescence based approach to isolate specific interactions with different Abeta species (some unpublished progress has been made on the fluorescence work).
The study is only one of handful that have identified specific interactions in terms of a structure of Abeta (the new structure we have is the only high-resolution structure not in detergents in organic solvents). ML binds at a specific site on the structure, and looking back at the literature, you can see a similar binding site for many of the compounds in the literature. That to me at least is interesting.
In conclusion, it is not a complete story by any means, just a progress report. But a complete story with Abeta and Alzheimer's is going to take a very long time.
Note: I'm turning off comments here, so they can continue to thread in the previous post. I may have some more to say on this myself, but I'll leave that to another entry.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease
January 9, 2014
A reader sent along this paper that's come out recently in JACS, from a Michigan/South Korea/UCSB team of researchers. It's directed towards a possible therapeutic agent for Alzheimer's disease. They're attempting to build a molecule that binds beta-amyloid, coordinates metals, and has antioxidant properties all at the same time.
An uncharitable view would be that they have also taken aim at the year 1995, which is about when all three of these ideas were also being worked on for AD. But it's not like the field has cleared up too many of these questions since then, so perhaps that gets a pass, although it should be noted (but isn't in the paper) that no one has ever been able to find any significant effect on Alzheimer's from treatment with either antioxidants or metal chelators. The debate on whether anyone has been able to see anything significant with agents targeting amyloid is still going on (and how).
I bring that up partly for mechanistic plausibility, and partly because of the all-in-one aspect of the molecule that the paper is studying. Any such drug candidate has to justify its existence versus a mixture of therapies given simultaneously, especially since the odds are that it will not be as efficacious against all (or even any) of its subtargets compared to a cocktail of more specific agents. With Alzheimer's, it's tempting to say that well, we're hitting all three of these mechanisms at once, so that has to be a good thing. But are all three of them equally important? The fraction of your compound that's binding amyloid is presumably not available to serve as an antioxidant. The ones that have chelated metals are not available to bind amyloid, and so on.
Most of the paper details experiments to show that the ligand does indeed bind amyloid, both in the soluble form and as fibrils. But there's room to argue there, too. Some in the field think that altering the distribution between those populations could be important (I'm agnostic on this point, as I am about amyloid in general). If you're binding to all of them, though, what happens? There's information on the compound's effect on amyloid oligomerization, but the connection between that and Alzheimer's pathology is also up for argument. These questions, already complicated, are made harder to think about by the absence of any quantitative binding data in the paper - at least, if it's there, I'm not seeing it yet. There are mass spec, LC, and NMR experiments, but no binding constants.
There's also little or no SAR. You'd almost get the impression that this was the first and only compound made and tested, because there's nothing in the main body of the paper about any analogs, other than a comparison to a single quinolinemethanol. Even without binding data, some qualitative comparisons might have been made to see how the amyloid binding responded to changes in the structure, as well as how it balanced with the metal-binding and antioxidant properties.
There's some cell-assay data, viability in the presence of amyloid (with and without metals), and it looks like under A-beta-42 conditions the cells are about 70% viable without the compound, and around 90% with it. (It also looks like the cell viability is only in the lower 80% range just when the compound alone is added; I don't know what the background viability numbers are, because that control doesn't seem to be in there). They also tried the same neuroblastoma line with the Swedish-mutation APP in it (a huge risk factor for an early-onset form of human Alzheimer's), but I can't see much difference in the compound's effects.
But as with any CNS proposal, the big question is "Does the compound get into the brain?" The authors, to their credit, do have some data here, but it's puzzlingly incomplete. They show plasma and brain levels after oral gavage (10 mpk) in CD1 mice, but only at one time point, five minutes. That seems mighty early for an oral dose, at least to me, and you really, really want to see a curve here rather than one early time point. For what it's worth, plasma levels were around 6 ng/g and brain levels were around 14 ng/g at that point, but since this was just done by brain homogenate, it's unclear if the compound really gets in or not. No other tissues were examined.
There also don't seem to be any data on what else this compound might do. If you're seriously proposing it as a possible therapy for Alzheimer's, or as a starting point for one, it would be worthwhile to collect some numbers in selectivity screens. Alternatively, if you're not proposing this as a starting point for Alzheimer's therapy, then why do all this work in the first place (and why write it up for JACS)? This is another one of those cases where I'm honestly baffled by what I'm reading. My industrial perspective sees a single compound given a very labor-intensive in vitro workup on a hazy therapeutic rationale, with no analogs, no selectivity data, and no PK other than one time point, and I just shrug my shoulders with a puzzled look on my face. Why do it?
Well, universities aren't drug companies. And the groups involved are, presumably, not focused on making the next big Alzheimer's breakthrough. But what are they focused on? Training students? That's a really worthwhile goal, but I have to wonder if some way could have been found to train them that would have been a bit more congruent with the real world. Picking three rationales, thinking up a single compound to try to combine them, and then spending all your effort on it as if it's a real lead isn't (to my mind) a good fit. I realize that resources are limited, and that this same level of effort just couldn't have been applied to a whole series of compounds the way it would in an industrial setting (not that we'd have done it). But if you're going to do this stuff, a less-intense look at the amyloid-aggregating and cellular effects of a wider series of compounds could have been more valuable than a lot of information about just one.
I feel bad every time I write like this about academic drug-discovery papers, but I can't help it. From my perspective, there's a lot of confusion out there about what drug discovery really entails, and about the relative value of doing a little of it, or doing it in an odd way.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease
November 5, 2013
I've got to take my, uh, hat off to this idea. Rebecca Schuman at Missouri-St. Louis, who writes frequently on academic hiring, made an offer late last week that directly addresses the problem that many aspiring faculty members find themselves facing: search committees apparently want bushels of stuff. And the strong suspicion is that they really don't look at most of it - they just want to see you sending it.
So she simply offered to pay $100 to the first two people who submit proof that they enclosed a scan of their butt among their supporting documents. This had to be a legitimate application, and she (wisely) set herself up as the sole judge of whether the enclosed material was, in fact, a scan of the applicant's rear end. (Some things are too important to be left to anyone else).
The "Buttscan" idea took off in a big way, and by gosh, there's already a winner. I must admit, although I've never applied for an academic position, that I can see the appeal. At a previous job I found myself having to write lengthy reports every six months about what I and my lab had been up to, and I always wanted to include, smack in the middle of yet another paragraph about SAR trends, an offer to pay $5 to the first person who told me that they'd read that far. But I never had the nerve, sadly. On a related note, a former colleague of mine once threatened to slip into my office while my semi-annual report document was open on my computer, and slip the phrase "Help, I'm a woman trapped in a man's body!" into it. But no one would probably have read that one, either. . .
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August 15, 2013
A longtime reader sent along this article from the journal Technological Forecasting and Social Change, which I'll freely admit never having spent much time with before. It's from a team of European researchers, and it's titled "Big Pharma, little science? A bibliometric perspective on Big Pharma's R&D decline".
What they've done is examine the publication record for fifteen of the largest drug companies from 1995 to 2009. They start off by going into the reasons why this approach has to be done carefully, since publications from industrial labs are produced (and not produced) for a variety of different reasons. But in the end:
Given all these limitations, we conclude that the analysis of publications does not in itself reflect the dynamics of Big Pharma's R&D. However, at the high level of aggregation we conduct this study (based on about 10,000 publications per year in total, with around 150 to 1500 publications per firm annually) it does raise interesting questions on R&D trends and firm strategies which then can be discussed in light of complementary quantitative evidence such as the trends revealed in studies using a variety of other metrics such as patents and, as well as statements made by firms in statutory filing and reports to investors.
So what did they find? In the 350 most-represented journals, publications from the big companies made up about 4% of the total content over those years (which comes out to over 10,000 papers). But this number has been dropping slightly, but steadily over the period. There are now about 9% few publications from Big Pharma than there were at the beginning of the period. But this effect might largely be explained by mergers and acquisitions over the same period - in every case, the new firm seems to publish fewer papers than the old ones did as a whole.
And here are the subject categories where those papers get published. The green nodes are topics such as pharmacology and molecular biology, and the blue ones are organic chemistry, medicinal chemistry, etc. These account for the bulk of the papers, along with clinical medicine.
The number of authors per publication has been steadily increasing (in fact, even faster than the other baseline for the journals as a whole), and the organizations-per-paper has been creeping up as well, also slightly faster than the baseline. The authors interpret this as an increase in collaboration in general, and note that it's even more pronounced in areas where Big Pharma's publication rate has grown from a small starting point, which (plausibly) they assign to bringing in outside expertise.
One striking result the paper picks up on is that the European labs have been in decline from a publication standpoint, but this seems to be mostly due to the UK, Switzerland, and France. Germany has held up better. Anyone who's been watching the industry since 1995 can assign names to the companies who have moved and closed certain research sites, which surely accounts for much of this effect. The influence of the US-based labs is clear:
Although in most of this analysis we adopt a Europe versus USA comparative perspective, a more careful analysis of the data reveals that European pharmaceutical companies are still remarkably national (or bi-national as a results of mergers in the case of AstraZeneca and Sanofi-Aventis). Outside their home countries, European firms have more publications from US-based labs than all their non-domestic European labs (i.e. Europe excluding the ‘home country’ of the firm). Such is the extent of the national base for collaborations that when co-authorships are mapped into organisational networks there are striking similarities to the natural geographic distribution of countries. . .with Big Pharma playing a notable role spanning the bibliometric equivalent of the ‘Atlantic’.
Here's one of the main conclusions from the trends the authors have picked up:
The move away from Open Science (sharing of knowledge through scientific conferences and publications) is compatible and consistent with the increasing importance of Open Innovation (increased sharing of knowledge — but not necessarily in the public domain). More specifically, Big Pharma is not merely retreating from publication activities but in doing so it is likely to substitute more general dissemination of research findings in publications for more exclusive direct sharing of knowledge with collaboration partners. Hence, the reduction in publication activities – next to R&D cuts and lab closures – is indicative of a shift in Big Pharma's knowledge sharing and dissemination strategies.
Putting this view in a broader historical perspective, one can interpret the retreat of Big Pharma from Open Science, as the recognition that science (unlike specific technological capabilities) was never a core competence of pharmaceutical firms and that publication activity required a lot of effort, often without generating the sort of value expected by shareholders. When there are alternative ways to share knowledge with partners, e.g. via Open Innovation agreements, these may be attractive. Indeed an associated benefit of this process may be that Big Pharma can shield itself from scrutiny in the public domain by shifting and distributing risk exposure to public research organisations and small biotech firms.
Whether the retreat from R&D and the focus on system integration are a desirable development depends on the belief in the capacities of Big Pharma to coordinate and integrate these activities for the public good. At this stage, one can only speculate. . .
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Industry History | The Scientific Literature
August 5, 2013
Here's more on the problems with non-reproducible results in the literature (see here for previous blog entries on this topic). Various reports over the last few years indicate that about half of the attention-getting papers can't actually be replicated by other research groups, and the NIH seems to be getting worried about that:
The growing problem is threatening the reputation of the US National Institutes of Health (NIH) based in Bethesda, Maryland, which funds many of the studies in question. Senior NIH officials are now considering adding requirements to grant applications to make experimental validations routine for certain types of science, such as the foundational work that leads to costly clinical trials. As the NIH pursues such top-down changes, one company is taking a bottom-up approach, targeting scientists directly to see if they are willing to verify their experiments. . .
. . .Last year, the NIH convened two workshops that examined the issue of reproducibility, and last October, the agency’s leaders and others published a call for higher standards in the reporting of animal studies in grant applications and journal publications. At a minimum, they wrote, studies should report on whether and how animals were randomized, whether investigators were blind to the treatment, how sample sizes were estimated and how data were handled.
The article says that the NIH is considering adding some sort of independent verification step for some studies - those that point towards clinical trials or new modes of treatment, most likely. Tying funding (or renewed funding) to that seems to make some people happy, and others, well:
The very idea of a validation requirement makes some scientists queasy. “It’s a disaster,” says Peter Sorger, a systems biologist at Harvard Medical School in Boston, Massachusetts. He says that frontier science often relies on ideas, tools and protocols that do not exist in run-of-the-mill labs, let alone in companies that have been contracted to perform verification. “It is unbelievably difficult to reproduce cutting-edge science,” he says.
But others say that independent validation is a must to counteract the pressure to publish positive results and the lack of incentives to publish negative ones. Iorns doubts that tougher reporting requirements will make any real impact, and thinks that it would be better to have regular validations of results, either through random audits or selecting the highest-profile papers.
I understand the point that Sorger is trying to make. Some of this stuff really is extremely tricky, even when it's real. But at some point, reproducibility has to be a feature of any new scientific discovery. Otherwise, well, we throw it aside, right? And I appreciate that there's often a lot of grunt work involved in getting some finicky, evanescent result to actually appear on command, but that's work that has to be done by someone before a discovery has value.
For new drug ideas, especially, those duties hae traditionally landed on the biopharma companies themselves - you'll note that the majority of reports about trouble with reproducing papers comes from inside the industry. And it's a lot of work to bring these things along to the point where they can hit their marks every time, biologically and chemically. Academic labs don't spend too much time trying to replicate each other's studies; they're too busy working on their own things. When a new technique catches on, it spreads from lab to lab, but target-type discoveries, something that leads to a potential human therapy, often end up in the hands of those of us who are hoping to be able to eventually sell it. We have a big interest in making sure they work.
Here's some of the grunt work that I was talking about:
On 30 July, Science Exchange launched a programme with reagent supplier antibodies-online.com, based in Aachen, Germany, to independently validate research antibodies. These are used, for example, to probe gene function in biomedical experiments, but their effects are notoriously variable. “Having a third party validate every batch would be a fabulous thing,” says Peter Park, a computational biologist at Harvard Medical School. He notes that the consortium behind ENCODE — a project aimed at identifying all the functional elements in the human genome — tested more than 200 antibodies targeting modifications to proteins called histones and found that more than 25% failed to target the advertised modification.
I have no trouble believing that. Checking antibodies, at least, is relatively straighforward, but that's because they're merely tools to find the things that point towards the things that might be new therapies. It's a good place to start, though. Note that in this case, too, there are commercial considerations at work, which do help to focus things and move them along. They're not the magic answer to everything, but market forces sure do have their place.
The big questions, at all these levels, is who's going to do the follow-up work and who's going to pay for it. It's a question of incentives: venture capital firms want to be sure that they're launching a company whose big idea is real. The NIH wants to be sure that they're funding things that actually work and advance the state of knowledge. Drug companies want to be sure that the new ideas they want to work on are actually based in reality. From what I can see, the misalignment comes in the academic labs. It's not that researchers are indifferent to whether their new discoveries are real, of course - it's just that by the time all that's worked out, they may have moved on to something else, and it might all just get filed away as Just One Of Those Things. You know, cutting-edge science is hard to reproduce, just like that guy from Harvard was saying a few paragraphs ago.
So it would help, I think to have some rewards for producing work that turned out to be solid enough to be replicated. That might slow down the rush to publish a little bit, to everyone's benefit.
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July 22, 2013
Here's an update on the NIH's NCATS program to repurpose failed clinical candidates from the drug industry. I wrote about this effort here last year, and expressed some skepticism. It's not that I think that trying drugs (or near-drugs) for other purposes is a bad idea prima facie, because it isn't. I just wonder about the way the way the NIH is talking about this, versus its chances for success.
As was pointed out last time this topic came up, the number of failed clinical candidates involved in this effort is dwarfed by the number of approved compounds that could also be repurposed - and have, in fact, been looked at for years for just that purpose. The success rate is not zero, but it has not been a four-lane shortcut to the promised land, either. And the money involved here ($12.7 million split between nine grants) is, as that Nature piece correctly says, "not much". Especially when you're going after something like Alzheimer's:
Strittmatter’s team is one of nine that won funding last month from the NIH’s National Center for Advancing Translational Sciences (NCATS) in Bethesda, Maryland, to see whether abandoned drugs can be aimed at new targets. Strittmatter, a neurobiologist at Yale University in New Haven, Connecticut, hopes that a failed cancer drug called saracatinib can block an enzyme implicated in Alzheimer’s. . .
. . .Saracatinib inhibits the Src family kinases (SFKs), enzymes that are commonly activated in cancer cells, and was first developed by London-based pharmaceutical company AstraZeneca. But the drug proved only marginally effective against cancer, and the company abandoned it — after spending millions of dollars to develop it through early human trials that proved that it was safe. With that work already done, Strittmatter’s group will be able to move the drug quickly into testing in people with early-stage Alzheimer’s disease.
The team plans to begin a 24-person safety and dosing trial in August. If the results are good, NCATS will fund the effort for two more years, during which the scientists will launch a double-blind, randomized, placebo-controlled trial with 159 participants. Over a year, the team will measure declines in glucose metabolism — a marker for progression of Alzheimer’s disease — in key brain regions, hoping to find that they have slowed.
If you want some saracatanib, you can buy some, by the way (that's just one of the suppliers). And since AZ has already taken this through phase I, then the chances for it passing another Phase I are very good indeed. I will not be impressed by any press releases at that point. The next step, the Phase IIa with 159 people, is as far as this program is mandated to go. But how far is that? One year is not very long in a population of Alzheimer's patients, and 159 patients is not all that many in a disease that heterogeneous. And the whole trial is looking at a secondary marker (glucose metabolism) which (to the best of my knowledge) has not demonstrated any clinical utility as a measure of efficacy for the disease. From what I know about the field, getting someone at that point to put up the big money for larger trials will not be an easy sell.
I understand the impulse to go after Alzheimer's - who dares, wins, eh? But given the amount of money available here, I think the chances for success would be better against almost any other disease. It is very possible to take a promising-looking Alzheimer's candidate all the way through a multi-thousand-patient multiyear Phase III and still wipe out - ask Eli Lilly, among many others. You'd hope that at least a few of them are in areas where there's a shorter, more definitive clinical readout.
Here's the list, and here's the list of all the compounds that have been made available to the whole effort so far. Update: structures here. The press conference announcing the first nine awards is here. The NIH has not announced what the exact compounds are for all the grants, but I'm willing to piece it together myself. Here's what I have:
One of them is saracatanib again, this time for lymphangioleiomyomatosis. There's also an ER-beta agonist being looked at for schizophrenia, a J&J/Janssen nicotinic allosteric modulator for smoking cessation, and a Pfizer ghrelin antagonist for alcoholism (maybe from this series?). There's a Sanofi compound for Duchenne muscular dystrophy, which the NIH has studiously avoided naming, although it's tempting to speculate that it's riferminogene pecaplasmide, a gene-therapy vector for FGF1. But Genetic Engineering News says that there are only seven compounds, with a Sanofi one doubling up as well as the AZ kinase inhibitor, so maybe this one is the ACAT inhibitor below. Makes more sense than a small amount of money trying to advance a gene therapy approach, for sure.
There's an endothelin antagonist for peripheral artery disease. Another unnamed Sanofi compound is being studied for calcific aortic valve stenosis, and my guess is that it's canosimibe, an ACAT inhibitor, since that enzyme has recently been linked to stenosis and heart disease. Finally, there's a Pfizer glycine transport inhibitor being looked at for schizophrenia, which seems a bit odd, because I was under the impression that this compound had already failed in the clinic for that indication. They appear to have some other angle.
So there you have it. I look forward to seeing what comes of this effort, and also to hearing what the NIH will have to say at that point. We'll check in when the time comes!
Update: here's more from Collaborative Chemistry. And here's a paper they published on the problems of identifying compounds for initiatives like this:
In particular, it is notable that NCATS provides on its website  only the code number, selected international non-proprietary names (INN) and links to more information including mechanism of action, original development indication, route of administration and formulation availability. However, the molecular structures corresponding to the company code numbers were not included. Although we are highly supportive of the efforts of NCATS to promote drug repurposing in the context of facilitating and funding proposals, we find this omission difficult to understand for a number of reasons. . .
They're calling for the NIH (and the UK initiative in this area as well) to provide real structures and IDs for the compounds they're working with. It's hard to argue against it!
+ TrackBacks (0) | Category: Academia (vs. Industry) | Clinical Trials | Drug Development
June 19, 2013
Over at Forbes, John Osborne adds some details to what has been apparent for some time now: the drug industry seems to have no particular friends inside the Obama administration:
Earlier this year I listened as a recently departed Obama administration official held forth on the industry and its rather desultory reputation. . .the substance of the remarks, and the apparent candor with which they were delivered, remain fresh in my mind, not least because of the important policy implications that the comments reflect.
. . .In part, there’s a lingering misimpression as to how new medicines are developed. While the NIH and its university research grantees make extraordinary discoveries, it is left to for-profit pharmaceutical and biotechnology companies to conduct the necessary large scale clinical studies and obtain regulatory approval prior to commercialization. Compare the respective annual spending totals: the NIH budget is around $30 billion, and the industry spends nearly double that amount. While the administration has great affection for universities, non-profit patient groups and government researchers (and it was admirably critical of the sequester’s meat cleaver impact on government sponsored research programs), it does not credit the essential role of industry in bringing discoveries from the bench to the bedside.
Terrific. I have to keep reminding myself how puzzled I was when I first came across the "NIH and universities discover all the drugs" mindset, but repeated exposures to it over the last few years have bred antibodies. If anyone from the administration would like to hear what someone who is not a lobbyist, not a CEO, not running for office, and has actually done this sort of work has to say about the topic, well, there are plenty of posts on this blog to refer to (and the comments sections to them are quite lively, too). In fact, I think I'll go ahead and link to a whole lineup of them - that way, when the topic comes up again, and it will, I can just send everyone here:
August 2012: A Quick Tour Through Drug Development Reality
May 2011: Maybe It Really Is That Hard?
March 2011: The NIH Goes For the Gusto
Feb 2011: The NIH's New Drug Discovery Center: Heading Into the Swamp?
Nov 2010: Where Drugs Come From: The Numbers
August 2009: Just Give It to NIH
August 2009: Wasted Money, Wasted Time?
July 2009: Where Drugs Come From, and How. Once More, With A Roll of the Eyes
May 2009: The NIH Takes the Plunge
Sep 2007: Drugs From Where?
November 2005: University of Drug Discovery?
October 2005: The Great Divide
September 2004: The NIH in the Clinic
September 2004: One More On Basic Research and the Clinic
September 2004: A Real-World Can O' Worms
September 2004: How Much Basic Research?
September 2004: How It Really Works
There we go - hours of reading, and all in the service of adding some reality to what is often a discussion full of unicorn burgers. Back to Osborne's piece, though - he goes on to make the point that one of the other sources of trouble with the administration is that the drug industry has continued to be profitable during the economic downturn, which apparently has engendered some suspicion.
And now for some 100-proof politics. The last of Osborne's contentions is that the administration (and many legislators as well) see the Medicare Part D prescription drug benefit as a huge windfall for the industry, and one that should be rolled back via a rebate program, setting prices back to what gets paid out under the Medicaid program instead. Ah, but opinions differ on this:
It’s useful to recall that former Louisiana Congressman and then PhRMA head Billy Tauzin negotiated with the White House in 2009 on behalf of the industry over this very question. Under the resulting deal, the industry agreed to support passage of the ACA and to make certain payments in the form of rebates and fees that amounted to approximately $80 billion over ten years; in exchange the administration agreed to resist those in Congress who pressed for more concessions from the drug companies or wanted to impose government price setting. . .
Tauzin's role, and the deal that he helped cut, have not been without controversy. I've always been worried about deals like this being subject to re-negotiations whenever it seems convenient, and those worries are not irrational, either:
. . .The White House believes that the industry would willingly (graciously? enthusiastically?) accept a new Part D outpatient drug rebate. Wow. The former official noted that the Simpson-Bowles deficit reduction panel recommended it, and its report was favorably endorsed by no less than House Speaker Boehner. Apparently, it is inconceivable to the White House that Boehner’s endorsement of the Simpson-Bowles platform would have occurred without the industry’s approval. Wow, again. That may be a perfectly logical assumption, but the other industry representatives within earshot never imagined that they had endorsed any such thing. No, it’s clear they have been under the (naïve) impression that the aforementioned $80 billion “contribution” was a very substantial sum in support of patients and the government treasury – and offered in a spirit of cooperation in recognition of the prospective benefits to industry of the expanded coverage that lies at the heart of Obamacare. With that said, the realization that this may be just the first of several installment payments left my colleagues in stunned silence; some mouths were visibly agape.
This topic came up late last year around here as well. And it'll come up again.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Current Events | Drug Development | Regulatory Affairs
May 15, 2013
Speaking about open-source drug discovery (such as it is) and sharing of data sets (such as they are), I really should mention a significant example in this area: the GSK Published Kinase Inhibitor Set. (It was mentioned in the comments to this post). The company has made 367 compounds available to any academic investigator working in the kinase field, as long as they make their results publicly available (at ChEMBL, for example). The people at GSK doing this are David Drewry and William Zuercher, for the record - here's a recent paper from them and their co-workers on the compound set and its behavior in reporter-gene assays.
Why are they doing this? To seed discovery in the field. There's an awful lot of chemical biology to be done in the kinase field, far more than any one organization could take on, and the more sets of eyes (and cerebral cortices) that are on these problems, the better. So far, there have been about 80 collaborations, mostly in Europe and North America, all the way from broad high-content phenotypic screening to targeted efforts against rare tumor types.
The plan is to continue to firm up the collection, making more data available for each compound as work is done on them, and to add more compounds with different selectivity profiles and chemotypes. Now, the compounds so far are all things that have been published on by GSK in the past, obviating concerns about IP. There are, though, a multitude of other compounds in the literature from other companies, and you have to think that some of these would be useful additions to the set. How, though, does one get this to happen? That's the stage that things are in now. Beyond that, there's the possibility of some sort of open network to optimize entirely new probes and tools, but there's plenty that could be done even before getting to that stage.
So if you're in academia, and interested in kinase pathways, you absolutely need to take a look at this compound set. And for those of us in industry, we need to think about the benefits that we could get by helping to expand it, or by starting similar efforts of our own in other fields. The science is big enough for it. Any takers?
+ TrackBacks (0) | Category: Academia (vs. Industry) | Biological News | Chemical News | Drug Assays
May 14, 2013
Crowdfunding academic research might be changing, from a near-stunt to an widely used method of filling gaps in a research group's money supply. At least, that's the impression this article at Nature Jobs gives:
The practice has exploded in recent years, especially as success rates for research-grant applications have fallen in many places. Although crowd-funding campaigns are no replacement for grants — they usually provide much smaller amounts of money, and basic research tends to be less popular with public donors than applied sciences or arts projects — they can be effective, especially if the appeals are poignant or personal, involving research into subjects such as disease treatments.
The article details several venues that have been used for this sort of fund-raising, including Indiegogo, Kickstarter, RocketHub, FundaGeek, and SciFund Challenge. I'd add Microryza to that list. And there's a lot of good advice for people thinking about trying it themselves, including how much money to try for (at least at first), the timelines one can expect, and how to get your message out to potential donors.
Overall, I'm in favor of this sort of thing, but there are some potential problems. This gives the general pubic a way to feel more connected to scientific research, and to understand more about what it's actually like, both of which are goals I feel a close connection to. But (as that quote above demonstrates), some kinds of research are going to be an easier sell than others. I worry about a slow (or maybe not so slow) race to the bottom, with lab heads overpromising what their research can deliver, exaggerating its importance to immediate human concerns, and overselling whatever results come out.
These problems have, of course, been noted. Ethan Perlstein, formerly of Princeton, used RocketHub for his crowdfunding experiment that I wrote about here. And he's written at Microryza with advice about how to get the word out to potential donors, but that very advice has prompted a worried response over at SciFund Challenge, where Jai Ranganathan had this to say:
His bottom line? The secret is to hustle, hustle, hustle during a crowdfunding campaign to get the word out and to get media attention. With all respect to Ethan, if all researchers running campaigns follow his advice, then that’s the end for science crowdfunding. And that would be a tragedy because science crowdfunding has the potential to solve one of the key problems of our time: the giant gap between science and society.
Up to a point, these two are talking about different things. Perlstein's advice is focused on how to run a successful crowdsourcing campaign (based on his own experience, which is one of the better guides we have so far), while Ranganathan is looking at crowdsourcing as part of something larger. Where they intersect, as he says, is that it's possible that we'll end up with a tragedy of the commons, where the strategy that's optimal for each individual's case turns out to be (very) suboptimal for everyone taken together. He's at pains to mention that Ethan Perlstein has himself done a great job with outreach to the public, but worries about those to follow:
Because, by only focusing on the mechanics of the campaign itself (and not talking about all of the necessary outreach), there lurks a danger that could sink science crowdfunding. Positive connections to an audience are important for crowdfunding success in any field, but they are especially important for scientists, since all we have to offer (basically) is a personal connection to the science. If scientists omit the outreach and just contact audiences when they want money, that will go a long way to poisoning the connections between science and the public. Science crowdfunding has barely gotten started and already I hear continuous complaints about audience exasperation with the nonstop fundraising appeals. The reason for this audience fatigue is that few scientists have done the necessary building of connections with an audience before they started banging the drum for cash. Imagine how poisonous the atmosphere will become if many more outreach-free scientists aggressively cold call (or cold e-mail or cold tweet) the universe about their fundraising pleas.
Now, when it comes to overpromising and overselling, a cynical observer might say that I've just described the current granting system. (And if we want even more of that sort of thing, all we have to do is pass a scheme like this one). But the general public will probably be a bit easier to fool than a review committee, at least, if you can find the right segment of the general public. Someone will probably buy your pitch, eventually, if you can throw away your pride long enough to keep on digging for them.
That same cynical observer might say that I've just described the way that we set up donations to charities, and indeed Ranganathan makes an analogy to NPR's fundraising appeals. That's the high end. The low end of the charitable-donation game is about as low as you can go - just run a search for the words "fake" and "charity" through Google News any day, any time, and you can find examples that will make you ashamed that you have the same number of chromosomes as the people you're reading about. (You probably do). Avoiding this state really is important, and I'm glad that people are raising the issue already.
What if, though, someone were to set up a science crowdfunding appeal, with hopes of generating something that could actually turn a profit, and portions of that to be turned over to the people who put up the original money? We have now arrived at the biopharma startup business, via a different road than usual. Angel investors, venture capital groups, shareholders in an IPO - all of these people are doing exactly that, at various levels of knowledge and participation. The pitch is not so much "Give us money for the good of science", but "Give us money, because here's our plan to make you even more". You will note that the scale of funds raised by the latter technique make those raised by the former look like a roundoff error, which fits in pretty well with what I take as normal human motivations.
But academic science projects have no such pitch to make. They'll have to appeal to altruism, to curiosity, to mood affiliation, and other nonpecuniary motivations. Done well, that can be a very good thing, and done poorly, it could be a disaster.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Business and Markets | General Scientific News
March 27, 2013
Senator Ron Wyden (D-Oregon) seems to be the latest champion of the "NIH discovers drugs and Pharma rips them off" viewpoint. Here's a post from John LaMattina on Wyden's recent letter to Francis Collins. The proximate cause of all this seems to be the Pfizer JAK3 inhibitor:
Tofacitinib (Xeljanz), approved last November by the U.S. Food and Drug Administration, is nearing the market as the first oral medication for the treatment of rheumatoid arthritis. Given that the research base provided by the National Institutes of Health (NIH) culminated in the approval of Xeljanz, citizens have the right to be concerned about the determination of its price and what return on investment they can expect. While it is correct that the expenses of drug discovery and preclinical and clinical development were fully undertaken by Pfizer, taxpayer-funded research was foundational to the development of Xeljanz.
I think that this is likely another case where people don't quite realize the steepness of the climb between "X looks like a great disease target" and "We now have an FDA-approved drug targeting X". Here's more from Wyden's letter:
Developing drugs in America remains a challenging business, and NIH plays a critically important role by doing research that might not otherwise get done by the private sector. My bottom line: When taxpayer-funded research is commercialized, the public deserves a real return on its investment. With the price of Xeljanz estimated at about $25,000 a year and annual sales projected by some industry experts as high as $2.5 billion, it is important to consider whether the public investment has assured accessibility and affordability.
This is going to come across as nastier than I intend it to, but my first response is that the taxpayer's return on this was that they got a new drug where there wasn't one before. And via the NIH-funded discoveries, the taxpayers stimulated Pfizer (and many other companies) to spend huge amounts of money and effort to turn the original discoveries in the JAK field into real therapies. I value knowledge greatly, but no human suffering whatsoever was relieved by the knowledge alone that JAK3 appeared to play a role in inflammation. What was there was the potential to affect the lives of patients, and that potential was realized by Pfizer spending its own money.
And not just Pfizer. Let's not forget that the NIH entered into research agreements with many other companies, and that the list of JAK3-related drug discovery projects is a long one. And keep in mind that not all of them, by any means, have ever earned a nickel for the companies involved, and that many of them never will. As for Pfizer, Xeljanz has been on the market for less than six months, so it's too early to say how the drug will do. But it's not a license to print money, and is in a large, extremely competitive market. And should it run into trouble (which I certainly hope doesn't happen), I doubt if Senator Wyden will be writing letters seeking to share some of the expenses.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | Drug Prices | Regulatory Affairs
March 1, 2013
You'll have heard about Yuri Milner, the Russian entrepreneur (early Facebook investor, etc.) who's recently announced some rather generous research prize awards:
Yesterday, Milner, along with some “old friends”—Google cofounder Sergey Brin, Facebook CEO Mark Zuckerberg, and their respective wives—announced they are giving $33 million in prizes to 11 university-based biologists. Five of the awards, called the Breakthrough Prize in Life Sciences, will be given annually going forward; they are similar to prizes for fundamental physics that Milner started giving out last year.
At $3 million apiece, the prize money tops the Nobels, whose purse is around $1 million. Yet neither amount is much compared to what you can make if you drop out of science and find a calling in Silicon Valley, as Brin, Milner, Zuckerberg did.
Technology Review has a good article on the whole effort. After looking over the awardees, Antonio Regalado has some speculation:
But looking over the list (the New York Times published it along with some useful biographical details here), I noticed some very strong similarities between the award winners. Nearly all are involved in studying cancer genetics or cancer stem cells, and sometimes both.
In other words, this isn’t any old list of researchers. It’s actually the scientific advisory board of Cure for Cancer, Inc. Because lately, DNA sequencing and better understanding of stem cells have become the technologies that look most likely to maybe, just maybe, point toward some real cancer cures.
Wouldn't surprise me. This is a perfectly good area of research for targeted funding, and a good infusion of cash is bound to help move things along. The article stops short of saying that Milner (or someone he knows) might have a personal stake in all this, but that wouldn't be the first time that situation has influenced the direction of research, either. I'm fine with that, actually - people have a right to do what they want to with their own money, and this sort of thing is orders of magnitude more useful than taking the equivalent pile of money and buying beachfront mansions with it. (Or a single beachfront mansion, come to think of it, depending on what market we're talking about).
I've actually been very interested in seeing how some of the technology billionaires have been spending their money. Elon Musk, Jeff Bezos, David Page, Sergey Brin, etc., have been putting some money behind some very unusual ventures, and I'm very happy to see them do it. If I were swimming in that kind of cash, I'd probably be bankrolling my own space program or something, too. Of course, those sorts of ideas are meant to eventually turn a profit. In that space example, you have tourism, launch services, asteroid mining, orbiting solar power, and a lot of other stuff familiar to anyone who ever read an old John W. Campbell editorial.
What about the biopharma side? You can try to invest to make money there, but it's worth noting that not a lot of tech-era money has gone into venture capital in this area. Are we going to see more of it going as grants to academia? If so, that says something about the state of the field, doesn't it? Perhaps the thinking is that there's still so much basic science to be learned that you get more for your dollar investing in early research - at least, it could lead to something that's a more compelling venture. And I'd be hard pressed to argue.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Who Discovers and Why
January 24, 2013
Chemistry World has really touched a lot of nerves with this editorial by economics professor Paula Stephan. It starts off with a look back to the beginnings of the NIH and NSF, Vannevar Bush's "Endless Frontier":
. . .a goal of government and, indirectly, universities and medical schools, was to build research capacity by training new researchers. It was also to conduct research. However, it was never Bush’s vision that training be married to research. . .
. . .It did not take long, however, for this to change. Faculty quickly learned to include graduate students and postdocs on grant proposals, and by the late 1960s PhD training, at least in certain fields, had become less about capacity building and more about the need to staff labs.
Staff them we have, and as Prof. Stephen points out, the resemblence to a pyramid scheme is uncomfortable. The whole thing can keep going as long as enough jobs exist, but if that ever tightens up, well. . .have a look around. Why do chemists-in-training (and other scientists) put up with the state of affairs?
Are students blind or ignorant to what awaits them? Several factors allow the system to continue. First, there has, at least until recently, been a ready supply of funds to support graduate students as research assistants. Second, factors other than money play a role in determining who chooses to become a scientist, and one factor in particular is a taste for science, an interest in finding things out. So dangle stipends and the prospect of a research career in front of star students who enjoy solving puzzles and it is not surprising that some keep right on coming, discounting the all-too-muted signals that all is not well on the job front. Overconfidence also plays a role: students in science persistently see themselves as better than the average student in their program – something that is statistically impossible.
I don't think the job signals are particularly muted, myself. What we do have are a lot of people who are interested in scientific research, would like to make careers of it, and find themselves having to go through the system as it is because there's no other one to go through.
Stephan's biggest recommendation is to try to decouple research from training: the best training is to do research, but you can do research without training new people all the time. This would require more permanent staff, as opposed to a steady stream of new students, and that's a proposal that's come up before. But even if we decide that this is what's needed, where are the incentives to do it? You'd have to go back to the source of the money, naturally, and fund people differently. Until something's done at that level, I don't see much change coming, in any direction.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Business and Markets | Graduate School
January 22, 2013
There's a new Viewpoint piece out in ACS Medicinal Chemistry Letters on academia and drug discovery. Donna Huryn of Pittsburgh is wondering about the wisdom of trying to reproduce a drug-company environment inside a university:
However, rather than asking how a university can mimic a drug discovery company, perhaps a better question is what unique features inherent in an academic setting can be taken advantage of, embellished, and fostered to promote drug discovery and encourage success? Rather than duplicating efforts already ongoing in commercial organizations, a university has an opportunity to offer unique, yet complementary, capabilities and an environment that fosters drug discovery that could generate innovative therapies, all the while adhering to its educational mission.
A corollary to this question is the converse—what aspects of drug discovery efforts within a university might be inconsistent with its primary goal of education and research, and can solutions be found to allow success in both?
Her take is that a university should take advantage of whatever special expertise its faculty have in particular areas of biology, pharmacology, etc., which could give it an advantage compared with the staff of a given pharma company. This isn't always easy, though, for cultural reasons:
While it seems that a university should have the tools to make significant contributions to drug discovery by taking advantage of the resident expertise, a cultural change might be required to foster an environment that values the teamwork required to make these efforts successful. Certainly funding agencies are moving in this direction with the establishment of multi-Principal Investigator designations that are designed to “maximize the potential of team science efforts”. Additionally, internal grants offered by academic institutions often insist that the proposed research involve multiple disciplines, departments, or even schools within the University. However, it seems that a concerted effort to “match-make” scientists with complementary expertise and an interest in drug discovery, finding ways to reward collaborative research efforts, and even, perhaps, establishing a project management-type infrastructure would facilitate a university-based drug discovery program.
She also makes the case the universities should use their ability to pursue higher-risk projects, given that they're not beholden to investors. I couldn't agree more - in fact, I think that's one of their biggest strengths. I'd define "high-risk" (by commercial standards) as any combination of (1) unusual mechanism of action, (2) little-understood disease area, (3) atypical chemical matter, and (4) a need for completely new assay technology. If you try to do all of those at once, you're going to land on your face, most likely. But some pharma companies don't even like to hear about one out of the four, and two out of four is going to be a hard sell.
And I think Huryn's broader point is well taken: we already have drug companies, so trying to make more of them inside universities seems like a waste of time and money. We need as many different approaches as we can get.
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November 28, 2012
So here's a question that a lot of people around here will have strong opinions on. I've heard from someone in an academic group that's looking into doing some high-throughput screening. As they put it, they don't want to end up as "one of those groups", so they're looking for advice on how to get into this sensibly.
I applaud that; I think it's an excellent idea to look over the potential pitfalls before you hop into an area like this. My first advice would be to think carefully about why you're doing the screening. Are you looking for tool compounds? Do they need to get into cells? Are you thinking of following up with in vivo experiments? Are you (God help you) looking for potential drug candidates? Each of these require somewhat different views of the world.
No matter what, I'd say that you should curate the sorts of structures that you're letting in. Consider the literature on frequent-hitter structures (here's a good starting point, blogged here), and decide how much you want to get hits versus being able to follow up on them. I'd also say to keep in mind the Shoichet work on aggregators (most recently blogged here), especially the lesson that these have to be dealt with assay-by-assay. Compounds that behave normally in one system can be trouble in others - make no assumptions.
But there's a lot more to say about this. What would all of you recommend?
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays
October 19, 2012
My post the other day on a very unattractive screening hit/tool compound prompted a reader to mention this paper. It's one from industry this time (AstraZeneca), and at first it looks like similarly foul chemical matter. But I think it's worth a closer look, to see how they dealt with what they'd been given by screening.
This team was looking for hits against PIM kinases, and the compound shown was a 160nM hit from high-throughput screening. That's hard to ignore, but on the other hand, it's another one of those structures that tell you that you have work to do. It's actually quite similar to the hit from the previous post - similar heterocycle, alkylidene branching to a polyphenol.
So why am I happier reading this paper than the previous one? For one, this structure does have a small leg up, because this thiazolidinedione heterocycle doesn't have a thioamide in it, and it's actually been in drugs that have been used in humans. TZDs are certainly not my first choice, but they're not at the bottom of the list, either. On the other hand, I can't think of a situation where a thioamide shouldn't set off the warning bells, and not just for a compound's chances of becoming a drug. The chances of becoming a useful tool compound are lower, too, for the same reasons (potential reactivity / lack of selectivity). Note that these compounds are fragment-sized, unlike the diepoxide we were talking about the other day, which means that they're likely to be able to fit into more binding sites.
But there's still that aromatic ring. In this case, though, the very first thing this paper says after stating that they decided to pursue this scaffold is: "We were interested to determine whether or not we could remove the phenol from the series, as phenols often give poor pharmacokinetic and drug-like properties.". And that's what they set about doing, making a whole series of substituted aryls with less troublesome groups on them. Basic amines branching off from the ortho position led to very good potency, as it turned out, and they were able to ditch the phenol/catechol functionality completely while getting well into (or below) single-digit nanomolar potency. With these compounds, they also did something else important: they tested the lead structures against a panel of over four hundred other kinases to get an idea of their selectivity. These is just the sort of treatment that I think the Tdp-1 inhibitor from the Minnesota/NIH group needs.
To be fair, that other paper did show a number of attempts to get rid of the thioamide head group (all unsuccessful), and they did try a wide range of aryl substituents (the polyphenols were by far the most potent). And it's not like the Minnesota/NIH group was trying to produce a clinical candidate; they're not a drug company. A good tool compound to figure out what selective Tdp-1 inhibition does is what they were after, and it's a worthy goal (there's a lot of unknown biology there). If that had been a drug company effort, those two SAR trends taken together would have been enough to kill the chemical series (for any use) in most departments. But even the brave groups who might want to take it further would have immediately profiled their best chemical matter in as many assays as possible. Nasty functional groups and lack of selectivity would surely have doomed the series anywhere.
And it would doom it as a tool compound as well. Tool compounds don't have to have good whole-animal PK, and they don't have to be scalable to pilot plant equipment, and they don't have to be checked for hERG and all the other in vivo tox screens. But they do have to be selective - otherwise, how do you interpret their results in an assay? The whole-cell extract work that the group reported is an important first step to address that issue, but it's just barely the beginning. And I think that sums up my thoughts when I saw the paper: if it had been titled "A Problematic Possible Tool Compound for Tdp-1", I would have applauded it for its accuracy.
The authors say that they're working on some of these exact questions, and I look forward to seeing what comes out of that work. I'd have probably liked it better if that had been part of the original manuscript, but we'll see how it goes.
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September 18, 2012
See Ahr Oh has a handy map of all the big recent faculty moves in the organic chemistry world, to help you keep up. Note that Nicolaou-to-Rice is still a dotted line.
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July 23, 2012
I wrote here about the Cronin lab at Glasgow and their work on using 3-D printing technology to make small chemical reactors. Now there's an article on this research in the Observer that's getting some press attention (several people have e-mailed it to me). Unfortunately, the headline gets across the tone of the whole piece: "The 'Chemputer' That Could Print Out Any Drug".
To be fair, this was a team effort. As the reporter notes, Prof. Cronin "has a gift for extrapolation", and that seems to be a fair statement. I think that such gifts have to be watched carefully in the presence of journalists, though. The whole story is a mixture of wonderful-things-coming-soon! and still-early-days-lots-of-work-to-be-done, and these two ingredients keep trying to separate and form different layers:
So far Cronin's lab has been creating quite straightforward reaction chambers, and simple three-step sequences of reactions to "print" inorganic molecules. The next stage, also successfully demonstrated, and where things start to get interesting, is the ability to "print" catalysts into the walls of the reactionware. Much further down the line – Cronin has a gift for extrapolation – he envisages far more complex reactor environments, which would enable chemistry to be done "in the presence of a liver cell that has cancer, or a newly identified superbug", with all the implications that might have for drug research.
In the shorter term, his team is looking at ways in which relatively simple drugs – ibuprofen is the example they are using – might be successfully produced in their 3D printer or portable "chemputer". If that principle can be established, then the possibilities suddenly seem endless. "Imagine your printer like a refrigerator that is full of all the ingredients you might require to make any dish in Jamie Oliver's new book," Cronin says. "Jamie has made all those recipes in his own kitchen and validated them. If you apply that idea to making drugs, you have all your ingredients and you follow a recipe that a drug company gives you. They will have validated that recipe in their lab. And when you have downloaded it and enabled the printer to read the software it will work. The value is in the recipe, not in the manufacture. It is an app, essentially."
What would this mean? Well for a start it would potentially democratise complex chemistry, and allow drugs not only to be distributed anywhere in the world but created at the point of need. It could reverse the trend, Cronin suggests, for ineffective counterfeit drugs (often anti-malarials or anti-retrovirals) that have flooded some markets in the developing world, by offering a cheap medicine-making platform that could validate a drug made according to the pharmaceutical company's "software". Crucially, it would potentially enable a greater range of drugs to be produced. "There are loads of drugs out there that aren't available," Cronin says, "because the population that needs them is not big enough, or not rich enough. This model changes that economy of scale; it could makes any drug cost effective."
Not surprisingly Cronin is excited by these prospects, though he continually adds the caveat that they are still essentially at the "science fiction" stage of this process. . .
Unfortunately, "science fiction" isn't necessarily a "stage" in some implied process. Sometimes things just stay fictional. Cronin's ideas are not crazy, but there are a lot of details between here and there, and if you don't know much organic chemistry (as many of the readers of the original article won't), then you probably won't realize how much work remains to be done. Here's just a bit; many readers of this blog will have thought of these and more:
First, you have to get a process worked out for each of these compounds, which will require quite a bit of experimentation. Not all reagents and solvents are compatible with the silicone material that these microreactors are being fabricated from. Then you have to ask yourself, where do the reagents and raw materials come in? Printer cartridges full of acetic anhydride and the like? Is it better to have these shipped around and stored than it is to have the end product? In what form is the final drug produced? Does it drip out the end of the microreactor (and in what solvent?), or is a a smear on some solid matrix? Is it suitable for dosing? How do you know how much you've produced? How do you check purity from batch to batch - in other words, is there any way of knowing if something has gone wrong? What about medicines that need to be micronized, coated, or treated in the many other ways that pills are prepared for human use?
And those are just the practical considerations - some of them. Backing up to some of Prof. Cronin's earlier statements, what exactly are those "loads of drugs out there that aren't available because the population that needs them is not big enough, or not rich enough"? Those would be ones that haven't been discovered yet, because it's not like we in the industry have the shelves lined with compounds that work that we aren't doing anything with for some reason. (Lots of people seem to think that, though). Even if these microreactors turn out to be a good way to make compounds, though, making compounds has not been the rate-limiting step in discovering new drugs. I'd say that biological understanding is a bigger one, or (short of that), just having truly useful assays to find the compounds you really want.
Cronin has some speculations on that, too - he wonders about the possibility of having these microreactors in some sort of cellular or tissue environment, thus speeding up the whole synthesis/assay loop. That would be a good thing, but the number of steps that have to be filled in to get that to work is even larger than for the drug-manufacture-on-site idea. I think it's well worth working on - but I also think it's well worth keeping out of the newspapers just yet, too, until there's something more to report.
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June 15, 2012
The biggest pharma companies increasingly seem to feel as if they need universities nearby. We've talked about this trend before, and Pfizer's current strategy makes it quite clear.
Partnerships between industry and academia, of course, aren’t new. Yet Pfizer, Sanofi, Merck & Co. (MRK) and other drug companies are putting a new twist on the arrangement by stepping up their level of collaboration with universities. In the case of Pfizer, the world’s largest drug company is embedding operations in Boston, San Francisco, New York and San Diego, often in the very same buildings where famed academic institutions have labs.
“No matter how much money you have, nothing compares to the innovation going on out in the world,” said Jose Carlos Gutierrez-Ramos, the director of the [new Pfizer lab in Cambridge], in an interview. “We want to be here, integrated into this fabric.”
Right. As I said earlier, I can definitely see the benefit to putting your research center in Cambridge or South San Francisco as opposed to Duluth or Reno. There are a lot of qualified people in the area who might be interested in moving over to join you, for one thing, and for small companies, that's where the (knowledgeable) money tends to hang out. But I still wonder about this cozy-up-to-the-academic-luminaries approach. Pfizer, for example, is making a big deal out of collaborating with Harvard, and their vision of how this is going to work doesn't quite fit into reality as I've come to know it:
Gutierrez-Ramos said he is trying to create an atmosphere at the lab where outside researchers easily come and go, and Pfizer’s scientists visit neighboring academicians on their turf.
Pharmaceutical companies, which historically are highly secretive about their work because of competition, need to be willing to take more risks in the future, he said, creating access to its inner sanctums to develop drugs earlier.
What Pfizer offers academic researchers are “extraordinary” resources for drug development that nearby university labs can’t match, said Harvard’s [Hal] Dvorak.
The problem with all this my-lab-is-your-lab stuff is that money gets involved. Don't think Harvard doesn't appreciate that, either - anyone who imagines a big pharma company snookering the unworldly Harvard Square luftmenschen should go try to do a deal with the university's technology transfer people. Undervaluing the worth of its own research is not one of Harvard's problems. And matters of intellectual property get involved, too pesky little matters that lead to Jarndyce v. Jarndyce style lawsuits. No, I have trouble imagining people breezing in and out of each other's labs like some sort of drug-discovery effort set in the Seinfeld universe.
What's interesting is that stories like the one I've linked to say that the drug companies are doing this because money is tight, and they need new revenue streams - thus the collaborations. And the universities are doing it because money is tight, and they need new revenue streams. The only way money is going to come out of these deals in order to fulfill both those expectations is for new drugs to be discovered and marketed, and that's a ten-to-fifteen year process. For now, the money is flowing from the drug industry towards academia.
Let's hope that the success rate of the targets improves. Don't get me wrong - I think that collaborations with academia can be useful, and I'm all for both groups getting to understand each other more. But I wonder if people are building expectations up a bit too much, too soon.
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June 8, 2012
I gave my talk at the Drew University Medicinal Chemistry course, and it got me to thinking about when I was there (1990 or 1991), and my early days in medicinal chemistry in general. There are a lot of things that have to be learned when coming out of a synthetic organic chemistry background, and a few that have to be unlearned. I've written about some of these in the past, but I wanted to bring together some specific examples:
1. I had to appreciate just how strange and powerful metabolizing enzymes are. I approached them from the standpoint of an organic chemist, but p450 enzymes can epoxidize benzene, and I don't know any organic chemists that can do that too well. Ripping open piperazine rings, turning cyclohexanes into cyclohexanols - there are a lot of reactions that are common in metabolic clearance that are not, to put it lightly, part of the repetoire of synthetic organic chemistry.
2. I also had to learn a rough version of the Lipinski rules - basically, that physical properties matter, although the degree to which they matter can vary. You can't increase molecular weight or lipophilicity forever without paying for it. Small polar molecules are handled fundamentally differently than big greasy ones in vivo. This was part of learning that there are many, many different potential fates for small molecules when dosed into a living animal.
3. Another key realization, which took a while to sink in, was that biological assays had error bars, and that this was true whether or not error bars were presented on the page or the screen. Enzyme assays were a bit fuzzy compared to the numbers I was used to as a chemist, but cell assays were fuzzier. And whole-animal numbers covered an even wider range. I had to understand that this hierarchy was the general rule, and that there was not a lot to be done about it in most cases (except, importantly, to never forget that it was there).
4. As someone mentioned in the comments here the other day, alluding to an old post of mine, I had to learn that although I'd been hearing for years that time was money, that grad school had been a poor preparation for learning how true that was. I was used to making everything that I could rather than buying it, but I had to reverse that thinking completely, since I was being paid to use my head more than my hands. (That didn't mean that I shouldn't use my hands, far from it - only that I should use my head first whenever feasible).
5. I also had to figure out how to use my time more efficiently. Another bad grad school habit was the working all hours of the day routine, which tended to make things stretch out. Back then, if I didn't get that reaction set up in the afternoon, well, I was coming back that evening, so I could do it then. But if I was going to keep more regular working hours, I had to plan things out better to make the best use of my time.
6. There were several big lessons to be learned about where chemistry fit into the whole drug discovery effort. One was that if I made dirty compounds, only dirty results could be expected from them. As mentioned above, even clean submissions gave alarmingly variable results sometimes; what could be expected from compounds with large and variable impurities from prep to prep? One of my jobs was not to make things harder than they already were.
7. A second big lesson, perhaps the biggest, was that chemistry was (and is) a means to an end in drug discovery. The end, of course, is a compound that's therapeutically useful enough that people are willing to pay money for it. Without one or more of those, you are sunk. It follows, first, that anything that does not bear on the problems of producing them has to be considered secondary - not unimportant, perhaps, but secondary to the biggest issue. Without enough compounds to sell, everything else that might look so pressing will, in fact, go away - as will you.
8. The next corollary is that while synthetic organic chemistry is a very useful way to produce such compounds, it is not necessarily the only way. Biologics are an immediate exception, of course, but there are more subtle ones. One of the trickier lessons a new medicinal chemist has to learn is that the enzymes and receptors, the cells and the rats, none of them are impressed by your chemical skills and your knowledge of the literature. They do not care if the latest compound was made by the most elegant application of the latest synthetic art, or by the nastiest low-yielding grunt reaction. What matters is how good that compound might be as a drug candidate, and the chemistry used to make it usually (and should) get in line behind many more important considerations. "Quickly", "easily", and "reproducibly", in this business, roughly elbow aside the more academic chemical virtues of "complexly", "unusually", and "with difficulty".
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June 1, 2012
I do hate to bring up rhodanines again, but I'm not the one who keeps making the things. This paper from ACS Medicinal Chemistry Letters turns out dozens of the things as potential inhibitors of the cellular protein dynamin, in what a colleague of mine referred to as a "nice exploration of the rhodanome".
He did not say it with a straight face. But this paper does: "The rhodanine core is a privileged scaffold in medicinal chemistry and one that has found promise among many therapeutic applications." Well, that's one way to look at it. Another viewpoint is that rhodanines are "polluting the scientific literature" and that they should "be considered very critically" no matter what activity they show in your assay.
The usual answer to this is that these aren't drugs, they're tool compounds. But I don't think that these structures even make safe tools; they have the potential to do too many other things in cell assays. But if people are going to go ahead and use them, I wish that they'd at least make a nod in that direction, instead of mentioning, in passing, how great the whole class is. And yes, I know that they cite two papers to that effect, but one of those two mainly just references the other one when it comes to rhodanines. My viewpoint is more like this paper's:
Academic drug discovery is being accompanied by a plethora of publications that report screening hits as good starting points for drug discovery or as useful tool compounds, whereas in many cases this is not so. These compounds may be protein-reactive but can also interfere in bioassays via a number of other means, and it can be very hard to prove early on that they represent false starts. . .
And I endorse this view as well:
. . .Barriers to adoption of best practices for some academic drug-discovery researchers include knowledge gaps and infrastructure deficiencies, but they also arise from fundamental differences in how academic research is structured and how success is measured. Academic drug discovery should not seek to become identical to commercial pharmaceutical research, but we can do a better job of assessing and communicating the true potential of the drug leads we publish, thereby reducing the wastage of resources on nonviable compounds.
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May 31, 2012
Anonymity is a topic that comes up whenever you talk about commenting on published scientific work. Some people are very uncomfortable with the idea of others being able to take potshots at them from behind convenient rocks, while others think that without that ability, a lot of relevant discussion will never take place.
Similar concerns apply to academic research grants. A big name never hurts - but what if all the names were stripped off the proposals? Many people have wondered this over the years, but now the NSF has been giving it a try:
Known as The Big Pitch and launched 2 years ago by officials in the agency's Molecular and Cellular Biosciences (MCB) Division, the effort aims to find out if making proposals anonymous—and shorter—has an impact on how they fare in the review process. “We wanted to find ways to identify transformative ideas that are getting lost in the regular peer-review process,” says Parag Chitnis, head of the MCB division. “So we asked: What would happen if we strip off the name of the PI [principal investigator] and institution and distill proposals down to just the big question or the core idea?”
What happens is a lot, according to the first two rounds of the Big Pitch. NSF's grant reviewers who evaluated short, anonymized proposals picked a largely different set of projects to fund compared with those chosen by reviewers presented with standard, full-length versions of the same proposals.
They're tried this twice, in two different research areas, each time with some 50 to 60 proposals to work with. Both times, the full-proposal rankings were almost completely different than the anonymous-pitch ones. I can see some problems with drawing conclusions here, though: for one thing, if two different teams of evaluators look over the same set of proposals (in either format), how closely do they agree? I'd like to see the NSF try that experiment - say, three different panels rating each set. And I'd include a third group, the condensed proposals with the names still on them. That might help answer several questions: how much do such panels diverge in general? Is the spread larger or smaller with the condensed proposal format? With the names stripped off? How much of the difference in rating is due to each factor?
These ideas have occurred to the people involved, naturally:
The experiment was not designed to separate out the effect of anonymity, but it may have been a factor. In both Big Pitch rounds, reviewers evaluating the anonymous two-pagers were later told the identity of the applicants. In some cases, Chitnis says, panelists were surprised to learn that a highly rated two-pager had come from a researcher they had never heard of. In others, he notes, reviewers “thought they knew who this person is going to be” only to find that the application came from a former student of the presumed bigwig, working at a small institution.
In their next round, the NSF plans to try to sort some of these factors out. I very much hope that this sort of thing continues, though. There should be a mixture of funding mechanisms out there: programs that fund interesting people, no matter what they're working on, and ones that fund interesting ideas, no matter where they came from.
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May 22, 2012
The NIH's attempt to repurpose shelved development compounds and other older drugs is underway:
The National Institutes of Health (NIH) today announced a new plan for boosting drug development: It has reached a deal with three major pharmaceutical companies to share abandoned experimental drugs with academic researchers so they can look for new uses. NIH is putting up $20 million for grants to study the drugs.
"The goal is simple: to see whether we can teach old drugs new tricks," said Health and Human Services Secretary Kathleen Sebelius at a press conference today that included officials from Pfizer, AstraZeneca, and Eli Lilly. These companies will give researchers access to two dozen compounds that passed through safety studies but didn't make it beyond mid-stage clinical trials. They shelved the drugs either because they didn't work well enough on the disease for which they were developed or because a business decision sidelined them.
There are plenty more where those came from, and I certainly wish people luck finding uses for them. But I've no idea what the chances for success might be. On the one hand, having a compound that's passed all the preclinical stages of development and has then been into humans is no small thing. On that ever-present other hand, though, randomly throwing these compounds against unrelated diseases is unlikely to give you anything (there aren't enough of them to do that). My best guess is that they have a shot in closely related disease fields - but then again, testing widely might show us that there are diseases that we didn't realized were related to each other.
John LaMattina is skeptical:
Well, the NIH has recently expanded the remit of NCATS. NCATS will now be testing drugs that have been shelved by the pharmaceutical industry for other potential uses. The motivation for this is simple. They believe that these once promising but failed compounds could have other uses that the inventor companies haven’t yet identified. I’d like to reiterate the view of Dr. Vagelos – it’s fairy time again.
My views on this sort of initiative, which goes by a variety of names – “drug repurposing,” “drug repositioning,” “reusable drugs” – have been previously discussed in my blog. I do hope that people can have success in this type of work. But I believe successes are going to be rare.
The big question is, rare enough to count the money and time as wasted, or not? I guess we'll find out. Overall, I'd rather start with a compound that I know does what I want it to do, and then try to turn it into a drug (phenotypic screening). Starting with a compound that you know is a drug, but doesn't necessarily do what you want it to, is going to be tricky.
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May 21, 2012
Here's a good example of phenotypic screening coming through with something interesting and worthwhile: they screened against Entamoeba histolytica, the protozooan that causes amoebic dysentery and kills tens of thousands of people every year. (Press coverage here).
It wasn't easy. The organism is an anaerobe, which is a bad fit for most robotic equipment, and engineering a decent readout for the assay wasn't straightforward, either. They did have a good positive control, though - the nitroimidazole drug metronidazole, which is the only agent approved currently against the parasite (and to which it's becoming resistant). A screen of nearly a thousand known drugs and bioactive compounds showed eleven hits, of which one (auranofin) was much more active than metronidazole itself.
Auranofin's an old arthritis drug. It's a believable result, because the compound has also been shown to have activity against trypanosomes, Leishmania parasites, and Plasmodium malaria parasites. This broad-spectrum activity makes some sense when you realize that the drug's main function is to serve as a delivery vehicle for elemental gold, whose activity in arthritis is well-documented but largely unexplained. (That activity is also the basis for persistent theories that arthritis may have an infectious-disease component).
The target in this case may well be arsenite-inducible RNA-associated protein (AIRAP), which was strongly induced by drug treatment. The paper notes that arsenite and auranofin are both known inhibitors of thioredoxin reductase, which strongly suggests that this is the mechanistic target here. The organism's anaerobic lifestyle fits in with that; this enzyme would presumably be its main (perhaps only) path for scavenging reactive oxygen species. It has a number of important cysteine residues, which are very plausible candidates for binding to a metal like gold. And sure enough, auranofin (and two analogs) are potent inhibitors of purified form of the amoeba enzyme.
The paper takes the story all the way to animal models, where auranofin completely outperforms metronidazole. The FDA has now given it orphan-drug status for amebiasis, and the way appears clear for a completely new therapeutic option in this disease. Congratulations to all involved; this is excellent work.
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Mat Todd at the University of Sydney (whose open-source drug discovery work on schistosomiasis I wrote about here) has an interesting chemical suggestion. His lab is also involved in antimalarial work (here's an update, for those interested, and I hope to post about this effort more specifically). He's wondering about whether there's room for a "Molecular Craigslist" for efforts like these:
Imagine there is a group somewhere with expertise in making these kinds of compounds, and who might want to make some analogs as part of a student project, in return for collaboration and co-authorship? What about a Uni lab which might be interested in making these compounds as part of an undergrad lab course?
Wouldn’t it be good if we could post the structure of a molecule somewhere and have people bid on providing it? i.e. anyone can bid – commercial suppliers, donators, students?
Is there anything like this? Well, databases like Zinc and Pubchem can help in identifying commercial suppliers and papers/patents where groups have made related compounds, but there’s no tendering process where people can post molecules they want. Science Exchange has, I think, commercial suppliers, but not a facility to allow people to donate (I may be wrong), or people to volunteer to make compounds (rather than be listed as generic suppliers. Presumably the same goes for eMolecules, and Molport?
Is there a niche here for a light client that permits the process I’m talking about? Paste your Smiles, post the molecule, specifying a purpose (optional), timeframe, amount, type of analytical data needed, and let the bidding commence?
The closest thing I can think of is Innocentive, which might be pretty close to what he's talking about. It's reasonably chemistry-focused as well. Any thoughts out there?
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May 14, 2012
A reader sends along this query, which I thought asked a very useful question:
". . .as a member of a growing biopharma company I am tasked with evaluating the effectiveness of industrial post-docs from both a business perspective and the post-doc's experience. Specifically, we are considering adding one for a short-term (2yr) to add headcount to a project. This adds resources without the long term commitment and also gives the scientists on site a chance for a paper they otherwise might not have time to work on. The candidate obviously gets a well-paid post-doc experience, and an industrial foot in the door. But, does this model work? I imagine that if it were that cut and dried you would see more of them."
Good point. Industrial post-docs are still relatively rare, although I've certainly seen a few. Come to think of it, though, those were mostly in biology, as opposed to chemistry. So, what do people think? From my end, I'd say that traditionally, companies have felt that temporary positions are best filled with experienced temporary employees, who presumably don't have to be trained as much. And if you're going to hire someone to learn the ropes, they might as well be good enough to be brought in as a full-time employee.
From the other end, an industrial post-doc has always been seen as less prestigious than an academic one, and there are some hiring managers who probably don't know what to think when one shows up on a c.v. There's often a feeling that if the person did a really good job during the post-doc that the company would have tried to offer them something permanent. And since they didn't, well. . .
Even so, it does seem as if there are situations where an industrial post-doc could be a good fit, and in today's job market, anything looks good. Anyone out there experienced this, from either end?
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April 27, 2012
Inspired by a discussion with a colleague, I'm going to take one more crack at the recent discussion here about the J. Med. Chem. DHFR paper. Those of you with an interest in the topic, read on. Those whose interest has waned, or who never had much interest to start with, take heart: other topics are coming.
It's clear that many people were disappointed with my take on this paper, and my handling of the whole issue. Let me state again that I mishandled the biology aspects of this one thoroughly, through carelessness, and I definitely owe this apology to the authors of the paper (and the readers of this site) for that.
Of course, that's not the only arguable thing about the way I handled this one. As I spent paragraphs rambling on about in yesterday's post, there's a chemical aspect to the whole issue as well, and that's what caught my eye to start with. I think one of the things that got me into trouble with this one is two different ways of looking at the world. I'll explain what I mean, and you can judge for yourself if I'm making any sense.
The authors of the paper (and its reviewer who commented here) are interested in D67 dihydrofolate reductase, from a biological/enzymological perspective. From this viewpoint - and it's a perfectly tenable one - the important thing is that D67 DHFR is an unusual and important enzyme, a problem in bacterial resistance, interesting in its own right as a protein with an odd binding site, and for all that, still has no known selective inhibitors. Anything that advances the understanding of the enzyme and points toward a useful inhibitor of it is therefore a good thing, and worth publishing in J. Med. Chem., too.
I come in from a different angle. As someone who's done fragment-based drug discovery and takes a professional interest in it, I'll take a look at any new paper using the technique. In this case, I gave the target much too cursory a look, and filed it as "DHFR, bacterial enzyme, soluble, X-ray structures known". In other words, a perfectly reasonable candidate for FBDD as we know it. Once I'd decided that this was a mainstream application of something I already have experience with, I turned my attention to how the fragment work was done. By doing so, I missed out on the significance of the DHFR enzyme, which means, to people in the first camp, that I whiffed on the most important part of the entire thing. I can understand their frustration as I brushed that off like a small detail and went on to what (to them) were secondary matters.
But here's where my view of the world comes in. As a drug discovery guy, when I read a paper in J. Med. Chem., I'd like to see progress in, well, the medicinal chemistry of the topic. That was the thrust of my blog post yesterday: that I found the med-chem parts of the paper uncompelling, and that the application of fragment-based techniques seemed to me to have gone completely off track. (I havne't mentioned the modeling and X-ray aspects of the paper, as Teddy Z did at Practical Fragments, but I also found those parts adding nothing to the worth of the manuscript as a whoel). The most potent compounds in the paper seem, to me, to be the sort that are very unlikely to lead to anything, and are unlikely to show selectivity in a cellular environment. If the paper's starting fragment hits are real (which is not something that's necessarily been proven, as I mentioned in yesterday's post), then it seems to me that everything interesting and useful about them is being thrown away as the paper goes on. From the other point of view, things are basically the opposite - the paper gets better and better as the compounds get more potent.
But here's where, perhaps, the two viewpoints I spoke of earlier might find something in common. If you believe that the important thing is that selective inhibitors of D67 DHFR have finally been discovered, then you should want these to be as potent and selective as possible, and as useful as possible in a variety of assays. This, I think, is what's in danger of being missed. I think that a fragment-based effort should have been able to deliver much more potent chemical matter than these compounds, with less problematic structures, which are more likely to be useful as tools.
I'll finish up by illustrating the different angles as starkly as I can. The authors of this paper have, in one view of the world, completed the first-ever fragment screen against an important enzyme, discovered the first-ever selective inhibitors of it, and have published these results in a prestigious journal: a success by any standard. From my end, if I were to lead a drug discovery team against the same enzyme, I might well see the same fragment hits the authors did, since I know that some of these are in the collections I use. But if I proceeded in the same fashion they did, prosecuting these hit compounds in the same way, I would, to be completely honest about it, face some very harsh questioning. And if I persevered in the same fashion, came up with the same final compounds, and presented them as the results of my team's work, I would run the serious risk of being fired. Different worlds.
Update: Prof. Pelletier sends the following:
I certainly have been following this with interest, and learning much from it – not just science.
Throughout the week, I have appreciated your civil tone – many thanks. I willingly accept your apology, just as I accept the constructive criticism that will improve our future work. I think your ‘two-worlds’ point of view smacks of truth. The bottom line from my point of view is that I’m open to collaboration with a real fragment library: if anyone is interested in making this better, they should contact me. I’d be delighted to work with more than what can be scavenged from neighbouring labs in an academic setting.
Your bloggers’ response to this come-and-go was fascinating: the process was admired to an extent that surprised me. A number of responders point out that there are currently few occurrences of open exchange on these blogs and – sorry to disappoint hard-core bloggers – it does not endear me to the blogging process. I don’t blog because I can’t stand anonymous, frequently disrespectful and sometimes poorly researched comments. I nonetheless hope that this will open the door to a more transparent blogging process in the long run.
For any who care, I am brave, not at all desperate, and definitely a woman. ; )
If you feel any of this would be of interest for your blog, please feel free to post. Thanks for seeing this through rather than shaking it off.
+ TrackBacks (0) | Category: Academia (vs. Industry) | The Scientific Literature
April 6, 2012
We've talked about the NIH's Molecular Libraries Initiative here a few times, mostly in the context of whether it reached its goals, and what might happen now that it looks as if it might go away completely. Does make this item a little surprising?
Almost a decade ago, the US National Institutes of Health kicked off its Molecular Libraries Initiative to provide academic researchers with access to the high-throughput screening tools needed to identify new therapeutic compounds. Europe now seems keen on catching up.
Last month, the Innovative Medicines Initiative (IMI), a €2 billion ($2.6 billion) Brussels-based partnership between the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA), invited proposals to build a molecular screening facility for drug discovery in Europe that will combine the inquisitiveness of academic scientists with industry know-how. The IMI's call for tenders says the facility will counter “fragmentation” between these sectors.
I can definitely see the worth in that part of the initiative. Done properly, Screening Is Good. But they'll have to work carefully to make sure that their compound collection is worth screening, and to format the assays so that the results are worth looking at. Both those processes (library generation and high-throughput screening) are susceptible (are they ever) to "garbage in, garbage out" factors, and it's easy to kid yourself into thinking that you're doing something worthwhile just because you're staying so busy and you have so many compounds.
There's another part of this announcement that worries me a bit, though. Try this on for size:
Major pharmaceutical companies have more experience with high-throughput screening than do most academic institutes. Yet companies often limit tests of their closely held candidate chemicals to a fraction of potential disease targets. By pooling chemical libraries and screening against a more diverse set of targets—and identifying more molecular interactions—both academics and pharmaceutical companies stand to gain, says Hugh Laverty, an IMI project manager.
Well, sure, as I said above, Screening Is Good, when it's done right, and we do indeed stand to learn things we didn't know before. But is it really true that we in the industry only look at a "fraction of potential disease targets"? This sounds like someone who's keen to go after a lot of the tough ones; the protein-protein interactions, protein-nucleic acid interactions, and even further afield. Actually, I'd encourage these people to go for it - but with eyes open and brain engaged. The reason that we don't screen against such things as often is that hit rates tend to be very, very low, and even those are full of false positives and noise. In fact, for many of these things, "very, very low" is not distinguishable from "zero". Of course, in theory you just need one good hit, which is why I'm still encouraging people to take a crack. But you should do so knowing the odds, and be ready to give your results some serious scrutiny. If you think that there must be thousands of great things out there that the drug companies are just too lazy (or blinded by the thought of quick profits elsewhere) to pursue, you're not thinking this through well enough.
You might say that what these efforts are looking for are tool compounds, not drug candidates. And I think that's fine; tool compounds are valuable. But if you read that news link in the first paragraph, you'll see that they're already talking about how to manage milestone payments and the like. That makes me think that someone, at any rate, is imagining finding valuable drug candidates from this effort. The problem with that is that if you're screening all the thousands of drug targets that the companies are ignoring, you're by definition working with targets that aren't very validated. So any hits that you do find (and there may not be many, as said above) will still be against something that has a lot of work yet to be done on it. It's a bit early to be wondering how to distribute the cash rewards.
And if you're screening against validated targets, the set of those that don't have any good chemical matter against them already is smaller (and it's smaller for a reason). It's not that there aren't any, though: I'd nominate PTP1B as a well-defined enzymatic target that's just waiting for a good inhibitor to come along to see if it performs as well in humans as it does in, say, knockout mice. (It's both a metabolic target and a potential cancer target as well). Various compounds have been advanced over the years, but it's safe to say that they've been (for the most part) quite ugly and not as selective as they could have been. People are still whacking away at the target.
So any insight into decent-looking selective phosphatase inhibitors would be most welcome. And most unlikely, damn it all, but all great drug ideas are most unlikely. The people putting this initiative together will have a lot to balance.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Biological News | Drug Assays
March 16, 2012
So the news is that Merck is now going to start its own nonprofit drug research institute in San Diego: CALIBR, the California Institute for Biomedical Research. It'll be run by Peter Schultz of Scripps, and they're planning to hire about 150 scientists (which is good news, anyway, since the biomedical employment picture out in the San Diego area has been grim).
Unlike the Centers for Therapeutic Innovation that Pfizer, a pharmaceutical company based in New York, has established in collaboration with specific academic medical centres around the country, Calibr will not be associated with any particular institution. (Schultz, however, will remain at Scripps.) Instead, academics from around the world can submit research proposals, which will then be reviewed by a scientific advisory board, says Kim. The institute itself will be overseen by a board of directors that includes venture capitalists. Calibr will not have a specific therapeutic focus.
Merck, meanwhile, will have the option of an exclusive licence on any proteins or small-molecule therapeutics to emerge. . .
They're putting up $90 million over the next 7 years, which isn't a huge amount. It's not clear if they have any other sources of funding - they say that they'll "access" such, but I have to wonder, since that would presumably complicate the IP for Merck. It's also not clear what they'll be working on out there; the press release is, well, a press release. The general thrust is translational research, a roomy category, and they'll be taking proposals from academic labs who would like to use their facilities and expertise.
So is this mainly a way for Merck to do more academic collaborations without the possible complications (for universities) of dealing directly with a drug company? Will it preferentially take on high-risk, high-reward projects? There's too little to go on yet. Worth watching with interest as it gets going - and if any readers find themselves interviewing there, please report back!
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March 7, 2012
I have a reader who's in the process of moving from an industrial setting to teaching medicinal chemistry. He wanted to know if I'd ever written about that topic, and I have to say, I don't think there's been a post dedicated to it yet. I know that many people have done just this (and there are many more who are thinking about it).
So let's talk - are there are others out there who've made the switch? What are some of the things to look out for? I know that this answer will vary, depending on the job and the type of academia, but it'll be worthwhile hearing some first-hand experiences. Anything from dealing with funding, to integrating your industry experience into your teaching, to the whole culture shift - comment away, and thanks!
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February 28, 2012
I last wrote about the Molecular Libraries program here, as it was threatened with funding cuts. Now there's a good roundup of opinion on it here, at the SLAS. The author has looked over the thoughts of the readership here, and also heard from several other relevant figures. Chris Lipinski echoes what several commenters here had to say:
Lipinski notes that when the screening library collection began the NIH had little medicinal chemistry experience. "I was a member of an early teleconference to discuss what types of compounds should be acquired by the NIH for high-throughput screening (HTS) to discover chemical biology tools and probes. Our teleconference group was about evenly split between industry people and academics. The academics talked about innovation, thinking out of the box, maximum chemical diversity and not being limited by preconceived rules and filters. The industry people talked about pragmatism, the lessons learned and about worthless compounds that could appear active in HTS screens. The NIH was faced with two irreconcilable viewpoints. They had to pick one and they chose the academic viewpoint."
He says that they later moved away from this, with more success, but implies that quite a bit of time was lost before this happened. Now, we waste plenty of time and money in the drug industry, so I have no standing to get upset with the NIH about blind alleys, in principle. But having them waste time and money specifically on something that the drug industry could have warned them off of is another thing.
In the end, opinions divide (pretty much as you'd guess) on the worth of the whole initiative. As that link shows, its director believes it to have been a great success, while others give it more mixed reviews. Its worth has surely grown with time, though, as some earlier mistakes were corrected, and that's what seems to be worrying people: that the plug is getting pulled just when things were becoming more useful. It seems certain that several of the screening centers will not survive in the current funding environment. And what happens to their compounds then?
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February 17, 2012
Here's the streaming video of the session I did at SLAS2012 on collaboration between academia and industry. I'm not sure how long it'll be up, so if you want to see it, you probably should go ahead and check it out. A lot of people probably wish they could fast-forward (and pause) me during regular working hours!
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February 6, 2012
This is not the sort of academic-industry interaction I had in mind. There's a gigantic lawsuit underway between Agios and the Abramson Institute at the University of Pennsylvania, alleging intellectual property theft. There are plenty more details at PatentBaristas:
According to the complaint filed in the US District Court Southern District Of New York, the Institute was created by an agreement between The Abramson Family Foundation and the Trustees of the University of Pennsylvania. The Foundation donated over $110 Million Dollars to the Institute with the condition that the money was to be used to explore new and different approaches to cancer treatment.
Dr. Thompson later created a for-profit corporation that he concealed from the Institute. After a name change, that entity became the Defendant Agios Pharmaceuticals, Inc. Dr. Thompson did not disclose to the Institute that at least $261 million had been obtained by Agios for what was described as its “innovative cancer metabolism research platform” – i.e., the description of Dr. Thompson’s work at the Institute. Dr. Thompson did not disclose that Agios was going to sell to Celgene Corporation an exclusive option to develop any drugs resulting from the cancer metabolism research platform.
Such are the accusations. There's more of Thompson's defense in this New York Times article:
Three people with knowledge of Dr. Thompson’s version of events, two of whom would speak only on condition of anonymity because of the litigation, said that the University of Pennsylvania knew about Dr. Thompson’s involvement with Agios and even discussed licensing patents to the company, though no agreement was reached.
“When you start a company like this, you want to try to dominate the field,” said Lewis C. Cantley, another founder of Agios and the director of the cancer center at the Beth Israel Deaconess Medical Center in Boston. “The goal was to get as many patents as possible, and it was frustrating that we weren’t able to get any from Penn.”
Michael J. Cleare, executive director of Penn’s Center for Technology Transfer, declined to discuss whether negotiations had been held but said, “Yes, Penn knew about Agios.”
So, as the lawyers over at PatentBaristas correctly note, this is all going to come down to what happened when. And that's going to be determined during the discovery process - emails, meeting minutes, memos, text messages, whatever can establish who told what to whom. If there's something definitive, the whole case could end up being dismissed (or settled) before anything close to a trial occurs - in fact, that would be my bet. But that's assuming that something definite was transferred at all:
A crucial question, some patent law and technology transfer specialists said, could be whether Dr. Thompson provided patented technology to Agios or merely insights.
“If somebody goes out and forms a company and doesn’t take patented intellectual property — only brings knowledge, know-how, that sort of thing — we wouldn’t make any claims to it,” said Lita Nelsen, director of the technology licensing office at the Massachusetts Institute of Technology.
In its complaint, the Abramson institute does not cite any specific patents. It says Penn did not pursue the matter because Dr. Thompson had told the university that his role in Agios did not involve anything subject to the university’s patent policies. The lawsuit says the institute did not find out about Dr. Thompson’s role in Agios until late 2011.
There will probably be room to argue about what was transferred, which could get expensive. That accusation of not finding out about Agios until 2011, though, can't be right, since he's mentioned all over their press releases and meeting presentations at least two years before that. But no matter how this comes out, this is not the way to build trust. Not quite.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Patents and IP
January 25, 2012
So, what questions should be asked? I've been asked to moderate a panel discussion ("Bridging the Valley of Death") at the upcoming Society for Laboratory Automation and Screening conference in San Diego. It's a session moderated by Bill Janzen from the University of North Carolina and Michelle Palmer from the Broad Institute, and the panelists are John Luk from the National University of Singapore, Rudy Juliano from UNC, Mao Mao from Pfizer (San Diego), Alan Palkowitz from Eli Lilly, and John Reed from Sanford-Burnham.
The discussion will be live-streamed (I'll put up the link that day), so if you're interested in that sort of thing, tune in. And as it says here, questions will be gathered "through social media sites, expert opinions and audience participation". And since this is one of those social media sites, more or less, I'd like to do some preparation by asking the question that I led off this post with. What would you like to see asked? What are the biggest issues and stumbling blocks? What should this audience get from all this?
Feel free to add suggestions in the comments, which are much appreciated. I'll run up some Twitter hashtags as the event gets closer, as well as keeping an eye on this post. Thanks!
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October 26, 2011
With all the recent talk about the NIH's translational research efforts, and the controversy about their drug screening efforts, this seems like a good time to note this interview with Francis Collins over at BioCentury TV. (It's currently the lead video, but you'll be able to find it in their "Show Guide" afterwards as well).
Collins says that they're not trying to compete with the private sector, but taking a look at the drug development process "the way an engineer would", which takes me back to this morning's post re: Andy Grove. One thing he emphasizes is that he believes that the failure rate is too high because the wrong targets are being picked, and that target validation would be a good thing to improve.
He's also beating the drum for new targets to come out of more sequencing of human genomes, but that's something I'll reserve judgment on. The second clip has some discussion of the DARPA-backed toxicology chip and some questions on repurposing existing drugs. The third clip talks about the FDA's role in all this, and tries to clarify what NIH's role would be in outlicensing any discoveries. (Collins also admits along the way that the whole NCATS proposal has needed some clarifying as well, and doesn't sound happy with some of the press coverage).
Part 5 (part 4 is just a short wrap-up) discusses the current funding environment, and then moves into ethics and conflicts of interest - other people's conflicts, I should note. Worth a lunchtime look!
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development
October 21, 2011
Science is reporting some problems with the NIH's drug screening efforts:
A $70-million-a-year program launched 7 years ago at the National Institutes of Health (NIH) to help academic researchers move into industry-style drug discovery may soon be forced to scale back sharply. NIH Director Francis Collins has been one of its biggest champions. But the NIH Molecular Libraries, according to plan, must be weaned starting next year from the NIH director's office Common Fund and find support at other NIH institutes. In a time of tight budgets, nobody wants it.
The fate of the Molecular Libraries program became “an extremely sensitive political issue” earlier this year when NIH realized it would not be easy to find a new home for the program, said one NIH official speaking on background. . .
. . .John Reed, head of the Sanford-Burnham Medical Research Institute screening center in San Diego, which receives about $16 million a year from the Common Fund, says his center has so far attracted only modest funding from drug companies. He expressed frustration with the Common Fund process. “NIH has put a huge investment into [the Molecular Libraries], and it's running very well,” he says. “If there's not a long-term commitment to keep it available to the academic community, why did we make this hundreds of millions of dollars investment?”
Good question! This all grew out of the 2003 "NIH Roadmap" initiative - here's a press release from better days. But it looks partly to be a victim of sheer bad timing. There's not a lot of extra money sloshing around the drug industry these days, and there sure isn't a lot in NIH's budget, either. You wouldn't know that there's a problem at all from looking at the program's web site, would you?
Since I know there are readers out there from both sides of this particular fence, I'd be interesting in hearing some comments. Has the screening initiative been worthwhile? Should it be kept up - and if so, how?
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September 23, 2011
I have just enough time today to link to this - which is simultaneously a nasty prank to pull on someone, and (for anyone who's been to grad school), completely hilarious. A message went out over a mail server list in Europe, after a post-doc position in Germany had been posted. It, um, clarified the nature of the position:
I am desperately searching for eager victims - postdocs or PhD students - mine or other supervisors' - to make my workhorses and to plunder ideas from. . .I cannot do research myself because I'm narrow-minded, rigid-brained, and petty. Therefore, I have to recruit desperate scientists from anywhere in the world and then manage (harangue) them into submission. The smarter you are relative to me, the more I will hate you. . .
It goes on in that vein for a while, winding up with the usual boilerplate legal language: "I am entitled to success because supremacy is my birthright".. Read it, cast you mind back to your own grad student/post-doc days, and imagine the temptation to do the same!
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September 8, 2011
Here's another article in the Guardian that makes some very good points about the way we judge scientific productivity by published papers. My favorite line of all: "To have "written" 800 papers is regarded as something to boast about rather than being rather shameful." I couldn't have put it better, and I couldn't agree more. And this part is just as good:
Not long ago, Imperial College's medicine department were told that their "productivity" target for publications was to "publish three papers per annum including one in a prestigious journal with an impact factor of at least five.″ The effect of instructions like that is to reduce the quality of science and to demoralise the victims of this sort of mismanagement.
The only people who benefit from the intense pressure to publish are those in the publishing industry.
Working in industry feels like more of a luxury than ever when I hear about such things. We have our own idiotic targets, to be sure - but the ones that really count are hard to argue with: drugs that people will pay us money for. Our customers (patients, insurance companies, what have you) don't care a bit about our welfare, and they have no interest in keeping our good will. But they pay us money anyway, if we have something to offer that's worthwhile. There's nothing like a market to really get you down to reality.
+ TrackBacks (0) | Category: Academia (vs. Industry) | The Scientific Literature
September 2, 2011