The editor of the journal Life has published an attempt at detailing how the notorious Andrulis paper managed to make its way into print. See how convincing you find it. In the course of explaining that it can be hard to find reviewers for interdisciplinary topics, and how the journal tries to find reputable people in each field (and carefully checks author suggestions for reviewers), we have this:

Life is a new journal that deals with new and sometime difficult interdisciplinary matters. Consequently, the journal will occasionally be presented with submitted articles that are controversial and/or outside conventional scientific views. Some papers recently accepted for publication in Life have attracted significant attention. Moreover, members of the Editorial Board have objected to these papers; some have resigned, and others have questioned the scientific validity of the contributions. . .

. . .In the case of the Dr. Andrulis’s long paper, the two reviewers were both faculty members of reputable universities different than the author’s and both went to considerable trouble presenting lengthy review reports. Dr. Andrulis revised his manuscript as requested, and the paper was subsequently published.

Really? Is that how it really went? I know what I would have said if they'd sent the paper to me: that it was a perfect example of what happens when an active, learned mind begins to slip loose from its moorings, and that while the paper appeared to have no scientific merit at all, it was quite useful as a diagnostic sign of oncoming psychosis.

If you only read the Life editor's remarks without reading any of the original paper, you might find them reasonable. But that's because you haven't been exposed to a theory that purports to explain the abiotic origins of life, the underlying principles of biochemistry, the formation of the solar system, the expansion of the universe, global weather patterns, the structure of cellular membranes, the distributions of comets and asteroids, the origins of riboviruses, the protein folding problem, the nature of biological aging, and the unification of quantum mechanics with general relativity. I have not made any of that up, it's all in the paper, and I would very much like to see a reviewer who could let all that go past. "Publish with revisions", sure.

From several reports, here's what I have on AstraZeneca's plans in Waltham: they've told people there that cuts are coming. But they haven't gotten very specific on when, or who, or how many. All those questions (that is, all the questions there could be) are under review.

Pfizer has done this to their people before, as have other companies in the throes of layoffs, and it's the only way I know to actually push morale and productivity down even further in such a situation. You come to work for weeks, for months, not knowing if your, your lab, or your whole department is heading for the chopping block. All you're sure of is that someone is. And will your own stellar performance persuade upper management to keep you, when the time comes? Not likely, under these conditions - it'll more likely be the sort of thing where they draw lines through whole areas. Your fate, most people feel at these times, is not in your own hands. A less motivating environment couldn't be engineered on purpose.

But that's what AZ's management has chosen to do at their largest research site in North America. I hope that they enjoy the results. But then (and more on this later), these are the people who have chosen to spend billions buying back their own stock rather than put it into research in the first place. It's not like the score isn't already up there on the big screen for everyone to see.

Update: as mentioned in the comments, this does at least give everyone a warning bells, and a chance to explore other options, as they say. And that's true. AZ employees, though, have been seeing nasty cuts for a while now, and have been well aware that they're not in a stable environment. It's hard to make the decision to leave, but there have been plenty of chances to think about it in the last two or three years.

But I was actually arguing against the company's Waltham strategy from the viewpoint of upper management, on their terms. It's better for employees to have some warning, but I think it's better, for a company, to cut if you're going to cut, and get it over with. If you say that deep cuts are coming, you should do the actual deed as soon as you can. Then you tell the departments that are left, "OK, the storm has passed. Let's try to turn this thing around". But this current situation is the worst of both worlds. "All right, people, here come the big cuts: this site's closed, that site's closed. But your site, well, we don't really want to close it, but we still haven't had time to work out how much to shrink it. Yeah, this was supposed to be the big announcement, but it's just been really busy - you know how it is. We're going to get around to you. Pretty soon. And pretty deep. But we don't know which parts to lop off, not just yet. Back to work, everyone!"

Fluorine NMR is underused in chemistry. Well, then again, maybe it's not, but it's one of those thing that just seems like it should have more uses than it does. (Here's a recent bookon the subject). Fluorine is a great NMR nucleus - all the F in the world is the same isotope, unless you're right next to a PET scanning facility - and the different compound show up over a very wide range of chemical shifts. You've got that going for you, coupling information, NOE, basically all your friends from proton NMR.

There's a pretty recent paper showing a good use of all these qualities (blogged about here at Practical Fragments as well). A group at Amgen reports on their work using fluorine NMR as a fragment-screening tool. They can take mixtures of 10 or 12 compounds at a time (because of all those different chemical shifts) and run the spectra with and without a target protein in the vial. If a fragment binds, its F peak broadens out (you can even get binding constants if you run at a few different concentrations). A simple overlay of the two spectra tells you immediately if you have hits. You don't need to have any special form of the protein, and you don't even need to run in deuterated solvents, since you're just ignoring protons altogether.

Interestingly, when they go on to try other assay techniques as follow-up, they find that the fluorines themselves aren't always a key part of the binding. Sometimes switching to the non-fluorinated version of the fragment gives you a better compound; sometimes it doesn't. The binding constants you get from the NMR, though, do compare very well to the ones from other assays.

The part I found most interesting was the intra-ligand NOE example. (That's also something that's been done in proton NMR, although it's not easy). They show a case where 19F ligands do get close enough to show the effect, and that a linked version of the two fragments does, as you'd hope, make a much more potent compound. That's the sort of thing that fragment people are always wanting to know - what fits next door to my hit? Can they be linked together? Fragment linking has its ups and downs, going back to the Abbott SAR-by-NMR days. That was a technique that never really panned out, as far as can be seen, but this is at least an experimentally easy way to give it a shot. (Of course, the chances of the fluorines on your ligands actually being pointed at each other is probably small, so that does cancel things out a bit).

Overall, it's a fun paper to read - well, allowing for my geeky interests, it is - and perhaps it'll lead a few more people to think of things that could be done with fluorine NMR in general. It's just sitting there, waiting to be used. . .

Update: it's all true. 7,300 job cuts in total. Montreal and Soedertaelje (Sweden) to close. And AZ seems to be all but getting out of pain/CNS, cutting down to a few dozen people who will do external collaborations. Oh, and they're buying back 4.5 billion dollars worth of stock, instead of spending that money on what the company tries to make a profit on. So there is that. If you'd like to hear AZ tell you how all this is making them more productive, here's the press release.

I've been hearing reports, which I hope are incorrect but as yet have no reason to doubt, that the AstraZeneca site in Montreal is set to close as a result of this latest round of layoffs. The official announcement is coming in a few hours - I wanted to put up this post so that more details can be added in the comments as people get them.

This will be bad news for the Montreal research community, which has already been taking it pretty hard over the last few years. As that link shows, though, they least had a number of employers to start with, as opposed to some of the UK sites (and others) that had been R&D monocultures when their closures hit. But there's no way to really put a bright face on this stuff. . .

Noted chem-blogger Milkshake seems to have had a close call with a fire started by a tiny potassium hydride residue. It looks like he made it through without serious injury, but that sort of thing will definitely shake a person up.

I hate potassium hydride. Its relative sodium hydride is a common reagent, but it's much tamer (and even so, can cause interesting fires - I knew someone who ignited a heap of it on the pan of a balance while he was weighing it out, which slowed things down a bit). Sodium hydride is usually sold as a 60% dispersion, a dark grey powder soaked with mineral oil to keep it from deteriorating too quickly (and to keep it from setting everything on fire). You can buy 95% sodium hydride, the dry stuff, and there are people who swear by it, but I tend to sweat at it. You never know if it's been stored properly; you may be adding a slug of sodium hydroxide to your reaction without knowing it. And there's the fire part. You'll want to move briskly if you're using the 95%, and I'd pick a day when the humidity is low.

But potassium hydride, that's another beast entirely. It makes the sodium compound look like corn meal, in terms of how forgiving it is. You can't get away with the clumpy oily powder form at all - traditionally, KH is sold as a gooey dispersion of grey powder sitting under a few inches of mineral oil. If it's well dispersed, it's supposed to be 35%. You shake the stuff up until you think it's even mixed, then pipet out the amount of gunk that corresponded to the KH contained therein. Sure you do. What actually happens is that you pipet out the stuff, noticing while you do that it's already settling out inside the pipet, thereby to clog it up when you try to transfer it. No fun.

It's becoming available now dispersed in a block of wax, which is not such a bad idea at all. Wax isn't any harder to get out of your reaction than oil is, and you can carve off chunks and weigh them without so many what-am-I-doing moments. But Milkshake worries that this ease of use will lead to more fires during workups (which is where his reaction ran into trouble), and he may well be right. If you're going to use KH, don't let your guard down.

At Xconomy, Luke Timmerman has words of wisdom for people in the small biotech world: "Never back smug". That's a quote from venture capitalist Bob More, and it rings true to me as well. Says TImmerman: ". . .it strikes me that life sciences has more than its share of spinmeisters, hypesters, smoke-and-mirrors actors, and worse."

Then there’s smugness, that arrogance or sense of superiority. Developing innovative new drugs or devices requires a strong ego, high IQ, stamina, an inspiring personality that attracts other people, and other things. Often, that combination spills over into smugness or arrogance. More says he watches for a lot of the same cues that his sister, a teacher, watches for. . .

I suspect that many readers will have encountered this trait (very occasionally) in their careers. There's a particular danger in the sciences, because (on the one hand) there's so much to know, that a given person does indeed have a good chance of knowing something that others don't. But on that inevitable other hand, this knowledge is set against a background of the huge, vast, pile of what we don't know - and if you keep that perspective, that knowing little smile just starts to look ridiculous.

And consider the audience - scientists, good ones, pride themselves on curiosity and being able to master new material. That means that "You don't have to know about that" or "Don't you worry about that, that's my department" (not to mention "Oh, you probably wouldn't understand") aren't going to get a good reception, not from anyone who could be of any help, anyway. Someone with that kind of attitude ends up driving away people who are smart, competent, and motivated - they won't put up with it.

The fallout from the bizarre Andrulis paper continues. Carl Zimmer reports that editorial board members are resigning from the journal, having had no idea that their names would wind up over something like this.

Naturally, that brings up the question of just who did let this thing through the review process, but my bet is that we'll never know. Whoever signed off on it is no doubt running for cover.

Another useful feature this affair has had is the chance to see who just posts press releases for fun and profit, and who has some tiny residual bit of editorial discretion. In the former category, apparently, are PhysOrg.com and ScienceDaily.com (the latter has taken down their post. But then again, the Times of India bit for it as well. . .

OK, this is one of those less-than-cheerful mornings on the blog, apparently. Word is in the British press that AstraZeneca is preparing to announce thousands more job cuts later this week. No more concrete details yet - all the company has said is that "clear focus on cash and value creation will continue", and isn't that just about the most encouraging thing you've ever heard? More as this develops.

Someone has been soaking up the atmosphere at a large pharma company, for sure. "Look, I'm a chemist. I thought you hired me to do chemistry. But so far, all I've heard is gibberish. . .don't you do chemistry here?".

Some of you may enjoy that, but for others, it might just be a bit too realistic to be amusing. . .

The same user has several other videos on YouTube, such as this one, which (in addition to a few four-letter words), features the phrase "Get off the Kool-Aid!" Clearly someone needs to go through some more training. (Thanks to Pharmalot for the original link).

This one mixes two categories on the blog: "Regulatory Affairs" with "How Not to Do It". A small company called Cell Therapeutics (catchy name) has been developing pixantrone for last-ditch non-Hodgkin's lymphoma. You'll note from that Wikipedia article that this compound has been knocking around for a long time, and it's had a very hard road towards any sort of approval.

In 2010, an FDA advisory committee voted it down 12-0, and from the sound of things, it wasn't even that close. But the company appealed and resubmitted, since hope springs eternal and all. They were heading towards an FDA decision next week, and the company's CEO was apparently been going around to investors telling them how confident he was of approval. You see, one of the drug's major critics at the FDA, he claimed, had been disciplined for his totally unfair review of the drug back in 2010. So how could they lose?

Like this. The company has announced that they're withdrawing their application, citing communication difficulties with the FDA. I'm sure they have some. The agency keeps trying to tell the company that the drug isn't approvable, and the company keeps on not hearing it.

Here's one of the strangest things I've ever seen in the scientific literature. A new journal, Life, apparently solicited papers for their inaugural issues, and one of them was from Erik Andrulis at Cast Western's School of Medicine. The manuscript came in at 105 printed pages, which should have rung at least a tiny alarm bell, you'd think. And if that wasn't a bit concerning, perhaps the title ("Theory of the Origin, Evolution, and Nature of Life") might have seemed a bit sweeping? Or the abstract, which promises that "The theoretical framework unifies the macrocosmic and microcosmic realms, validates predicted laws of nature, and solves the puzzle of the origin and evolution of cellular life in the universe." No? Nothing to worry about yet?

But editors aren't supposed to just look at page counts, titles, and abstracts. Just a riffle through the actual manuscript should have been enough to convince anyone that, rather than a Theory of Everything, that this work is, most unfortunately, the product of a disordered mind. P. Z. Myers has excerpts from the paper on his blog - take a look and see what you think. Here's a sample, and it should really be sufficient:

The ultimate state of gyromnemesis is the stably adapted particle or gyronexus in the gyrobase. . .Finally, although a diquantal IEM (X'') undergoes gyrognosis as the gyrobase of a primary majorgyre, it undergoes gyromnemesis as the gyrapex of an alternagyre.

Right. The paper ranges through the origins of life, organic chemistry, cosmology, geology, astronomy, and who knows what else, all of it explained in language exactly like the above. And yes, there is a multi-page glossary of all those gyro-terms, and no, it does not help. As Myers points out, the spectacularly weird thing is that not only did this paper get published, it got press-released by Case Western. Here, check it out. Whoever put this thing together has gamely attempted to summarize the paper, and not only that, to highlight its importance for the greater glory of Case Western:

To test his paradigm, Dr. Andrulis designed bidirectional flow diagrams that both depict and predict the dynamics of energy and matter. While such diagrams may be foreign to some scientists, they are standard reaction notation to chemists, biochemists, and biologists.

Dr. Andrulis has used his theory to successfully predict and identify a hidden signature of RNA biogenesis in his laboratory at Case Western Reserve University School of Medicine. He is now applying the gyromodel to unify and explain the evolution and development of human beings.

Oh, go take a look and tell me if you see any standard notation. (Update: I see from RetractionWatch that the university has pulled the release from their own sites, saying that they're "evaluating our processes regarding media outreach". I'll bet they are(. Now, I realize that picking up a text on, say, quantum electrodynamics could lead to the same what-is-this-stuff feeling. But any text on QED starts with a grounding in the physical world and the connections of the theory to known physics. And this sort of thing is different in both degree and kind (for one thing, QED has nothing to say about lunar craters). There's a difference between a work that makes you think "Boy, I don't understand this" and one that makes you think "Boy, this person has lost it". The near-infallible signs of scientific derangement include the "Why, this explains everything" aspect, the "Everything you thought you knew is wrong" one, and the intricate details-within-details style, almost always taken to unbearable lengths.

What the Andrulis paper reminds me of, actually, is Alfred Lawson and his Lawsonomy. That one also explains everything from bacteria to the composition of the moon, and brings in "zig-zag and swirl" motions to do so, at excruciating length. No, if you've had any exposure to the fill-the-margins-with-green-ink thinkers, you'll recognize Andrulis' problem, and hope that he can get some sort of help for it. Here's a book-length collection of such, very interesting for what it shows you about the ways that human reason can go off the rails.

That's something I've thought about for a long time - in fact, here's an entry on this blog from ten years ago on that very subject. It's interesting to me that there are a limited number of relatively defined mental illnesses; I think that says something about the deeper structures of human consciousness. The Andrulis paper is a flawless example of one of those categories - the wildly intricate, over-systematized Key to the Universe. I've just never seen one in a scientific journal.

Roche is not only a big drug company, it's a big diagnostics company. And that's what's driving their unsolicited bid for Illumina, a gene-sequencing company from San Diego. Illumina has been one of the big players in the "How quickly and cheaply can we sequence a person's entire genome" game, and apparently Roche believes that there's something in it for them.

But as that Reuters link above shows, a lot of other people don't agree, and would rather partner than acquire (Chris Viehbacher, CEO of Sanofi, seems to have been waiting for the opportunity to unburden himself of thoughts to that effect). He may well be right. Sequencing has been a can-you-top-this field for some time, and I don't think that the process is finished yet. What if you buy a technology that's superseded before it has the time to pay off? What if the market for sequencing doesn't get as large, as quickly, as you're hoping? Those were Illumina's worries, and now they're going to be Roche's; you can't buy the promise without buying those, too.

Matthew Herper at Forbes is having very similar thoughts, and points out that Roche has done this sort of thing before. For now, we'll see what Illumina might be able to come up with to avoid being Roched.

You may not have heard much about the arsenic-bacteria controversy recently, but you're about to hear quite a bit more. Rosie Redfield of UBC, one of the fastest and most vocal critics of the original paper, has been trying to reproduce it in her own group. There's a manuscript in preparation, but since she's been blogging on some of the progress, the import is clear: it hasn't been going well for the "bacteria can take up arsenic in their biomolecules" hypothesis. Scrolling back at that link will give you the story.

Here's a summary at Nature News (with a clarification from Redfield on one point). I look forward to seeing how this plays out - but remember, the startling results always have to prove themselves by happening again. Einmal ist keinmal.

Update: there's another story here, too. Redfield has been posting results as they come along, in a very prominent example of "open science". The first question is: will this affect journal publication? That is, will some editors look askance? The second point is to be found in that Nature News article, where Felisa Wolfe-Simon refers to those "website experiments", and how she basically can't discuss them until she sees them in a journal. Note that it's not "the UBC experiments" or "Redfield's experiments" - they're "website experiments", and thus (apparently) have more to prove.

I always regret it when politics creeps into this blog. But I just finished reading this post over at The Economist's "Free Exchange" glog, and I can't resist linking to it. The author focuses on a few lines from the President's State of the Union speech, and gets rather agitated:

Later, the president added: "Don’t let other countries win the race for the future."

The context, innocuously enough, was in calling for greater support for American research and development efforts. But the language of this statement is either daft or ghastly, depending on how charitably one is willing to read it. Is Mr Obama so dense as to miss that when America invents things other countries benefit, and vice versa? If a German discovers a cure for cancer, shouldn't we be ecstatic about that, rather than angry? Indeed, shouldn't we be quite happy and interested in ensuring that Germans and Britons and Indians have the capability and opportunity to develop fantastic new technologies? In the more nefarious reading, Mr Obama seems to accept that only relative standing really matters. A sick, poor world in which America always triumphs is preferable in all cases to one in which America maybe doesn't "win" the race to discover every last little thing that's out there to be discovered. And hell, one has to ask again whether the easiest way to prevent other countries from winning the race for the future isn't simply to blow up their labs.

Look, I understand the forgiving interpretation of these remarks. Americans are motivated by competition and patriotism, and if that's the only way to rally the country behind fundamentally sound policies like subsidies for basic research, then that's the card you play. And, in practice, Mr Obama's reforms will probably not do much more than offset the crummy, mercantilist choices made by other governments elsewhere. . .

I don't see that that's an acceptable excuse. People who live outside of America are people just like Americans, and we should all rejoice in their rising prosperity, the more so when it occurs through additions to the stock of human knowledge that will benefit people everywhere. If an American president can't communicate that simple idea to his citizenry, out of fear that he'll be drummed out of office on a wave of nationalistic outrage, then he doesn't deserve to be president and his country doesn't deserve to win a damned thing. . .

I'm very far from a zero-sum person, myself. The world really has gotten wealthier, and if we have disagreements about how that wealth is distributed, fine - as long as we first realize that we're sharing a much, much, larger pile of it than we used to. Much of that wealth has come from human ingenuity, from science and technology, and on those days when I can get my experiments to work, I like to imagine that I'm adding a bit to the pile.

And yes, I think that this was just speechmaking. But if it reflects, as it might, "permanent tendencies of heart and mind", then I have to say, I don't much like it.

Back to science after this. No more politics until November, I hope, and maybe not even then.

There's a new paper out in Nature Chemistry called "Quantifying the Chemical Beauty of Drugs". The authors are proposing a new "desirability score" for chemical structures in drug discovery, one that's an amalgam of physical and structural scores. To their credit, they didn't decide up front which of these things should be the miost important. Rather, they took eight properties over 770 well-known oral drugs, and set about figuring how much to weight each of them. (This was done, for the info-geeks among the crowd, by calculating the Shannon entropy for each possibility to maximize the information contained in the final model). Interestingly, this approach tended to give zero weight to the number of hydrogen-bond acceptors and to the polar surface area, which suggests that those two measurements are already subsumed in the other factors.

And that's all fine, but what does the result give us? Or, more accurately, what does it give us that we haven't had before? After all, there have been a number of such compound-rating schemes proposed before (and the authors, again to their credit, compare their new proposal with the others head-to-head). But I don't see any great advantage. The Lipinski "Rule of 5" is a pretty simple metric - too simple for many tastes - and what this gives you is a Rule of 5 with both categories smeared out towards each other to give some continuous overlap. (See the figure below, which is taken from the paper). That's certainly more in line with the real world, but in that real world, will people be willing to make decisions based on this method, or not?

The authors go for a bigger splash with the title of the paper, which refers to an experiment they tried. They had chemists across AstraZeneca's organization assess some 17,000 compounds (200 or so for each) with a "Yes/No" answer to "Would you undertake chemistry on this compound if it were a hit?" Only about 30% of the list got a "Yes" vote, and the reasons for rejecting the others were mostly "Too complex", followed closely by "Too simple". (That last one really makes me wonder - doesn't AZ have a big fragment-based drug design effort?) Note also that this sort of experiment has been done before.

Applying their model, the mean score for the "Yes" compounds was 0.67 (s.d.0.16), and the mean score for the "No" compounds was 0.49 (s.d. 0.23, which they say was statistically significant, although that must have been a close call. Overall, I wouldn't say that this test has an especially strong correlation with medicinal chemists' ideas of structural attractiveness, but then, I'm not so sure of the usefulness of those ideas to start with. I think that the two ends of the scale are hard to argue with, but there's a great mass of compounds in the middle that people decide that they like or don't like, without being able to back up those statements with much data. (I'm as guilty as anyone here).

The last part of the paper tries to extend the model from hit compounds to the targets that they bind to - a druggability assessment. The authors looked through the ChEMBL database, and ranked the various target by the scores of the ligands that are associated with them. They found that their mean ligand score for all the targets in there is 0.478. For the targets of approved drugs, it's 0.492, and for the orally active ones it's 0.539 - so there seems to be a trend, although if those differences reached statistical significance, it isn't stated in the paper.

So overall, I find nothing really wrong with this paper, but nothing spectacularly right with it, either. I'd be interested in hearing other calls on it as it gets out into the community. . .

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!

As a follow-up to that post on open offices (and the others referenced in it), I've had a letter from a reader who wonders the following:

(1) How many recent research buildings have been built with open offices, as opposed to cubicles or actual office space? Is this the wave-of-the-future, or is it just a few high-profile examples getting attention?

(2) Does anyone know of any examples where a research department has tried an open-office plan and moved back from it after the experience?

Just to clarify, I don't mean large, relatively open lab spaces (those are pretty common, and often seem to work just fine). What's in question are the wide-open no-walls office and desk areas, with the extreme being the ones where no one has any actual assigned space at all. Thoughts?

Things are running around here again, after some problems with the comment system. Unfortunately, it looks like everything from about Monday mid-day disappeared into the Great Bit Bucket. That's unfortunate, since I know that there must have been some good stories in that "Weirdest Presentation" post - if anyone has the energy to add them again, there would be an audience for them!

I've noticed that comments to today's posts seem to have stopped appearing sometime around noon EST. Rooting around under the hood is ongoing; I'll let everyone know what the outcome is. With any luck, things can be rescued!

Since the topic of open offices in lab design has come up around here several times, I thought I'd point out this op-ed from the New York Times. It's from the author of a new book, Quiet: The Power of Introverts in a World That Can't Stop Talking, and you can guess her point from that title:

SOLITUDE is out of fashion. Our companies, our schools and our culture are in thrall to an idea I call the New Groupthink, which holds that creativity and achievement come from an oddly gregarious place. Most of us now work in teams, in offices without walls, for managers who prize people skills above all. Lone geniuses are out. Collaboration is in.

But there’s a problem with this view. Research strongly suggests that people are more creative when they enjoy privacy and freedom from interruption. And the most spectacularly creative people in many fields are often introverted, according to studies by the psychologists Mihaly Csikszentmihalyi and Gregory Feist. They’re extroverted enough to exchange and advance ideas, but see themselves as independent and individualistic. They’re not joiners by nature.

Well, I wish that I could describe myself as "spectacularly creative", but the rest of that last sentence sounds pretty much like me, anyway. I have no problem talking with people when I meet them. I speak up at meetings, and I really enjoy giving talks to audiences. At the same time. I find that my best thinking is done very much alone. Once I've got something worked out in my head, I'm fine with roaming up and down the halls telling people about it and hearing the reaction. But that working-out has to be done in silence. The phone rings, and my thoughts all take off like like a flock of pigeons. Getting to settle back into their assigned places is not the work of a moment.

For all I know, the new book addresses this problem, but we really need a wider spectrum of words other than "introvert" and "extrovert". There are people who absolutely need human company, human noises and chatter around them. Others would rather have a bit of that, but feel it can be overdone, or just need it in defined amounts, like a meal. And some people don't mind much one way or another, while others are irritated or even panicked by it. You can sort people out, in similar fashion, by their responses to solitude and silence. Given that any research organization is going to have a variety of types in it, you'd think that there would need to be some places where the quiet types could hang out, just as there should be some where the gregarious ones can find what they need.

Friday's mention of the Brindley lecture prompts me to throw this question out: what's the most weirdly memorable scientific presentation you've ever seen?

I'll put one out there that still sticks in my mind. Back in 1998, I was attending the Gordon Conference on Heterocycles. One of the speakers was a young faculty member from Montana, who was supposed to be speaking on metal-catalyzed reactions of indoles. Instead, he came in with a completely different slide deck on origins-of-life chemistry, which made it clear, rather quickly, that he not only did not buy into the "RNA world" hypothesis, but considered it (and much other origins-of-life work) to be the next thing to a conspiracy.

The audience took this in with some visible discomfort, as the talk itself became more passionate and agitated. The whole topic was something that clearly upset and offended the speaker, but I can't say that he made many converts. There were a couple of questions from the floor at the end, but I think that many people were just hoping to get this one over with and move on. The speaker himself moved on shortly to a small Adventist school, in a department that says that it hopes to provide a "scriptural perspective" on scientific issues, but he doesn't seem to be listed on the faculty there now, and I've been unable to trace him after that. . .

Depends on your perspective! Since it's Friday, I present this memoir of the infamous Brindley lecture from 1983. G.S. Brindley appears to have been a pioneer in urology, and in fact discovered the first useful therapies for erectile dysfunction.

But the way he chose to announce these discoveries to the world was. . .well, read the article. Let's just say that he was intent on leaving no doubts, and that no doubts were left.

The news is that Alnylam, the RNAi company just down the street from where I'm writing, is cutting about a third of its workforce to try to get its best prospects through the clinic. This is a familiar story in the small-pharma world; there's often money to try to get things through the clinic, or to pay everyone in the earlier-stage R&D - but nowhere near enough money to do both. There are companies that have gone through this stage several times, sometimes rehiring the same people when the money began flowing again.

You could see this coming, what with the news in that research space over the last couple of years. It's going to be a race to see if Alnylam can get something that will bring the income before time and resources get too tight. I wish them luck - I think there's really something there in their pipeline, but is it going to be enough, and will it be ready soon enough?

You may well recall the excitement around the late-stage clinical data for Zelboraf (vermurafenib, PLX4032) in metastatic melanoma. The drug was approved late last summer, but (like all the other therapeutic options in oncology), it has its issues.

One of those appears to be speeding up the course of squamous cell carcinoma. (Here's the NEJM article and the accompanying editorial). A significant number of patients on Zelboraf have turned up with this other form of skin cancer. To be sure, they surely had these cancerous cells beforehand (which tend to feature RAS mutations), but the effects of the drug on the MAP-kinase pathway seem to kick up their activity. (The same effect is seen on melanoma cells that don't have the V600E mutation - if you give Zelboraf without genotyping the patient first, you risk making things much worse). One obvious fix would be to give a combination, something to target those squamous cells, and thus the idea of co-administering an MEK inhibitor. Squamous cell carcinomas can be removed, and are nowhere near as bad as melanoma (particularly metastatic melanoma), but this is still a problem.

A bigger problem is that (as mentioned in my older post on this drug) resistant melanoma crops up pretty quickly after initial treatment with Zelboraf. Virtually all of the people taking the drug will eventually die of metastatic melanoma; it's just going to take longer. But how much longer, we don't know. The numbers still aren't quite in on overall survival - it's going to be more than the previous standard of care, but it's probably not going to be overwhelmingly more. Of course, the definition of "more" and the value that an individual patient places on it (or an insurance company places on it), well, those are the very things that keep us arguing about health care. Maybe that MEK co-therapy will make it an easier call?

To no one's surprise, the FDA has rejected dapagliflozin, an SGLT2 inhibitor for diabetes. The advisory panel voted it down back during the summer, and the agency has asked AstraZeneca and Bristol-Myers Squibb to provide more safety data. As it stands, the increased risk of bladder and breast cancer (small but significant) that was seen in the clinic just outweighs the drug's benefits.

That's the sodium-glucose cotransporter 2, and what it does normally is reabsorb glucose in the kidney to keep it from going on into the urine and being lost. It's been the subject of quite a bit of drug development over the last few years, with the thought being that spilling glucose out of the bloodstream, as an adjunct to other diabetes therapy, might be more of a feature than a bug.

Not with that safety profile, though. And since this compound has been through nearly a dozen different advanced trials in the clinic, I really don't see how anyone's going to be able to provide any safety data at this point to change anyone's mind about it. Type II diabetes is an area with a lot of treatment options, and while all of them have their advantages and disadvantages, taken together, there's quite a bit than can be done. So if you're going to enter a crowded field like this, a new mechanism is a good idea (thus SGLT2). But you're also up against a lot of things that have proven themselves in the real world, some of them for a long time now, so your safety profile has to be above reproach.

Canagliflozin, from J&J, is still out there in the clinic, and you can bet that the folks there will be digging through the data from every direction. Are dapagliflozin's problems mechanism-related, or not? Would you care to spend nine figures to find out? That's how we do it around here. . .

2,800 over the next four years. More of them are in Europe than in the US (via the Nycomed acquisition), but there are hundreds of positions to be lost in this country, too. For now, the company seems to be just saying that they'll be in all parts of the organization, without much in the way of details. Those will, in time, become all too apparent.

Add that to last week's Novartis announcement (about 2,000 jobs, mostly in sales and marketing), and we're not off to a great 2012 on this front, are we?

I noted that the Nature Publishing Group has come out against the proposed Research Works Act, which would roll back the requirement that research funded by the US government be made freely available after (at most) one year. They are, I believe, the largest and most prominent journal publisher to take such a stand (although I'll be glad to be wrong about that):

NPG and Digital Science do not support the Research Works Act.

NPG and Digital Science exist to support the creation and dissemination of human knowledge on a sustainable commercial basis. We seek to enable the open exchange of ideas, especially in scientific communities, in line with the requirements and objectives of relevant stakeholders.

Update: from the comments, the AAAS (publishers of Science) have also come out against the RWA, saying that they're fine with the current system, and that their membership in the AAP does not mean that the organization speaks for them on this issue. How about the American Chemical Society? As far as I can tell, the ACS has made no statement, and silence speaks loudly.

Meanwhile, Rich Apodaca at Depth-First surprised me with this post coming out in favor of the RWA. But read the whole thing. He is, as the Marxists used to say, interested in "heightening the contradictions", and sees the scientific publishing industry bringing down the roof on its head even faster if the act passes. And the sooner that happens, he says, the sooner we can get rid of an outmoded system:

Any scientist who has been an active participant in scientific publication as an author, reviewer, and consumer recognizes that the only remaining value added by scientific publishers today is imprimatur. Imprimatur is the implied endorsement received by authors who publish in certain scientific journals, particularly in those that earned a high level of prestige during the pre-digital period of publication scarcity.

Ironically, imprimatur remains so valuable in science that it has kept numerous publishers afloat despite wave upon wave digital destruction being visited on sister industries such as book publication and newspapers.

But imprimatur can lose its luster, particularly in an environment in which fewer and fewer scientist can actually read the publications appearing in ‘high-impact’ journals. Prestige counts for nothing in science if your peers can’t read your papers. Nevertheless, that’s where scientific publication is heading.

I'm not sure which way is faster, myself. But we agree that the current scientific publishing model is being eroded, and that this is an opportunity, not a disaster that has to be repaired with legislation.

Now here is an amazingly stupid move: a medicinal chemist at Sanofi (Yuan Li) downloaded a large set of proprietary compounds from the company's files, and founded another company on the side to sell them.

Strangely enough, someone at Sanofi noticed that their in-house compounds were appearing for sale at Abby Pharmtech, of Newark, Delaware. (Better take a look at that web site while you can). It is supposedly the US subsidiary of Xiamon KAK, of Xiamen, China. According to this criminal complaint (thanks to Pharmalot for the link), Sanofi found (in May and June of last year) 6,000 of their internal compounds showing up on SciFinder as available from Abby. A search of Li's computer at Sanofi showed all sorts of useful stuff - a listing of 144,000 compounds in a file called "Abby Pharmtech" (complete with internal Sanofi registration codes), tax forms showing her as a partner and co-founder of Abby (confirmed by IRS records), and so on.

The penalty? There's been a plea agreement (again, thanks Pharmalot), and sentencing is scheduled for April 23. There's a maximum potential prison term of 10 years, and a maximum fine of at least $250,000 - all that is up to the judge. This is in addition to restitution to Sanofi ($131,000) and a very high likelihood of immigration proceedings. It is safe to say that this master plan has not worked out too well.

What, just what, was this person thinking? How lucrative could this idea have possibly been, compared to the risks? And how could they have imagined that this would fly at all - that no one at Sanofi would ever notice that stuff from their own files and lab notebooks was now for sale? You just never know what people can get up to.

If you've been looking around the literature over the last couple of years, you'll have seen an awful lot of excitement about epigenetic mechanisms. (Here's a whole book on that very subject, for the hard core). Just do a Google search with "epigenetic" and "drug discovery" in it, any combination you like, and then stand back. Articles, reviews, conferences, vendors, journals, startups - it's all there.

Epigenetics refers to the various paths - and there are a bunch of them - to modify gene expression downstream of just the plain ol' DNA sequence. A lot of these are, as you'd imagine, involved in the way that the DNA itself is wound (and unwound) for expression. So you see enzymes that add and remove various switches to the outside of various histone proteins. You have histone acyltransferases (HATs) and histone deacetylases (HDACs), methyltransferases and demethylases, and so on. Then there are bromodomains (the binding sites for those acetylated histones) and several other mechanisms, all of which add up to plenty o' drug targets.

Or do they? There are HDAC compounds out there in oncology, to be sure, and oncology is where a lot of these other mechanisms are being looked at most intensively. You've got a good chance of finding aberrant protein expression levels in cancer cells, you have a lot of unmet medical need, a lot of potential different patient populations, and a greater tolerance for side effects. All of that argues for cancer as a proving ground, although it's certainly not the last word. But in any therapeutic area, people are going to have to wrestle with a lot of other issues.

Just looking over the literature can make you both enthusiastic and wary. There's an awful lot of regulatory machinery in this area, and it's for sure that it isn't there for jollies. (You'd imagine that selection pressure would operate pretty ruthlessly at the level of gene expression). And there are, of course, an awful lot of different genes whose expression has to be regulated, at different levels, in different cell types, at different phases of their development, and in response to different environmental signals. We don't understand a whole heck of a lot of the details.

So I think that there will be epigenetic drugs coming out of this burst of effort, but I don't think that they're going to exactly be the most rationally designed things we've ever seen. That's fine - we'll take drug candidates where we can get them. But as for when we're actually going to understand all these gene regulation pathways, well. . .

There are small drug firms and there are small drug firms - if you know what I mean. Which category is Warp Drive Bio going to fall into?

If you've never heard of them - and that name is rather memorable - then don't worry, they're new. Its founders are big names on the industry/academic drug discovery border: Greg Verdine, Jim Wells, and George Church. Here's the rundown:

Warp Drive Bio is driving the reemergence of natural products in the era of genomics to create breakthrough treatments that make an important difference in the lives of patients. Built upon the belief that nature is the world's most powerful medicinal chemist, Warp Drive Bio is deploying a battery of state-of-the-art technologies to access powerful drugs that are now hidden within microbes. Key to the Warp Drive Bio approach is the company's proprietary "genomic search engine" and customized search queries that enable hidden natural products to be revealed on the basis of their distinctive genomic signature.

Interestingly, they launched with a deal with Sanofi already in place. I've been hearing about cryptic natural products for a while, and while I haven't seen anything that's knocked me over, it's not prima facie a crazy idea. But it is going to be a tricky one to get to work, I'd think. After all, if these natural products were so active and useful, might they not have a bit higher profile, genomically and metabolically? I'm willing to be convinced otherwise by some data; perhaps we'll see some as the Sanofi collaboration goes on. Anyone with more knowledge in this area, please add it in the comments - maybe we can all learn something.

One other question: with Verdine founding another high-profile company, does this say something about how his last one, Aileron, is doing in the "stapled peptide" business? Or not?

Looks like the former Merck site in Newhouse is beginning to get some tenants as part of "Biocity Scotland". I wish everyone involved good luck - we need more smaller firms, because that's the only way to get larger firms. Isn't it?

Back in December, a short bill was introduced in the House called the "Research Works Act". Its backers, Darrell Issa (R-CA) and Carolyn Maloney (D-NY), describe it as something that will maintain the US's standing in scientific publishing. After looking over its language and reading a number of commentaries on it, I have to disagree: this looks to me like shameless rent-seeking by the commercial scientific publishers.

And it pains me to say that, because I know several people in that business. But it's a business whose long-term model has problems. (See the Addendum below if you're not in the field and want a brief summary of how scientific publishing works). The problem is, the work of the editorial staff has changed a good deal over the years. Back when everyone sent in hard copies of papers, in who knows what sort of format, there was a good deal of work to do just turning the good ones into a consistent journal. Electronic submission has ironed a lot of the grunt work out - it's still work, but it's not what it used to be.

That leaves the higher editorial functions themselves, and here's where the arguing starts. Most, and in some cases all editing of content is done by unpaid peer reviewers. There are journals whose editors exist mainly to keep the flow of submissions moving to the reviewers, and from them back into the official journal, while hardly ever laying a finger on the copy itself. They function as Peer Review Mailroom Managers. And while that's a necessary job, it's the center of the argument about scientific publishing today. How much, exactly, is it worth?

Scientific journal are expensive. I mean, really, really expensive to subscribe to. And if you're not a subscriber, access to individual papers is pretty steep, too - typically in the $15 to $50 range. This is the business model for commercial scientific publishing: create a space with value (reputation, name recognition) and charge the maximum that that traffic will bear. And that's fine; there are a lot of businesses that work the same way - if they can.

The problem is, the information-sharing capabilities of the Internet blow a large hole in some of the traditional publishing model. And another problem is that a large number of papers that come into the journals from US academic researchers have had some (or all) of that work paid for by government grants (NIH, NSF, DOE and so on). As it stands, articles funded by the NIH are available in PubMed Central for free access, no later (by law) than 12 months from the initial journal publication. Researchers can also submit their work to "open access" journals (such as those from the Public Library of Science), which charge a fee to authors to defray editorial costs, but then allow immediate unlimited access to all comers once a paper is accepted. (I should note that some commercial journals get away with "page charges" as well, and some have a model where the authors can pay extra to bring their paper out from behind the paywall).

And here's where we have the Research Works Act. It would forbid any publication in an open access journal for anything funded in academia by US government grants, and it would forbid any public-access repository for such work. That's its purpose. Well, to be more accurate, its purpose, as described by the head of the Association of American Publishers, is that it "ensures the sustainability of the industry". Yep, make my business model part of statutory law, and beggar my competition: what else is a government for, anyway?

Update: see the comments section. I'm interpreting the text of the law to mean the above, but another way to read it - probably the correct one - is that it's mainly rolling back the 2008 law that mandates that NIH-funded papers go open-access after a year. But that's bad enough as it stands.

To their credit, the MIT Press looks like the first big academic publisher to defect from this position. But the commercial publishers (Elsevier, Wiley, and so on) will never give up on this goal. Yes, the RWA, according to them, is aimed at "preventing regulatory interference with private-sector research publishers". Here's Congresswoman Maloney using Elsevier's own press release language, sentence by sentence, as detailed by Michael Eisen, co-founder of PLoS. (He also has an op-ed in the New York Times on this issue).

I see no reason why we should make the current scientific publishing system a matter of law. I think it should change - and be allowed to change - as new technology allows it to. And I think that the Research Works Act is nothing more a blatant attempt to hold on to a profitable business plan.

Addendum: For those outside the scientific world, here's a brief summary of how things have traditionally worked. As a scientist (academic or industrial), you take the time and effort to write up your results for a journal. You have to pick your journal at the start of the process, since each of them have their own ways of organizing a paper, their own preferred way of citing other papers as references, and so on. Anyone can send anything to any journal they feel like, although you'd be well advised to target your paper to the ones that (a) have the best chance to actually accept it and (b) will do you good to have a paper published in. The overlap between those two may not be large, or may not exist at all, depending on your paper. These days, most journals have templates for Word or the like, which standardizes the submissions, and have some sort of automatic PDF generation during the submission step step so you can see how the paper will look when formatted in the journal's style and page layout.

Now at this point, traditionally, the work of assembling the accepted papers into a printed journal kicks in on the editorial side. And it still does, but that process is becoming less and less important. I honestly can't tell you when I last saw a hard copy of any of the journals I read regularly. Even the idea of separate issues is becoming antiquated, since new papers (in the case of many journals) just plop out onto the web site (and into the RSS feeds) as they emerge from the review process.

I'm getting all the press releases from Bill Sardi, of Resveratrol Partners, as he does damage control from the Das scandal at UConn. And I have to say, he's putting in the hours getting these together. Problem is, on some key points, he doesn't know what his biggest problems are.

The latest one is titled "World Without Resveratrol: Researcher Falsely Accused", and claims that this may all be a plan to "send a message" to any academic who collaborates with the makers of resveratrol pills. The release goes on about how these are old accusations, which Das has refuted since then, and asks why these ancient concerns are coming up now, eh? The phrase "orchestrated hit job" is used. But that glosses over the times of the whole investigation, which has been a very detailed and involved one, and glosses over the amount of due process involved as well. There are a lot of problems with the publications from the Das lab, as detailed in the report that I linked to the other day, and tying them together has involved a lot of work.

But here comes my favorite part of the latest Sardi release:

". . .I asked Dr. Das directly, did he altered (sic) western blot images, or directed others in his lab to do so. While his initial answer was no, meaning he had not fabricated or altered any scientific finding, altering western blot images are a common practice in laboratories for reasons other than deception. The university chose to present their findings in a derogatory manner. Dr. Das explains that editors at scientific publications commonly request researchers enhance faded images of western blot tests so they can be duplicated in their publications. Western blot tests are frequently altered to remove backgrounds, enhance contrast and increase dots-per-inch resolution so they are suitable for publication. This had been fully explained to university officials long before. . .

No, no, no. The problems with the Das papers have nothing to do with enhancing the contrast on Western blots. They have to do with cutting and pasting sections of them, rearranging them, reusing them, and creating them out of pieces of other experiments. Look at that report. These people appear to have spent a ridiculous amount of time assembling "Western blots" out of miscellaneous digitized chunks. The resulting figures purport, in many cases, to represent particular experiments, but they do no such thing. They represent a bunch of previous bands from other experiments entirely, sliced and diced in a way that would seem to have no other possible motive than to deceive. Come on.

Oh, but there's more. Here, according to the press release, is how a cutting-edge academic lab works these days:

"As I drilled Dr. Das’ former students with questions, I found that lead researchers like Dr. Das do not do any lab bench experiments. Students do all the work and submit their results to him via e-mail or by directly downloading data into his computer. Dr. Das says when he is not traveling his office is open and students can enter and download data directly onto his computer. I had previously visited Dr. Das at the University of Connecticut and noticed his office door was left open and anyone could have access to his computer.

One former student told me that typically lead researchers like Dr. Das write the introduction and conclusion of experiments and the students enter all the data, before publication in scientific journals. Dr. Das, who is busy lecturing all over the globe because of his groundbreaking studies, does not directly oversee tests that are performed, and neither do most other lead researchers. The University of Connecticut report says the university holds Dr. Das responsible for all of the data. Probably most lead researchers in scientific laboratories around the globe are vulnerable to errors or even fabrication of data by their students."

Where to start? What the heck is this "download data directly into his computer" stuff? And what about all the doctored files found on other machines in the group? And yes, while lead authors are indeed vulnerable to errors and fabrication, this sort of thing typically does not involved years of work spread out across dozens of papers in multiple journals. Even the busiest and most distracted principal investigator might be expected to take the time to notice, eventually, that his group's work is a tower of fraud. And yes, the University should hold Dr. Das responsible for the data in his papers. His name is on the grants, his name is on the office door, he's the one with a high-paying tenured position while the students are cranking away under low salaries and stipends, and it's his name with an asterisk next to it on all those papers, as the contact person for any questions about them. Damn right he's responsible. He's responsible for making sure that anything going out into the literature with his name on it is something that he can stand behind.

Ah, but not to worry. It's all being taken care of:

"Dr. Das says many editors at scientific journals don’t believe the University of Connecticut report. They full-well know that editing of western blot tests is common practice and that the tests in question in no way invalidate his work and were only one part of the evidence provided in his papers from which Dr. Das drew conclusions. This is the case of scientific fraud that wasn’t."

That would explain why Dr. Das has been pulled from the co-editor job he had at one of those journals. They must believe him. And that would also shore up all those allegations of prejudice against East Indian researchers, since the editor of that journal is. . .well, he's Indian too, but you know what I mean. (Personally, if I were from India myself, I'd be furious at Das for helping to drag the reputation of my country's scientists through the mudhole, but maybe that's just me.)

No, I hope these press releases keep on coming. So far, we have lots of elaborate reasons why Dr. Das had nothing to do with all these fabricated Western blots, but who cares, right, since they're only a tiny part of his papers, which are great and important work even though he really doesn't write them anyway, and no, he has almost no connection with Longevinex and Resveratrol Partners, which is why the head of the company is spending all this time defending him in this case of minor stuff he never did, all 600 pages of summary and 60,000 pages of investigation material, and that explains why the journals that believe him are ditching him from their mastheads and publishing retractions of those great papers. Because it's all a conspiracy. Yeah. That's it.

You don't want coverage like this: "Biogen CEO Tries to Refill Early-Stage Pipeline He Decimated". That would be George Scanos:

. . .Scangos and his research chief eliminated about 17 early-stage drug projects in 2010 and last year to hone the company's focus, leaving it with only about four early-stage compounds. Biogen exited oncology and cardiovascular research and is now targeting drugs to treat neurological and autoimmune conditions. . .

"We didn't want to fund projects that were unlikely to generate value," Scangos said in an interview on the sidelines of the J.P. Morgan health-care conference in San Francisco this week. . .But even if Biogen's late-stage pipeline delivers successful new drugs soon, the company needs more compounds in early-stage testing to sustain long-term growth. So it is licensing drugs from other companies. . .

The article itself (from Peter Loftus, originally in the Wall Street Journal isn't quite as harsh as the headline. As as that excerpt shows, part of the problem is that Scanos thought that the company was in some therapeutic areas that they shouldn't have been in at all, so that pipeline he's refilling isn't exactly the same one he cleared out. (And a note to the WSJ headline writers: "decimated" isn't a synonym for "got rid of a lot", although that horse, I fear, left the barn a long time ago. The mental image of decimating a pipeline isn't the sharpest vision ever conjured up by a headline, either, but I understand that these things are done on deadline.)

No, if I had to pick the biggest expensive reversal done under Biogen's new management, I'd pick the construction site a few blocks from here where they're putting up the company's new Cambridge headquarters. Those are the offices that used to be in. . .well, Cambridge, until former CEO Jim Mullen moved them out to Weston just a couple of years ago. I don't know how long it's going to take them to finish those buildings (right now, they're just past the bare-ground stage), but maybe eventually they can all work there for a few months before someone else decides to move them to Northhampton, Nashua, or Novosibirsk.

So, we've been talking here since yesterday about what looks like large-scale fraud, but there's small-scale stuff that goes on inside various labs (often in academia, which is where people like this are supposed to wash out). Many readers will have encountered, in their grad school days, the person whose reactions won't quite reproduce, who comes in while you're not around and "borrows" your reagents, and who can't quite locate that key procedure when it's time to look at it closely. (And yes, I've had dealings with members of this tribe before, and they're no fun at all).

Here's a reminiscence from a professor at Nebraska of how he dealt with someone like this, and his technique may be something that others have tried (or been tempted to). It worked, though. This is the flip side of the laboratory sabotage discussed here and here, used for good instead of for evil. Are such methods justified? Used carefully, and in extreme cases, I'd say yes. Thoughts?

My inbox has exploded with the story that many reports on the effects of resveratrol appear to be fraudulent. Prof. Dipak Das of Connecticut is at the center of what looks like a huge research stink bomb, which is being well covered by Retraction Watch (here and here), among others. The Chronicle of Higher Education has a lot of good info as well.

Here's what's known so far: UConn has a press release saying that Das has been under investigation for the last three years, and that the university (along with the Office of Research Integrity) has uncovered substantial evidence of fraud and misconduct.

An extensive research misconduct investigation has led the University of Connecticut Health Center to send letters of notification to 11 scientific journals that had published studies conducted by a member of its faculty. Dipak K. Das, Ph.D., a professor in the Department of Surgery and director of the Cardiovascular Research Center, was at the center of a far reaching, three-year investigation process that examined more than seven years of activity in Das’ lab. . .

. . .The investigation was sparked by an anonymous allegation of research irregularities in 2008. The comprehensive report, which totals approximately 60,000 pages, concludes that Das is guilty of 145 counts of fabrication and falsification of data. Inquiries are currently underway involving former members of Das’ lab; no findings have been issued to date.

Here are the details, in a long PDF, if you want them. What that report shows are a lot of manipulated Western blots, with obvious copy-and-paste artifacts. Well, they're obvious once you're alerted to them, at any rate - the first thing you think of when you see a gel isn't "Hmmm. . .I wonder if that's been Photoshopped?" At any rate, examination of presentation slides on various hard drives also showed Westerns with various regions - in some cases, every single damn band on the whole thing - which had been moved around with the "Group" and "Ungroup" tools, starting from separate unrelated files. And they've even tracked down the original images which formed the basis for the figures in so many other papers, once they'd been sliced and diced. Classy stuff. Dr. Das, for his part, told the investigators that he had no idea who had prepared any of these figures, a position that (since he's the lead flippin' author on them), strains belief. "Dr. Das has been of no help in this matter", states the report, and I'd say that still overstates his contributions.

UConn has notified the editors of 11 journals where Das and his group had published suspect results - and on three of these journals, according to Retraction Watch, he had editorial or advisory responsibilities. Looking over the list, it's not exactly the most high-profile publication record that you could imagine. Das's papers do seem to have picked up a number of citations, in many cases, but I don't really get the sense that he was driving the field. (That Chronicle link above quotes David Sinclair, of sirtuin fame, as saying that he'd never even heard of Das at all, and for what it's worth, I hadn't either).

Meanwhile, Retraction Watch has received a press release from Das' lawyer, and it looks like he's not going down without firing all his ammo. To wit, Das claims that:

. . .the charges against him involve prejudice within the university against Indian researchers. Six other East Indian researchers were also named as “potential respondents” to charges of scientific fraud, but no researchers of other ethnicities. . .

. . .Another party, a university internal investigator whom Dr. Das accuses of long-standing prejudice against foreign-born researchers, reportedly broke the lock on Dr. Das’ office door, removed computer files and personal items such as bank records and a passport, and could have manipulated data in his computer files. Dr. Das says this university investigator has had a long-standing vendetta against him going back to 1984. . .

There's a lot more in the same vein (and great big steaming heaps of it in Das' official response to the investigation) and it all points to a long, ugly process. The lawyers involved will have plenty to keep themselves occupied.

There's one last big issue: Das appears to have had a business relationship with Longevinex, a well-known supplier of resveratrol supplements. I note that Bill Sardi, the managing partner of the firm that runs Longevinex, has showed up on this site in the comments section before, as have many fans of the product itself. (I know that David Sinclair has heard of those guys, because they were throwing around his name for a while, which seems to have led to talk of possible legal action). And it's worth noting as well that Dr. Das had published work suggesting that Longevinex was superior to garden-variety resveratrol. That paper (and that journal) does not appear to be one of the ones named specifically in the fraud investigation. But one of the authors on it (other than Das) figures prominently in the UConn report. Who feels inclined to trust it?

Now for the last big issue: what does this do to the whole resveratrol/sirtuin field? Not as much as you might think. As mentioned above, Das really doesn't seem to have been that big a figure in it, despite cranking out the publications, and a lot of interesting (although often confusing) work has come from a variety of other labs. The people who did this study in humans, for example, are (to the best of my knowledge) above reproach. But (as that post shows in its various links), there's a lot of conflicting data about resveratrol in animal models. The whole topic is deeply confusing. But this UConn/Das business does not help clear anything up, not at all - it's a big bucket of mud and slop dumped into the tank, which is just what we didn't need.

And as for sirtuins, well, I don't think anyone would disagree with the statement I made here, that resveratrol has so many off-target effects that it's completely unsuitable as a tool to understand sirtuin biology, which is quite difficult enough to understand already, thanks very much. Sirtuins have their own wild complications and (seeming) contradictions, separate from resveratrol - this latest scandal is off to the side of that topic completely, or should be.

But I don't mean to minimize Das' apparent misconduct here, not at all. He's not at the center of his field, but he looks to be at or near the center of something very dishonorable, very dishonest, and very wrong.