If you're interested, here's the FDA's draft of their guidance on biosimilars, up on their site today. This is a slow-moving story that's going to end up having a big effect on the industry. Look at the number of top-selling drugs that are biologics, look at how long they're lasting on the market (patent protection or not), and you wonder how much competition will emerge, how successful it'll be, and how tricky it will be to approve things. If I were a real-time journalist, I'd mark this "Developing", but while that's true, in this case it means "Developing. . .over the next ten years".

I'd like to take a few minutes to remember someone that everyone in R&D should spare a thought for: Roger Boisjoly, If you don't know the name, you'll still likely know something about his story: he was one of the Morton Thiokol engineers who tried, unsuccessfully, to stop the Challenger space shuttle launch in 1986.

Here's more on him from NPR (and from one of their reporters who helped break the inside story of that launch at the time). Boisjoly had realized that cold weather was degrading the O-ring seals on the solid rocket boosters, and as he told NPR, when he blew the whistle:

"We all knew if the seals failed the shuttle would blow up."

Armed with the data that described that possibility, Boisjoly and his colleagues argued persistently and vigorously for hours. At first, Thiokol managers agreed with them and formally recommended a launch delay. But NASA officials on a conference call challenged that recommendation.

"I am appalled," said NASA's George Hardy, according to Boisjoly and our other source in the room. "I am appalled by your recommendation."

Another shuttle program manager, Lawrence Mulloy, didn't hide his disdain. "My God, Thiokol," he said. "When do you want me to launch — next April?"

When NASA overruled the Thiokol engineers, it was with a quote that no one who works with data, on the front lines of a project, should ever forget: "Take off your engineer hat," they told Boisjoly and the others, "and put your management hat on". Well, the people behind that recommendation managed their way to seven deaths and a spectacular setback for the US space program. As Richard Feynman said in his famous Appendix F to the Rogers Commission report, "For a successful technology, reality must take precedence over public relations, for nature cannot be fooled".

Not even with our latest management techniques can nature be fooled, no matter how much six-sigma, 4S, and what-have-you gets deployed. Nothing else works, either. Nature does not care where you went to school, what it says on your business cards, how glossy your presentation is, or how expensive your shirt. That's one of the things I like most about it, and I think that any scientist should know what I'm talking about when I say that. The real world is the real world, and the data are the data.

But it's up to us to draw the conclusions from those numbers, and to get those conclusions across to everyone else. It may well be true, as Ed Tufte has maintained, that one of the tragedies of the Challenger launch was that the engineers involved weren't able to do a clear enough presentation of their conclusions. Update: see this account by Boisjoly himself on this point. It might not have been enough in the end; there seem to have been some people who were determined to launch the shuttle and determined to not hear anything that would interfere with that goal. We shouldn't forget this aspect of the story, though - it's incumbent on us to get our conclusions across as well as we can.

Well, then, what about Nature not caring about how slick our slide presentations are? That, to me, is the difference between "slick" and "effective". The former tries to gloss over things; the latter gets them across. If the effort you're putting into your presentation goes into keeping certain questions from being asked, then it's veered over to the slick side of the path. To get all Aristolelian about it, the means of persuasion should be heavy on the logos, the argument itself, and you should do the best job you can on that. Steer clear of the pathos, the appeal to the emotions, and you should already be in a position to have the ethos (the trustworthiness of the speaker's character) working for you, without having to make it a key part of your case.

But today, spend a moment to remember Roger Boisjoly, and everyone who's ever been in his position. And look out, be very careful indeed, if anyone ever asks you to put your management hat on.

Here's a helpful translation, and there's more truth in it than there should be. My rule of thumb is to be extremely suspicious of a methods paper that doesn't have at least a couple of low-yielding or "NR" entries. If they aren't there, it means that someone didn't do enough experiments (or, worse, that they're not telling you about those little details).

Announcing layoffs along with a stock buyback - let's think about what that means. AstraZeneca did that just the other day, and they're far from the only ones in this industry (or others) spending billions to buy back their own shares while they're cutting costs elsewhere.

We already know what the companies have to say about what it means. All you have to do is say "shareholder value" and you're most of the way there. Mix in "continued commitment" and "cost containment", fit 'em all together with a verb or two, and you've got yourself an instant press release. And we also know what the investment community thinks: they like it. Go back over the news stories that have come out when a buyback is announced, and all the quotes will be about how large the amount is, whether it's in line with what people were expecting, or if it's one of those good moments when the company is spending even more to buy back its shares. No one would be so foolish as to announce a truly inadequate-looking stock repurchase.

That's a key point. As far as I can tell, share buybacks have two purposes. There's the obvioius one of trying to provide some steady buying activity in the stock and (in theory) a floor for its price, while retiring shares to decrease the float (and increase earnings-per-share). But the other reason is signaling. "We think our stock's worth buying at this price", the company is saying, "and so should you. We care enough about our existing shareholders to spend money tending the share price for them. Please don't sell us, or downgrade us. We'll buy back even more - promise!"

Signaling is, I think, the greater of those two. There's a lot of room to question the actual financial effectiveness of stock buybacks. As one person in that link notes, if you want to reward current shareholders with cash, you should pay them a dividend. Trying to keep your stock price up (even if the plan were to work) only really rewards the people who sell your stock and realize the gains. (See below for who some of those people are, though).

That signaling had better be worth something. It goes without saying, or should, that the money being used to buy back shares could also be put back into a company's actual business. That's another signal, one that makes me grit my teeth. To me, a stock buyback has always said "We're willing to tell the world that we think that buying our own shares will provide a better return than investing in what we're supposed to be doing for a living." And why would you tell the world something like that? Isn't that also saying "We can't think of much else to do with this cash, what with our business in the shape it's in, and parking it in an investment fund would be sort of embarrassing, So we might as well use it to bribe the Street. God knows it's the only language they understand."

There are other people willing to put it in just those terms. That "Marketplace" link above features a quote from William Lazonick of UMass-Lowell (note: affiliation fixed after original post), who's not keeping his views bottled up:

"Here we have all these companies obsessed, basically with keeping their stock prices up, and saying the best thing that they can do with their money is spend billions of dollars on stock. And my view of that is, any company that says that they have nothing to better do with their money, the CEO should be fired."

A CEO's reply to that might well be that this attitude is why Lazonick's a professor rather than a CEO himself. But is he wrong? Here's a recent paper of his, which contends that the problem is that share buybacks are all too effective. Lazonick says that the problem is tied to the increasing compensation of top executives in shares and options, and that using company money to prop up the stock price is, basically, market manipulation to reward the executives.

He has some figures from our own industry: From 1997 to 2009 "Amgen did
repurchases equal to 99 percent of R&D expenditures, Pfizer 67 percent, Merck 62
percent, and Johnson & Johnson 57 percent." It could be worse - companies in the IT sector have often managed to spend even more than their R&D budgets on repurchases, partly because they increased the number of shares outstanding so hugely during the dot-com boom years.

One complication with the market-manipulation view is that stock buybacks don't correlate very well with total stock returns. If anything, the correlation is negative: companies (and sectors) that spend the most on repurchases have lower returns. Of course, there's a correlation/causation problem here - perhaps those returns would have been even lower without the buybacks. But there's clearly no slam-dunk financial case to be made for repurchases.

Except one: that they're often the easiest and least controversial use of the money. Companies get criticized if they sit on cash reserves, and they get criticized for missing earnings-per-share numbers. Why not try to address both at the same time? And without having to actually think very hard about what to invest in? I think that Pfizer's Ian Read is being truthful when he says things like this:

Pfizer declined to make an executive available to discuss its policy. But in a statement, the company said it “remains committed to returning capital to shareholders through share buybacks and dividend payments.”

As for the cut in research spending in February, Pfizer said it has “accelerated our research strategy and made important changes to concentrate our efforts to deliver the greatest medical and commercial impact.”

In a conference call with analysts this month, Pfizer’s chief executive, Ian C. Read, said his company would “continually look” for acquisitions that would increase revenue growth. But in deciding how to use the proceeds from recent asset sales, he said “the case to beat is share repurchase.”

And that, truly, is a shame.

Well, we last got into arguments about industrial espionage here in December, so it's what? February already? Then here we go: from C&E News, we have this:

Federal prosecutors charged last week that Chinese government officials played a role in the theft from Dupont of technology to manufacture the paint pigment titanium dioxide.

According to a document filed on Jan. 31 in U.S. District Court for the Northern District of California, Federal Bureau of Investigation officials obtained letters in a search of the home of Walter Liew. The letters show that Liew “was tasked by representatives of the People’s Republic of China government to obtain technology used to build chloride-route titanium dioxide factories,” prosecutors say.

Here are more details from Reuters. More on this as it develops. . .

I've been meaning to mention the very interesting work that's shown up on tau protein in Alzheimer's. That's generally taken a back seat to amyloid in the protein-pathologies-of-Alzheimer's derby, but no one has been able to rule it out as a causative event, either. And the progress of tau pathology through the brain is quite suggestive - it tends to start in one region (the entorhinal cortex) and spread from there. The question is, what's driving that process? Is it tau itself spreading, or perhaps something inside the cell that causes tau problems is spreading, or is it some set of external conditions (that lead to tau pathologies) which is spreading?

This latest work goes a good way towards settling that question. (Here's one group's paper in PLoS One; the other paper in Neuron doesn't seem to be up yet, which has caused some controversy). The researchers in question engineered mice that express human tau protein localized to the entorhinal cortex (EC). They then sat back and watched what happened, taking sample along the way.

And what happened was a spectacular result. They found human tau in the EC initially, as expected. But over time, it began to show up in brain regions that are synaptically connected to the EC, and then it spread to the regions that are connected to those. This is human tau protein, remember - the only cells in the brains of these mice that should be able to make it are in the EC. In other words, the protein itself appears to be spreading from neuron to neuron, apparently through the synaptic junctions:

In general, our NT mouse model replicates the spatial and temporal aspects of the earliest stages (I–III) of Braak staging of tauopathy in Alzheimer's disease. We have demonstrated that tau pathology initiating in the EC can spread to other synaptically connected brain areas as the mice age, supporting the idea that AD progresses via an anatomical cascade as opposed to individual events occurring in differentially vulnerable regions.

They also now have a very interesting (and potentially very useful) mouse model of Alzheimer's pathology. There are still a huge number of open questions about Alzheimer's, don't get me wrong. But this is a real advance, in a field that doesn't see as many of those as everyone would like. Now to figure out how that protein is spreading (How's it excreted from the cell? How's it taken up by the next ones in line?) and why.

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.

I'm sitting in the main conference hall at the SLAS meeting as things get going. And I have to say, it's a big crowd, and there are some very interesting things on the agenda. But I've just seen something I've never seen before: an ad being played on the screens for the entire attending audience, just before the keynote address. Thermo Scientific has clearly put a lot of money into this meeting (as well they should), but sitting through a NFL-voice-over style ad during the kickoff to a scientific meeting ("The power to win!" is a real first.

As mentioned before, I'm going to be moderating a panel today on industry-academic collaborations in drug discovery at the SLAS meeting in San Diego. It starts at 10:30 AM Pacific Time, and you can access a live stream of the event here (scroll down).

And if anyone has more questions on the subject they'd like to see raised (or things that they'd rather not see raised again!), please add them to the comments for this post. I'll be checking it during the day.

For a really stunning electron micrograph of the thinnest possible layer of glass, see here. (If you don't have journal access, here's a release with some details). What's even more striking is that the semi-random arrangement of atoms is basically an exact match of a hypothesis from 1932 by W. H. Zachariasen at Chicago.

And maybe it's just me, but high-resolution images of molecular structure like this still give me the shivers. I mean, I've seen all sorts of electron density maps from X-ray crystallography, but somehow this sort of thing gives one a more direct feeling of looking at the individual atoms. And for some reason, that seems like something Man Was Not Meant to Do - perhaps it's all those old elementary school textbooks that told me that atoms could never be seen. (Then again, philosopher Mortimer Adler made the same assumption, as I found to my surprise when I read his Ten Philosophical Mistakes, on page 184 if you're keeping score at home.

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?