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.

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.

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. . .

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.

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.

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.

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.

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.

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!"

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. . .

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. . .

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.