Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
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 Indiabit 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!
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?