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: firstname.lastname@example.org
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?
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 rejecteddapagliflozin, an SGLT2 inhibitor for diabetes. The advisory panel voted it down back during the summer, and the agency has asked AstraZeneca and Bristol-Myers Squibb to provide more safety data. As it stands, the increased risk of bladder and breast cancer (small but significant) that was seen in the clinic just outweighs the drug's benefits.
That's the sodium-glucose cotransporter 2, and what it does normally is reabsorb glucose in the kidney to keep it from going on into the urine and being lost. It's been the subject of quite a bit of drug development over the last few years, with the thought being that spilling glucose out of the bloodstream, as an adjunct to other diabetes therapy, might be more of a feature than a bug.
Not with that safety profile, though. And since this compound has been through nearly a dozen different advanced trials in the clinic, I really don't see how anyone's going to be able to provide any safety data at this point to change anyone's mind about it. Type II diabetes is an area with a lot of treatment options, and while all of them have their advantages and disadvantages, taken together, there's quite a bit than can be done. So if you're going to enter a crowded field like this, a new mechanism is a good idea (thus SGLT2). But you're also up against a lot of things that have proven themselves in the real world, some of them for a long time now, so your safety profile has to be above reproach.
Canagliflozin, from J&J, is still out there in the clinic, and you can bet that the folks there will be digging through the data from every direction. Are dapagliflozin's problems mechanism-related, or not? Would you care to spend nine figures to find out? That's how we do it around here. . .
2,800 over the next four years. More of them are in Europe than in the US (via the Nycomed acquisition), but there are hundreds of positions to be lost in this country, too. For now, the company seems to be just saying that they'll be in all parts of the organization, without much in the way of details. Those will, in time, become all too apparent.
Add that to last week's Novartis announcement (about 2,000 jobs, mostly in sales and marketing), and we're not off to a great 2012 on this front, are we?
I noted that the Nature Publishing Group has come out against the proposed Research Works Act, which would roll back the requirement that research funded by the US government be made freely available after (at most) one year. They are, I believe, the largest and most prominent journal publisher to take such a stand (although I'll be glad to be wrong about that):
NPG and Digital Science do not support the Research Works Act.
NPG and Digital Science exist to support the creation and dissemination of human knowledge on a sustainable commercial basis. We seek to enable the open exchange of ideas, especially in scientific communities, in line with the requirements and objectives of relevant stakeholders.
Update: from the comments, the AAAS (publishers of Science) have also come out against the RWA, saying that they're fine with the current system, and that their membership in the AAP does not mean that the organization speaks for them on this issue. How about the American Chemical Society? As far as I can tell, the ACS has made no statement, and silence speaks loudly.
Meanwhile, Rich Apodaca at Depth-First surprised me with this post coming out in favor of the RWA. But read the whole thing. He is, as the Marxists used to say, interested in "heightening the contradictions", and sees the scientific publishing industry bringing down the roof on its head even faster if the act passes. And the sooner that happens, he says, the sooner we can get rid of an outmoded system:
Any scientist who has been an active participant in scientific publication as an author, reviewer, and consumer recognizes that the only remaining value added by scientific publishers today is imprimatur. Imprimatur is the implied endorsement received by authors who publish in certain scientific journals, particularly in those that earned a high level of prestige during the pre-digital period of publication scarcity.
Ironically, imprimatur remains so valuable in science that it has kept numerous publishers afloat despite wave upon wave digital destruction being visited on sister industries such as book publication and newspapers.
But imprimatur can lose its luster, particularly in an environment in which fewer and fewer scientist can actually read the publications appearing in ‘high-impact’ journals. Prestige counts for nothing in science if your peers can’t read your papers. Nevertheless, that’s where scientific publication is heading.
I'm not sure which way is faster, myself. But we agree that the current scientific publishing model is being eroded, and that this is an opportunity, not a disaster that has to be repaired with legislation.
Now here is an amazingly stupid move: a medicinal chemist at Sanofi (Yuan Li) downloaded a large set of proprietary compounds from the company's files, and founded another company on the side to sell them.
Strangely enough, someone at Sanofi noticed that their in-house compounds were appearing for sale at Abby Pharmtech, of Newark, Delaware. (Better take a look at that web site while you can). It is supposedly the US subsidiary of Xiamon KAK, of Xiamen, China. According to this criminal complaint (thanks to Pharmalot for the link), Sanofi found (in May and June of last year) 6,000 of their internal compounds showing up on SciFinder as available from Abby. A search of Li's computer at Sanofi showed all sorts of useful stuff - a listing of 144,000 compounds in a file called "Abby Pharmtech" (complete with internal Sanofi registration codes), tax forms showing her as a partner and co-founder of Abby (confirmed by IRS records), and so on.
The penalty? There's been a plea agreement (again, thanks Pharmalot), and sentencing is scheduled for April 23. There's a maximum potential prison term of 10 years, and a maximum fine of at least $250,000 - all that is up to the judge. This is in addition to restitution to Sanofi ($131,000) and a very high likelihood of immigration proceedings. It is safe to say that this master plan has not worked out too well.
What, just what, was this person thinking? How lucrative could this idea have possibly been, compared to the risks? And how could they have imagined that this would fly at all - that no one at Sanofi would ever notice that stuff from their own files and lab notebooks was now for sale? You just never know what people can get up to.
If you've been looking around the literature over the last couple of years, you'll have seen an awful lot of excitement about epigenetic mechanisms. (Here's a whole book on that very subject, for the hard core). Just do a Google search with "epigenetic" and "drug discovery" in it, any combination you like, and then stand back. Articles, reviews, conferences, vendors, journals, startups - it's all there.
Epigenetics refers to the various paths - and there are a bunch of them - to modify gene expression downstream of just the plain ol' DNA sequence. A lot of these are, as you'd imagine, involved in the way that the DNA itself is wound (and unwound) for expression. So you see enzymes that add and remove various switches to the outside of various histone proteins. You have histone acyltransferases (HATs) and histone deacetylases (HDACs), methyltransferases and demethylases, and so on. Then there are bromodomains (the binding sites for those acetylated histones) and several other mechanisms, all of which add up to plenty o' drug targets.
Or do they? There are HDAC compounds out there in oncology, to be sure, and oncology is where a lot of these other mechanisms are being looked at most intensively. You've got a good chance of finding aberrant protein expression levels in cancer cells, you have a lot of unmet medical need, a lot of potential different patient populations, and a greater tolerance for side effects. All of that argues for cancer as a proving ground, although it's certainly not the last word. But in any therapeutic area, people are going to have to wrestle with a lot of other issues.
Just looking over the literature can make you both enthusiastic and wary. There's an awful lot of regulatory machinery in this area, and it's for sure that it isn't there for jollies. (You'd imagine that selection pressure would operate pretty ruthlessly at the level of gene expression). And there are, of course, an awful lot of different genes whose expression has to be regulated, at different levels, in different cell types, at different phases of their development, and in response to different environmental signals. We don't understand a whole heck of a lot of the details.
So I think that there will be epigenetic drugs coming out of this burst of effort, but I don't think that they're going to exactly be the most rationally designed things we've ever seen. That's fine - we'll take drug candidates where we can get them. But as for when we're actually going to understand all these gene regulation pathways, well. . .
There are small drug firms and there are small drug firms - if you know what I mean. Which category is Warp Drive Bio going to fall into?
If you've never heard of them - and that name is rather memorable - then don't worry, they're new. Its founders are big names on the industry/academic drug discovery border: Greg Verdine, Jim Wells, and George Church. Here's the rundown:
Warp Drive Bio is driving the reemergence of natural products in the era of genomics to create breakthrough treatments that make an important difference in the lives of patients. Built upon the belief that nature is the world's most powerful medicinal chemist, Warp Drive Bio is deploying a battery of state-of-the-art technologies to access powerful drugs that are now hidden within microbes. Key to the Warp Drive Bio approach is the company's proprietary "genomic search engine" and customized search queries that enable hidden natural products to be revealed on the basis of their distinctive genomic signature.
Interestingly, they launched with a deal with Sanofi already in place. I've been hearing about cryptic natural products for a while, and while I haven't seen anything that's knocked me over, it's not prima facie a crazy idea. But it is going to be a tricky one to get to work, I'd think. After all, if these natural products were so active and useful, might they not have a bit higher profile, genomically and metabolically? I'm willing to be convinced otherwise by some data; perhaps we'll see some as the Sanofi collaboration goes on. Anyone with more knowledge in this area, please add it in the comments - maybe we can all learn something.
One other question: with Verdine founding another high-profile company, does this say something about how his last one, Aileron, is doing in the "stapled peptide" business? Or not?
Looks like the former Merck site in Newhouse is beginning to get some tenants as part of "Biocity Scotland". I wish everyone involved good luck - we need more smaller firms, because that's the only way to get larger firms. Isn't it?
Back in December, a short bill was introduced in the House called the "Research Works Act". Its backers, Darrell Issa (R-CA) and Carolyn Maloney (D-NY), describe it as something that will maintain the US's standing in scientific publishing. After looking over its language and reading a number of commentaries on it, I have to disagree: this looks to me like shameless rent-seeking by the commercial scientific publishers.
And it pains me to say that, because I know several people in that business. But it's a business whose long-term model has problems. (See the Addendum below if you're not in the field and want a brief summary of how scientific publishing works). The problem is, the work of the editorial staff has changed a good deal over the years. Back when everyone sent in hard copies of papers, in who knows what sort of format, there was a good deal of work to do just turning the good ones into a consistent journal. Electronic submission has ironed a lot of the grunt work out - it's still work, but it's not what it used to be.
That leaves the higher editorial functions themselves, and here's where the arguing starts. Most, and in some cases all editing of content is done by unpaid peer reviewers. There are journals whose editors exist mainly to keep the flow of submissions moving to the reviewers, and from them back into the official journal, while hardly ever laying a finger on the copy itself. They function as Peer Review Mailroom Managers. And while that's a necessary job, it's the center of the argument about scientific publishing today. How much, exactly, is it worth?
Scientific journal are expensive. I mean, really, really expensive to subscribe to. And if you're not a subscriber, access to individual papers is pretty steep, too - typically in the $15 to $50 range. This is the business model for commercial scientific publishing: create a space with value (reputation, name recognition) and charge the maximum that that traffic will bear. And that's fine; there are a lot of businesses that work the same way - if they can.
The problem is, the information-sharing capabilities of the Internet blow a large hole in some of the traditional publishing model. And another problem is that a large number of papers that come into the journals from US academic researchers have had some (or all) of that work paid for by government grants (NIH, NSF, DOE and so on). As it stands, articles funded by the NIH are available in PubMed Central for free access, no later (by law) than 12 months from the initial journal publication. Researchers can also submit their work to "open access" journals (such as those from the Public Library of Science), which charge a fee to authors to defray editorial costs, but then allow immediate unlimited access to all comers once a paper is accepted. (I should note that some commercial journals get away with "page charges" as well, and some have a model where the authors can pay extra to bring their paper out from behind the paywall).
And here's where we have the Research Works Act. It would forbid any publication in an open access journal for anything funded in academia by US government grants, and it would forbid any public-access repository for such work. That's its purpose. Well, to be more accurate, its purpose, as described by the head of the Association of American Publishers, is that it "ensures the sustainability of the industry". Yep, make my business model part of statutory law, and beggar my competition: what else is a government for, anyway?
Update: see the comments section. I'm interpreting the text of the law to mean the above, but another way to read it - probably the correct one - is that it's mainly rolling back the 2008 law that mandates that NIH-funded papers go open-access after a year. But that's bad enough as it stands.
To their credit, the MIT Press looks like the first big academic publisher to defect from this position. But the commercial publishers (Elsevier, Wiley, and so on) will never give up on this goal. Yes, the RWA, according to them, is aimed at "preventing regulatory interference with private-sector research publishers". Here's Congresswoman Maloney using Elsevier's own press release language, sentence by sentence, as detailed by Michael Eisen, co-founder of PLoS. (He also has an op-ed in the New York Times on this issue).
I see no reason why we should make the current scientific publishing system a matter of law. I think it should change - and be allowed to change - as new technology allows it to. And I think that the Research Works Act is nothing more a blatant attempt to hold on to a profitable business plan.
Addendum: For those outside the scientific world, here's a brief summary of how things have traditionally worked. As a scientist (academic or industrial), you take the time and effort to write up your results for a journal. You have to pick your journal at the start of the process, since each of them have their own ways of organizing a paper, their own preferred way of citing other papers as references, and so on. Anyone can send anything to any journal they feel like, although you'd be well advised to target your paper to the ones that (a) have the best chance to actually accept it and (b) will do you good to have a paper published in. The overlap between those two may not be large, or may not exist at all, depending on your paper. These days, most journals have templates for Word or the like, which standardizes the submissions, and have some sort of automatic PDF generation during the submission step step so you can see how the paper will look when formatted in the journal's style and page layout.
Your manuscript is given a quick check to make sure that it's appropriate for review. A few of of the higher-end journals make this a key step, because they can afford to turn down even rather interesting papers as not necessarily worth their time to go on checking. But in most journals, unless there's something obviously off, your paper goes out for peer review. Two or more scientists from Out There Somewhere look it over and send in comments. Those comment forms have a section for the original authors to see, and a section for remarks that go just to the editorial staff, and you can use those as you see fit. (I, for example, once used the latter forum to ask the editors to please stop sending me papers from a certain author, because I'd done three of them and couldn't stand to see any more. They honored my request.)
As an author, you see the comments when they come back and get a recommendation from the journal - usually it's "Publish as is", "Publish after minor revisions", "Publish after major revisions", or "Go away". That last one usually isn't expressed in quite those words. The middle two are the most common, since most stuff eventually gets published somewhere if the authors are persistent enough (and are willing enough to have their work appear in the Zambodian Journal of Chemistry or what have you).
Now at this point, traditionally, the work of assembling the accepted papers into a printed journal kicks in on the editorial side. And it still does, but that process is becoming less and less important. I honestly can't tell you when I last saw a hard copy of any of the journals I read regularly. Even the idea of separate issues is becoming antiquated, since new papers (in the case of many journals) just plop out onto the web site (and into the RSS feeds) as they emerge from the review process.
I'm getting all the press releases from Bill Sardi, of Resveratrol Partners, as he does damage control from the Das scandal at UConn. And I have to say, he's putting in the hours getting these together. Problem is, on some key points, he doesn't know what his biggest problems are.
The latest one is titled "World Without Resveratrol: Researcher Falsely Accused", and claims that this may all be a plan to "send a message" to any academic who collaborates with the makers of resveratrol pills. The release goes on about how these are old accusations, which Das has refuted since then, and asks why these ancient concerns are coming up now, eh? The phrase "orchestrated hit job" is used. But that glosses over the times of the whole investigation, which has been a very detailed and involved one, and glosses over the amount of due process involved as well. There are a lot of problems with the publications from the Das lab, as detailed in the report that I linked to the other day, and tying them together has involved a lot of work.
But here comes my favorite part of the latest Sardi release:
". . .I asked Dr. Das directly, did he altered (sic) western blot images, or directed others in his lab to do so. While his initial answer was no, meaning he had not fabricated or altered any scientific finding, altering western blot images are a common practice in laboratories for reasons other than deception. The university chose to present their findings in a derogatory manner. Dr. Das explains that editors at scientific publications commonly request researchers enhance faded images of western blot tests so they can be duplicated in their publications. Western blot tests are frequently altered to remove backgrounds, enhance contrast and increase dots-per-inch resolution so they are suitable for publication. This had been fully explained to university officials long before. . .
No, no, no. The problems with the Das papers have nothing to do with enhancing the contrast on Western blots. They have to do with cutting and pasting sections of them, rearranging them, reusing them, and creating them out of pieces of other experiments. Look at that report. These people appear to have spent a ridiculous amount of time assembling "Western blots" out of miscellaneous digitized chunks. The resulting figures purport, in many cases, to represent particular experiments, but they do no such thing. They represent a bunch of previous bands from other experiments entirely, sliced and diced in a way that would seem to have no other possible motive than to deceive. Come on.
Oh, but there's more. Here, according to the press release, is how a cutting-edge academic lab works these days:
"As I drilled Dr. Das’ former students with questions, I found that lead researchers like Dr. Das do not do any lab bench experiments. Students do all the work and submit their results to him via e-mail or by directly downloading data into his computer. Dr. Das says when he is not traveling his office is open and students can enter and download data directly onto his computer. I had previously visited Dr. Das at the University of Connecticut and noticed his office door was left open and anyone could have access to his computer.
One former student told me that typically lead researchers like Dr. Das write the introduction and conclusion of experiments and the students enter all the data, before publication in scientific journals. Dr. Das, who is busy lecturing all over the globe because of his groundbreaking studies, does not directly oversee tests that are performed, and neither do most other lead researchers. The University of Connecticut report says the university holds Dr. Das responsible for all of the data. Probably most lead researchers in scientific laboratories around the globe are vulnerable to errors or even fabrication of data by their students."
Where to start? What the heck is this "download data directly into his computer" stuff? And what about all the doctored files found on other machines in the group? And yes, while lead authors are indeed vulnerable to errors and fabrication, this sort of thing typically does not involved years of work spread out across dozens of papers in multiple journals. Even the busiest and most distracted principal investigator might be expected to take the time to notice, eventually, that his group's work is a tower of fraud. And yes, the University should hold Dr. Das responsible for the data in his papers. His name is on the grants, his name is on the office door, he's the one with a high-paying tenured position while the students are cranking away under low salaries and stipends, and it's his name with an asterisk next to it on all those papers, as the contact person for any questions about them. Damn right he's responsible. He's responsible for making sure that anything going out into the literature with his name on it is something that he can stand behind.
Ah, but not to worry. It's all being taken care of:
"Dr. Das says many editors at scientific journals don’t believe the University of Connecticut report. They full-well know that editing of western blot tests is common practice and that the tests in question in no way invalidate his work and were only one part of the evidence provided in his papers from which Dr. Das drew conclusions. This is the case of scientific fraud that wasn’t."
That would explain why Dr. Das has been pulled from the co-editor job he had at one of those journals. They must believe him. And that would also shore up all those allegations of prejudice against East Indian researchers, since the editor of that journal is. . .well, he's Indian too, but you know what I mean. (Personally, if I were from India myself, I'd be furious at Das for helping to drag the reputation of my country's scientists through the mudhole, but maybe that's just me.)
No, I hope these press releases keep on coming. So far, we have lots of elaborate reasons why Dr. Das had nothing to do with all these fabricated Western blots, but who cares, right, since they're only a tiny part of his papers, which are great and important work even though he really doesn't write them anyway, and no, he has almost no connection with Longevinex and Resveratrol Partners, which is why the head of the company is spending all this time defending him in this case of minor stuff he never did, all 600 pages of summary and 60,000 pages of investigation material, and that explains why the journals that believe him are ditching him from their mastheads and publishing retractions of those great papers. Because it's all a conspiracy. Yeah. That's it.
You don't want coverage like this: "Biogen CEO Tries to Refill Early-Stage Pipeline He Decimated". That would be George Scanos:
. . .Scangos and his research chief eliminated about 17 early-stage drug projects in 2010 and last year to hone the company's focus, leaving it with only about four early-stage compounds. Biogen exited oncology and cardiovascular research and is now targeting drugs to treat neurological and autoimmune conditions. . .
"We didn't want to fund projects that were unlikely to generate value," Scangos said in an interview on the sidelines of the J.P. Morgan health-care conference in San Francisco this week. . .But even if Biogen's late-stage pipeline delivers successful new drugs soon, the company needs more compounds in early-stage testing to sustain long-term growth. So it is licensing drugs from other companies. . .
The article itself (from Peter Loftus, originally in the Wall Street Journal isn't quite as harsh as the headline. As as that excerpt shows, part of the problem is that Scanos thought that the company was in some therapeutic areas that they shouldn't have been in at all, so that pipeline he's refilling isn't exactly the same one he cleared out. (And a note to the WSJ headline writers: "decimated" isn't a synonym for "got rid of a lot", although that horse, I fear, left the barn a long time ago. The mental image of decimating a pipeline isn't the sharpest vision ever conjured up by a headline, either, but I understand that these things are done on deadline.)
No, if I had to pick the biggest expensive reversal done under Biogen's new management, I'd pick the construction site a few blocks from here where they're putting up the company's new Cambridge headquarters. Those are the offices that used to be in. . .well, Cambridge, until former CEO Jim Mullen moved them out to Weston just a couple of years ago. I don't know how long it's going to take them to finish those buildings (right now, they're just past the bare-ground stage), but maybe eventually they can all work there for a few months before someone else decides to move them to Northhampton, Nashua, or Novosibirsk.
So, we've been talking here since yesterday about what looks like large-scale fraud, but there's small-scale stuff that goes on inside various labs (often in academia, which is where people like this are supposed to wash out). Many readers will have encountered, in their grad school days, the person whose reactions won't quite reproduce, who comes in while you're not around and "borrows" your reagents, and who can't quite locate that key procedure when it's time to look at it closely. (And yes, I've had dealings with members of this tribe before, and they're no fun at all).
Here's a reminiscence from a professor at Nebraska of how he dealt with someone like this, and his technique may be something that others have tried (or been tempted to). It worked, though. This is the flip side of the laboratory sabotage discussed here and here, used for good instead of for evil. Are such methods justified? Used carefully, and in extreme cases, I'd say yes. Thoughts?
My inbox has exploded with the story that many reports on the effects of resveratrol appear to be fraudulent. Prof. Dipak Das of Connecticut is at the center of what looks like a huge research stink bomb, which is being well covered by Retraction Watch (here and here), among others. The Chronicle of Higher Education has a lot of good info as well.
Here's what's known so far: UConn has a press release saying that Das has been under investigation for the last three years, and that the university (along with the Office of Research Integrity) has uncovered substantial evidence of fraud and misconduct.
An extensive research misconduct investigation has led the University of Connecticut Health Center to send letters of notification to 11 scientific journals that had published studies conducted by a member of its faculty. Dipak K. Das, Ph.D., a professor in the Department of Surgery and director of the Cardiovascular Research Center, was at the center of a far reaching, three-year investigation process that examined more than seven years of activity in Das’ lab. . .
. . .The investigation was sparked by an anonymous allegation of research irregularities in 2008. The comprehensive report, which totals approximately 60,000 pages, concludes that Das is guilty of 145 counts of fabrication and falsification of data. Inquiries are currently underway involving former members of Das’ lab; no findings have been issued to date.
Here are the details, in a long PDF, if you want them. What that report shows are a lot of manipulated Western blots, with obvious copy-and-paste artifacts. Well, they're obvious once you're alerted to them, at any rate - the first thing you think of when you see a gel isn't "Hmmm. . .I wonder if that's been Photoshopped?" At any rate, examination of presentation slides on various hard drives also showed Westerns with various regions - in some cases, every single damn band on the whole thing - which had been moved around with the "Group" and "Ungroup" tools, starting from separate unrelated files. And they've even tracked down the original images which formed the basis for the figures in so many other papers, once they'd been sliced and diced. Classy stuff. Dr. Das, for his part, told the investigators that he had no idea who had prepared any of these figures, a position that (since he's the lead flippin' author on them), strains belief. "Dr. Das has been of no help in this matter", states the report, and I'd say that still overstates his contributions.
UConn has notified the editors of 11 journals where Das and his group had published suspect results - and on three of these journals, according to Retraction Watch, he had editorial or advisory responsibilities. Looking over the list, it's not exactly the most high-profile publication record that you could imagine. Das's papers do seem to have picked up a number of citations, in many cases, but I don't really get the sense that he was driving the field. (That Chronicle link above quotes David Sinclair, of sirtuin fame, as saying that he'd never even heard of Das at all, and for what it's worth, I hadn't either).
Meanwhile, Retraction Watch has received a press release from Das' lawyer, and it looks like he's not going down without firing all his ammo. To wit, Das claims that:
. . .the charges against him involve prejudice within the university against Indian researchers. Six other East Indian researchers were also named as “potential respondents” to charges of scientific fraud, but no researchers of other ethnicities. . .
. . .Another party, a university internal investigator whom Dr. Das accuses of long-standing prejudice against foreign-born researchers, reportedly broke the lock on Dr. Das’ office door, removed computer files and personal items such as bank records and a passport, and could have manipulated data in his computer files. Dr. Das says this university investigator has had a long-standing vendetta against him going back to 1984. . .
There's a lot more in the same vein (and great big steaming heaps of it in Das' official response to the investigation) and it all points to a long, ugly process. The lawyers involved will have plenty to keep themselves occupied.
There's one last big issue: Das appears to have had a business relationship with Longevinex, a well-known supplier of resveratrol supplements. I note that Bill Sardi, the managing partner of the firm that runs Longevinex, has showed up on this site in the comments section before, as have many fans of the product itself. (I know that David Sinclair has heard of those guys, because they were throwing around his name for a while, which seems to have led to talk of possible legal action). And it's worth noting as well that Dr. Das had published work suggesting that Longevinex was superior to garden-variety resveratrol. That paper (and that journal) does not appear to be one of the ones named specifically in the fraud investigation. But one of the authors on it (other than Das) figures prominently in the UConn report. Who feels inclined to trust it?
Now for the last big issue: what does this do to the whole resveratrol/sirtuin field? Not as much as you might think. As mentioned above, Das really doesn't seem to have been that big a figure in it, despite cranking out the publications, and a lot of interesting (although often confusing) work has come from a variety of other labs. The people who did this study in humans, for example, are (to the best of my knowledge) above reproach. But (as that post shows in its various links), there's a lot of conflicting data about resveratrol in animal models. The whole topic is deeply confusing. But this UConn/Das business does not help clear anything up, not at all - it's a big bucket of mud and slop dumped into the tank, which is just what we didn't need.
And as for sirtuins, well, I don't think anyone would disagree with the statement I made here, that resveratrol has so many off-target effects that it's completely unsuitable as a tool to understand sirtuin biology, which is quite difficult enough to understand already, thanks very much. Sirtuins have their own wild complications and (seeming) contradictions, separate from resveratrol - this latest scandal is off to the side of that topic completely, or should be.
But I don't mean to minimize Das' apparent misconduct here, not at all. He's not at the center of his field, but he looks to be at or near the center of something very dishonorable, very dishonest, and very wrong.
Someone in a position to know has told me that Sanofi's Bridgewater, NJ site, which has long been a focus of layoffs, is now closing even faster than people thought. Originally, it was supposed to be "by the end of 2012". According to my source, though, they told everyone there yesterday that the last day would be Friday (!). No buyer for the site is known - rumor have had it that Allergan is interested, but that would seem to be far off, if indeed it's happening at all. Any more details out there?
English has no word of its own for schadenfreude, so we've had to appropriate the German one, and we're in the process of making it our own - just as we did with "kindergarten", not to mention "ketchup" and "pyjamas", among fifty zillion more. That's because the emotion is not peculiar to German culture, oh no. We can feel shameful joy at others' discomfort with the best of them - like, for example, when people start to discover from experience just how hard drug discovery really is.
John LaMattina has an example over at Drug Truths. Noting the end of a research partnership between Eli Lilly and the Indian company Zydus Cadila, he picked up on this language:
“Developing a new drug from scratch is getting more expensive due to increased regulatory scrutiny and high costs of clinical trials. Lowering costs through a partnership with an Indian drug firm was one way of speeding up the process, but the success rate has not been very high.”
And that, as he correctly notes, is no slam on the Indian companies involved, just as it won't be one on the Chinese companies when they run into the same less-than-expected returns. No, the success rate has not been very high anywhere. Going to India and China might cut your costs a bit (although that window is slowly closing as we watch), but for early-stage research, the costs are not the important factor.
Everything we do in preclinical is a roundoff error compared to a big Phase III trial, as far as direct costs go. What we early-stage types specialize in, God help us, are opportunity costs, and those don't get reported on the quarterly earnings statements. There's no GAAP way to handle the cost of going for the wrong series of lead compounds on the way to the clinic, starting a program on the wrong target entirely, or not starting one instead on something that would have actually panned out. These are the big decisions in early stage research, and they're all judgment calls based on knowledge that is always incomplete. You will not find the answers to the questions just by going to Shanghai or Bangalore. The absolute best you can hope for is to spend a bit less money while searching for them, and thus shave some dollars off what is the smallest part of your R&D budget to start with. Sound like a good deal?
Relative to the other deals on offer, it might just be worthwhile. Such is the state of things, and such are the savings that people are willing to reach for. But when you're in the part of drug discovery that depends on feeling your way into unknown territory - the crucial part - you shouldn't expect any bargains.
Today marks my ten-year blogging anniversary. That doesn't seem possible, but there it is: ten years since I sat down and chose a Blogger template and starting typing away into the void. So what have I learned in all that time (and after all that blather?)
Where It Fits and How It's Done
I may well have been the first science blogger, because it didn't take me long to start talking about drug discovery, as opposed to current events and the like. (Even in 2002, I thought that blogging the news was an overcrowded field, and little did I know how much more crowded it would become). But blogging drug discovery still isn't a very crowded field at all, for various reasons. One of those surely is that most of it is done in an industrial setting, and very few people have felt comfortable blogging from inside a drug company.
The fact that I do so might be due to circumstances that are hard to repeat. It helped that I started out before most people had any idea of what a blog was, and it probably helped that my company's highest management levels at the time were on another continent and spoke another language. And naturally, it's also helped that I've carefully avoided ever being seen as a spokesperson for any company I've worked for. (Or a source of inside information, God forbid). But there are so many topics to write about that this has never been a real problem. When I started, I wondered if I'd be able to keep things up, but there's hardly a day when I don't find something to write about. The material just keeps coming, and I'm glad of it.
That's because I actually enjoy doing this - I don't suppose I could have lasted this long if I didn't! I compose quickly, and type quickly, which helps keep blogging from becoming a chore. As for what to write about, keeping up with the literature and the industry is something that I would have been doing already, and it really doesn't add much time to sit down and write up something about what I've been reading and thinking. (It helps, in fact, to clarify my thoughts - I'm sure that I retain a lot more information for having blogged about it).
Who Reads It, Anyway?
As it happens, a lot of people really do seem to be interested in this stuff. That was my hope - one reason for blogging was that every time I talked to people outside science about what I did for a living, they seemed to think (1) that it was a really neat job, and (2) that they'd never heard of it being a job at all. No one really seemed to know where drugs came from, and despite my efforts (!), most people still don't.
I get letters all the time, though, from non-scientists who read the site, and they make me very happy. Not everything here is accessible or interesting to non-scientists, but I try to make sure that enough of it is to keep people hanging around. And then there are the scientist readers themselves, who make of the bulk of the audience around here. To them I owe a rare distinction: one of the highest signal-to-noise ratios in in the entire world of blog comments. That's really the case - other bloggers have asked me many times what I do to keep things from devolving, and I tell them that it isn't me, it's the people who come here. It's not like every comment thread is a river of gold, but there's a lot more gold there than you'd expect from general run of the blog world.
Readership has increased steadily over the years. Here's the chart, minus the first couple of years, which tail off just the way you'd think, and minus a few months back in 2006, around the time the Wonder Drug Factory was running into trouble and I forgot to save the stats.
Basically, every time I think that the numbers have plateaued, they haven't. Most recently, mid-2010 to mid-2011 had pretty much the same readership levels, but lately things seem to be rising yet again. (And note that my stats don't pick up people who see the blog on RSS feeds, which I think has been an increasing percentage over the years). Far more people are willing to read about chemistry and drug discovery than I ever imagined.
Day-to-day, posts about misery (huge layoffs and the like) get a lot of traffic, which says something about human nature that close observers will have already noted. But a steady diet of misery lacks a number of essential nutrients. The "Things I Won't Work With" posts get the largest non-scientific readership, which is why I'm whacking them into book shape (to appear first on the Kindle, etc.) And posts about patents and IP issues almost always drive a small but noticeable number of people away - if I did a solid week or two of those, who knows if the site would ever recover.
Overall, though, the site has had what I think is a fairly consistent tone over its whole history. That may be because I have a fairly consistent tone myself. A few years ago, I was unnerved when I started looking over some of my older posts and thought that they were clearly better than anything I was turning out at the time. But that seems to be a general psychological effect - older posts always, eventually, look more polished to me because I still have the fresh experience of tumbling the new ones out onto the page. The old ones felt the same way at the time, though. Hindsight polishes them up.
The drug industry is a very different place than it was when I started blogging. Basically, every time I've thought that the worst had passed, it hadn't. I hate to be that negative-sounding, but it's hard to deny that the last ten years - especially the last six or seven of them - have been some of the roughest water that drug R&D has ever experienced. I never thought that I'd have to work at keeping the site from becoming the Blog of Constant Pharma Layoffs, but I've had to.
But that said, the way the industry works hasn't really changed over that time, not in any fundamental ways. (Those two trends may not be unrelated). We have some techniques now that weren't used much back then, but the broad strokes of the business are identical: find some hits, most likely through screening. Develop them into leads, and turn the med-chem people loose on them to do SAR. Fix the potency, fix the selectivity, fix the PK, and then put them into tox and cross your fingers. Send the winning compound to the clinic, put it into Phase I and cross your fingers, this time on both hands. Send it to Phase II, crossing all your fingers, your toes, and your lower intestines. And send it to Phase III, crossing all those body parts while sacrificing a two-headed goat and barbecuing it over bales of money. You know, the usual grind.
The scientific literature has changed, though - and in almost every way, it's become more like blogging and less like it used to be. Print journals have looked archaic for some time, and will likely continue their vanishing act. I haven't seen a hard copy of any of the journals I read in. . .months? Years? Articles get published online, discussed online (shared, boosted, or picked apart), and their authors, their publishers, and their readers are paying attention to things like traffic stats, comments, and links. That'll continue, too, and I think that science will be better off for it.
For the industry? I have no idea. Well, that's not completely true. I have several ideas, but they can't all be right at the same time. For this blog? That's easier - I have every intention of keeping it going, because I still enjoy it. And it's opened up a lot of opportunities that I never would have had otherwise. I had no idea what was going to happen when I started it, although it's safe to say that I wasn't exactly planning on it becoming one of the key turning points of my life. But that's what happened. Here's to more of it!
The JP Morgan Healthcare Conference is underway this week out in San Francisco, so there are a lot of biotech/pharma headlines to come out of that. Luke Timmerman over at Xconomy has "Five Myths" to come out of the conference. Unfortunately, two of them are that biotech IPOs are picking up, and that the general mood is upbeat. . .
For a look into a possible drug-discovery future (from the computational optimist viewpoint), you might want to check out a brief bit of science fiction, "Alpha Shock", in the Journal of Computer-Aided Molecular Design. Some excerpts to give you the general idea:
". . .Of course, the compounds were of little value if they couldn’t be formulated. Sanjay was pressed for time, and nanobot development still took several weeks, so he had to go “old school.” Sanjay accessed World Crystallography Repository’s (WCR) formulation suite and entered the 2D structures of his compounds. The system linked to the Amazon Hyper-Cloud and initiated a series of quantum chemical calculations to develop a custom force field for the solid phase simulations. Unfortunately the preliminary results were disappointing, even after more than 100 million combinations of excipients, particle sizes, focusing tails, and polymorphs had been analyzed in detail. He would run a more complete search overnight, but the chances were that the 10-min simulation was telling him what he needed to know: don’t expect these exact compounds to be quite right. . .
. . .“In fact,” Dmitri continued, “I think the best tactic is to turn down the interaction of this transcription factor”—a protein popped out of one node on the map—“with that protein”—another protein materialized—“and this stretch of DNA.” A 3D model of the complex assembled in front of him, slowly rotating, with the most likely binding sites and points of intervention highlighted. “Of course, you only want to disrupt this interaction in the hippocampus, and only when D7 receptor functioning is high.” The relevant pathway maps showed the effects of the blockage on downstream signaling. “Oh, and naturally you also want to turn down oxphos in the mitochondria. So we need either a single molecule that can do both things, or a two-drug combo.”
The overall impression is a bit like Charles Stross, in its deliberate you-haven't-extrapolated-wildly-enough approach. But Stross doesn't put in as many computational chemistry inside jokes, which is probably better for his sales. My first impulse is the same one I have to, say, Ray Kurzweil, that all this stuff may (in fact probably is) on its way, but not by the dates stated. That position allows me to take flak from both sides, which must be some sort of feature that I value.
If you had SciFinder access, but are now unemployed and would like to use it during your job hunt, CAS now has a program to make that possible for free. I'm glad to see them taking this step; a lot of people have asked for something like this for some time now.
Some of the discussions that come up here around clinical attrition rates and compound properties prompts me to see how much we can agree on. So, are these propositions controversial, or not?
1. Too many drugs fail in clinical trials. We are having a great deal of trouble going on with these failure rates, given the expense involved.
2. A significant number of these failures are due to lack of efficacy - either none at all, or not enough.
2a. Fixing efficacy failures is hard, since it seems to require deeper knowledge, case-by-case, of disease mechanisms. As it stands, we get a significant amount of this knowledge from our drug failures themselves.
2b. Better target selection without such detailed knowledge is hard to come by. Good phenotypic assays are perhaps the only shortcut, but a good phenotypic assays are not easy to develop and validate.
3. Outside of efficacy, a significant number of clinical failures are also due to side effects/toxicity. These two factors (efficacy and tox) account for the great majority of compounds that drop out of the clinic.
3a. Fixing tox/side effect failures through detailed knowledge is perhaps hardest of all, since there are a huge number of possible mechanisms. There are far more ways for things to go wrong than there are for them to work correctly.
3b. But there are broad correlations between molecular structures and properties and the likelihood of toxicity. While not infallible, these correlations are strong enough to be useful, and we should be grateful for anything we can get that might diminish the possibility of later failure.
Example of such structural features are redox-active groups like nitros and quinones, which really are associated with trouble - not invariably, but enough to make you very cautious. More broadly, high logP values are also associated with trouble in development - not as strongly, but strong enough to be worth considering.
So, is everyone pretty much in agreement with these things? What I'm saying is that if you take a hundred aryl nitro compounds into development, versus a hundred that don't have such a group, the latter cohort of compounds will surely have a higher success rate. And if you take a hundred compounds with logP values of 1 to 3 into development, these will have a higher success rate than a hundred compounds, against the same targets, with logP of 4 to 6. Do we believe this, or not?
I should mention that Science is publishing some letters that it received in response to Andy Grove's proposal to rework the clinical trial system for drug development.
Sidney Wolfe and Michael Carome of Public Citizen aren't too happy with the idea, as you might expect. Their take, as I would reword it, could be summarized as "Hey, the existing system allows the drug industry to spew unsafe crap all over the market, and this would make it even worse". Actually, the language in their letter isn't far off:
A. Grove proposes returning to the era before the enactment of the 1938 Federal Food, Drug, and Cosmetic Act, when new drugs were marketed in the United States without evidence that they were safe or effective. His irrational and dangerous proposal, which would limit the Food and Drug Administration's (FDA) premarket review of new drugs to phase 1 clinical trials, is premised on the fundamental misunderstanding that such trials can provide proof of a drug's safety and on the misguided belief that it is not necessary to establish proof of efficacy. . .
Grove's proposal would subject patients on a massive scale to haphazard, uncontrolled, poorly regulated experimentation involving drugs with unknown safety and effectiveness. Such a flawed proposal does not deserve serious consideration.
Norman Marcus of the Virginia Cartilage Institute is more even-tempered, and his view is closer to my own blog post:
. . .Grove's proposed system needs some fine-tuning.
Grove correctly leaves the safety issues to the FDA, but he does not address dosage issues, which should also be determined before distribution. He does not explore how virtual clinical research organizations of the future would monitor issues of compliance and establish fair methods of measuring response. Replacing the heralded phase 3 trial with a self-administered trial would indeed save money and introduce the product much sooner to at least part of the potential market, but pharmaceutical companies would need some shielding of liability to protect them from the increased risks inherent in this plan. Because patients and third-party payers would undoubtedly see the new drugs as experimental, the pharmaceutical companies should be required to offer them at nominal cost.
That said, experimenting (carefully) is exactly what we should be doing. . .
Finally, David Borhani and J. Adam Butts (of DE Shaw Research) go right to what I've named the Andy Grove Fallacy:
. . .Compared to the semiconductor industry's gains over the past 50 years, the pharmaceutical industry's productivity must seem disappointing. There exists, however, an important distinction between engineering integrated circuits and discovering drugs. The semiconductor industry's realization of Moore's Law has always benefited from a fundamental understanding of solid-state physics. Conversely, we still don't know how living organisms work; new “components,” as well as interactions between well-known components, are discovered daily. . .This ignorance is the real reason why 90% of drug candidates fail in clinical trials: They simply don't work. The trial process is doing just what we ask of it.
None of these are unexpected reactions, and I'm sure that Grove himself has heard them before (and anticipated these). So where does this leave us? Status quo ante, with everyone having stated their positions?
A new paper in Angewandte Chemie tries to open another front in relations between academic and drug industry chemists. It's from several authors at GSK-Stevenage, and it proposes something they're calling "Lead-Oriented Synthesis". So what's that?
Well, the paper itself starts out as a quick tutorial on the state and practice of medicinal chemistry. That's a good plan, since Angewandte Chemie is not primarily a med-chem journal (he said with a straight face). Actually, it has the opposite reputation, a forum where high-end academic chemistry gets showplaced. So the authors start off by reminded the readership what drug discovery entails. And although we've had plenty of discussions around here about these topics, I think that most people can agree on the main points laid out:
1. Physical properties influence a drug's behavior.
2. Among those properties, logP may well be the most important single descriptor,
3. Most successful drugs have logP values between 1 and perhaps 4 or 5. Pushing the lipophilicity end of things is, generally speaking, asking for trouble.
4. Since optimization of lead compounds almost always adds molecular weight, and very frequently adds lipophilicity, lead compounds are better found in (and past) the low ends of these property ranges, to reduce the risk of making an unwieldy final compound.
As the authors take pains to say, though, there are many successful drugs that fall outside these ranges. But many of those turn out to have some special features - antibacterial compounds (for example) tend to be more polar outliers, for reasons that are still being debated. There is, though, no similar class of successful less polar than usual drugs, to my knowledge. If you're starting a program against a target that you have no reason to think is an outlier, and assuming you want an oral drug for it, then your chances for success do seem to be higher within the known property ranges.
So, overall, the GSK folks maintain that lead compounds for drug discovery are most desirable with logP values between -1 and 3, molecular weights from around 200 to 350, and no problematic functional groups (redox-active and so on). And I have to agree; given the choice, that's where I'd like to start, too. So why are they telling all this to the readers of Angewandte Chemie? Because these aren't the sorts of compounds that academic chemists are interested in making.
For example, a survey of the 2009 issues of the Journal of Organic Chemistry found about 32,700 compounds indexed with the word "preparation" in Chemical Abstracts, after organometallics, isotopically labeled compounds, and commercially available ones were stripped out. 60% of those are outside the molecular weight criteria for lead-like compounds. Over half the remainder fail cLogP, and most of the remaining ones fail the internal GSK structural filters for problematic functional groups. Overall, only about 2% of the JOC compounds from that year would be called "lead-like". A similar analysis across seven other synthetic organic journals led to almost the same results.
Looking at array/library synthesis, as reported in the Journal of Combinatorial Chemistry and from inside GSK's own labs, the authors quantify something else that most chemists suspected: the more polar structures tend to drop out as the work goes on. This "cLogP drift" seems to be due to incompatible chemistries or difficulties in isolation and purification, and this could also illustrate why many new synthetic methods aren't applied in lead-like chemical space: they don't work as well there.
So that's what underlies the call for "lead-oriented synthesis". This paper is asking for the development of robust reactions which will work across a variety of structural types, will be tolerant of polar functionalities, and will generate compounds without such potentially problematic groups as Michael acceptors, nitros, and the like. That's not so easy, when you actually try to do it, and the hope is that it's enough of a challenge to attract people who are trying to develop new chemistry.
Just getting a high-profile paper of this sort out into the literature could help, because it's something to reference in (say) grant applications, to show that the proposed research is really filling a need. Academic chemists tend, broadly, to work on what will advance or maintain their positions and careers, and if coming up with new reactions of this kind can be seen as doing that, then people will step up and try it. And the converse applies, too, and how: if there's no perceived need for it, no one will bother. That's especially true when you're talking about making molecules that are smaller than the usual big-and-complex synthetic targets, and made via harder-than-it-looks chemistry.
Thoughts from the industrial end of things? I'd be happy to see more work like this being done, although I think it' going to take more than one paper like this to get it going. That said, the intersection with popular fragment-based drug design ideas, which are already having an effect in the purely academic world of diversity-oriented synthesis, might give an extra impetus to all this.
They note a new trend - for new data to appear when a retraction is called for (or made), but without any clarity about whether these new corroborative results have been peer-reviewed themselves. And they're absolutely right that a retraction should state exactly why the paper is being retracted; those "This paper has been withdrawn by the authors" notices are less than useless.Their experiences have them calling for a different way of looking at scientific papers in general:
". . . It is important to point out that an increase in retractions isn't necessarily a bad thing, because they correct the scientific record. But the greater visibility of papers and retractions today adds to the evidence revealing why editors need to handle retractions more transparently. In turn, researchers need to stop emphasizing the paper so much.
What is needed, instead, is a system of publication that is more meritocratic in its evaluation of performance and productivity in the sciences. It should expand the record of a scientific study past an individual paper, including additional material such as worthy blog posts about the results, media coverage and the number of times that the paper has been downloaded."
It's true that more and more of this is being done out here on the internet, in public, and in real time. (I'm glad to say that some of it is done on this site). The new Crossmark system (now being tested) might be a way to keep up with all these extensions, and link them to the original paper. Such a system would have come in very handy indeed during the "arsenic bacteria" business, during which just finding all the useful comments was a real job in itself. There are authors who will not care for this sort of thing, but when you publish a paper, you're opening the door to public comment (and criticism). It's just that now we have the tools to do that more quickly and thoroughly.
The topic of whether stem-cell therapies are overhyped - OK, let me show my cards, the topic of just how overhyped they are - last came up around here in November, when Geron announced that they were getting out of the business. And yesterday had a good example of why people tend to hold their noses and fan away the fumes whenever a company press-releases something in this area.
I'm talking about Osiris Therapeutics, who have been working for some time on a possible stem cell therapy (called Prochymal) for Type I diabetes. That's certainly not a crazy idea, although it is an ambitious one - after all, you get Type I when your insulin-producing cells die off, so why not replace them? Mind you, we're not quite sure why your insulin-producing cells die off in the first place, so there's room to wonder if the newly grown replacements, if they could be induced to exist, might not suffer a similar fate. But that's medical research, and we're not going to figure these things out without trying them.
This latest work, though, does not look fit to advance anyone's understanding of diabetes or of stem cells, although it might help advance ones understanding of human nature and of the less attractive parts of the stock market. Osiris, you see, issued a press release yesterday (courtesy of FierceBiotech) on the one-year interim analysis of their trial. The short form: they have nothing so far. The release goes on for a bit about how well-tolerated the stem-cell therapy is, but unfortunately, one reason for that clean profile might be that nothing is happening at all. No disease markers for diabetes have improved, although they say that there is a trend towards fewer hypoglycemic events. (I think it's irresponsible to talk about "trends" of this sort in a press release, but such a policy would leave many companies without much to talk about at all).
It's only when you look at Osiris and their history that you really start to understand what's going on. You see, this isn't Prochymal's first spin around the track. As Adam Feuerstein has been chronicling, the company has tried this stem cell preparation against a number of other conditions, and it's basically shown the same thing every time: no adverse effects, and no real positive ones, either. Graft-versus-host disease, cardiac events, cartilage repair, Crohn's disease - nothing happens, except press releases. You'd never know anything about this history if you just came across the latest one, though. The company's web site isn't a lot of help, either: you'd think that Prochymal is advancing on all fronts, when (from what I can see) it's not going much of anywhere.
So if you're looking for a reason to hold on to your wallet when the phrase "stem cell therapy" comes up, look no further. The thing is, some stem cell ideas are eventually going to work - you'd think - and when they do, they're going to be very interesting indeed. You'd think. But are any of the real successes going to come out of fishing expeditions like this? You don't want your clinical research program to be so hard to distinguish from a dose-and-hope-and-sell-some-stock strategy - do you?
Looking over the startup funding landscape, Bruce Booth finds some reasons for optimism. I hope he's right. There's a notch cut out of the small pharma/biotech ecosystem, a gap representing all the companies that didn't get formed in the last few years. Filling that has to be a good thing.
Let's see here. . .145 messages in the work e-mail queue, but most of them are automated reminders that reminded me of the same thing every day of the break. Now to the lab bench. . .now, that was a good idea, making sure that everything was labeled before leaving. As I've said here before, too many times you come back to a bunch of stuff that you were just sure that you're remember every detail of, and feel like a moron as you look at the label on the vial or flask: "Second batch". "Mostly clean". "Large run". Fascinating! Large run of what, exactly? I have, in years past, been reduced to running NMR and LC/MS on my own reactions just to try to figure out what they were, and that's not right.
Reagents that I'd ordered back before the break have come in, and I do recall why I ordered them, at least. You don't want to put in a request for anything sensitive in late December, though, not if it's going to sit out on your bench at RT for a week or ten days. I'm glad I'm not a cell-culture person or a rodent-raiser; my stuff doesn't need to be fed, washed, or watered, and I have the luxury of just walking away from it.
Big pile of junk on the desk, though, some of which never should have stopped there on its way to the recycling bin. I saved this for this morning, since I thought clearing things off would be a good way to jump-start my brain into work mode again. It's different now than it used to be, though - paper's more ephemeral. I have the PDFs of these papers stored, so the hard copy's just a convenience, and if I can't figure out what use it is by looking it it, into the bin it goes without a worry. In the days of paper files, I had to spend a bit more time wondering if I'd regret tossing something that was hard to obtain and actually useful. No more: if it looks useless or unrecognizable, into the blue bin it goes.
And then, for those of us in industry, the company starts waking up. Meeting invitations begin to arrive, to fill out the new year's calendar. Looking at your own schedule, you see the first repeating meetings from last year starting to show up, although some of these will get canceled because there's nothing to talk about yet. People who wanted something from you back in December will start to remember what it was, at about the same time that you remember the people that you wanted something from.
Time, shortly, for the first reaction, the first LC/MS trace, the first NMR, the first lab assay result of the new year. And for some of us, the first blog post. Welcome back!