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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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: derekb.lowe@gmail.com Twitter: Dereklowe

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January 30, 2007

BMY-SNY?

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Posted by Derek

So, could Bristol-Meyers Squibb really be merging with Sanofi-Aventis? Even though this is a poorly sourced story from one French paper, the answer is still: they certainly could. That deal has been kicked around for a long time now, partly as a way of making more out of the Plavix revenue stream. Both companies seem to feel as if their pipelines could use some help, and they're no doubt looking to realize some cost savings through layoffs and site closures. If the formal announcement came one day after a successful outcome in the Plavix patent case, it would surprise no one.

But does that make it a good idea? I've criticized Pfizer relentlessly for growing into such a leviathan, and I think that a Sanofi-Synthelabo-Hoechst-Marion-Roussel-Rhone-Poulenc-Rohrer-Marion-Merrill-Dow-Bristol-Meyers-Squibb might, just might, suffer from similar problems. I still think the research productivity is the thing that doesn't scale in these mergers, and research productivity has to increase, eventually, or the whole mighty monument is going to topple over. You have to have something to sell, and it should come from your own research. Going out and just buying the good stuff ends up raising its price - the good stuff is, naturally, in rather limited supply, and other companies might want it just as much as you do.

You can't buy your way out of trouble in research. More people and more money, after some point, can actually make things worse.

Comments (23) + TrackBacks (0) | Category: Business and Markets

January 29, 2007

Open For Business

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Posted by Derek

Tuesday is my last day at the Wonder Drug Factory. I've been hauling out boxes, emptying the freezer, signing forms, and shaking a lot of hands.

I don't have anything lined up immediately, although I'm pursuing a couple of possibilities. My hope is to stay in Connecticut (I live near New Haven), but that narrows things down quite a bit. As I run through the possibilities, I'll be opening up the search toward the mighty vortex of Boston and Cambridge if need be.

For now, in my between-jobs phase, I'd like to announce that I'm available as a consultant. I have over seventeen years of drug discovery experience that I'd be glad to use on the behalf of anyone who feels that it might be valuable. I won't be bringing in any proprietary information from my recent projects, naturally - I'm respecting the Wonder Drug Factory's IP, in the same way that I'll respect that of anyone else who hires me on.

I can probably do the most good in the preclinical stages (while I've taken many compounds to the clinic, I haven't been the person responsible for getting them through). There have been some inquiries already, I'm glad to say, which prompts me to hang out the sign officially. Please feel free to contact me at derek-lowe@sbcglobal.net.

Comments (6) + TrackBacks (0) | Category: Closing Time

Blogroll Update

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Posted by Derek

Some may have noticed that the blogroll at left has been modernized a bit. I've tried to separate out the chemistry and drug industry sites - please let me know if yours has come down on the wrong side of the line.

And more sites have been added, as the relentless wave of chemical blogging continues to crest. Some of these sites are young, and others I just had neglected to link. Welcome to Occam's Blog, Pharma's Cutting Edge (the renamed Crownstone blog), the QDIS Blog, Curly Arrows, Thesis Sprint (which I hope can eventually get renamed once everything is done), Molecule of the Day, Hdreioplus, Levorotation, The Crimson Canary, the Chemistry World Blog from the folks who are now carrying a regular column of mine, Totally Mechanistic, The Synthetic Referee, Regulatory Affairs of the Heart, and Synthetic Environment!

Comments (6) + TrackBacks (0) | Category: Blog Housekeeping

January 28, 2007

What Can Academia Do?

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Posted by Derek

So, as reader CalProf asked in a comment the other day, what should academic scientists who want to help discover drugs be doing?

As a first approximation, I'd say not drug discovery. That sounds a bit strange, I know, but there are some good reasons behind it. Modern drug discovery takes a lot of resources, from several rather widely separated fields, and it's not easy to bring all the necessary people together in an academic environment. You need med-chemists to make the compounds, pharmacologists and molecular biologiss to develop and run the primary and secondary assays, in vivo people to dose and evaluate effects in the animal models (which they'll also need to develop, in many cases), toxicologists, formulation chemists, computer modelers, scale-up chemists. . .and it's a great help to have people in each of these departments who've done this kind of thing many times and know all the obvious pitfalls. It's a lot easier to organize this as a company where everyone is hired to do their specialty, rather than try to run it with whatever post-docs and grad students you have handy.

But that doesn't mean that academia can't play a big role. They already do, of course, in doing much of the basic biochemical research that leads to new drug targets. Unraveling which protein interacts with which in some important cellular process is as basic as it comes, and most of the time that won't lead to drug one - but once in a while those experiments will set the entire industry off on a chase.

Another place where some academic thinking could come in very useful would be in attacking the important pharmaceutical processes that we don't understand: things like pharmacokinetics, oral availability, human versus animal toxicology, and (lots of) better disease models. The inefficiencies in these areas caused by our lack of knowledge are costing everyone billions of dollars - any improvement at all would be good news. Of course, it's not like the industry hasn't taken a crack at them, too (after all, there are those billions of dollars out there to be rescued from the bonfire). But we really need every approach we can get, and some fresh thinking would be welcome.

Want some more in that vein? Better ways to dose large proteins. New formulations, so that insoluble gunk like Taxol could be given in a dosing vehicle that doesn't occasionally give people anaphylactic shock. Some hope of predicting blood-brain barrier penetration. More understanding of active transport of drug-size molecules, and how it varies between species and among different cell types. Make no mistake, these are hard problems. But whoever can make real progress on them will get plenty of recognition, plenty of funding, and will be a flat-out benefactor of humanity to boot.

Comments (35) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development

January 25, 2007

The Big Picture

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Posted by Derek

The Economist has a good, if rather chilling, overview of the state of the drug industry. They start from Pfizer's troubles, which are a pretty accurate summary of what's been going wrong recently.

Disagreement sets in about whether this is just another darn cyclical downturn, or the death throes of an outdated business model. The question isn't resolved - hey, it can't be resolved, not for some years yet - but a lot of good points are made along the way. A few not-so-good ones creep in, though, inevitably:

. . .one explanation for how Big Pharma's research laboratories got into trouble: the shift from conventional chemistry to the “new science” of biotechnology. Most of the dramatic scientific advances in genetics, proteomics and pharmaco-genomics have come not from the industry's cosseted and costly research centres but from academic labs and biotechnology start-ups.

Horse's nose, meet cart. That makes it sound as if these fields were some sort of drug bonanza that the industry clumsily missed out on. The problem is, those dramatic scientific advances have so far, almost without exception, not produced a single new marketed drug. They don't look to for a while yet, either. Genomics, for example, has been a frightful money pit as far as the drug industry is concerned. Most of the press releases about its wonderful impact on profitable drug discovery aren't worth the effort it would take to compost them. Ask us again in ten years.

And if you want costly, total up the money that's been spent in these areas by Big Pharma so far, in-house and on collaborations. We didn't hose it all away ourselves - no, in many cases we gave it to other people and let them hose it away for us. Outsourcing, y'know.

There's one other quote from the article that I can't let slide. Check this attitude out:

Ranbaxy, a big Indian generics firm, gobbled up six competitors last year and is now talking with private-equity firms about a bid for the generics arm of Germany's Merck. Ranbaxy's boss, Malvinder Singh, scoffs that Big Pharma “is struggling to come up with true innovation”.

He'd better hope we do, though. Where else is Ranbaxy going to get those generic drugs to sell, do you think? From elves?

Comments (41) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History

Way Out Here

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Posted by Derek

Those Pfizer predictions I posted last week were accurate in outline, but not in detail. (The company must be doing a reasonable job of clamping down on leaks). La Jolla and St. Louis survived, confounding expectations, and Michigan got hit very hard indeed.

That's sad, and ironic. The very research facility (ex Warner-Lambert) that discovered and developed Lipitor, the drug that's been most important in keeping Pfizer afloat, is getting the axe. I know some people up there, and I have a lot of sympathy for them. Not only are they out of a job, but they're out of a job in a part of the country that will almost certainly not be able to absorb them.

I'm having enough of a time trying to keep the moving vans away here in Connecticut, and my state has a real pharma/biotech presence. Nothing compares to the obvious always-find-something locations, though: Boston/Cambridge, SF/Bay Area, San Diego/La Jolla, New Jersey from Philadelphia to New York.

On the other hand, the classic example of going out on a location limb is Eli Lilly. Indianapolis, whatever its other charms (like reasonably priced housing), is not a hotbed of drug discovery research once you leave the Lilly premises. The company has generally paid people well, and it's understood that the premium is partly to offset the risk of moving to a part of the country where there's basically only one place you can work. (Well, there's Abbott in Chicago, and there used to be Searle, but it's not like anyone's going to want to commute from Indianapolis to Chicago).

Lilly's the biggest example I know of, but there are plenty of smaller companies located in unlikely places. Nominees are invited for the Most Isolated Company Award - and I'll kick things off by mentioning Albany Molecular.

Comments (51) + TrackBacks (0) | Category: Drug Industry History

January 24, 2007

Back on the Air

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Posted by Derek

I just wanted everyone to know that things have been quiet here because of some Movable Type maintenance behind the Corante scenes. Things seem to be working now, though, and rather more zippily than before. There seem to be a number of comments that were backed up in the pipes which have now appeared, too. I have a backlog of things to talk about (Pfizer! Dichloroacetate!) and regular blogging will resume this evening or tomorrow morning. Even though I'm soon to be unemployed, the blog will live on.

Another update: my manuscript for the "Vial Thirty-Three" paper has been put on hold for a bit, because of some data in it, not related to its main point but still unremovable, that need to wait before being disclosed. A little later on this year I should be clear to publish, though. It's frustrating, but since I did this work at the company's expense, they certainly have the right to say when it gets released.

Comments (4) + TrackBacks (0) | Category: Birth of an Idea | Blog Housekeeping

January 17, 2007

Pfizer's Pfinances

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Posted by Derek

Pfizer's making a big announcement next Monday: but what are they announcing? People inside the company don't seem to have a good handle on the details, which means that the people outside it know even less. But here are the most popular guesses, which together add up to the conventional wisdom:

1. Whacking big cuts in the sales force (yes, on top of the whacking big ones already announced). Europe takes it harder than the US. And yes, I'm tempted to add "for once", but that would be petty of me.

2. Less extensive cuts in front-office type jobs, with the pain spread around pretty evenly.

3. Research mostly escapes with absolutely flat budgets (which beats getting cut, for sure). Pfizer's under a pretty general hiring freeze, which might or might not stay in place - depends on if management considers attrition a bug or a feature.

4. If nasty things happen to research, their nastiness will be roughly proportional to the square of the distance from the site(s) in question to Groton, Connecticut. For what it's worth, which probably isn't much, La Jolla (ex-Agouron) and St. Louis (ex-Monsanto) are being mentioned most often on the downside. Michigan? Good question.

I should emphasize that I have no inside track on any of this. I know people inside the company, but they don't know anything specific on what's coming, either. Having been through several rounds of this kind of thing, I can attest to the fact that in most of these situations, the old Wall Street adage holds: those who say don't know, because those who know aren't saying. But, for what it's worth, this is what the Pharma Street thinks will happen. On Monday, we'll check in with reality.

Comments (22) + TrackBacks (0) | Category: Business and Markets

January 16, 2007

How Not to Do It: Sophomore Organic Edition

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Posted by Derek

I had a lot of long days when I was a teaching assistant. One semester I had three lab sections of sophomore organic chemistry to TA, and sometimes after the first lab of the week I knew that I was in for a rough ride.

Such was the case when we took the students through the good ol' Grignard reaction, as I mentioned here. The problem wasn't the reaction (I have to admit that I can't remember what we had everyone quench the reagent with, actually). The problem was the ether. We didn't have nearly enough fume hood space for all these reactions, so out on the bench tops they were. Two dozen steam baths hissing and gurgling, two dozen round-bottom flasks belching out ether vapors. By the third run-through of the week, I was teaching the lab section from out in the hall, trying to avoid another whiff of the damn stuff so I wouldn't have to run back in and puke in the sink.

The isoamyl acetate synthesis was another one in that vein. That's banana ester, the source of all the cheap, penetrating, one-note artificial banana flavor in the world. It's a pretty dramatic demonstration, in its way, because isoamyl alcohol and acetic acid (the starting materials) smell nothing like bananas, believe me. The workup was extraction with saturated sodium bicarbonate, a perfectly reasonable thing to do since there's an acid catalyst in the reaction.

But you do have to remember to vent the separatory funnel, oh yes. Close the stopcock, pour everything in, put in the stopper, shake it around - but never forget that shaking acid around with bicarb makes plenty of fizzy carbon dioxide. Especially don't forget about it until you've shaken the thing for, like, a minute and a half. And then open the stopcock. While it's pointed at your lab partner. This poor girl comes up to me with this huge stain all over the front of her dress, smelling like a shipwrecked banana boat, saying "I think I need to go back to the dorm and change".

The other thing that I can't help remembering is the day we had everyone do an oxidation with nitric acid, glucose to gluconic acid, I believe. Now, no one does that any more, at least since Emil Fischer keeled over from tasting his own compounds (a fact his Wikipedia article neglects to mention; I should edit that in there). And I'm not sure why that experiment was even in the lab curriculum. We did manage to get everyone into the fume hoods for it, though, thank God, except for one lunatic. He hauled his beaker of hot nitric goodness over to me, stuck it under my nose, and asked "Is this done yet?" I was coughing for three days. No matter where I end up over the next few months, at least no one's going to do that to me.

Comments (19) + TrackBacks (0) | Category: How Not to Do It

January 15, 2007

Novo Nordisk Axes Med-Chem

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Posted by Derek

Here's one that I didn't see coming: Denmark's Novo Nordisk, a longtime major player in the field of diabetes, has decided to cut its small-molecule research completely. They're focusing on peptides and proteins instead. In a time when the big protein-based biotech companies (Amgen and Genentech) are trying to expand their small-molecule capabilities, Novo has decided to break the other way.

That Reuters article has various analysts talking about how this is no big surprise, that NN has never been that big in small molecules, etc. But I had a different impression. The company seemed to have a pretty good presence in many areas of diabetes research. If there was a good target to work on, you could generally count on them being in there, and they showed up in some of the less-trodden areas as well. Their patent and publication stream always looked quite strong, too.

Whether this is a trend, or the beginning of a trend, is a good question. I'm not at all convinced that it's cheaper to do protein therapies as opposed to small molecules (and it's not that I've heard anyone from Novo Nordisk making that argument, either). They must have seen more opportunities in their own biologics pipeline, and not had enough money to realize them if they kept working on the organic chemistry side of things. I'm not sure that this is a good long-term strategy, but they might be figuring that if they don't cut costs somewhere, there's not going to be a long term. So this might be specific to NN, or to companies of their size and financial standing. We shall see. . .

Comments (6) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

January 14, 2007

Problems and Solutions

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Posted by Derek

I had some e-mail from a graduate student in a good lab the other day, and I thought the questions raised were worth a blog post. He wrote:

One thing which stands out to me is your enthusiasm for chemistry,
after having been in pharma for a while. This is something which I am
afraid I might lose getting out of academics. I actually was strongly
leaning academically until recently. It just seems the chemical problems you
would be presented in industry are very vanilla....the problem is I
really don't have a good grasp on what these are (especially in drug
discovery).

Then I imagined in drug discovery, you can use any chemistry you want,
so the "cutting edge" (i.e. new organometallic transformations with way
too much expensive catalyst) is still very relevant. I guess I'm just
curious how you stay as passionate about the science as you are. Do you
see this/has this changed since you started in industry? As you move up
the ranks and further from the bench does chemistry get less and less
important?

These are definitely worth asking. My reply was:

?As for the enthusiasm part, I may be a little bit odd, but not all that much. There are still plenty of people who enjoy what they're doing.

But part of it is realizing that chemistry is a means to an end in the drug business, not an end in itself. People are enthusiastic about finding something that works as a drug - that's why we don't mind mundane reactions as much, because those give you a lot more shots at making a drug than something that needs 2 days to set up. Of course, if you do nothing but (say) make sulfonamides all day, every day, you'll go nuts. But things vary too much for that to be a problem (most of the time). There's always another new structure idea that you have to figure out how to realize, another new core to work on, etc.

And the chemistry problems are just as knotty as you'd get in academia - how do I set these stereocenters, how do I do this reaction selectively so I can avoid a protecting group, etc. Sometimes they're on a different wavelength as well: How can I make this stuff in fewer steps? How can I avoid that evil mercury reagent? How do I get this stuff to form the right polymorph? How can I get to an intermediate that'll let me sit back and crank out a few analogs, instead of making everything from the ground up?

But, as I said, chemistry is means to an end. And the non-chemical problems are a lot harder: how do I get these compounds to have higher blood levels? (Next question - why are they so low now? Do they not get in through the gut, or are they getting whacked by the liver, or are they partitioning into some other tissue, or getting hosed out extra fast by the kidneys?) Why does this compound work, but the one without a methyl group kill the rats? (I've had that exact situation - truth be told, we never did completely figure out what was going on. . .) Why does this thing work so much better in mice than rats, and which one is going to be more predictive of humans - if either? And so on.

So, in a way, the chemistry problems take up less of your time the further on you go. Biology and development problems pick up the slack, and then some."

I'd be interested in hearing other takes on these, and I'm sure my correspondent would, too. Any industrial readers care to add some details?

Comments (11) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs

January 12, 2007

Ghost Town

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Posted by Derek

I'm nearly finished with two manuscripts to send out before departing the Wonder Drug Factory. One is the last paper from an earlier project - it's interesting stuff, but now I'm one of the last people on the author list who's still (nominally) with the company. Everyone else left (or was laid off) even before the final act. The other paper is the "Vial Thirty-Three" work, which has been a fair amount of work to bring together. But it makes a pretty good story now that I see it in one place, and I'm very hopeful of finding a good home for it in a high-end journal.

These will both be going out very soon, mainly because I'll be going out very soon myself. The last possible day for anyone in research is January 31, but the site is well on its way to emptying out already. As you go down the halls, there are people scattered here and there at desks, working on presentations or finishing up manuscripts or notebooks. But there are more empty spots than occupied ones, and the labs themselves are almost all darkened. It's an odd sight - like a perpetual 6 AM. You feel like you're the first one in the place all day long.

Some folks have found positions, others are out interviewing, and others are still waiting for the phone to ring - but not all of that needs to be done from work, clearly. Between the departures and the people who have no need to show up, the research organization that used to be here is now like a box of marbles spilled on the floor. The really difficult trick would be rounding everyone up again. One side effect of all this is that all of us are going to end up with contacts all over the industry, which could certainly come in useful. (The networking sites like LinkedIn are filling up with ex-Wonder Drug employee profiles these days, including mine).

I've polished off my notebooks and done some lab cleanup, but the rest of the lab (and most of my office) have been waiting on these manuscripts. Now that they're nearly ready to submit, it's about time to empty out the file cabinets and clean off the shelves. The end is most definitely in sight. And like a lot of people around here, I'm more than ready for the beginning of something else.

Comments (13) + TrackBacks (0) | Category: Closing Time

January 11, 2007

An Innocent Question

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Posted by Derek

If you're on the editorial staff of J. Med. Chem., and you've got one of those "Perspective" review articles to go over, and it's on the very important (and very complex) topic of the binding of kinase inhibitors, something that's going to catch the eyes of lots of people all over the place. . .wouldn't you (and your referees) want to make sure that the paper has the correct structures in it? Even down to the level of obscure drugs like, say, Gleevec? Kinase Pro is just asking. . .

Comments (4) + TrackBacks (0) | Category: Cancer | The Scientific Literature

January 10, 2007

Upside Down Activity

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Posted by Derek

After yesterday's post, several people brought up the issue of inverted screening cascades. What happens when your compound works better in the mice than it did in the cells? Worse, what if it would have worked in the mice, but you never put it in there because it was so weak in the cell assays?

These kinds of questions are worth worrying about, because we almost never get a chance to answer them. For obvious reasons, the vast majority of compounds that make it into animal models are ones that looked good in the earlier steps. You'd have to think that the hit rate in vivo would be much lower for the dud compounds, but you'd have to be pretty arrogant to think that it would be zero, too.

As I recall (and I was just down the hall when it happened), the discovery of Schering-Plough's cholesterol absorption inhibitor came out of a compound that made it into an animal model and worked well, even though it turned out later to be a loser at the project's original target. (I believe that the in vitro assay was down that week for some reason, but one of my former colleagues will probably set me straight if I'm wrong about that). This sort of thing is food for thought, all right, extreme example though it might be. Even if your compounds don't suddenly hit a new target, there's still room for plenty of surprises in pharmacokinetics and the like.

But it would be unethical just to shove everything into animals, tempting though it is sometimes. And it would cost an insane amount, too - let's not forget that. But I do advocate getting as close to the real disease as quickly as possible. You can really waste time and effort by over-optimizing in vitro, all the time convincing yourself that you're doing the right thing.

Then there's the ultimate question in this line: how many compounds are there that don't work well in the animal models, but would be good in humans? I've wondered about this for many years, and I'm going to go on wondering, because data points are mighty scarce. Human biomarkers might eventually lead to some companies crossing their fingers and going into man with a compound that they expect to outdo the animal models. But it's going to take a lot of nerve. (And here's another complication - those upside surprises that might show up in the animals? How many of those are going to translate to humans, do you think? Not all of them, clearly. . .)

I have no doubt that there are many potentially useful drugs that are abandoned early. False negatives are probably on the shelves all around us. I don't see that as a strong argument against animal use (what, after all, is the alternative?), but it sure isn't a big argument for it, either. It's just, for now, the way things are.

Comments (11) + TrackBacks (0) | Category: Clinical Trials | Drug Assays | Drug Development

Reality, Here In This Little Dish

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Posted by Derek

I've noticed a few stories making the rounds recently about possible new cancer therapies. Johns Hopkins has press-released the work of a group there on, and several news outlets have picked up on a British study on the effect of vanilloid agonists (such as the hot-pepper compound capsaicin) on cancer cells.

And all this is fine, until the word "cure" starts being tossed around. It always is. The number of times you see it, though, is inversely proportional to how reliable your favorite news source is. I wish the Nottingham and JHU people all the best in their research, and I hope that their projects lead to something good. But they have a long way to go, which you might not realize from the "Johns Hopkins Patents Cancer Cure" and "Hot Peppers Can Cure Cancer" headlines.

You see, these studies are all on cell cultures. I've worked on several cancer research programs, and I'm sure that other readers who've done the same can back me up here: unless you've seen cancer drug discovery work at close range, you may have no idea of just how many compounds work against cancer cells in a dish. It isn't that hard. I have absolutely no idea of how many thousands of compounds I could dig up from our files that will just totally wipe out a lot of the common cancer cell lines - in culture, that is.

We don't even bother looking at a compound unless it goes through cultured cell lines like a flaming sword. Problem is, a good number of those compounds will go through normal cells in the same fashion, which isn't exactly what the oncology market is looking for. And of the ones that are left, the ones that aren't hideous toxins - well, a lot of those hit the skids when they go into a live mouse model. Drug candidates that rip through the cell assays but fizzle in the mouse are very easy to come by. Anyone who does oncology drug discovery can furnish you with piles of them, and you're welcome to the darn things.

Now comes the really ugly part. We've ditched the nonselective cell killers, and we've shaken out the compounds that can't cut it in a live animal. How many of these actually work in human beings? Nowhere near as many as we'd like, that's for sure. AstraZeneca's drug Iressa is always useful to keep in mind. That one was going to be a huge hit, back when it was in development. But in real patients, well. . .for the vast majority of them, it just doesn't do much at all. There are a few responders (some of whom we can screen for), but otherwise, you'd have to call the compound a massive failure in the real world. Oh, but you should see it kick through the cell assays, and watch what it'll do for the mice.

Our assays just aren't that predicitive. It's a big problem, and everyone in the field knows it, but so far (despite crazy expenditures of time, money, and brainpower), no one's been able to improve things much. Anyone who does cancer work knows not to celebrate until the human trials data come back, and you'd better be careful even then. So the next time you read about some amazing thing happening to cells in a dish, well - wish the researchers luck. And go back to what you were doing before. There's time.

Comments (11) + TrackBacks (0) | Category: Cancer | Drug Assays | Drug Development

January 9, 2007

That Smell

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Posted by Derek

You know, I was seeing some more headlines about the powerful natural-gas smell in New York City the other day, and a thought crossed my mind:

You organic chemists over that way, at Columbia, NYU, Hunter College, etc. . .just by chance, did any of you happen to run a great big alkanethiol reaction? Or dump, for some odd reason, a liter or two of the neat stuff down a convenient waste pipe?

Just asking. How much ethanethiol would it take to stink out Manhattan, anyway? Depending on wind conditions, it might not be as much as you'd think.

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January 8, 2007

PLoS One

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Posted by Derek

So, what's this "PLoS One" thing I was talking about, anyway? PLoS is, as many will know, the acronym for the Public Library of Science, one of the beacons of the open-access science publishing movement. They had about half a dozen journals (almost entirely in the medical/biological fields) until recently, when they added PLoS One.

No, it's not the one with fewer calories. I'm not sure why the name was chosen, except perhaps as an attention-getting device. (Is there going to be a PLoS Two?) It is a fairly radical publishing move, establishing something that's part preprint server, part refereed journal, and part user-ranked content site. Papers can be submitted in just about any area of science, and will be checked to make sure that they're methodologically sound - that is, that their conclusions can reasonably be drawn from the evidence that they present. And that's it. Once past that point, everything gets in.

So how do you find out what's worth reading? Here's where the user-generated part comes in. You can leave comments on any aspect of any paper, and as long as they're presented reasonably, they're in to stay. The more comments/recommendations a paper gets, the more attention it will continue to draw. And (although they're not enabling this yet), there will be a ranking system, where readers can assign scores to each paper they're read, with visible aggregated ratings: Science meets Slashdot (or Digg, or Reddit, and yeah, I know that readers of each of these sites spend a fair amount of time making fun of each other). The PLoS people are bypassing most of the debate about how to referee papers, setting up what's essentially a garbage filter and letting the readers sort things out after that.

Papers can also be annotated, with comments attached to specific points in the manuscript. This (and the rating system) are the parts I'm most interested in seeing in action. As far as I can tell, they're going to have anonymity, although you'll have to register (confidentially) to use these features. The guidelines for commenting and annotating seem reasonable:

1. Language that is insulting, inflammatory, or obscene will not be tolerated.

2. Unsupported assertions or statements should be avoided. Comments must be evidence-based, not authority-based.

3. When previously published studies are cited, they must be accurately referenced and, where possible, a DOI and link to a publicly accessible version supplied.

4. Unpublished data should be provided with sufficient methodological detail for those data to be assessed. Alternatively, a permanent Web link to such information should be provided.

5. Arguments based on belief are to be avoided. For example the assertion, "I don't believe the results in Figure 2." must be supported.

6. Discussions should be confined to the demonstrable content of papers and should avoid speculation about the motivations or prejudices of authors.

I can see that they've devoted some thought to what might happen. I think that this will be a critical-mass phenomenon - if enough papers get annotated and ranked, it'll become the norm. And if not, these features might wither on the vine, which would be a shame. I've registered with the site as of this morning. Let the experiment begin!

(More useful commentary here at Evolgen, at The Unbearable Lightness. . ., Sciencebase, Bugs n' Gas Gal, ContentBlogger, Digging Digitally, Evangelutionist, and Notes From the Biomass.

Comments (11) + TrackBacks (0) | Category: The Scientific Literature

January 7, 2007

Good Stuff and Bad Stuff

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Posted by Derek

It's been a while since I opened up the floor on a general question, so I thought I'd toss a couple out. Since thoughts of leaving one company and starting up at another (yet-to-be-determined) one are much on my mind, I'd like to target the industrial side of my readership with these:

What's the one thing about your company's research culture that you'd change if you could?
This can range from things that just plain get on your nerves all the way up to grave structural failures that you think will eventually take the whole place down. You don't necessarily have to offer a solution, partly because too many of those might involve building a catapult to launch specific people into the trees, but if you have something specific in mind, feel free. "Buy enough crates to ship the entire (X) Department to Zanzibar", though, isn't necessarily the appropriate level of specificity, but hey, if that would do the trick. . .

And then there's:
What's one research-related thing that you think your company really gets right?

Even companies with problems generally have at least one or two parts that seem to be working well. Uncommon examples would be particularly useful, because there might actually be something that everyone else could swipe.

Comments (25) + TrackBacks (0) | Category: Drug Industry History | Life in the Drug Labs

January 4, 2007

Take Your Shots (For Real, This Time?)

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Posted by Derek

Late last year, Nature made some noise with their experiment in open peer review. They invited authors, if they wished, to allow their submitted manuscripts to be opened for comments online. As the journal's summary of the process makes clear, though, very few were willing to try it. (My look at the situation back in September wasn't very encouraging, either).

Only 5% of the papers sent out for review during the trial were made available by their authors, and these 71 papers went on to attract very little notice on the peer-review site itself. The editors counted 92 comments total, despite decent amounts of traffic and numerous attempts to drum up interest. As an aside, the statistics would seem to indicate a power-law distribution, which should surprise no one, with a few papers getting a strong plurality of the comments and many getting none at all.

The experiment has ended, and Nature is through with the idea of open peer review for now. But you still have to wonder if there's merit there - and if so, what flaws led to this underwhelming performance. I'd like to suggest one gigantic, ground-shaking factor, which sat right down and made itself at home immediately: lack of anonymity. Does anyone doubt that one reason that traditional peer review works (to the extent that it does) is its anonymous format? Would people be willing to say the things that they do about papers that they're refereeing if they knew that the authors would have their e-mail address and phone number?

I sure wouldn't. In my career I've reviewed for several journals, and even though I've let more papers through than I've rejected, sometimes my assent has been less than enthusiastic - on the order of "Well, this isn't too exciting, but you publish lots of other things just like it, so why not?" And I'm pretty hard on abuses of literature citations - like not citing clearly anticipatory work from some other group, or results which challenge the paper's own conclusions. "Publish only if they fix this part" is a common report from me in those cases. When I do reject a paper, it's not because it's a borderline case, though, because I try to let those through (with suggestions for improvement).

I would feel very inhibited indeed if I knew that the authors of the papers I've criticized were able to contact me directly (or to file my name in their "To Have Dirt Done To" folder). Many more comments would have come in during Nature's experiment if people had the ability to use anonymous screen names (and had the assurance that their real identities would not be revealed, just as in standard peer review). The journal could have reserved to right to delete libelous comments, of course, which in Great Britain is a pretty wide mandate.

But how many authors would have willingly offered up their papers to such a process? Probably far fewer than the 5% who tried system as it was, I'd say. But think of how our current peer review system would go over if we didn't have it already. "You're telling me," says the distinguished first author, "that you're going to send my paper out and let various unknown people rip into it? And you'll never tell me who they are? And I don't get a say in any of it? And this is going to be a major factor in whether my paper even gets accepted?" Imagine dropping that on an unprepared scientific community. It'd never fly

(Note: John Timmer at Ars Technica had a similar response to the anonymity issue, as did Information Week. TechDirt delivers another obituary).

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January 3, 2007

You'll Be Safe Under Here. Maybe.

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Posted by Derek

I see that there's a new edition of the book that organic chemists just call "Greene"; otherwise known as "Protective Groups in Organic Synthesis". This is the fourth, and I'm of an age to remember the first one back in about 1981, when I was still an undergraduate. The new volume could swallow the old one whole - it must be five times the length. Back then the book had some competition, but now it has none at all.

For the non-chemists in the crowd, a protecting group is the molecular equivalent of masking tape. It's a temporary group that you tack on to some reactive part of a molecule to keep it from messing things up while you work on the rest. Ideally, this would be something totally selective for the functionality you're trying to protect, which goes on easily and comes off just as lightly without affecting anything else. Oh, and it has to stand up to every other kind of reaction known to science along the way. That protecting group does not yet exist, or if it does, no one's told me about it. But there are some pretty decent ones, depending on what you're asking them to put up with before their removal.

Everyone who does organic synthesis has to use these things at some point. Because I did carbohydrate-based synthesis in my grad school work (all those hydroxyl groups), I had to use the things constantly, and the trick was to keep them straight and removable in each other's presence. But it's safe to say that no one likes using them. There's a persistent feeling of. . .well, inelegance that attaches to them, no matter how nifty the conditions used to apply and remove them. After all, that's two more steps added to your synthesis, and two which more or less cancel each other out after all that work.

You can't help but think that really advanced organic chemistry will find a way around such problems. We aren't there. For now, it's duct-taped umbrellas, cement-spotted plastic domes, and jammed-on crash helmets for our molecules, and not much we can do about it. Greene's book has all the ugly but necessary details anyone needs.

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January 2, 2007

That Can't Be Right - Try Again

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Posted by Derek

There was an interview in yesterday's New York Times with Harvard Business School professor Clayton Christensen. (Not one of your shy and retiring professors, I should add). He's saying that the US healthcare system is terribly inefficient, and proposes (among other things) that some diagnostic tasks be opened up to a larger field of practitioners than just M.D.s. That's a worthy topic of discussion, but for one of the pure med-blogs, I'd say, rather than over here.

What struck me about the interview was something else - the tone of some of the questions. It's part of an "Armchair MBA" series by William J. Holstein, but the interview seems to have been conducted by Elizabeth Olson, so I'm not sure of the source. Here's the part that gave me pause:

Q. An example of what you mean?

A. A hundred years ago, there was a big disease that nobody understood and was often fatal, called consumption. . .what we thought was a single disease was a whole bunch of different diseases. You had tuberculosis there, at least three types, and you had pneumonia. We thought it was all one disease. So the care had to be left with doctors because they were the ones with the training and the judgment, but once you could precisely diagnose the cause of the disease, you could then develop a cure. It was so rules-based that you didn’t need a doctor any longer. Today a technician can diagnose those diseases and a nurse can treat them.

Q. Are you saying doctors rather than the pharmaceutical industry are the root cause of what’s gone wrong?

A. The pharmaceutical industry has been focused on therapy, not diagnosis. The medical profession has simply accepted that many of these diseases are well-diagnosed, when in fact they aren’t. As a consequence, we haven’t moved the health care profession into a world where nurses can provide diagnosis and care. Regulation is keeping the treatment in expensive hospitals when in fact much lower cost-delivery models are available.

Q. Wouldn’t your solution require a dramatically different regulatory environment?

A. It differs state by state. In Massachusetts, nurses cannot write prescriptions. But in Minnesota, nurse practitioners can. So there has emerged in Minnesota a clinic called the MinuteClinic. These clinics operate in Target stores and CVS drugstores. They are staffed only by nurse practitioners. There’s a big sign on the door that says, “We treat these 16 rules-based disorders.” They include strep throat, pink eye, urinary tract infection, earaches and sinus infections.

These are things for which very unambiguous, “go, no-go” tests exist. You’re in and out in 15 minutes or it’s free, and it’s a $39 flat fee. These things are just booming because high-quality health care at that level is defined by convenience and accessibility. That’s a commoditization of the expertise. . .

Q. Aren’t the pharmaceutical companies also profiting?

A. They are. But in general, pharmaceutical breakthroughs that involve a precise diagnosis of a disease and an effective therapy save the system a tremendous amount of money even though the drugs may appear to be high-cost.

Now, I've never found the tone of the NYT's business section particularly warm where drug companies were concerned. But this really seems to be pushing things along. "You mean it isn't all Big Pharma's fault? But your idea would still allow them to make money!" Do I have my gain setting turned up too far, or is this as obvious to other readers as it is to me?

Comments (27) + TrackBacks (0) | Category: Press Coverage

And The Winner Is. . .

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Posted by Derek

I didn't do any year-end awards around here, but the folks at ChemBark are charging ahead. If you were a reader of Paul Bracher's previous site, you'll have no doubt about who his Chemical Villian of the Year might be. The other awards are coming out as well, and are worth checking out.

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Out With the Old

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Posted by Derek

Now this is a new experience for me. Starting off the new year in the lab has usually been a time for me to clean up the office and bench and think about what I'm getting done (and how that matches up, if at all, with what I should be doing). And I'm doing all that - more of them than ever - but doing it in a research site that's shutting down does turn up the contrast a bit.

Officially, my last day here is at the end of the month. People are more or less free to go, however, if they've completed all their close-out tasks. I'm only partway through, but even so, I certainly don't anticipate making it all the way through January here in this office. Iit's actually nice to know that, rather than just wondering if it's going to be that way or not. Outside of the standard checklist, the main things I need to have done are to finish up a couple of papers (Vial Thirty-Three and another one) and to make sure I've got a coherent interview talk ready to go.

Said office, rather than just being cleaned up, is looking downright Spartan these days, especially since I took all my plants home before Christmas. (I have a large window here, so the orchids are now under a grow-light at home to ease the transition). The shelves are being cleared to an unnatural state, too, and it obvious the minute I open the door that something big is up.

The lab, for its part, looks identical to the last day I worked in it (which may well have been the last day anyone here worked in the lab, because I really pushed it). But that's going to start changing today. The afternoon will be for attacking the bench, and the morning is for writing manuscripts. If I need a break, I can sign notebook pages or see which of my files should be tossed out due to age or irrelevance.

Every year, you wonder how different the new one will be from the old. For me, the fix is in.

Comments (4) + TrackBacks (0) | Category: Closing Time