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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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December 23, 2008

Holiday Break

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Posted by Derek

Posting will be intermittent around here until after January 1st. I'm going to be doing various important tasks at home, such as wrapping presents and making another chocolate pecan pie for folks who didn't get any the last time around. There's also some snow to be shoveled, particularly if I want to get the telescope out during this period of new moon. There's 15 to 20 inches out there on the ground, which is not much of a stable surface for the equatorial platform to sit on, nor do I relish wading through it while hauling the telescope tube itself.

My workplace is very quiet indeed today, I can report, and later on I'll be doing my part to keep it that way. I suspect it's the same across a lot of labs today and for the next few days, and that's a good thing. It's impossible to have good ideas when you're grindstoning away the whole time; you need to clear your head every so often and take a look at what you're actually doing versus what you should be.

This is one of the only times when sleeping late and eating pecan pie come under the heading of "clearing one's head", so I'm going to take full advantage of it. I hope that many of you can do the same!

Comments (19) + TrackBacks (0) | Category: Blog Housekeeping

December 22, 2008

Publish Your Work The Easy Way

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Posted by Derek

I say unkind things about various scientific journals here on occasion. But I have to say that I've never encountered a situation in chemistry that matches the affair of M. S. El Naschie, editor of the Elsevier journal Chaos, Solitons, and Fractals. It's nice to see the editor-in-chief show up with an occasional paper in his own journal - keeping one's hand in and all. But El Naschie has published three hundred and twenty-two papers in the journal since he assumed editorship. He has five in the December issue alone!

The N-Category Cafe, a math blog from the University of Texas, has the full story here. Briefly, El Naschie seems to have been running this journal as his own private kingdom for some time now. While I'm not qualified to referee his works, those who are report that his papers don't make much sense - "undisciplined numerology larded with impressive buzzwords" is one review at the UT site. (That's a phrase I'm going to have to remember for future use; it's bound to come in handy).

Would you like to subscribe to this fine journal, and get the latest updates from El Naschie-land? That'll run you $4520/year. As a library, you'll be getting that as part of a bundle of other presumably more useful journals, so you won't be paying full whack. But still. Why pay anything for a vanity press full of nonsense? (And if there are some real papers in there from other groups, then I pity them for having to appear alongside the gibberish).

Elsevier seems to have finally caught on, after many recent protests. The journal's home page now states:

The Founding Editor for Chaos, Solitons and Fractals Dr El Naschie will retire as Editor-in-Chief. This will be announced in the first issue of 2009. The publisher will work with the editorial board and other advisors to identify a new editor, as well as reviewing the aims and scope of the journal, as well as the editorial policies and submission arrangements.

I'll bet they will. What's puzzling is why this took so long - isn't anyone at Elsevier paying attention? And why did it take some math bloggers to get things rolling - where has everyone else been in the field all this time? Just rolling their eyes and chucking the issues into the circular file, apparently. As I say, I don't know of anything close to this in chemistry - if anyone has info to the contrary, let's get on it ourselves. . .

Comments (44) + TrackBacks (0) | Category: The Scientific Literature

December 19, 2008

My Compound Goes Where the Wild Goose Goes

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Posted by Derek

A colleague and I got to talking yesterday about something that I'm sure many chemists have noticed. Have you ever chased down some reaction or compound in the literature, only to find yourself wild-goosing back to some obscure journal that no one has ever read - just because no one can be bothered to publish a modern procedure?

Here's how that typically works. You run a SciFinder search on Molecular Structure X. A list with a dozen references comes up. There's a Tet. Lett. from 2002, but what are the chances it'll have any spectral data (or anything useful at all?) Ah, there's one from Tetrahedron in 1995, that should do. So you look over the PDF, search for your compound. . .there it is, number 17. Now to the experimental. . .and you find in the first paragraph that "Compound 17 was prepared according to a published procedure", footnote thirty-eight. And the footnote is to. . .ay, it's to a Chem. Ber. paper from 1932. Ausgezeichnet!

Oh-kay. Back to that SciFinder reference list. How about that Tet. Lett. paper? Nope, on inspection, it turns out to reference the 1995 paper you just looked at. What else? There's a JOC from 1984, let's try that. Good ol' JOC, solid stuff. Well, digging up that PDF, you find that it refers to a 1980 paper from the same group from Synthesis. Hrm. So you chase that one down, there it is, compound 9, and the experimental for it is. . .footnoted to the 1932 paper. Again.

And that's how it goes. Like as not, you can go through the whole list and find that it's made of tissue paper where your compound of interest is concerned. The whole presence of the compound in the literature is, in the end, based on some obscure German university's report from the last days of the Weimar Republic. What's irritating is that while those 1932 folks clearly must have made the compound, it's not always easy to get those papers immediately. And chemistry has, in fact, changed a bit since those days. Papers from that era rely on distillation and crystallization: there are no chromatographic purifications, because there was (by our standards) no such thing as chromatrography. Spectral data? Hah! UV/Vis was cutting edge back then. You'll get a melting point, an adjective-laden description of the appearance of the crystals, and maybe even a note about how the stuff tastes. Great.

You know that the people who re-made the stuff during the last 25 years didn't steam-distill their product or fractionally crystallize it from some mixture of benzene and carbon disulfide or whatever. They ran a quick column and they took an NMR. So why can't they publish that data? The only reason I can usually see is laziness. Why bother? It's a known compound; just reference it and get that manuscript out the door. . .

Comments (27) + TrackBacks (0) | Category: The Scientific Literature

December 18, 2008

When Placebos Were All There Were

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Posted by Derek

Yesterday's discussion of how to deal with various forms of pseudoscientific hoo-hah naturally brought up several mentions of the placebo effect. And that prompts me to bring in the late Lewis Thomas's The Youngest Science, his memoir of a life in medicine. We should never forget that there was a time, not all that long ago, when drug therapy was almost all placebos. Here's a description of the way Thomas's father practiced in the 1920s:

Nevertheless, despite his skepticism, he carried his prescription pad everywhere and wrote voluminous prescriptions for all his patients. TThese were fantastic formulations, containing five or six vegetable ingredients, each one requiring careful measuring and weighing by the druggist, who pounded the powder, dissolved it in alcohol, and bottled it with a label giving only the patient's name, the date, and the instructions about dosage. The contents were a deep mystery, and intended to be a mystery. The prescriptions were always written in Latin, to heighten the mystery. The purpose of this kind of therapy was essentially reassurance. . .They were placebos, and they had been the principle mainstay of medicine, the sole technology, for so long a time - millennia - that they had the incantatory power of religious ritual. My father had little faith in the effectiveness of any of them, but he used them daily in practice. They were expected by his patients; a doctor who did not provide such prescriptions would soon have no practice at all. . .

That's the world as it was. Thomas later recounts the profound shock he experienced as an intern when sulfanilamide was introduced: patients given up for dead got up out of their hospital beds and asked for something to eat. It was then, he says, that he realized that the medical profession he was entering might be turning into something different from what his father knew.

We should never forget: it's our job to make our children look back on today's medicines with the same mixture of pity and alarm. To cure disease, stop the damage, make people given up for dead stand up and walk out of the room to see their families. Things aren't going very well for us now in this business, because these are all very hard things to do, and the amount of time and money needed to do them is nearly unbearable. But not quite. We can see that such things are possible, and it's up to us to figure out how to make them real.

Comments (17) + TrackBacks (0) | Category: Drug Industry History

December 17, 2008

Awkward Conversations

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Posted by Derek

We need a lighter topic today, and I’ve got one appropriate to the season, since many people will be having parties and family get-togethers over the next couple of weeks. And although some of these will be full of scientists, there are others where you might be the lone representative from the world of chemistry, biology, or medicine. That can be a good thing – or not so good, depending on how the conversation turns. A reader e-mailed me an account of a recent encounter with a relative who assured him of the benefits of foot-bath detoxification to cure what ails you. As you'd imagine, he didn't quite sign on to that idea, and the discussion went through a few rocky rapids.

I know that this sort of thing has happened to me several times. I’ve had to deal with the topics of how no, it’s not a conspiracy of the drug companies to make vitamin-based therapies illegal – and how yes, I have been working for X number of years in the drug industry without discovering a single thing that’s on the market, and how that’s statistically rather likely. And I’ve explained how it’s hard to come up with a cure for Alzheimer’s when you don’t even know what causes Alzheimer’s, which argument generally meets with agreement. But that reasonable discussion gets canceled out by plenty of others.

Dealing with the crazier propositions takes some real tact. I’m a pretty even-keeled guy, so I generally take a calm approach, just telling them how it is for me after X years of experience in the drug industry. I've found it's harder for people to spout craziness when there's some reasonable person sitting across the table from them who makes a living on the opposite side of their beliefs. And, truth be told, many of the wilder beliefs in the health field aren't necessarily all that strongly held. Most of them don't stand up to much scrutiny (and contradict each other, to boot), and I've found that people pick up and discard them with relative ease.

But you do run into passionate believers now and then. I'd be interested in hearing from people how they've dealt with conversations like this. My usual progression goes something like:

1. That's interesting - where did you hear about this?
2. No, it's true, I really have been working on those diseases for years now. As far as I can tell, they're pretty hard to deal with.
3. Gosh, that anecdotal evidence sure does sound convincing. Pity the FDA won't let us use any of that where I work. Those nutritional supplement manufacturers sure have it easy since the Hatch-Waxman act, don't they?
4. Hmm, since Fact X seems to be true about Disease Y, based on all that I know about the subject, how do these fit together?
5. Well, you know, the laws of physics/chemistry/math that I learned don't seem to cover that particular effect - have they added some recently?
5. No, I think that if there were any conspiracy that big, I probably would have noticed it at some point. Unless you're suggesting that I'm part of the cover-up?
6. Actually, people in the drug industry die from Disease Y, too. You'd think that if we were sitting on the cure for it, we'd have some sort of employee program or something. . .

Comments (30) + TrackBacks (0) | Category: General Scientific News

December 16, 2008

Layoffs. More Layoffs.

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Posted by Derek

I’m told by several people that today Bristol-Myers Squibb is announcing layoffs in research (and perhaps other areas). I don’t know how extensive these are, or how they’re spread across the New Jersey and Connecticut sites. What I do know is that accounting practices make these things especially rough, since a disproportionate number of such cuts take place before year’s end, which doesn’t do much for anyone’s holiday season. (Of course, I suppose it could be even worse – you could be working for Pfizer, and spend the holidays not knowing if your job was going to be there in January or not). In a smaller but deeper cutback, I also note that Entremed, a company that’s been struggling to survive ever since its turn in the spotlight with Judah Folkman’s anti-angiogenic peptides, has announced that sixty per cent of its employees will be let go. Since that includes the CEO and CFO, you have to conclude that the situation there is not good.

Having been through the layoff process myself, I know what the people involved are going through, and I wish them every hope of landing new positions. If anyone out there knows of companies that are hiring now in research, or even planning to, I’d be glad to list such in a separate post in order to provide some leads.

One other related item: I’ve heard from Linda Raber at C&E News who’s working on a "Careers in Pharma" story for them, and wants to write about all the chemistry layoffs this year. She’d like to hear from people who are willing to be quoted on what things have been like. (Update: you don't have to be identified - see the comments section for contact info!) I was quoted in a similar story after the Wonder Drug Factory layoffs, actually; this sort of piece is turning into more of a perennial than anyone would like.

Comments (53) + TrackBacks (0) | Category: Business and Markets | Current Events

December 15, 2008

Insider Trading in Drug Stocks? Not Unknown. . .

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Posted by Derek

With all the financial scandals going on these days (really, a multibillion-dollar Ponzi scheme run by the former head of NASDAQ?), it’s worth asking how often such shady dealing goes on with the stocks of drug companies. From what I can see, it does happen, but it’s certainly not endemic.

The first thing that comes to mind is insider trading. Since many companies see their stock move abruptly on the single news items pertaining to clinical trials results, regulatory actions, adverse events, and so on, front-running is always going to be a problem. And I’m sure that it goes on, but I also know that companies put a lot of effort into trying to keep it from happening. For clinical trial results, that means that such information is strictly need-to-know, and believe me, not that many people need to know. Most companies have a rather short list of people who see such numbers before a public release, which makes tracking down suspicious trades a bit too easy for comfort, if you’re inclined to reach for the easy money. I’m certainly not on any such list myself, and never have been.

There are other kinds of material information, but it’s still rare for anything that goes on in my end of the industry to affect the stock price. We’re just too far from the clinic and from the FDA to make that much of a difference. But in any case, I agree with a definition of “material information” that I once heard: if it makes you think about trading the company’s stock, and it’s not in a press release already, it’s material information. And you act on it at your peril.

But that doesn’t mean that people don’t act. Sam Waksal of Imclone is merely the most famous executive to place a phone call to his broker at an inopportune time. The chief legal counsel over at Biogen Idec got in hot water a couple of years ago about a suspicious options trade around the time of the bad news about the company’s Tysabri. (The case was settled with the SEC, with no language about wrongdoing involved - there was still some reasonable doubt about the timing of the trade, although it would have been far more prudent to not have made it). A few years before that, the chief attorney at Vertex got into trouble with another ill-advised trade of his own company's stock. And there are others, naturally.

Then there's the problem with theoretically-embargoed information from the big clinical meetings like ASCO. In recent years, it's become clear that this stuff is leaking out in one form or another, because interesting trading patterns become evident in the run-up to the meetings themselves. I think that sending out an abstract book while trying to keep the lid on them is probably futile. Of course, in many cases the real stock-moving news in such cases doesn't come from anything in the abstract book, but from the information in the presentations themselves, which is all later-breaking stuff added long after the abstract submission deadline. So you could argue that people trading on the pre-meeting stuff are still kidding themselves. . .

The closest I've ever come to this sort of thing myself was some years ago. A colleague attending a clinically-oriented meeting in a particular medical specialty called some of us back at our company to say that an anticipated series of posters and talks from another company didn't look like it was going to materialize. No one from that organization was putting anything up for the poster session. We guessed that there was some last-minute problem with their compound - and so it proved in a press release the next morning.

It occurred to me during that afternoon that a stock or options trade could well be profitable, but I didn't go through with it. It would have been profitable (especially the options, naturally), but in the end I didn't quite have the nerve. I still don't think that it would have been illegal, but I didn't like the idea of explaining actions of mine in those terms. "Not illegal as far as I know" isn't exactly the rock on which one wishes to make one's stand, you know?

Comments (10) + TrackBacks (0) | Category: Business and Markets | The Dark Side

December 12, 2008

The Worst Biotech CEO?

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Posted by Derek

I'm pleased to note that Adam Feuerstein over at TheStreet.com has announced his first-ever "Worst Biotech CEO" award. In what was surely a contested field, he's named Elan's Kelly Martin as the winner. I was pulling for Ariad's Harvey Berger, who seems to have come close. Well, there's always next year - and yes, I do need to update the Ariad story soon.

Martin's win is a result of the troubles with the anti-Alzheimer's antibody bapineuzumab this year. When pivotal trial results came out back in July, they weren't too exciting. Investors, though, had been very excited indeed, and Elan's stock took a terrible beating as a result. According to Feuerstein, Martin's cheerleading for the drug was the reason for this unprofitable disconnect from reality.

He certainly wouldn't be the first CEO to beat the drum for his company's drug, but this kind of thing has a big risk of backfiring. How do investors believe you after they've been burned in this fashion? You don't want to have to depend on fresh crops of people who haven't heard your story yet. Alzheimer's is a tremendously difficult field to make headway in, and everyone who wants to buy into something in it needs to understand that. As an investment, such drugs are worth taking a flier on, but with a clear understanding that the odds are long. I think that Elan (and their partner, Wyeth) deserve credit for going after something as unusual as an immune-based therapy for the disease, but there's no excuse for making people think that it's working if it really isn't.

Anyway, be sure to check out Feuerstein's take, along with the comments on Vanda, Medarex, and other favorites. I hope he keeps this up year after year: there will never be any shortage of contenders.

Comments (7) + TrackBacks (0) | Category: Business and Markets

December 11, 2008

Pfizer's Restructuring Grinds Along

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Posted by Derek

So, Pfizer: it seems as if they’ve been going on about cutting their research staff for months now. Well, its has been months, and the whole thing is turning into a rather bitter joke for people in Groton, from what I can tell. This current wave of restructuring has been rumbling along since back in the summer, and they told people about the layoffs in the fall. How long is all this going to take?

The latest announcement from the higher layers is that the company will announce its plans “sometime in January”. Lee Howard, a reporter at the New London paper The Day, has a copy of a letter from Pfizer’s Rod MacKenzie (head of discovery research worldwide) to employees, saying that because the changes in research are so complex, he won’t be able to communicate them by the end of the year. I’m not sure if the letter includes his greetings for a Merry Christmas and a Happy New Year; maybe that one will arrive in time for Valentine’s Day. Here's the article, the comments to which erupt in a lot of vituperative town-vs-gown New London crossfire.

From what I’m hearing, the coming changes are going to be quite profound in chemistry. Pfizer seems to be dividing its chemists up into people who think up molecules, and people who make them, with no real overlap. You’re probably thinking sure, that’s how the Germans and the Swiss tend to do it, the PhDs in the offices and the BS/MS folks out at the hood. But apparently there are PhDs on the “make the molecules” side in Pfizer’s new scheme, although I think the “design the molecules” side will have no one who isn’t. At any rate, the traditional medicinal chemist, someone who has an idea for a new molecule and then goes out to the lab and makes it, will seemingly have no place at Pfizer. You do one, or you do the other.

And I’ve heard from several sources that major outsourcing will be a big part of the new system as well. The “drug designers” will also be resource managers, spending their time figuring out what compounds and series to ship over to China, and what to have the local groups work on. As readers here well know, I think that outsourcing definitely has its place, but Pfizer seems to be going even further down that road than the rest of the industry – how well that’s going to work is an open question. A lot of the outsourcing work I’ve seen over the years has been. . .OK. Used judiciously, that’s fine, but I don’t know if I’d want to base whole programs on it if I didn’t have to.

I think it’s safe to say that morale and productivity in the labs in Groton must be drooping a bit these days. How could it not be, with everyone waiting for months to see who’s going to be let go, and in this economic climate? I understand that it’s a big organization, and that figuring out what to do is a complicated job. I certainly wouldn’t want it. But the way this is being done has not reflected well on the company’s management and how it treats its employees. But we’ll just have to add this one to the existing lists in both categories. . .

Comments (57) + TrackBacks (0) | Category: