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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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July 31, 2006

Hobson's Choice

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Posted by Derek

One of the things I've noticed over the years is that I rarely stay on a project long enough to have the kind of familiarity with the molecules that I had with the ones I worked with in graduate school. I'm not complaining. I knew my PhD project molecules like an infantryman knows the hundred-pound pack on his back - that is, much more than I ever wanted to or believed possible. I knew tiny details in their NMR spectra, things like long-range coupling constants and NOE enhancements, and the moment something changed I would point like a hunting dog.

But now, my lab stays on a project for a few months, maybe a year at the outside. And during that time, we'll work on several varied groups of molecules - usually with the same core, but with all sorts of things coming off of it. We get a working knowledge of them, but we're always being surprised by little details that would have been second nature after a good solid three years of the same series. Of course, after that good solid three years we'd all be good and solidly sick of the chemistry, too, but that's the price tag.

I used to tell people in grad school, while I hauled yet another load of synthetic intermediates up the mountainside, that the grunt work left me a choice of two moods: bored, or angry. If everything was working just the way it always had, I was bored. And if a reaction decided to unexpectedly fail, then. . .not much of an emotional range, is it? No, I'll take what I have now, where boredom doesn't have as much of a shot at me, and I don't have the chance to stay angry about any one thing for long. Variety, the spice of chemistry. (One of my "Laws of the Lab" covers this topic - I'll get to that later in the week).

Comments (12) + TrackBacks (0) | Category: Graduate School

July 30, 2006

Pfizer's Man at the Top

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Posted by Derek

I'm actually going to try to show some restraint and not make snide comments about Pfizer's announcement of a new CEO. True, Hank McKinnell is retiring at least a year before he said he was going to. But hey, I wouldn't want to be running Pfizer right now, either. And true, Pfizer's stock is down over 35% over his tenure - but as you can see from this chart, it wasn't until the first part of 2004 that PFE and the S&P 500 index definitively parted ways. And it's true that the new CEO, Jeffrey Kindler, is a lawyer rather than a scientist or businessman, has only been in the drug industry since 2002, and came to Pfizer from McDonald's.

The reason that I'm not throwing a fit about this is because I think, to a good first approximation, that it doesn't matter very much who the CEO of a large company is. As long as they're reasonably confident and competent, and not noticeably larcenous, it doesn't matter. I realize that I've just contradicted whole shelves of business books, but keep in mind that many of these are written by CEOs and/or the people that love them. I don't have much use for cults of personality, and that's what I think you get when you make too big a deal out of the top job. You can fill in the outlines of my opinion of, say, Jack Welch.

So I wish Jeffrey Kindler luck. As he's probably already noticed, he's in a rather different industry than the ones he's worked in before - and he shouldn't trust anyone who tries to tell him different. He should also show anyone the door who tries to make a case for exceptionalism, that Pfizer can succeed as a great behemoth because they're just so darn Pfizery. No, all he needs are a lot of smart, hard-working people, a lot of money, and - not least - some good fortune. Which is all anyone needs to be a success.

Comments (11) + TrackBacks (0) | Category: Business and Markets

July 27, 2006

Good News, Now That I Think About It!

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Posted by Derek

I have the results of my latest experiment. A thing of beauty it isn't - two of the four control arms showed false-positive effects in their blank runs, which makes interpreting them impossible. Those of you who've been following this story - and you have my sympathy - may recall that I saw this exact thing happen before. I wondered for a good part of the day why that might have happened, and maybe I've become slightly more intelligent in the intervening weeks, because on the drive home an idea hit me that would explain it quite well. I'll set up a short run of experiments to go over the weekend to test that out - if I'm right, it's an avoidable artifact and a complete red herring. Another arm of the experiment was a check on whether I could get away with running these things for a shorter time course, and the answer to that is: nope, I can't.

But there were good parts: the effect I'm looking for, the "Vial Thirty-Three" experiment, did repeat again, which is always reassuring. And the two other control arms behaved normally in their blank reactions - no weird positives - and they did just what I hoped they would do under the experimental conditions. This is good news, because they have very little in common with each other, and it's hard to see how they could do the exact same thing unless my hypothesis about them is correct. The more I look at those numbers, the happier I get. It's been slowly dawning on me that these may be the results I'm looking for.

But before I can be sure about that, the next item is to see if I can explain those blank-vial positives, and to also try a couple of variations on the runs that seemed to work. There are some minor changes I can make to them which should tune them up and down or flip them back the other way, and it's time to see if they're thinking the same way I am. I think I can feel the ground becoming more solid under my feet, though. . .

Comments (5) + TrackBacks (0) | Category: Birth of an Idea

July 26, 2006

Pfizer Recalculates

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Posted by Derek

That Pfizer article I was blogging about yesterday made much of their new HDL-raising therapy, torcetrapib, and the company's plans to only sell it as a combination therapy with Lipitor. That's been a controversial idea, naturally, given the number of people (and the number of insurance companies) who would rather be able to take it alone or with the statin of their choice.

But according to today's New York Times, Pfizer has dropped the idea. Torcetrapib (I await announcement of its brand name, so I don't have to type that) will be available alone as well as in combination.

The drug is an inhibitor of cholesteryl ester transfer protein, CETP, which is mostly bound to HDL particles in the blood. It spends its days shuffling cholesteryl esters and triglycerides among different lipoproteins, generally evening things out among the various lipoprotein fractions. But cholesteryl esters mostly come in as a component of HDL, so the overall effect of CETP is to transfer the cholesterol compounds away from HDL to LDL and other fractions. (Triglycerides, for their part, tend to be moved in the opposite direction). If you could inhibit CETP, the HDL-bound fraction of total cholesterol should increase, and that it does. And since it's been known for some time that loss-of-function mutations in CETP seem to be cardioprotective, the mechanism seems pretty sound. The drug is expected to be huge.

So why did Pfizer about-face? The Times article quotes a Pfizer official as saying that all the criticism was certainly a factor - "We didn't appreciate how this would be perceived", he said. That sounds rather unlikely to me, given that a child of ten would have been able to immediately appreciate how Pfizer's bundling strategy would be perceived. No, I think it's time to apply my general rule that most questions that start with "I wonder how come they. . ." can be answered by "money".

In this case, it may well have been some advance pushback from the various managed-health organizations. Everyone involved knows that this is about the time a decision would have to be made on whether torcetrapib would be sold solo or not, given the regulatory and manufacturing lead times, and I'm sure some strong opinions on the subject were quietly exchanged. Like any other company, Pfizer does nothing, or at least tries to do nothing, that is not in the best interest of Pfizer, and they've no doubt decided that bad publicity is one thing, but putting a possible limit on their new drug's sales potential is quite another.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease

July 25, 2006

The Sun Shines at Pfizer

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Posted by Derek

The New York Times ran an article last week profiling Pfizer's head of research, John LaMattina, as "Dr. Optimistic". He seems to be earning the title:

But in two recent interviews, Dr. LaMattina said the pessimists, on and off Wall Stret, were about to be proven wrong. "The science has exploded and all sorts of things are happening," he said over tea last month at the Carlyle Hotel in Manhatan, where Pfizer executives were meeting to discuss the company's strategy for 2007.

He insists that Prizer - the entire industry, for that matter - is on the verge of a new age of drug discovery, one that will turn cancer, diabetes, and other debilitating illnesses into manageable conditions. Decades of research into the mechanisms of disease have given drug makers hundreds of promising new cellular and genetic targets to study.

I've got to disagree with the man here. While I think we are in the process of turning (some kinds of) cancer into a manageable disease, and while progress is being made in a lot of other areas, I'm having trouble picturing hundreds of promising new targets. In fact, I'd challenge anyone to name a hundred cancer targets. I'm sure it could be done, actually, although not without some spadework, and I can guarantee that you won't be reaching for the word "promising" by the time you get even halfway through the list. "Interesting", yeah. "Speculative", absolutely. But "promising", well, I'd rather not promise that much.

I should mention that some of LaMattina's sunny outlook seems to have rubbed off on Alex Berenson of the Times, because he makes special mention of Sutent as an important drug because it came out of Pfizer's own labs. Well. . .sort of, if by that you mean "out of the labs of a company that Pfizer bought, changed the name of to Pfizer, pillaged, and closed", then it's perfectly true. Otherwise, not so true.

But LaMattina sounds like a reasonable person otherwise, which like many people, I define as someone who shares my opinions:

Dr. LaMattina said that, given the complexity of the science underlying drug discovery, he tried not to become too optimistic or pessimistic about any new compound. "I have seen too many research heads be too absolute about, 'This is a good program; kill this program' ", he said. "It's very easy for someone to come in and say 'Kill it.' "

I wish him well. But I don't share his outlook, not completely. It's true that we're accomplishing some big things in the industry, but we're spending a ferocious amount of time and money to do it, and the outcome is not yet clear. And that goes, with cherries on top of it, for Pfizer - one phrase that doesn't appear in the article is "Lipitor patent expiration", and you can't write about the future of the company and ignore that one.

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

Back To Life

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Posted by Derek

It's been a little while since I updated everyone on my long-running series of experiments, but I do have some news. At last report, I'd set up a large crucial experiment, and actually seemed to get it to work in the notorious Vial Thirty-Three. Of course, when you get something remarkable to happen in the lab, the first thing to do is see if you can make it happen again, and that's where the trouble started. The first repeat was rather nasty, and the second one was no better. I was baffled, since the first run had looked so promising.

My colleague Joanne, who was analyzing these samples for me, was puzzled, too, but she at least knew something to do about it. There's a huge benefit to working with people who know what they're doing. She took that third run and ran the samples for me again, this time in a much longer gradient on the LC/MS. (For the non-chemists out there, this means that the purification part of the method was extended, spreading out the various components of the mixture more). The control vials looked just like they had in the first run - not much, which is what controls are supposed to look like. The experimental vials had looked the same way, though, but with this new run my data appeared as if the results had come out from behind a cloud. Suddenly it looked like the first run again!

They'd been in there all along, as it turns out, and a cloud of ion suppression is what they were hidden by. This is a real problem with mass spec methods using mixtures of proteins (and the stuff that keeps them happy). There are a lot of reasons for this, only some of which are well understood, but having your analytes disappear and reappear unpredictably on you is apparently a widely shared experience.

I tried to see if there was some single component in my brew that I could leave out and thus fix my problem, but I should have saved my effort. That rarely seems to be successful - the real solution, as would have been clear to a real chemical biologist, is to run things the way you have to, and then clean up your samples before they go into the machine. The best way to do that is probably solid-phase extraction (SPE), which entails loaded your mixture onto some sort of powdered polymeric stuff which binds the analyte you care about. That lets you wash all the gunk out of the system, and then you use a different wash to elute the good stuff.

Here's an older review that illustrates the principle. These days, there are dozens of competing SPE technologies from all the major lab vendors. I evaluated a set of the more popular ones by setting up a row of dummy experiments - all my proteinaceous stuff, spiked with a constant amount of my desired product. All of them improved things, but one in particular (the Waters Oasis MCX, for those curious) seemed to do the best job, although I'm sure that there are others that would work as well. The method I worked out for it was the most complicated of all the ones I tried, but it's probably washing out the most sludge, too, because I'm getting ten- to twenty-fold more signal than I did before.

So, late last week I set up my first "Vial Thirty-Three" experiment again and worked it up with the SPE. It reproduced perfectly, to my great happiness, which takes me right back to the edge of things. Before I left the lab on Monday, I set up another run, this time with six different control and experimental arms, in duplicate, the most comprehensive look at this effect I've ever taken. I'm working it up today. Results in a couple of days, most likely. I'll keep everyone informed.

Comments (7) + TrackBacks (0) | Category: Birth of an Idea

July 23, 2006

Hexacyclinol Rides Again

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Posted by Derek

The hexacyclinol controversy has taken a very interesting new twist, which I learned about on Friday from Dylan Stiles. To recap: the molecule is a complex natural product, which was the subject of a total synthesis paper earlier this year by James La Clair. The paper had several unusual features, such as single authorship with acknowledgements to several unnamed co-workers, an odd source (the "Xenobe Research Institute" and "Bionic Bros. GmbH" and (not least) several key chemical steps that appear to make little sense, backed up by fishy NMR data.

Then Prof. Scott Rychnovsky of UC-Irvine popped up with a proposal that the structure of hexacyclinol had been wrongly assigned in the first place. He assigned a completely different structure, with rather solid-looking reasoning behind it, which raised the question of just what La Clair had synthesized. How can you get the right spectral data by making the wrong structure, when the structures are so different as to make that impossible?

Turns out that Rychnovsky had another ace to turn over. The web site for Angewandte Chemie, where the original La Clair paper ran, has now put up advance notice of a paper on the synthesis of the revised structure of hexacyclinol, which appears to indeed match the published spectral data. This grenade is from Paul John Porco at BU, some of his students, and. . .Scott Rychnovsky, who apparently wasn't going out on as much of a limb as I thought.

La Clair has seen the writing on the wall, and apparently realizes that he has indeed been weighed in the balance and found wanting. During the day on Friday, the Xenobe Research Institute web page was updated. It now features Rychnovsky's revised structure (Update: or does it? See the comments!), with this text:

Desoxoudol (previously named desoxohexacyclinol)...

Efforts are underway to identify pathways that regulate the growth and development of four parasites responsible for Malaria, Plasmodium vivax, P. malariae, P. falciparum and P. ovale. Our first study conducted on desoxohexacyclinol, currently renamed as desoxoudol, is a terpene isolated from cultures of a German Borstiger Knäueling mushroom (Lentinus strigosus = Panus rudis Fr.). Earlier 2006, Dr. La Clair published the synthesis of desoxoudol demonstrated its conversion to udol and 5-epi-udol. Due to the unconventional nature of this effort, efforts are now underway to repeat this isolation and synthesis. Samples of these intermediates will be verified through analysis by a panel of external laboratories.

Unconventional. . .well, yeah, in a way. It's unconventional to synthesize a complex molecule and get the NMR structure of something completely different, that's for sure. But it's very conventional indeed to go back and attempt to spray-paint the record to make it appear as if something strange and embarassing hadn't happened. Oh, that part happens all the time. And that's exactly what I think is going on here.

For more comments on all this, see the Stiles link and The Chemblog. This is turning into the biggest stink-bomb in organic synthesis in many years.

Comments (12) + TrackBacks (0) | Category: Chemical News

July 20, 2006

Peptide Craziness

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Posted by Derek

Since I was talking about peptide synthesis yesterday, and the usefulness of peptides in general, I thought a few back-of-the-envelope calculations would be interesting. After all, if we're going to be making the things, we should know what we're getting into.

How about a combichem library of the things? Let's see. . .since someone mentioned vasopressin and oxytocin, let's figure that other 9-mers could have some interesting activity. What if we want them all? With the twenty most common amino acids in hand, and our peptide synthesizer machines recently serviced and reloaded, we throw the switch and. . .a mere five hundred and twelve billion peptides later, our library is ready for screening.

Ahem. That's well more than ten thousand times the number of organic substances that are indexed in Chemical Abstracts. This exponential stuff gets out of hand pretty quickly. Storing the stuff will be a problem. At, say, ten milligrams per compound, we're looking at five million kilos of peptides, and that's before the glass vials are added in. Protein folks look aghast if you talk about producing as much as ten milligrams of any given peptide, but hey, if we're going to turn the things into drugs, we have to get ready to work on scale.

And if we're going to make drugs, we're probably going to have to deal with some unnatural amino acids to improve metabolic stability. That has an effect, too, as you'd figure. Adding in one extra gives you an extra two hundred and seventy billion peptides, which is certainly value for your synthesis dollar. If you're going to get the deluxe package, with the D and L forms of the nineteen chiral ones, that'll run your screening file up to 200 trillion total, which is going to put a real strain on the chemical synthesis capacity of the entire world economy. Call ahead.

So a library of 26-mers, the size of Fuzeon, is going to be really hard to handle. That comes to a cool 6.71 times ten to the thirty-third power, which is beginning to get into the realm of really substantial numbers. At ten mgs per compound, we're down to the 6.7 times ten to the 25th metric tons, which is only a bit more than. . .ten thousand Earths. Well, ten thousand Earths made up of an even mixture of the twenty amino acids, that is, rather than boring old inorganic rock.

Let's just say that there's a lot of patent space, and plenty of reduction-to-practice loopholes, and leave it at that. . .

Comments (11) + TrackBacks (0) | Category: General Scientific News

July 19, 2006

Fuzeon's Fallout

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Posted by Derek

I wrote some time ago (Ay! Four years ago - have I been doing this for that long?) about the Roche/Trimeris HIV drug Fuzeon (T-20, enfuvirtide), and its costly manufacturing process. Roche built a factory in Colorado just to make the drug, which is a 26-amino acid peptide. And instead of doing it recombinantly, they're producing it the good old chemical way, by peptide coupling. (Here's a not incredibly competent collection of whiz-bang photos of the place, which at least have no purple spotlights in them)

Back in 2002, I had some thought that Roche had perhaps lost its corporate mind. But as this article from Chemical and Engineering News points out (subscriber-only, I think), they've actually done everyone a favor, whether by losing their minds or not. Their decision to go fully synthetic, and the massive investment that followed, has lowered the cost of all sorts of peptide synthesis reagents, starting materials, and equipment, to the point that it's now become enough of an industry to attract a lot more production interest. (And one of the big players in the contract business is. . .Roche's Colorado facility!)

As the article points out, recombinant technology (producing the peptide in engineered cells) is a wonderful thing, but only when it's working perfectly. And getting it to that point can be a long, expensive task. There are a lot of potential cell lines to choose from, each with its own advantages and disadvantages, and uncountable ways to engineer them and culture them. Even then, the purification of the target protein can be a whole new nightmare - as one chemist interviewed by C&EN says, at least synthesis doesn't give you back ten times as many different things as you put into it.

Peptides still aren't anyone's first choice for development when there's a small-molecule alternative. But for the targets that no small molecule is going to hit, they're worth looking at. Recent years have seen improvements in metabolic stability and duration of action, as people come up with all sorts of nifty delivery systems and conjugate polymers. You could do a lot worse.

But perhaps Roche could have done better. There were all sorts of glowing forecasts about Fuzeon when it was first approved, and all sorts of grumbling from people who took the optimistic numbers and calculated that Roche would be making its money back in two or three years at the prices they'd set. Well, that hasn't happened yet, since the drug isn't selling nearly as well as had been hoped.

Another two or three years should do it, if nothing better comes along to cut into Fuzeon sales. And stipulating that (which is no sure bet) Roche might be selling it for a long time to come, since the barrier to generic manufacture is going to be rather high. So, even after that wild factory in Colorado, they're still probably going to go into the black on Fuzeon, but it does make you wonder how the return compares to some of the other drugs in Roche's portfolio.

But that's their problem. In the meantime, it looks like they've helped everyone else in the business by making industrial peptide synthesis more affordable. Adam Smith's invisible hand strikes again. . .

Comments (11) + TrackBacks (0) | Category: Drug Development | Drug Prices | Infectious Diseases

July 18, 2006

Getting and Spending

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Posted by Derek

Well, we're now into earnings report season in the drug industry. Not that we notice much in the labs, mind you, but the stockholders do sit up and pay attention. Profits seem to be up, which prompted a colleague of mine to wonder today when the first New York Times story will appear noting this with worry and disapproval. They have some people that I enjoy reading, but a tone does tend to creep in that suggests that any profitable industry must necessarily be extorting The Masses.

Well, I can cheer them up. The thing about drug industry profits is, they're pretty much all based on wasting assets. The drug business is an endless treadmill. Most businesses have this problem to some extent, but it's very explicit in our case. When your big patent runs out, the music stops very abruptly these days, so you'd better have something to replace it.

But you know, I'm not complaining about that. Patents should have defined lifespans, although we can argue about how to set them. Knowing that they're going to go away, though, keeps us moving. (For similar reasons, I wish that copyright hadn't been extended a few years ago). If we had big whopping patent terms, the temptation to just sit around and roll in the money would be too great. The pace of discovery would slow. I see it as the function of government to discourage that kind of inertia, although not by just yanking all the cash away, which position I realize also has some support.

Nope, it's the middle ground for me: enough time to make good money, but not so much time that everyone becomes too lazy. Here's the question, though: stipulating that that's what we want, are the current patent terms too short, too long, or on target?

Comments (24) + TrackBacks (0) | Category: Business and Markets | Patents and IP

July 17, 2006

Pounding Sand

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Posted by Derek

My chemistry readership is used to thinking in terms of reaction mechanisms. Those of you outside the field who've gone as far as organic chemistry will have come across them, too: pushing electrons for fun and profit. Chemists really do think in those terms, I can tell you - it's not just something they torture the sophomores with.

Here's a page with some good examples of classic mechanisms. (Update: that link may not be able to handle the attention. Other mechanism pages can be found here and here, and there's a well-done Flash site here.) Non-chemists will note mainly the profusion of curved arrows curling around the page, and wonder what we must be getting out of that stuff. The idea, though, is that chemical reactions involve bonds between atoms breaking, forming, and rearranging, and those bonds are formed through electrons. So most of what goes on in organic chemistry can be thought of - very successfully - as the movement of electrons, and that's what the mechanisms are showing schematically.

But reaction mechanisms are also one of the things that chase people out of the field completely as students. The problem is, the lazy way to teach an organic chemistry course is as a Huge Heap of Reactions, to be memorized and tested on. Buy while there's no way around learning and understanding these things, teaching them as if they were species names in zoology is a crime.

There's an easier way, which more competent professors point out. The thing is, electrons don't just zip around randomly. They're negatively charged, so they prefer to go toward things with positive charges and away from other negatively charged ones. The various chemical elements can be more electron-withdrawing or electron-donating, so that means that any bond between two different ones is likely to be an unequal affair. The electrons are going to settle more on the end of the bond that's pulling on them, giving it a bit of a negative charge, and leaving the other end with a bit of a positive one. If you can keep track of full and partial charges, which isn't that hard, you're a long way toward solving any mechanism that a test can throw at you.

That page I linked to has some carbonyl (carbon-double-bond-oxygen) mechanisms, and I'm telling you the truth: the few things on that page are the foundation of umpteen dozen reaction mechanisms, which means that you have a choice when you're studying organic: you can memorize the whole shaggy list, or you can learn the fundamentals and apply them over and over in different combinations. Why anyone would do it the hard way escapes me.

But I've seen people take on a lot of tasks that way. When I was in high school, we still had to memorize and recite poems - not especially good ones, stuff like Longfellow's "The Builders" and the end of William Cullen Bryant's "Thanatopsis", poems fit to give Aaron Haspel the shakes, but poems nonetheless. (Good to see that he seems to be blogging again, by the way). And I recall one guy standing up to take on one of these set pieces, and as I listened to him slowly, haltingly stumble through it ("So. . .live. . .that. . .when-thy. . .summons. . . comes-to. . .join. . ."), my opinion of his skills evolved. At first, I thought that he was terrible at memorizing a poem. And, well, I still thought that when he finished, which was quite a while later. But what I came to realize was that he was a lot better than I was at memorizing a long string of random words, which is what he'd reduced "Thanatopsis" to. He went through all the commas, all the phrases like a snowplow. None of it meant anything; it just had to be shifted by brute force. And that's how he did it, and how some chemistry students do it still. It doesn't have to be that way.

Comments (19) + TrackBacks (0) | Category: General Scientific News

July 16, 2006

The Future is Unwritten

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Posted by Derek

What I would miss, if I had to go into another line of work besides research, would be the surprises. I'd miss other things, but that might be one of the first. At this point, I don't know what I'd do with a job where I always knew what was coming. I should clarify that - I'm well aware that if, say, I was the head chef in a restaurant, that I wouldn't know what order was coming in next, or how many we were going to be hit with at once. But people would mostly order things that were on the menu, wouldn't they? No one would come in and demand stir-fried sargasso on a bed of wood chips or a coelocanth en croute.

But that level of craziness can be achieved in a good research project. What I enjoy is the occasional result that just makes no sense at all, that reminds us that we really don't know what we're doing. This happens all the time in chemistry - it's a very inexperienced organic chemist who thinks that everything's under control. There's no reaction so reliable that it can't turn on you under the right (wrong) conditions, and as the process chemists know, there aren't many that can't be tamed if you're willing to spend enough time and money. To partially make up for those, there are also times when something works wonderfully even though you gave it almost no chance.

If the chemistry has random elements, then you can imagine how things start to act once you move toward living systems. The dosing behavior of a new compound is, almost without fail, impossible to predict, and a stone solid fortune is waiting for anyone who can say different and prove it. Tiny changes to a molecule's structure will suddenly make its blood levels soar (or flatline completely), and if we knew that that was going to happen, we wouldn't have run the experiments, would we?

Toxicology is, without question, the poster child for unexpected results. As I've said before, if you don't hold your breath when your drug goes in for tox testing, you haven't been doing this very long. I had a project once where adding a single methyl group to the a molecule changed it from being an infallible overnight rodent-killer to something that could be given for two weeks straight at ten times the normal dose. Clearly we managed to slip out of whatever protein target it was dealing death, but these things can't be modeled or predicted.

What would I do with myself if I knew how these things were going to come out? What scientist could stand it? I can picture a nightmare world of time-to-make-the-donuts folks in lab coats, shuffling in to press the buttons and turn the cranks to produce yet another winner. It'd be like watching a baseball game where every batter hit a home run. Medicinal chemistry's not going to get there in my lifetime, but if it ever threatened to, I'd pack up and move off to the frontier, wherever in the scientific world that might be by then, to the place where I could once again look at my results and say "Well, why the @#$! did that happen"?

Comments (12) + TrackBacks (0) | Category: Life in the Drug Labs

July 13, 2006

A Friday Linkfest

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Posted by Derek

There are a lot of interesting blogs that I need to catch up with, so here we go. First off is On Pharma, which focuses on the manufacturing end of things, with a lot of good stuff about FDA approvals and the clinical world. Note this recent post on the "cGMP Priesthood", which is something I fortunately don't have to deal with.

Life of a Lab Rat is a view from the bench in Sydney (no, not the beach, the bench), and Pipette Monkeys provides one from Heidelberg. Is This Thing On? has a biotech/bioinformatic perspective, and I've been wondering when someone was finally going to invent the Eastern Blot. And finally, the group at Nobel Intent is always worth checking.

Update: And how could I forget The Chemblog?

Comments (5) + TrackBacks (0) | Category: Blog Housekeeping

J&J Shrinks Their Labs Again

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Posted by Derek

I'm starting to wonder what Johnson & Johnson is up to with their research departments. Earlier this year they had layoffs and reorganizations on the East coast, and now they're announcing similar cutbacks at their sites in California.

J&J had bought Scios in 2003, and it looks like that site is no more. Some employees are being shifted to other sites, but several hundred jobs are vanishing in the process. There had been some layoffs there at Fremont back in February, but at the time there was plenty of talk about how R&D wasn't being touched. Well, it's being touched now. Jobs are also being lost at J&J's Alza subsidiary.

One problem is that Natrecor, which is the product that made Scios, has been running into potentially severe safety problems since last year, and sales are correspondingly dropping. (And as bad as the current cuts are, this could have been even worse for Scios if they'd remained an independent company taking a hit to their lone moneymaker). Ironically, Natrecor had a rough time even getting through the FDA in the first place, and it was only due to the persistance of the Scios people that it became a success for a few years.

So, what's J&J's strategy? They seem to be doing a lot of big collaborations and inlicensing deals, but they're scaling back their in-house research pretty drastically, at least by the standards of profitable big pharma companies. Is this their new business model?

Comments (28) + TrackBacks (0) | Category: Business and Markets

July 11, 2006

More Purple Radiance

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Posted by Derek

Hmm, my post on colored-spotlight lab photos seems to have hit a couple of nerves. I note that a few photographers have defended their gel-shooting ways in the comments:

"Photos help create interest in your work. Adding a little Hollywood glitz is the price you pay if you want to continue getting paid."

And:

"As a photographer, I would only note that my colleagues and I simply may have been trying to make the pictures interesting enough to bring *more* people in to read the stories. Which, of course, is where they would learn about what you were actually doing.

The profile of scientists is far too high as it is, I think. I doubt you can safely walk the streets in anonymity these days. The last thing you guys need is more visibility, what with all of the unsolicited, excess grant money rolling in. I mean, how can a scientist burn through that kind of green with just 24 hours in a day?

. . .Amazingly in the 21st century, some photographers are still trying to increase the interest and visibility levels of science.

What a waste."

Well, let's clear up a couple of things. First off, fortunately, I'm not dependent on grant money. I work in industry, for a very large company, and we raise and spend our own cash. And believe me, we have no problem burning money - it's trying to figure out how not to burn all of it that occupies our time. That means that what I'm really dependent on is people buying our drugs, and on my lab (and the others like it) coming up with new ones. Interestingly colored pictures of our work will do very little to advance either of those.

Second, although I didn't make a big point of it, this brochure was (as mentioned in the first paragraph) in-house. Its target audience was people who already work for the company, which made the colored gels even more laughable than they would be otherwise. This wasn't for the local newspaper's color front page. There was no public outreach involved.

But as for that, well, that's one reason I have this blog. I'd found over the years that almost no one I met had any idea of what it was like to do drug discovery research, so I jumped at the chance to talk about it. Much of what people think they know is incorrect, too - if my salary depended only on what a good opinion people have of drug companies, I'd be in trouble. No, I think it's great for people to find out what this job is like - I just think that glitzed-up photos are a poor way to do that.

Why? For one thing, they're a cliché. These shots have been a joke for many, many years among scientists, and if you tried to count up all the purple glows (or red-green-blue colored flasks) out there in print, you'd never finish the job. I think that for every person who (unaccountably) finds such a picture compelling enough to read the accompanying article, there must be two who flip past it in boredom. They've seen it a thousand times before; it's not an eye-catcher any more.

But that's a practical matter. A larger one is the problem of falsification. It's not just that our labs don't look like that, although they sure don't. It's that one group of viewers will take away the wrong message (that lab work is constantly exciting and dramatic, like on TV), and another more suspicious group,will take away another wrong message: that it's so boring that it has to be tarted up to be bearable at all.

The truth's in between. Exciting stuff happens, but it doesn't happen the way a screenwriter (or an art director) would lay it out. And while the exciting stuff isn't happening a lot of routine work is getting done, and a lot of dead ends are explored in what is (in retrospect) horrible detail. The job takes a particular personality type, and if you get frustrated easily or have a short attention span - in other words, if you're the type who needs the stimulus of bizarre colors to find something worth looking at - then it's not going to work out well for you as a career.

I'll close with one other photographer's comment:

"Science is about accurately representing data. Photography is about making an interesting image.

True enough, although photography - not promotional photography, admittedly - can also be about accurately representing reality. But what would a bunch of photographers think of some pictures allegedly showing them at work, but with no cases of equipment in sight, no encumbering battery packs or extra camera bodies. . .just dynamic-looking poses of them holding cameras which, for some reason, are glowing orange and green and purple? If you won't do that to each other, why will you consent to do it to us?

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July 10, 2006

Aluminum: Friend or Foe?

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Posted by Derek

One of the comments to the previous post mentioned having some trouble with a procedure out of one of the lesser journals. "Trouble", in this sense, meant "vigorous unexpected fire". But when he mentioned that it involved a mixture with aluminum chloride, I knew to look out.

Chemists everywhere live by thermodynamics. And one of the basic principles is that if a reaction's starting materials are more energetic than its products, then it's favorable. It doesn't mean that it's always just going to take off spontaneously - sometimes the intermediate step is much higher in energy, and the reaction can't get over the hump. But if there's not too high a levee between the two energy states, things will indeed flow downhill for you.

It's a good thing, too, since one such reaction is burning the nitrogen in the air, thereby changing it into poisonous nitrogen oxides. (Correction: late-night brain freeze there - I had in mind the fixation of nitrogen to ammonia, which is energetically favorable but has a high activation energy. Oxidation of nitrogen itself to NO is an uphill process, but under high temperature/high pressure conditions, like those found in your car engine, it does take place). Another one of those is burning aluminum, which also has a good-sized barrier to get past (otherwise using aluminum foil in your oven would be a spectacularly bad idea). The product of that reaction, aluminum oxide (or alumina) is one of the most below-sea-level compounds I can think of, compared to the metal or many of its compounds. Give 'em a chance, and they'll take off on you.

The classic example of this is the thermite reaction: aluminum + iron oxide goes to aluminum oxide + iron. Oh, and some heat. Well, OK, a lot of heat, enough to spray molten iron all over the place. (YouTube) You have to set the reaction off with something pretty hot (burning magnesium ribbon is traditional), but once it gets going, it tosses off enough spare heat to roll right along.

So no, I'm not surprised that some aluminum chloride would take off on someone. Regard all aluminum compounds without a bond to oxygen with a little suspicion. Many of the them (and all the aluminum metal you see) came from alumina, and they're scheming to get back.

Comments (13) + TrackBacks (0) | Category: General Scientific News

July 9, 2006

Down the Chute: Your Call

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Posted by Derek

I haven't thrown a question out to the readership in a while, and this one has been on my mind. Let's give it a try: what journal(s) would you just as soon see vanish from the earth?

A few ground rules: let's try stick to organic chemistry and associated fields, for now. If we start slamming the other scientific disciplines, we'll never get things under control. If this is a popular feature, we'll take on the others in due course. And I'd suggest these criteria for marking a journal for death:

1. You don't read it regularly.
2. You don't even read it occasionally.
3. You assume that any paper in it wasn't good enough to appear somewhere else.
4. You can't recall the last time you even got some reference data from it.

Those are pretty stringent criteria. For example, I never look at Synthetic Communications, but I do occasionally get a procedure from it (and they occasionally work). I picked up some analogous-compound data from a Heterocycles paper a year ago, so it doesn't quite make #4, but otherwise it's one that I'd mark for the trash heap.

And you?

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July 7, 2006

Memo to the Public Relations Department

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Posted by Derek

After seeing a recent in-house promotional brochure, I'd like to issue a brief request on behalf of my fellow researchers. This is addressed to all professional photographers: please, no more colored spotlights.

I know that you see this as a deficiency, but scientists do not work with purple radiance coming from the walls behind them. Not if we can help it, we don't, and if we notice that sort of thing going on, we head for the exits. In the same manner, our instruments do not, regrettably, emit orange glows that light our faces up from beneath, not for the most part, and if they start doing that we generally don't bend closer so as to emphasize the thoughtful contours of our faces. When we hold up Erlenmeyer flasks to eye level to see the future of research in them, which we try not to do too often because we usually don't want to know, rarely is this accompanied by an eerie red light coming from the general direction of our pockets. It's a bad sign when that happens, actually.

I know that your photos have lots more zing and pop the way you do them. And I'm sorry, for you and for the art department, that our labs are all well lit (with boring old fluorescent lights, yet), and that we all wear plain white lab coats (which tend to take over the picture), and that our instrument housings are mostly beige and blue and white. It would be a lot easier on you guys if these things weren't so.

But that's how it is. And when you get right down to it, you're actually doing us a disservice by trying to pretend that there's all sorts of dramatic stuff going on, that discoveries are happening every single minute of the day and that they're accompanied by dawn-of-a-new-era lighting and sound effects. We'd rather that people didn't get those ideas, because the really big discoveries aren't like that at all. It doesn't make for much of a cover shot, but if one of us ever does manage to change the world, it'll start with a puzzled glance at a computer screen, or a raised eyebrow while looking at a piece of paper. Instead of getting noisier, everything will get a lot quieter. And if there are any purple spotlights to be seen, we won't even notice them. . .

Update: A follow-up post is here, written after several comments by photographers came in. . .

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July 5, 2006

More Statin Skirmishing

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Posted by Derek

The word today is that AstraZeneca and Abbott are going to combine two of their cardiovascular therapies. Crestor, AZ's statin, and a new fibrate, the successor to Abbott's TriCor, will be sold as a single pill. Its name will, I feel sure, end in "-or". This is part of the next wave of cholesterol drugs (and drug mixtures), which are aiming to simultaneously lower LDL (via the statin) and raise HDL (the fibrate's contribution, in this case). A number of other "statin-plus-something-to-raise-HDL" projects are in the works (including a bet-hedging one from AstraZeneca with a totally different drug candidate from a small company called Atherogeneix).

As for these two components, Crestor is a powerful statin indeed, bordering perhaps on too powerful, and if it's possible to describe a billion-dollar drug has having disappointing sales, this is the one. (After all, if you listened to the analysts back before it was introduced, it was supposed to be selling three times that amount by now). And TriCor is a fibrate, one of a mechanistically baffling class of lipid-modifying drugs which have been in use for quite a while now. If you look through the literature, particularly in patent claims, you can see that the idea of combining statins and fibrates has been proposed many times before. It's a sensible combination, although (as with many of these ideas) it's something that you could probably also achieve by taking two separate medications. It would be interesting to know how many people are doing just that at present.

Another thing that would be worth knowing is how well this idea works with Abbott's next-generation fibrate compared to generic fenofibrate, and how well either one would work when combined with, say, generic simvastatin (Zocor) instead of (on-patent) Crestor. That's the flip side of these combination therapies - the insurance companies start to wonder if they can assemble the same sort of thing for a much lower price, and who can blame them? Of course, all this has already occurred to the various companies involved, who will be working hard to show that a single pill is better - that the dosing schedule makes a difference, that patient compliance is better, and so on. Everyone in this field is making sure not to miss any tricks.

AstraZeneca, for example, has been watching Merck and Schering-Plough do well with Vytorin, the combination of Zocor and the cholesterol absorption blocker Zetia, so they ran a trial of their own - Crestor and Zetia. That seems to have done very well indeed, although (as that Matthew Herper Forbes article points out), this was an open-label trial in patients with very high cholesterol numbers to start with.

But A-Z might find themselves arguing that patients should definitely go with a single pill when it's Crestor and the Abbott drug, oh yes, but to feel free to mix and match Crestor with Zetia. That'll be an interesting pitch. And things are just going to get more complicated as time goes on in this area. (Money will do that). But don't forget, the reason that there's so much money involved is that there are a lot of therapies that seem to have value. So it's nerve-wracking (but profitable) to be a drug company in this area, and it's tough to be an insurance company. But if you're a patient, well, it's not as bad as it used to be. . .

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Comments (5) + TrackBacks (0) | Category: Cardiovascular Disease

July 4, 2006

Now With the Great Taste of Fish!

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Posted by Derek

When I was in grad school, I tested out some new-fangled separatory funnel idea that some small company was trying to launch. I can't locate a picture of one of the things, but it had a sort of piston/reservoir arrangement at the bottom, which let you draw the lower layer down and pour off the upper one. I tried it out some, and didn't find it any more convenient or effective than the good ol' standard model.

Even if it had been, so what? How much better could it have been? I'm not sure how much improvement there is to be had in the classic sep funnel design. Those things haven't been around for a century or two for nothing. What led this inventor to think that the world was waiting for him to fix this nonexistent problem, I don't know. And that's something that everyone who's trying to invent something needs to keep in mind: even if your brainchild works, will anyone want it?

I think that some innovative types miss this in their drive to get all the kinks out of their latest invention. It's easy to misdirect this sort of energy, particularly when all that hard work can be employed to keep you from dwelling on such disturbing questions. I'm not suggesting that people sell themselves and their ideas short - just that they think them through as much as they can. If you're not attacking a real problem, it's likely that no one is going to be interested.

If someone tried to sell me on a wonderful new gizmo to, say, spot my TLC plates for me, I don't think I'd be jumping up and down to try it out. A glass capillary, home-made or store-bought, works just fine, and I rarely have any cause to complain. And besides, it only takes a second or two. How much time and irritation could a new device save? On the other hand, I would be very interested in a fivefold-faster rota-vap, should some bright person figure out how to make one. Moving up the scale, if you have something that will allow me to predict (really predict) oral absorption for a new drug candidate, then you can name your own price.

But no one's offering me either one of those, as far as I know. So in the interim, remember: not everything new is improved, and not everything is improved enough to be worthwhile.

Comments (15) + TrackBacks (0) | Category: Who Discovers and Why

July 3, 2006

Pyrotechnic Days

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Posted by Derek

Many of my US-based readers in the industry probably aren't even at work today - having July 4th fall on a Tuesday definitely puts a dent in the Monday before it. (I'm not at the Wonder Drug Factory myself). No doubt the grad students and post-docs are cranking away in the lab, though, and I hope that none of them have any fireworks that they didn't plan for.

That's a part of chemistry that gets a lot of attention - the way that our day-to-day work can, once in a while, catch on fire. It's not all that common, compared to the amount of time we spend without flames in our fume hoods, although compared to (say) cost accounting things must still look pretty lively. But I have to admit that we chemists don't do anything to help our reputations. No, not when everyone in the lab has a repetoire of their favorite lab accident tales, we don't. I'm as guilty as anyone else, with my "How Not to Do It" category.

But it should be noted that most of the best stories come from a person's graduate school days, when the teller (and their co-workers) were younger, probably more foolish, and certainly less experienced. The only way to discover just how spirited some reagents are is to use them yourself, but after you've done that, you remember them forever. (No one, for example, who's ever dealt with a pure lower-dialkylzinc reagent ever needs a reminder about treating them with respect). Experience also gives you a better chance of stopping a small accident before it can become something that people still talk about twenty years later. You know, for example, that there's likely going to be a flame burning on the tip of your syringe when you take it out of that bottle of tert-butyllithium, so you don't jerk your arm in surprise and hose the stuff spectacularly across the back of your hood.

Another factor, not to be neglected, is that with time some of the folks who generate the best explosion stories decide that they should probably look into other careers. I can tell you that in industry we don't have some of the more exotic types that you find earlier in academia, leaving trails of Pyrex fragments wherever they may wander. The left-hand side of the distribution tends to drop off, as was ever the case, and a good thing, too.

In almost seventeen years of industrial research, I hardly have a story that can compare with what went on in any single year of my graduate work. And no, that's not a complaint.

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