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About this site

Here we'll review recent developments in drug discovery and medicine and the IP issues and financial implications they have, along with general thoughts about research. Also likely to make an appearance: occasional digressions into useful topics like which lab reagents smell the worst.

About this author

Derek Lowe mugshot

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.


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A boy and his chemicals!
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(The famous neurologist was nearly a chemist. . .)


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IN THE PIPELINE: drug discovery

By Derek Lowe


Tuesday, December 30, 2003

Carpe Annum

Looking back, I didn't have much good to say this time last year about the year in drug research. And I could easily go on the same way about 2003 - I mean, just look at the place. Debris from all those wrecked clinical candidates is still all over the floor, for one thing. And we only barely just kept the roof from falling in under a torrent of price controls.

But doom-n'-gloom is too easy. There's always a nasty case to be made; that's why we see so much of it. Pick any field - when did it ever have an age when people didn't think it was going to Hell on a handcar? Look to that maniac Yeats, and his overquoted The Second Coming. "Things fall apart, the center cannot hold." Yeah, and? You're complaining about entropy? Things are always falling apart, and it's up to us to be always putting them back together.

So I'm not going to spend my last post of the year moaning. Oh, I could: Those price controls I said the industry's avoided? They're probably coming anyway, and damned if I know how to stop them. Those abandoned clinical programs? Our pipelines looked pretty parched even before that happened, thanks. And on a more local level, my company shed workers this year like a dog shaking off water. I'm just glad to not be sitting here in my underwear, reading the ads in the back of Chemical and Engineering News.

But enough of that. There are some good things happening. Those employment ads, for example, are starting to come to life. Drug companies are hiring researchers again, some of them, which sure wasn't the case earlier in the year. And the pressure of finding new drugs is stimulating some rather desperately creative thinking around the industry. A lot of odd ideas are getting a hearing, which has to be a good thing in the long run. And back on the local level, I'm likely to publish more papers and patents this coming year than I've ever done, if current plans hold up.

And, as I've mentioned, I'm working on the biggest idea I've ever put a hand to. It scares me sometimes. The chance to breath the air at this scientific altitude, to even see these peaks and cloud formations, is enough to counter any pessimism I can scrape up. My job is something that would have thrilled me if I'd known about it when I was eight years old, and I still wake up on weekdays eager to see what comes next. How, how can anyone in such a position complain with a straight face?

So 2003 is on the shelf, and nothing of 2004 is written down yet. Any scientist, any writer or artist worth their salvage value has to respond to a blank page by wanting to fill it with something that's never been seen before. Here's our chance. Pick up those petri dishes, pick up those pens!


posted at 9:37 pm

Monday, December 29, 2003

Try It At Home!

The last day or two have been occupied here at home with trying to get a tropical fish tank set up for our kids. I'm still waiting for the pH to settle down before adding the first lucky fish, since I've no desire to explain to my 3- and 5-year-old children why they're floating around upside down in there. It'll be time to see if the nitrate/nitrite bacteria can do their thing in time. Once we get things established, I'll take a sample out to show the kids under the microscope - they get the full scientific treatment around here.

If I have to, I may just, er, borrow a bit of phosphate buffer from the lab, at the risk of giving a head start to algae in the tank. That's just one of the many useful chemicals to be found around the lab. Most chemists have dipped into the potassium hydroxide pellets to open a clogged drain at home, for example. Just the thing.

While I was doing my post-doc in Germany, I got a testy note from my landlady about the water stains in the bathroom of my apartment. As some readers will know, testy notes are a speciality of German landladies. I had to resist firing one back asking her what I was supposed to do about the mineral level in the local water - after all, she could have pitched me out on the street. Instead, I assured her that I could take care of the problem.

As I could. I can recommend concentrated hydrochloric acid for any pesky water stain problems you may be experiencing. Well, I can recommend it with some reservations. Conc. HCl cleans right down to the shine and then keeps on going, so you want to use it with care. And in a poorly ventilated room, it'll frizz your nose hairs for you something fierce. But it'll clear out those stains to everyone's satisfaction, especially if you're only going to be in your place another month or so.

I knew that my landlady would be letting herself in while I was gone, as she was perfectly within her right to do under German law. I was gone that coming weekend, so Friday night I fizzed away with the HCl, opened the windows to clear out the noxious vapors, and then left a note for her. "Impressive, isn't it?" I wrote in German, and carefully taped it to the underside of the lid of the toilet, which I left closed. When I came back on Sunday night, the note was gone, and I heard no more about water stains.

Better living through chemistry, all right. But I won't go into the time that I tried to clear out the pipes in my graduate school apartment with chromic/sulfuric acid. That would be a violation of several laws these days, and it was a violation of common sense even then. Believe me, you don't want to try that one, not if you value your pipes, or your floor.


posted at 9:56 pm

Sunday, December 28, 2003

An Appeal

Here's hoping that Christmas and the other holidays have been going well for all my readers who celebrate them. It's been a good break here, with several more days to come.

But the world goes on, doing what it does. My wife is Iranian (which makes our kids rare Persian-Arkansan hybrids, I guess), and we've been following the news of the terrible earthquake in southeastern Iran. I wanted to mention this link, the National Iranian American Council which is coordinating donations for disaster relief. Consider stopping by and supporting them.

I've seen many pictures of the ancient citadel in Bam, and I regret that I'll never get to see it in person now. And beyond that, there's the regret that whatever the many victims might have accomplished will now go undone. That's one of the things that, as a scientist, you think about: loss of human potential. How many great discoveries do we miss out on, because the people who could have made them, who could have been the right person with the right insight, never get the chance to do so?

It's not just natural disasters, either. There are so many constraints - of poverty, of government, of dogma - that keep people in so many places from accomplishing what they could. One of the few things that Marx and Engels Rousseau wrote that I can truly agree with is "Man is born free, and is everywhere in chains." And where do I find the link for donations to help remove them?


posted at 9:58 pm

Sunday, December 21, 2003

Holiday Schedule

Blogging's going to be mighty thin on the ground around here for the next week or so. Tomorrow is my last official day at work for the year, for one thing, and I'll be busy here at home Christmasing around (with a 3-year-old and a five-year-old in the house, Christmas is a strenuous holiday.) I think that a good fraction of my readership will be taking time off, too. In the interim, I can strongly recommend checking out some of the links over there to the right; there's never a shortage of interesting things to read in the blogosphere.

As usual, part of my time tomorrow will be spent making sure that I remember what's going on when I come back. Cleaning off my desk, labeling flasks (OK, I know that they're supposed to already be labeled, but you know how it is,) making notes about what needs doing in January. . .if I don't do this stuff, I'll hit the ground sprawling after New Year's.

The new set of experiments that I spoke about recently is being run, but will be in the freezer over the break. Won't hurt 'em a bit. They'll be ready to be go for when my HPLC/mass spectroscopy colleages aren't so rushed by year-end requests. This sort of thing is a luxury of chemistry, not enjoyed by my colleagues in the various biology labs that have to deal with cells or animals. Both have to be fed, cleaned up after, and generally cared for no matter what their human colleagues feel like doing. And if you want your results to mean everything, you'd better do it just exactly the way you've been doing it all year. No cutting corners allowed!

There's one other potential holiday hazard down in the tissue culture labs. If you've been baking Christmas cookies, fine. Come on in. But if you've been making any yeast breads, then your labmates will kindly ask you to stay the heck out until you're sure that you're cleaned up. Nothing like some of that rip-roaring rapid-rising sure-fire yeast powder to completely destroy a bunch of high-strung engineered cell lines. Believe it, it's a disaster.


posted at 10:57 pm

Thursday, December 18, 2003

Sold!

Over at Matthew Holt's site, there's been a running debate about Crestor, Lipitor, and the other statins. Well worth a look. (I particularly like this post, which makes yet another case that Pfizer is living in a fantasy world.)

I don't talk much about these post-approval marketing fights over here. They can be fun to watch, but for someone in basic research like me, it's just a cloud of dust on the horizon. It's hard to find two more different cultures inside a drug company than the marketing/sales people and the research staff. We regard each other as strange creatures, vaguely humanoid, with alien motivations and concerns. About the only thing we have in common is an abiding interest in drugs that do something that people would be willing to pay for.

It takes very different personality types to excel in those two areas, clearly. But there's one place where researchers could take a few lessons from the sales people: presenting their results. There's a long list of great discoveries in science that weren't recognized at the time because the discoverers did such a poor job of getting their message across. Often the problem is that people assume that the experimental results speak for themselves. I wish they did. But spending time watching people draw completely different conclusions from the same data should tell everyone that it isn't so.

No, good results need to be sold to be effective. The trick is to do it without making it look like you're trying to put something over on your audience. People are so into their own data that they unconsciously assume that everyone else will be right up to speed with them when they present it. Believe me, they aren't. Are you, when you listen to someone else? An effective presentation hits people over the head with its most important points, more than once, and has plenty of hard data to back them up.


posted at 10:32 pm

Wednesday, December 17, 2003

You Shouldn't Have

If you're still shopping for gifts after buying all my Amazon titles below, I have just enough time tonight to give you the answers you're looking for. Check out these ties and scarves, each of which features a color photomicrograph pattern of an infectious agent. Cholera, anthrax, vaccinia, strep - they've got 'em all. I have to say, some of them are really pretty decent looking. I see worse all the time (but keep in mind that I'm a chemist; your mileage may vary.)

And this appears to be the hottest item in the molecular biology world this Christmas: your very own James Watson bobble-head doll. Never mind that a plurality of people buying it might be sticking pins into it; it's still a great idea.


posted at 10:43 pm

Tuesday, December 16, 2003

Welcome

I really need to take a moment to welcome the latest Corantean, Carl Zimmer of The Loom. I recommended his site when it was at another location, and now he's part of the mighty blog-team over here. He's very much worth adding to the regular reading list.


posted at 10:41 pm

A Merck Mystery

A couple of weeks back, I mentioned the problems that Merck has been having, with several of their advanced clinical compounds cartwheeling down out of the sky. One of these flameouts was a compound that they'd been developing with Kyorin of Japan, known as KRP-297 or MK-767, depending on which company's numbering system you use.

It's a dual agonist for two nuclear receptors, PPAR-gamma and PPAR-alpha. The former is a target of the marketed drugs Avandia (rosiglitazone) and Actos (pioglitazone), and is a very useful means to increase insulin sensitivity in Type II diabetics. The latter is an important player in lipid handling, so the combination has held out promise of going after the dyslipidemia that diabetics also demonstrate - pretty close to an all-in-one therapy.

A host of pharmaceutical companies have pursued this idea, but so far it seems like a real minefield. GSK has had a crack at it, and so has Novo Nordisk, but both of their compounds failed for one reason or another. In Novo's case, they'd licensed in a candidate from Dr. Reddy's in India, the exotically named ragaglitazar. But that compound was abruptly pulled from the clinic in 2002 when long-term rodent studies showed bladder tumors. At the time, Novo's line was that they were going to evaluate the compound and perhaps start the human trials again if they could find evidence that this was a rodent-specific effect. As of this date, the compound remains dead, however, which isn't a good sign.

Now we get to the interesting part. According to the Merck press release, KRP-297 was dropped because "Merck’s long-term safety assessment program identified a rare form of malignant tumors in mice." What enquiring minds around the drug industry want to know is: was this compound associated with bladder cancer, too? It's structurally rather different from ragaglitazar, but it could be a mechanism-based effect - in which case, a number of other companies are going to have to hit the brake pedal, and fast.

Merck, as far as I've been able to find out, isn't saying. And given the stakes involved, I'm having a hard time figuring out why. Speak up, guys!


posted at 10:38 pm

Monday, December 15, 2003

The Solution to Your Solution Problems

I spent some time this afternoon trying out different solvents in an effort to get a clear solution of one of my compounds. This was just to have it checked out by the analytical group, not for anything more advanced, but it was still a problem. (They don't like injecting cloudy samples with things floating in them into their hundred-thousand-dollar instruments - go figure.) I finally found something that would work, but it was trial and error.

Actually, it's always trial and error with solubility, which is something of a dark art. There have been attempts to model the process and estimate the solubility of new structures, but as far as I know, none of these have amounted to much. There are too many factors - heck, there are too many kinds of solubility. Different solvents take compounds up in different ways. You can always - well, almost always - get things to dissolve in DMSO, if you're desperate, but it's not a good solvent to use if you ever want your compound back. The stuff is like pancake syrup. And DMSO isn't much good if you're trying to get a solution to dose animals with, either. It's on the black list, and for good reason.

So how soluble does a drug have to be, anyway? You can start a lively argument with that question. No one doubts that the proverbial brick dust wouldn't work out too well - a compound has to have some solubility. But once past the powered-teflon stage, how much time should you spend trying to get a clear solution to dose? The argument ends quickly when you're dosing something i.v. Dosing a powder suspension intravenously is a good recipe for an instant embolism, so a drug basically has to be in solution, and in one of the limited range of acceptable vehicles, at that. There are all sorts of things you can do for an oral formulation that just don't cut it for injection.

Consider cremophore, which is what they have to use to get taxol into solution for i.v. chemotherapy. It's a chemically modified form of castor oil, of all things, and it's vicious stuff, but taxol is such a rock that there's no alternative. The problem is, it causes terrible allergic reactions in some people, which can be life-threatening - certainly the last thing you need when you're undergoing aggressive cancer treatment. The stuff does the same thing to dogs, and how, and is near the top of the no-way list for dog testing. On the other hand, rodents don't like it, but they can handle it better than most animals, being better adapted to consuming all sorts of garbage in the first place. (There's no telling what kinds of insane vehicles we could get away with if the possum was an accepted species for drug testing, come to think of it.)

Now when you dose orally, you can start to broaden your horizons, since the stomach lining is a lot sturdier than the vascular endothelium. For one, you can dose suspensions, although it's a good idea to try it with a solution, too. And there are a lot more things you can add to your formulation to keep things dissolved, or to keep the suspension from clumping up. And it's in oral dosing that the correlation between solubility and drug behavior really stops making sense. You'd think that the more soluble, the better, but the correlation isn't nearly as good as that. There are too many confounding factors.For a suspension, you have particle size and shape, presence or absence of dispersing agents, and how all these behave when they hit stomach acid (and keep in mind that different species of test animals can have different levels of acidity.) For a solution, the first thing to check is to see if it really remains a solution when it hits the gut, or if you're just forming another suspension in situ. If your compound has an acidic or basic functional group, you can form any number of salts, all of which will behave differently. It's a full-time job, and there are plenty of people in the drug industry who do this sort of thing all day. I'm glad I'm not one o them, but they're glad that they're not me, so it all works out.


posted at 9:36 pm

Sunday, December 14, 2003

And As For Today's Other News. . .

I will merely, and happily, add: what he said!


posted at 9:45 pm

Nor All Your Tears Erase A Word of It

I'm not a fan of Michael Crichton's novels. To me, they read like barely fleshed-out screenplays; I find them irritating. So you'll have to excuse me while I choke down some of this crow over here. I just read the text of a speech Crichton gave in San Francisco, via Arts and Letters Daily, which sounds like it could have been downloaded directly from my head. Rarely have I come across anything with which I so thoroughly agree.

I won't quote from it - it's worth reading in its entirety. The speech is inflammatory enough that I think you could place yourself in some physical danger (especially in the Bay Area) by reading it loudly in public. His topic is the environment, and our ways of thinking about it. I still can't stand the man's fiction, but his head is somehow in the right place.

Some of the same habits of mind he talks about can spill over into my area of expertise. Take the idea that the default setting of the human body is perfect health. If something bad takes place, well, something external caused it. Some chemical gave you cancer, some food gave you heart disease.

Now, it's certainly true that some chemicals can give you cancer. Benzidine, for example. When I was in graduate school, I briefly occupied an office in a deserted laboratory. One evening, trying to avoid studying quantum mechanics, I wandered over and looked at the old reagents stored on the shelves - which included half a kilo of said benzidine, enough to induce bladder cancer in a herd of giant ground sloths. Things like that, you should be scared of. And it's true that there are foods that can increase your risk of heart disease. The country ham of my native Mid-South would be a good candidate, being a brick of proteinaceous salt surrounded by fat. It's delicious, needless to say, but a steady, heavy diet of it would probably prove lethal in the long run.

But most cancers, I'm willing to say, are just the result of bad luck - a passed-over error in DNA copying, a botched mitosis that missed its appointment with apoptotic cell death. These things happen, generally for no reason. If they happen in the wrong place and at the wrong time, you're in big trouble, through no fault of your own. What Crichton points out about nature is as true inside the body as out: nature doesn't give a damn, and there never was a time when it did.

Scientists should know this better than the general population. Exposure to research should be enough to prove that the physical universe will do whatever it feels like doing, and that only when it's darn good and ready. This vast indifference can be hard to take. But in science, you don't recognize it and come to terms with it. The Firesign Theatre guys were being way too optimistic when they proclaimed "In the Next World, You're on Your Own!" It's this one, too.


posted at 9:39 pm

Thursday, December 11, 2003

Bits and Pieces

Work and home have conspired to leave little time for fresh blogging tonight. I'd like to mention that I've added a some fresh links to the sidebars, though: Matthew Holt's health care strategy blog, for one. There's also a chemoinformatics blog, Cosmas (check the domain name on that one.) Then there's a new graduate-student biology blog, catchily titled My Lab Is On Fire. Hey, guys - when an organic chemist says that, it's not just a figure of speech!

I've also added a few new books to the Amazon links below. I mention that because it's only my longest posts that make people scroll down that far, so I'm not sure how often they get seen.

One record-keeping note, for those who notice these things. I managed to delete my post titled "Naming of Names," about GlaxoSmithKline, etc. I'll try to pull it out of an archive and re-post it this weekend.


posted at 9:49 pm

Wednesday, December 10, 2003

Protection Racket

I actually ran three reactions at work today, which is a pretty good pace for anyone, let alone me. A majority of the people at my level in a drug company don't do much lab work at all, which is often - I think - a mistake. Well, not in every case, true. There are some people who need to get the heck out of the lab so they can do something that they're better at. (Of course, what they find to do in their offices may still not qualify. . .)

But the reason I was able to run things that quickly is because some of these were taking off protecting groups. Many of the molecules we deal with have multiple reacting groups on them, and sometimes they're bound to interfere with each other. You have to either find the perfect set of reaction conditions, to just dink the end of the molecule you're working on, or you have to nail the other end down for a few steps. Generally, we do the latter; the former is a black art, and black magic takes time.

So there's a whole list of standard protecting groups for the different sorts of reactive functional groups that we need to keep under wraps (alcohols, amines, carboxylic acids and so on.) And for each of those, there are groups that come off in acid (but not in base) and vice versa, and some that require more specialized conditions (oxidation, hydrogenation over a catalyst, even shining light on them.) Years ago, it got to the point that you needed a book-length reference to keep track of them all - and that's the book that everyone knows just as Greene.

In medicinal chemistry, we seldom have more than two of these raincoats on our molecules simultaneously, so selecting some good ones isn't a problem. But in total synthesis projects, like you find in academia, things can get rather hairy. I know whereof I speak, since I did carbohydrate-based total synthesis in graduate school. All those OH groups! The challenge was designing your work so you wouldn't require more orthogonal protecting groups than currently existed. "Now let's see. . .this one comes off in base, this one with acid, this one with fluoride, this one by oxidation, this one by catalytic hydrogenation, perfect, and now I just need one more that. . .um. . .oops" I nearly painted myself into this corner a couple of times.

Today I took a Boc group off a nitrogen, and falling off a log is definitely more of a challenge. Boc is your buddy: it laughs at just about any base short of disastrous volcanic conditions, but strong acid blows it off like a warm breeze. It's a workhorse, and it did its job for me. The related Cbz (or just "Z") group is just about as impervious to base, and holds up to reasonably hairy acids as well. But catalytic hydrogenation wipes it right off. I'd as soon stick with those two than deal with most of the other nitrogen protecting groups, which tend to cluster into those that won't stay on and those that won't come off.

In that category is an old-time group called trityl, triphenylmethyl to those who haven't been introduced. Now, trityls have worked for me, but that's because I treat them like fine china. And because I know the best way to take one off. OK, fellow chemists, sure, you use acid, right? But you didn't know that there was a more reliable method, did you? Yep, the foolproof method to remove a trityl group is to depend on the damn thing. Trust in it, count on it, and I'll guarantee that you'll practically be able to hear your molecule shedding the thing with a faint "clang!"


posted at 10:02 pm

Tuesday, December 9, 2003

Run For Your Lives!

Tomorrow is the Nobel award ceremony, and if you live within fifty miles of Raymod Damadian, I advise you to flee to higher ground. He's gonna blow. As readers of the New York Times (and probably the newspapers in Stockholm) know, Damadian has continued his "I was robbed" campaign. In recent days, he's expanded to double-page spreads, which largely serve to make his original ads seem comparatively sane.

Oh, they're something: "The shameful night of Dec. 10. . .the truth is not so malleable as they would like. . .the damage to the Prize will be lasting" It goes on in that same screeching, label-crumpling manner, illustrated by a border of pictures of (no prize for guessing) Raymond Damadian, captioned by a rather. . .personal version of the history of MRI, in what looks like 6-point type. "Enjoy what follows," this part enjoins us. But how?

If the Times had offered to print this screed in green ink, I'm sure Damadian would have sprung for it. This ad looks like something an ambulatory schizophrenic would hand to you in the street. There's one part that I'm absolutely sure of, though: the damage will be lasting. You can bet on it. This is one of the most disgraceful and embarrassing performances I've seen in a long time.


posted at 10:05 pm

Monday, December 8, 2003

The British Press vs. GSK

Allen Roses, the ex-Duke researcher who's VP of genetic research at GlaxoSmithKline, gave a talk at GSK's recent pipeline-fest in England. That's no surprise; every senior research manager that could be rounded up was giving a talk. The whole day was a festival of dogs and ponies, designed to convince investors that GSK is on the right track.

But whether they are or not has become a side issue. (For the record, I think they mostly are, not that their drug pipeline is in much better shape than everyone else's.) No, what has seized the imagination of the British papers is a statement by Roses that many prescription drugs didn't work as well for some people as they do for others.(

You'd have thought he admitted that all GSK's drugs were made out of tapioca or something. Here's the reaction of the Independent, which has been leading the charge:

"A senior executive with Britain's biggest drugs company has admitted that most prescription medicines do not work on most people who take them. . .It is an open secret within the drugs industry that most of its products are ineffective in most patients but this is the first time that such a senior drugs boss has gone public. . ."

Check out the language. . ."admitted" (a confession that you've done something wrong), "open secret" (but only within the scheming drug industry), "drugs boss" (is that anything like a crime boss?), "gone public" (with the dirty laundry that is now revealed!) What a story, guys! The only problem is, it's something that everyone pretty much knew already.

And it's not just old news to us scheming devils in the research labs, either. Ever spoken to someone who's going through different medications for high blood pressure, looking for an effective one? Someone who's had to try more than one antibiotic for an infection? A cancer patient who's had to switch chemotherapy regimens? Do any of these sound newsworthy?

Well, they sure were for the Independent, although I should expect as much from a newspaper that proudly advertises Robert Fisk's foreign affairs reporting. According to the Telegraph, GSK has already fired back, as they should. With any luck, the British papers will now proceed to attack each other instead of GlaxoSmithKline.

What Roses was really talking about was the state of research on pharmacogenomics. That's a useful and important topic, which I'll go into in more detail in another post. But for now, anyone who takes a few minutes to look at those links will be way out in front of the unfortunate readers of the Independent.


posted at 10:34 pm

Sunday, December 7, 2003

Good News, Backing Slowly Through the Door?

It's a good time to give a brief update about the experiments that I'm running at work. (The last time I spoke about them was here.) For those who haven't seen one of these posts, I've been chasing an odd idea for months now, on and off. So far, the tests that I've put it to have come up negative - or at least not positive, which is often something different. I've continued to refine my thinking about what's going on while searching for a better system to work with.

The other thing that newcomers to this site need to know is that I can't tell you exactly what this idea is. Now there'ssome great blog material, eh? But I'm hoping that folks will understand. If I were in academia, I wouldn't talk because I would be afraid that someone would scoop me and get priority by publishing first. Since I'm in industry, I worry both about that and the proprietary advantages that this stuff might bring. (If it works out well, there certainly could be some.) Actually, come to think of it, academics think that way too these days, don't they?

I'll try not to be too reminiscent of the South Sea Bubble scam artist that Charles MacKay talks about - the one who advertised partnerships for sale in "An undertaking of great advantage and no man to know what it is." He took in a large sum within a couple of days, and as MacKay tells it, he "was philosopher enough to be content" with his profits, bailed out to France and was never heard from again. At least I'm not selling shares.

On to the news. In my last, er, thrilling installment, I was about to set up (with the help of a colleage over in a pharmacology lab) a new experiment which would be the best shot yet. Well, it took a while to get this one analyzed, during which time the solutions sat patiently in the freezer. I had to remake a standard compound for my colleagues in the analytical group, and they had to work out good methods to run the samples with, which needed something else first, and so on. But we got things together last week, and got the data. And, well. . .the thing might have actually worked.

I was running four separate variations on the same system, and all four did some of what I wanted, apparently. They did it to different degrees, and in a pattern that (if it's real) is quite suggestive. But the whole thing was getting close to the limits of detection - not so close as to make the results totally suspect, fortunately, but everyone involved would be more comfortable with a higher signal/noise ratio.

These results have immediately suggested some follow-up experiments, which I'm going to do with the most promising of those four variations. There are three more components of the system that I'd like to vary. One of them should (helpfully) lead to a stonger signal, which should vary as a function of the component we're adding. That'll be a useful check. And the other two experiments will go the other way and wipe out the effect completely, each by a different route, but only if things are happening by the mechanism I'm postulating. These experiments will carve great swaths through Explanation Space, blanking out whole regions of potential false-positives.

And if these runs go according to predictions, well, I'm going to be in the position of the dog who finally caught a car. Scientists can relate to those dogs, you know. What makes us different from the dogs is, we all know just how we would drive the thing if we caught it, and just where we'd want to go. Woof.


posted at 9:46 pm

Thursday, December 4, 2003

Ask and Ye Shall Darn Well Receive

The latest issue of The Economist has an article titled "Big Trouble for Big Pharma." It's definitely worth a look, although some of the points it makes will be familiar to regular readers here.

The article focuses on something that I don't usually talk about, though - top-line expenses. It claims that pharma companies spend too much money on administrative expenses and other overhead compared to other industries. I don't know if this is true, but it's certainly not impossible. I'm not sure how much working on that will help our situation, but it probably couldn't hurt. Their point about companies spending too much time chasing blockbusters is well taken, but their comparison (the costs for an orphan drug for an infectious disease) is about as skewed as you can get. Besides, they have that development cost as being as much as one-fifth the cost of their comparison blockbuster. What if it only brings in one-tenth the money? Still, the pursuit of only home-run drugs is indeed counterproductive. There has to be a mix of stuff in your research portfolio.

There's one other alleged innovation that I have to comment on:

"Wyeth is encouraging its researchers to perform their tasks better by changing how it pays them. Unusually for the industry, its scientists get to share a bonus pool which depends, in part, on how many new drugs they launch each year. There used to be a temptation for Wyeth's early-stage researchers to throw their work “over the wall” before it was ready to the scientists who run clinical trials, says Robert Ruffolo, the firm's head of research. Because early-stage researchers now share incentives with later-stage scientists, the later-stage researchers have begun to “pull” the development of the most promising compounds forward. A corresponding “push” from early-stage workers hastens the process."

Hey, I'll bet it does! I'm sure they really get behind 'em and shove - that's how I've seen those plans work in the past. And if you have a lean year, well, you'd be surprised how elastic the definition of a "promising compound" can get. Long about November, all sorts of stuff starts to look promising; you can just hardly stand the excitement. (This sort of bonus system isn't a new idea, as you may have gathered from my tone of voice, no matter what The Economist might believe.) Another problem with paying people for drugs launched is that the process takes years and years. By the time you launch, many of the folks who did the actual work will be at another company, and many of the people sharing in the bonus will have shown up after the work was finished. Companies have tried to tie bonus pools to earlier milestones to get around this, and usually the same sort of bracket-creep sets in there, too. Subsidize something, and you'll get it - a law of nature if there ever was one.


posted at 10:00 pm


posted at 9:50 pm

Wednesday, December 3, 2003

Anthrax - Again

The latest issue of Science magazine (Nov. 28, 302, 1492, no free link for non-subscribers) has disturbing article on the notorious anthrax powder from the fall of 2001. Journalist Gary Matsumoto has been covering the story for some time, and his piece here (a long one by Science's standards) seems driven by his despair at the FBI's handling of the case.

Now, I wrote a series about chemical weapons back before the Iraq war, on my Lagniappe site, and I thought about expanding it to biological weapons at the time. But it's a difficult and depressing subject - the chemical weapons were bad enough, but at least they're antiquated. Biowarfare is (unfortunately and damnably) state of the art. But Matsumoto's eyebrow-raising article is enough to make me return to the topic. Besides, most of what he's talking about is chemistry - and some of it is actually pharmaceutical chemistry.

The big question has always been: were the anthrax spores made by civilian technology? Could they have been? Or did they have the signs of classified-level expertise? There have been conflicting reports, to say the least, and the FBI (these days, anyway) is not talking about the subject at all. Some of the obvious tests couldn't answer the question. For example, initial investigations showed that the anthrax was the Ames strain, which didn't narrow things down very much. (Well, it did show that the spores's producers had picked a virulent strain and hadn't cultured something out of the nearest barnyard.)

So Matsumoto concentrates on the processing of the spores: their particle size, and their possible coatings and treatments to make them disperse better. This is where the homebrew/high-tech distinction should be clear, and this is just where the available information has the most contradictions. Initially, reports were that the spore samples had very small, very uniform particle sizes, and may well have had additives to them to keep them from aggregating. Alan Zelicoff, of Sandia, was quotedat the time saying that whoever made the Senate anthrax had "the keys to the kingdom." (I remember reading that, and having a sudden, terrible vision of just what kingdom that was.) But you can now find leaks and reports that dispute both of these contentions, though. The difference is especially marked in statements the FBI has made in the last few months, which make the spores sound much less well-processed than their earlier reports. As Matsumoto puts it:

The reversal was so extreme that the former chief biological weapons inspector for the United Nations Special Commission, Richard Spertzel, found it hard to accept. "No silica, big particles, manual milling," he says: "That's what they're saying now, and that radically contradicts everything we were told during the first year of this investigation."

One of these contradictions is around the question of whether the anthrax spores were electrostatically charged. If they all were given a static charge, they would tend to repel each other, staying as separate particles and dispersing more readily. Some now claim the spores had no charge, others say that they did, but it was an artifact of the postal sorting machinery, and others say that it was a deliberate and sophisticated bit of processing.

Another controversy is whether the spore samples contained silica. That's in there to make the spores bumpy at a microscopic level, which keeps their glycoprotein-rich coats from contacting each other closely. Unrestrained contact causes severe clumping, because there are so many hydrogen bonds and van der Waals forces involved that. Different bioweapons programs over the years have used different sorts of silica (making it a potentially important marker).

Even more exotic, and distinctive, are potential coadditives to make the silica particles bind to the spores, such as some sort of polysiloxane (known, rather inaccurately, as "polymerized glass.") I say exotic from a pharmaceutical perspective, since they're generally not additives that are used (or needed) for drug preparations. But polysiloxanes, as compounds, are quite well-known; there's all kinds of literature on them. Just go to the paints and coatings industry, and you'll find all you'd want to know. What's obscure, though, is their use in weaponizing bacterial spores. . .you'd have to have done that research on your own, or be in contact with those who did.

So, who knows about these techniques, then? Well, there are two places that do a lot of research into finely milled inhaled powders: secret bioweapons labs, and pharmaceutical companies. I don't have many web links to offer for the former, but drug companies are glad to talk about their efforts, and to try to sell you their services (as are some ). The second half of this PDF presentation will give you an overview of what's going on in the pharmaceutical dry-powder inhalation field. Nektar, formerly Inhale Therapeutics, has deals with Aventis and Pfizer for several projects, most famously their long-running attempt to make an inhaled insulin powder for diabetics. Another company pursuing the same goal is Aradigm. And Dura was taking a crack at inhalation technology, before being bought by Elan three years ago.

Has the FBI investigated these research efforts? I'd be surprised (and disappointed) if they hadn't. But, needless to say, drug companies don't spend a heck of a lot of time working with anthrax spores. Not much of a market for an anthrax inhaler, you know. But there's one intersection of the pharmaceutical world and the classified-defense-contractor world that comes to mind: Battelle. Not only do they have sophisticated particle technology, as that link will demonstrate, but (according to Matsumoto) another Battelle division has, in the past, actually done research-scale anthrax production for Defense Dept. and US intelligence. The FBI says that it has interviewed Battelle personnel, but has no further comment.

It's important to note, as Matsumoto stresses, that there is no evidence linking Battelle to the 2001 anthrax. (Nor is there any to link another logical site on the bioweapons side of things, the Army's Dugway Proving Ground in Utah.) But if it's true that the anthrax showed signs of sophisticated technology, places like this (or their equivalents in foreign countries) are the ones to investigate. Matsumoto hammers on the point that the FBI's basement-anthrax theories have come to a dead end. They and the Army appear to have been unable to reverse-engineer the Senate anthrax using home-style technology.

We still don't know where the 2001 anthrax came from. The story has just become more confused as time goes on. But what worried me then, and worries me now, is that if you're going to go to the trouble of making this stuff, you might as well make a good-sized batch. Remember the note, in the letter that was sent to Daschle's office? "We have this anthrax," it said. I thought at the time that it meant "We have this anthrax," meaning, the good stuff. I remember that I was surprised when the anthrax attacks stopped. I wonder if they really have.


posted at 10:36 pm

Tuesday, December 2, 2003

In Progress

Glenn Reynolds of Instapundit alerted me to this exchange on nanotechnology that's coming out in the next Chemical and Engineering News.

Eric Drexler and Richard Smalley go after each other on the topic of molecular-scale manufacturing. Drexler thinks it's possible, and Smalley disagrees, to give you an instant scorecard. They do talk past each other a bit, but both of them score some points. It's what diplomats would call "a frank exchange of views," and I'd like to urge everyone with an interest in the topic to read it. An excellent summary of information on the topic, from Ray Kurzweil's pro-Drexler position, is here. I'm working on a post myself, but it's not whipped into shape yet.

As a chemist, I've more than a passing interest in this field. Nanotechnology is chemistry, through and through. It's done (going to be done, I should say, if Drexler's right) by other means than the ones I'm used to, but it's atoms and bonds all the way. As a solution-phase classical organic chemist, I look on the advent of what Drexler calls "machine-phase" synthesis with equal parts anticipation and dread. The dread isn't because of some looming catastrophe, just the fear that I'll eventually be invented out of a job.

I can tell you right now that I'm going to come down in between the two of them on this issue - I think that molecular-scale manufacturing is going to be possible, but I think that Drexler is glossing over some key difficulties that will have to be overcome. More when I get my thoughts in order.


posted at 9:18 pm

Monday, December 1, 2003

Kornberg's Commandments

I've been reading Arthur Kornberg's update to his "Ten Commandments of Enzymology," which was published in the October issue of Trends in Biochemical Sciences. Kornberg's well over 80 years old by now (here're his memoirs), and he won his Nobel before I was born, so he's pretty much seen it all. And as you'd expect, there are a lot of good points in his advice.

His first commandment, which was also in his 1990 version is "Rely on enzymology to resolve and reconstitute biologic events." This is a warning not to expect genomics to answer all your questions, and it's advice that has been amply borne out in the last few years. Everyone has ransacked the genome, looking for sequences that code for new enzymes, and we've largely come to the end of it. But what has that effort told us?

Kornberg's answer would be "Not much!" The best that a sequence can tell you is what family an enzyme might belong to - some sort of serine protease, some kind of kinase. And even then, genomic data tell you very little about what substrate an enzyme might actually be acting on. But past that, Kornberg correctly emphasizes that enzymes have two other faces to them besides their catalytic activity. For one thing, almost all enzymes have regulatory sites on them, regions designed for fine tuning of their activity. These can be phosphorylation sites (to be acted on by still more enzymes!) or totally separate binding sites that pick up completely different ligands than the ones the catalytic site deals with. These are much less well understood.

Then there's what he calls the social face. It's easy to forget that enzymes don't live in a vacuum - the inside of a cell is a very crowded, highly structured place. That's Kornberg's 7th commandment, actually, to be aware that "cells are gels." (Frankly, if cells were the kind of well-mixed homogeneous containers that we use in chemistry, there's no way that they could work.) Enzymes have a physical place with defined neighbors, and their surfaces are constantly interacting with these scaffolds and partners.

And we don't understand these things well at all. Kornberg's plea is to try to work these things out in cell-free systems, piece by piece, since we don't have the tools to see what's going on in the real system. Without checking each step, we won't be sure if we're looking at an important puzzle piece, or just an artifact. As he says: "Few multi-step pathways have been fully reconstituted and the urge to tackle them has diminished. The refined genetic analyses of events in cell biology and developmental biology cry out for efforts to observe them in a cell-free system. . ."

The proteomics people are taking a crack at the problem, working out arrays of protein interactions, and these could be a starting point for the reconstituted pathways that Kornberg advocates. But it's important to realize that proteomics, as it stands now, is just that: a necessary start. Figuring out what goes on at the molecular level in a living cell (where it all becomes chemistry, I chauvanistically add) is going to keep us occupied for a long time to come.


posted at 9:44 pm









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