Lagniappe (science, business, and culture)

Tuesday, April 30, 2002
Acrylamide Redux
Paul Orwin writes to mention that acrylamide has more problems than its carcinogenicity. It's a neurotoxin, which is something you have to watch out for when you handle the pure stuff (it's sold as a fine powder for use in making electrophoresis gels, as I mentioned yesterday.)

That's certainly true, which is why I'd handle it with gloves when using it. But that's a different effect than you'd expect to see with the potato-and-grain news item.

One immediate difference is the dosage, which is far lower. For many (most?) things, there's a threshold below which they essentially aren't toxic. Some stuff has a very low threshold, of course - tetrodotoxin (the poison found in fugu, puffer-fish sushi) and nerve gas come to mind. But a single molecule of even those won't do you any detectable damage. That's a reducio ad absurdum,but it gets the point across.

There are even things which are essential nutrients, yet poisonous, like selenium. Try categorizing that one! It all depends on the dose.

A modification of that rule holds for things that the body can't metabolize and/or clear well, and which accumulate with time. Heavy metals such as lead and mercury are in this category, as are some radioactive isotopes. In those cases, small repeated doses, individually not particularly harmful, can add up to something dangerous. An organic chemical that comes to mind in this category would be MPTP, which leads to Parkinson's disease by a selective toxic mechanism targeting the substantia nigrain the forebrain. In that case, because the damage (once done) can't be undone, the effect accumulates.

But that's not the case with most organic chemicals. Any damage they might do would be to a single (expendable) cell. They're mostly metabolized and shunted out the kidneys before they can even do that.

The second difference with exposure to acrylamide in its powdered form versus its french-fry form is the route of administration. Skin contact and inhalation are nasty routes by which to take in a toxin, because they bypass a lot of the metabolic safeguards. (Of course, that's why drug companies want to use those routes to administer things that get chewed up if you take them orally, like insulin.) If you have to get exposed to something toxic, my advice is to eat it. That way, you've got the enzymes in your gut and liver on your side.

The only time that breaks down are with things where the metabolic effects of the liver actually turn a compound into something worse. That's what happens to benzene and benzopyrene - the liver, while just trying to do its job, inadvertantly turns these into really foul reactive epoxides, which can do a lot of damage. The odds of this damage leading to carcinogenesis are small, but over time and repeated exposure, it adds up.

As you can see, toxicity is quite a minefield. Trying to answer the question "Is this stuff toxic or not?" tends to lead to pages of on-the-one-handing, which drives everyone nuts. But that's the way it is.

Monday, April 29, 2002
You Want Acrylamide With That?
I'd like to be able to comment in detail about the recent news item that acrylamide is present in many common foods at greater levels than thought. Unfortunately, no one's seen the data, as far as I can tell. It hasn't been published, only press-released. Considering that people have been eating bread, cooked rice, baked potatos and french fries for some time now, I don't see what the rush was.

Of course, acrylamide isn't something you want to pour on your corn flakes. If I handle it in the lab, which I've only need to do once or twice, it's with gloves on, and in a fume hood. Molecular biologists handle it more often, since it's a component of the gels they use for analysis. Studies in rodents have indicated that's it's a potential carcinogen (for what that's worth, and high-dose studies aren't always a good measure of carcinogenicity.)

And it's possible that this is, indeed, an unrecognized problem that needs attention, although what we're going to do about it is a real head-scratcher. But in the absence of data, who knows?

Someone who would have useful things to say about this would be Bruce Ames. Here's an interview with him a few years ago (conducted by Virginia Postrel, no less) which gives you a good idea of his thinking. More Ames links can be found here.

In short, his opinion is that humans have evolved to deal with low levels of most things that are found in food, and he doesn't distinguish between natural and synthetic compounds there. He's pointed out, rightly, that many of the compounds found in broccoli (to pick one example) would be considered carcinogenic if someone bothered to purify them and test them the way food additive are tested. The dose makes the poison, as Paracelsus put it, and toxicity generally doesn't scale to infinitely small doses.

It may well be that the acylamide business will fit into this category. I think that reasonably likely, and until I see the data, that's where I'm filing it.

Sunday, April 28, 2002
I've noticed a good number of people showing up from the new permalink over at Instapundit (thanks, Glenn!)

Welcome to all new visitors, of course. I spend my time here talking about the pharmaceutical industry, about what doing research (specifically chemistry) is like, and speculating on some general scientific topics. Not too much politics get transacted here, although one current of the site is the business and financial aspects of science. I even unload thoughts on things like the Japanese economy from time to time - we're due for more of that soon.

Hope you enjoy it, and check in every so often. If you like this sort of thing, this is the sort of thing you'd like, to borrow Lincoln's line.

A Tiger's Tail?
Posting may be a bit spotty this week. I've been working hard in the lab (and at my desk) on a new idea - actually, a series of them. This started kicking around in my head a few weeks ago, but I've been extending and amplifying on it recently. Our (nearly) two-year-old daughter woke up in the middle of the night last week, for a short time, and for once I was the one who couldn't get back to sleep. I got to thinking about this area, and had a series of thoughts and speculations that kept me up the rest of the night, which isn't the way my brain usually works.

It's going to be frustrating to write about this stuff here, because I really can't go into details (my employer has a right to any really good medicinal chemistry ideas I have, since I'm going to use their money and facilities to try them out.) So bear with me; I promise that I'll be talking about other things as well.

All I can say is that this is either one of the best runs of thinking I've ever had, or one of the wilder goose chases I've ever set out on. Those two aren't mutually exclusive, come to think of it. I hope to put some of these ideas to the test in two or three weeks, and if they start working, I'll be posting some nonspecific elated noises.

Friday, April 26, 2002
The Waiting Game
Merck was out the other day with an overview of their drug pipeline. Note that the link takes you directly to their press release, so there's a fair amount of cheerleading you'll have to dig through. The unspoken message is the one all the big companies are trying to semaphore to Wall St.: "We're not Bristol-Meyers Squibb!"

As far as I can tell, the key to Merck's near-term future is the drug called Zetia (ezetimibe,) which they're co-developing with its discoverer, Schering-Plough. It's a cholesterol absorption inhibitor that works on some protein in the gut wall. The companies have an application in to the FDA for use of the drug as a stand-alone therapy, but the real action will be when it's combined with a statin - ideally, from Merck's viewpoint, their own Zocor.

The statins, of course, inhibit the body's cholesterol synthesis. So if you block that, and block absorption from the diet. . .what's left? Not much, probably. The clinical trials show, so far, that Zetia adds to the effect of taking a statin, and gives you results that you probably can't get with monotherapy.

The FDA submission for the Zetia/Zocor combination is slated for next year, but you have to figure that if the stand-alone drug gets approved before then, there's going to be a lot of off-label prescribing as a mixture with existing statins. (Are off-label prescriptions 1. an example of free-market initiative, or 2. a shady marketing practice? Either one, depending on the situation, I'd say. There are examples both ways, with some particularly notorious ones in the latter category.)

Well, full disclosure: I know the people at Schering-Plough who discovered the drug, so of course I'm rooting for them. And I own some Schering-Plough stock, too, and I'm rooting for that to finally get up off the carpet. If Zetia takes off, that might do the trick. Of course, if it reallytakes off, Merck might just decide that it makes more sense to just buy Schering-Plough rather than pay them. . .

Wednesday, April 24, 2002
A Law of the Lab
When I was in graduate school, I sat down one evening in the lab and made out a list of what seemed to be inescapable laws of organic chemistry. (Evenings, weekends, holidays, and any time left over were generally spent in the lab, of course. It took me the better part of a year to get cured of that habit after I got my PhD, but that's another story.)

I circulated the list among my friends, and some copies made their way around to research groups at other schools - for all I know, there are yellowing copies of those early versions still taped to someone's hood, somewhere. Looking back at the list, it's clear that I was not in a good mood when I wrote it out - but I did say that I was in graduate school, didn't I? No need for redundancy, then.

None of the laws are particularly original, in the sense that most chemists will look at them and go "Yep!" For example, Law #1 is:

You can never have too much starting material.

I sure proved that one over and over during my graduate days. My project got so long and unwieldy that it sucked in every available gram of material. I'd start off again, on larger and larger scales, only to find myself back up at the frontier, holding this little flask with some 20 milligrams or so of clear syrup: all that remained of all that time and effort. I went to crazy, ridiculous scales - initial reactions that used the biggest round-bottom flasks and buckets I could find. No avail, it all led back to yet another little flask with a little product in it.

Nothing I've seen since has persuaded me that this law isn't universal. Oh, it's true that the occasional project will crash right after a big bucket of starting material has been made. Into storage it goes, until someone thinks up a use for it. But those cases are far outnumbered by the ones where each lab hoards their precious material, and every new batch gets a parade of supplicants asking for - well, not all that much, really - just enough to do a couple of things we've been trying to get around to for a while - I think all we'd need is, oh, not even more than half of what's in the flask. . .excuse me?

Tuesday, April 23, 2002
A Quick One
Very little time to blog tonight, so I'll just mention that my latest article is up over at Tech Central Station. This one is a look at the prospects for an HIV vaccine.

While you're over there, I can also recommend Charles Murtaugh's article on cloning. If you've been following his site, you'll know where he's coming from, but it's a good summation all the same.

Monday, April 22, 2002
More Colors and Smells
I've had several letters about chemical colors. One chemist friend points out that for wild colors, the indoles are the way to go. I haven't done too much indole chemistry (which is OK, since they can reek), but he's right about that. You can get all sorts of pinks and purples as side products. The classical indigo pigment is a derivative of this structural class, so it makes sense. Of course, none of the colorful ones are going to be drugs, most likely, since they have lots of weirdly conjugated bonds that make them both colorful and reactive. Not something you'd fork over for at the pharmacy.

Another letter points out that I misstated Carl Sagan's term for the organic goo found in the outer planets (and in my fume hood at work.) It's "tholin", not "thiolin," which removes my objection completely. And it's what I get for doing these things from memory, when I could reach three feet over to the bookshelf and check it out.

The same reader mentions that recent calculations have shown that if someone manages to make 1,3-difluoroazulene, the color should shift from blue to emerald green. That would be worth seeing, but it's still not enough to get me to do serious fluorine chemistry. You can mess things up very thoroughly with some of those fluorination reagents (and I, unfortunately, can tell you what xenon difluoride smells like, so I have no desire to investigate the other possibilities!) For the record, it's not really a bad smell, just not something that should necessarily be smelled. . .

That reminds me of an entry in the Merck Index. I don't have a copy at hand (this time!), but I think it's for something hideous like fluorine oxide. The entry notes "extremely poisonous. . .attacks lungs even in traces. . .peculiar smell." I've always thought that rather evocative. That last observation sounds like someone's last words, frankly.

I've reworked the links at left a bit, adding and rearranging. I really should have mentioned this the last couple of times I did it (adding Orwin and Simberg, as I recall,) but I'll try to make sure to in the future.

Fun While It Lasted
The realization has gradually crept up on pharmaceutical chemists that the Great Hiring Wave of the last few years is over. For a while there, it was the biggest one ever. It swept in plenty of people fresh out of grad school, and probably decreased the percent of PhDs doing post-docs, since the offers were good whether you did one or not. It also allowed lots of experienced people to jump companies (and here's where I raise my hand, since that's what I did.)

Some history: there last was a noticable hiring phase in the industry in the late 1980s and early 1990s (which, fortunately, is when I was looking for my first job after my own post-doc.) It wasn't anything like what we've just finished, but my impression is that 1986-1991 or so wasn't bad, either. All this came to a screeching halt with the political fights over the Clinton health care proposals. 1993 and 1994 were absolutely terrible years to get a job in the drug industry. Everyone was pulling back and battening down the hatches. 1995 and 1996 returned to somewhat normal levels.

But around 1997, things really began to roll. Several large companies began hiring more aggressively as they expanded their facilities. There was a building boom going on across the industry, and those new labs had to get filled up. Salary offers increased for new hires, and the headhunters began to ring the phones of experienced chemists with some pretty good offers, too (which is what happened to me.) Things kept on hopping for the next two or three years.

I should go back and count ad pages in Chemical and Engineering News to prove this, but I think that last year there was a noticable slowing down. And this year, with all the worries that companies have about their R&D pipelines, there's no doubt about it. My sympathies to those organic chemists who are just finished up degress or post-doc appointments and are ready to hit the interview trail; it's going to be harder (though not impossible.) It's not like 93-94, fortunately. But it's not 1998 any more, either.

Friday, April 19, 2002
You Read It Over Here, Too
Since I mentioned the Wall St. Journal article, I should point out that today's NY Times has almost the exact same piece in it (I'll post the link soon when I get my Times online access straightened out.) For many of the same thoughts on the state of drug-company pipelines and why they've gotten that way, see my postings on Feb 17, 7, and 24 (among others) in the archives at the left margin. As Glenn Reynolds would say, Advantage: Lagniappe!

Of course, this means that article I wrote summarizing all this is going to end up lining a parrot cage or wrapping a fish rather than getting published. Although, come to think of it, that's what it would have ended up doing even if it did get into print. . .hmm. . .

Colors May Fade
A recent view of Jupiter through my telescope made me wonder, as it usually does, just what sort of weird chemicals must be floating around up there. All the ingredients are there, and the intense heat and pressure in the lower layers would be enough to drive most any reaction you could think of. The various colors of the clouds (yellow, brown, red) are a clue that there's plenty going on.

I've seen those colors before, and my organic chemist readers will know exactly where I mean: stuck to the top of the silica columns that I use to purify compounds. Side products in organic chemistry reactions can give you some intensely colored materials, which resemble the colors in Jupiter's clouds quite closely. (Early in his career, Carl Sagan coined the word "thiolins" for these colorful organic mixtures. To a chemist's ear, that makes it sound like sulfur is the most important component, which isn't necessarily true.)

Frankly, though, none of ever really characterize the stuff. We're just trying to get rid of it as fast as possible. Medicinal chemists know that there are mightly few maroon or chocolate-colored wonder drugs; most small organic molecules have no color at all. A few of them are yellow, but a faint yellow color that's usually a sign that you've got a small amount of something that's reallyyellow mixed in there.

OK, there are exceptions, like azulene, a small hydrocarbon which is a startling blue color. It's a useless compound to a medicinal chemist, but I've always been tempted to order some for my lab just so I can have one blue compound in the place. I'm not aware of any organic molecule that's green without the help of a metal like nickel or copper. There are a few honest purples, but they're usually weird anions, nothing that you'd keep around in a bottle.

The corollary to that is that the photos you see of keen-eyed researchers holding up Erlenmeyer flasks of green liquid are faked. It's food coloring. I've been in the lab when they come around for annual-report publicity shots, and they always want to dress things up. The same goes, in spades, for movies and TV shows. If anyone out there has a copy of Ebert's Little Movie Glossaryby Roger Ebert (1994), you'll see my contribution on page 59, the "Law of Colorful Chemicals." (That's not my current address in there, by the way.)

The oddest color I think I've seen was a fluorescent shocking pink compound that turned up in the lab next door when I was an undergraduate. This stuff hurt your eyes; it was dazzling, and completely unexpected. The guy who made it darn near dropped the flask.

Thursday, April 18, 2002
You Read It Here First (If You Read It At All!)
Today's Wall St. Journal (no free link) has a front-page article on the problems that drug companies are facing trying to fill their pipelines. It hits many of the same themes that I have over the last three months or so: many of the easy targets have been done, the latest technologies have been better at posing questions than coming up with answers, etc.

This might be one reason why the Journal dinged me with such speed when I had the nerve to pitch an op-ed on the exact same subject to them recently. (Actually, the news and editorial staffs of the paper are pretty much on different planets, I'm told.) The fact that they probably get about 3000 pitches a day might have a bit more to do with it. As does the fact that I'm not exactly a household name. . .maybe they think I pitch for the Red Sox.

That should be about enough blogrolling and promotion for the night. Back to the science tomorrow!

Unknowns Anonymous
Among those other pseudonymous bloggers is "Sydney Smith", aka Medpundit. I have to say that I wasn't on the ball enough to realize that that was an alias! After the English reverend and writer (who resided at the outermost fringe of my memory) perhaps?

That brings up a point made by Ray Davis, that the use of famous pseudonyms (such as Musil and Dodgson) does cause some trouble. You'll have a low signal-to-noise ratio when people try to Google you out - I should know, sharing my name with a Red Sox pitcher (not to mention some guy who's heavily into body piercing and seemingly all over the web.)

Still, I notice that I come up #6 in a Google search for my name these days, which is a lot higher than I expected. The Musil and Dodgson blogs show up as #4 in searches for those names, for that matter. But there must be plenty of other pages that refer to any of us, and you'd have to string a lot of minus-signed search terms into Google to root them out.

Wednesday, April 17, 2002
A Tough Call
I see that my esteemed colleage Charles Murtaugh has thrown down the gauntlet to the "Godless Capitalist" blog that I linked to (by coincidence) on the 15th.

Charles is calling for an embargo on linking to pseudonymous bloggers, and while I can see his point, doing so would keep me from linking to "Robert Musil" and "Charles Dodgson" among others. (Again, coincidentally, the latter of those two spends no small amount of time attacking the former.)

Heck, I toyed at first with the idea of going anonymous myself, since I wasn't sure what my employer would think of my freelance pharamceutical comment. (As it turns out, they're fine with it, as long as I'm not seen to be speaking in their name, which solution makes both of us happy.)

As for the Capitalist blog, though, I'm with Charles on the thing that set him off, the attitude displayed there towards John McWhorter. I agree that McWhorter is, in fact, the real deal, an extremely valuable man (and I would assume, an extremely valuable faculty member as well.)

Patent Not Necessarily Pending
One of the things that we're faced with in the drug industry is the constant search for chemical matter that we can actually own - that is, that we can patent. It's getting harder. There are more patents filed than ever, and the patent offices are getting so overloaded that, frankly, they're letting all kinds of stuff through. The idea seems to be that anything important will just have to get ironed out in court. (I should complain - the folks who deal with software and business-method patents have it even worse, as a perusal of Greg Aharonian's site will make clear.)

So, when you see a patent application that claims everything out to the orbit of Neptune (as many do,) you never know these days whether someone's actually going to let the darn thing issue. When might that actually happen? If it does, will the company involved try to defend it? If they do, who'll prevail in court? These questions, like electron wave functions, have only probabilities for answers.

Well, if they claim a zillion compounds, but only make (or enable, as we patent mavens say) a small fraction of those, you can always have hopes you'll prevail in a fair fight. But no one really feels comfortable basing a long, expensive drug discovery effort on those hopes. You're always better off having something free and clear.

The problem there is that the compounds we make are only novel the first time. After that, they're prior art, and you can't own the "composition of matter." What this means in practical terms is that eventually some well-trodden areas of chemistry are going to get patented-out. You can already see this happening in certain popular medicinal chemistry templates. I won't mention any specific ones, for fear of giving away what my colleagues and I are interested in, but those of you in the business know the things I mean. You just throw up your hands if you get active compounds in these series, because you know you probably can't get patentable ones.

This problem isn't going away, but we can hold it at bay, of course, by making new compounds in new classes. That's worked for a long time, and it'll no doubt work for some time to come. But no one really knows for how long. . .

Tuesday, April 16, 2002
No Good Deed Goes Unpunished
All I can say about my work at the moment is that my lab is faced with a classic scientific situation: all the data say things should happen one way, and they stubbornly persist in happening the other. I can't go into much detail - well, any detail, to be honest, but I can tell you that it's simultaneously interesting and frustrating. "We're doing everything right!" is the shout, but the cells in the dish refuse to hear us. . .

Well, we already have several ideas of how to fix this, based on several ideas of what might be going wrong. Although I can't tell you all what the problem is, I guess I can let everyone know if we ever fix it!

Cloning Ban Update
My calls to the offices of my state's Senators told me that they've already received a good amount of feedback. There was no down time - as soon as I mentioned "S. 1899" the staffers I spoke with were asking which side of the cloning issue I was advocating.

My use of the phrase "Much as I hate to find myself on the same side of an issue as Tom Daschle. . ." must have given them a chuckle.

Monday, April 15, 2002
A Treadmill Pill?
There was quite a wave of publicity about a possible "exercise pill" recently. The folks over at Godless Capitalist asked me to take a crack at explaining what all the noise is about. As you might imagine, though, the original research that set this off is a bit less sensational: "Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK" is the catchy title, from a joint effort of teams at Duke and Southwestern/Dallas.

For a long time, it's been known that the key to a muscle's capacity is the number of mitochondria in its cells. Those, of course, are the organelle responsible for energy production. The more you have, the longer you can go without fatigue (which is really just a buildup of toxic waste products formed when the mitochondria can't keep up with demand, and the cell has to switch to other, less efficient pathways.)

It's also been known for decades that exercise causes more mitochondria to be produced inside muscle cells (along with plenty of other changes,) but the genes that are turned on and off to do that are still pretty obscure. One of the things that happens with exercise is elevated calcium levels in the cells, which sets off the activity of several enzymes. These researchers engineered a form of one particular enzyme, CaMK-IV, so that it would be activated even without raised calcium levels. They also took out the section of the protein that would normally keep it inactive under baseline conditions, so the enzyme was set to be set to full activity the entire time.

The transgenic mice made with this mutation are interesting animals. Their pattern of gene expression (and the corresponding levels of various proteins) make their muscles look very similar to normal muscle after extended physical training. Thus the "exercise pill" hype - the mice seem to have developed with pre-exercised muscle tissue.

And, sure enough, microscopic examination showed that the mutant mice had about 50% more mitrochondria in their muscle cells. The teams also identified raised amounts of a protein (PGC-1) that's known to be very important in metabolic balance in fat and muscle tissue. The best guess is that the engineered activity of the CaMK-IV enzyme set off production of more PGC-1, which led to more mitochondria. No one had made that enzyme-PGC connection before - it'll be useful to know that, because PGC-1 has key roles to play in obesity and diabetes, as well as in exercise.

So, now we have a better idea of how muscles figure out how to respond to exercise. Do we have an exercise pill? Nowhere near. Keep in mind that these mice had to be genetically altered to get the activated enzyme. Getting that effect with a drug won't be easy.

One problem is that it's more or less impossible to get an enzyme to do what it does better or more quickly. They're built for speed already. What you can do is find some other system that's naturally slowing it down, and try to gum that pathway up instead, freeing the enzyme of interest to do its thing. (A general motif of medicinal chemistry is that we're a lot better at throwing wrenches into the works than we are at tuning them up to work better; millions of years of evolution are hard to outdo.) There's no guarantee that we'd be able to do this trick with CaMK-IV.

And if we did, there's no telling what might happen (although I'm sure that someone's going to give it a try, and more power to them.) Genetically altered mice, who've had their entire embryonic development to deal with some mutation, can behave very differently from normal adult mice that get suddenly thrown into the same state. A number of these gain-of-function enzyme experiments, for example, have yielded results that don't seem to apply well to the real world (although this one, admittedly, makes a lot of sense.) Don't cash in the health club membership just yet.

Sunday, April 14, 2002
Willie Stark Goes Biotech
Virginia Postrel noted the brevity of my response to the online petition against the cloning ban before the Senate. It's true that things have been pretty busy around here - for example, I'd wanted to comment on the "exercise pill" headlines, but that'll have to wait until tomorrow.

I wanted, though, to recommend again that everyone who cares about this issue both sign the Franklin Society petition and be sure to call the local offices of their Senators. My calls in these situations are along the lines of "My name is so-and-so; I'm registered to vote in this town/district; I have never missed a general election. If Sen. X votes for this bill, I will be certain to vote against him or her at the next opportunity, and I'll encourage everyone I know to do the same."

Politically, the key is to make it more damaging for a Senator to vote for the cloning ban than it is to vote against it. Emphasizing the potential benefits from the research is one way to make that balance tip - that way, you can be painted as voting against the hope of getting people out of wheelchairs or off their Parkinson's medications. No politician wants that.

From the Senator's perspective, against all that is the potential political benefit of voting to protect us all against some nightmare spectre of human clones rolling out of the maternity wards. That's an emotional issue, all right, and in some cases it'll be tough to make that look like the less politically attractive position. Most politicians would relish the chance to run against Dr. Frankenstein; ol' Frank doesn't poll too well.

Note that I haven't said anything about the hypothetical Senator's personal principles. I'm assuming that that's only important in a minority of cases, frankly. In defense of that view, I can say that my father was active in local politics when I was growing up back in Arkansas. The lessons I learned back then have stuck with me, and they've rarely let me down.

Friday, April 12, 2002
A Less-Than-Subtle Plan
It seems that someone got very lucky just before the bad news hit at BMS (see the April 4 posting below.) That's one explanation, and I hope that whoever it was is ready to defend it.

Today's Wall St. Journal reports that the day before the profit warning, some serious option transactions took place in BMS. Ten minutes before the close, orders came in to buy thousands of put contracts, at strike prices of 35 and 40. This was a most unusual spike in volume.

For those who aren't into options, that was a heavy bet that the stock price would fall. Option contracts have a built-in time limit. Each contract gave the holder the right to sell BMS stock at a set price ($35 per share for some of them, $40 per share for the others) at any time before April 20. When those were bought, the stock was at 37, so the right to sell at 40 for the next three weeks is worth at least $3 (the instant profit you could make by buying the stock and selling it at your locked-in price.) In practice, it's worth that $3 plus some extra premium. That extra depends on how long the option's good for and how volatile everyone thinks the stock will be.

Meanwhile, with the stock at 37, the right to sell at 35 isn't worth too much - just the premium based on the chances everything thinks it might have to actually go that low in the time remaining for the option. The only reason you'd buy an "out of the money" option like that is if you expect the stock to drop below 35 in pretty short order. At the very least, even if you don't believe that personally, you must think that a lot of other people are going to believe it, and soon.

Of course, this little transaction (which at its peak value could represent the selling of about 37 million dollars of stock!) paid off very well indeed. BMS promptly closed at about 32 the next day, and has dipped below 30 since. Those options have returned many times their original worth (although it's hard to tell if they're still being held, or held by the original buyers.)

This is the transaction for someone who's not satisfied with a measly 15% overnight profit. They want an overnight 500% to make it worth their while. Accordingly, option trades are one of the first things the exchanges (and the SEC) look at when there's a sudden move in a company's stock. It's like waving a red flag that says "Investigate me!"

I'd hate to have to explain how I got so darned lucky all of a sudden. Good luck to whoever placed these trades. You'll need it when they knock on your door.

Thursday, April 11, 2002
And People Ask Me, "Why Do You Sell Short?"
You've probably heard about the indictment handed down against Merrill Lynch and a number of their analysts. But since many newspapers won't publish the good parts, there's no substitute for reading the real thing. (Note: this is a PDF file.)

It's certainly entertaining to hear the talk among Merrill's own staff, calling stocks "such a piece of crap" or "a powder keg", and giving opinions like "nothing positive to say", "fundamentals horrible" and "this has been a disaster." What a world it would be if analysts spoke like this publicly!

Of course, for public consumption, all these were rated varying degrees of "buy." The indictment, I have to say, is a bit willfully naive about this. Anyone who truly knows anything about the stock market knows that there's a vast amount of positive bias built in. Merrill's internet group, for example, rated stocks (supposedly) on a five-point scale, but stated that they wouldn't cover anything worse than a 3. In practice, what that meant was that a "3" rating meant bad news - to quote an internal document, "major red flag - short."

There's the word! And to think of all the abuse that retail investors heap on the heads of short-sellers. Here are the very people who know the most about a given stock saying that that's the best thing you could do with it.

Well, if you don't know what it means when a brokerage house drops coverage of a stock without saying a word (which is what Merrill did instead of giving a lower rating), then good luck to you. I can't share the indictment's "shocked, shocked" tone about that sort of thing. And it doesn't surprise me for a minute that the investment banking fees drove the stock recommendations.

But that doesn't make it legal, either. Just as the investor should know what a "neutral" rating really means, the analysts should have known that someday the law might actually be enforced. It'll be interesting to see where this goes. . .

Wednesday, April 10, 2002
On the Digital Dotted Line
Very little time to post tonight, due to a work-related dinner and the looming tax deadline. I'd like to pass on, via Charles Murtaugh, the news of a petition against the proposed blanket ban on human cell cloning being considered by the Senate. I think the bill, as written, is far too restrictive and will unnecessarily restrain a lot of valuable research. If you agree, the petition is here.

And take the time to call the local office of both your state's Senators, too - I'm not sure how much attention they pay to electronic communication sometimes, but I know that they care about phone calls.

Tuesday, April 09, 2002
And Another Thing
That Fitzgerald reference is, of course, the quote about the sign of a first-rate mind being the ability to hold two contradictory statements at the same time. Like several of his other quotes, that one has the germ of spectacular error in it - similar to his line about there being no second acts in American lives. That one gets trotted out with great regularity, as we prove that some lives are made up of nothing but second acts.

Anyway, I'd say that that ability is as often the sign of a third-rate mind or lower. Another example of these contradictions came to mind after I read my mail about the last couple of postings. One correspondent pointed out that we have people watching for every food additive that might be shown to cause cancer, but thanks to Hatch-Waxman we're also letting people swallow almost anything as long as it's labeled as a "nutritional supplement." Some of these are the same people, actually.

Tropical leaves that starving tapirs wouldn't touch, roots whose previous function was to sterilize unwary nematodes, seeds and kernals that would give a buzzard the trots. . .grind it up; it's all fine. You don't really have to test anything for safety, and you don't have to prove it does anything (costs money to do that, anyway.) Just be sure to say that it's "not intended to treat, cure, or affect any disease" and you're rolling.

The latest issue of the fine review journal Trends in Endocrinology and Metabolismhas an article detailing cases where imported traditional "herbal preparations" have turned out to be laced with actual pharmaceuticals. While that reminds me of is the story of W.C. Fields spitting out the contents of his on-set swigging flask, which he always maintained was full of pineapple juice. Someone put him to the test, and his shout was "Who put pineapple juice in my pineapple juice?"

Imagine a traditional preparation of herbal goodies that turns out to be cut with man-made antihistamines or sulfonylureas, rather than Nature's own bounty of alkaloids and cardiac glycosides. Here you are, expecting the usual gut-bomb of all-natural ephedrine, caffeine, or hepatotoxic enzyme inducers, and you get something scraped out of a vat instead. The nerve!

The problem is, it's not just that some fly-by-nighters are slipping pharmaceuticals in. The article also includes harrowing cases of preparations that contained whacking loads of mercury or arsenic, for reasons unknown. Why people swallow the ads for these things, much less swallow the pills, is a mystery to me.

Monday, April 08, 2002
F. Scott Fitzgerald Had Something to Say About This
Not much time to post tonight, since our 22-month-old came down with a sudden fever. She's fine otherwise, though, in case anyone's wondering. I'm sure that, as a blog-baby, she'd play well with "Gnat" Lileks.

I've already had several e-mails about my snake-oil outburst in the previous post. No one's come out for the pro-snake-oil position yet; I guess that audience doesn't read me, which is something I can certainly live with.

It was probably the contrast between the ads I mentioned and what I know that medicine can accomplish (see 4/4 and 4/2 postings below.) I've noticed that Sydney Smith over at Medpundit takes issue with both the degree of my gloom and the degree of my optimism. He's got a point about some of the things we can do now (vaccinations are always a good example to adduce,) but I wonder about the popular perception of medical treatment. Large groups of people are worse than I am, in both directions.

There are two mutually exclusive wrong ideas that the general public has about medicine, I think. The first is that there's nothing useful out there, they're just going to mess around with you and waste your time and money, you're going to get what you're going to get, why fight it, etc.

Contrast that weltanschaungwith the second major group: the ones who feel entitled to have everything that goes wrong with them fixed. If one doctor doesn't give them the satisfaction they're after, they go to another. If one medication doesn't cut it, then there's another that will. Generally, there's a sense among this population that any condition can also be traced back to its cause, that person, action, or thing that made them sick. After all, the default setting is perfect health, so something must have happened!

There's a subset of people who manage to believe both of these things at once: these are the big-conspiracy types, who are sure that the doctors and the evil drug companies are ganged up against everyone. (It's an odd viewpoint, when you consider that those two groups - although they need each other - don't always get along very well.) I've had people seriously explain to me that "they" have cures for all these terrible diseases already lined up - "they're" just waiting until everyone's sick enough to make the market really huge.

I give those folks my standard answer to all conspiracy buffs: "Yeah. . .that's what they want you to think. . ."

Sunday, April 07, 2002
Get Your Miracle Elixir
For Monday, I'm just going to send everyone to a wonderful article from the Washington Monthly. (I came across this one over at Arts and Letters Daily.)

It's a strongly worded look at the alternative/holistic medicine area, with particular emphasis on the recent attempts to subject these treatments to clinical proof. Many of the practicioners are simply ignoring the studies if they don't give them the answers they want to hear (which, as you can well imagine, they generally don't.)

I can tell you that my blood heats up when I hear the radio ads for potions - excuse me, dietary supplements - to "cleanse your liver" or "sharpen your memory." Not to mention all the miracle weight-loss or hair-growing pills. I feel like I've slipped through some wormhole and ended up in 1910.

Just look at the ancient shucks that are still in business: magnet therapy, iridology, can read all about this stuff in Martin Gardner's first "Fads and Fallacies" book, which is nearly 50 years old. The true and inescapable mark of a pseudoscience is that it doesn't learn a thing. It never changes; the theory is never overthrown; it just keeps on plugging away obliviously. Who cares about facts?

And while I'm on the subject of pedigreed nonsense: if I see another gaudy display of homeopathic dishwater near the checkout of a pharmacy again, I may do something quite reckless. I can only imagine what my medical colleague over at Medpundit thinks about that stuff; I know the herbal supplements really get on his nerves. As they should.

I'll come back later to the subject of the Hatch-Waxman Act, which is one of the things that got us into this fix. For now, check out that article link for a table-pounding good time.

Friday, April 05, 2002
Can't Go Wrong
Since it's Friday, I thought I'd throw in something literary. The latest issue of the Atlantic Monthly (a very good magazine indeed, these days) has an appreciation by Christopher Hitchens of Lucky Jim.(The article's not online yet.)

That is, of course, Kingsley Amis's first novel, and it deserves the praise that Hitchens ladles out. "Just try to suggest a more hilarious novel from the past half century," he says, and I really can't. If I had to try, I might bring up son Martin's Money,or something by George MacDonald Fraser, but Lucky Jimis really in a class by itself.

What sets it apart is that it's a fiercely moral book at the same time that it's being funny. There are unpleasant people in it, who do things they really shouldn't be forgiven for, and they eventually get the hearty horselaugh handed to them. This isn't the only proper response to such types, but it's an important one, and we shouldn't forget it. Jim Dixon has plenty of faults (as he knows more than anyone,) but he spends the whole book trying terribly hard to live up to what he thinks he should be.

So many comic protagonists are antiheros (G. M. Fraser's Flashman, again.) But Jim's one of the most sympathetic characters I can think of, and anyone who doesn't root for him is someone I don't think I should have lunch with. Run out and buy a copy today!

Thursday, April 04, 2002
If It Weren't So Late, I'd Quote Moliere, Too
"Robert Musil" has a very interesting post on the economic end of the blogdom medical-progress discussion (which I contributed to yesterday, below.)

His point that medicine will likely occupy a greater part of the economy is well taken. This seems like the natural end of the move from manufacturing to a service economy - if anything can be defined as a service, health care is it, and it's often the most valuable one imaginable.

His analogy of medical care to education is also interesting. One outcome is the one he foresees: that medical treatment eventually becomes like schooling is now. A basic level is provided by the state, and money will buy you more and better. (One place the comparison breaks down: there's no direct medical analog for the role of merit scholarships in education, not that I can see.)

Anyway, there's another, worse, outcome: that medical care becomes egalitarian in the wrong direction. Not "everyone should have the best, and hang the expense," but "because it's so expensive, everyone should have the same low standard." It's less likely that we'd go this way, which is arguably what some of the Europeans have ended up with (while trying for the first option, mind you.) We haven't gone that direction in education, either (while again, I think some of the Europeans have - no really lousy universities, but no really good ones, either.) Here's hoping we don't.

. . .But It Pours
A hideous day for stockholders of Bristol-Meyers Squibb. An unnerving profit forecast sent the stock down nearly 15%. Everyone expected the picture to be pretty bleak, but not quite as bleak as it turned out to be.

It's a combination of the Imclone deal (ranted on about here several times), the Vanlev fiasco (ditto), and loss of some key patent terms (such as Glucophage, which folks are now buying as plain old metformin.) Metformin itself must cost about ten bucks a ton. Those profits were propping up a lot of BMS's research, which has (like the rest of us have) been drilling a lot of dry holes lately.

Folks were stopping by my lab today and asking me if I thought now was the time to buy BMS stock (look for it as BMY, although almost no one in the industry knows them by those initials.) I'm not sure. . .they're a real takeover target now, but probably not at any major premium. And I don't see much good news on the horizon.

Wednesday, April 03, 2002
Meanwhile, Back at the Coal Face
Work's pretty busy these days, so I won't have as much time to do mega-posts like yesterday's. Med-chem projects move along to their own rhythm, which features long pauses with the same note struck repeatedly ("Not active...not active...not active.")

Then, with no warning, comes some weird compound that (to everyone's surprise) works better that anything that's been made. That immediately suggests several other ideas to people, and they get cracking. Then everyone wants to combine someone else's new features with the parts of the molecule that they're specializing in, and another wave of new compounds hits.

Everyone runs around doing the new stuff, until the new area has been trampled on thoroughly. Then you get back to the grind, when you've hit the limits of the ideas you have, but you don't know it yet. Not active. . .not active. . .when do you decide you're unproductively banging your head against the wall, and when do you stay put and try to break through? Tough call.

This environment can make it tricky to decide where ideas come from, which is an issue at patent-writing time. Some of the good compounds just seem to have precipitated out of the air like rain - you can't point to any one person and say it was theirs. The patent lawyers don't like hearing that, of course, but they're used to it. Or they say they are, at least. . .

Tuesday, April 02, 2002
Branch Office
The folks over at Tech Central Station kindly asked me to comment on some current medicinal and chemical issues. My first column for them, on the HIV situation, is up. More are in the works!

Nothing Like It in the World
Glenn Reynolds over at Instapundit posted an interesting exchange, which started off as a comment on a post from Kausfiles:

(Mickey) Kaus sees medical advances as inevitably expensive. I think it's more complex
han that. Medical expenses actually follow a bell-like curve, like most technology. When
you can't do anything, ("here, eat this root and hope for the best") it's cheap. Then you
get treatments that are expensive and marginally effective (sanitariums for TB). Then,
back on the downslope of the curve, you get treatments that are cheaper and more
effective (antibiotics for TB). Cancer treatments now are very expensive. It's entirely
possible (I'd say likely) that in 40 years they'll be cheap and much more effective.

UPDATE: Reader Bruce Hay responds: "Yeah, but the cutting-edge treatments will always
be expensive. You're right that what's cutting edge today will be tomorrow's familiar (and
relatively cheap) treatment. But a new cutting edge will take its place, it will be costly, and
every patient will demand it." This is a good point -- though it suggests that the real
problem is the appetite for cutting-edge treatments, rather than the movement of the
cutting edge. And, actually, there is a natural limit to this progression, which occurs when
nearly all physical ills are readily curable. And I think that date may happen within the next
40 years. Or, to be more accurate, people who know a lot more than me, and whose
opinions I respect, think that.

Well, as someone from the drug industry, do I think that too? Sometimes I do, actually. But some days I wonder. Both Glenn and his correspondent are correct in their ways. It's true that the latest treatment generally is expensive (since it's usually more complex, and its inventors are trying to make back their discovery costs.) But it's also true that eventually you reach a point where there is no better treatment possible, and then the cost has nowhere to go but down.

A side issue: in a nasty, authoritarian society, you'd expect the opposite: that the treatment's cost would have nowhere to go but up, as the squeeze was applied tighter and tighter to the helpless customers. I know full well that there are people who believe that we live in that sort of society already, but is it necessary to say that I think they're deluded? I despair of convincing anyone with that worldview, because you can't use reason to argue a person out of a position they didn't get into through reason. It's like trying to remove a screw with a claw hammer; it's the wrong tool for the job. But I just don't know what the right tool is in such cases. . .

OK, back to curing everyone. Time for a brief shower of cold water (stick with me, I get more cheerful.) As it stands now, we don't have such wonderful therapies for much of anything, frankly. We've got some good stuff, it's true, but put it up against the ideals and the limitations are clear. There's nothing that makes headaches disappear in seconds or instantly heals a cut, nothing which can quickly and permanently reduce your blood pressure or clean out your arteries. There's no way to really cure almost anything that can go wrong with your liver, pancreas, or kidneys. Sometimes we can stop things from getting any worse. We can fix some cancers (but not many) and those still require some mighty unpleasant therapy. Arthritis? Osteoporosis? Alzheimer's? Parkinson's? We can only treat symptoms, and those rather poorly.

How about infectious diseases? It's a constant struggle, since even the organisms we can actually beat are always coming up with new resistance strategies. Others we can only fight to a vicious standstill, and plenty more are basically stand-back-and-hope. Most viral diseases fall into that category. The viral disease with the absolute widest number of treatment options today is AIDS (which makes sense, but many people don't realize that it's true.) If you're unfortunate enough to come down with viral encephalitis, you'll have to wait it out. If you come down with something like Marburg, you'll die in short order. (Unless you're very lucky indeed. There's a philosophical problem - if you were that lucky, you probably wouldn't have contracted a hemorrhagic fever!)

Well, after that mighty dose of gloom, why do I still think we're going to get all these things sorted out? Because, even though I've spent two paragraphs running modern medicine into the ground, I'm still mindful of the context. Compared with ideal treatments, our treatments are primitive. But compared with the historical standard, they're like having magic powers. Read the opening chapters of Lewis Thomas's "The Youngest Science" for a good perspective on this. A telling quote is from Oliver Wendall Holmes, who said that if the entire pharmacopeia of his time were dumped into the sea, it "would be all the better for mankind, and all the worse for the fish." We're going to make the best therapies of today look just as feeble.

Medical knowledge has been growing insanely fast. My hopes spring from my belief that we're still just in the early lift-off phase of that exponential growth curve. New tools are coming along every year that add to our knowledge at an even faster pace. In a way, we're suffering a bit because of it. I've said before that the pace of pharmaceutical innovation seems to be slowing, but that's partly because we have more clues than we know what to do with. We don't know yet which ones to pursue (or how best to do it.) We'll figure it out, though, because there are vast rewards waiting for those who do it.

In the long run, I fully expect gene therapy and antisense to fix what can be fixed at the genomic level. Downstream, I think we'll eventually get control of protein expression, which should take care of another huge swath of trouble. Small-molecule folks like me (or the next generation after me) will take care of the rest. And as we go after diseases, we'll also be figuring out how to deal with the normal damage of aging. I don't know how long the human life span can be extended, but I'm certain that we don't have to live it in poor health. We may not know the exact mechanism of Alzheimer's, for example, but we know that it's the result of something going wrong, something that can be fixed. Damn it, show me something that can't be fixed!

How long will all this take? I've no idea. But it's coming. Better stand back - or better still, come on down and help out. There's room for everyone, there really is.

Monday, April 01, 2002
Enzymes, Right and Wrong
A post of mine from February 26 mentioned in passing the side effects of the anti-HIV protease inhibitor drugs. There's nothing inherent in their mechanism that should cause lipid profile changes and insulin resistance, so the hunt has been on for what other target is responsible.

Now a team at Washington University in St. Louis seems to have picked up the scent. They've found that one of the drugs, Crixivan (indinavir) shuts down the action of a protein called Glut4. Metabolism and endocrinology folks will find that connection pretty believable: Glut4 is one of a family of glucose transporter proteins, whose lot in life it is to take glucose out of the blood stream and pump it into cells. They're found everywhere, with different levels of activity, but Glut4 is key one that responds to insulin stimulation - its action is the primary reason why a shot of insulin lowers blood sugar.

Inhibiting it, then, causes some of the most important actions of insulin to be less effective, which is a back-door route into a state much like Type II diabetes. Lipids and glucose are tied together physiologically, since they're the two main circulating fuels available. You can't mess around with one system without the other responding.

I'm not aware of any other molecules that selectively inhibit Glut4 - as you can imagine, doing that hasn't been a priority for anyone. There's not much of a market for a compound that pushes you toward diabetes. Now, if you knew a way to activatethe transporter, or to keep it working longer, then the metabolic-disease researchers would be ringing your phone pretty quickly. No one's been able to do those things, and many of the steps in Glut4 activation aren't well worked out.

And as far as I can tell, the mechanism by which this new inhibition takes place isn't worked out yet, either. The drugs that cause the side effects are structurally rather different, so the best guess is that they're all hitting some other enzyme that's necessary for Glut4 function. It would just be bad luck that this enzyme, whatever it is, looks enough like HIV protease at the molecular level for drugs to shut down both of them.

If we can find the culprit, then we can try to come up with compounds that are more selective, or find some other treatment to compensate. At the same time, figuring out that problem could shed light on some longstanding problems in diabetes research, too. Stay tuned.