Lagniappe (science, business, and culture)

Thursday, February 28, 2002
Who Dares, Wins?
I'd like to take the time to sympathize with Elan Pharmaceuticals over what's happened to their Alzheimer's trial. They had the initiative (and the nerve) to pick up and run with an unusual discovery: that a protein that precipitates in the brains of Alzheimer's patients, beta-amyloid, can be attacked by an immune response.

I'm not going to take sides in the "does amyloid cause Alzheimer's, or does Alzheimer's give you amyloid" controversy. Most money is on the first choice, but there's a vocal minority for the second that makes some good points. At any rate, the idea of going after amyloid deposits by raising antibodies to them was pretty gutsy.

In general, you want to think twice about raising an immune response to one of your own proteins. It's like the old rule of black magic - don't call up anything that you don't know how to send back down. It seems, though, that amyloid, weird and insoluble stuff that it is, looks useless and foreign enough that it can be treated as an invader.

The brain is also considered an immune-privileged organ. You wouldn't have high hopes for a vaccine approach to work there. But they actually cleared amyloid deposits from the brains of rodents (in a special strain bred to have amyloid problems.)

Elan took this into human trials as fast as they could. Unfortunately, they've run into what some feared might be the downfall of the whole approach. Several patients are showing signs of central nervous system inflammation. The immune response appears to have gotten out of hand.

There may be a way to fix this, but it'll be a while before anyone is able to try this approach again. A lot of ground work will have to be done first. It's a pity, because this had the potential to be a home run against a disease that's consumed minds, lives, and a vast amount of research time, money, and talent.

Wednesday, February 27, 2002
More Imclone, More Food for Thought
As you've no doubt heard, Imclone issued a press release this morning about their FDA meeting. It seems that if they can come up with more clinical data from Merck KGaA's European trials, along with clarifying some of their own numbers, then the FDA has agreed to look at a resubmission. Bristol Meyers-Squibb has been notable for their complete silence so far, which doesn't make them look very enthusiastic.

And as you've no doubt calculated, my short sale of Imclone's stock yesterday did not turn out to be very lucrative. Nor will it be, most likely. But I'm keeping the position for now, looking to escape fairly soon without too much financial damage. This FDA news, while not the worst that could have happened for the drug's development, isn't all that good, either.

The European data won't be available until the end of the year, even if all goes well. That trial is still in the enrollment phase, and it looks like Germany's Merck is being very careful about which patients go in (caution made even more important by the FDA's reaction to Imclone's data.)

That brings the drug to market a year late - again, if everything works like it's supposed to. That's bad news for the cancer patient population, because the patients who would benefit most immediately from the drug may not be around in another year to take it. And it's bad news for Imclone and BMS, too, because competing therapies aimed at the same molecular target (the epidermal growth factor receptor) are coming along. Some of these aren't antibodies, like Imclone's candidate - they're small drug molecules. If those work, they'll be easier and cheaper to produce in quantity. If they don't set off too many side effects, they could be real competition.

Who to blame for all this? The Wall St. Journal weighs in with another Imclone editorial (no free link,) as they did back on Feb. 13th. I'd been kicking around the idea of commenting that one out paragraph by paragraph, and now I'm already behind.

They came down hard on the FDA both times, suggesting that the government changed the requirements in mid-stream, and that the efficacy standards are too stringent. As odd as it feels for a pharma researcher, I have to come to the FDA's defense here. It was Imclone's (and, let's not forget, BMS's) responsibility to make sure that the clinical data were ready for approval. Arguing about what the FDA should be is beside the point: every drug company knows what the FDA is.

And every large drug company knows what sorts of submissions have a more solid chance of being approved. Imclone chose to do the shortest, smallest trial they possibly could get away with, and it backfired on them. One reason for that trial design was to be able treat cancer patients more quickly - that's a huge motivating factor for everyone in the field, and I don't want to minimize it. But another reason for Imclone's hurry is the hoofbeats that they can hear coming up behind them. They need this drug to be first to market. Bristol-Meyers Squibb, for their part, is already on the hook for two billion dollars for only 40% of the drug's profits. And every delay decreases their chances of ever earning that money back.

Tuesday, February 26, 2002
New Drugs for HIV
Megan McArdle points out the recent news (which has shown up in Tuesday's NY Times and other outlets as well) about new HIV treatments with possibly fewer side effects. She asks if the same technique can be applied to other diseases, and I thought for the benefit of the non-pharma audience that I'd go into some detail on that.

Actually, there's no particular new technique involved - just good ol' drug development. These compounds work by different mechanism than the stuff we've had so far. Here's a (fairly) quick explanation, centering around one of the therapies highlighted in the press reports, the one from Schering-Plough.

The specific target of that compound is a protein called CCR5, which sits straddling the outer membrane of some types of cells. Part on the outside, part loops to the inside. It's one of a huge class of proteins called receptors, whose lot in life is to latch onto specific other molecules if and when they come by. When they do, that binding event sends a signal into the cell, and these signals can be tied into just about every cell process you can think of. This is one general way that you can enable some molecule floating outside the cells to set off changes inside them.

The subject, like most molecular pharmacology, rapidly reveals its career-worthy godawfulness on closer inspection. All those things in the above paragraph vary hugely and interrelatedly. To give you an idea, various receptors are a key step in the actions of things as important (and as unrelated) as insulin, cocaine, growth hormone, and caffeine. They're still counting up how many different receptors there are from the human gene sequences, but it's probably going to be in the low thousands when the dust settles.

In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.

This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. So far, it seems to work, and congratulations to the Schering-Plough team for it. Although I haven't talked to them about it - not that they'd tell me anything, either - I know several of the chemists who worked on this project. They and their biology colleagues deserve the success.

But will this lead to a marketed HIV drug? Good question. It's obviously made it through the animal toxicity testing I spoke about the other day, because the compound has shown efficacy in humans. Those are both big steps. Now come more studies, with more patients, to make the case to the FDA. It's not an early-stage drug any more, and the odds are fairly good that it'll make it, but there are still several places where it could banana-peel and slip off the tightrope.

If it does, will it have fewer side effects than the protease inhibitor cocktails? Another good question. Right now the only thing you can be sure of is that the side effects will be different. All drugs, every single one of 'em, have side effects. Some are major, some are minor, and some are minor only relative to the disease that's being treated. Since this doesn't work on HIV protease, it presumably will avoid the problems of those drugs, which is good news. But there could always be others out there waiting.

There could mechanism-based tox, for example. We really won't know until larger, longer trials are conducted what might happen when you block CCR5 for an extended period, what happens when you block it while you're taking other drugs at the same time, or if there's some subset of the patient population that will react unusually.

Or there could be non-mechanism-based tox, which is what happened with the protease inhibitors: keep in mind that (when the research began) no one expected the body-fat remodeling and the other side effects of that class. Those seem to have nothing to do with blocking HIV protease, and arguments rage as we speak about what causes them. Is there some other protease that you can't avoid hitting when you go after the one in HIV? Could be. Is there some totally unrelated thing with (by sheer bad luck) a similar-looking binding site, so that most anything that binds HIV protease will hit it, too? Can't rule it out.

None of these arguments are specific to the HIV therapy field, of course. Investigative drugs go down the tubes all the time for just these sorts of reasons. And sometimes even the large trials aren't enough to catch bad side effects that occur at very low frequency, and you get the serious bad news after the stuff has gone to market. That seems to be what happened with the diabetes drug Rezulin (troglitazone,) and it's not the only example. When that happens, so many lawsuits start flying that it looks like it's snowing.

Am I a gloomy researcher or what? Nah, just realistic. I'm actually fairly perky most of the time, so I'll end on an optimistic note:. What we have now are some new ways to treat a terrible disease. The more routes of attack we have, the better. Along the way, we're learning a lot that can help out in other fields as well. The great thing about drug discovery, about science in general, is that nothing's ever really in vain, and no good work is ever really wasted. It all adds up, and keeps adding up. And what we're building, I truly believe, is the greatest work of the human race.

My Money Where My Mouth Is
I don't want this to turn into a stock investment site although that could have been lucrative a couple of years ago. But since I expressed scepticism about Imclone's chances with the FDA today, I thought I might mention that I shorted some of their stock this morning on that same conviction.

The Yahoo! stock message boards typically have a very low signal-to-noise ratio, but Imclone's today set what might be a new record. There was no signal to be had, all day, and as of this writing there still isn't. I have to think that no news might not be good news.

A Certain Tension in the Air
Well, today is Imclone day at the FDA (see Jan 31 and Feb. 6 postings.) All parties will be meeting to decide what the path forward is: reworking the existing data, supplementing it with whatever else the companies can dredge up, or new clinical trials.

Analysts have raised the possibility of using some clinical data from Merck KgaA (German Merck, not the US company.) They're the licensees in Europe. But most of their data is for head and neck cancer, which won't cut it for Imclone's colon cancer application. Merck has apparently done a couple of small trials in colorectal patients, but most of their data for that indication's European filing was supposed to come from Imclone. There might not be enough new data to salvage things, considering how negative the FDA was the first time around.

If Imclone gets to reapply without new data, I'd chalk that up to the work of experienced regulatory-affairs people from BMS. I assume they've brought in everyone they can find. Of course, that brings up the question of where those folks were for the first filing, doesn't it?

I wouldn't be surprised if it turns out to be new trials, which is of course what the companies want to avoid. If that happens, look for more now-we're-really-mad statements from BMS, and another round of nasty press releases.

The pity of all this is that Erbitux very likely works. That puts pressure on for approval. You already see comments about the mean ol' FDA hasseling this small company with their wonder drug, but that's missing the point. If you want to get mad at someone, get mad at Imclone for doing the absolute minimum they thought they could get away with. And get mad at BMS: I still think they should have caught this before it went to the FDA at all.

Monday, February 25, 2002
All the Not-So-Myriad Ways
The mention of schizophrenia last week brought up something I've thought about since I worked in the field: the limited forms of mental illness. When you first read about insanity (or deal with them firsthand,) it's easy to think that everyone who's insane is sui generis.The varieties of symptoms seem limitless.

But the more I've thought about it, the more I think the opposite. There are only a set number of ways in which humans go insane. Think of any given case of dementia, and you can come up with plenty of similar ones: you have paranoids convinced that their thoughts are being read - by their TV, by aliens, by invisible beams - or that the people they see on the street are all agents. There are the people who let piles of paper and garbage crowd them out of their houses. And the obsessives convinced that they are good friends with, are going to marry, are already married to some celebrity. You'll certainly find differences among these and among the many other types. But they're variations on the same master templates, differences of degree rather than kind.

Contrast the familiar dementias with superficially similar ones that don't seem to exist, like an inverse paranoid: someone who's convinced that people are sneaking around behind his back, helping him out and doing him favors.

Now, the nuts-and-bolts biochemistry of the brain is overwhelmingly complex. That's one of the big reasons that drug development in the field is such a slog. But at a systems level, it may be that there are several broad pathological states that the neuronal net can fall into. These could be based on an uncorrectable excess (or deficiency) of signaling in some part of the network, or some defect of timing in the handoff of processing from one region to another.

It might be analogous to similar low-energy states of a chemical or physical system, local minima on a surface. There could be any number of genetic and/or environmental factors that push the brain into one of these conditions, just the same way that you can tumble into a hole by coming from any direction on the surface. But you end up in one of a set number of places, one defined hole or another.

Sunday, February 24, 2002
It Ain't Me, Babe
Credit goes to "Charles Dodgson" at Through the Looking Glass for his recognition that I'm the Red Sox pitcher in blog-disguise.

Well, not quite, although I have had fun with that coincidence up in Massachusetts. Pharmaceutical salaries aren't bad, but you don't find many scientists earning what a good curveball could bring them. By the way, if you Google my name (and manage to filter out all the baseball links, which is no small feat), note that I'm not the guy who's into body piercing, either.

I'll continue to talk now and then about some topics that won't necessarily be news to those inside the pharma industry. I see from my traffic stats that most of the hits are from outside it, although there are increasing numbers from both my own company and the competition.

Thoughts of work prompt me to quiz non-specialists: at what point do you figure most drug projects fail? Ever thought about that one? You can be sure that everyone inside the industry has, oh yeah. There are plenty of data points to study - the sound of failing projects is this constant clanging in the background.

Failure in clinical trials get the most press attention. They're certainly bad enough to deserve it. You lose lots of candidates in Phase I, because they turned out to be toxic in normal volunteers. (Well, at least toxic in the sort of person that signs up for Phase I studies, but that's another story.) Then you lose some of those non-toxic candidates in Phase II, because they didn't work well enough, or at all. Failure at those stages is particularly expensive and frustrating; it's late in the game. And it means that your animal models turned sour on you somehow, by telling you the compound would be safe and that it would be efficacious.

Your disease models are what tell you the latter, and they vary from target to target. As I mentioned the other day, the ones for CNS ailments are particularly hairy; other fields have it easier (but not easy!) The animal toxicity tests for general safety, though, don't vary much between therapeutic areas. They're a notorious hurdle.

Tox is a long and expensive study, by preclinical standards. It usually calls for the largest batch of your drug candidate that you've made until then, and it's the usually the longest animal study you've run, too. And it makes everyone involved hold their breath, because it's a complete black box.

It really is. That's actually where more projects wipe out than any other, in my experience. We really have no idea what's going to happen. Well, you may have some clue about toxicity based on your drug's mechanism, and you're already braced for that (and hoping it cuts in at much higher levels than you need to show the beneficial effects.) But it's that non-mechanistic tox that's out there waiting for all of our projects, and when it hits all you can do is run for cover. Kidney? This protein isn't even expressed in the kidney, what the. . .liver? But the tests on hepatocytes all came back OK. . .spleen? Who ever heard of a drug showing tox in the spleen? Heck, who needs a spleen anyway? And so on.

As I've alluded to in the past, you can sell just about anything to a big drug company if you promise to do something about the failure rate. If anyone has a bright idea for how to predict toxicity before we go into animals (or, God help us, humans,) then here's your chance to cash in. The management would be thrilled at all the time and money that doesn't go down the pipe. The scale-up chemists would be thrilled not to have to make buckets of loser compounds. Even the animal-rights people would be happy.

Note that the obvious ideas have probably already been tried. But don't be afraid to ask.

Friday, February 22, 2002
Cartesian Aging
As I mentioned previously, I've been reading the letters of both Kingsley Amis and Philip Larkin. One thing you notice in any Collected Letters book (try Evelyn Waugh's) is old age creeping up on the writers. It's less noticable in Larkin's case; his personality famously made him sound about 70 years old for decades. But with Amis, it's clear that you're reading the thoughts of a young, a middle-aged, and then an old man. This process is chronicled from just outside in his son Martin's book Experience

Don't get me wrong - Amis's letters are wonderful, even the late ones. But a sort of hardening of the personality takes place, kin to atherosclerosis, and it's a common thing to see. What I wonder is how much is due to just plain experience and weariness with the world (seeing the same mistakes being made the same ways, again and again,) and how much has a neurologic base.

Circulatory problems, Alzheimer's (we won't get into the debate about what causes it,) any number of other biological causes affect the number and activity of the neurons. And that, in turn affects higher functions of thought and personality. But that statement broad-jumps over a huge pit of unknown detail. These questions are going to keep everyone in the biomedical sciences busy for a long time, and won't the world be an odd place when answers start to show up?

More on this later. There are many things coming much sooner from modern neuroscience, and we'll have our hands full with those just the same.

Thursday, February 21, 2002
Bush and Japan
It'd be interesting to know what Bush and his entourage told the Japanese behind the scenes during his visit. Of course, the press conferences and public statements are all about having great confidence in, fully believing, and so on. But the private talks must have been pretty awkward. Koizumi seems to have a choice: he can (try to) do what the country needs (but doesn't want,) or he can stay prime minister. And hand it off to the next guy, the way the problems were handed off to him.

As I mentioned earlier, the end of March is the deadline for something to happen. Look for some big plan to be announced before then. But if it doesn't include some banks going out of business, it's probably just another application of makeup and hair dye.

And That Settles It
Talking with some fellow chemists this evening, I mentioned that one of the things I like about science is that you can eventually answer questions. It can take a while, but you really can prove a point. For example, X-ray crystallography is The Convincer in an argument about chemical structure, if the data are good. You pull out the X-ray and everyone shuts up, because that's what the structure is. The biomedical questions we deal with in the drug industry are trickier, which is why we spend the big bucks trying to answer them, but answer them we do.

This line of thought quickly leads to the whole "science wars" topic that has been raging for some years now, recently more quietly. I'd like the think that that's because the more ridiculous practitioners of the "all truth is socially constructed" school are hiding out. Come on down and socially construct some NMR spectra for me, guys.

Physics was always the science that those idiots liked to borrow from - see Sokal and Bricmont's Fashionable Nonsense for chapter and verse on this. I'm not sure why chemistry escaped. Perhaps we don't seem to delve into the nature of reality as much as quantum physicists do, and we don't generate so many neat-sounding paradoxes.

Chemistry: Ignorance Saves the Day
As one of the few chemist-bloggers out there (here's another!), I should have caught this story about an attempt to poison Rome's water supply with cyanide. Well, not exactly with cyanide - with something (potassium ferrocyanide) that had the word "cyanide" on the label, but isn't poisonous at all.

Stephen den Beste over at USS Clueless does a complete wrap-up on this story, chemistry lesson and all. The only bad part about this is all the wire-service coverage will make it less likely that would-be terrorists will make this mistake again. Fortunately, there are plenty of other stupid mistakes to be made. Collect 'em all, guys.

Wednesday, February 20, 2002
In Memoriam
I missed a chance yesterday to note an anniversary. Giordano Bruno was something of a crank, not normally the sort of person I'd be commemorating. But in his time, it didn't take very much to be considered either of those, or worse, and we have to make allowances.

He was headstrong. We can see now that he was sometimes eerily right, other times totally wrong. Either way, many of these strongly held positions were sure sources of trouble for anyone who advocated them. All living things were made up of matter, and that matter was the same across the universe - that one was not going to go over well in the late 16th century.

There was more. The stars, he said, were nothing more than other suns, and our sun was nothing more than a nearby star. He saw no reason why these other suns should not have planets around them, and no reason why those planets should not have life: "Innumerable suns exist; innumerable earths revolve around these suns in a manner similar to the way the seven planets revolve around our sun. Living beings inhabit these worlds."

He went on at length. And as I said, much of it was, by scientific standards, mystical rot. His personality was no help whatsoever in getting his points across. He appears to have eventually gotten on the nerves of everyone he dealt with. But no one deserves to pay what he did for it all.

Bruno was excommunicated and hauled off in chains. He spent the next several years in prison, and was given chances to recant up until the very end. He refused. On February 19th, 1600, he was led into the Campo dei Fiori plaza in Rome, tied to a post, and burned to death in front of a crowd.

Mystic, fool, pain in the neck. I went out tonight to see Saturn disappear behind the dark edge of the moon, putting the telescope out on the driveway and calling my wife out to see. Then I came inside, sat down at my computer, wrote exactly what I thought, and put it out for anyone who wanted to read it around the world. While I did all that, I remembered that things haven't always been this way, haven't been this way for long at all, actually. And resolved to remember to enjoy it all as much as I can, and to remember those who never got to see it.

Monday, February 18, 2002
A Couple of Days Off
I won't be posting for another day or two; I'm taking tomorrow off from the Wonder Drug Factory and heading out with the family. My chemistry can get along without me just fine, and the people that report to me will most likely be even more productive without me around.

Leaving the lab for a few days was much harder back in graduate school, of course. The main reason was psychological. It took at least six months after I got my PhD for that voice in the back of my head to stop telling me to get back in lab, that I was wasting time. Every hour that I wasn't trying to finish my project was an extra hour that I was going to spend in grad school. This mental nudging didn't just occur when it should have. No, I felt this way when I was doing frivolous stuff like buying food, or putting gas in the car.

The second problem with leaving the lab was that I had a lot of chemistry going on simultaneously. I persisted in thinking that I'd remember every tiny detail when I got back. So I'd return and find a bunch of flasks, helpfully labeled with things like "large batch," "other fraction," or "N." My first day back in the lab always involved a lot of staring up at the ceiling, trying to remember what the heck I was doing.

Of course, many of my days in the lab involved some staring up at the ceiling. The difference was, on those occasions, my lips were moving.

New Books
I'll be working my way through some new books, given to me as presents by my wife. There are two volumes of collected letters, Kingsley Amis's and Philip Larkin's. That'll be an odd experience, since many of their letters were to each other. Neither suffered fools gladly, and in both cases their definition of "fool" was remarkably inclusive.

Another new one is from James Lileks: The Gallery of Regrettable Food. Allow me to plug this book - I'm sure he won't mind a bit. With my site's traffic, I might sell as many as two extra copies for him. This is a collection of absolutely hideous cookbook illustrations from the 1940s to the early 1970s, complete with the original stomach-churning photos. I have a weakness for this kind of thing, myself (the style of the illustrations, not the food), and it's a relief to me to see that I'm not alone. Trust me; nobody has a weakness for this food.

Sunday, February 17, 2002
More Japan Blight - from The Economist
As if to prove that I'm not a ranting paranoid, The Economist leads off this week with a cover story on Japan's economic troubles. Thanks to Justin Slotman at Blogistan for pointing this out even before I got my copy in the mail.

The Economist folks aren't as worried as I am about a complete collapse, although they do say the danger of that is the worst it's been. Rather, they think it's likely that Japan will just stagger through this latest patch, slapping duct tape and super-glue on all the parts of their economy that are falling apart. Which is most of them.

That's been the plan for the last ten years. Why stop now? Well, one good reason is that they're in danger of (if not collapsing,) then slipping genteely into the second, and then the third, rank of nations. Eventually, no one's going to care very much what Japan does or says. For a country that looked like it would be a major power, it's humiliating to be mutating into a sort of Paraguay-with-sushi.

A Drug Drought?
Something that gives us pharma-types the shivers is the way companies like Merck and Glaxo-SmithKline are complaining about their drug pipelines. Or, if not openly admitting that they're a bit sparse, they're quietly going around making large deals with other companies.

And not with Imclone or its clones, either. They're dealing with real companies that have real experience (and real products.) Merck is partnering with Schering-Plough, for example, on a cholesterol-lowering combination, and GSK is going to help market Bayer's new competitior for Pfizer's Viagra. Of course, Pfizer fired all bow tubes a couple of years ago and boarded Warner-Lambert, mostly just to get Lipitor. Rumors keep going around about Merck doing something similar to Schering-Plough if the new drug looks like it's going to work out.

The reason I bring up these specific big companies is that they're thought to have some of the broadest and deepest research efforts in the industry. And they're all complaining about not having enough good drugs in development. . .that's what makes the rest of us uneasy. What exactly does it take, then, if not what these people have been doing?

For whatever reason, there seem to be far more big drugs going off-patent these days than big hits being launched. Is this really the case, and if so, why's it happening? Has the whole business just gotten harder over the years as we've picked more and more of the low-lying fruit? Have we taken a wrong turn in the way research is usually done? Or are expectations just set too high?

Friday, February 15, 2002
By the way, there's at least one rational reason for the popularity of gold sales in Japan: fear of a forced devaluation of the yen. A sudden inflation by fiat would get pretty ugly, given the sudden price ripples it would send into other countries, but it can't be ruled out.

But I'd be willing to bet that many of the gold customers are just buying because they think things are in bad shape, and never mind what variety of bad shape it is. They just know that gold is supposed to be safe when your economy is tanking.

Thursday, February 14, 2002
That neuroscience business came up, I guess, because I have a minor background in it. I broke into the drug business doing work on schizophrenia, and followed that with several years on Alzheimer's.

If some of the people in the field read this - well, don't take it the wrong way - but I'd almost as soon have a job breaking concrete with my nose. The central nervous system is a very, very hard area to work in. That's partly because brain function is hideously complex: it's an interesting question whether a human brain even has enough ability to comprehend its own workings. But it's partly because a key part of the drug-testing cascade is often missing.

That's animal testing. (And it really is a key part - eventually I'll get into it with the anti-in vivopeople, and I'll argue that position as long as it takes.) The problem with many central nervous system targets is that the animal models either don't exist, or (even worse) exist but are untrustworthy. That last situation is a killer: the models persist because there is a constituency that believe in their relevance. You'll be running into those folks over and over if you try to do without, and they're going to refuse to believe in your drug candidate unless it's been through the wildebeest swim maze, the platypus tail flick assay, whatever.

The models are so hard because you're often trying to affect behavior that is unique to humans - like remembering phone numbers. Whether a rat can remember not to run into the electrified part of the cage is of doubtful relevance. I think that there are many kinds of memory storage, and I don't believe that rats partake of the kinds that we're most worried about. It's true that there must be common molecular mechanisms for all types of memory (at some level) but messing with those processes indiscriminately (the only way we know how, in many cases) is a recipe for trouble. Let's not even get started on the topic of animal models for schizophrenia.

There's been a lot of progress in Alzheimer's the last two or three years. I enjoy reading about it, and I wish everyone working there all the luck in the world. I may need your compounds some day, guys, so keep banging away. But I'm glad that I'm not having to bang away with you.

Wednesday, February 13, 2002
A general lesson from the Japanese situation (and from most economic problems) is that we don't do very well with gradually developing problems. The time scale is wrong for our perceptions; we can't see what's going on.

Judging from neuroscience, consciousness seems to tick along in bursts of small fractions of second (that's about the right range, anyway.) Fire a bunch of sensory impressions (frames) at us at about that rhythm or a bit faster, and we merge them together without even noticing the gaps.

We still do OK in the first slower orders of magnitude, the time scale of motions that are of direct interest (or are possibly a direct threat.) But our brains seem (evolutionarily?) wired not to pay nearly as much attention to things that don't look like they've moved or changed in a while. It would probably be too much of a strain to constantly check and refresh all that detail - we take the same shortcuts that animators do in creating frames of film.

I believe that it was in Swift's Laputia that Gulliver met the king who could observe the movement of the minute hand on a clock. Anyone who could really do that would have to have that ability turned off most of the time, to avoid ending up like Ireno in Borges's "Funes the Memorious," nearly incapacitated by his perceptions.

All that just gets at the same point that half the business consultants in the world make, when they tell stories about heating up a frog's water very slowly. (For once, I'd like to see a consulting firm quote Borges!) It's hard to get worked up about long, slow, changes and far-off threats.

Tuesday, February 12, 2002
While I was writing that, I came across the latest issue of Forbes, which has a similarly gloomy article (link requires registration) making many similar points. This sort of coverage, along with articles in the business sections of the major papers, is where this story has been living. It has, unfortunately, a likely future on the front page.

Argentina's collapse, unfortunately still in progress, is getting the headlines. That's because it came up suddenly for most people, and because the visuals are dramatic. Most everyone can understand hyperinflation and runs on the banks, and pictures of street riots need no explanations at all. But there's another country in big trouble, whose collapse means even more. It hasn't been getting much play outside the business pages, but Japan is currently sliding off the table and shattering on the floor.

Ten years ago, that would have been pretty hard to imagine. All through the 1980s and early 90s, the Japanese economy was this mighty force that was going to overwhelm the world. How many trophy buildings and famous artworks were the Japanese going to buy? How many business books were written to teach us their mysterious ways? I recall a NY-area car dealer in 1990 urging customers to Buy American. Soon, they said, you'd be driving that imported car of yours into Manhattan, to see the Christmas tree at "Hirohito Center."

Does anyone remember the talk about the 100-year (200! 500-year!) business plans the Japanese companies supposedly had? While we were grasshoppering away over here, went the story, the Japanese were carefully saving their money and planning, planning things out. They had the next generation of computers down cold - heck, they were going to skip that one and leapfrog to the generation after that. Plenty of people made a good living retailing the wonderous threat that was Japan (Lester Thurow comes to mind.)

All that slowly evaporated in the 1990s as the real estate bubble burst, followed by a long slide in the Tokyo stock market (down about 70% now from its highs.) For a while, it just looked like a business-cycle problem, an inevitable breather. But as time has stretched on, it's become clear that things are severely out of whack. Try to imagine the Dow spending the next ten years slowly sinking under 3000, and you can see what a relentless grind it's been. Over here, we have manic bargain-hunters who seem conditioned to jump in and buy if stocks have gone down for a whole week at a time. Anyone who's tried that in Tokyo has had their head taken off.

Japan's problems are different from Argentina's, but one difference is that they're worse. For example: the Japanese are still saving their money like they used to. In fact, they're saving (not spending) so much of it that their economy is actually deflating, starving for demand. The resulting gloom further convinces consumers that times are bad. Then they pull back on spending even more to batten down the hatches, and so it goes. NPR reported recently that Japanese gold bullion dealers are doing a brisk business, which is flat-out perverse when you consider that gold is supposed to be a hedge against inflation.But that's the gloom for you.

And where else can all the money go? A lot goes into bank instruments that pay the closest to zero percent ever seen in an industrialized country. For businesses, overnight rates are so low that transaction costs actually make deposits money-losing propositions. You'd be better off putting your yen in a hollow tree. The Japanese central bank has lowered interest rates until they've run out of room; they have no leverage left.

All those piles of deposits (coupled with essentially free credit) should be setting off huge capital spending by businesses. But companies are pulling back, reeling up the slack, because no one seems to want to buy any products. And the banks themselves? Here we get to the real rot. The money is pouring in, true, but you don't make a profit by paying interest to people, even miniscule interest. You make money when you lend it out, of course, but no one's borrowing. The only place Japanese banks can lend money is overseas, where there are at least real rates of return.

Meanwhile, the same banks are carrying older loans on their books that no mustard is ever going to cut, to steal a phrase from James Blish. Businesses and banks used their inflated stock portfolios and real-estate holdings as collateral; now that those have wilted, there's nowhere to turn. Huge sums were loaned out domestically during the boom, and even in the first years of the decline (when no one thought it could last for long.) Those massive hoards of cash, impressive though they are, still can't measure up to the even more massive piles of outstanding debts.

The banks have refused to face reality and take the write-offs. The Japanese government has refused to face reality and let some banks go out of business. Instead, in a team effort, the banks went to the government for aid, and they got it. And a few years later, they came back for some more, and they got that. The same (remarkably roomy) hat will be passed again very soon.

So, adding things up, you have a country that internally is a swamp of debt and externally is a massive creditor. It's an odd situation to be in. If there's ever a real run on the Japanese banks (and all that gold-buying makes you wonder,) they might have to ditch some of those foreign loans. It would hurt the banks to bring their money back to the land of zero-percent interest rates, but it would hurt them even more to go bankrupt. But if they start asking for their money back, a massive worldwide economic crisis would be hard to avoid.

Actually, people have been scaring themselves for years with this yen-repatriation idea. Michael Lewis, in The Money Culture,)pictured it happening in 1989 as a result of a Tokyo earthquake. But at the rate they're going, the Japanese government and its business sector (which are nearly the same thing, unfortunately) might end up engineering their own earthquake substitute.

March is going to be a critical month. The banks have finagled for years to avoid booking their losses in the stock market, but as it stands now, they're finally going to have to do it when the fiscal year ends on March 31. Prime Minister Koizumi rode in on a promise to reform things and get the economy moving, but if he lets the banks slide again on this, then the only new thing about him is his hairdo.

The New York Times reported last Thursday that the Japanese banks are selling vast heaps of long-term bonds to raise cash, preparing for the day of accounting reckoning. Unfortunately, nobody really wants Japanese bonds at the moment, especially not long ones, so their yields are rising. They're still not high enough to make them really attractive to anyone, though, and the government is coming in as the buyer of last resort. That amounts to a direct bailout of the banks already, and a sign that real change isn't on the way. Private investors are buying only the short-term bonds, the ones with the lowest risk and the near-zero rates.

It's hard to imagine a stronger vote of "no confidence" than lining up for zero-percent yields just because you feel that you'll escape with your money that way. Keep an eye on all this stuff as we get closer to the end of March. It's been long, and it's been slow; it's been bad news pretty much all the way, and it could already be getting worse.

OK, next up is the blast of economics that I spoke about. I've become more and more interested in this sort of thing over the years, but I recognize that this isn't necessarily shared by the rest of humanity. Feel free to skip it, of course, but it does tie in with the financial interests of this site so far. I'll have some more directly pharma-relevant comments about Japan at a later date.

Well, Imclone's board has more or less told Bristol-Meyers Squibb to take a hike. I still see this as the first act of a drama which is intended to make shareholders of both companies feel like they're getting their money's worth. I'm certainly getting mine watching the show. . .more on this as it develops.

Monday, February 11, 2002
I should warn everyone: sometime in the next couple of days I'm going to put on my World Pundit outfit and get all macroeconomic on y'all. Perhaps people should listen to my economic advice about as much as I'd listen to an economist's chemical plans, but I won't let little things like that slow me down.

There were press reports today that Pharmacia gave up on the lead kinase inhibitor they got when they bought out Sugen. It's easy for me to say now, but I never cared for the structure of that one much. Nor did most medicinal chemists who saw it, if my sampling is valid.

There are some structures that just look a lot more like drugs than others. In fact, there's been quite a bit of effort the last few years to quantify that look in automated scoring systems, with mixed success. By most standards, the Sugen compound was pretty ugly. (To be fair, it was an antitumor agent, a field where such standards are deservedly looser.)

I should talk. I'm fond of telling people that the best compound I've made in my career (so far) was one step away from being a practical joke. The structure had a group in it that's not usually associated with successful drugs - one that's probably more associated with successful poisons, to be truthful about it. I had a note directly from one of the higher-ups about that one, and it got right to the point: "I don't want to see anything else that looks like this." Fortunately, we tested it anyway, and it worked better than anything else we'd yet made on the project.

As usual, the lesson to draw from this isn't to send in only practical-joke compounds. Not quite. But med-chemists have to learn not to automatically fear them, either. It's true that there are some structures that are so obviously insane that they're not going to be drugs under any circumstances. But there are plenty of structures in a grey area: not appealing, but not quite bad enough to write off. And sometimes that's what you've got to work on, because all the more pleasant compounds have wiped out along the way.

I probably would have written off the Sugen structure. But here it went to late in the clinic, which is a lot further than anything I've worked on has ever gone. So, who's the fool here? The line between "inspired" and "nuts" is pretty hard to trace.

Sunday, February 10, 2002
An odd side effect of Enronitis has been the sudden rehabilitation of short selling - or, more to the point, of short sellers. In down markets, shorts have traditionally been about as popular as head colds. When stocks go down, many small investors are convinced that the evil short-sellers are out their vulturing away their investments.

Take a look at the Yahoo message boards, or listen in to a financial call-in show. You'd get the idea that there's a huge Manichean struggle going on between the forces of Light (who want stocks to go up) and the forces of Darkness, who for some reason perversely want them to go down. It's a small leap to the conviction that the short-sellers are all that's causing the stocks fall. Of course, given the typical short volume in a stock, that's like being convinced that your alarm clock is making the sun rise. But we're not dealing with logic here - we're dealing with personal investments, which tow a huge wagon of emotional baggage.

The reputation of short-sellers would be just as poor in up markets, but no one's paying attention then. As Fred Schwed put it in the classic Where Are the Customer's Yachts?: "Before October, 1929, no one objected to the short sellers except their own families. The families objected to going bankrupt."

Jim Chanos (the pro I mentioned earlier) has been interviewed all over the place. No doubt his fund is taking in plenty of new customers. It wouldn't surprise me if more people decide to try to go short themselves, which may not be such a good thing. Most will probably bail, at a loss, on their first positions pretty quickly - it takes a peculiar psychology to hold on to short positions if they take even a small move against you.

I'll confess to that psychology myself. I've been taking short positions on and off for over ten years. I've made some pretty good money, but I've also been peeled like a carrot out there, too. Whenever I get cocky, I try to remember my early 90s experience shorting Herbalife stock. What a disaster that was! Or to translate it to Herba-Speak: "Lose Money Now! Ask Me How!"

Friday, February 08, 2002
A quick quote from G. K. Chesterton for the weekend, from the first chapter of his odd 1904 novel, The Napoleon of Notting Hill:

The human race, to which so many of my readers belong, has been playing at children's games from the beginning. . .and one of the games to which it is most attached is called "Keep Tomorrow Dark," which is also named "Cheat The Prophet." The players listen very carefully and respectfully to all that the clever men have to say about what is to happen in the next generation. The players then wait until all the clever men are dead, and bury them nicely. Then they go and do something else. That is all. For a race of simple tastes, however, it is great fun.

This is the game we all play in scientific research, only we don't have to wait so long for the results. Actually, it's the game that science plays with all of us.

Nothing I've seen since my earlier posting has changed my mind about Imclone. (To be fair, there are people who would say that nothing I see ever changes my mind about anything, but it's too late to fix that!)

The board of directors get to feel the pressure. The phrase "fiduciary obligation" is probably getting a workout, and theirs is, of course, to the shareholders. Not to the Waksal brothers, founders and chief executives though they are. I still think that Imclone's best chance to get their drug to market lies with BMS. If the board thinks otherwise, everyone will be under huge pressure to get a deal done with someone else. It's hard to see how that could turn out better than what they have now.

Thursday, February 07, 2002
The pharmaceutical industry is overdue for another crazy idea. Go back to the mid/late 1980s, for example, and you hit the first swell of computer-aided "rational" drug design. It's hard to remember, but the hype was that random screening and old-fashioned analog synthesis were both dead. Shooting arrows blindly, hoping to hit your target? Stale! Armed with the structures of the enzymes and receptors, the computationally literate would zzzziiip-thunk! right into the bulls-eye with just a few - heck, maybe even one - compound.

That description may sound exaggerated, but it's not far from how Vertex and others were selling themselves at the time. Lilly used to have their supercomputer facility as part of the visiting-bigwigs tour, to give you the idea that this mighty machine was cranking out wonder drugs even as you watched. Agouron used to take folks into their wide-screen 3-D room to watch molecules docking with receptors in sort of a med-chem IMAX experience. All this really put the fear into people, and I don't think a single company didn't feel the cold wind blowing on them.

The way you dealt with that was to go out and buy some hardware, and hire some people who seemed to know how to use it. Pretty soon, you could see beautiful electron-density-map renditions of your very own molecules, docking into your very own drug targets. Was that really the structure of your compound as it met the protein? Heck, was that really the structure of the protein as it met your compound? Well. . .

Did any of this get anywhere? Not the first wave, that's for sure. The technology was relentlessly oversold. Looking back on it, the idea of doing computational drug design with, say, 1987 technology is good for a sardonic chuckle. We have enough trouble doing it with 2002 technology, thank you very much.

Mickey Kaus's fine site just put me on to another, The Man Without Qualities. It's a site from someone who obviously knows his finance and banking, and he has some interesting, detailed thoughts on the companies I've been talking about. If you like that sort of thing, as Abraham Lincoln is supposed to have said, then this is the sort of thing you'd like.

Who the site's author really is, I don't know ("Robert Musil," indeed - if he's really read Musil's forever-incomplete novel, I'll be even more impressed with him.) I sometimes wonder if I should have stayed anonymous when I started this one up. Not that it crossed my mind at the time.

Wednesday, February 06, 2002
The Bristol-Meyers Squibb / Imclone story has taken a real bad-movie turn. (See my postings on this last week if you're not up on this one so far.) BMS has served up an ultimatum that I don't recall every seeing before: Ditch your CEO, or we walk.

Actually, it's even livlier than that: Ditch the CEO, ditch his brother (the chief operating officer,) give us control of your dealings with the FDA. . .oh yeah, and give us a bigger share of the profits from the drug. Or we walk.

It's an interesting threat, and I can't wait to see Imclone's response. Who will back down? You can argue that Imclone has to, since BMS is their best hope to get the drug to market - and at this point, the deal is still better than anything they're likely to get from anyone else. Their stock will sink even lower if BMS actually does walk, putting them in a weak negotiating position.

But you can argue that BMS has to back down, too. They've already sunk 1.2 billion into this, and to walk away after that (with no drug and some rather depreciated stock) would make the shareholders furious. (It's not like they're in a good mood already, although the tough talk must have cheered everone up.) And if they leave, their cancer pipeline is status quo ante- that is, still in the shape that made them think they needed to spend billions to improve it fast.

Much as I think that Imclone deserves what's happening to them, it doesn't take away from the fact that BMS didn't investigate this the way someone spending a billion dollars should have. There must be some pretty embarrassing PowerPoint presentations left on people's hard drives, talking about what a great job everyone's doing on the clinical and regulatory end. Eventually, BMS is going to have to figure out how this mess could have happened. It won't be easy, since everyone who even got close to the deal is probably hiding behind their nearest tree.

My prediction is that Imclone, with great protesting, will end up agreeing to almost all the terms. They might salvage some of the milestone payments that BMS wants to get rid of, or be able to talk them down a bit on their profit-percentage demands. But getting Erbitux through is probably their only hope for survival, and BMS is probably their only hope for getting it through.

Tuesday, February 05, 2002
So why do huge natural product molecules still get made, if the thrill is gone?

Well, for one, not everyone agrees about the thrill. Total synthesis is one of the areas with real summits to plant flags on, and you really can be the first to climb them. And (unlike mountaineering!) you don't run out of mountains. They keep on coming, higher and trickier, year after year. Of course, as I went on about on Sunday, the technology keeps on improving, too. I'd argue that we're getting close to an expertise that allows us to hack our way up most any molecular mountain, one way or another.

Another reason the work goes on is that it used to be a great way to find totally new chemistry. Back in the day, you often had to invent new reactions just to have a chance of making these molecules, and that was one of the main justifications for the whole effort. Unfortunately, now that we don't necessarily have to invent the new reactions, many total-synthesis types don't.

I don't want to exaggerate, because it's still no cookbook. Many steps in a big total synthesis require lots of tricky modifications from the normal way you'd run a reaction. And there are lots of reactions that should work and don't; the first thing out of the book usually doesn't do the trick. But, still, very seldom now is new chemistry invented during a major synthesis. People will discover a new reaction, and think of a natural product to demonstrate it with, but they won't discover the new reaction in media res.

That's because it takes too long to do it. The advances in the science are making it gradually trickier to find totally new reactions, or new applications of old ones. If you're in a race to be the first to synthesize Megatoxin, you're not going to spend a few months (or a few years) to see if you can come up with a new reaction that'll save you six steps. You'll just hack out the six steps and get on with it - even if no one else is racing you, which is almost always the case these days.

There's one reason, though, that I can't argue with. Total synthesis is a great way to train chemists. You have non-stop problem-solving under very trying conditions, you experience all sorts of chemistry, and you end up with the hands to do just about any reaction there is. The drug companies love to hire total synthesis people. They figure (correctly) that dealing with the adversity of that work is good training for drug discovery, where most things don't work, either.

Monday, February 04, 2002
The Wall Street Journal (no free link) has an interesting story on Tyco, a conglomerate that makes more things than you can shake the sticks they make at. Their accounting is of Enronian - or should that be Amazonian - complexity, and at the moment they're getting hammered for it. The Journal reports that over the last few years, Tyco has made what seems to be several hundredacquisitions, without ever really reporting them.

It won't be easy unraveling all that, since merger and acquisition accounting is pretty hairy under normal conditions. Tyco says that none of the transactions was truly material, and since you're only supposed to report material transactions. . .you know. . .

The market didn't take that explanation very well. I wish I could believe that this is a permanent outbreak of good sense, but I'm afraid the fit will eventually pass.

For Tyco's sake, and for their shareholders, this had better not turn out to be too similar to Enron's off-the-books practices. But both are examples of the "Oh, you wouldn't be interested in that"school of disclosure. Wouldn't you rather see our great pro forma earnings - excluding certain items, but you wouldn't find those very interesting, so let's move on to our forecast for next quarter!

ImClone (see earlier posts) probably tried something similar, either on Bristol-Meyers Squibb or (to judge from the way their filing was received) even on the FDA. Well, mundus vult decipi,as James Branch Cabell used to say. "The world wishes to be deceived," and so it does, most of the time. Just look out for the times when the world's not in the mood.

I've had some interesting mail about the Jan. 28th posting on circular mistakes. One from John Costello (who has a background in archaeology and anthropology) pointed out that the Maya were a catastrophic example of doing the same bad idea until you collapse.

Their slash-and-burn agriculture was the only way they knew to work their (rather poor) soil. Besides, crops came from the power of the local ruler and (through him) from the Gods, anyway. As their society got more and more complex, they chewed up more of what decent land there was by building bigger temples, and had to recycle worn-out farmland more and more often.

Does anyone know of an example where a non-falsifiability mistake of this magnitude has ever been fixed in time?

Sunday, February 03, 2002
Any particle physics people who read that last post will probably send me nasty mail. Their problems make a chemist's time-and-money complaints look pretty minor: they'd be absolutely thrilled to be able to accomplish something with just a million-dollar grant (as opposed to special appropriations bills spread across twenty congressional districts, and so on.)

But time and money, which like energy and mass are the same thing in the end, are twin gods of the pharmaceutical industry. If we can't make something easily enough to make a slew of analogs for testing, we're in trouble. And if we can't make it cheaply enough on a thousand-kilo scale, we're sunk. The only way we'll do a monster natural product molecule is if we can literally farm it (or a close intermediate) from plants or cultured organisms.

I mentioned the team-of-Sherpas approach to making molecules, but that's something that (fortunately) I haven't had to do much in recent years. In drug discovery, we try to avoid anything involving that kind of chemical labor - the rest of the drug development stuff is enough to keep everyone busy, thanks. Contrast that to some academic organic chemistry, where molecules that need pyramid-construction-size teams are sometimes the whole point.

I did big-molecule natural product synthesis for my PhD, and I don't miss it for a minute. (I don't miss a lot of things about my PhD for a minute, for that matter, but that's another story.) It's a specialized world inside organic chemistry, which during its glory days was for many the only world that mattered. It's hard to put exact dates on that, but you could start in the 1950s, end sometime in the late 70s or early 80s, and not set off too many arguments.

It's not that huge and difficult molecules aren't made any more. They are, and some of them are weird enough to have made the old titans like R. B. Woodward choke on their Scotch. But it's different somehow; I think it's because we've gotten a little too good. There are a lot of reactions we can pull out now that Woodward's generation never lived long enough to see, reactions that do things they never knew could be done. So now, when some massive team of postdocs makes Voodoomycin, Whateverol, or some other molecule that looks like your structure-drawing program malfunctioned all over the page, it doesn't set off the awe that the older syntheses did. It can't. There are dozens, hundreds, thousands of people who look at the resulting paper and say "Hey, give me a team of fifty smart, highly trained workaholics and a million dollars from NIH, and I'll make Whateverol, too."

We can make almost anything (given enough sweat, time, and money,) but most complex molecules still use up far too much of all three. It's not the boundries of the science that hold us back any more, just the boundries of the real world. Those who aren't well acquainted with the field figure it can do most anything, but those inside it know, for practical reasons, that we often can't.

Friday, February 01, 2002
I can't talk about rain forest drug discovery without mentioning the (pretty bad) 1992 Sean Connery movie Medicine Man. He plays an alleged biochemist who comes up with a Miracle Drug, more or less by finding it under a leaf.

Plenty of large and small stuff is misportrayed, but I did say it was a movie. (One of these days someone will have to make a list of jobs that movies actually get right.) The part of this one that drug discovery people particularly enjoyed, though, was when some crude extract is fed into an impressive device that immediately displays the structure of the active compound. "I want one of those!" was the universal reaction.

I believe that this was supposed to be the one active component of a complex mixture, the plot hinging on being able to find it and isolate it. Of course, Shaman's business model (see previous post) depended on being able to do this sort of thing, and you see where it got them.

I only wish we could find things out as suddenly and dramatically as they do in films like these. As is true in most areas of research, medicinal chemists spend a fair amount of time looking at printouts (or up at the ceiling tiles,) wondering just what the heck happened in the last experiment. Determining chemical structures is easier than it's ever been (read: in most cases, it's possible to do it), but for natural products it still isn't trivial. My Connery-ometer remains on back-order.