Lagniappe (science, business, and culture)

Thursday, January 31, 2002
Over on Charles Murtaugh's site, he mentions in passing that:

It used to be voguish in Green circles to promote saving the rain forest because of its untapped medicinal riches. Hand-in-hand with this argument was an appeal to the wisdom of traditional peoples. Scientists would drop in on some isolated, very hirsute tribe, find out that they rub some unappreciated jungle weed on their scalps, and this would clue them in on a new, scientific cure for baldness. For all I know, this approach may have actually worked.

Well, it's worked a little bit over the years, but not as much as everyone once hoped. It's true that there are zillions of odd natural products out there, and the rain forest is a good place to find things. (All the competition means that organisms develop whatever advantageous chemicals they can.) And there's no lack of local cures and potions, if the tribes involved will talk to you.

A few years ago, a company called Shaman Pharmaceuticals had a whole business plan developing these. As fate would have it, though, their success rate wasn't high enough to keep things going. The actual percentage depends on who you talk to, and how you define success, but it's not in dispute that their success rate at getting FDA-approved drugs was zero.

Some ugly problems intervened. The first was that while there are many jungle remedies out there, only a smaller subset of these are for anything that corresponds to a recognized disease, or produce any useful medical effect. There are, though, any number of things that will make you throw up, for example. That may be a useful adjunct therapy, but it's not exactly a billion-dollar market.

The second problem was actually finding what the active principals might be. Many of these concoctions are eye-of-newt brews that have had all sorts of bells and whistles stuck to their formulation. Narrowing down to what particular root or plant might be the business end of the mixture isn't easy. Many times, the mixture couldn't be broken down into an active principal at all. There was some polypharmacological thing going on, where a dozen different active compounds were combining to give some weird effect. That's intellectually quite interesting, but a nightmare to understand and develop - plus, you're guaranteed to have huge patient-to-patient variability even if you tried.

Shaman threw in the towel about three years ago. The large pharmaceutical companies continue to isolate and screen natural products, though (thus the bioprospecting agreements in many tropical countries.) But no one's trying to make a whole company work this way.

Speaking as a medicinal chemist, the prospect of working on a natural-product based lead fills me with dread. Those compounds can be very weird, very complex, and very hard to make if you don't have a team of dedicated lab-fanatics cranking away all day and all night (and a team of lab-Sherpas busy making intermediates for them!)

Wednesday, January 30, 2002
While we're on the subject of messing things up (and a roomy subject it is,) I wanted to pass on an item from Greg Aharonian's PatNews mailing list. Although I doubt if I see eye-to-eye with him on all the intellectual property issues he covers, he's a valuable source of information about the inescapable craziness of the field.

This one isn't from the pharmaceutical industry (sigh of relief.) US patent 6,107,147 (to Texas Instruments, issued August 2000) is for an amorphous silicon gate used in circuit fabrication. Everything seems fine with it until you get to the Detailed Description section, which rattles along in the usual brain-locking patent lingo - until these phrases in ALL CAPS start to intrude. Like voices from an oracle, like schizophrenic breaks with reality, they say I NEED A BETTER DESCRIPTION. They ask, DECREASED HOW?, or (is there) SOMETHING THAT WOULD MAKE THE INVENTION DETECTABLE?

Yes, they're the draft comments of TI's legal counsel, fossilized like dinosaur footprints, right there in the issued patent. This is the legal equivalent of spray-painting the double yellow line right over the road kill, and both Texas Instruments and the Patent and Trademark Office should be embarrassed.

Am I being too hard on BMS and ImClone in that last post?

Well, it's not unusual for a big pharmaceutical company to do a deal with a small outfit just to get one advanced drug candidate. And it's certainly true that new drugs have a significant failure rate at the FDA, and it seems particularly rough over the last year or two.

But it isunusual for the big company to pay the smaller one 10 to 20 timesthe going rate for their drug candidate. And then to have the FDA reject the thing out of hand a mere five months later, after such an enormous vote of confidence, begins to stretch "unusual" past its usual range of meaning.

I glancingly referred to ImClone a few days back, and the story has grown horns and fangs in the interim. (At least, that's how it must seem to Bristol-Meyers Squibb.) To recap, they're a small biotech that signed a large deal with Bristol-Meyers Squibb last September.

BMS paid about one billion dollars for 20% of Imclone and for 40% of the profits from their EGFR-targeted monoclonal antibody IMC-C225, known as Erbitux. (Although you can bet that only the folks in Marketing called it that.) Another billion was possible if all the milestones were met. This made a lot of noise, because that's an awful lot of money for one compound. In an unrelated deal, BMS had earlier paid an awful lot of money to buy out DuPont's pharma business, so maybe that's just their style.

If you rewind to November, you see press releases such as: "We believe in the potential for ERBITUX, an exciting new possibility in the treatment of cancer which represents the finest tradition of Bristol-Myers Squibb Oncology." Even up to December 13, BMS was using the words "blockbuster potential."

Then the steering wheel came off in their hands. On December 28th, in a traditional Friday-afternoon bad news release, ImClone announced that the FDA wasn't going to review their application. Actually, what they said was that the agency was not "accepting the filing in its current form." Their CEO, Sam Waksal, said in the ensuing conference call that he didn't think the FDA wanted a new study, and that they rejected the drug over "documentation" issues.

Not strictly accurate, it seems. A trade newsletter, The Cancer Letter, got a copy of the actual communication, and it turns out that the FDA's concerns were not just those of librarians. In recent days, both the SEC (bad news) and the Department of Justice (hideous news) have opened investigations into whether investors were misled about C225's progress, both before and after the FDA letter.

I haven't spoken to anyone I know at BMS about this, and I don't know anyone at ImClone. So from here, this is just my own speculation. But, based on watching the behavior of small biotechs and the big companies that sign deals with them, I would guess things went like this:

1. Imclone stuck smiley-face stickers all over everything.
And they may have fooled themselves as much as they fooled BMS. Their data, and their FDA application may have even looked fine to them by the time they'd been living with all of it for so long.

2. BMS missed the problems.
This is the due diligence part, and this is where the finger-pointing is probably most intense. It's expected that a small company is going to put the best possible face on the numbers, but it's also expected that someone is going to look things over with a critical eye. The FDA's refusal to even consider the application means either they've blown a fuse, or (more likely) that there are serious problems with the clinical data. If that's the case, someone should at least have noticed stuff that the FDA might question, even if everyone else thought it looked fine. Applications are about what the FDA thinks, not what you think.

3. BMS missed the problems again.
I'm not trying to be especially hard on them, but someone higher-up probably blew this, too. There should have been more than one level of review - not up to BMS's CEO, whose background is in Marketing, anyway, but at a scientific level. I think someone took someone else's word for it, more than once, when they should have checked things out independently.

Well, it'll all come out eventually, especially with the SEC and DoJ in there. And someone, externally or internally, will get blamed for it. But it looks like a team effort to me.

Monday, January 28, 2002
I came across a quote from V. S. Naipul (in an article in the February Atlantic) which set me to thinking. It's from Among the Believers,his famous (among some, infamous) book on the Islamic world. About the slow post-independence rot of Pakistan, he wrote:

The state withered. But faith didn't. Failure only led back to the faith. . .If the state failed, it wasn't because the dream was flawed, or the faith flawed; it could only be because men had failed the faith. A purer and purer faith began to be called for.

This seems to me to not only be true, but to be true about many more things than Islamic politics. What it reminded me of was from a David Foster Wallace essay inA Supposedly Fun Thing I'll Never Do Again,where he defines a harmful addiction as something that presents itself as the cure for the very problems it causes.This applies immediately to physical dependencies like alcoholism ("If you had my problems, you'd drink too",) but Wallace goes on to show how it fits the habit of, say, watching five hours of TV a night.

I'm not making Islam = addiction connections here (or TV watching = religion ones, either!) What occurred to me is the general problem of systems whose only remedy for failure is to cycle back around again. And if that doesn't work, the only remedy is to do it again, preferably longer, louder, and harder this time.

A blind spot is built into these systems; you need it for them to get to the harmful stage. No failure can be the fault of using the system itself - if that were possible, then other courses of action would be possible, too. But without that chance, it's a circular highway without any exit ramps.

Look around, and you'll see plenty of these. At your workplace, is there some policy that does nothing but worsen the problem it addresses? And is there any mechanism at all for the policy itself to ever be at fault? Everyone's encountered folks who are so convinced of their own correctness that they just get crazier and crazier. Lots of terrible managers work the same way.

One of the things that has made science, as a system, work so well for so long is that it doesn't rule explanations out very readily. The possibility that a whole system might be at fault is always there; what's more, there are usually some eager researchers ready to try to tear it down. Individuals will make the circular-problem mistake, holding on to untenable theories by making them more and more complicated rather than abandoning them. But for a whole field, it's harder to get bogged down. And we're the better for it.

Saturday, January 26, 2002
A question that last posting begs is: if Enron's SEC filings made no sense, how did someone get enough information to decide to go short? Well, post hoc ergo propter hoc,in this case: because this supposedly cutting-edge company with huge earnings growth didn't (or couldn't) reallly explain where the money was coming from, Chanos decided to bet against them. It's not a bad rule, in my experience. When money is involved, people who act like they have something to hide usually have something to hide.

It applies a bit differently in research, though. I have a list of "Lowe's Laws of the Lab" that I'll post eventually, a set of rules that I wrote down in grad school while in a bad mood. That last part is redundant, now that I think about it. Anyway, one of the rules is that "No one leaves details out of a paper without a reason."

Of course, the scientific literature is just sedimented with papers that don't give full details, to no one's concern. Look at the growth of the "Letters" or "Communications" sections of journals, where the first thing to go are the experimental sections. When things are omitted in this context, it doesn't suggest misconduct, as it would in the securities world. In the sciences, the reason referred to can be lack of desire/time to write a full paper, excess of desire (to publish the same results as a communication in one place and a full paper in another,) or haste to get credit in a competitive field. As the Jan. 24th posting shows, there can be dicey papers in chemistry that go on to give piles of detail.

Friday, January 25, 2002
NPR interviewed two of my financial heros tonight, Jim Chanos of Kynikos (mentioned a few days ago while I was going on about Enron) and James Grant of Grant's Interest Rate Observer. Chanos is a professional short-seller, and Grant is a professional wet blanket. He certainly seemed that way for several years, anyway, patiently shaking his head at the valuations of stocks and predicting reckoning.

Maybe I'm a wet blanket, too. I sell stocks short; I roll my eyes at valuations. I didn't short Enron, worse luck, and if I'd listened to Wall St. I certainly never would have. Dozens of analysts recommended that we all buy Enron, some of them even after it started to crater. None of them could have known how bad it was, true, which is where the shady (and criminal) behavior comes in. But none of them understood Enron's financial statements even before the roof caved in. Enron's financial statements were not comprehensible.Not that that stopped anyone.

The analogy with the punditocracy's early take on Afghanistan seems exact to me. Everyone Knew that Enron was a hot growth company. Fortune magazine said so, all the brokerages said so, people who earn major money to do the numbers said so. And back in October, here were rank upon rank of seasoned, veteran commentators, old hands wise in the ways of the world, going on about quagmires, bogging down in the quagmires, yes. . .

Back in grad school, I had a sign on my lab wall that said "Everything You Know is Wrong." What I was getting at was more precisely put by Kin Hubbard back in the 1800s: "It's not the things you don't know that get you; it's the things you know that just aren't so." It's worth thinking about just how many things there have been recently that just weren't so, and wondering how many more are still out there.

The topic of fakery usually makes me think of this passage from Martin Amis's novel London Fields:

Unquestionably you could still earn a decent living at it, at chearing. Yet no one seemed to have thought through the implications of a world in which everyone cheated. The other morning Keith had bought five hundred vanity sachets of Outrage, his staple perfume. At lunchtime he discovered that they all contained water, a substance not much less expensive than Outrage, but harder to sell. Keith was relieved that he had already unloaded half the consignment on Damian Nobel in the Portobello Road. Then he held Damian's tenners up to the light: they were crude forgeries. He passed on the notes without much trouble, in return for twenty-four bottles of vodka which, it turned out, contained a misty, faintly scented liquid. Outrage! The incident struck Keith as a sign of the times. . .

The novel is full of good stuff like that, but its its predecessor, Money,his high point, actually makes it look pretty bad. Unfortunately, London Fieldsitself makes the Amis novels that come after it look pretty bad. He's had a lot of room to descend, but if he doesn't watch out, he's going be writing a plain old bad novel (opinions vary, but he may have done that already.) With any luck, though, his recent memoir Experience(which is pretty good) repacked his bearings and balanced his tires.

Thursday, January 24, 2002
The recent plagiarism accusations against Stephen Ambrose, Doris Kearns Goodwin, Michael Bellesiles, and other unlucky historians (to be named later?) came to my mind yesterday.

I was reading the organic chemistry literature, which generally doesn't have too big a problem with plagiarism. Of course, a few weeks ago, no one thought that best-selling historians had much of a plagiarism problem either, so I guess you never know. There have been cases in chemistry, true, notably filching unpublished things like grant proposals., but there seem to be more instances where things were just made up out of thin air. (See Slate for an interesting discussion of the personality differences that make over-creative minds go down one of the paths over the other.)

There's a paper out now (which for those of you in the field is Synthesis, 29 (2002)), that belongs to the select group of articles whose sole purpose is to demolish another one. The now-discredited article was in the same journal over a year ago, presenting an interesting reaction that I thought we could make use of in my lab. (Keep in mind that the classic definition of "interesting" in the scientific literature is "interesting to me!") We actually tried the chemistry out. It flopped cleanly and completely, giving exactly the wrong product. I chalked it up to the weirdness of our current compounds, which is not to be underestimated. Some things work on them; some don't. We poured the reaction into the red waste can and did something else, which is one of the perogatives I like most about medicinal chemistry.

The author of the latest article, though, had the same thing happen to him, and he didn't take it as quietly. Going back over the original examples, he shows that the published work won't, didn't, and can't go the way it was reported to. Some of this can be put in the "honest mistake" category, subheading "really sloppy honest mistakes," but I'm afraid, in the end, that some of it can't.

On the Recently Exposed Historian scale, we're moving away from the Ambrose zone and heading more towards Joseph ("In Vietnam? Sure I was!") Ellis. You wonder what day-to-day life is like for people who just make the stuff up as they go along, but it's probably not as stressful as it seems. Waking up in a fix this: "Here's a paper you've fabulated that'll go down in flames as soon as anyone takes a close look at it. It's a reaction that people are going to want to try, and it's in a journal that some people actually read," well, that would have me banging my head on the floor within minutes. But the sort of person who actually does these things didn't just wake up to it, of course. They long since moved in with that kind of thinking, took up housekeeping with it.

Wednesday, January 23, 2002
There's a front-page story in today's Wall St. Journal (no free link, though) about some U.S. physical science professors who contributed a few years back to an "Islamic science" teaching project. Unbeknownst to most of them, the whole thrust of it was to pile up evidence that major scientific advances had been foretold in the Koran, and could only have been there by divine revelation. This is a widespread belief in the Moslem world (I've heard it myself from people raised there.) The backers of the project (including, inconveniently, Osama bin Laden) felt that this would be a valuable tool for converting backsliders and unbelievers.

Well, as you can imagine, I certainly don't buy into any of the alleged evidence. But what's interesting is imagining what Moslems of an earlier century (or Christians with their church, too) would have made of the whole idea. It's easy to picture one of the Caliphs (or a 16th-century Pope) having an absolute rug-biting fit at the idea that the spread of the faith would be helped if only you could show close it was to the scientific evidence.

As a footnote to the 1/22 post below, medicinal chemists are used to being able to tease their colleagues at the end of their projects, once a clinical candidate is chosen. Most of the time, it seems like you can look at the structure of what they started with, hold it up next to what they finished with, and say "It took you (six months, three years, whatever) to do that?"

Tuesday, January 22, 2002
There's a good article in the Jan. 21 issue of The New Republic: "Fighting Chance - The Case for Funding Curiosity." Siddhartha Mukherjee at Mass General/Harvard uses some recent discoveries about anthrax to make a case against highly targeted "programmatic research" (the apex of which is usually considered the Manhattan Project,) and for more flexible, open-ended approaches which can yield unexpected connections.

I agree with this (and it seems redundant to add "of course.") I think that most scientists instinctively would agree, since we've all (no matter what our field) been raised on stories of serendipity. Most of us have seen it in person, for that matter, when some odd bit of knowledge suddenly takes on importance you never thought it would have.

But I have to say that I hadn't really paid attention to the article's list of the "numerous exhortations to the nation's scientists" to start in on large anti-terrorism projects. It seems to me that every national-scale problem even remotely subject to a technical solution gets a few "new Manhattan Project" banners draped over it. The calls for massive-effort-this and war-on-that just become part of the background after a while, the grinding noise produced when science and politics rub against each other. I'm sure that Mukherjee is seriously concerned, but I hope for all our sakes that this turns out to be more of the same.

That said, as someone who works in the pharmaceutical industry I have to put in a word for what I'd call "modestly targeted" research. There's an intermediate path to discovery between let-a-thousand-flowers-bloom and 1944 Los Alamos, and most drug-company work follows it. A key feature is working on something more immediate: the more focused the goal, the better the fit with a focused approach. Rather than a goal of, say, "cure cancer," you set your sights on "inhibit this enzyme and see if it'll work on cancer." That problem breaks down into hosts of smaller ones (How do you get the enzyme so you can test it? How do you know it's the right one working the right way? What chemical compounds inhibit it? How good are they, and how can they be modified to work better? How do you know when it's working well enough - that is, what system of cells and animal models will you test it in?) If you start with "cure cancer," breaking the problem down into components like this becomes a mighty project (and a mighty problem) all its own.

Everyone in such an environment has a pretty defined role. These folks produce and purify the enzyme, these use it to screen all the chemical compounds in the files, these follow up on the best leads with tougher assays, these others start making compounds like the structures that survive, and so on. I'm one of that last group. This is how pharmaceutical research is done, with minor variations, all around the world. Moving between companies, which is something that medicinal chemists do reasonably often, doesn't require a huge mental adjustment. It's mostly learning who the new people are doing those same jobs, and learning any particular different styles the company might have in doing them.

Once inside that role, though, there's not much regimentation (at least, not at any company that you'll ever get me through the front door of.) My job is to make a better molecule than the one I started with, any way I possibly can, using whatever ridiculous chemistry will get it done the fastest. If I try nothing but wild, bug-eyed, death-or-glory ideas, it's true that management will start tapping their feet. But if I try nothing but working-at-the-sawmill chemistry, management should (and generally does!) expect more, particularly from someone with twelve years experience. You need a mix.

Of course, this research setup can't exist by itself. Notice that I assumed that there was some enzyme that looked like it was worth working on. Those targets can come from a company's own research, but more often they come from academia, from just the curiosity-driven researchers that Mukherjee praises. Many drug companies (too many for my ideal liking) have felt pressured to cut back on the more blue-sky basic research (if they did much in the first place,) focusing more on getting clinical candidates out the door. Given the increasing amounts of time and money it takes to do that, I can see their point, and squeezing things from the other direction is what seems to be a slow contraction of the number of good drug targets in general. I'll get around to that topic some other time; it could be an illusion, or it could be a very large and important bell beginning to sound out over the horizon.

Anyway, I really hate to use a business buzzword, but this research is synergy in whatever sense the word has meaning. People who like particular aspects of cell signaling, say, just for the thrill of unraveling them, provide the fuel for people like me and my colleagues, trying to find small molecules that make things run faster, or in reverse, or sideways. Maybe we can turn them into drugs, but even if we don't, it provides new tools for the first group to go back in and tweak the system in ways they couldn't before. Eventually, in maddening, lurching fits and starts (see the earlier post below!) we get somewhere.

This all works pretty well; actually, I could actually ask for even more money to be specifically set aside for low-probability high-payoff ideas, or things that don't seem to fit in anywhere (there's another topic for another day.) I'm with Mukherjee in opposing truly regimented science, largely because I think it ends up being driven by political ends. The central control that's either needed or felt to be needed, the sums of money involved - there's no way that it couldn't end up that way. But if there really is the clamor for big projects that he's noticed, we'll have to deal with those folks carefully. Specifically, we shouldn't do such a good job convincing them to let inquiry take its natural course that they end up thinking that approach will get there in just the way the lean, efficient research machine of their dreams does. Convincing them that it'll do an even better job, although it might be the truth, might backfire even more unfortunately. The basic research behind the Manhattan Project had already been done by the curiosity-seekers, but someone who doesn't appreciate that will always be measuring any other approach against an unrealistic mental model.

It could be important not to shock people who don't realize how odd the work really is. I can't help thinking that your average appropriations committee would be horrified by seeing how much time even wildly successful research efforts spend falling into mudholes and caroming off trees.

Monday, January 21, 2002
Another book recently finished is Martin Amis's "The War Against Cliche," his collection of literary criticism. (As an aside, I'm not sorry to see Talk magazine go under. I never picked up, was never even close to picking up a copy, and it seems I had plenty of company. But Amis's book comes under the Talk Miramax imprint, and it's printed so cheaply that its thin $35 hardback covers are already curling like potato chips. But I digress.)

Two of Amis's literary heros are Saul Bellow and Vladimir Nabokov, but those two are what the chemical safety literature would list as an incompatible mixture, since Nabokov had nothing good to say about Bellow's fiction. That made me think of what some of my own favorites made of each other. I've long enjoyed Martin's father's work, and I'll sign up gladly for Nabokov, too. But Kingsley Amis was famous for an essay on "Lolita," wherein he pickaxed his way through the book so fast that by the end he'd started in on Nabokov himself as an author, as a human being, and as a life-form fit to consume oxygen.

Meanwhile, Nabokov disliked T. S. Eliot, one of my favorite poets, so thoroughly that he took time out in (again) "Lolita" to have his deranged narrator deliver vicious parodies of both "The Waste Land" and "Ash Wednesday." What Eliot thought of that (and of Nabokov) I don't know, nor do I know if he had any time for Kingsley Amis. Knowing Amis's taste in poetry, I seriously doubt if he had any for Eliot, so at least he and Nabokov could have agreed, in a pinch, to hate Eliot together.

A fine free-for-all would have ensued had the three of them been stuck in an elevator together, which in the early 1960s would have been theoretically possible. Given the weapons of choice, (Nabokov's butterfly net, a rolled-up umbrella for Eliot, and in Amis's case probably an empty bottle of green Chartreuse) who knows if anyone would have made it out?

In case anyone's wondering, I wasn't trying to be ironic in the last line of the 1/18 post. One of the things I really enjoy about research is not knowing what's going to happen. Of course, that's a useful definition of research, but after you've done it for a while it really hits home: compared to most jobs, this is a weird one. People tend to love the uncertainly or hate it.

At my previous company, there was a (quickly abandoned) plan to get serious about the "goals statements" that so many corporatations make their people fill out every year. Serious, in this case, meant that people would take an immediate pay cut, and could earn their way back to what they used to make by meeting the goals they'd set out (or, in theory, earn even more by exceeding them.) This wasn't a lone inspiration; a variation of this scheme had already been floated in an industry trade publication.

What a fun time the HR department had with the research staff! The two groups tend to regard each other anyway as bizarre life-forms, presumably hostile, and this really didn't bridge the gap. We kept hearing "But we just want you to really think about it, and put down what you're going to be working on this year. Even just what you're planning to get done in the next six months!" And we kept saying "We don't know. We can't know. If we knew, it wouldn't be research. We might still be trying to get this one compound made. We might all be chasing another one. Maybe we'll all be on a different project because this one kills rats. No telling."

Communication was never established.

Sunday, January 20, 2002
I caught part of yet another NPR Daniel Schorr commentary on Enron this morning, before my wife switched it off, saying "You know, that Weekly Standard parody page wasn't too far off. . ." That's the one that has Tom Daschle saying to reporters: "We're not going off on a witch hunt here. We're having a super-de-dooper mega-mondo witch roast extraordinaire!"

The last time I heard Schorr dilating on this subject, he was shaking his head about how the White House had been "penetrated" by Enron. Today, what I caught was a long roundup of shredded-document scandals, lovingly recounted. No doubt there was a disclaimer, of sorts, at the end, but I never made it that far.

Of course, I recall clearly hearing lots of Vietnam-quagmire talk from him back around October. What a useful thing it's been for so many people to have been so mistaken, so publicly. It gives you perspective - of course, you might think that it would give the speakers some, too, and in a better world than this, perhaps it would.

Friday, January 18, 2002
Meanwhile, back at the drug industry, it seems that Bristol-Meyers Squibb had a rough day at the FDA, losing out on some approvals and labeling changes. All that and the failure of a drug from their partner Imclone, too. Some of the folks there must be wondering why exactly they're in the business, rather than something more stable, like spreading asphalt or selling vinyl siding.

I can sympathize, having gone through some periods like that at the companies I've worked for. All the drug companies have this feast-or-famine problem that drives the upper management crazy. CEOs (and Wall St.) would be a lot happier with a more predictable business model - even if you had to give up the industry-wide quest for blockbusters. Just a steady, even stream of modest money-making drug launchs would do fine.

Of course, no one has the faintest idea of how to do that. Evidence suggests that such a way doesn't exist, because by now most variations of how to get there have been tried. To wit: putting all your heavy, powerful resources on just a few targeted projects, the ones you think have the best chances. . .or spreading things out to as many projects as you can possibly run, realizing that there's a high failure rate to overcome. . .then there's the technique of beating as much uncertainty out of a clinical candidate as you can before you take it into trials - after all, most of the money gets spent at that stage, and you'd better be sure. . .or, conversely, running things up to clinical trials as fast as you possibly can, because if you're going to fail (which you are, most of the time), you might as well do it fast before you blow more money and time. . .how about co-promoting drugs with the other big companies, spread the development and marketing costs around? Or rather than spread the profits around, too, which that strategy surely does, how about not relying on your in-house research so much - licence in as many leads as you can from small companies who need the cash.

All these have been run in all their variations, as far as I can tell, and still every company holds their breath when a drug candidate goes into testing, and holds their breath again when it goes to the FDA, and turns royal blue holding their breath when and if the stuff ever makes it to the market. No one escapes.

Naturally, this level of stress has bred a cloud of consultants who swarm about offering relief. They get a receptive ear, too often, from the management side of the industry (as opposed to the researching "bench" side.) In business school they teach you to manage risk, to amortize it, to outsource and quantify and hedge it. The idea that a major industry might be based on bug-eyed leap-off-the-cliff-backwards risk taking just doesn't seem right to many of these folks so trained. "If you people would just bring in some modern management techniques," goes the refrain, "you wouldn't have to do it this way. How about Six Sigma? How about Continuous Improvement? How about Total Quality? Matrix Management? Core Competencies? I bet those would fix things up if you'd really give 'em a try!"

As far as I can tell (and I've lived through several of these,) they don't. Research is just as crazy and random as it always was, and the accountants and managers just as rattled and frayed as they always were. It cheers me up just thinking about it.

Wednesday, January 16, 2002
You can't pretend to talk about current events and not talk about Enron - at least for the next couple of weeks. I don't think this is going to be much of a political scandal, since, after all, the company went spectacularly bankrupt with great losses all around. It's hard to see how a good scandal can end up with everyone losing money. I even count the corporate officers as among the losers. Not that I have any sympathy for them (since I think they're culpable) but they'd still probably prefer to have their jobs back and the stock at $70 a share, too.

The financial end of things interests me more, and is probably of more consequence (funny how those two criteria line up so well.) This was, of course, the original angle on the story. It started on the front pages and slowly decamped to the business sections of the papers, where it would certainly have stayed if it weren't for the (seemingly specious) whiff of politics.

Enron used all the influence it could to trade in as unregulated a manner as it could, doubtless with the expectation of riches. Coining money during the California power crunch probably made them more certain that they were the fastest, most profitable beast going. But the opaque and misleading financial statements the company kept issuing makes many wonder if they really were as good as they looked - if you really are raking the profits in, why all the fancy footwork?

Two deadly sins are probably enough to explain that one, and a lot of what goes on in the financial markets besides: greed and pride. The off-the-books partnerships seem to have been a way to take on massive debt without setting off alarm bells among analysts and shareholders. You don't go into hock on that scale without a really good use for the money, or at least what seems like one. They must have felt their energy trading was going to really start gushing profit, and they didn't feel like explaining the details to anyone else. As I said, greed and pride.

As a publicly traded company, hiding your financial status like that is (of course) illegal, although you can certainly pay a large accounting firm to tell you otherwise and validate what you were going to do anyway. You can also decide that you're too smart and fast to even let them in on all your great ideas = after all, once the money's been made, you can pay them even more to fix things up.

Enron's downfall seems to have been their large bias for rising oil prices in all these schemes, which was a reasonable idea at the time. (Betting everything you've got and plenty that you don't on it, though, is probably an unreasonable idea.) As the world knows, energy prices have just kept on falling these last few months, which sent Enron's operations (both on and off the books) irretrievably into the red. And since this was done with borrowed money, the red came on even faster and thicker.

The official line during all this was the Enron made its money by running an energy exchange, which was supposed to turn a profit no matter which way prices went (as long as the trading volume held up.) Had the financial statements been upfront, investors could have made their decisions on the stock based on whether they agreed that energy prices were going up. As it was, they were sold a completely different story - not that many people needed much persuading, and not that anyone could really make sense of the statements as they were written.

This leads into a discussion of short selling, which I'll put off for later. No, I didn't sell Enron short, dang it all, although one of the best in the business (Jim Chanos and his firm Kynikos) certainly did, and on a large scale.

Tuesday, January 15, 2002
I've been reading "No Other Book", a collection of the poet Randall Jarrell's essays that my wife gave me for Christmas. You can only be impressed by how good a critic he was, how strong his opinions were, and how well he put them across. All those, and by how few today can play in his league. This isn't a "they don't make 'em any more" complaint, in one way, because they didn't make too many of 'em, then, either. Jarrell was off in his own division the whole time.

But something has happened, all the same. One of his essays ("The Age of Criticism") makes you glad he didn't live to see what time has made of English departments. Jarrell fearlessly threw around terms like "good" and "bad," and judged everything strictly on the merits as he saw them. That won't get you anywhere, hasn't gotten you anywhere for some time. He seemed incapable of realizing that everything (every single thing there is and ever was) is about race, class, and gender. It's all Oppressors and the people they Oppress: that's the message that's been coming from most of academia for so many dry, pointless years now.

What a strange tunnel that is through which to view the world! And what a waste of intellect and human potential it is to live that way.

Sunday, January 13, 2002
It's tough to pick on Ted Rall and not feel like you're piling on. Look at all the grief that the likes of Ken Layne, Glenn Reynolds, Matt Welch and others have given him (every particle of it deserved.) Likewise, it's hard to stand out from the crowd by picking on the New York Times, considering that hands it to them day after day.

But I still have to ask: why does the Times feel like it has to give us a Ted Rall cartoon damn near every Sunday in the "Week in Review" section? Is he just too witty, too on-target to skip? Combing through all the editorial cartoons of the week, is it really Ted Rall that seems to hit the spot time after time? The thought of someone at the Times grinning and chuckling at this stuff while they shake their head and admit that once again we just can't leave out ol' Ted, that rascal, . . .it makes me shiver. But, then, many things about the Times make me shiver.

Friday, January 11, 2002
Welcome! This will be a spot to go on about topics I find interesting or important (not that those two categories always overlap very well.) Among these will be current events and politics (that staple of self-publishers everywhere,) as well as literature and other arts, and science (with an emphasis on medicinal and pharmaceutical topics.)

That last category is how I make a living. I'm a medicinal chemistry researcher, employed for a dozen years now by a couple of large drug companies. Particularly interesting news in the field will get a mention here, and particularly stupid ideas about it will, time permitting, get a beating.

I'm just another guy who went to college interested in everything, but realized that something would become the day job (and everything else would happen outside that.) I finally decided that it was going to be easier to have a library in my basement than to have a lab. . .