Lagniappe (science, business, and culture)

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

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

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

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

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

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

Sunday, March 31, 2002
Real Life, Part Two
Back on February 1, I took a pot-shot at the movie Medicine Manfor its less-than-realistic chemistry. There's another scene common to movies but rare in real life: the whooping, high-fiving scientific breakthrough moment.

One quick reason for that is that we have fewer scientific breakthroughs. Screenplays zip along at a pace that real life can't match, and that goes for any human activity. But deeper reasons are that experienced scientists know that things that look like great moments often aren't, and that the really big ones are usually only seen in retrospect.

I'm pretty far upstream in the drug discovery process, and there are major, mighty things that can and do go wrong after a compound leaves my lab. Companies only start really breathing easy after a drug has been approved and on the market for a year or so, and that could easily be ten years after someone like me first made the thing. So although we certainly appreciate good results (since our normal diet is the other variety!), we also know that what happens to us isn't the end of the story.

As for the second reason, really big discoveries usually start out as an odd or irritating thing you can't explain. Many people ignore these, and that's usually the thing to do if you're trying to get something else done. But it's also the thing to do if you never want to win a Nobel. Hitting the right anomalous result, realizing it for what it is, and having the nerve and tenacity to follow up on it are the things the really great scientists do. It's what Pasteur meant by fortune favoring the prepared mind.

The big moment for things like those usually comes when some key confirming experiment comes back positive. The usual example is the test of Einstein's General Relativity in the solar eclipse of 1919. Would the observed positions of stars near the blacked-out solar disk be changed by the sun's gravity, as predicted? It worked out perfectly, but Einstein didn't high-five anyone. Years later, he said that Max Planck, for example, never really understood physics. Planck stayed up all night waiting for the eclipse results, but Einstein said that "if he'd really understood the theory he would have gone to bed like I did."

Friday, March 29, 2002
Mix and Match
With the usual rounds of merger speculation in the industry intensified by the problems over at Bristol-Meyers Squibb, there are plenty of combinations being kicked around. Perennial names mentioned are the middle-to-large US companies: Schering-Plough, Lilly. . .you used to always have Warner-Lambert in this list, but you see how things go. Merck might rethink their long-standing independence; Novartis and Roche might turn into SwitzerPharma, Inc. Another possibility is that one of the larger biotechs - Amgen? - will decide to swing over into the chemistry side of the business and do a deal. Disney might buy - whoops, maybe not, although I can think of a couple of companies that would be improved by that one.

One variation that people used to bring up, but you never hear a word about any more, is a deal with one of the Japanese companies. Of course, there's the Takeda-Abbott collaboration, and some other deals here and there. But the Japanese companies, who looked in the 1980s and into the 1990s like they would move into the big leagues, are off everyone's screen.

There - I finally connected my occasional rants about Japanese economics with the rest of my usual subject matter! Now I can take the weekend off in good conscience.

Thursday, March 28, 2002
Cruel to Be Kind
There's an interesting post over at A Dog's Life about the comments that the reviewers of scientific papers make. These comments are (ahem) supposed to be confidential, but good ones do get around.

I don't have enough of those to contribute much to Gregory Hlatky's list, but I do have one that shouldn't be left out (although it's one of those jokes that's largely only funny to chemists.) A famous prize-winning chemist, unnamed by me, was being visited by the second-hand-source of my story. Although getting old, the famous one was still publishing plenty of papers - perhaps more papers than some people wanted to read.

In fact, he'd just had a paper rejected by the Journal of the American Chemical Society, where he was accustomed to publish. "Look at these referee comments!" he said, showing the reviewer's report to my source. "Can you believe they can write things like this?" This fellow's biggest problem wasn't believing it; it was keeping a straight face as he read: "This paper should be substantially reduced. Either that, or it should be completely oxidized."

Not Like Law School
After swapping stories, which some of did again at work recently, you wonder how anyone physically survives their academic chemistry training. Chemists usually come out of their degree programs with a stockpile of good yarns, filed under headings like "Idiotic Lab Explosions" and "Maniacs I Have Worked Next To, And Their Life-Threatening Ideas." Your own explosion stories usually start "One time when I was up in the lab at three AM. . ."

I'll pass some of these along every so often, to give folks outside the field an idea. Before doing that, though, I should mention that the litany of explosions drops off dramatically when you get into industry - and no, I don't miss them. The responsible factors are experience, better facilities, not working all hours of the night, and a certain weeding-out of the real hard-core crazies.

I recall one party I went to back in grad school. Several of us from Chemistry were standing around telling ball-of-flame stories, to the great interest of some law students. One of the guys down the hall from me, though, piped up and said "I don't know what y'all are going on about - I've never had an explosion in my life."

Well, the Chemistry Gods listen to you when you say things like that, and they reach for their bottles of laxative. The next morning, my friend was cleaning out a solvent distillation pot. . .and here's where my organic chemistry readership all start to grin. Cleaning out solvent stills is the all-time leading method of starting lab fires in synthetic chemistry, because you tend to distill many solvents from mixtures involving metals like sodium or (God help you) potassium. Bits and chunks of these lively substances tend to hide under layers of sludge as you try to inactivate them, only to jump out and do their thing long after you're sure everything's been quenched.

Which is just what happened that morning. My friend was sure everything was fine, and rinsed the (theoretically) tamed mixture down the sink (which they won't let you do any more, for the most part, but this was back in the mid-80s.) A couple of seconds went by quietly, then there was a muffled "thoongh!" from deep in the pipes - followed at speed by a three-foot geyser of flaming gunk straight up from the sink drain. I heard the shouting, and came down to find him standing wide-eyed in a thin haze of smoke, still holding the flask. "I never should've said that, should I?" were his words. . .

Wednesday, March 27, 2002
Easier to Start Than to Finish
A side effect of working in the drug industry is that I can't talk much about what I'm working on. That's a disadvantage for day-in-the-life career=blogging. A diary entry like "I made a bunch of compounds today for some disease that I can't mention, and I can't tell you if they work or not" isn't going to bring the site visits pouring in.

What I can tell you is that we're running into a typical situation in my lab these days. For some years now, the trend has been for medicinal chemists to make as many simultaneous compounds as possible. That's not really combinatorial chemistry - we don't vary enough groups at the same time to really qualify. It goes under various names, like high-throughput synthesis, parallel synthesis, and so on.

We've always tried to make plenty of variations - you never know what's going to do the trick, so you want to place as many bets as possible. But an industry has now grown up, making all sorts of hardware to help you with multiple reaction setups. That's fine, but the trouble comes after you've run all this chemistry, when you have to purify the things you've made.

It's a branching-tree problem. Physically, you can set up almost all your chemistry in the same sort of apparatus. It's just solvent, things being added in some order or another, then heating or cooling with stirring. But the methods of working up the reaction and purifying products vary a lot more. Even with a given method (column chromatography) you'll have varying conditions for each compound. Each reaction needs its own column, each one needs a different solvent (which you have to figure out empirically), and each one will have its product emerge at a different time.

The same companies that make the other equipment have taken some good cracks at this problem, but it's a long way from being solved. Come up with an automatic reaction-cleaner-upper, and we'll all buy it.

Tuesday, March 26, 2002
If They Can Put A Man on the Moon. . .
That's usually how the complaint starts, and it ends ". . .why can't they find a cure for the common cold?" Viropharma's recent failure (see the March 20th post below) gives a clue about what the answer might be. It comes down to how bad the disease is, versus how bad the cure might be. Keep in mind the immutable law of pharmaceuticals: all drugs have side effects.

The key question to ask before you start developing a therapy are: What's the unmet clinical need? That's a multilayered one, which includes how widespread the disease is, how severe it is, and how much doctors and patients would want (and pay for) a therapy. Then you balance that against what you're likely to be able to come up with.

For incurable killers, it's an easy calculation, as in the example I used earlier: People would tolerate all kinds of side effects from your drug if it got rid of pancreatic cancer. And, although it sounds crass to put it like this, people would pay a lot for that, too - but what that really means is that you can develop very complex, hard-to-manufacture drugs for such diseases and not go bankrupt in the process.

The next step down are diseases that are terrible and incurable, but don't quite actually kill you (like Alzheimer's, or schizophrenia.) Following are the ones that are marginally less awful chronic ones like osteoporosis or arthritis, and so on down the line.

For each of these, you run the numbers on the competition. There are diseases for which there's nothing at all, the ones for which there's nothing that's any good, and the ones where you're going to have to show a real advantage over what's already there. (That last category is where BMS found themselves with Vanlev, see the March 21 post.)

But what about something that's not deadly, and goes away by itself - that is, a cold? Even if there's nothing to cure it, there are plenty of symptomatic remedies. What this means is that your drug is going to have to be very effective, and pristinely non-toxic. The same considerations would apply to several other conditions that people wonder why there aren't cures for.

We could go after some of these in the industry - if we felt like losing our shirts in the process. Someone would have a bad reaction, worse than the disease, and sue us for all we had. It's not worth it, in the end.

Monday, March 25, 2002
Slight Irregularities
I'll be adding another post on Tuesday morning EST, for those of you who check this site in the EST overnight hours. (The European, Australian and South African hits I can understand during that period - it's the US hits at 3:30 AM that are another matter. Maybe these are people with small kids who've been going through what my wife and I have for the last year or so. . .)

Over the next couple of weeks, things will be a bit irregular around here. I have several non-blog non-work time sinks to take care of, one of which is a monstrously long Schedule D to fill out. It's been fun reliving some of those trades, but pretty soon I'm going to get to a few that weren't quite as enjoyable!)

Sunday, March 24, 2002
What's A Project Manager to Do?
One of the things that strikes experienced drug-company people is the cyclic nature of the industry. There's the boom-and-bust productivity cycle that's long characterized it, which I've had several chances to remark on. (Doubtless I'll have plenty more.)

But there are others. For example, how long should a drug discovery project take until it recommends something to the clinical development folks? A couple of years? Five years? As long as it darn well takes? Or if you think that's headed in the wrong direction, how about eighteen months? A year? Anyone for nine months? You can find companies that are trying all of these.

What happens, I think, is that a crop of managers get their experience under a given system, and while doing so they note the grievous failures all around them. Of course, there are some occasional winners, but there are always plenty more that never make it: fine projects, worthy ideas that never worked out because they just didn't have enough time (or just dragged on too long and got sidetracked, on the other hand.)

So, when they get the chance to run things, they resolve that they won't make the same mistakes. Nope, we're not having things drag on forever around here any more: you folks have a year to put it in the net, or you do something else. Or, conversely, we're not going to kill off perfectly good projects when they don't hit some arbitrary deadline: you folks keep at it until you get it right this time, OK?

This illustrates a general principle: just because you can screw things up in one direction doesn't mean you can't screw them up in another. It's a Manichean with-us-or-against-us fallacy that trips people up all the time. There's a case to be made both ways, of course, which is why this mistake has been around so long.

You really can run projects too quickly, sending half-baked slapped-together clinical candidates on to Development. And you really can let things drag on too long, pouring money and effort into a sinkhole because, hey, you've come this far already, and if you quit now you're just admitting failure, right? So the reverse approach, whichever one it is, breeds its own crop of should've-worked projects, and the managers in training resolve that they're not going to make those mistakes again. . .

Ideally, you'd split the difference, but that's the hardest way to do it. Alternately cracking the whip and witholding it can breed resentment at the perceived unequal treatment: How come those guys get to keep going when we're under pressure? How come that group got to present that junk as a candidate when they're still making us fix ours? Instead of just hearing one class of complaint, you get the whole spectrum.

Note, of course, that all the choices involve researchers complaining. It wouldn't be research, then, would it?

Friday, March 22, 2002
Glad It's Over
Well, another fun-filled week of science draws to a close, as the people in my lab are probably tired of hearing me say. Several companies in the business are probably glad that this one is over!

With any luck, I'll get a chance soon to write about some drugs that got approved, rather than about ones that go down in flames. But the good news this week is that the system worked the way it's supposed to: you get the best and most complete data you can get; you take your best shot. I think that the FDA committee was correct in rejecting Picovir, and I think that BMS deserves applause for going after Vanlev as hard as they did (and sympathy now that it looks like a failed project.)

If it were easier to make good drugs, we'd have more of 'em. Better luck next time, if there is one. There are more people, more companies lined up to take their swings. It never stops, and that's the glory of it.

Thursday, March 21, 2002
You'll Only Get Answers
Bristol-Meyers-Squibb has received another pummeling. They've been trying for some time to get Vanlev (omapatrilat) approved for cardiovascular indications. It's similar to the known ACE inhibitors for high blood pressure, which reduce the amounts of the vasoconstricting peptide angiotensin II. Omapatrilat has that, and the same molecule also inhibits neutral endopeptidase (NEP), which is a new feature. Inhibiting that enzyme should give you higher blood concentrations of the things that it would normally clear out, which includes cardiovascular agents such as bradykinin and several natriuretic peptides. It's a reasonable thing to try.

We sound again the recurring theme: drug development isn't all that susceptible to reason - at least, not yet. BMS had extremely high hopes for this one, with talk of it being the biggest drug in the world, of 3 billion dollars/year in sales, and so on. You'll have to go back to 1999 for the best examples of that sort of optimism, though. It was supposed to be launched in 2000, but that never happened. Known side effects of hypertension drugs seemed to be coming up even more than usual, and BMS pulled their application from FDA consideration. It was clear that they needed convincing data that the drug was safe, and convincing data that it was more effective than the competition - Merck's ACE inhibitor Vasotec (enalapril.)

The time it would take to get that proof would hurt, because Vasotec's patent life was running out. It would have been a fair fight in 2000, but when Vasotec went generic, BMS would be up against a far cheaper drug as well.

I'll give them credit; they went right for the sorts of studies that would give them the answers they had to have. No messing around: they launched a 25,000-patient trial, head-to-head against Vasotec, to look for incidence of side effects. I don't even want to think about how much that must have cost. At the same time, they ran a smaller study (God knows, most studies are smaller than that first one!) in patients with severe congestive heart failure. That was also head-to-head with Vasotec, this time looking for better efficacy.

And they took it right on the chin both times. In that second, smaller trial, Vanlev worked no better than Vasotec. If they'd had more heart patients - thousands more - they might have been able to show a statistical effect, but it wouldn't have been enough to make anyone sit up.

That's bad enough, but in the massive safety comparison, that huge number of patients established once and for all that Vanlev causes side effects at a measurably greater rate than Vasotec, too. These two results would seem to spell the end for the compound. Today's New York Times quotes an analyst who makes the point more bluntly: "The drug is toast."

And it might be the end of more than that. Bristol-Meyers-Squibb has had one costly problem after another for the last couple of years. Their stock is at a five-year low, and their pipeline doesn't look good. Merger and takeover speculation has already started. That makes me wonder (again) if all this merger business in the pharmaceutical industry is what it's cracked up to be. BMS is, by anyone's standards, a huge drug company. If they're having all these problems, maybe size isn't correlated as well with success as folks would like to believe.

Wednesday, March 20, 2002
If It Were Easy. . .
As I mentioned yesterday, Viropharma's compound Picovir (pleconaril) was turned down unanimously by an FDA panel. This could be the end for an interesting compound that's been kicking around for many years, going back to the days (1990 or so) when Sterling-Winthrop still existed as a drug company.

Kodak took over Sterling in 1988, looking to get into the high-margin drug industry (they already had a chemicals business, the Eastman side of things.) As it turned out, you couldn't have paid a gang of saboteurs to do a worse job running Sterling, and the whole deal was a costly disaster that lasted some six years. The pieces of Sterling were sold off (at a mighty loss) to the French firm Sanofi, among others. During the chaos, some of the Sterling people left to form Viropharma, negotiating with Sanofi for the rights to pleconaril.

It's an interesting compound, with a mechanism that (to my knowledge) isn't shared by any other antiviral candidate. It binds to a site on the surface of the virus, keeping it from infecting cells. Viropharma kept plugging away at it, trying it out for meningitis and respiratory infections, but without notable success.

The last couple of years were a particularly wild ride. If you go back and look at the stock chart, you can see a huge run-up, followed by an equally hair-frizzing decline. What happened was some media reports in December of 1999 convinced various clueless investors that VPHM had, yes, the cure for the common cold. That was indeed what Viropharma had started trying pleconaril against, the meningitis data having proven unimpressive. The compound was far from a miracle cure.

But try telling that to the notorious stock promoter Tokyo Joe. Remember Joe? Viropharma stock was one of his calls during this period, and his people piled into it hugely, followed by a swarm of tag-along momentum players. They had a real fiesta for a while there, but NASDAQ was in all-fiesta mode back then, anyway.

Momentum investing means, of course, buying stocks just because other people are buying them. It's the Bigger-Fool theory in action, and it's always struck me as similar to the way some jackrabbits dart in front of 18-wheel trucks. (This is coming from someone who shorted Imclone at what turned out to be their low point, so I'm no stranger to risk.) In this case, the 18-wheeler appeared in the form of new clinical data showing that pleconaril wasn't particularly effective against colds, which led to the roll-off-the-table section of the stock chart.

I'm happy to say that I was short VPHM when that happened. Of course, I'd shorted them at about 50 and promptly watched the stock jump like it had been hit with a cattle prod, right up over 100, and mighty quickly, too. Swallowing hard, I shorted some more. I just couldn't see the drug working that well based on the clinical data the company had already shown. Meanwhile, Tokyo Joe's people on the stock message boards were already making VPHM out to be the next Pfizer. That's a quote from some guy - another table-pounder kept going on about how you'd have liked to have bought into penicillin in 1940, wouldn't you? Right? Here's the chance of a lifetime, again! Some other maniac saw the compound as basically the savior of the human race. Then the bad news hit. I'd like to have a videotape of me trying to dial my broker right after I saw the stock quote that morning (down 43 5/8 or something like that.) I kept missing the buttons on my phone; it took three tries before I successfully dialed my broker to take my profits.

The data that came out of those studies helped keep the compound from being recommended yesterday. Pleconaril, taken three times a day, starting very early in the course of a cold, reduces the duration of cold symptoms by a day or two. And that's about it, and that's just not enough. That's an awful lot of drug to load your system with for a relatively minor disease, and it would presumably involve spending a fair amount of money that an HMO might not be keen on reimbursing.

Viropharma kept making their case, of course. One point was that dosing with the drug reduced what's descriptively called "virus shedding," which could make you less infectious to others. To the best of my knowledge, no clinical data was ever collected to put that idea to the test, though. They got a big company to buy into the compound, namely Aventis (known to longtime pharmaceutical people by its heritage, as Hoechst-Marion-Merrel Dow-Roussel-Rhone-Poulenc-Rohrer, which sounds like a white-shoe law firm.)

But, in the end, the combination of lackluster efficacy with some extra safety concerns (possible interactions with the menstrual cycle in a few women, for example) doomed the compound. The effects they saw would have meant nothing for a compound that treated, say, pancreatic cancer, which is otherwise a death sentence. But for a cold?

To their credit, you can see that Viropharma realized all this. That's why they started trials on viral meningitis. When that didn't work out, they went to serious respiratory infections. No dice. Finally, they were left with colds. They did the best with what they had, but it wasn't enough.

Tuesday, March 19, 2002
In the Works
There are more interesting stories surfacing than I have time to work up right now. Coming along is the report on "Vedic Math" - that turns out to be more of a swamp than I'd anticipated, but onward anyway. Today there was an FDA dismissal of an interesting antiviral compound from Viropharma. Having traded their stock several times over the last couple of years, I have some things to say about that one. Finally, Pfizer just reported disappointingly ambiguous results from an ambitious attempt to treat atherosclerosis with antibiotics - nope, that's not a misprint. More on this one in the next couple of days, too, but the whole New Germ Theory is a tough thing to summarize.

Mirror Stars
No longer can I say that the topic of allergenic extraterrestrial life hasn't been taken on in science fiction. Patrick Neilsen Hayden of Electrolite, who is certainly in a professional position to know, passes on the word that the 1999 novel BIOS (by Robert Charles Wilson, reviewed) includes this very idea.

On a related topic, a number of old sf stories made use of the chirality of amino acids and the resulting proteins, with a plot point usually being the possiblity of starvation when trapped in an environment full of the wrong-handed food source. Given that such enantiomeric compounds can have very different properties in the body, I'd think that such an environment would not only be non-nutritious, but extremely toxic.

But are there any such places (stipulating an abudance of life-as-we-know-it in the universe to make it more possible)? That gets right into the question of how we ended up with only L-amino acids (and only D-sugars, which get less attention, undeservedly.)

There are plenty of theories. One thing that most everyone agrees on is that what we see now is a founder's effect - life got started with the series that we know, and stuck with it ever since, across billions of years. (Reminds me of Microsoft.) But was it a pure 50/50 chance at the beginning, or was the deck stacked? For that to happen, you have to have a chiral environment somewhere for it to develop.

Explanations such as seeding by meteorites containing chiral amino acids (or planetary formation from a cloud containing a chiral mix of compounds) just push the question back a bit. Where did those excesses come from? I should note that a paper on the amino acid ratios in the Murchison meteorite was just presented at the same meeting that Jay Manifold has been reporting from over at "A Voyage to Arcturus." Maybe he can give us a report.

For some years, the explanation that was hauled out invoked the weak nuclear force, which is the first place you can find symmetry breaking down in the laws of physics. Trouble is, that's such a small effect on the thermodynamics (if there's an effect at all!) that it's really like sticking with the 50/50 chance.

Another interesting idea was that circularly polarized radiation, potentially from neutron stars, preferentially breaks down one enantiomer of simple molecules over another. This still doesn't give you much of an edge, but it's a lot more compelling explanation that the weak nuclear force.

Last year a theory was proposed that formation of simple biomolecules on rock surfaces (a hot topic in origin-of-life research) might have something to do with it. Calcite seems to absorb different enantiomers on different faces of its crystals, which could have led to local excesses - too local, some say - of one enantiomer. If one of these microenvironments was the first to start things on the road to life, though, that would be all you need. It's still another form of 50/50 chance, depending on what crystal face you pick, but at least (as with polarized radiation) you have a semi-plausible mechanism for generating an excess of one chiral form.

These ideas and others are discussed on this site, but note: that page also brings up an experiment from a few years ago that suggested that magnetic fields could induce chiral chemistry. This result has since been throroughly discredited. No one could ever reproduce it, and it turned out that one of the original graduate students faked the results. Not a smart career move, considering how much interest (and scepticism) the first report got.

Monday, March 18, 2002
Life as We Don't Know It
The latest data from the Mars Odyssey (plenty of subsurface water, from the looks of it) brought to mind some thoughts about the chemistry of extraterrestrial life.

I'm in the camp that thinks that life (the kind we can recognize) is probably fairly common. There's so much water out there, so many piles of small-molecule building blocks, so much energy, so much time, and so many chances. Of course, taking that position puts me right in the bulls-eye of Fermi's paradox: if there's intelligent life out there, where is everyone? I won't get into arguing the terms of the Drake equation; we just don't have enough data. But I admit that there's a disconnect between my estimates of life's ubiquity and the apparent lack of detectable intelligent forms. There's something really interesting going on that we're not grasping yet.

Let's stay at something like that bacterial level. It's a successful design, and it seems likely that its small, self-contained, chemical-energy-using template would be found again and again. What would Martian microbes really look like, though? I'll bypass the possibility that they might look exactly like ours, although that's what the late Fred Hoyle would have bet on. It could be that sample exchange between the two planets seeded one of them with the other's bacterial flora, but I have to say that I'd be a bit disappointed if that turned out to be true.

And if they're really alien? Well, one clue are the organic molecules that you can find spectroscopically, in planetary atmospheres and in interstellar space. All the small stuff is out there - water, formaldehyde, hydrogen cyanide, hydrogen sulfide, methane, and so on. That takes you straight into just the sorts of more complicated molecules you can find here on Earth. And in fact, those next-step compounds (amino acids, for example) have already been found in carbonaceous chondrite meteorites (like the Murchison.)

Well, if there are simple amino acids and the like swimming around in water, will alien microcritters still look familiar? This is where the real speculating starts. Given that amino acids form readily, it's quite possible that proteins would also be a part of some other series of life. I'll stipulate that much; they're just too useful and available. But there's no particular reason (that we know of) that the suite of amino acids that we have should be replicated. There are already some odd ones used here (like ornithine in birds, and even weirder ones in out-of-the-way bacteria.) You can buy a lot of unnatural amino acids from the catalogs; it wouldn't surprise me if some of those are the natural ones somewhere else.

And do the proteins have to be all amide-linked? I've always wondered about the use of more sulfur compounds. There are sulfonic acid compounds (like taurine) already used in Earth's biosphere. The corresponding sulfonamides are much harder to hydrolyze, but it's nothing that a decent enzyme shouldn't be able to hack. I don't know if you'd find a whole proteome (to use a fashionable word) made up of aminosulfonic acids. But you might find some sprinkled in to add variety to the 3D structure and properties of the resulting proteins. How about phosphorus? Some phosphonic and phosphoric acid derivatives would certainly liven things up. Our own biochemistry makes endless use of plain phosphate esters (hanging off pretty much everything you can think of,) so I don't see why some other phosphorus chemistry might not find its way in.

If there are protein-like molecules out there with such things woven into them, they'll be pretty interesting (well, interesting if you find proteins themselves interesting - if not, not, as Gertrude Stein said.) They'd have properties and catalytic abilities far different than our own collection. Those are wildly diverse enough as they stand, and giving us fits trying to figure them out.

There's one other property that alien proteins could have, one that I have yet to see come up much in science fiction. They could possibly be amazingly, catastrophically - allergenic. You can see why that theme hasn't been explored much. The brave space explorer meets up with alien life for the first time - and the tiniest fragment of it sends him into anaphylactic shock. Not the sort of thing one of Robert Heinlein's heros would have put up with. On another level, the mental picture of Mr. Spock watching curiously as Captain Kirk breaks out in hives and sneezing fits makes the whole thing sort of worthwhile.

Sunday, March 17, 2002
Well, I tried to hold off on this until the first week of April, but I can't take it any more. (For my previous ranting on this subject, see the Feb. 12 post.) It's time to put on the World Pundit hat and go. . .

Back to Tokyo
The weird recent rise in the Nikkei index is one thing that's setting me off. It's gone up something like 25% since its low point in early February, which strains belief. I still think that buying Japanese stocks at this point is like Ambrose Bierce's definition of a second marriage: the triumph of hope over experience.

Given the way Japan works, cui bonois the first question to ask whenever something financially unusual takes place. The first obvious beneficiaries here are the banks. They're carrying plenty of equities, counting them as part of their capital. Any rise in the stock market immediately improves their books. Admittedly, the market would have to do some serious rising to bail out some of them, with their own stocks down in the penny range. But every little bit helps, and there's not much good news coming from anywhere else.

The second grateful parties are the big construction companies, politically very well connected to the ruling party. The goverment is strong-arming the banks to bail them out, and you can imagine what shape your books must be in to be bailed out by a Japanese bank.

It's an artficial rally. Despite the happy talk emanating from Tokyo, I don't see how the economic situation has changed. Japanese stocks can't stage a sustained rise without an improvement in the economy. And the economy can't improve without addressing its fundamental flaws, which the Japanese government is still showing no appetite for doing. The first thing on the list would be dealing with the massive debt hangover left from the speculative bubble of the 1980s and early 1990s.

It's getting to be a long time since those days, isn't it? You'd think that the normal business cycle would have ironed things out a bit by now. But the Japanese establishment, with its longing for order and consensus, has never liked the business cycle much - nor the free market, for that matter. If things worked the way they should, banks would be going out of business, and people who paid amazing prices for real estate, golf club membeships, Impressionist paintings would have to come clean about the losses, take their medicine, and try to move on. It isn't happening.

It's true that if everyone suspends disbelief, things could float up - for a while. But - again - I don't see how anythign substantial has changed. Consumer demand would have to pick up for anything to really get going, and getting Japanese consumers to suspend disbelief at this point is going to be difficult. They're still piling into gold, which is hardly a sign to break out the party hats. Worse, some of them seem to be buying it specifically because they fear an artifical inflation of the yen - which is just what may be in the cards. It's going to be hard to get these folks to play along when they're already one step ahead of you.

The fiscal year closes on March 31, which gives you a good idea of when the Nikkei should start heading back down. You'd figure that there would be people going short now, getting ready for that very thing. But the Japanese government has just put in strict rules making it much harder to sell short. Why would you need such things if the market - and the economy - has really turned the corner? What could they be afraid of?

Friday, March 15, 2002
He Meant It, Too
I'll sign off for the weekend with a quote from H.L. Mencken. You can always find something worthwhile in the Sage of Baltimore, and this is from his 1925 essay "Off the Grand Banks:"

This, at least, I have observed in forty-five years: that there are men who search for it [truth], whatever it is, wherever it may lie, patiently, honestly, with due humility, and that there are other men who battle endlessly to put it down, even though they don't know what it is. To the first class belong the scientists, the experimenters, the men of curiosity. To the second belong politicians, bishops, professors, mullahs, tin pot messiahs, frauds and exploiters of all sorts - in brief, the men of authority. . .All I find there is a vast enmity to the free functioning of the spirit of man. There may be, for all I know, some truth there, but it is truth made into whips, rolled into bitter pills. . .

I find myself out of sympathy with such men. I shall keep on challenging them until the last galoot's ashore.

Thursday, March 14, 2002
NMR Revisited
Speaking of NMR, it's a good thing for chemists to remember that this tool wasn't always there for us. For those of you not in the field, I can say without exaggeration that we'd have to close up shop without it. It's such a valuable thing that it's crowded out older, perfectly reasonable techniques like infrared spectroscopy.

Fellow chemists, raise your hands: Who's taken an IR spectrum in the last six months? OK, you folks who are characterizing compounds for your dissertations can put yours down. Anyone from Switzerland who's writing a paper for Helvetica Chimica Acta (where every new compound is characterized practically down to how it tastes) can put their hand down, too. Anyone left?

I didn't think so. It's a lost art. You can see all sorts of structural information in an IR, but why would you bother? NMR will tell you the same thing and plenty more at the same time, things you could stare an an infrared spectrum until your eyes cross and never be able to determine.

For an even more lost art, consider ultraviolet/visible spectroscopy. Go back to the 1940s and 50s and the journals are full of UV/Vis spectra, reproduced in all their near-featureless glory. I took a few as an undergraduate, and I don't recall ever doing any since. Physical chemists, inorganic chemists even - they can be interested in these. Darn few synthetic organic chemists are.

Not that I'm asking to return to the days when those techniques meant something. Far from it. But every so often, when we're complaining that the NMR machine is taking an extra couple of minutes to automatically run our sample, it's worth taking a minute to think about the alternative.

More Truth-on-Demand
Some interesting e-mail has come in responding to "In Cranium Veritas" below. (Should that be "cranio" intstead? Someone with more Latin than I have should write.)

First off, it turns out that there's a 1996 science fiction novel exploring this idea: The Truth Nachine, by James L. Halperin. I haven't read that one, nor anything by Halperin (although I have, over the years, read a goodly amount of sf.) The mid-1990s was about when this whole idea began to occur to me as well, and doubtless to many others even earlier.

Secondly, some actual research has been reported. This Reason article from last November does a good job summarizing it, with appropriate links. They even interview the author of the above novel for his take on it.

I'd missed these by Googling for "PET" and truth/lie combinations. A similar search using "fMRI" would have turned up all this. Goes to show you what I should have remembered from all my scientific literature searches: you can't ask the question too many times, or in too many different ways.

Functional MRI has some real advantages over PET. You don't need short-lived positron-emitting radiolabeled compounds, for one. (The organic synthesis papers describing how to make those are pretty bizarre; it's the synthetic chemistry equivalent of speed chess.) I suspect that there are plenty of tricks still to be wrung out of the NMR imaging data, in much the same way as chemists are still making the standard NMR technique yield more information.

Wednesday, March 13, 2002
Another Unsolved Problem
After writing that piece on pain relief and placebos, I heard a really harrowing piece on NPR this evening from author Reynolds Price. Some years ago, he had a tumor removed from his spinal column, and the nerve damage that ensued during treatment left him both in a wheelchair and in constant pain.

It was a disturbing segment indeed, as he described (or tried to describe) what it's like. One of his main points was that no one could come close to imagining the pain if they hadn't experienced it - no description was adequate. The best therapies, he said, relieved perhaps 20% of it.

I know several companies are working on chronic pain, but I have to admit that I don't know the latest research status. I'm going to look into it, and try to post an overview. It's a tough problem, since the reason for the condition is still so poorly understood. Some of the mechanisms you could use to attack it would not be things you'd want to turn loose on the rest of your nervous system, either.

But how bad would a therapy have to be before it was worse than the condition it treats? That's a constant question in drug development, and we adjust our expectations to the therapeutic area. A candidate for intractable tumors, for example, can (and often does, unfortunately) have toxicology that would have stopped other drug leads in their tracks. An agent for the kind of pain that Price described would have a pretty high threshold, too.

Tuesday, March 12, 2002
In Cranium Veritas
Writing about PET scans brought to mind a speculative idea that I had several years ago. I'll throw it out here for general use and comment.

As I mentioned, the spatial and temporal resolution of brain imaging is getter better all the time. It seems very likely to me that we're going to be able to spot patterns of brain activity long before we have a good idea of what they mean. This is already the case, but I expect even more fleeting and complex systems to show up.

Doesn't it seem likely that the brain activities involved in answering a question truthfully would differ from the ones involved in deliberate lying?

That's it in a nutshell. The implications start popping up immediately. There are complications, of course. Lying "on the fly" in real time would certainly be different than having a practiced story, for one thing. And different people would attach greater or lesser emotional content to the act of lying (which is what polygraph testing - which I think is often just this side of voodoo - attempts to do now.) It would be fascinating, once we start to unravel this stuff, to put a real no-holds-barred con man or sociopath in the imager and see how his brain deals with falsehood.

But those are refinements. I can imagine a courtroom scene years from now, where it's entered into evidence that "the defendent has been classed as a type III-a-4 truthteller in matters that do not involve his personal safety, and a IV-c-1 in those that do, therefore, your honor, it is clear from the response to question sixteen that. . ."

Does anyone else buy into this? And if it comes true, what would the legal system do with truth on demand?

Monday, March 11, 2002
All CNS Drugs Should Work This Well
Everyone knows that double-blind trials are the only form of clinical evidence that most drug companies (and most regulatory agencies!) will trust. The negative control in those trials is a placebo dose, which practice causes periodic controversies. The most recent one has been about whether the "placebo effect" even exists.

There's an interesting article in the March 1 issue of Science that helps clear up how it works, though. The research team used PET imaging to study brain activity in volunteers who took pain medication versus those who (unknowingly, of course) took a placebo. Both groups experienced painful and non-painful levels of heat on their hands.

(For those not familiar with PET, it measures areas of increased blood flow in the brain, which correlate strongly with brain activity. These studies have been turning up extraordinary data for some time now. As the resolution (spatial and temporal) gets better and better, their value (and that of the complementary NMR imaging method) is getting hard to overestimate. There's no substitute for watching the brain in action.)

The results? If the volunteers were told that they were taking a strong analgesic, but were given placebo instead, many of the sameregions of the brain lit up as in the people who really got the drug. It's not a one-to-one match, but the similarities are striking.

Overall, the pain-relieving effect of the placebo does seem to work through the body's endogenous opioid system. This fits in with older pharmacological studies, which showed that placebo pain relief could be blocked by opioid antagonist drugs. Experience of pain is notoriously variable, but the study found different brain activity between those who responded strongly to the placebo and those who didn't.

There's more to the story. Some work from 1999 suggests that there can be another form of placebo analgesia, not involving the opioid system at all. Outside of the area of pain relief, a remarkable study last year showed that patients with Parkinson's disease respond to placebos as well. Their brains release dopamine when they're told that they're getting medication, which is quite interesting considering how damaged the dopaminergic system is in that disease.

What other brain signaling systems respond to this sort of trickery? And what pathways allow this sort of conscious (or partly conscious) control? These sorts of questions should keep everyone in the field busy for a while. The placebo effect appears to be alive and well.

Sunday, March 10, 2002
Separation Anxiety
Sepracor's really taken a pounding after an FDA "non-approvable" letter for their antihistamine compound. But they haven't been a quiet drug stock to be in, and it isn't a quiet company.

They certainly don't have a quiet business plan, either. As readers who are in the business are well aware, Sepracor doesn't develop any really new drugs. Instead, they look for "improved versions" (pure enantiomers or active metabolites) of existing ones. As the company says:

"In contrast to traditional new drug development, the safety and efficacy of the racemates and parent drugs of Sepracor's pharmaceuticals under development are often well understood before clinical trials begin. Parent drugs have been successfully taken through clinical studies and may have been on the market for years."

Well, yes, but what that leaves unspoken is that someone else did all that. And what it reallyleaves unspoken is that they didn't do it so that Sepracor could cash in with a second-generation compound. Friday's Wall Street Journal article on their stock plunge contained a line about Sepracor helping Schering-Plough develop their successor to Claritin, Clarinex. If you were to ask Schering, they'd probably tell you that Sepracor helped develop that one in much the same way that Blackbeard helped with jewelry shipments. Lilly felt the same way about the single-enantiomer version of Prozac that they ended up licensing.

Both companies were beavering away on these projects when Sepracor showed up with really unwelcome news: They informed Lilly and Schering that they had patent rights for the use of these second-generation compounds. This (as far as one can tell) completely blindsided both companies, who were sure that (as usual) their chemical matter and its uses was covered under their own patents.

Oops. Sepracor had done a more careful job of reading the existing patent claims, it turned out. There was great gritting of teeth at the companies involved (and probably great public flogging of the Legal departments,) but they both went ahead and signed deals. Sepracor got money upfront and a piece of the profits if the drugs made it to market.

They ended up going 1-for-2 on these, but not calmly. The Prozac enantiomer project with Lilly went into the clinic, where it proved, as expected, to be more active. It also proved to be more toxic. Oops. With that one gone, they needed Schering's compound, more than ever. It's finally hitting the market, but not without delays. Schering's problems with the FDA over manufacturing issues have caused Sepracor plenty of trouble. While Schering's stock price felt the pain, Sepracor (with fewer drugs in its portfolio) felt it even more. Clarinex was finally approved last December, and Sepracor went up almost 6% in one day.

They have several other examples of this strategy. The most successful has been licensing the second-generation form of Seldane back to Hoechst (now Aventis), where it's now known to the world as Allegra. So, what went wrongt this time? This compound was an active metabolite of Johnson and Johnson's Hismanal. While that worked with Clarinex, the danger is that active metabolites are new compounds, with new properties all the way. It's not like the single-enantiomer drugs, where at least patients have been getting dosed with the compound already. In this case, there were toxicology problems that Hismanal doesn't seem to have.

And what now for Sepracor? As has been apparent for many years now, their business model is based on a non-renewable resource - incomplete patent coverage. Those loopholes have closed decisively, since everyone now knows what will happen if they aren't. In that way, Sepracor's influence has been a good one on the industry, keeping everyone on their toes.

They've talked over the years about becoming a real, research-driven drug company, but I'll believe it when I see it. That requires costly infrastructure that they don't have, and entails a success rate that (last week's setback notwithstanding) is lower than they're accustomed to. And instead of fishing for drugs from a secluded spot, it would put them right in the big tank with the rest of the sharks.

Friday, March 08, 2002
In Memoriam
One sad note is the passing of a member of organic chemistry's Old Guard, Prof. Henry Rapoport.

Like many other working chemists, I have several publications from his research group in my files, selected from his long career in natural products chemistry, heterocycles, amino acids, and other areas. The papers are worth reading, and you can be sure that everything in them works. That's not anywhere near as common a statement as it should be.

Left as his legacy are not only his body of work, but the many people he trained. You can't go far in the field without running into someone who studied under "Rap." Si monumentum requiris, circumspice.

Back On the Air
I didn't get a chance to post anything last night, and figured I'd put something up this morning. Unfortunately, I got caught in the Great Blogger Upgrade, and couldn't get anything in before I had to go to work. I don't post during the day, since my employer has a reasonable expectation that I'll spend that time discovering wonder drugs.

So I'll wait until Monday and start things up again. This'll give me a chance to fix some broken links (like the Iressa article from Mar. 6 below.) Next week's topics will include Sepracor (check that stock chart - shorting them would have made up for Imclone!) I'm also planning a closer look at the odd world of Vedic math (see March 5th post.) Long-term, I'll be revisiting the wilting Japanese economy (see Feb. 12th post) at the end of the month, when we see if the banks there actually have to face the music.

All of the above is subject to revision of course. If, say, Merck merges with Disney or Honda announces a bubble-fusion powered minivan, we'll probably detour for a bit.

Wednesday, March 06, 2002
Imclone Update
Well, I'm out of my short position - at a whacking fine loss, thanks. Investors today took the news of the renegotiated Bristol-Meyers Squibb deal as very good news indeed. I'm sticking by my interpretation of events (see earlier posts,) but I've no desire to put up that much capital to try to be proven right. Trying to wait these things out can be torture; sense can take a long time to return, if it ever does.

Note that there are several analysts who take the same positions I do on Imclone's share price and prospects for a profitable drug. Those opinions and a dollar will buy me a can of soda, but it does make me feel better.

When I referred to the hoofbeats coming up behind Imclone and BMS, AstraZeneca's drug Iressa was one of the things I had in mind.

Bubble Fusion Update
Disclaimer: I'm not a physicist. I'm about as good at that as particle physicists are at medicinal chemistry. It's in the best interest of mankind if we don't switch jobs.

That said, looking over the documents on the Science web site brings up several observations. The common theme is that (whether the paper is correct or not) this isn't a replay of 1989.

For one, that work claimed a completely new process (cold fusion) with no plausible mechanism at hand. This study claims a very unusual way to induce the already-known hot fusion reaction. The method (collapse of sonication-induced cavities) is already known to produce tiny points of very high temperature - orders of magnitude, it was thought, less than you needed for fusion, but the idea had at least been speculated on before this.

Secondly, the main paper contains a great deal of detail. The 1989 report was very skimpy, and key details were simply not reported. This paper gives everyone who wants to reproduce the effect a fighting chance to do it. We should have much quicker and cleaner attempts at confirmation this time.

Finally, the authors have already responded to criticism, something that Pons and Fleischman didn't do well at all in '89. The article refers to an Oak Ridge internal report that couldn't reproduce the claimed fusion. The reply addresses the issues and shows how the non-confirming data could be incorrect, and why. As I said, I'm not qualified to say who's right - I'm just glad that the apparatus and the data are the focus of the arguments. That's how we're going to figure this out.

Tuesday, March 05, 2002
Let Them Eat Astrology
Reading about scientific cranks (see March 3rd post) is a reasonably safe activity. But what do you do when they're running the country? That's the position that India finds itself in under its Hindu nationalist BJP government. The recent headlines have been about flareups of Hindu-Moslem violence, which is bad news indeed, the last thing India needs. But there seems to be some slow, long-term bad news from the educational system as well.

I'd noticed in a Sceptical Inquirer article that Lucknow University now has a degree program in astrology. Everyone at the SI's parent organization, the Committee for the Scientific Investigation of Claims of the Paranormal (CSICOP) moans audibly when astrology gets recognition like this, and I don't blame them. I had this filed under "irritating news" until I saw Monday's Wall Street Journal (no free link.)

They report on the astrology program, complete with its professor telling students that they need to become "antennae of cosmic energy," and saying "It's a science. . .I don't criticize philosophy or literature. Why should they complain about astrology?" (Why? Well, maybe because none of those are sciences,you - aargh, I'll hold back for now.) But things are apparently worse than I thought. BJP-affiliated groups now talk about "spiritulization of education" in India, and that includes the astrology, diploma programs in Hindu rituals, and something called "Vedic math," which seems to argue that religion can help with calculus homework. The article doesn't mention it, but I'm assuming that there's going to be a generous dose of Ayurvedic medicine thrown in, too. Bring in the whole lot; a civilization as old as India's has had time to pick up all sorts of stuff.

What's terrible about this foolishness is that India has a tremendous pool of scientific talent. For many years, much of it has left: you'd be hard pressed to find a technology-based US company of any decent size without Indian nationals working there. But they're finding plenty to do at home now, and they could keep on doing it. Or everyone could get into astrology - that's an option, too, and it has the benefit of being spiritual. You're damn well going to need a spiritual outlook if you go across a bridge that was built using Vedic math.

Everyone knows about the Indian software industry. Not many people realize that there are a lot of seriously good chemists there, too. India's past practice of ignoring international patent law has led to a large talent pool of process chemists, handy at coming up with efficient ways to knock off patented drugs. But now there's a strong home-grown pharmaceutical research firm (Dr. Reddy's) which is licensing new drug candidates to large companies in Europe and the US. So, should they keep on doing that?

Or should India's biomedical future look like this: Monday's New York Times carries an article about trouble with a vitamin-dosing program in northeast India (Assam.) It's been found that providing children with enough vitamin A cuts down on mortality and many developmental problems. It's easy to do, it's cheap, and it alleviates terrible and useless human suffering - what could go wrong? What could go wrong is that rumors spread that the vitamin preparation is poisonous, that it's part of a plot by big drug companies to do terrible things. Why? Because they're big drug companies, apparently.

Now people are refusing to let their malnourished children be treated. The Indian health workers trained to do it are being harassed. This week, a polio-vaccination campaign is foundering for the same reasons.

These children need medicine.Astrology is not going to keep them from getting polio. Vedic sutras are not going to keep them from malnutrition. This mystical nationalism is the absolute last thing that India needs. How the people that promulgate it can sleep at night is beyond me.

Elan Update
Just a few days after the Feb. 28th posting, Elan announced that they're discontinuing the trials of their Alzheimer's vaccine. While Elan says that they have several other "potential treatments" for Alzheimer's, I have to wonder if any of them are going be immunology-based after this result.

If not, don't hold your breath. That puts Elan right back with the rest of the pack, as far as I can see. There are a number of inhibitors of suspected amyloid-forming enzymes being developed, and I believe that someone's going to get one with good penetration into the brain. (That particular problem - the blood-brain barrier - is one of the biggest reasons that central nervous system therapies fail in pre-clinical work.)

Others are working on ways to make the amyloid stop aggregating into plaques, but that's more speculative. We know that we can inhibit proteases; protein aggregation isn't as well worked. Of course, all this presupposes that amyloid is the causative agent of Alzheimer's, but that's as good a place to start as any.

Monday, March 04, 2002
Dare to Hope
I've been working on a rather ill-tempered article about some news from India, but that one's going to have to wait. Something enormous could be happening.

This story, datelined about 6 PM EST and the latest version I can find right now, is potentially a world-changer. There is apparently a paper coming out in Science that claims tritium production and high-energy neutron emission from sonication of deuterated acetone. Here it is, from the source, with commentary.

That would mean nuclear fusion, at ambient temperature. In acetone, of all things.

We've all been here before. Easter of 1989 was when the (now infamous) cold-fusion report from Pons and Fleischmann came out. I was doing a post-doc in Germany at the time (West Germany, as we called it back then. . .) and heard the news on the radio. I ran out to the train station to buy a copy of the Financial Times newspaper, the first one to break the story. I still have it, the FT's pink newsprint turning a bit darker with age.

For several days, I was completely elated - at the discovery, at what it could mean, that I was living in a world where such things were possible. And if that was, what else couldn't be?

The slow unraveling of that work was a terrible letdown, and maybe we're all going to get that treatment again. This paper has been simmering in the physics community for a while now, it seems, with disagreements and controversy about the results. I can only hope that there's something here this time. If you're a physicist with the gear, break it out and check these results. The world's waiting.

Sunday, March 03, 2002
The Green Ink Connection
To add to the Feb. 25 post about the limited forms of insanity, I can direct you to Donna Kossy, whose 1994 book Kooks is a good source of evidence. It's an overview of various cranks - political, religious, scientific, and several whose subject is unclassifiable. It looks at first reading like a huge variety of craziness, living up to the book's subtitle ("A Guide to the Outer Limits of Human Belief".) But on inspection, the underlying tone is remarkably similar from crank to crank.

This might be a selection effect - after all, these were culled by Kossy as the most interesting from her collection (which must be a sight.) Said collection is a subset of the off-kilter who are moved to put their thoughts on paper. Even correcting for all this, the similarities are striking.

The similaries of presentation are the most obvious. What is it that makes these people fill up every open space on a piece of paper - sideways, upside down - and lurch into ALL CAPS? Physicist Jeremy Bernstein has an article (collected in Cranks, Quarks, and the Cosmos) on the crank mail that he and others in that field receive. The no-wasted-paper look was an instant giveaway, as was the use of green ink. He was able to cull his mail almost on sight. It was his impression that physicists were the outlet for more of these people than chemists or biologists. (Of course, as mentioned here on Feb. 21st, physicists are more afflicted with the socially-constructed-truth cultural studies people, too. Not that there's any connection. . .)

But there are similaries in style and subject as well. Some of the book's subjects are paranoids - no one more than Francis Dec. Some are obsessed with various celebrities or politicians. Many others have some huge, important, world-saving news they have to impart (the boundry between these people and the paranoids gets fuzzy.) Changes in the Earth's gravity, aliens among us, religious revelation - all get their due and more. Another class, such as the striking Mrs. Eigar, for whose works I can (fortunately?) find no web link, seem wrapped up in the world of their own biology. Individuals they all are, but they all fall into categories, and there aren't many more of those than the ones I've listed.

You could do worse than divide everyone into big-picture cranks and small-picture cranks. There don't seem to be many medium-picture cranks, which is where the missing chemistry lunatics would fall. Biology gets the medical lunatics, who are either (big) world-changers or (small) private obsessives. You don't see many other biological types - if there's someone out there writing dense green-ink screeds about rotifers or field ecology, I haven't about them.

At a guess, the neural circuits involved with reward, attention, and response to threat might combine to give you many of these behaviors - or at least give the various behavioral flavors to the underlying pathology. More than that, I'm not competent to speculate. Too much more than that, I don't know if anyone is, unfortunately.