Lagniappe (science, business, and culture)

Tuesday, December 31, 2002
Happy New Year
No one in my line of work is going to miss 2002. I'll be going into details over the next week or so, but it was mostly one big mudslide in the pharmaceutical industry, from start to finish. We generally don't have two years like that in a row, but y'know, we generally don't have years like this at all, so who knows what 2003 will bring? Here's hoping we do a little statistical regression towards the mean.

In the larger world of science, which I talk about as well, it's been another year of glorious chaos: all sorts of crashing and banging as old theories get the wrecking ball and new ones get hammered together. Looking over the general literature, it's hard to overestimate the pace of discovery these days - it's enough to make me think that Vernor Vinge might eventually be on to something.

And in the larger world of the larger world - well, that's not something I spend much time talking about here. But it seems clear to me that 2003 will be a very important year indeed, and that we'll come out of it in a very different world than the one we see around us tonight. I think, and hope, that it'll be a better one. And which of those two verbs means more?

Monday, December 30, 2002
Back on the Air
After a (reasonably) refreshing holiday break, Lagniappe is back. Thanks to everyone who kept doggedly hitting this site during the last few days - I admire your persistance.

I notice from my site's counter that I get a small but steady flow of Google hits for various miracle cures. I said some nasty things about the Budwig flaxseed-oil diet a while back, for example, and I still get Googled for that one. For those visitors, here's a post that (with any luck) will show up for a long time to come.

To put it in one sentence, distrust simple cures for complex diseases. Cancer is a complex disease, so are arthritis, MS, Alzheimer's and diabetes. What's a simple disease? An infectious one: there's a proximate cause, and a path to cure it. Get rid of the bacteria, and your septicemia goes with them. Clear out the parasites, and no more malaria. (You'll note that we don't have a universal malaria cure yet, which should say something about how hard even the simpler diseases are.)

The really tough ones, though, are all things that originate from some misfiring of the body's own systems. It's true that there are single-gene diseases, which would be simple to treat if we only knew how to get gene therapy to work. You'll find most of those listed in Goodman and Gilman, over to the left in the Bookshelf section, but most of them are rarities, diagnostic zebras that many physicians will never see. The ones that every physician sees are multifactorial and very hard to deal with.

I've spent a lot of time on this site talking about autism recently, and there's a common factor. I believe that many diseases only look like single conditions, which turn into dozens of other diseases on closer inspection. There's no such disease as "cancer," for example. Cancer is the name we sloppily apply to the end result of dozens, hundreds of metabolic or genetic defects and breakdowns, all of which end up as vaguely similar cell-differentiation diseases. It wouldn't surprise me if Alzheimer's ends up as something that can be caused several different ways, all of which end up in the same alternate low-energy state for the brain's metabolic order. (I speculated on this back in the first month of this blog's existence.)

And autism, too, could well be the name we're giving to several different diseases, distinguished by their time course, onset, and severity, caused by all sorts of intricate interplay - the wrong chord played on the instrument at just the wrong time.

You can, at times, find single factors that lead into these diseases - a compound called benzidine leads to bladder cancer, for example, although not in every person exposed, and at unpredictable exposures over unpredictable times. But that doesn't mean that everyone who has bladder cancer has been exposed to benzidine - not many people ever are these days. And stomach cancer, for example, has nothing to do with benzidine at all. Even the simple cases aren't too simple.

Remember the power line scare? How those electromagnetic fields from high-tension lines were messing up everyone's lives? You could see stories about how power-line exposure had been linked to brain cancer, to kidney cancer, to skin cancer. The problem was, one study would show a barely-there tenuous link to brain cancer - but not to anything else. Another would show the same wispy possible connection to kidney cancer - but not to anything else. And so on - after looking over all the data, the best conclusion was that this was all statistical noise. Beware statistical noise - that's another long-running theme around here.

Epidemiology hasn't been a simple field since the days of yellow fever, if it even was then. And medicine hasn't been a simple one since the first days that ever counted. As time goes on, we're clearing out more and more of the easy stuff. The really hard stuff is what's left, and it's going to be resistant to simple fixes.

Tuesday, December 24, 2002
Merry Christmas to All. . .
. . .and to all a good night. I have plenty of presents still to wrap, and a slice of homemade lime pie to eat (have to fortify myself for all the cutting and taping, you know.)

Seasons' Greetings to everyone. I'll try to post a little bit for Friday, but otherwise Lagniappe will resume on Monday (unless some large-scale science or pharmaceutical news crops up.)

Sunday, December 22, 2002
Clearance Sale
While I'm on the subject, I'll mention some details that will be familiar to my fellow medicinal chemists. The body has a lot of mechanisms to deal with foreign substances. We assume that all our drugs are going to be handled by them, one way or another, and we just try to keep the stuff around long enough to work. (And that's usually the case - once in a while you'll come across a compound that binds to some protein so tightly that it doesn't disappear until that population of protein molecules is metabolically recycled, and that's bad news. Altering a protein that permanently can cause more effects than you're looking for, the worst of which is setting off an immune response.)

The two sorts of systems that clear out unrecognized molecules are divided into Phase I and Phase II enzymes. The Phase I crowd rips into anything that fits into their active sites, which are biased toward greasy structures, and tears the molecules up in ways to make them more water-soluble. The so-called P450 enzymes in the liver are the big players here, and they can oxidize just about anything that comes their way. If the newly torn-up substance is sufficiently water-soluble, out it goes into the urine next time it hits the kidneys.

If it isn't, it hangs around long enough for a Phase II enzyme to get ahold of it. These attach what are basically disposal tags to molecules, groups that are made to be pulled out of the blood and into the urine. A sugar called glucuronic acid is a common tag, and another molecule called glutathione does a lot of this, too. Sometimes Phase II pathways are the main way a drug is eliminated - depends on its structure. One way or another, the body finds a way to get rid of things.

And if it doesn't, that can mean trouble. If the body's exposed multiple times to something that isn't cleared well, the stuff can accumulate in one tissue or another. And while that's not always harmful, there's no way it can help, either. This is the problem with heavy metals like lead or mercury. They're not the sort of thing that can fit well into the P450 enzymes, and they're generally already oxidized as far up as they can be, anyway. Compared to drugs, they're handled poorly. Metals are often excreted bound to sulfur-containing proteins, or as the salt with cysteine itself (the amino acid unit that contains the reactive SH group.) There's a lot of oxidation-reduction chemistry involved - a dose of a metal salt may end up being excreted as the reduced element itself.

That takes us back to tonight's thimerosal theme. The recent Lancet study found that most of the mercury was eliminated through the GI tract, mostly as inorganic (elemental) mercury. The faster it gets converted to that, the better, I'd say, because doses of mercury metal itself are virtually harmless. It's just too insoluble to get into trouble. They also found much quicker excretion than they expected, which was good news, too (as I mentioned on December 4, below.) The follow-up study is going to look at the early pharmacokinetics of thimerosal, to see if there's some sort of maximum-concentration spike that's being missed.

As has been pointed out, if thimerosal is a cause of autism (I'll reiterate that I doubt it,) then it only happens in a few children. So the criticism can always be made that a small study would likely miss testing the sort of child that might be affected. This is true, but if the levels are low, with little variation in the individuals studied, then you have to assume that there's a subpopulation that is quite different. If you have to string together enough assumptions, then you start to rule out the hypothesis - that's as close to proving a negative as you can get in science. We'll see what the numbers have to say.

Thimerosal - A Chemical Point
I haven't posted on this issue recently (although I'm working on a column for TechCentral Station,) but Dr. Manhattan has been writing some good pieces on it (check the comments sections for more.)

There's one thing I'd like to add, as an organic chemist. A persistant statement that I see about thimerosal is that it's "49% ethylmercury by weight." This makes it sound like it's a mixture of components, one of which is ethyl mercury, which really isn't the case. Thimerosal is a single compound, a mercury with an ethyl group and a thiosalicylate (the mercury is in the +2 oxidation state.) When sulfur is bonded to mercury, its reactive characteristics change quite a bit. A dose of thimerosal would not be expected to be the same as a dose of ethyl (more correctly, diethyl) mercury. And it isn't.

Friday, December 20, 2002
Trials of Trials
As I mentioned yesterday, I think the kind of study that compared diuretics with other hypertension medicines was a very good thing. So why don't we see more of these?

There are several reasons. It's worth thinking about the different levels of testing, and what questions they're designed to answer. At the first level, you have questions about specific drugs - is Drug A safe to take, compared with taking nothing? Does Drug A work, compared with taking a placebo? These are the usual subjects of Phase I and II clinical trials.

There's a third question, namely, how good is drug A versus other drugs that work the same way? That one doesn't get answered as often as it should, because the FDA generally only requires testing against placebo. A debate has been going on about when it's appropriate to run head-to-head trials rather than placebo-controlled, and it happens more often than it used to. Drug companies aren't always eager to try this, because they sometimes fear that the advantages of their new compound may turn out to be more subtle than they'd like. But if they think they've got a clear edge, then a trial like this is just the thing. I think we're going to be seeing more and more FDA requests for these sorts of trials, which will definitely make life harder for drug development, but in a good cause.

Beyond specific drug questions, you get to mechanism issues: Does therapy A work better than therapy B? That's what the diuretic study was designed to answer, and it's the rarest kind of all. It's a situation, though, like the old proverb that says when you strike at a king, you have to kill him. If you run one of these trials and your advantage isn't there, you're probably sunk - and if a safety liability shows up versus the existing therapy, you're completely sunk. This is what happened to Bristol-Meyers Squibb when they run Vanlev (omepatrilat) against Vasotec (enalapril) for hypertension. Vanlev's never going to see the light of day, and neither is any other ACE/neutral endopeptidase inhibitor combination.

As one of the interviewees in Wall Street Journal noted:

Duke's Dr. Catliff says it isn't reasonable to expect the pharmaceutical industry to onduct head to head studies needed to answer questions of both science and money. "It's sort of an all or nothing game," he says. There is a potential gain for the winner, but a huge risk for a loswer. Some results could essentialy kill the market for a drug. "The industry can't afford to take that kind of risk."

Well, whether it's reasonable or not, he's right that companies aren't going to line up to do this sort of study. The business is risky enough already, thanks. No one company is going to try it unless they're forced to (like BMS.) That goes double when you're comparing existing therapies, things that are already on the market. But that doesn't mean that I don't think this kind of study should be done - on the contrary. I think that the NIH's model for the ALLHAT hypertension study could be the way to go - let people run the study who won't be cutting their own throats by running it. It'll be interesting to see if they get a general mandate (and funding) to do just that.

Wednesday, December 18, 2002
Hypertension and Marketing
There were plenty of stories in the press today about the ALLHAT study, which showed that diuretics are still the most effective way to treat hypertension in most people. Let me say right off that I really like this kind of study, and I think that there should be more of them (more on this tomorrow - the Wall Street Journal did the best job covering this angle today.) And I don't disagree with these findings, either - the study seems, as much as I've seen of it, to have been done very well and I think the data speak pretty clearly.

Most of the press coverage has been heavy on the "if not for drug company greed" angle. The New York Times gave this aspect its own story and headline. The critics have a point: pharma companies have aggressively marketed the newer mechanisms as they've come along, both by saying the new ones are good and that the old ones aren't.

But if there's any business that works differently, then I'd like the Times to tell me what it is. Some of the coverage makes it sound like Big Pharma is one large company, and Big Pharma abandoned diuretics in order to blow the horn for its more expensive drugs. But these were individual companies, and the first companies with, say, ACE inhibitors (like Merck) naturally came into the market talking about how great their new drug with the new mechanism of action was. This wasn't Big Pharma talking, this was Merck trying to gain advantage over its competition. Nobody sent around an industry memo saying Drop Diuretics, Push ACE Inhibitors.

And as the ACE inhibitors became wildly successful, other companies got into the field, or decided that they needed to come up with new mechanisms of their own. That's part of the free market, too - we in the pharmaceutical business get forced to come up with new stuff, because the me-too business can only go on so long. (In the case of the ACE inhibitors, it went on longer than usual, because the first generation of them had a dry cough side effect that made people stop taking them.)

You don't hear about many of those other hypertension projects, because they didn't live up to their potential: endothelin converting enzyme, anyone? Renin inhibitors? There were quotes today about all the excess money spent by patients over the years (by not taking diuretics.) The various drug companies who chased these (and other) mechanisms during the 1980s and 1990s would like to have some of that money back, too.

So, once we got them to work, did the drug companies push the newer hypertension medications? Well, yeah, like crazy. That's what we do. But what we do includes the "new" part as well as the "push" part of that sentence. (The "crazy" part is another subject!)

A couple of other points: the main Times story waits until paragraph 26 to mention that there were other factors other than the Greed of Big Pharma for the move away from diuretics:

A factor in the switch from use of diuretics to newer drugs was a Swedish study reported in The New England Journal of Medicine in 1989. It found that diuretics could cause biochemical changes that were thought to increase susceptibility to heart attacks.

The other thing I'd like to mention is that some of the figures given for market share of diuretics make them seem more ignored than they are. The Wall Street Journal ran a pie chart, but it's done by dollar sales. Because the diuretics are cheaper, they don't make nearly as much impact in that sort of presentation. The Times ran a better graphic showing total number of prescriptions, and there's some interesting stuff there:

While it's true that diuretics only have about 27% of the total number of prescriptions for hypertension, they outdid ACE inhibitors every year until 2001. And they've beaten calcium-channel blockers (another big part of the ALLHAT study) every year, because those drugs, heavily marketed though they are, have only grown 3% in prescription volume since 1997. ACE inhibitor scrips have been up 39% in that period - and diuretics, with virtually no advertising, have been up 29%. Maybe Big Pharma isn't getting as much bang-for-the-buck as it could with all those marketing campaigns (and maybe physicians are doing a better job exercising their judgment than today's coverage gives them credit for.)

(Post edited next morning for clarity, emphasis, and to correct late-night typos.)

Tuesday, December 17, 2002
Looking Back (Looking Forward)
I've been Christmas shopping for my two kids (ages 4 and 2 1/2) and have seen plenty of things that they'll be getting when they're older. Like chemistry sets - although the ones they sell now (standard chemist's complaint coming) are wimpy and underpowered.

But there are ways of fixing that. When I was around 9 years old, I was given a chemistry set augmented through the efforts of my father, who rounded up some more interesting chemicals then the ones provided. For example, there was a 100 gram cardboard container of copper (II) sulfate, whose deep blue crystals I was immediately taken with. (I haven't had to use that compound in several years now, but every time I see it in the lab I recognize an old friend, unchanged.)

There was some sodium potassium tartrate, which meant, years later, that I was probably the only first-year chemistry student at my college who knew what "Rochelle salt" was. I still use that one once in a while, too, to complex out aluminum from a reduction - since it doesn't have a distinctive color, though, I have to remind myself every so often that I'm using a compound that I've known since I was ten. Dishing out its rod-shaped crystals is more of a reminder than the solution can be.

Rochelle salt is pretty innocuous. But my father had bought some potassium permanganate, which is a rather high oxidation state for a kid to have on his shelf. You can get in some actual trouble with permanganate, since it would just as soon slide down to the mud of manganese dioxide and ditch plenty of energy along the way. I was always amazed by its color, the very definition of purple as it dissolved in water. (If you left the solutions standing around, though, they would find a way to turn back into muck.) As I experimented with it, I came across several mixtures that gave it room to run, sometimes violently, with plenty of heat and fizz.

Some of those involved elemental sulfur, so I'm sure I got some whiffs of sulfur dioxide and other odd gases along the way. I used plenty of that stuff in a research project at my former company, but its smell induced no Proustian recollections - getting a good dose of it was more like standing in a steaming extraterrestrial swamp. What takes me back immediately, though, is powdered sulfur itself. Every time I come across it, I think "Now that smells like a chemistry lab!"

I didn't have any of the things that I use more often now - no hexane, no ethyl acetate or any of the other dozen solvents under my fume hood. The only organic solvent I had was some carbon tetrachloride, for a butterfly kill jar, and I never used it with the rest of the chemicals, since I knew that the salts wouldn't dissolve in it. Certainly I had no air-sensitive reagents, and probably a good thing, too. (I was impressed to read in Oliver Sacks's Uncle Tungsten that he had actually prepared things like phosphine as a boy - that's something I'd think twice about handling even now.)

Actually, my ten-year-old self would have been a bit puzzled by a career choice in organic chemistry, as opposed to inorganic (although the news that I was a working scientist would have gone over well.) I had my father's college copy of the CRC Handbook, from back in the days when it really was a handbook, and I used to skip over the organic chemical tables and the half-breed organometallics. Those sections of the book had to wait a few years to become intelligible to me (like the tables of integrals - what an odd feeling it was to leaf through those after taking calculus and suddenly finding myself able to read them.)

That handbook is up on a shelf in this room as I write, over my left shoulder. And my two children are asleep down the hall. A few years from now, we'll all sit down together.

Two of the blogs over on the left-hand margin have combined recently, so they're now listed under their new title of "Asymmetric Information." Highly recommended!

The Bookshelf's been changed a bit over there, too. By the way, I'd like express some gratitude to whoever bought those two snow throwers through my Amazon link (and no, I'm not making that up!) Lagniappe: your source for science commentary and clean driveways.

Monday, December 16, 2002
Now that I've had a chance to look over the Wall Street Journal's article on Bristol-Meyers Squibb, it occurs to me that I've seen this behavior many times. I don't mean the financial voodoo (although I've seen that at second hand, just like anyone else who pays attention to the markets.) What I mean is the attitude that leads to it.

BMS got into this trouble because they promised 12% sales growth, right into the headwind of patent expirations on things like Glucophage and Taxol. The failure of Vanlev took them by surprise, just like it took everyone else, but it's not like they didn't know that those patent expirations were coming. Promising that kind of growth was arrogant and completely unrealistic, and that's the attitude I'm talking about.

Now, there are plenty of arrogant scientists in this world. But we're all supposed to look at the data and be willing to listen to what it says, even if we don't like it. You really can't make it in science unless you're willing to do that, and it keeps you from getting as full of yourself as you might otherwise get. Some of your ideas are just not going to work, because the universe isn't set up to let them work.

But there's a worldview common to athletic coaches, motivational speakers, and CEOs, and it says that failure is not an option. If you do fail, then you obviously didn't have the killer instinct, the grit, the tenacity, the fire in the belly. You just didn't want it enough. Sound familiar? This outlook can work when you're dealing with things that can be browbeaten (like other people.) It might work on scientists, but a lot of good that'll do, because it won't work on their science.

Now, it's true that your researchers need to be motivated, and need to keep pushing to accomplish things. That's why, in spite of all its inefficient craziness, I think that having dozens of drug companies fighting it out is a good thing, because it keeps us all on our toes. And you need tenacity to do good research, because most good ideas only get around to working after about the eighteenth try. These things are necessary - my point is that they're not sufficient.

And that's where this hard-charging attitude breaks down. It's all very well to yell at the sales force - it might even stir them up, until they all go find other jobs, since they're people dealing with other people. But are you really going to do that with the researchers and patent lawyers, with the clinical teams and the bioinformatics people? I've sat through meetings where people tried, and if eye-rolling made a noise, you wouldn't have been able to hear yourself think.

No amount of table-pounding will make a clinical trial turn out the way you want it to. No talk is tough enough to convince a protein assay to tell you that your compounds are active. You can rant at the rats all you want, but they'll continue to do whatever pleases them, and it's up to you to figure out what it all means. The physical universe cannot be sweet-talked, conned, or intimidated. It is what it is, and it does what it does.

Well, Blogger ate the post that I was working on last night, and did the same to all my subsequent attempts to say that there wouldn't be new Lagniappe content today. I have a fairly narrow blogging window in the evenings, and working without a net deprived me of it.

In the works are more comments about the Bristol-Meyers Squibb number-fiddling, and (I hope) the beginning of a response to the New Republic article on drug research. Rather unfair of them to print that one while I'm otherwise occupied, I thought - or then again, perhaps that's part of their subtle plan. . .

At any rate, apologies to the readership today. I'll try to make it up during the rest of the week!

Thursday, December 12, 2002
VX?There are reports that Iraq has passed on what may be the nerve agent VX to a Lebanese group, as I'm sure everyone knows. It's a pretty nebulous story, and it's not at all clear that a nerve agent is even involved.

What would be more revealing would be the reverse story: if any group shows up with VX, then they would probably have ties to a government-scale research effort somewhere. As I mentioned in my chemical warfare series back in September, VX is probably the most effective nerve gas, and it's also one of the hardest to make. (Tabun is the nerve-agent starter compound.)

None of the cholinesterase inhibitors are do-it-yourself projects, though (and that's a good thing.) But anyone who shows up with VX has been involved with someone who's put real time and money into the business. . .

A Rough Business
The front page of today's Wall St. Journal featured a long story on just exactly how Bristol-Meyers Squibb cooked their books to make sales and earnings appear better. They're in the middle of restating a couple of years worth of financial results, so the article was timely. I haven't been able to see all of it yet (told you I was busy!) but what I've seen makes interesting - and disturbing - reading.

BMS had promised the Street 12% sales growth a year for five years - in the face of some patent expirations - and this unkeepable promise led them to try whatever they could think of to make the numbers. And it seems to have been made clear to managers that you made your numbers or they found someone who could. . .so they made them. By hand, from whatever materials came their way. . .

Wednesday, December 11, 2002
A Quick One While He's Away
This is one of those nights I warned about, when there's not much time for blogifying. My book chapter is headed out via overnight delivery tomorrow, full of corrections. That's not as bad as it sounds - they're things like a missed patronymic initial on a Soviet-era reference's co-author's name. A few are larger than that, but not too much larger. Considering some of the galley-proof horror stories I've heard, I consider myself quite fortunate.

And this is another one of those times I'd like to be able to talk about my work without being fired, because there's a lot of interesting stuff happening on that front, too. Oh, well, you'll have to wait to read the J. Med. Chem. paper. Who am I kidding - you'll probably read it in "Acta Retracta", if at all (you can tell if someone's a scientific literature geek by whether or not they laugh at that line, in much the same way that no synthetic organic chemist can avoid cracking a smile at the phrase "plutonium enolate.")

Or you can, if you're a real masochist, read the patent when it comes out. Speaking of which, I just downloaded a key patent the other day, with a lot of bearing on my current work, which turns out to an unrelieved torrent of hundreds of pages of Japanese. I truly hate it when that happens, because a patent that huge is bad enough in English. I can actually plow through katakana, which a lot of chemical names and concepts are rendered in, but there's no remedy for this beast, other than really being able to read Japanese. Fortunately, a couple of my co-workers do, being Japanese themselves. Unfortunately, they tend to shut their doors when they hear me coming.

Tuesday, December 10, 2002
Don't Wait - Patent Today!
GlaxoSmithKline won an interesting patent fight in Canada the other day. This has been going for quite a while, as you'll be able to tell when I mention that involves AZT. Canadian generic companies Aponex and Novopharm had been trying to show that Glaxo's patent was invalid - and Glaxo had been trying to recover the money that they claimed they didn't make because of low-priced competition from those two.

The two generic companies argued that Glaxo's patent shouldn't have been issued for human treatment of AIDS, because at the time the compound had been tested only in mice. I'm relieved to say that this argument was rejected. Unless you've read the patent literature, you have no idea how many patents claim human therapy on the basis of even less data than that.

The generic companies claimed that Glaxo "had no way of reasonably foreseeing at that stage that its drug would ultimately work for humans." Well, fine - but who has such a way? I mean, what other sorts of data would you have by the time you file for a patent? There's always a timing decision to make on when you file, but I've never heard of anyone hesitating when they have proof of principle in an animal model. Would you wait until the compound had already gone into man? That takes years, of course, and you'd be working without a net the whole time - just one publication or patent filing and your work would be pulled out from under you. I think not.

At the same time, the judge in the case held that claims had to be in accord with the knowledge available at the time the patent was written. You can't just write all sorts of speculation in and hope to hit on a lucky chance. The fighting will come when two sides disagree over whether something was a reasonably sure extrapolation or sheer guesswork.

As an aside, Glaxo and Novopharm are no strangers in court - they fought a protracted battle (through most of the 1990s) over some Xantac (ranitidine) patents, which I'll post about some time. It's a very interesting one, and is a key case to study regarding the issue of disclosing the best mode of an invention (versus keeping it as a trade secret.) Actually, generic drug makers aren't strangers to anyone in court; they basically live there.

Monday, December 09, 2002
Sweet, Maybe, But Trouble Too
As I mentioned in that last post, I did carbohydrate-based chemistry back in grad school. (I still break out the sugars once in a while, but there aren't as many opportunities in medicinal chemistry.) Back then, I was on a project that was using them as starting materials to try to synthesize a large antibiotic molecule from scratch. The idea's fairly sound - the antibiotic has a lot of chiral carbons in it, and sugars are a rich source of strings of chiral carbons.

But there were complications. There's no carbohydrate with just the sort of backbone you'd need (if there had been, the synthesis would have been pretty trivial.) So the project involved taking some of the available ones and tweaking them around - remove a hydroxy group here, flip one over down there, change this to a branching carbon over around this way. The synthetic steps really start to add up after a while, I can testify. A lot of the difficulties came from starting out with such highly functionalized molecules. You had to first protect all those hydroxy groups, and do it in such a way that you could take each protecting group off at just the time you needed it. Pretty soon, you run out of possible protecting groups!

I pulled the plug on the whole thing at about 27 linear steps, and it wasn't finished then. It really seemed to me that we had reached the point of diminishing returns, which opinion of mine time has completely confirmed. It would have taken me another year, at the rate things were going, and that would have been a really bad trade. Even as it was, I was spending most of my time making starting material (as my readers in the organic synthesis field can readily imagine.) And no matter how large a flask (flask? how large a bucket) I started the chemistry off in, I always seemed to get to the frontier of the synthesis with about 20 milligrams. I felt like the guys painting the bridge - as soon as I finished, it was time to start again.

Some time I'll tell the story about what my PhD advisor did when I shared the news with him that I wasn't going to finish the molecule. He wasn't taken with the idea.

I'll bet that this is the only hit for a Google search for that word! I typed it out as I was thinking about how some major classes of biomolecules - protein, carbohydrate, lipid, and nucleic acid - are perceived. If you look at the number of papers published, and the number of details worked out in their field, you'd think that proteins are the single most important constituent of a living cell, followed by DNA / RNA. Are they?

I think this is partly an artifact of how easy things are to work with. There are only five purine / pyrimidine bases used in all DNA and RNA, and only two sugars (ribose or deoxyribose.) That level of simplicity is what's allowed sequencing techniques to become so automated so quickly. I'm not saying that there isn't plenty of complexity in the area - you get all sorts of hard-to-sequence hairpins and the like - but having only a few building blocks has helped enormously.

Proteins are the next step up. There are twenty-odd amino acids that you have to worry about, which gets pretty combinatorially complicated. (If you wanted to make, say 100 milligrams for your compound files of every 20-amino-acid protein combination there is, you'd run into a severe problem having to do with the amount of available carbon on earth.) Direct protein sequencing can be done, but it's nowhere near as easy as it is for DNA. Proteins have the advantage of being much easier to handle than nucleic acids, though, and many of them are robust enough to stand all kinds of mistreatment. That helped biochemists get a good start on enzymes before any other aspect of molecular biology got on its feet at all.

So, how about lipids? Here's where things start to get ugly. There are a *lot* more than 20 or 30 kinds of lipid molecules in a living system - all sorts of chain lengths, unsaturations, cis/trans isomers, mono-di-and-triglycerides and so on.(I won't even get into phosphorylation, since that's a big variable in the protein world, too.) And what about steroids, prostaglandins, and all the other lipid-derived stuff? All of these things are a real a pain to work with, too, since they're often found transiently or at very small concentration and their solubility is almost always awful by definition. It takes some really good techniques to separate the various lipid constituents out of the greasy mess.

And carbohydrates? I worked a lot with smaller ones in my graduate school days, and people still look at me funny for it. Sugars are as bad as they come for complexity - there are plenty of them, and they can be connected any number of ways to make macromolecules. By contrast, proteins are basically linear front-to-back chains (curled up, twisted, fractal-dimension space-filling chains, but chains nonetheless.) Complex carbohydates branch out all over the place, and they'll really make your life miserable. Despite years of work, there's not a general way (yet) to automatically sequence one, although the situation is getting better. But if we had to depend on carbohydrate sequencing to read the genetic code, we'd be up the creek for sure. Their physical properties can be quite squirreley, too, making them very little fun to purify.

So there are at least two important classes of biomolecules that probably don't get their due, because they're a lot more hostile to work with. And that should tell you how well we can handle the mixes between them - glycosylated proteins, nucleic-acid protein complexes, lipid conjugates. Pretty poorly, is how. It's a mess out there.

Sunday, December 08, 2002
A Bit Light on the Content
Blogging will be reduced this coming week. Several things at work and home are taking up time. First thing tomorrow, for example, I've got to seriously finish off a big proofreading job on a book chapter I've written - nothing too exciting, unless you need to know something about oxazoles (and in my chapter's case, their spectroscopic properties.) If you do, then this chapter (and the book it'll be part of) will make your day. Unfortunately, if you first need to know what an oxazole is, my chapter is going to be a pretty poor place to find out.

Friday, December 06, 2002
Small Changes
I'm slowly modifying the blogroll over on the left-hand side, which I hope to do a bit more frequently. The new sites may already be familiar to many readers, but they're certainly worth visiting.

And I'm continuing to add to and rearrange the Lagniappe Bookshelf over there, too. I'm trying to keep the graphics down to a reasonable number, so I'm shifting some of the book recommendations to text-only links. More to come in that department, too! By the way I'm grateful for (and a bit surprised at) the number of books that you folks have ordered. Gizmodo I'm not, but it's welcome nonetheless.

Thursday, December 05, 2002
A Quick Tour Through the Mudhole
Before leaving this subject (for now,) I thought I'd take a look at some of the sites I mentioned that pop up when you do a Google search for thimerosal. I hope you all will pardon me for not directly linking these people. I'm not particularly interested in sending them any traffic.

From a law firm:
Recently evidence has surfaced linking Asperger's Disorder and other pervasive developmental disorders associated with Autism to mercury poisoning in infants as a result of childhood vaccines containing thimerosal. Thimerosal is preservative that pharmaceutical companies added to vaccines in order to mass package them, which is far less expensive then individually packaging each vaccine dose. Unfortunately this attempt to save money appears to have endangered thousands children in the United States.

And from another, under the heading "Have You Been Injured by a Thimerosal Vaccine?":
Symptoms of mercury toxicity in young children are extremely similar to those of autism. This can explain the recent increase in the numbers of children diagnosed with autism since the early 1990's. The numerous amount of children diagnosed with autism seems to directly correlate with the recommendation of both the hepatitis B and HIB vaccine to infants in the early 1990s.

Here's a whole group of legal firms, with a corresponding rise in the amount of misinformation:
The high mercury content of Thimerasal (sic) poses a serious health risk for children. In the first few months of a baby's life, an infant may have already received up to 15 vaccinations. The levels of toxic mercury in these vaccinations can cause lasting and serious developmental and neurological problems in these children. The Centers for Disease Control and Prevention has linked mercury-containing vaccines and developmental disorders.

And one more, just to get the flavor of the business:
A full generation of children in America was exposed to dangerous doses of highly toxic ethyl mercury from 1990 through 2000. Children were injected with the toxic mercury that was a major ingredient in a chemical product called thimerosal. . .With each dose of vaccine that contained thimerosal, a child would also get an injection of toxic mercury. Each one of those mercury injections exposed the child to levels of toxic mercury in excess of the federal government's own safety guidelines. Mercury is widely known to cause neurological damage, often permanent. Current clinical and epidemiological research suggests that the mercury-laden thimerosal so widely given to children by the drug companies in the 1990's might cause a range of neurological and neurodevelopmental injuries, including autism. Compounding this public health disaster is that the toxic exposure was entirely avoidable. . .Thimerosal had nothing to do with vaccine safety, and everything to do with the profits and convenience of packaging for the pharmaceutical companies.

All right, enough. I hardly need to say that I find the above excerpts to be full of misinterpretations, half-truths, distortions, and out-and-out falsehoods, and that's just the beginning of what's out there. You'd think the drug industry was full of Mengeles, high-fiving each other when another child gets sick and another nickel drops into the hopper.

I hope that I've been able to show (or at least point people to) some of the complexities of the whole thimerosal question (that Institute of Medicine report I've linked to will really give you the authentic scientific experience, I can tell you.) But tort lawyers have no need of complexity. All they need are desperate clients and a deep-pocketed defendant or two. . .

More on Autism (and Mercury)
After reading my post below, I thought I should clarify a couple of things. I realize that some who believe in a thimerosal-autism link probably don't argue for a specific brain lesion effect (which spent yesterday's post argues against.) Rather, the general effects of organomercury toxicity could be the cause. I don't think that this argument holds up - see this section of the Institute of Medicine report on thimerosal. Mercury causes a wide variety of neurological symptoms, and it generally causes them all at once.

Autism is probably too specific a condition to ascribe to a general organomercury effect. But, as I argued yesterday, it's still too general a condition to ascribe to some specific MPTP-like thimerosal toxicity. That doesn't close out the possible explanations; there's still room in there. But it does set bounds on them, and the size of the space that's left - coupled with the Rochester data that I mentioned previously - make it increasingly likely that this isn't the answer.

Wednesday, December 04, 2002
One reason that I have doubts about thimerosal as a cause of autism goes back to mechanism of action. Are there any specific compounds that are know to cause specific neurological problems? (There are plenty that cause more diffuse symptoms, often motor-related, such as tardive dyskinesia.)

Well, there's one prominent example: MPTP, known to the trade as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. It's a reasonably simple organic molecule, and to a medicinal chemist it certainly looks like a central nervous system agent (if I had a dollar for every CNS-active piperidine or piperazine that's been reported in the patent literature, I could retire.) But no one could have predicted what it actually does.

The compound gets oxidized by monoamine oxidase B, which is a common fate for molecules of its type. That produces a pyridinium compound which is the real problem. As fate would have it, it's a fine substrate for the dopamine transporter protein, which imports dopamine into cells that require it. And in a further stroke of bad luck, the same compound is also an inhibitor of a key enzyme in mitochondria - and you don't want to do anything to your mitochondria. Cell death follows in short order if you shut them down too hard.

So everything's set up for a disastrous cascade: MPTP's turned into something dangerous, which is taken up selectively into cells that import a lot of dopamine, which process then kills them. Unfortunately, the cells that import the most dopamine are those in the substantia nigra, up in the forebrain. Which is why in the late 1970s and early 1980s, a number of young drug users started showing up in emergency rooms on the west coast with what appeared to be some sort of catatonia. They didn't move; they weren't responsive - everyone waited for whatever it was to wear off so they could start to recover.

It didn't, and they didn't. At first, no one recognized what was going on, mainly because no one had ever seen a twenty-year-old with advanced Parkinson's disease before. These patients had taken batches of some sort of home-brewed meperidine (better known as Demerol) or a derivative, and the synthetic route had produced some MPTP as a contaminant. Quality control isn't a big feature of the basement drug industry.

The affected users improved slightly when given L-Dopa, as you'd expect from a Parkinson's patient. But not much, and not for long. The damage is permanent - they skipped years of the normally slow progression of the disease and went straight to its worst phase in one night. Is this what's happening with thimerosal and autism?

I strongly doubt it. Here's why: Parkinson's is caused by a lesion in a specific area of the brain, in a specific (and unusual) cell type. MPTP is toxic to some specific and unusual cell types, and it's just a terrible stroke of misfortune that they happen to overlap. But despite a tremendous search, no one has been able to tie autism to primary lesions in a specific region of the brain, much less down to certain cells. I'm not saying that it's impossible - just that it's been looked for strenuously, and thus far in vain. Studies of brain activity in autistic patients show a variety of differences, but nothing that can be pinned down as a cause.

The other half of the story is the reactivity of thimerosal itself. There's nothing known about the compound that would suggest that it has a particular affinity (or particular toxicity) to any one type of cell over another. Organomercury compounds are (in high doses) pretty bad news in general, causing all sorts of neurological problems. They just don't seem to be specifically toxic.

So there's no evidence, mechanistically, on either side of the hypothesis. That doesn't disprove it, of course - it's not impossible that there would be some sort of subtle effect that we've missed so far. It's just that I believe that the odds are very much against it. We'd have to string together too many (big) assumptions in a row, and the evidence isn't nearly compelling enough to make us do that.

If thimerosal is cleared as a possible agent for autism, that'll be good news and bad news. The good news is, of course, that we haven't been damaging children without realizing what we're doing. The bad news will be that we still won't know why some children become autistic and others don't, a lack of knowledge that's hard to bear.

The only other good news I can think of - and a hard, sour piece of good news it is - would be that parents of autistic children who have feared that they were the cause of their children's condition - just by having them vaccinated - could at least put that part of their burden down. It's not enough, but it's something. Believe me, I have two small kids myself, and the thought of either of them showing signs of neurological trouble makes me start to double over. I can't even imagine what it must be like. But to those in that situation, all I can say is that I really don't think that some doctor did it to your child. Or that some drug company did it to your child. Or that you did, either. For what it's worth.

Tuesday, December 03, 2002
Doing Justice to Thimerosal, And To The Story
Like Charles Murtaugh, I've been trying to get around to writing something about the thimerosal issue for some time. There are so many angles to the story that it's hard to know where to begin. They are, in no particular order:

Is thimerosal safe?
Was it safe when kids didn't get so many vaccines, but became less so as the exposures multiplied?
If it isn't safe, what does it do?
Is it a cause of what some people call an autism epidemic?
Is there a rise in autism, or just a rise in its diagnosis?
If there was harm done, who bears the blame for it?
Who put the paragraphs into the homeland security bill that seem to let Eli Lilly off the hook for thimerosal lawsuits?
When and how should vaccine makers be insulated from legal action, anyway?

And that's just off the top of my head. But I wanted to point out that some new data may be helping to clear things up, at least those first couple of points. Last year, the Institute of Medicine issued a lengthy report that basically said that there was no evidence that thimerosal, even when given in multiple vaccine doses, was harmful. But there was no evidence that it couldn't cause harm, either, and organomercury compounds are known to be trouble, in principle. Thus the recommendation that it be phased out, under the better-safe-than-sorry principle.

The University of Rochester studied 61 children who had received thimerosal-containing vaccines. Blood levels of mercury were lower than expected, well under the toughest EPA standards. And the mercury was found to be cleared much more quickly from the children's system than had been expected (a week versus the predicted 45 days.) This goes a way toward clearing things up, because it makes it less likely that there's an accumulation of mercury with multiple vaccinations. A key part of the anti-thimerosal case has been that exposure to it was allowed to creep up over the years - the hypothetical autism epidemic is much more recent than the use of thimerosal per se.

Anti-thimerosal groups point out that we still don't know what the peak levels of mercury are in the blood after dosing, which is true (although there are studies in the works to check that.) But the entire story, to my medicinal chemist's eye, is based on the med-chem properties of clearance and area-under-the-curve (AUC,) rather than Cmax (peak concentration.) And that is addressed well by the Rochester work. I look forward to seeing more data, but I think that the odds are heavy that thimerosal isn't doing harm. (I'll reserve judgment on whether some people are possibly much more sensitive to it than others - not impossible, but not proven.)

And I'll close by mentioning a not-unrelated fact: when you search "thimerosal" on Google, the first ad that appears on the right-hand side of the screen is for "Thimerosal attorneys." I'm not saying that inserting the stuff into the Homeland Security bill was a good idea, because it wasn't. It makes everyone look guilty, like there's something to hide. And I really don't think there is. The industry has enough problems without bringing more down on its head.

Monday, December 02, 2002
Europe, Again
Stephen den Beste has a good article about European innovation in science and technology. Well, actually, it's about the lack of it, as a symptom of the increasing differences between the US and Western Europe in general.

Along the way, he mentions the bright spots in what he calls a "high-tech disaster area," among them the Swiss pharmaceutical industry. That's on target, although Roche, for one, hasn't had any big news in a while. (They have had the nerve to commercialize T-20 as an HIV therapy, which may end up being a little too innovative - see "Better Them Than Me" on August 8.) And I've had a quote posted over my desk from Andrea Vasella, chairman of Novartis, for several years now. In an interview, he said "If you don't want to spend the big money and take the big risks, you shouldn't be in the pharmaceutical business," which is unimprovably correct.)

But note that Roche's drug is being produced in Colorado, not Basel. And note that Novartis is expanding their drug discovery research in a huge new facility, but not in Basel. It's in the former Necco wafer factory in Cambridge, MA.

Why are they doing that? Unfortunately for Europe, the reason is of a piece with the rest of den Beste's article, and the one he refers to. It's unavoidable: America is home to most of the innovative drug discovery research in the world today. Foreign companies, almost without exception, really can't be considered major forces without a US research presence. For example, the only European country that can be considered a pharmaceutical rival to Switzerland is Britain, and its companies - GlaxoSmithKline and the half-Swedish AstraZeneca - have huge US research operations. Germany and France aren't quite in the same league, but their biggest companies (Bayer, Aventis) do plenty of work here, too.

People who want to do this kind of research at the highest level have a good chance of either ending up here, or seriously considering it. It's not the Europe doesn't have plenty of smart and capable people (a point den Beste also makes.) It's just that there are plenty of Europe's top people over here, compared to how many of America's best are over there.

Why does research seem to thrive more in the US? You can talk about the money that's spent here, but some of that money has put into research because of its historical payoff, leaving you with the same question to answer. I think that there are common American attitudes which turn out to be crucial for successful scientific research: a tolerance for risk-taking, a willingness to try out ideas that might sound unworkable, and a persistence in trying to find solutions, one way or another. And there's another important attitude that isn't often given its due. Andrew Sullivan refers to it in his Thanksgiving essay when he relates a story that British journalist Henry Fairlie used to tell:

He was walking down a suburban street one afternoon in a suit and tie, passing familiar rows of detached middle-American dwellings and lush, green Washington lawns. In the distance a small boy - aged perhaps six or seven - was riding his bicycle towards him.

And in a few minutes, as their paths crossed on the pavement, the small boy looked up at Henry and said, with no hesitation or particular affectation: "Hi." As Henry told it, he was so taken aback by this unexpected outburst of familiarity that he found it hard to say anything particularly coherent in return. And by the time he did, the boy was already trundling past him into the distance.

In that exchange, Henry used to reminisce, so much of America was summed up. That distinctive form of American manners, for one thing: a strong blend of careful politeness and easy informality. But beneath that, something far more impressive. It never occurred to that little American boy that he should be silent, or know his place, or defer to his elder. . .

That's it, right there: we don't know our place, and it's a good thing. Fairlie was right to pick up on this, and to celebrate it. It's important in manners, in politics, and in science as well. No groundbreaking work was ever done by anyone who knew their place in the world and was completely content with it. You have to feel that there's something missing from your knowledge, something that needs to be figured out. And no major scientific advances have come from people who deferred at all times to their elders, either. Such advances necessarily involve things that said elders never thought of (at best,) or things that show up their omissions and mistakes (at worst.)

I've talked about this with colleagues from France, Germany, Italy and other countries. Even among people who disagree with me on many other social and political points, the American primacy in science has been unquestioned, as has its connection with our culture. We're an odd bunch, and it's to our benefit.

I did my post-doctoral work in Germany, myself, so I can end this with a little personal history. At one point there, I was doing some photochemistry. My fellow chemists know that there are quite a few degrees you can go to with those reactions. Running them in (expensive) quartz glassware next to your ultraviolet lamp is one extreme, since quartz lets it all through and spares not. And from there you go down through various filters, progressively cutting out the hard short wavelengths until you get to the mildest light that'll still do what you want.

I tried my chemistry first in plain quartz, and cooked my poor reaction to a rich brown in no time. I needed an intermediate-cutoff filter, but there were none to be had (and we weren't about to spend the money on one, either, a situation common to academic labs the world over.) I found some old literature, though, that suggested some silver salt solutions that would do the job - not great, but a lot better than nothing. Silver salts, we had. The best way to use them was to have them in the chilled water that circulates in the jacket past the blazing hot UV lamp.

But we had no pump for the job. And when I suggested one to our grad student in charge of ordering supplies, he looked grave and said, yes, perhaps we could do that, but of course it would take several weeks even if we could spend the money, yes. . .I was already out the door, heading to my car, and heading to the shopping district in the center of town. I found a pump just where I thought I might. So I paid for it out of my own pocket, drove right back to the lab, hooked things up and within the hour was merrily photolyzing away.

The system was purring along when the supply guy came by to see what was up. I told him that I had a pump now, no need to order anything, thanks and all that. . .when I noticed him looking at my reaction setup with a puzzled expression. "Where did you find this pump?" he asked. I just pointed to light shield I'd rigged up, a piece of cardboard decorated with drawings of bright tropical fish. "Why, from the pet store," I told him, "where else?"

Sunday, December 01, 2002
An Odd Name, But Worth Knowing
Here's a good summary of an interesting use for a pretty obscure-sounding genetic sequence. Wigglesworthia glossinidia is a bacterium that lives in tsetse flies, and nowhere else. This arrangement strongly suggests that it does something for the fly in return for its unique home. This conclusion was supported by treating the flies with antibiotics - once the bacterium was gone, the flies became infertile.

The (very short) gene sequence is most instructive: it turns out that Wigglesworthia produces at least 10 B-vitamins and other nutrients, which is quite a processing load for an organism with such a small genome. By no coincidence at all, that sort of thing is just what a tsetse fly needs on its restricted diet of blood. (Sounds like the beginning stages of how our cells got their mitochondria, actually.)

This could obviously lead an effective back-door method of attacking the tsetse fly. Expect more and more surprises like this as genetic sequencing gets relentlessly faster and cheaper.

Place Your Bets
Something I mentioned in a post last week got me thinking. . .does anyone want to put some money down on whether the European Union will accept the new strain of rice I was speaking about? After all, it's genetically engineered, no doubt about it - what's more, it has genes that didn't even come from plants at all, but were spliced in from bacteria. Sounds just like the sort of thing that they've been putting their feet down about.

That wouldn't be much of a problem, normally - not a heck of a lot of rice gets grown in Europe (well, Arborio strains in Italy, yeah, but most of the rest of the continent isn't really warm enough.) And its not like the enhanced cold tolerance of the new plants will convince European farmers to start growing it, either, because - genetic fears aside - the EU already produces more food than it knows what to do with.

No, the problem is that other, poorer, countries have been leery of growing genetically modified crops because they trade with the EU. And the Europeans are worried that some of these modified strains might make it, by mistake, into their own countries. You may have read about Zambia (not a country that can really afford to turn down free food) rejecting offers of grain from the US because of fears of European retaliation. A recent effort by Denmark has dragged several other European countries, kicking and screaming, into accepting small amounts of inadvertantly mixed genetically-modified grain, but at a very strict level. Perhaps more African nations will feel safe to feed their starving populations with free food, once everyone in Brussels thinks about the situation a while longer in some really good restaurants. (A cheap shot, I know, but this sort of thing really gets on my nerves.)

So, how about it? Will Europe nervously sidle away from evil Franken-rice - part grain, part bacteria, all terrifying? Or will they have come slightly back to their senses by the time this livesaving innovation is released to the public domain?