Lagniappe (science, business, and culture)

Tuesday, October 01, 2002
There an article in the latest New Republic on innovation in the drug industry. As far as I'm concerned, it draws good conclusions from faulty premises (which, admittedly, is a lot better than drawing bad ones from a good starting point!)

The author, Nicholas Thompson, says that

shares in the pharmaceuticals index, meanwhile, are down 25 percent. And the industry deserves it. For years it has squeezed consumers the world over, endlessly arguing that it needs its huge profits in order to invest in new, lifesaving innovations. But while that might once have been true, lately the industry hasn't been innovating at its past rate--and that's probably the main reason investors have started to back off.

Well, that last part rather goes without saying. But, talk of "deserving it" aside, his reasons why this has happened are a little too glib:

The cliché of the moment is that pharmaceuticalcompanies have picked the low-hanging fruit, developing drugs that interact with the limited number of enzymes and molecules that we already understand and have thoroughly modeled.

Sounds like he's been reading this site. Some things get to be truisms because they're true.

But people have always mourned the loss of the low-hanging fruit--and then smart and innovative folks built taller ladders. The tools and computational abilities available to drug companies today dwarf those that companies employed to develop the blockbusters that fueled the 1990s boom. Scientists now have access to the human genome and a vastly increased understanding of everything from gene expression to organ physiology as well as extraordinarily powerful computing and modeling capabilities. In many ways, discovery should be easier and cheaper now than ever before.

You'd think so, wouldn't you? Problem is, all that knowledge has also bred more complications. Look at gene expression: we can now look at thousands and thousands of genes going up and down when we administer our drug candidates. What percentage of that do we actually understand? You'd be hard pressed to get a knowledgable answer that gets out of the single digits. As for computational ability, the big news the other day was that we finally (after decades of trying) predicted a protein's structure from knowing its amino acid sequence. Another few hundred thousand of those and we'll be in business. Then we can start figuring out how they interact with each other, and then we can start figuring out how to make drugs that do the same. It'll be a great day when we do - but that day isn't here.

And the very successes of the industry over the last 25 years have led to the bar being raised. Some things that were huge blockbusters back then wouldn't stand a chance today - too many side effects, for example. Racemic compounds (Prozac, to pick an example from the article) don't stand much of a regulatory chance today; the FDA wants single enantiomers. (Ironically, the active enantiomer of Prozac actually has a worse window for tox effects - the same compound might not have made it at all today.)

Thompson goes on to decry the amount of money put into marketing, and I can't argue with him much there (tomorrow I'll try to talk about the new government guidelines issued today.) But I think he's fallen into a post hoc, ergo propter hoc fallacy: in many cases, the marketing has been cranked up because the drug pipeline is thin. The money spent on marketing isn't necessarily what thinned it out.

Where he strikes gold is when he starts talking about the patenting of "upstream" products: assays, research tools, biological pathways, and methods of treatment. He goes over some examples familiar to readers of this blog (Ariad!) and correctly points out that this sort of thing is fast becoming a crippling influence. Actually, I think it's been a lesser contributor to the productivity decline so far, but it's set to pile on top of what's already a tough situation. Then we really be up the creek.

His solution? Right on target, to my thinking:

The best thing for the pharmaceutical industry would probably be to maintain its strong protection over downstream products while opening access for upstream products.

Preach it, and speed the day! I've been working on some pieces addressing this issue (guess I won't be selling them to TNR, dang it all.) We haven't heard the last about this issue - at least, not if I have anything to do about it.

Silver Tongues, Golden Hands?
I've been thinking more about Sam Waksal's interesting career (see the September 29 post below, and this link for an online version of the story - thanks to Charles Murtaugh for coming up with it.) What I'm specifically wondering about is the phenomenon of the silver-tongued hot-talking scientist that he represents.

Charles mentions that he's run across a few of these himself (and I'm pretty sure we overlap on a couple of them, research being the world that it is.) There's no doubt that in every scientific field, some people are better at creating a mystique, at getting other people to talk about them and their work. My question is: is there any correlation between the ability to do these things and the ability to do great science?

If you go Cartesian and map out four quadrants, you get these categories:

Fluent Talker and Really Good Scientist (the late Peter Medawar comes to mind here, but there are a number of examples)
Awkward Speaker but Really Good Scientist (even more examples - think about the various Big Cheeses you've heard giving seminars.)
Fluent Talker but Poor Scientist (Waksal and his ilk.)
Awkward Speaker and Poor Scientist (legion, unfortunately.)

I'm willing to hazard that if there's a correlation, that it's a slightly negative one. Scientific prowess and a gift for communication can be orthogonal to each other, because the results can speak for themselves (they don't, always, but if they hit at the right moment, they can.) Meanwhile, if someone does low-quality work, the only way for them to achieve recognition is to be able to talk a good game.

By the way, I'm simplifying here by classing written and spoken fluency as the same thing. They certainly aren't - Vladimir Nabokov, for example, said once that he thought like a genius, he wrote like a distinguished author, and he spoke like a child. (Which is why he never gave extemporaneous interviews!) I'd say that the spoken fluency is more important for making a big splash, the written more important for lasting impact.

That doesn't mean, of course, that you should give the next wonderful scientific speaker you hear a fishy glance of suspicion. Sometimes a person's verbal facility outruns their scientific ability, but they don't necessarily use it for harm. It's the BS artists that we have to watch out for - the ones who can spin out wonderful ideas and stories, and who always make sure to leave themselves a starring role.

Monday, September 30, 2002
Where Credit's Due
My post from September 18th ("As Others See Us") on Alan Murray's Wall St. Journal column drew some interesting mail. I quoted a line of his:

"Almost no politician in America is willing to stand up and utter this simple truth: The nation's pharmaceutical makers have done more to extend and improve the lives of ordinary Americans than any industry in history."

A friend of mine in the medical profession wrote to differ:

"I just could not let this one pass. One of our Med School teachers would say, "Farmers and Plumbers have saved more lives than any doctor." I think he is right. . . Clean water and uncontaminated food are essential elements of public health. Without these two things, most of us would not live long enough to need a pill for ulcers, type II diabetes, high cholesterol or hypertension. By the way, I believe that providing a supply of vaccines is The Industry's biggest contribution to increase in longevity experienced in the US. "

It's hard to argue with that, actually. It's been pointed out that money spent on clean water supplies in Third World countries is probably the most efficient way to save lives there is. Vaccination has to rank pretty high up there, too. I don't think many drug projects can compete with a good public-health cleanup.

And it's true that many drugs are targeted toward diseases of weathier countries, where the basic measures are already in place and life expectancy takes you into the years where things like arthritis, adult-onset diabetes, and hypertension become problems. A major challenge is figuring out incentives for work on tropical diseases like malaria. There's actually been some recent progress in that area (the incentives, as well as the malaria,) which I'll write about soon.

My friend goes on to say:

"If the writer had said, "The nation's pharmaceutical makers have done more to try to extend and improve the lives of ordinary Americans than any industry in history, " then perhaps he would have been more on target." (Emphasis in the original!)

Ouch! Point taken. The past few years, we've spent a lot more money trying than we have succeeding. And that worries me on several levels - one of the higher ones is that it will only exacerbate the problem of making drugs targeted at wealthy populations, A lot of capital has gone down the tubes, and the natural tendency will be try to make that money up somewhere.

Sunday, September 29, 2002
A Rake's Progress
Friday's Wall Street Journal has an extraordinary front-page story on the career of Sam Waksal, late of Imclone. If you haven't heard, it turns out that at every stage in his research career, these pesky. . .questions arose, bred by these nagging. . .doubts that what he was saying about his work was true.

The reporter, Geeta Anand, has obviously done a tremendous job on this one. You can't help but think that the folks at Bristol-Meyers Squibb found it pretty damn interesting. Here's the short history:

1974: post-doc at Stanford with Leonard Herzenberg. Asked to leave after a story about obtaining antibodies from another lab doesn't check out.
1975-1977: National Cancer Institute. Not offered a permanent position because of "disturbing patterns" in his research.
1977-1982: Tufts (Cancer Research Center.) Draws suspicion (results not backed up by actual research, trouble delivering actual data when backed to the wall on it.) Asked to leave.
1982-1985: Mt. Sinai. Asked to leave suddenly under circumstances which are still sealed. Rumors of falsified data.
1985: Founds Imclone.

Quite a trail. The article spends time trying to figure out how someone like this could go on from position to position without anyone ever putting a stop to him. A number of reasons are aired (potential legal action waiting if you trash someone in a recommendation, e.g.) - but there's another factor that I don't think is mentioned. That is, the desire to get someone the heck out of your lab.

And the best way to do that is provide them with a recommendation that'll get them employed somewhere else, where they can be somebody else's problem. I've seen this in action several times myself - grad students who went off to post-doc positions with everyone breathing a sigh of relief that they were finally out the door, post-docs hired in because everyone at their old lab was greasing the skids to shoot them out of the place.

And I've seen one or two people who were Waksal-ish, in a small-time way. I actually heard a "my NMR spectra were stolen" story - like someone needs a stack of NMRs. (You can tell that that one is from the days before digitized spectra, can't you?) And one post-doc I knew of spent some time on a large natural product project before floating off to another lab, leaving a pile of spectral data that the next guy had to sit down and figure out before he could get started. After going through the whole pile (two hours of stony silence, broken only by swishing paper,) this unlucky fellow looked up and said "This is not a very funny joke."

There has to be something more that we can do about such people. Any ideas?

Thursday, September 26, 2002
On the Money
Greg Hlatky over at A Dog's Lifeis right on target in his post of Tuesday the 24th. And that's not just because he said that my posts always make him think - of course, he could always be thinking "What's with this maniac, anyway?"

No, he's completely correct about the uses of time and money in academia versus industry. He points out that:

Industry and academia each have major constraints. At colleges and universities, it's money. Money is always in short supply and grants have to be used to cover the administration's greed in charging overhead, tuition and stipend for the students, purchase of laboratory chemicals and equipment, and so on. The money never seems enough and professors are always rattling their begging cups with funding agencies to continue their research.

What graduate programs have lots of is time and people. Research groups have hordes of post-docs and graduate students who can be kept working 16 hours a day, seven days a week, since graduate school is the last bastion of feudalism. The product of these two factors is a maniacal stinginess about chemicals and equipment - acetone and deuterated solvents are recycled, broken glassware is patched up over and over, syntheses start from calcium carbide and water - combined with a total lack of concern as to whether these rigors are time-efficient.

Oh, yeah. And it gets perpetuated as well by the feeling that if you're in the lab all day and all night, you must be productive - no matter how worthless and time-wasting the stuff you're doing. I've seen a number of people fall into that trap; I've fallen into it myself.

For a good example of the attitude Greg's talking about, see the recent long article by K. C. Nicolau in Angewandte Chemie. It's an interesting synthetic story, that's for sure (Nicolau and his group don't work on any boring molecules.) But it's marred by mentions of how this reaction was done at 2 AM, and how this sample was obtained on Christmas Eve, and how when I walked into the lab at 6 AM on Sunday, my people rushed up with the latest spectrum. . .there's just no need for this sort of thing. Of course, Nicolau's people work hard - they couldn't make the things they make, as quickly as they make them, without working hard.

I recall during my first months in industry when it finally dawned on me that it was a lot better idea to order expensive reagents rather than make them, considering what I got paid and what delays would cost the projects I worked on. A liberating feeling, I can tell you. I've never looked back. Since then, I can spend a departmental budget with the best of 'em.

Wednesday, September 25, 2002
Different Opinions About A Difference That Makes No Difference
Since Monday's posting was about the terrible consequences of changing one amino acid, I thought I'd stick with that theme. Today's outcome isn't life-and-death, fortunately for everyone involved.

But it does involve the patent rights to a $500 million/year antibody, so it's not without interest. Particularly if you think that another company has blatantly ripped off your patent, after doing a licensing deal with you that was supposed to preclude that sort of thing. The patent holder is Celltech, a UK company with a technique for generating humanized monoclonal antibodies in mice.

Antibodies are very useful, of course, but getting good ones isn't easy. There's no way to make them other than from a living organism (cell cultures, usually.) Ideally, you'd want to generate them in the same species that they're to be used in. Otherwise, you run a high risk of setting off an immune response in the treatment animal - instead of the antibody doing its thing and alerting the host's immune system to something else, it gets recognized as a foreign object all by itself. Whatever immune signal it's trying to send gets lost in the ensuing confusion, which can range from local irritation all the way up to anaphylactic shock. A humanized antibody has a generally human immunogluobulin structure with some specifically mouse-generated immunoreactive sections in it. These can pass, for the most part. It's a very useful technology, but rather tricky and sometimes hard to generalize.

Medimmune developed Synagis (palivizumab) as a treatment for respiratory syncytial virus (RSV,) which can be severe in infants. It's pretty much the only thing out there for it. No vaccine exists, for example: the first attempts to develop one in the 1960s backfired tragically when it turned out that treated children actually had a worse outcome if they were exposed to the real virus later on. (Here is a thorough report on Synagis and RSV, courtesy of

Celltech claims that Medimmune's antibody, though, is equivalent to something they've already patented. It's a point worth arguing: of the over 1300 amino acids in the antibody's chain, there's one that differs between Celltech's patent and Medimmune's drug. (Specifically, it's a threonine for serine, which is a mighty small change indeed: just one methyl in the side chain. That makes the Dutch mutation I spoke of yesterday seem like a total makeover.)

I can hear the groans now from the cognoscenti who can tell what's coming next: yes, this is going to turn on the Doctrine of Equivalents and the Festo decision. I wrote about this at length back on June 5, but I'd caution you if you go back to read that post.

Gary Pulsinelli of Tennessee's law school (yep, just down the hall from Glenn Reynolds, I gather) wrote to point out that I'd thoroughly smeared together the issues of infringement and patentability. That I did! My own background biased me into thinking in terms of battling patents, and that led me astray. It's important to keep in mind, for example, that something can be found not to infringe someone else's patent, but at the same time not be patentable on its own.

The Festo case was all about infringement. Here's a distilled version:
1. Festo (of Long Island) starts selling a nifty mechanical cylinder device.
2. SMC (of Japan) starts selling a nifty (and hauntingly familiar) mechanical cylinder device.
3. Festo sues SMC for patent infringement. They claim that the doctrine of equivalents prevents SMC from making a minor modification and calling it theirs.
4. SMC claims that Festo doesn't get to invoke the doctrine, because they made changes to the relevant claims while the patent was going through the approval process. That's "prosecution history estoppel," which has been the counterweight to overly broad doctrine of equivalents interpretations. If a claim gets narrowed during the pre-approval prosecution of a patent application, you can't go back (for example) and try to get D of E protection based on the original broader claim. After all, the Patent Office presumably narrowed the claim because they thought the broader one wasn't patentable in the first place.
5. Festo wins in the District Court, and the decision is kicked upstairs on appeal, to no one's surprise. It bounces around the Appeals Court for a while, with another big patent case (Warner-Jenkinson) complicating the issues in the meantime.
6. To everyone's surprise, the Federal Circuit eventually reverses the decision and takes the hardest line yet on using the doctrine of equivalents. Saying that the case-by-case approach had led to a mess, the court decides to draw the line so everyone can see it: Just about any changes made to a claim during the prosecution of the patent, the court now says, trigger prosecution history estoppel. Their take-home is something like "write your claims better from the start, and we wouldn't have these problems." The decision applies to a huge number of patents that were written and prosecuted while the parties still had a stronger doctrine of equivalents in mind. Confusion reigns.
7. Festo appeals to the Supreme Court. They don't hear many patent cases, but this is the biggest one since Warner-Jenkinson. Heavy amicus curiae briefs are filed in support of both upholding and reversing the Circuit Court's decision.
8. The Supreme Court largely reverses the lower court. The doctrine of equivalents is given new life, and the court attempts to clarify the no-man's-land between it and prosecution history estoppel by setting some new criteria. All interested parties in the intellectual property world settle down to figuring out the new landscape, and waiting for the first major court cases that'll hammer out the details.

That leaves out a lot of tricky stuff (such as the details of those new criteria ,) but I think it gets the main points across. Celltech, as you might guess, filed a brief urging that the lower-court decision be junked. If you weaken the doctrine of equivalents, they said in essence, you're going to open up everyone in biotech to what MedImmune is doing to us. Meanwhile, MedImmune claimed that this sort of time-wasting litigation was just what the lower court was trying to prevent by drawing its clear, bright line. If Celltech wanted to claim this protein, then they should have claimed it, was their point of view - it's time to stop hiding in the bushes, waiting to whack people in the head with the doctrine of equivalents if they think they can lay claim to something valuable.

The rest of the biotech industry was split along roughly these lines, with the likes of Chiron siding with the original doctrine of equivalents, and Genentech (among others) wanting the limitations imposed by the Circuit Court to stand. I like the first approach better. While I take the point that there's a lot of deliberately broad or vague claim language out there, I think that's the lesser evil compared to what this case is showing us.

If single amino acid changes are enough to break a patent, then what isn't? Instead of wasting time on post-patent litigation, we'd all be wasting our time writing incredibly precise and intricate claims (and doing a lot more running in circles trying to come up with data to enable them.) Celltech should win this one, and I hope they do.

Tuesday, September 24, 2002
The Wall Street Journal versus the FDA
Here we are again. Back in February (see the Feb. 27th post), the FDA asked for more data for Imclone's cancer therapy, Erbitux, saying the existing studies were not sufficient to approve the drug. The Wall Street Journal's editorial page threw a memorable fit about what they saw as the FDA's intransigence (to which piece I responded on June 18th.)

Now comes AstraZeneca to the FDA, similarly looking for fast-track approval of their similarly targeted (see the August 20th post) small molecule therapy, Iressa. The FDA's advisory panel met today, and ended up appoving the drug. The reviewer comments in the briefing documents suggested on Monday, though, that AZN was in for a hard time - and because of similarly unconvincing data.

And once again, the Journal weighed in today with a table-pounding editorial. Allow me to comment on their worldview:

Earlier this year, Astra-Zeneca reported very encouraging results from a couple of small trials totaling about 400 patients. The drug shrank tumors in 10 to 19% of lung cancer patients who had not responded to chemotherapy, and improved symptoms in about 40%. Most importantly, it appeared to add to the length and quality of life.

Sounds impressive when you put it that way! Let's look at the trial that AstraZeneca is using as their showpiece: 216 patients with non-small cell lung cancer who had failed standard chemotherapy. Unfortunately, the FDA contends that only 139 of those patients had truly not responded to earlier treatments. (The presence of these patients muddies the statistical evidence quite a bit, and it's just this sort of thing that helped to get Imclone's application in trouble.)

How many of these 139 responded to Iressa? Ten percent. Is a 10% response rate good enough to provide real-world clinical benefits? Is it enough reason to approve a drug on an accelerated schedule? Both those questions are very much open to argument, and even if the answer to the first one is "yes," reasonable people can believe that the answer to the second one is "no"

How about those improved symptoms? We have AstraZeneca's word that 40% showed some improvement in coughing and shortness of breath. But these results are not compared to any sort of control group, making them very hard to interpret - actually, it flat out makes it hard to determine that they're not an illusion. Other medications were also administered during the trial, and the study design makes it difficult (perhaps impossible) to say if those were responsible.

Most importantly, it appeared to add to the length and quality of life. Studies of Iressa in other cancers, such as head-and-neck, and yielding similar results.

That last statement is, unfortunately, true. The overall response rate in the head and neck trial (reported in May at the ASCO meeting) was 11%. As for quality of life, measuring that is hard enough under any circumstances, and measuring it without a control group is, I believe, basically impossible.

How about the other studies? The ones that this impassioned editorial doesn't mention? The two lung cancer studies that dosed Iressa plus standard chemotherapies - you know, the studies that actually had control groups? Iressa didn't have a 10% response rate in those. It had a zero per cent response rate - it didn't add to the effects of either one of the standard agents at all. The FDA found itself in the position of being asked to approve a drug that has completely failed to work in two studies, and shown marginal effects in two more.

. . .it is actually a repudiation of the speedier approval process the FDA has come to accept in drugs for terminal disease. . .that means approval base don smaller, so-called Phase 2 trials, along with compassionate use data to help establish safety. . .compassionate use programs can make a nit-picking bureaucrat's life difficult, by getting good drugs into the hands of many doctors and patients, who thereafter become a constituency urging formal FDA approval.

Nice use of the adjective. Compassionate use can also make a drug company's life difficult, as an avalanche of requests comes pouring in. It can make a scientist's life difficult, because the data obtained are usually of poor quality - heterogeneous and not well controlled.

But let's get emotional, since the Journal does: compassionate use can also make things damned difficult for terminally ill patients and their families. Remember, patients know they're getting an experimental drug, their last chance for survival. The FDA heard from some of those patients today, and I'm glad that they're still here to testify. And let's talk about those "good drugs": remember, in the lung cancer trials, 90% of the patients who took Iressa as monotherapy did not respond. And 100% of the patients who took it in combination therapy saw no added benefit. We didn't hear from these patients today. Many of them aren't around to talk about how hopeful they were that this new drug might save their lives.

The point here isn't to quibble with the FDA's suggestion yesterday that the data could be better. Studies can always be larger.

Yep. That helps. And drugs could always show some convincing efficacy; that would help, too. That's one good definition of the data being better.

The point is that this isn't a good reason, and certainly not an ethical one, for delaying approval. Particularly in cases of terminal disease, any safe drug with even a hint of effectiveness should be brought to market as quickly as possible.

An uncontrolled trial of powdered milk could end up showing "a hint of effectiveness," guys. Iressa's better than that, of course, but where do we draw the line? If we don't insist on solid statistics from well-run trials, we might as well just throw open the floodgates. The FDA is trying to get companies focused on proving that their therapies actually do something, while (because of the state of the industry) many companies are focused on trying to get their drugs on the market by the quickest route possible, cutting the clinical trials as thin as they can. Imclone's a much more spectacular example of that, but AstraZeneca should still count itself lucky to have gotten Iressa through.

Reading the editorials that the Journal has pumped out over the last few months, you get the mental picture of mustache-twirling FDA baddies snickering as cancer patients expire all around them. It's a caricature of the truth. It feels odd for me to stick up for a regulatory agency, but I'll stick up for this one. Speaking as a researcher in the industry, I can say that the FDA drives us all nuts, but we need them. We need people to poke holes in the studies, to question the data, to give us a hard time. It's called science. It's how we've made it as far as we have.

Monday, September 23, 2002
Another Law of the Lab
It's been a while since I mentioned my "Lowe's Laws of the Lab," so I thought I'd bring up another one. So far, I've gone over the vital "You can never have too much starting material" and the equally useful "Think hard before junking the old synthetic route, or you will spend months saving time." This time, it's the slanderous

You should only believe yields in Tetrahedron Letters papers if you also send off for everything you see advertised on late-night TV

Well, that's a little unfair. Not completely unfair - just a little. There are papers in Tet Lett whose procedures are perfectly reproducible - I've used some of them. And on the other hand, there are impressive full papers in JACS that have steps whose efficiency could only be reproduced by angels or omnipotent space aliens. I shouldn't be so hard on one particular journal. But I'll stand by the principle behind this one, and extend it to include other brief communications in journals that specialize in them. Chemical Communications is a worthy example from England, and Chemistry Letters gets the nod from Japan, and how.

Why the scepticism? I know that the current editors of Tet Lett have been trying to remedy the situation, and things have certainly improved from the days when I wrote that law back in grad school. But people try to use these journals as dumping grounds of one sort or another. When there's not enough room to write out full experimentals, who can say you're wrong? Three carbon-carbon bonds formed in the same reaction. . .hmmm. . .how about 85% yield? Do I hear 96? If the scheme in the paper just has a lithium reagent drawn over an arrow, who's to say that they didn't optimize it out the wazoo with some esoteric blend of solvents and temperatures?

There's always going to be a residue of doubt around a paper that lacks full experimental details. (Apologies to the non-chemists in the audience; it's time for some lingo.) You say you took off a trityl group and your THP stayed on? Show me. Tell me just how you did that, so I can see if I believe it. You say you got a 94% conversion with that exotic chiral zinc reagent? Peachy! Tell me how you made it - and that includes what kind of zinc it was, and where you bought the darn stuff. I'd like to do that reaction, too, and seeing a bunch of arrows and yields isn't going to help me much.

The idea of the shorter-length journals (or should I say, the ideal) is that they'd be used for preliminary communications of work that would be reported in full later on. Sometimes they are, but I'd like for someone to go to the trouble of seeing just how often that really happens. No one, as far as I know, has ever done that (and I'm not holding my breath, because it'd be a bibliographic nightmare,) but it would be interesting.

Sunday, September 22, 2002
Sleeping Dragons
One of the things that gives me the willies about biochemistry is the nonlinearity. If anyone were to ever come up with a set of equations to model all the ins and outs ofa living organism, there would be all these terms - way out in the boonies of the expression - with things to the eighth and tenth powers in them.

Of course, the coefficients in front of those terms would usually be zero, or close to it, so you'd hardly know they were out there. But if anything tips over and gives a little weight to that part of the equation. . .suddenly something unexpected wakes up, and a buried biological effect comes roaring to life out of nowhere.

Here's the real-world example that got me thinking in that direction. When I used to work on Alzheimer's disease, I first learned the canonical Amyloid Hypothesis of the disease. Briefly put, at autopsy, the brains of Alzheimer's patients always show plaques of precipitated protein, surrounded by dying neurons. It's always the same protein, a 42-amino-acid number called beta-amyloid. A good deal of work went into finding out where it came from, namely, from a much larger protein (751 amino acids) called APP. That stands for "amyloid precursor protein," in case you thought that acronym was going to tell you something useful

The ever-tempting hypothesis has been that an abnormal accumulation of beta-amyloid is the cause of Alzheimer's. This isn't the time to get into the competing hypotheses, but amyloid has always led the pack, notwithstanding a vocal group of detractors who've claimed that Alzheimer's gives you amyloid deposits, not the other way around.

So what's APP, and what's it good for? It took all of the 1990s to answer that one, and the answers are still coming in. It's found all over the place, and seems to have a role in cellular (and nuclear) signaling. Normally, it's cleaved to give smaller protein fragments other than the 42-mer that causes all the trouble.

(To get away from my main point, whether beta-amyloid has any normal biochemical use is a question that can still start some major arguments. Vast amounts of money and time (a very tiny percentage of it mine) have gone into trying to find the proteases that clip it out of APP, and to finding small drug-like molecules to inhibit them. We're finally to the point of having those, and the amyloid hypothesis is getting the acid test in the clinic. That'll all be a topic for another day.)

At any rate, one of the stronger arguments for amyloid as an Alzheimer's cause came from the so-called "Dutch mutation," which is what got me to thinking. As was worked out in 1990, there's a family in Holland with a slightly different version of APP. One of the 751 amino acids is changed - where the rest of the world has glutamic acid, they have glutamine - almost the same size and shape, but lacking the acidic side chain.

So. . .there's one amino acid out of 751 that's been altered. And that's in one protein out of. . .how many? A few hundred thousand seems like the right order of magnitude for the proteome, maybe more. And what happens if you kick over that particular grain of sand on the beach? Wll, what happens is, you die - with rampaging early-onset Alzheimer's (and a high likelihood of cerebral hemorrhage) before you're well into your 40s.

As it happens, that amino acid is right in the section of the protein that becomes beta-amyloid. Altering it makes it much easier for proteases to come and break the amide bond in the protein backbone, so you start accumulating beta-amyloid plaques early. Much too early. Bad luck - the change of just a few atoms - snowballs into metabolic disaster. Since then, a href="">many other mutations have been found in APP, and many of them are bad news for similar reasons.

But it's not like every amino acid substitution in some random protein causes death, of course. There are any number of silent mutations, and plenty that are relatively benign. Most of the time, those high-exponent terms out there in the mathematics sleep on undisturbed. And it's better that way.

Thursday, September 19, 2002
More Fun With Patent Expirations
Sometimes I think I should write some sort of script to insert that headline automatically. Not that I want the site to become "Patent Wrangling News," but that's where the action seems to be these days. (If you don't have the new drugs, then fight over the old ones, I guess.)

There's one of these that I haven't talked about yet that could be coming to a decision soon - AstraZeneca versus a host of generic companies, fighting over Prilosec (omeprazole.) (The Wall Street Journal also covered this issue in its "Heard on the Street" column on September 10.)

"Who cares?" might be the first reaction. Omeprazole's off-patent anyway, right? That's why AZN's been trying to convince everyone to take Nexium instead - for the millions who shouldn't take a lower-cost drug that works just fine. All that's true (or my firmly held opinion, in the last clause,) but this case could turn around and affect Nexium as well.

While omeprazole, as a chemical substance, is no longer covered by a patent, there are some formulation patents are the subject of litigation. That's because just taking the compound by itself won't do anyone much good, because it's unstable to stomach acid. AstraZeneca claims (in a patent that won't expire until 2007) to have invented a proprietary coating technology that allows the pill to make it to the small intestine.

The thing is, acid-resistant (enteric) coatings are no big deal in the drug industry, which is just the point that Andrx and several other companies are trying to make. They say that they have an equivalent coating which nonetheless doesn't infringe AZN's patent. "Equivalent" is a key word here, because if the generic behave differently, then it's not really a generic, is it? Andrx would have a new formulation on their hands, and would have to do more extensive testing to get FDA approval. Meanwhile, AstraZeneca is making their coating technique sound like it's the most complicated thing next to an interstellar warp drive, and about as easy to discover.

There's also a manufacturing patent on the same sort of technology. While AZN claims that several generic companies are infringing the first patent, Andrx is the lone defendant in the manufacturing fight. Needless to say, if Andrx wins on the first point but loses on the second, they'll still be stuck. You can't make money off a drug if you can't legally manufacture it. This has all been going on since late last year, and rulings are expected Real Soon Now.

Reversals for AstraZeneca could lead to trouble for Nexium, because the same formulation is used for that one, too (as you'd expect.) Nexium is, as the world should know, merely one pure optical isomer from the racemic mixture that is Prilosec. AZN's position is that the two substances are as different as asphalt and chocolate mousse, and that their separate patents on the optically pure form are as solid as can be. But if the first Nexium firewall (the formulation) is breached, the generic companies may attack the chemical substance itself.

What are the chances? This issue is being fought out in several cases. In Europe, the EPO seems to have clearly stated (as much as that phrase can apply in patent law) that a known racemate doesn't necessarily affect the novelty of the two optical isomers it contains.

But novelty is only one component of patentability. Showing a inventive step can be tricky, because it's widely assumed that one isomer is going to have more biological activity than the other one. It's been held that "an enhanced effect cannot be adduced as evidence of inventive step if it emerges from obvious tests." Now we start arguing about what "obvious" is, and it's just another day in the life of an intellectual property lawyer. Challenges in the US, where single optical isomers have been patented frequently, might well take this "lack of inventive step" tack.

Wednesday, September 18, 2002
As Others See Us
The "us" of that title refers to those of us in the drug industry (a reasonable percentage of my readers, but far from a majority.) Many may have noticed that Tuesday's Wall Street Journal had two two articles side-by-side under the "Politics and Policy" heading. They made an interesting (and surely non-accidental) contrast.

One was on the various ways that the pharmaceutical companies want the FDA to ease up on advertising and promotional restrictions (with particular reference to Pfizer.) These include handing out reprints of literature articles that bear on off-label indications, for example, which I can see lands squarely in arguing territory. Companies are always trying to push that boundry, and the FDA pushes back. Fair enough.

But some of the "restrictions" that Pfizer objects to are less arguable. For example, they want to be able to stop printing the generic name of a prescription medication next to its brand name. Come on. Consumers are used to prescription drug ads by now, and they're used to seeing a second name printed right below the brand. This isn't confusing anyone, and I can't see how it affects the advertising campaigns at all.

Of course, what it does do is raise awareness of the compound's generic name, which could be an issue when the patent finally expires. That probably does make it a bit easier for the generic form of the drug to hit the ground running - when, say, people have been seeing "sildenafil citrate" written right next to "Viagra" all these years.

But let's be real. These days, when big-selling drugs go generic, their sales don't just slowly fade out like they used to: they drop off a cliff. HMOs aren't stupid, at least not when it comes to obvious cost-cutting measures. When Claritin goes off-patent, it's not going to matter whether or not the word "loratadine" is on everyone's lips; its sales are going to tank anyway.

Every drug company realizes this. So why is Pfizer (and the other companies that may be cheering them on) making such a request at all? It's not going to help; all it does is make the compan(ies) involved look slick and greedy. This is most definitely not the time to be looking slick and greedy.

Which is the point of the second article, the "Political Capital" column by Alan Murray. He correctly points out that running against Big Pharma looks like a winning political ploy these days. Democratic candidates, especially, are "standing up to the big drug companies," fighting for the little guy and all that, all over the place. However, says Murray, "Almost no politician in America is willing to stand up and utter this simple truth: The nation's pharmaceutical makers have done more to extend and improve the lives of ordinary Americans than any industry in history."

It does cheer me up to read that sort of thing. But, of course, that sentiment and a dollar will buy us a bag of chips. How did the drug industry get to be so unpopular? Murray suggests that much of the problem is internal - pharmaceutical PR has been so heavy-handed that people assume that we must have something to hide. He suggests that the industry lobbying group, PhRMA, give up the front-group ads and campaigns, and reign in the marketing excesses that make it look like we have to buy doctors to prescribe our drugs. He concludes "If the drug industry wants less criticism from the public, it will have to start by giving people less to criticize."

The man has a point.

Tuesday, September 17, 2002
Chemical Warfare, Part Five: The Real World
The previous posts have been a quick tour around the chemical weapons landscape. I have to say, it's a depressing place to visit, and I'll be glad to leave it. But I can't do that without some thoughts on what, in the end, the stuff is good for.

Well, killing people, obviously. Or threatening to kill them, more likely. That's leads to an old military issue: whether to make your fearsome weapons known or not. If other countries know that your state is armed to the teeth with nerve gas, this knowledge will probably serve as a deterrent should they think about attacking you. Of course, that means that anyone who does attack will be prepared for whatever you can throw at them (and, presumably, ready to respond in kind.) Perhaps you're better off hiding your worst stuff, so if you have to use it, it'll have the maximum effect. . .

This thinking can be seen in action in the First and Second World Wars. The German chlorine attacks in 1915 caught the Allies almost completely by surprise (despite a fair amount of intelligence beforehand, as is seemingly always the case with surprise attacks.) But the surprise didn't last long. Within ten days, Kitchener had directed that the British forces respond with chlorine of their own, and the race was on. As the chemistry (and the technology used to deliver it) evolved, so did protective gear and readiness. All in all, the gas warfare of WW I ended up as a reeking, corrosive stalemate.

World War II never went chemical, despite prewar expectations. This was in spite of a German technological advantage. As the last two posts outlined, they were alone in nerve gas technology, and they put significant resources behind developing it. Large stockpiles of ready-to-use nerve gas munitions were captured at the end of the war. Why weren't they fired?

For that matter, what about the World War I standbys, like mustard gas? Huge amounts of were ready on both sides, each ready to reply in kind if the other side used it. As an example, here's an account of the German raid on US military shipping at Bari, Italy in 1943. One of the ships destroyed was loaded with mustard gas, producing the only battlefield chemical casualties of the war. (Thanks to Stephen Den Beste for pointing this incident out to me.)

That knowledge, that both camps were stocked with mustard gas and protection against it, seems to be what kept it from ever being used. The experience of World War I strongly suggested that the situation would end up as status quo ante, albeit with everyone in protective gear and more destruction all around.

As for the Tabun, its initial use by German forces would surely have been effective, especially at first. No one was prepared for a chemical agent that lethal. But the fact of chemical warfare would have been immediately clear, even if the specific agent was new and unknown, and the retaliation would surely have been terrible. Recall that by the time the German military was desperate enough to use nerve gas, the Allies had increasingly established dominance in the skies, in huge bomber attacks. It's likely that these would have been used for chemical counterattacks, and the consequences of an RAF or 8th Air Force raid loaded with mustard gas would be terrible indeed.

At the same time, the German government wasn't completely sure that the Allies didn't have nerve gases of their own. Publications in the scientific literature on insecticide chemistry almost completely dried up during the war, a fact that was noted in Germany. They couldn't be certain that the US hadn't stumbled across the same discovery that Gerhard Schrader's group had. . .and if so, then those retaliatory bombers might even have been loaded with something like Tabun rather than mustard gas, with consequences that are difficult to imagine.

I'm prepared to argue that against a competent and prepared opponent, the known chemical weapons are essentially useless. The historical record seems to bear this out. Look at the uses of mustard gas since World War I. Morocco in the 1920s, Ethiopian villages in the 1930s, Yemen in the 1960s - a motley assortment of atrocities against people who couldn't retaliate.

The exception is the Iran-Iraq war, yet another way in which it reminded observers of World War I. Iraq surprised the Iranian forces with mustard gas (see this 1984 report from a Swedish arms-control group,) but eventually Iran was able to get its own chemical agents on line. Neither side ended up with much permanent advantage this way, although Iraq was able to compensate somewhat for its disadvantage in manpower. (By the way, the Iraqi government also lied constantly and inventively about its use of chemical agents. At one point they suggested that Iranian casualties must have somehow been exposed to mustard gas somewhere else.)

I see no reason to assume that the current chemical warfare situation with Iraq has changed. In a war with US and British forces, they would be facing the best-equipped and most technically competent militaries in the world, and they could not hope to tip any sort of balance by battlefield use of even large amounts of chemical weapons.

As the large PDF file I linked to yesterday makes clear, the quality of Iraqi agents during the war with Iran wasn't very high. They needed the stuff immediately and didn't want to invest the time and effort to purify things (by distillation, for example - there's another wonderful job for you.) Their nerve gases were typically contaminated with the hydrogen fluoride I spoke of, rendering them corrosive and unstable to long-term storage. One assumes that they've remedied this problem over the years, but this also means that Iraq may have even less supply of chemical agents than some have estimated.

So, if they're to be used at all, it would be against selected targets, and the only ones they'd be useful against are unprotected civilians. Iraq infamously ran field tests of various agents on its own Kurdish population in the late 1980s, and we can assume that they know what they're doing and how to do it. But what population of civilians could be attacked to Iraq's advantage? Certainly not those of the Arab states that are aiding the US military efforts (such as Qatar and Bahrain.) The only thing that makes any sort of (diseased) sense is an attack on Israel, similar to those in the (First) Gulf War.

That way, Saddam Hussein can make himself out to be the mighty warrior who gassed Israel, slaughtered the oppressor, took the battle to the common enemy of all Arabs. . .ah, you know the sort of thing. He might see it as the best way to try to split off any Arab or Moslem support and to ignite a full-scale Middle East conflict that would shuffle the deck. Of course, that appears to have been his calculation the first time around, and none of that came to pass. One would expect the Israelis to be even more prepared this time around

So much for the military uses of chemical weapons. I've alluded along the way to their uses in terrorism, which seem to me to be more worth worrying about. No one's expecting a chemical attack on a normal workday. If executed well, such an effort would, unfortunately, seem well worth a terrorist group's while.

I could go on for quite a while on that topic, but I don't think it's that great an idea. I can't talk about the problems involved without potentially giving someone a leg up on solving them. And I can't talk about what I'd be most worried about without giving someone a good starting point. The only thing, in good conscience, that I think I can do is end by quoting Wittgenstein: Wovon man nicht sprechen kann, darüber muß man schweigen. (Whereof one cannot speak, thereon must one remain silent.)

I'd like to thank all my visitors for sticking with me through these postings, which I hope have been worth the time to read. Pharmaceutical and science news will start again tomorrow. Here's hoping that we don't revisit this topic any time soon!

Monday, September 16, 2002
Chemical Warfare, Part Four: More Nerve Agents and Their Chemistry
A good short history of Tabun and other nerve agents, largely based on this book, can be found here. To summarize, in 1937 a report on Tabun made its way to the chemical warfare branch of the German military, and its value was recognized quickly. Gerhard Schrader's group was moved to new laboratory space and set to developing new agents in the same chemical class. Money and material was put on scaling up the synthesis of Tabun itself.

Now, that was no easy project to be assigned to. The biggest problem, of course, was the hideous toxicity of the product. The pilot plant had quite a containment system (double-walled enclosures with positive pressure and so on, very sophisticated for its time.) The workers wore rubber containment suits, which were rigorously cleaned and changed. People still got killed. The histories above give some examples - the one that sticks with me is the unfortunate who had two liters of Tabun suddenly pour down inside his rubber suit.

Even without the awful product, the chemistry by itself was pretty foul. To pick a major issue, it involved hot hydrofluoric acid. You really don't want HF around if you can help it. It attacks glass, for one thing, and goes after a number of metals. It leaves the really expensive ones untouched, though - if you read the old literature on the stuff, you find references to exotica like platinum dropping funnels and the like. The Germans had to use silver-lined reaction vessels in part of the plant; the sort of thing we'd use high-nickel alloys for today. On top of the corrosion problem, HF is also very toxic, and inflicts extremely dangerous time-delay burns. The idea of working in a process plant where hydrogen fluoride isn't the nastiest thing in the house gives me the shivers.

And just to top things off, the Tabun process also involves cyanide and produces HCN vapors, which have to be dealt with somehow. I spent a paragraph the other day talking about how HCN wasn't a very useful war gas (which it isn't,) but being cooped up in a factory with it is another matter entirely. All in all, this is a one-damn-thing-after-another process that no one would scale up under normal circumstances.

The route worked, though, although it took a couple of years to get it going reliably enough to where it wouldn't kill everyone in the vicinity. By the end of the war, Germany had produced 12,000 tons of Tabun, a figure to give anyone pause. (We'll talk about why they never used it in the next post.) Meanwhile, Schrader's group continued to work in the area, producing Sarin (or GB) in 1938 and Soman (GD) in 1944. While Tabun has largely disappeared (except for nations just getting into the nerve gas synthesis business,) Soman and Sarin are still very much with us. The chemical routes were just as nasty, though - they still hadn't found a way around the fluorine reagents, and Sarin has a fluorine group directly bonded to the phosphorus. At least the cyanide part was gone. Still, production of Sarin by the end of the war was merely a few tons, and Tabun still has the reputation, despite all the nasty steps, of being the easiest nerve agent to synthesize in bulk.

In the 1950s, post-war research led to the discovery of several other effective compounds, including VX, which still sets the standard. These were discovered in several countries, more or less simultaneously. VX has a structure reminiscent of the others, but where the fluorines (or cyano) groups are on the phosphorus, there's an aminoalkane linked through a sulfur atom. The Soviets stockpiled their own, very similar compound with almost identical properties. VX's structure wasn't publicly disclosed until the early 1970s, but as it turns out, a 1960s German patent had made its way into the various open databases which (to everyone's embarassment and surprise) had VX in it. The inventor was. . .Gerhard Schrader, still at the phosphorus chemistry after thirty years, and obviously a man with very good lab technique to have survived that long.

Improvements were made over the years to the syntheses of all these compounds, but I'm not going to go into the details. It's an interesting set of process chemistry problems, but you have to be conversant in that sort of thing to get the most out of the discussion, and I assume that a majority of my readers aren't. There are many discussions in the open literature. For example, see this large PDF file entitled "Technical Aspects of Chemical Weapon Proliferation," which has a vast amount of detail.

No matter what the route, anyone outside of a serious industrial setting who wants to try this chemistry runs a mortal risk. I've worked with some really toxic stuff in my years in the lab, but I wouldn't touch any of the nerve agents with a platinum pole. 10 milligrams of VX on the skin is the approximate lethal dose - is my lab technique really that good? Well, I think so. . .but is that the phrase that I want them to put on my tombstone?

No one knows if there's been much subsequent R&D in this area, but I doubt it. Chemical weapons have the reputation of being living fossils compared to how other weaponry has developed. A Russian report from the early 1990s spoke of a completely new chemical class of lethal agents, which is certainly possible - but why bother? The phosphorus-based ones are about as bad as it's possible to get. (An overview of their comparative properties with some similar historical background is here, and the link I provided yesterday goes into great detail, too.)

Of the agents that have been used in the real world, Sarin's the most volatile, and does a lot of its work by inhalation (it's likely that if Schrader's lab had made that one first that they all would have died.) Meanwhile, VX is more persistant, rather like mustard gas, and works mainly by contact. Both can be formulated so that the last chemical step in the syntheses takes place in the shell or bomb, after it's been fired or dropped. To the best of my knowledge, there has been no hostile use of these "binary" weapons, except for an alarmingly crude dump-and-seal technique tried by the Iraqis during the war with Iran.

So how does one deal with these things? In the way of organic chemistry, the same reactivity that allows these compounds to inactivate cholinesterase also gives you a handle to break them down. All these reactive groups attached to phosphorus can be hydrolyzed by things like sodium hydroxide or bleach, or reacted with a nucleophile like ammonia. The resulting phosphoric acids or phosphoramides are basically harmelss. (VX's hydrolysis product, though, is unusually toxic. Fortunately, it doesn't penetrate the skin.)

That's all very well for decontaminating a concrete wall, but what about decontaminating yourself? The fast action of the nerve agents makes speed the main consideration. Even potentially lethal exposures can be compensated for if treated quickly enough. There are two therapeutic approaches, which are generally used simultaneously: Oxime compounds can actually react with the cholinesterase-bound form of the nerve agent, knocking it out of the active site in the process and regenerating the enzyme. Meanwhile, out in the synapse, a cholinergic antagonist can block the receptors and keep the signaling at the neurons from getting out of hand.

One antagonist that's usually provided for this purpose is atropine, which under normal conditions is quite poisonous itself (since blocking acetylcholine signaling for no reason is arguably just as bad as overloading it.) Really heroic doses of the stuff can be used in nerve gas poisoning cases, though. An important part of any chemical-warfare supply kit is a supply of these antidotes, ready to inject. There's a picture of a standard apparatus in another of the links from yesterday's posting .

Finally, giving a reversible inhibitor of acetylcholinesterase can protect against nerve gas before any exposure. That seems rather odd at first, but the idea is that the inhibitor ties up a certain proportion of your enzyme (but not enough to cause trouble.) The reversible chemical equilibrium causes it to gradually be freed up, even after nerve gas exposure, and this gives you a reserve of active enzyme coming on line that hasn't been hit by the irreversible nerve agent. Used properly, this can be enough to prevent much of the damage. Here's a military manual on chemical agents that goes into more detail on treatments for exposure to all of them.

In the next post, which I hope will be tomorrow, I'll try to wrap things up with a strategic discussion - no, I'm not turning into Den Beste (he fills that role just fine!) - but now that I've talked about the history and properties of these things, it's time to see what's been done with them, and what might still be waiting.

Sunday, September 15, 2002
Chemical Warfare, Part Three: How Nerve Agents Work
Descending past mere irritants and past disfiguring killers, we arrive at the bottom of the pit. These are compounds that are to humans what a spray-can of insecticide is to flies.

I mean that literally. Back in the 1930s, a group at IG Farben in Germany was searching for new classes of compounds to kill insect pests. After trying out several classes of organofluorines, Gerhard Schrader's lab made a phosphoramide fluorine derivative in 1935. That was a pretty potent compound, and a whole new area of research opened up.

Two days before Christmas of 1936, Schrader used the fluorine intermediate to make the first compound of the type we know as nerve gas. This was what's now called Tabun or GA, and it was the one of the most potent insecticides the lab had produced. After the Christmas holidays, he and his lab assistant were continuing their work when they noticed that they were getting short of breath, and that their vision was dimming. They evacuated the lab, which was a good call - a few minutes more would surely have killed both of them.

Those side effects are among the earliest signs of nerve gas poisoning, no matter what the agent. That's because they all work by the same mechanism. Some of the compounds are easier to make than others, some are more potent (so you don't have to make as much,) and some are more stable (so you can keep them in storage until you feel the need to commit mass murder.) But all of them do the same thing: irreversibly inhibit esterase enzymes.

A little-known fact is how broad-spectrum that activity is, and how little that matters. There are probably dozens of enzymes that a nerve agent shuts down in vivo, and this wholesale disruption would probably cause death in hours or days. Those pathways never get the chance, though, because the enzyme that counts is acetylcholinesterase.

Here's why: a number of different compounds are used in the nervous signaling for neuron-to-neuron crosstalk, but real workhorse is a small one called acetylcholine. It's made in the neuron, stored in vesicles up near the cell surface, and released to float across the synapse. Once it makes it across, it binds to one or more members of two families of proteins (muscarinic receptors and nicotinic receptors.) That docking sets off further signaling inside the receiving neuron. Fellow medicinal chemists and biologists know this as a prime example of a G-protein coupled receptor mechanism; it's a theme that shows up in many other signaling pathways.

The thing is, a signal across the synapse isn't a continuous current. It's a pulse across a gap, and when the signal has been received, the synapse has to be cleared. That's the job of the acetylcholinesterase enzyme. It's extremely efficient at breaking down acetylcholine, insuring that the signaling pathway doesn't stay switched on.

And nerve agents are extremely efficient at deactivating the enzyme. One molecule of nerve gas, if it makes it to the enzyme, will shut it down. When you consider that each enzyme molecule would otherwise turn over thousands upon thousands of acetylcholines - well, things get out of hand very quickly. The acetylcholine piles up in the synapse, causing all the receptors on the receiving neuron to get switched to an unnatural full-on overload. The entire nervous system goes down within minutes (at best) under these conditions - no interpretable signals to the muscles can get through at all. The limbs, the heart, the lungs all shut down or spasm uncontrollably.

Schrader and his assistant felt what they did because those organs were the first to be affected by the Tabun vapors, which were absorbed by the moist tissues of the eyes and taken up through their lungs. Their intercostal muscles were being partially inactivated (shortness of breath,) and the blast of acetylcholine signaling switched on the M1 muscarinic receptors in their pupillary muscles, causing them to contract. [Note added later - the shortness of breath was more likely due to bronchial effects, or the beginning of effects on the diaphragm muscle. The effects on the eyes are complex, probably involving both m1 and m3 receptors.] Further exposure starts to affect other muscle groups, and you get a mixture of muscarinic and nicotinergic symptoms. The only people who can tell you how this feels live in Japan (thanks to Aum Shinrikyo) and in northern Iraq (thanks to Saddam Hussein.) I should warn you, the New Yorker article that link goes to is very difficult to take. It's vital reading for an understanding of chemical warfare in Iraq, but it'll give you bad dreams.

Another thing that isn't widely known is that cholinesterase inhibition actually has positive medical uses. It's one of the few therapies now available for Alzheimer's disease, for example. The idea, which is admittedly a crude one, is to crank up the volume of the brains' acetylcholine signaling to compensate for the damage of AD. It works, a little, for a while. Of course, the sorts of drugs you use for this therapy need to be a bit less. . .efficacious than nerve gas. Ideally, they're weak, reversible inhibitors of the enzyme (as opposed to butt-kicking irreversible ones,) and they should tend to concentrate in the brain while getting cleared from the rest of the body.

The dose makes the poison, indeed. We'll return to Gerhard Schrader in the next article, after he learned to treat his compounds with more respect.

[Post edited after inital version - cleaned up some pharmacology and added links.]

Thursday, September 12, 2002
Chemical Warfare, Part Two: Lethal Agents (Other Than Nerve Gas)
We'll cover three World War I compounds, saving the latter-day nerve agents for a separate posting. 1915 was a terrible year, one among many, because it saw the advent of militarized chlorine, followed shortly by phosgene. Those two (though technically obsolete) are still in play, because their manufacture is so low-tech. Mustard gas (bis(chloroethyl)sulfide,) which is really a liquid for the most part, was also famously effective. I'm not going to talk much about the arsenical agents like Lewisite - they're nasty, but of less relevence, I believe, to modern warfare or terrorism.

Some of the other things from that era, ones that you'd think would be quite destructive, turned out to be useless. Gaseous hydrogen cyanide is a notable example, and illustrates some of the complications. For one thing, HCN is too light - the vapor disperses rapidly, instead of hugging the ground like phosgene. It's also a little-appreciated fact that HCN isn't really that toxic below a certain threshold. I've smelled the stuff myself in the lab - by accident, I should make clear. (Its aroma is distinctive, but not as bitter-almondy as advertised, at least to me.) People can survive just fine around low concentrations of cyanide gas, although I'm not endorsing it as a lifestyle choice. Achieving lethal concentrations of it in the field just isn't very practical. Not that it wasn't tried.

The three agents from the first paragraph, though, suffer from no such limitations. Chlorine and phosgene are heavier than air, and accumulate in low places (such as a World War I trench) if there isn't a strong wind. They're both reasonably persistent as well. Mustard gas is very persistent indeed, to the point that it couldn't be used against positions that attacking troops were going to occupy any time soon. All three have effectively no minimum concentration below which they stop doing some sort of harm. Very low exposure to any of them certainly isn't fatal, and you can even get away with no lasting damage, but it's still unwelcome.

While not the most effective chemical warfare agents (we'll get to those next week,) these things are all easily purchased or made in quantity. No doubt they have some appeal for terrorists, and as such they're worth looking at in a bit more detail.

Chlorine is a basic industrial chemical, prepared in immense quantities by electrolysis of brine. This is the chlor-alkali process, a classic of chemical engineering which has been refined but never superseded. This technique means that wherever they make chlorine, they make sodium hydroxide, too, and generally they go on to make sodium hypochlorite bleach for you, too.

There's been tremendous back-and-forth about chlorine use and production in Iraq, since it's also used to purify drinking water supplies. While Saddam Hussein certainly would have no qualms about using it, it's still not the most effective war gas by a long shot (we'll be getting to those in the next post.) I believe that the more likely use of chlorine would be as part of a low-tech terrorist operation involving its transport through a population center.

Its effects can be completely mitigated by reasonable protective gear, but that's just what ordinary people won't have. It has severe effects on the lungs, which is how it kills. One thing that keeps it from being more destructive is that it has a powerful smell, even at low concentrations. No one gets exposed to chlorine without realizing it and trying to get away.

Phosgene is worse. It also causes severe lung damage, but it's harder to detect. There's certainly a distinct phosgene odor (sort of an acrid rotting-vegetation smell, supposedly not so bad a low concentrations.) But that means the gas can be present at dangerous levels (especially over time) without being particularly noticeable or offensive. And if you don't know what the smell is (and what it means) you can be badly injured without realizing the danger. The majority of chemical fatalities in World War I came from phosgene.

On a personal note, perhaps the single longest day I've spent in my chemical career came some years ago, after I thought I might have been exposed to some phosgene one morning. I didn't really notice the distinct smell, but here was also plenty of HCl vapor present, and I worried that it had masked the phosgene. Surely, I thought, I'd notice some immediate effects if I'd been exposed. . .so I went and did some reading, and that's when I really started to get the cold sweats. The symptoms of even a fatal exposure to phosgene can be, initially. . .nothing. Only with time does it hydrolyze inside the epithelial cells of your lung tissue, causing increasing and irreversible damage. I spent a rather jumpy day, checking my breathing while trying to correct for the unusual general shortness of breath I was feeling.

Phosgene is also a large-scale article of commerce. It's synthesized from carbon monoxide and chlorine, using various catalysts. Not something that you would make in your basement, but if you're a country with a thermoplastics industry, you make phosgene or you deal with someone who does. As far as I know, it's not usually shipped around or stored in large quantities, which makes it less of a civilian terrorist threat. If you have an industrial phosgene synthesis, you generally make it on-site as needed.

Finally, we have mustard gas (something of a misnomer, as I've mentioned.) It didn't cause as many fatalities on the battlefield, but its insidious nature made it an effective weapon. It's not immediately irritating to the eyes or lungs, and it can be tremendously harmful at levels well below those that can be smelled. It's persistent, and penetrates ordinary clothing very well. A few hours after exposure is when the trouble begins. It attacks the lungs (although with a different sort of action than phosgene) and causes terrible burns to exposed tissue - all of this long after you have the chance to do much of anything about it. That's the main reason for its military effectiveness, since full body coverage is needed rather than just eye/lung protection. As a weapon of terror, this might be the worst of the three, if the people involved were to disperse it well enough.

Fortunately, it's also the hardest to get. There's no industrial application for the compound, and no legitimate reason to produce it in any quantity. However, its immediate precursor compound, thiodiglycol, is used industrially, although in quantities that don't come anywhere near chlorine or phosgene. It shows up as a component in inks and dyes, mostly, which means that an unsavory government could claim that a particular factory was making ball-point pen ink or the like. Synthesizing the mustard itself from the precursor wouldn't be much of a feat for any decently equipped lab. You might not get the cleanest product in the world, but it would be bad enough.

Trying it in a garage (or a cave!) though, would be another matter entirely. We've now crossed over from the list of "things you can buy" (or "things you can hijack a truckload of") into the territory of "things you have to make." And even a one-step synthesis like mustard gas, if it's to be done on any harmful scale, needs some equipment that you're not going to have in your kitchen - that is, if you're not going to gas yourself in the process. None of the problems is insurmountable, unfortunately, but they do raise the bar.

I mentioned the problem of dispersal. I don't want to gloss over it, but I don't want to give anyone a road map, either. The use of chemical agents in World War I, for example, evolved from opening cylinders and letting the wind blow the stuff across no-man's-land (in early 1915) to various types of sophisticated gas artillery shells. That was a direct result of experience - the wind could blow the gas all over the map, or right back at you, while shells could be targeted where you needed them.

As we'll see later in the discussion of nerve gas, the Aum cult in Japan found that even highly toxic compounds aren't as effective as they could be when poorly delivered. We can assume that Iraq has a real supply of chemical munitions (more on this later on, too,) while less infrastructure-rich terrorists probably don't (unless they buy them off of the Iraqis or any of the many other governments that are holding on to this stuff.) If they're going to use chemical agents on their own, though, they'll have to figure out a way to do so effectively. And that is, fortunately, not trivial. Beyond that I will speculate no more in public.

Wednesday, September 11, 2002
Chemical Warfare, Part One: Introduction
I don't often deal with politics and world events on this site (much less than I thought I might when I started it.) There are usually plenty of other worthy writers out there who are saying just what I would, so I've settled on science (and the business of science) as my ecological niche in the Blogosphere. But these days, current events may be crossing paths again with chemistry, so I thought I'd use my scientific background to cover a topic that I fervently hope will end up being of no interest at all: chemical warfare.

There's a reasonable chance that an invasion of Iraq would trigger use of Saddam Hussein's remaining chemical weapons stores (either against US troops, or on a missile lobbed into Israel, as in the Gulf War.) The Iraqis themselves have credited their chemical warfare capacity with giving them an edge against the much larger Iranian forces in the 1980s, and Hussein has (infamously) used what appears to have been the nerve agent VX against his own Kurdish population.

On the home front, there are terrorist possibilities as well, both with industrial chemicals as well as with more specific war gases. I'll take on the subject in several postings over the next few days (with my more traditional blog material showing up in between, as time permits.)

To begin with, it's important to realize that chemical munitions, nasty as they are, do not have the same destructive potential as atomic or nuclear explosives. As readers will see, releasing a van full of (say) benzyl bromide would be a tremendous irritant. A vanload of mustard gas would be far worse than that. A similar quantity of nerve gas would, of course, be an atrocity.

But keep in mind that a fission (or worse, a fusion) weapon could be contained in the same van, and would be many orders of magnitude more terrible in every way. Fortunately, they're also many orders of magnitude harder to acquire. Much depends on keeping that difficulty as high as possible.

Chemical weapons are, then, more likely to actually be encountered, and they're plenty bad enough. The ideal chemical agent would be totally incapacitating or lethal, hard to detect, extremely potent, and easy to deliver and disperse. Since the advent of modern chemical warfare in the First World War, those qualities have largely led to the use of toxic gases or their corresponding liquids. The delivery problems of solid agents have kept them from being as fully developed.

Different compounds meet these criteria to different extents. A much wider variety of agents were tried out during the First World War than is generally realized, almost 40 different compounds. (See this excerpt from a 1926 US government report for a comprehensive list and a lot more detail than I have space to go into.) That list was a real surprise, personally, since I realized that I have a number of these things in my lab. I have to say, I'd never thought about loading them up and throwing them at someone - which is probably the same thought many chemists had during the war. Several of the things on the list are still relevant to today's situation.

Others aren't. Many substances from that era are little more than irritating tear gases. I've been exposed to some of them myself in my chemical career, most memorably a face full of benzyl bromide fumes in graduate school. It wasn't truly incapacitating - I still had plenty of capacity to lurch around the lab toward the eye wash fountain, cursing and banging into things. Such compounds would be of little use against anyone properly equipped, and would do little lasting harm even to unprepared civilians.

Some of the other World War I irritants were had a delayed onset, designed to make later gas-mask wearing very uncomfortable. By which time, the plan was, more lethal agents would be in the area, exposing troops who otherwise would have been better protected. This sort of thing is still a potential military problem, but there's still no point in enemy use of such compounds against civilians who won't have masks to start with.

No, for both battlefield use and in terrorism, the lethal agents are the ones to worry about. I'll be covering these in some detail over the next few posts - how they're obtained, how likely they are to be encountered, and how they're dealt with.

The Explosion
by Philip Larkin (1922-1985)

On the day of the explosion
Shadows pointed towards the pithead:
In the sun the slagheap slept.

Down the lane came men in pitboots
Coughing oath-edged talk and pipe-smoke
Shouldering off the freshened silence.

One chased after rabbits; lost them;
Came back with a nest of lark's eggs;
Showed them; lodged them in the grasses.

So they passed in beards and moleskins,
Fathers, brothers, nicknames, laughter,
Through the tall gates standing open.

At noon, there came a tremor; cows
Stopped chewing for a second; sun,
Scarfed as in a heat-haze, dimmed.

The dead go on before us, they
Are sitting in God's house in comfort,
We shall see them face to face -

Plain as lettering in the chapels
It was said, and for a second
Wives saw men of the explosion

Larger than in life they managed -
Gold as on a coin, or walking
Somehow from the sun towards them,

One showing the eggs unbroken.

Copyright 1974 by (the estate of) Philip Larkin. From "High Windows" (Farrar, Straus and Giroux)

Monday, September 09, 2002
Caveat Lector
Mentioning that interview brings something else to mind: the state of most public information about various drug companies, their pipelines, and their prospects. I'm not just talking about how mixed-up many popular press stories get (that's a subject for another day, though.) This is sort of a sequel to the August 26th posting ("Muddying the Waters for Fun and Profit") about how some stock analysts are going over the line to get what they hope is the real story. As the article I discussed makes clear, even lying their way into clinical trials didn't really give them any reliable news.

So what does that say about the rest of the information, the stuff that the companies actually want to make public? I'm not singling anyone out when I say that it's pretty useless. Drugs from all over the industry continue to show up on lists of "stuff that's in development" long after they've died and gone to Clinical Heaven, for example. Presentations at meetings are eagerly awaited by investors and the press, but some of these have so much spin on them that they emit humming noises. I recall one drug candidate a few years ago that was praised to the skies in company PR when its clinical data were unveiled at a meeting, and only later did it come out that the mortality in the treatment group was higher than in the treatment group. You could have looked all day in the Business Wire story for that useful information.

Well, I invest in a number of pharma and biotech companies, too, so I must be another fool like the rest of them. I try to discount for hype and wishful thinking, but it's hard to know how big a correction factor to apply. It's never zero, though. In the same way that you don't usually hear elected officials say exactly what they think about a controversial issue, you don't usually hear how a drug is really doing, or what its commercial prospects really are.

Of course, even if the companies told you their own private figures, it would turn out that they're sometimes full of hype and hoo-hah, too. We're not even immune on the inside!

Sunday, September 08, 2002
Merck and Its Competition
There's an interesting interview up at Business Week's site with Anthony Ford-Hutchinson, a Merck research honcho. Much of the interview is routine: "How's the new drug for XYZ coming along?" "Why, just fine!" But he does get in a few good cuts:

Q: How would you describe the culture of Merck's research and development?
A:" If you look at Pfizer's annual report and compare it to Merck's, theirs says something about wanting to be the most valued company in the world, whereas Merck's talks mainly about curing diseases."

That's the sound of a catapult in Rahway unloading a bag of overripe Jersey tomatoes in the direction of Groton. He goes on to say that "we don't go after the Nexiums and Clarinexes of the world." I have to applaud that sentiment, and I'm glad to hear someone say it out loud. But I have to note that Merck is coming along with a follow-up COX-2 inhibitor to bring up the slack behind Vioxx. . .I also note that that's a slam against Merck's current development buddy, Schering-Plough, which takes some nerve.

As for merging, he sticks with the Merck line of "no way." Some of his comments really make him sound like my soul brother:

" . . .every time you see a big drug merger, the research at those two companies grinds to a halt. Everybody starts worrying about their jobs. . . "

". . .the research can easily get screwed up when two companies merge. I think the effects of this may not be so apparent right away, but a decade from now the effects will undoubtedly be apparent."

All I can say to that is "Preach it!" Let's hope that we're all doing well enough in ten years to see who's right.

As an aside, if I ever form my own company, it's going to be hard to resist the temptation to have official titles like "research honcho" or "exalted pooh-bah." Maybe if one of my colleagues gets his drug company off the ground, he can use those. Right now, all he has is an evocative name, considering the genomics era. He wants to call it "InVivogen," and I can see the point!

Thursday, September 05, 2002
You Don't Hear "Eureka" That Often
I actually wasn't at work today - took the day off so that we could take the kids to the zoo. That probably means that something important happened; these things always seem to take place when I'm out of town.

And the rest of the time something important happens in the lab, I generally don't even realize it. It's not because I'm especially dense (no superfluous comments, those of you who read this site from my company!) It's that we usually only recognize important scientific moments in hindsight.

For instance, I've never been on a project when we've made a compound, tested it, and said "That's it. That's our clinical candidate right there." For one thing, the tests that a clinical compound has to pass can be spread out over several months. You need several weeks just for your minimal toxicity testing (and holding your breath that whole time, which is what you feel like doing if you have any sense, is a real strain.)

Another reason is that we always figure that we can do better. Every good compound seems to open up a whole new area to work in, and everyone jumps in and adds their two cents to the structure. It's only after you've run through those variations and tested them that you realize that the compound from a couple of months back was as good as things were going to get.

That's why most compounds sort of seem to back into the clinic. They're sometimes just the best of a bad lot, but they're always a retrospective pick, made by balancing the various factors and taking the least obnoxious candidate. A is going to be the easiest to formulate for clinical trials, but B is a lot faster to make. But C is almost as good, and comes from a cheaper starting material. Meanwhile, D had a better tox profile than the others, but was the difference real, or just noise? And so on. . .

It's the same principle as in engineering: you can't make it perfect, just as good as you can in the time and with the tools you've got. And if you don't get the thing out the door, it doesn't matter how good the data might have been. This isn't a license to do sloppy work - that's an even worse mistake. What it is is the lack of a license to go on refining things forever, long after they've reached the point of "good enough."

Wednesday, September 04, 2002
In Progress
I've had several responses to my most recent "How Not to Do It" posting below. As mentioned, chemists all have their explosion stories. I'll throw some in as time allows, or when news gets slow.

There's also a lead I received on a paper that might explain why biochemical systems settled on phosphate groups for so many functions, as I've wondered aloud a few times. I'll dig it up and report back. I still wonder why more sulfur oxidation chemistry isn't used biologically. (Well, plenty of bacteria make their living off of it, true.)

I'm trying to put together some more stuff on the Ariad patent lawsuit, but that's going slowly. It's not something that a lot of people want to comment on for the record, thanks to Ariad blasting away on the legal front the way they are.

That about covers the near-term stuff - I find that a majority of my postings happen outside of the stuff I've planned, though, so who knows what'll be showing up here. My project at work is approaching some critical periods as well, so I may not have time for some of the longer pieces for a couple of weeks. But there's always something to blog about (explosion stories excepted!)

Tuesday, September 03, 2002
The Patent Expiration Fun Continues
Meanwhile, Merck has a patent fight of its own going on. Their osteoporosis drug Fosamax (alendronate) is being targeted by Teva and Barr, but Merck (not surprisingly) has been filing suits against both of them over the last few months. The Barr lawsuits are in New York, Teva's is in Delaware, and we might see some decision on them in the next couple of months.

Merck doesn't seem to be arguing the point about composition-of-matter. What they're claiming is that they have patents covering the entire methods of treatment for bone resorption. These patents have expiration dates all the way out to 2018, which is a date that they can live with. After then, they say, you can do anything you want with alendronate. It's not clear what other sorts of compounds might fall under these treatment claims, but I haven't heard of any other companies that feel that they have a stake in this fight.

This is yet another test of the whole method-of-treatment patent idea. It's complicated in this case, because there are nine Merck patents involved, and they have all sorts of claims among them: chemical matter, processes for preparation, medical treatment, and who knows what else. I've looked into them a bit, but my head starts to pound a bit after about five or six patents in a row. Gets me right up around the eyebrows. . .but I digress.

There are plenty of compound-specific claims, of the sort that read "A method for treating diseases involving bone resorption, which comprises administering to a patient in need thereof a therapeutically effective dose of a compound of claim #. . ." Many of these don't seem to be for alendronate-type compounds, since this is the sort of claim that usually refers back to some novel chemical matter (which is the real subject of the particular patent.) But a closer reading would, I'm sure, find some that refer to alendronate itself, because these cases would have been decided already if there weren't some meat on the bones. [Note added 9/4: I edited this paragraph from its original version last night, which made even less sense.]

Barr and Teva say, as you'd expect them to, that the Merck patents are invalid and/or unenforceable. Unraveling all this won't be fun, and no doubt whatever verdict comes down will be immediately appealed. "Where it will all end, knows God" as the old New Yorker parody of Time magazine had it.

These sorts of court battles are routine, and it's easy to see why. While they go on, the status quo is preserved. The challenging generic company has its hands tied. As long as the drug brings in more money than you pay in legal fees, then you're ahead of the game.

Monday, September 02, 2002
Solvent Stills Redux
Greg Hlatky over at A Dog's Life was inspired to tell a couple of wild chemistry stories of his own. His solvent-still story parallels some of my experiences very closely.

As he says, the best way to dry several common solvents is from things like sodium or potassium metal. If you keep those around, and use them long enough, with enough different people handling them, you will have fires. Plenty of 'em. No amount of preaching or training will keep people from torching the place with that stuff, as far as I can tell.

A Last-Ditch Effort - Or Is It?
There's a rather weird legal fight going on between Glaxo SmithKline and the rest of the world. Like everyone else, GSK is fighting to hold on to profitable drugs that are losing patent protection. A lot of. . .creative. . .arguments are being deployed in these efforts, and I can't figure out if this is one of them or not.

The drug is Augmentin, which is actually two drugs in one. (For those readers old enough to remember it, you can now cue up the voice-over to the old Certs ad.) The antibiotic ingredient is plain old amoxicillin, a beta-lactam warhorse that's been generic for a long time now. Unfortunately, plenty of bacteria can chew right through amoxicillin and others of that era. I mean that literally: they use an enzyme called beta-lactamase to break open the four-membered ring at the core of all the penicillins.

That's where the second ingredient comes in, clavulinic acid (actually, its potassium salt.) It's a natural product that has a roughly similar structure, similar enough to fit into the active site of the beta-lactamase enzyme and gum up the works. Using the enzyme inhibitor leaves the amoxicillin free to do its work, and the combination is quite effective.

Well, amoxicillin you can order by the drum. But clavulinic acid is another matter. It's not economical to synthesize, not from the ground up (and neither are the beta-lactam antibiotics themselves, for that matter.) All these compounds are made (at least partially) by fermentation, which is just short of being a black art. You have to find strains of organisms (fungi for the 'cillins, bacteria for clavulinate) that produce unusually high amounts of the material, and you have to make them do it reproducibly. That means keeping them happy, but not so happy that they decide to give up the hard biochemical work of synthesizing your compound. And you have to find a good way to purify your stuff from the reeking fermentation broth - ideally in a continuous-feed mode so you don't have to run batch after batch. It's not trivial.

Perhaps you can guess where this is heading. GSK claims that they spent a lot of time and money developing a particular bacterial strain that produced clavulinic acid better than anything else known. And they're now claiming that some of these bacteria walked out of their facilities and are being used by their competitors (specifically Novartis as well as the generic companies Ranbaxy and Teva.) They seem to have a particular employee in mind, and a particular transaction history for the theft.

Problem is, that all happened starting in 1988. You wonder why GSK sat back for this long if they knew all this. . .and there are generic Augmentin formulations in Europe which don't figure into the suit. How'd they make their clavulinic acid? You do have to wonder if this isn't a desperation move.

On the other hand, this sort of theft isn't unknown. About twelve years ago, a New Jersey drug company had a former employee walk out with some of their engineered bacteria, which he later tried to sell to at least one small biotech outfit. They went to the Feds. The employee was caught on tape, thinking that he was selling the material to a Middle Eastern government, when he was really selling it to the FBI on two camera angles.

So GSK could be on to something, too. It'll be fun to watch.