Lagniappe (science, business, and culture)

Tuesday, July 30, 2002
The Ames Test And the Real World
Back to the question: what does the Ames test tell us? One thing it does is something that all toxicological tests do - that, as Paracelsus put it, "the dose makes the poison." There's hardly a more important tox principle than that. You can get a lot of things to show positive for mutagenicity if you're willing to load up on them.

Beyond that key point, Ames himself has made the argument that synthetic compounds and naturally-occuring ones have the same hit rate in these assays. Plants have evolved a variety of pesticides and antifeedant compounds, many of which are reactive and toxic at some level - therefore, most (as in 99.99%, according to his estimate) of the pesticides in the human diet are those found in the plants themselves. The cruciferous vegetables (broccoli, cabbage, mustard and so on) are particularly rich in compounds that will light up an Ames test. A fine article of his from 1990 (Ang. Chem. Int. Ed.,29, 1197) states that ". . .it is probably true that almost every plant product in the supermarket contains natural carcinogens."

And that's before cooking. Many of these reactive compounds are destroyed by heating, but many others are formed, especially in browning or charring of proteinaceous foods. There are two ways to react to news like this: either you can panic at the thought that every meal you take is full of mutagens, or you can decide that (since people aren't dropping all around you) that we've apparently got some method of dealing with them.

That we do: the digestive processes, gut and liver especially, the same things that are the bane of medicinal chemists for tearing up our carefully-designed wonder drugs. They give the same treatment to most everything you eat. In most cases, they're successful at detoxifying whatever compounds might be present, even if they were at harmful concentrations. But there's a limit - if you chow down on plants containing cyanogenic glycosides (raw cassava root, apricot pits, etc.,) nasty amino acids (some kinds of Lathyruspeas,) or fluoroacetic acid (some South African weeds,) then not much is going to help you.

Ames's point is that the mental division many people have between "artificial" or "synthetic" chemicals (bad) and "natural" ones (good) is nonsense. The same number of toxic compounds are found in each category, and we're exposed to far more of the latter. Instead of worrying about parts-per-billion of pesticide residues, we should worry about greater public health risks like smoking, alcohol, etc. Going crazy about the minute amounts of synthetic compounds that we can now detect not only diverts time and money from more useful concerns - it can lead to decisions that end up doing more harm than the compound residues ever could. Ame's article is a fierce broadside against this sort of thinking.

If you're going to sound the alarm about chemicals, he suggests, look at high-dose occupational exposures. Here we get into toxicity that has less to do with a compound's mutagenic potential. At very high doses, you're basically causing cell death, irritation, and tissue injury. That leads to increased rates of cell division, leading to an increased chance of carcinogenesis.

We're back to "the dose makes the poison." The principle applies not only to people who are exposed to huge doses of chemicals, but to unlucky lab rats as well. Ames has forcefully made the point that testing compounds in animals at or near their maximum tolerated dose (MTD) is a poor measure of their cancer-causing potential. About half the compounds so tested show up as carcinogens, but the dose-response curves aren't linear. It's a complete mistake to assume that half of all chemicals cause cancer, unless you're soaking your feet in solvent while doing ice-cold shots of fungicide.

The implications for the toxicity testing of pharmaceuticals? We don't usually test our drugs at such high levels in chronic studies. Instead of working down from the MTD, as an environmental toxicologist might, we work up from the MED, the minimum efficacious dose. If a compound makes it through OK at some multiple (10x, 50x, 100x) of the MED, then we feel safe enough to go on.

As for Ames testing of pharmaceuticals, since we also don't go to such high levels, we don't see that many true positives. There are some known pitfalls: antibiotics can be tricky to assay, as you'd guess, since the procedure uses bacteria. Some of the drugs that target DNA-manipulating enzymes (like the fluoroquinolones) will give you a false positive because of the way the bacteria have been crippled for the test.

Since a real Ames-positive is uncommon in the drug industry, we pay attention when we get one. Would these compounds really be mutagens in humans? And if they were, would they be carcinogenic? Maybe not! But for the most part, no one knows, and no one's going to find out, either. It takes a lot of nerve to continue developing such a compound, and there really aren't enough data points to draw a conclusion.

It's the same way with animal tests. If something serious happens with your whole-animal tox (especially if it happens across species,) you usually pack it in and cut your losses. No doubt some of these compounds could have gone on safely, but we'll never know. At least not until we're a lot better at this than we are now. . .

Monday, July 29, 2002
The Ames Test
One hears a lot about the Ames test (as a measure of carcinogenicity and other Bad Things.) It's sometimes held up by animal-rights types as a model of the sort of testing that could be done if, presumably, we weren't all so much into torturing the lesser species. I thought a look at the test would be worthwhile. This is another post where many of my readers in the industry will know the material, but since almost no one outside of it does. . .

The original Ames test dates to the mid-1960s, and the idea behind it is even older. First, you need some mutated bacteria, in this case mutant Salmonella bacteria that have lost the ability to produce their own histidine (an essential amino acid.) These guys can be grown on a medium that contains histidine, but if you try to grow them on something else, they'll die. Unless, of course, they mutate back to being able to make it on their own, and that's the basis of the test in a nutshell.

The original protocol was worked out after a long search for Salmonella mutants - some naturally occurring (although not for long!) and others induced by radiation or exposure to toxins. The modern form uses some engineered bacteria as well. There's a panel of standard strains, with different types of defects in the gene that's responsible for histidine production. Several also have hand-introduced glitches in their best DNA-repair enzymes. Losing those force the bacteria to use more low-tech cellular machinery to do the job, increasing the chance of random mutations. Finally, all the Ames test strains have defective polysaccharide outer coats, to make them more permeable to the test chemicals. These are not exactly the most robust Salmonella you'll ever see (but robust Salmonella would laugh at most of our test chemicals, which wouldn't be too informative.)

There are a number of different ways to run the test, but they all come down to this: you expose your bacteria to the test substance, and try to grow them without their required histidine. That really puts the selection pressure on - stumble back to making your own histidine, or die! So anything that survives is a mutation, and the more of those you get, the worse your test substance was. That's because the mutation occurred while the DNA was being repaired or replicated. Your test compound either caused the damage that had to be repaired, or it caused the replication process to fumble.

An added wrinkle involve taking your compound and exposing it to liver enzymes first, then taking that mix and running the Ames on it. That can pick up toxic metabolites that might form in vivo(not all of them, but it's a start.) Drug companies routinely do it both ways, just to be sure.

So that's an Ames test. What does it mean? Here's where the arguing starts, but there are some agreed-on facts: A dose-responsive positive in means that your compound damages DNA. There are a lot of ways for that to happen, and the behavior of the different Salmonella strains can point toward what kind it probably was. As you pile up the DNA damage, odds increase that you'll finally bollix some gene that shouldn't have been messed with, one that can start a cell on to road to cancer.

And that's what the test has traditionally been used for, as a proxy for carcinogenic potential. It's not a good surrogate for general toxicity, because there are plenty of toxic compounds that don't work by damaging DNA. Nerve gas, for example, would probably pass an Ames test, although I'm pretty sure that no one has been insane enough to actually take a look. Long-term carcinogenic potential is not a big issue for the typical nerve gas user.

Here come the harder questions, though: are all carcinogens positive in the Ames test? Do all the things that light up an Ames test cause cancer? And at what level of positive activity should you start to get worried? Bruce Ames himself started to wonder about these questions as the years went on. The answers were a bit surprising. . .(to be continued.)

Sunday, July 28, 2002
Our Buddies at the FDA
Another question I've had posed to me is whether the FDA standards for drug approval are too tight (no one who writes to me seems to worry that they might be too loose, although you can find groups who'd argue just that.)

Overall, I don't think so. There are really two sets of standards, for safety and for efficacy, and neither are really set in stone. From drug to drug and disease to disease, things can slide around - which is how it should be. Safety is an open-ended problem that has to be addressed by closed-ended regulatory solutions, and as time goes one, the bar is raised. We know a lot more that we used to about, say, QT-interval prolongation as a cardiac side effect, and that means that we have to test for it instead of crossing our fingers. If this weren't getting harder, neither the drug companies nor the FDA would be doing their jobs.

As for efficacy, I see the suggestion every so often that this requirement be done away with. I'm firmly opposed to that idea. It would open the door to even more Miraculous Herbal Tonics than we have already - all you'd need to do to get past the safety requirement is make sure your snake-oil doesn't have anything active in it. Honestly, you'd have people springing up selling powdered drink mix at $5 the glass to cleanse your liver, grow new hair, and make your genitalia go out in the morning and fetch the newspaper. What? You say we have that already? Well, now they'd be "FDA-approved" on top of it.

No, I'm all for making companies show that their drugs actually do something. In fact, I'm all for making sure that any medicine entering a served market is tested head-to-head with the competition. Of course, this is often mandated already. And companies often do it themselves so they'll have an edge in marketing - exceptwhen it's a patent extension of one of their own drugs. As I mentioned a while back, I'd make Astra-Zeneca test Nexium against Prilosec, for example, and we'd see who's fooling whom.

There's no doubt that the FDA's gotten pickier in the last couple of years, and all of us in the industry are feeling it. But it hasn't gotten to the point where I think they're stepping over the line.

Thursday, July 25, 2002
What To Do When the Rats Die On You
I've had some e-mail asking if the diabetes drug I mentioned the other day is dead or not, and if not, why not. I don't have any direct contacts in the companies involved, not that they'd tell me all about it even if I did, but I can make some informed guesses. They'll illustrate what happens in these cases.

Readers in the industry will know that this situation (dramatically worse tox results in one species versus another) is a common one. You'd think that mice and rats, for example, would be pretty similar, but there are real differences at every level (from gross anatomy to molecular biology.)

To get off topic for a minute, that's one reason that I'm only partially impressed by figures showing how humans and (fill in the species) share (fill in some high percentage) of their DNA sequences. It's interesting, in one way, but the differences that do exist count for an awful lot.

Differences in toxicology between species, of course, are why the FDA (and drug companies themselves) want to see tox results from more than one species. The more, the better. Most of the time, it's rats and dogs, sometimes rats and monkeys, sometimes all three. Mice aren't considered quite as predictive a species - they're OK for rough-and-ready tox screening (and you need a lot less compound to do it that way,) but not for real decision making.

That's why I'm sure that Novo and Dr. Reddy's weren't thrilled at seeing bladder cancer in the rats, with much less of it in the mice. If it had been the other way around, the path forward might have been a little bit easier, but it'd be hard no matter what. Their compound isn't dead yet, I assume. But what it'll need to go forward is an idea of what the mechanism of the carcinogenesis might be.

Is is the parent compound causing trouble, or some metabolite? Which one? How much of it is in the urine, and how long does it stay there? As mentioned the other day, do rats make more of any of the metabolites, or are they just more sensitive to them? And, the big question once those have been answered: what do we know about how humans might behave?

If the companies have a backup compound waiting in the wings, then we can assume that it's already in intense tox trials. If it's clean, then the original drug is dead, of course, and the backup goes on, more or less as if nothing had happened. But the prudent course would be to do the work outlined above anyway, so you can use it to show why you got the clean tox results you did on the new compound. That's the only way to feel really sure.

I've had animal rights people make the argument to me that such differences in toxicity prove that animal models are worthless. Untrue, untrue. Without testing on animals, no one would have known that this compound could cause bladder cancer in any species at all. The known differences between humans and various animals can then be used to estimate the risks if the compounds proceeds.

If there were an in vitroway to determine the risk, we'd all be lining up to use it. It would, by definition, be much faster, much cheaper, and much easier to apply earlier in the project before all that time, money, and effort gets wasted. If PETA and their ilk would like to devote themselves to developing such tests, I'll cheer them on.

Wednesday, July 24, 2002
Experimental Update
For the six or eight of you who might be wondering, the experiments that I've been talking about on and off for a few months now are back on again. (To catch up newer readers, I've been irritating folks with breathless references to an idea I've had, that I can't detail for proprietary reasons. It ends up like a demented variation of "Charades" where you don't want anyone to guess the answer.)

At any rate, I've found some more test systems that look promising, and that I can get to (chemically speaking) without working up too much of a sweat. These will be exciting to run, because I think they have a fairly good chance of working. And if they don't, that's going to put a dent, a palpable dent, in my hypothesis. Sometime in the next week or so, I'll know.

"And Always Keep Ahold of Nurse, For Fear of Finding Something Worse"
Since the Coleridge quote went over well the other day, I thought I'd return to the line above (from Hilare Belloc) to talk about why things advance slowly in the tox field. It's fear. Justifiable fear. When toxicologists find something that seems to work, they stick with it. They're not easily convinced by the latest gizmos. No one wants to be the first to rely on a new technique and have it backfire, because the consequences in patients are potentially so terrible.

Any new technology (gene chip assays, for example) has to piggyback on the existing stuff for a long time, until there are plenty of cases to show how well it correlates with the existing methods. Given the length of the drug development process, this is a matter of years, many years.

You also want to know when the new stuff might be likely to break down, so you know when to give less weight to the results. The worst thing you can have in a tox test is a false negative, because that can kill people. The second worse thing is a false positive, because that can kill drugs. There's not much room to fool around in.

Everyone Has to Link to The Onion Occasionally
What must be nearly the last word on pharmaceutical marketing to physicians, courtesy of The Onion, is here. A sample: "If Prilosec the drug is anything like Prilosec the pen, I bet it works every time."

Of course, last time I checked, the firewall at work wouldn't even let me see The Onion.How am I supposed to do my job without access to the latest data, I ask you?

Tuesday, July 23, 2002
A Lot More on Drug Pricing
The prolix "Jane Galt" has an excellent piece on the economics of the drug industry, which goes deeper into the details than I ever would dare to. It's well worth reading, and the comments (52 of them as of this writing) are worth reading as well.

Rats, For Fear of Worse
I've had some mail asking a good (and Frequently Asked) question: how good are the alternatives to animal testing? How close are we to not dosing animals to get toxicology information?

My short answer to the second question is, simultaneously, "A lot closer than we used to be" and "Not very close, for all that." The root of the problem is complexity. Toxicological properties are, to use the trendy word, emergent. You need the whole living system to be sure that you're seeing all there is to see.

You could try to mix and connect cell cultures, where the compound, after being exposed to one type of cell, then flowed off to another, and the original cells got a chance, if they'd been changed, to affect other different cell types. . .and so on. But by the time you got all the connections worked out, you'd have built an animal.

An example of a emergent tox problem is the recent withdrawal by Novo Nordisk of a clinical candidate that they were developing with the Indian company, Dr. Reddy's. Bladder cancer was the problem, seen in long-term dosing. But it's mostly a problem in rats - mice showed enough to notice, but it was the rat data that really set off the sirens.

There aren't a lot of good in vitro methods to predict carcinogenic potential. It's for sure that this compound had been through screens like the well-known Ames test for mutagenicity, for example. If it hadn't passed, it's unlikely that they would have carried the compound as far as they did. (I'll be writing more on the Ames test at a later date.)

Bladder cancer's a bit unusual. Playing the percentages, you'd have to guess that the problem isn't the compound itself, but some metabolite produced in the body which concentrates in the urine. And the rodent differences might suggest that rats produce more of this metabolite than mice do (or, alternatively, that they produce the same one, but that rat bladders are more sensitive to it.) Something like this would be the way to bet.

How much are you willing to bet, though? Are you willing to give people bladder cancer, or even put them at risk for it? (And are you willing to invite some many liability suits to land on you that you'll think it's snowing?) Your chances of getting through (and the chances of your customers!) depend on what the mechanism of the tox might be, and whether it operates in humans, as opposed to rats.

Novo and Dr. Reddy's are certainly going to take their time to thoroughly investigate what the problem might be, and whether it can be fixed. There was really no way to anticipate it without animal testing, though, since we don't have an in vitro system that mimics the bladder. Even if we did, they might have run their compound through it and gotten a green light, if the problem is in fact some later metabolic product. There's no substitute for the whole animal.

Monday, July 22, 2002
More on Drug Prices
I can strongly recommend this piece from Robert Bartley in the Wall Street Journal today. It's a clear-eyed look at the issues involved.

There are a couple of misconceptions in it, though. He mentions an "acquisition" of Imclone by Bristol-Meyers Squibb, but their deal was always about clinical candidates, not acquisition. BMS did make a large equity investment in Imclone (well, at the time it was large,) but not enough to have control of the company. That was left in the strong, capable hands of the Waksals.

Bartley also proposes that some drugs be allowed onto the market after Phase II trials are complete, but before the larger (and longer) Phase IIIs. It's easy to see why proposals like this come up, since that's one of the few places in the whole drug business where you can push costs down.

Bartley states that Phase I and II trials "establish safety and offer some evidence of efficacy" as opposed to Phase IIIs. Unfortunately, it's often the other way around. Getting through Phase I does indeed show that there aren't any immediate toxicological issues. And Phase II trials, if well-run, can be enough to establish efficacy. Phase IIIs, though, can be just as much about safety as they are about efficacy. As you expand the patient population and the length of the study, problems that never even broke the surface during the earlier trials can surface.

So, I'm afraid that putting drugs on the market after Phase II would require some sort of tort reform. The sorts of unpleasant surprises that show up in Phase III would be now be showing up in your patient population. And then the liability lawyers would swoop down with eager squawks, pick us clean, and leave our bones bleaching in the sun.

Sunday, July 21, 2002
You'll Only Get Answers
I mentioned the other day that I've usually had a good response when I tell people about what I do for a living. There are exceptions, though. A few years ago, my wife and I were walking through a shopping mall, when we were stopped by two scruffy teenage survey takers.

"Would you like to take a - "
" - survey about animal rights?"
That put a new light on things. "Actually, yes. . ."

So we split up, and started in on the questions. Was I familiar with the idea of animal testing? Yes indeed. Did I realize that the medicines I took had been tested on animals? I most certainly did. Was I in favor of this? Damn right I was.

That broke his stride a little bit, but he recovered. What would be my opinion of some medical product if I found out that it had been tested on animals? More favorable. Now my surveyor was bogging down, and he stopped to stare at me. "Well," I said, "I work in the pharmaceutical industry. I'm actually very happy when something I've made gets tested on animals, because that means it's something that might actually work."

I could see him briefly trying, and failing, to integrate that into his worldview. What, um, would my attitude be, er, about this list of products made by companies that had sworn to do no animal testing? My wife and her surveyor had reached this question, by a similar route, and I could hear her starting in on him: "I'm supposed to feel good because they're using stuff that's right out of the National Formulary? Because all the animal testing was done years ago by someone else, these people are more righteous?"

One of my wife's jobs, before we met, was in the lab at a cosmetics company, as fate would have it. Both of the teenagers stared at us, as if we'd pulled off latex masks and reveled ourselves as green-skinned aliens. "Any more questions?" A shaking of heads. We handed them back their lists of the elect and went on our way.

I'd like to think we left them, like Coleridge's wedding guest, sadder and wiser, but I'm sure we didn't. I think we left them wondering if they could just chuck our answers completely, since we were obviously pulling their legs. I mean, what other explanation was there?

Friday, July 19, 2002
The Dismal Science of Drug Prices
I'm a little disconcerted by Instapundit's endorsement today of the Wellstone drug reimportation bill. My position on this is closer to Andrew Sullivan's (and the reader he quotes here.)

That is to say, I believe prescription drugs aren't correctly priced in Canada and overpriced here. They're underpriced in Canada (and Europe,) and overpriced here to help make up for it. We can argue about individual drugs, and we can argue about just how much one side of the issue balances the other. But I've seen at first hand the amount of money that gets poured into projects that don't lead to a marketed drug, and that money's got to come from somewhere.

That's every single project I've worked on in my 13 years in the industry so far. No, that's an underestimate. I don't think that any of the projects to develop a completely new molecule at any of the companies I've worked for in the last 13 years has made it to market yet. I'm racking my brain, but I can't think of a single one. There are a couple of close calls in there, and a couple that look like they're going to make it, but so far, nothing. That's an insane amount of cash that we're never going to see again, and it's obvious that you can't run forever like that. What's going to give?

Thursday, July 18, 2002
Talk, Cheap and Otherwise
Chad Orzel over at Uncertain Principles has a couple of long posts on giving public presentations as a scientist. My experiences parallel his: a 45-minute talk to your peers isn't too hard to put together, while a 15-minute talk is. And a talk to a lay audience can be harder than either one! (I haven't had to give teaching lectures, so I can't rank those.)

Despite the time it takes to get a good talk together, over the years I've spoken to a lot of school audiences, from kindergarten to high school seniors. By now, I have a couple of standard talks that I use, depending on the audience, where I try to get across a realistic picture of what a medicinal chemist does all day. One thing I've found is that most people I've met are actually interested in the stuff, probably because most people don't know much about it. Those experiences are one of the factors that led to me starting this site, actually.

Research being such a weird job, by the usual standards, doesn't hurt, either. It's something for every working scientist to keep in mind: most jobs are more predictable than what we do. And most jobs don't revolve around turning over rocks in search of truths that no one's ever learned before, either. One thing that I find really throws people is when I tell them that I spend all my time in the lab making chemicals that have never been made or seen before, that if they've been made before we usually don't want them.

At my former company, they let school groups into the lab on tours, and mine was one of the regular stops. As I mentioned once here a few months ago, we kept right on working, and didn't spend any time cleaning up. "You folks have heard about the drug pipeline today, right?" I'd ask them. "Well, there's no pipeline here. This is where the water comes out of the bare rock." It's a weird job sometimes, I'd tell them - but if you like this sort of thing, there's not much else that'll satisfy you.

Wednesday, July 17, 2002
No Pfizer Tonight! Well, Other Than That Headline
The business news has been on top of the science news recently, that's for sure. Maybe we can go a week or so without accounting issues, mergers, and whatnot.

I wanted to call people's attention to a good article in July 8 issue of The Scientist (free, but registration required.) It's a history of a recently developed vaccine for the common bacterium Staphylococcus aureus, a common cause of adventitious infections and septic shock. "Recently developed" isn't too accurate, though, since the research has been going on since the mid-1960s.

I won't go into all the twists and turns of the story, but there are plenty of them. At every step, there were good reasons to think that the entire idea wasn't going to work. Some of these were: Staph aureus doesn't have a polysaccharide capsule, need for a vaccine - wrong. The ones that people cultured didn't have much of one, but the real-world organisms do, of a tricky and complex kind. You can't raise good immunity to that kind of polysaccharide, then - wrong. It took some doing, but an antibody response was seen. OK, but they won't be protective, because people have them already - right, but wrong, for various intricate reasons.

The end result was reported earlier this year in the New England Journal of Medicine, showing a statistically significant decline in S. aureus infections in dialysis patients who received the vaccine. It wasn't a knockout blow, but it was pretty effective for something that was long thought impossible. More trials are underway.

I'm not beating the drum for the vaccine (although I wish it, and its licensee, a company called Nabi, well.) I am beating the drum for sticking with projects through bad patches, as long as there are experiments to run that can get you out of them. There's no point in flogging a project that's come to a dead end, of course, and there's always some useless thing you can think of to try to keep working. But I'm talking about definitive experiments. You should never give up until you've run the best make-or-break tests you can think of.

It's a truism in the pharmaceutical industry that every great drug project has come close to dying at some point. This vaccine effort faced termination more than once, but stayed alive because it passed crucial tests at the crucial times. Maybe having near-death research experiences is actually helpful. They concentrates the mind on key data and key experiments, on the stuff that could be the most convincing evidence to keep things going.

Many projects come to those points and fail, of course. But the projects that I'd mourn are the ones that got killed off before they even got a chance to redeem themselves. Most of them would have failed, as well. Most projects do. But some of them could have been contenders.

Tuesday, July 16, 2002
By Any Other Name
Is it just me, or does it seem a little odd that there was no doubt about what the Pfizer-Pharmacia merged company would be called? Recall that Sandoz and Ciba-Geigy threw two well-established brand names out the window to become Novartis. And Aventis had no choice when it formed; it was such a mouthful that you'd have needed to shrink the letterheads to keep 'em within the margins. GlaxoSmithKline stayed with a modified agglutinative name (note the disappearance of "Beecham" along the way, not to mention "Burroughs-Wellcome.")

Oh well. When Pfizer boarded and captured Warner-Lambert, the joke was that the new company would take the "er" from "Warner" and keep the "Pfiz" from "Pfizer." Maybe the P will be from Pharmacia this time.

Marketing Ueber Alles
The Wall St. Journal's "Heard on the Street" column today made the case that Pfizer's expansion isn't really about scientific research. It's about marketing. They'll have a monstrously huge sales force, a big advertising budget, and so on. The article makes many of the same points that I've been harping on, though, about how getting larger doesn't buy you more drugs in your pipeline.

And they probably have a point about the marketing (bigger, for once, really is better) - but someone's got to do the research. Otherwise, what's there to market? There's only so much that a high-powered sales organization can do. Even internal ripoff drugs like Clarinex and Nexium take up research time (to prove that they're at least as good as the original,) and they're likely to get harder to sell as time goes on. Finding the new drugs is something that every company has to get around to doing, eventually, and that's where the research really has to go.

By the way, it wouldn't surprise me, in the long run, to see a requirement from the FDA to test patent-extension drugs like the above against their parent compounds. Right now, that just isn't done (the studies are generally run placebo-controlled, just like the original drug.) But a head-to-head trial of Claritin versus Clarinex (or Nexium versus Prilosec) would be a fascinating exercise. Let's see the marketing folks explain the results of those!

Monday, July 15, 2002
The Irish Elk. The Mongol Empire. And Other Things That Got Too Big to Work Well.
More thoughts on the Pfizer/Pharmacia deal: One thing that drug execs talk about during a merger, besides "synergy" (hard to get that one out with a straight face any more) and "economies of scale" is how the new megacompany will be able to pursue more lines of research than before. That's taken, rightly, to be a good thing on the whole - the more projects you can afford to run (properly staffed,) the more chances you have of something panning out.

But as far as I can tell, there can be a drift away from that principle as time goes on, similar to what happens when a big multiplex cinema gets built in a town. At first, the owners talk about how this will bring movies to town that otherwise would never make it, and how they'll keep a screen or two for small films or art-house fare. But come back in a couple of years, and they have the latest summer special-effects vehicle showing every single hour of the day on four screens.

Likewise, the temptation for a newly enlarged drug company is to go on with the usual process of picking which projects look good, and then staff them out the wazoo with all the new manpower. You can end up running the same number of projects, with a small army on each one. That can help, up to a point. But some of the delays, twists and turns of a drug development project aren't sensitive to headcount, and this keeps the timelines from scaling the way you'd want them to. Pretty soon, you're back in the same shape you were before, just on a grander scale. Things can end up like the Red Queen's race in Alice, where you're running as hard as you can just to stay in the same place.

What's hard to grasp is that the density of research ideas doesn't scale too well, either. Your new, larger company isn't automatically going to have twice the number of good projects going. Odds are excellent that the two research organizations were working, in many areas, on the same darn stuff. To avoid the trap of fewer, bigger projects, you're going to have to put bets down on some that wouldn't have quite made the grade before. Most of these aren't going to work, even now. But a few of them are, and the big organizations are the ones that have the resources to see those sorts of projects through.

Merck's Bonus Plan
Looking over Merck's proxy statement, it's hard to say just what the bonuses were predicated on. Sales figures are listed as one criterion, though, among other factors. The language leaves open the possibility that different officers of the company had their bonuses figured out according to different rules. There's specific reference to making Medco a success, so it seems to have been very much on the minds of the execs and the board. So, overall, no smoking gun, but no way to rule out the idea that year-end bonuses would have been affected by the Medco accounting, either.

Apatosaurus. Pyramids. The Spruce Goose.
The news this morning is full of the Pfizer/Pharmacia (aka Pharmacia-Upjohn) merger. Perhaps this will trigger the long-expected wave of further drug company consolidation (but, then again, the Pfizer/Warner-Lambert deal was supposed to do that, too.)

I hope it doesn't, but I have to admit that the industry is congealing, and has been for some years. One way or another, we seem to be heading for a world of three or four really humungous pharmaceutical companies in the US, maybe six or eight worldwide. It's not a situation I find very appealing, for many reasons.

Philosophically, I prefer having a multitude of companies, because that seems to be the best way to take a number of approaches to drug discovery. Scientifically speaking, the competition, which can come from anywhere, keeps everyone on their toes and keeps the research moving along. Aesthetically, I doubt if I'd enjoy the atmosphere of MegaPharmaConsoliCorp. Think of its HR department, and the budget they'd have!

And practically, fewer drug companies mean fewer places for people like me, and my colleagues and friends, to work. It's bad enough when a Bristol-Meyers Squibb goes through a bad patch and stops hiring (or starts firing.) What if there are only three big companies, and one or two of them go through a hiring freeze?

It's a real possibility. I've seen nothing to convince me that bigger is all that better in this industry. Small isn't fun, smaller than the giants is hard - but that doesn't have any bearing on what it's like to be a giant. We still don't know how to reliably crank out the wonder drugs, no matter how big the company. Or its HR department.

Sunday, July 14, 2002
Should Have Known
A brief item in the NY Times business section today suggested a reason for Merck's accounting, which is otherwise pretty hard to rationalize (see "Too Tricky for Their Own Good?" below.)

In my experience, a majority of questions that start out with "I wonder how come they. . ." can be answered "money." And so it is in this case. Merck's proxy statement, it seems, mentions that some executive bonuses were tied, among other things, to the yardstick of revenues. Not just earnings - revenues. The revenue that was - I thought needlessly - inflated by booking Medco co-pays (and then taking them right of as cost of sales.)

Sad to say, that makes sense. I'll get ahold of a Merck proxy statement and see what it has to say for myself, and report back.

(For those who saw this post before Monday morning EST, I've edited it to emphasize that revenue wasn't the only bonus factor. More details to come.)

Friday, July 12, 2002
More Pfizer Explosion Details
A short, but detailed story about the Pfizer explosion is here, from C&E News. While I was out on vacation, more details came out. I've been meaning to correct my earlier reports that the blast started with lithium t-butoxide.

It now appears that the cause was a drum of borane/THF, which makes even more sense. If something goes wrong with borane, you get plenty of hydrogen gas and overpressure. I haven't seen the stuff catch on fire personally, but I haven't been around a drum of it, either. THF burns just fine, though (I've seen plenty of that fire, I can tell you, and so have most other synthetic organic chemists.)

On long standing, I've been told, borane can start to react with the THF and open it up. I don't know if that's what was going on here, since that shouldn't lead to hydrogen production. Sounds like a breach of some seal is more likely. At any rate, they're fortunate that they got the fire put out quickly, since there was plenty more of the same stuff (and probably worse) stored nearby.

Thursday, July 11, 2002
New! Viruses So Potent, You'd Swear They Were Homemade!
The big science story at the moment seems to be the SUNY-Stonybrook polio virus synthesis.

To tell the truth, I thought this sort of experiment had already been done. I'm not at all surprised that it worked, and only a bit surprised that it worked as well as it appears to have. Viruses (especially the smaller ones) are rather simple things. Synthesizing the needed genetic material isn't a big obstacle (easier, again, for the smaller viruses.) The Stony Brook team worked out a good system to go from the naked RNA of the polio virus to functioning viruses themselves, and that step is to me the main novelty.

Anyone who uses this as a platform to rant about creation of life is going to have to defend the notion that viruses are alive. And that's a tough one - how can something that doesn't eat, doesn't excrete, and can be disassembled and reconstituted count as alive? A virus is a little von Neumann machine, emphasis on machine.

Using this as a platform to rant about bioweapons is a bit more excusable. The sequence of polio virus has been a matter of public record for a long time now, though, and the road to this experiment could have been taken by any number of competent researchers. Here is a report from 1997 pointing out that very thing. The report (from Columbia U) stated:

"Even if total virus destruction could be accomplished, the small size of the poliovirus genome, whose sequence is known and whose complementary DNA is infectious, would make it possible for a terrorist to synthesize a new stock."

That's five years ago, folks, which is a long time in molecular biology. If this experiment serves to show people how hard containment of knowledge is, then the lesson has been worthwhile. Since genies don't go back into their bottles, it's better if we find out all we can about the ones that are running around.

Wednesday, July 10, 2002
And Now What?
Merck seems to have given up trying to spin off some of Medco in a stock offering. After all the accounting hoo-hah, it's no wonder. But has anyone thought about the original idea?

It seems to me like a sign of desperation to be trying an offering at all in a market like this, a point that I think has gotten lost in all the furor. Wouldn't almost any time be a better time to float Medco? Is Merck really having to turn over that many rocks for capital?

Perhaps the Forbes article I linked to below is right, and the money would have been stored up to buy Schering-Plough. As the holder of a heap of deflating SGP stock, I can only hope - although I don't suppose Merck is going to offer a $50 per share premium, unfortunately. But that money's not going to be there now, so Merck's best chance (if they really want to do that deal) is to wait until Schering sinks even lower - which it's certainly capable of doing.

But if their joint cholesterol absorption inhibitor launch (Zetia) goes well, which is the whole reason for the takeover talk, both stocks will trade up, at least a bit. That deadline might account for the multiple attempts to do the Medco offering. So, if you buy into that whole chain of reasoning, the question isn't why Merck tried to sell off some Medco. The question is, what makes them so confident that Zetia will be a winner? They'd presumably be in a position to know. Then again, you could have said the same thing about Bristol-Meyers Squibb, more than once. . .

Fighting City Hall
A point I made in yesterday's post is worth expanding on - my scepticism about the advent of the Magic Pizza Pill. It's not just hard to develop an obesity drug. It's hard to fight almost any of the biological pathways, even when they're doing harm. Evolution has whittled some of them down to lean, mean, biochemical machines, and the ones that haven't had that treatment are often shaggy, baroque palaces of backup redundant redundancy.

Obesity (and feeding behavior in general) is a good example of the latter. Every year or two, another feeding/satiety signaling pathway is elucidated, and everyone gets excited that this might be the key. The peptide ghrelin is the current example. I hope it works, but the previous star players (leptin, neuropeptide Y, galanin, and so on and so on) have all fallen on their faces. It's often for the same reason: too many backup systems, too strong a thumb on the homeostatic scale. The body really resists delicate tinkering with something as important as eating.

Tuesday, July 09, 2002
Maybe They Can Formulate It In Madeleines
There's a report today that an Alzheimer's medication seems to help memory function even in people who don't have the disease. As reported in Neurology, pilots using a flight simulator performed better when repeating tasks learned while taking Pfizer's drug donepezil (Aricept - it's actually an Eisai drug that Pfizer licensed.)

Before anyone gets too excited, the changes, although statistically meaningful, were small. A quote in the NY Times science section today compared the size of the enhancement to that of the deficit imposed by, say, a hangover. For some people's hangovers that's probably an impressive yardstick, but it was meant to suggest a modest improvement. Still, there's an interesting concept here, and it's been much on the minds of researchers over the years.

Some background: Aricept is a cholinesterase inhibitor, which basically replaced the first such compound on the market, Tacrine (which had sporadically nasty liver toxicity.) As far as I know, it has most of the market for that mechanism. Other companies (such as Bayer) have tried to bring compounds to market, but getting them right can be difficult. After all, a good example of a truly effective, fast-acting cholinesterase inhibitor is nerve gas. You want to back away from that kind of activity for Alzheimer's patients, of course, but side effects are still possible.

And even if the compound is clean, there's only so much a cholinesterase inhibitor can do for someone with Alzheimer's. At best, you can hope to slow the progression of the disease a bit, and response rates vary. Some patients probably show improved quality-of-life, but others are likely wasting their time and money. The whole basis of cholinergic therapy for Alzheimer's (a field I've worked in,) is fairly crude: jacking up the levels of the neurotransmitter acetylcholine across the board. Admittedly, this idea can work for other neurotransmitters (dopamine in Parkinson's disease, or serotonin in depression.) But (just as in the Parkinson's case) it doesn't address the underlying disease; it just tries to ameliorate the symptoms while things get inexorably worse.

But what about people who don't have Alzheimer's? As mentioned above, I can tell you that that question has crossed the mind of everyone working in the memory-enhancement field. What if your drug makes diseased brains more normal, and normal brains. . .better than that? The FDA hasn't dealt much with such issues, understandably, and I can't think of a company that's had the nerve to ask them. But while the market for an effective Alzheimer's drug would be large, the market for a safe memory drug for the general population could be gigantic. The benefits could be similarly huge.

The closest analogy I can think of is the obesity market. Right now, there's no good drug therapy for obesity, period, although people spend billions of dollars trying to say otherwise. Most people's idea of a good obesity drug would be the Magic Pizza Pill - you know, the one you take, and then you can eat all the pizza you want. Don't hold your breath for it; I don't think it's possible. But even a reasonably effective obesity drug would be a huge seller.

And the unspoken assumption about any such drug is that a significant number of the people taking it would not necessarily be all that obese. There are certainly enough obese people to make for a successful drug, and more coming all the time, but there are plenty of folks who would just want to look a little better. Nothing wrong with that, since even modest weight loss is very likely a good thing. But the regulatory assumption is that weight-loss drugs would go primarily to the morbidly obese, whose lives are in more immediate danger. That's not nearly as large a potential market (although at the rate we're going, it could end up being one.)

Companies working on memory-enhancing drugs have had the same thoughts, and done the same math. That said, many of the current therapies being tried for Alzheimer's aren't in this category, since they're more specifically aimed at what seem to be the disease processes. Even among those groups working on memory in general, the odds of dramatically improving function are low. You'd figure that the system is fairly well optimized by now. But what if you did find one? How many people would line up for it? It would be an off-label indication with a vengeance.

I doubt if I would take it myself, not until plenty of others had done so for at least a few years. I'm very nervous and twitchy about CNS medications in general (probably from having worked in the field, as I mentioned!) I have no desire to mess with my brain chemistry unless absolutely necessary.

Local News
I've added two more links to the left - Chad Orzel, a physicist blogger, and MedRants, another interesting physician site. The ranks of the hard sciences in the Blogosphere continue to swell. . .

On another note, I seem to have bollixed up my HTML last night to the point where my counter wasn't working much today - at least I couldn't get it to increment by visiting the site from work, although it opened fine. I hope it did the same for everyone else, and that (contrary to indications) the number of visitors exceeded the single digits. For comparison's sake, I generally get about 200-250 hits per weekday, a number that makes me quite happy, and that continues to increase.

Monday, July 08, 2002
Too Tricky For Their Own Good?
The latest accounting scandal is an odd one. Merck, as the world knows by now, seems to have taken a very aggressive approach to booking revenue from its Medco pharmacy operation. Much of the coverage has taken the now-familiar "How Dare They!" tone. But, as pointed out in Forbes and in some puzzled asides in the Wall St. Journal's coverage, it's hard to see just what Merck thought they were doing.

They booked co-payments made to the pharmacies both as revenue and as costs. That cancels out, of course, so Merck's earnings weren't affected at all (a fact that isn't made clear in some of the commentary I've heard.) But inflating sales from Medco's operations doesn't really do Merck any good, and never has. As pointed out in the Forbes piece, one reason Merck is spinning Medco off (or trying to, at this rate) is that it's a low-margin business that many felt was accounting for too much of Merck's revenue. Sp now we know one reason the problem looked as bad as it did, and it comes to light just in time to wreck the public offering.

Merck's not poor, but they're not as rich as they once were, either. They could certainly use the money from the Medco offering: they've got drug pipeline problems like everyone else, and the game is just getting more expensive. So you have to wonder who thought of this accounting trick, and from what angle it looked good at the time.

Creeping Along Towards Bubble Fusion
In one of the few bits of real news on the Oak Ridge "bubble fusion" story from last March, the June 27th Nature says that a bureaucratic issue has stalled funding for an in-house replication of the experiment. The Department of Energy apparently doesn't allow their discretionary funds to be used for verifying existing work. If accurately represented, this policy is either stupid or insane, depending on your perspective - in any case, it illustrates a truly defective understanding of how science works.

At any rate, the replication team has a formal proposal for DOE funding in the works, which will wend its way through the python of paperwork and be excreted in several months. Meanwhile, the original team (led by Rusi Taleyarkhan) already has a new DARPA grant to continue on their own. They're apparently helping several other (unnamed) groups worldwide to set up the same experiment, and Taleyarkhan says that results might start showing up in four to six months. Maybe the Department of Energy will start to think about convening a working group to recommend that a committee look into the matter by then.

The slow pace of all this is frustrating, but I'm actually a bit encouraged by everything (save the DOE foolishness.) Measure twice, cut once: a flurry of unconvincing data could kill this research off very quickly. I'm also watching some other databases for this topic, because I'd expect to see a patent application publish from Taleyarkhan's group, probably sometime within the next six months to a year. That should be an interesting document.

Sunday, July 07, 2002
Looking Backwards
There are also some odds and ends from the last few weeks that I thought I'd update. First of all, on the Pfizer explosion: the most recent word that I had was that it was indeed set off by a large quantity of reactive reagent, specifically lithium t-butoxide. How that developed a leak I don't know, and I'm not sure they've worked that out at Pfizer, either. But it certainly would generate a lot of heat on exposure to air, as it pursued a career change to lithium hydroxide and t-butanol (plus a pile of kcals.) That would presumably explain the chemical burns mentioned in press accounts. And I'm sorry to hear it, because that must be a fierce injury indeed. Hydrofluoric acid is worse, but caustic of that strength is plenty bad enough.

Another topic I've mentioned on and off is the chemistry idea that I've been pursuing. Well, after several experiments using different starting materials and methods, it's safe to say that the way I'm doing it now just isn't working. But that hasn't dented my faith in the underlying idea all that much (a little - I'm not completely insane - but not seriously.) Although this seemed like a reasonable approach, the facts (so far) say otherwise.

So, it's time to try some other reasonable systems. I'm re-evaluating things, looking for some demonstrations that are closer to known chemistry. It's taking some time, since the reactions I'm looking at haven't been reviewed from the vantage point I need (good thing, too!) This stuff is scattered across the literature, and some of the areas I'm reading in are unfamiliar. But I hope to be back on the horse and going after windmills, er, results shortly.

Finally, I notice that the Weekly Standardhas another ad from the quack medical publishers I fulminated about on June 11. And now National Review has one from the same people! It's really distressing to see this sort of junk in reputable magazines. I wonder if anyone from National Review Online's "The Corner" ever reads this site? Time to find out!

In Media Res
Looking at the stories I've been writing about recently, I can see some that I think will be lying fallow for a while. Imclone, for example, is probably going to be a quiet subject for a bit, until the European trial data come in for Erbitux, or unless something happens involving their remaining Waksal. I don't plan to cover what's going to happen to Sam Waksal; I assume some sort of bargain will be struck to hammer him in exchange for sparing his family members the same treatment.

The same goes for the Martha Stewart side of the story. Some people inside Merrill Lynch seem to have been leaking copiously to the Wall St. Journal about this over the last few weeks. At any rate, that's where all the good dirt has appeared first, attributed to "sources close to the matter" or the like. I confess to just as much schadenfreudeas the next person, but I won't be covering this one closely, either, unless it flares up into something larger than it appears. For those wondering, I didn't short any of her stock (MSO,) which was a shame, since that would have been quite profitable. But if another batch of bad news drives down the price, it might be a reasonable purchase at this point.

As for the Ariad lawsuit, I'm going to continue to watch that one. But I expect things to move at the usual glacial legal pace, with no sudden twists and turns. I will be writing more on the subject of medical treatment patents in general, though.

Wednesday, July 03, 2002
Independence Day
I'd like to take a minute to wish everyone a happily uneventful Fourth of July. I'll be celebrating with our two children, who consider this an extension of our recent vacation trip.

Part of which was spent in Philadelphia: I explained to my 3 1/2 year old about how people here had once written to the King, telling him that they didn't want him telling everyone what to do any more. And that to this day, people from this country don't listen to kings and queens if they tell us what to do; we think about things on our own and we decide for ourselves.

To drag things back to the usual subjects of this site, that's why I'm a scientist, and that's why I think this country has been the greatest place in history to be one. The argument from authority doesn't cut it here. As scientists, we should have no emperors, caudillos, or mullahs telling us what to think about or what kinds of experiments to run.

It's true that there are barriers everywhere, from the simpler ones ("No one's done it that way,") all the way to "The holy books say that this must not be done." But we don't have to live like that; we can only begin to imagine what we're capable of, without the weight of all those chains.

No matter what country we live in, people who believe in free inquiry and the power of reason are all part of the same tribe. Our job was described for us by Francis Bacon: "The effecting of all things possible." Here's to that, to the places in this world where it can be done, and to this one in particular. Happy Fourth of July.

Tuesday, July 02, 2002
Now, Where Was I?
Well, I'm back from vacation, not quite as worn out as I'd feared. But I haven't been keeping up with the news, unless my son's frequent updates on the extinct status of Tyrannosaurs counts (they're still extinct, worse luck, in case you're wondering.)

I'll get oriented in the scientific world tomorrow at work, but it'll be a short week in generalm as mentioned in the previous post. I've had more interesting e-mails on the Ariad patent business, which move me to clear up something:

I don't have the list of roughly fifty companies that Ariad seems to have contacted. That info was from the Wall St. Journal story from last week, which is still one of the more complete write-ups. There's an AP story that several newspapers picked up, but it doesn't really give the flavor of the thing, and Ariad's Business Wire press releases aren't the most wonderful source, either.

If Ariad's really serious, I think we can assume that every company that works in cancer, inflammation, or autoimmune diseases has been contacted. That should give you fifty companies with no problem at all. It would be very interesting to know if anyone has actually agreed to terms with them, but my guess is that no one has. It's too early for anyone to have reacted to the issuance of their patent, and if anyone had licensed with them earlier, I feel sure that Ariad would have press-released the deal until hell wouldn't have it.

The other thing I'd like to make clear is that I have no position, long or short, in Ariad stock. Judging from the trading volume and the choppy look of their daily charts, not many other people do, either. Nor do I have any position in their options, not that there must be too many open contracts there, either. If I do take any positions, I'll state them publicly.