Lagniappe (science, business, and culture)

Friday, May 31, 2002
 
In Case Anyone's Wondering
I'm still working on the research idea I've been talking about. New data from some of my colleagues is helping out quite a bit, but it means changing the experimental design quite a bit, too. Beats flying blind, though, I have to say.

Things have moved from the blast-of-inspiration stage to the get-this-thing-to-work stage. That's a longer and slower one, where many ideas die from lack of nourishment. I'm not going to let that happen in this case - if this idea wipes out, it'll be because it just plain doesn't work, not because I didn't get around to properly testing it.

 
Endostatin - I Rest My Case
Not much time to blog for today, unfortunately. I can recommend this AP article from the 28th as an update on endostatin and angiogenesis therapies in general. Well, one reason I can recommend it is that it sounds almost as gloomy as I do most of the time, and it's nice to see that I'm not the only one. But it's a good overview of the field and its issues, too.

Thursday, May 30, 2002
 
Innovation and Its Discontents
Yesterday's report on pharmaceutical cost and innovation got a lot of play in the media, including the ABC special last night (which I didn't see much of.) I'm of two minds about it: there's some truth in it, but there are important things that it misses.

Companies will do everything they can think of to hold on to a lucrative market. It needs, as Shakespeare said, no ghost come from the grave to tell us this. Drug companies exist to make money, and this is a way to make money. Legal maneuvers to extend the patent life and make things difficult for generic companies are one strategy; internal me-too drugs are another.

As my May 2 post on Claritin and Clarinex shows, I believe that the industry does come up with drugs that have few (if any) advantages over their predecessors. Nexium vs. Prilosec is another example of this, as far as I can tell. Both these are largely designed to replace drugs that the companies already had which are going off-patent.

But the "me-too" label gets thrown around a bit too liberally when it comes to competition between companies. I can tell you, from personal experience, that for a serious R&D effort to be mounted, a project simply has to have some advantage versus the competition. I've never seen a project start off by saying "We're going to make the exact same thing as those guys did, and make up the difference with a huge ad campaign." Huge ad campaigns work better with something to hang them on.

The complexities of pharmacology give you plenty of chances to have differences between drugs that (in theory) might well work the same. Companies try to develop and promote those differences. If the combined size of the total market and the space for differentiation is large enough, you can have several companies piling into the same field, fighting it out.

That could be just plain old better efficacy, as Lipitor seems to have in the crowded field of cholesterol-lowering statins. It could be once-a-day dosing versus after-meals, fewer side effects, or fewer interactions with other drugs. It could be plain old lower price, too: the uncertainties of clinical development make it risky to start a project based on that alone, but it can come up by the end of the project. Ciba-Geigy (now Novartis) tried that with one of their statins a few years back, to pick one from the same area.

That's the free market, and may the best compounds win. Sometimes the differences that are promoted may not be enough to justify a new drug's existence, though. This happens (in my experience) along the way in the development process, when the plan for a bigger market advantage doesn't work out in the clinic. Ideally, such drugs wouldn't fly in the marketplace, but companies will sometimes try to make them take off anyway.

Physicians can feel stampeded when their patents come in asking for a new drug that they don't think is worth the cost. If they don't write for it, they think, someone else will. What we're seeing now, though, is a reluctance for managed-care plans to pay for some of these, a decision which is certainly their right to make. HMOs get to have their free-market fistfights, as well.

As for the general question of innovation, I can tell you that no company tries to make a living from just hopping into crowded fields where there's already competition. You have to innovate to survive. On the flip side, trying to break absolutely new ground every time out is a risky strategy, too, given the failure rate and the expenses involved. We can argue all day about just how much it takes to develop a new drug, but if you're the first-in-class in a new area, it's going to cost you more. But the potential payoff is bigger, too - you can have some real fun calculating the risk/reward, especially since some of the key numbers are impossible to truly quantify.

I'd also like to see a study like yesterday's address what happens to some of the groundbreaking drugs that they cite favorably. For example, they mention Avandia and Actos (rosiglitazone and pioglitazone) for diabetes in the category. Leave aside the fact that these two drugs work via almost identical mechanisms (with some slight differences, which the companies are, as per the above, trying to exploit.) And leave aside that they were developed at the same exact time, in sull knowledge that they'd be going head-to-head in the marketplace (which one was the me-too, if either one was?)

No, what I'd like to point out is that these innovative therapies weren't the first in that class. That would be Rezulin (troglitazone.) That was absolutely the first drug on the market to work by that mechanism, and the first to do what these compounds do for diabetes. Avandia and Actos were expected to have to go out and dethrone it; that's what the companies planned for. But Rezulin went down in flames due to toxicity, which only showed up when it got into a broad patient population. The lawsuits are still flying. If it had made it, then the other two drugs would surely be cited as more of those nasty, money-grubbing me-toos.

Where's that one in the sound bites about "nothing new in the drug industry"? The money spent to develop and market Rezulin is gone, and it's not coming back. Lots more is going to vanish, is vanishing right now, going to plaintiffs and lawyers. How do we make up for that?

Tuesday, May 28, 2002
 
Another Law of the Lab
Back on April 24 I mentioned a list of "Laws of the Lab" that I wrote up some years ago. Interestingly, a coworker of mine who reads this site told me that he'd seen a copy posted on the wall when he was in graduate school, and had had no idea that I was the "Lowe" in its title.

Last time, it was "You Can Never Have Too Much Starting Material." This time, it's "Think Twice Before You Get Rid of the Old Route, or You Will Spend Months Saving Time."

It's an insidious trap, that one, because you stay busy the whole time (and staying busy in the lab is what it's all about, right?) Back on May 6, I mentioned that almost any problem can be interesting, so you might as well work on the ones that are both interesting and important. The same principle applies here: almost anything will fill your days doing research. You can come up with enough work to keep you going 20 hours a day - alternate reactions, different conditions, back-up plans. But to what avail? It can be hard to slow down enough to ask yourself.

I've fallen for this one more than once, of course. I'll hit some roadblock in the science, and think about how to get around it. A plan sounds good, so I'll start in on it - and run into another hitch just trying to get that to work. But there's a way around, that, too, of course - just try this other reaction over here, and if that doesn't work. . .

Notice that at some point in there, things go off the rails. If I don't watch out, I'll end up working on the third alternate route to the reaction that could make the second way around the problem in my possible backup synthesis work. Busy? You bet, more work than I can handle! But productive? Well. . .depends on how you define productivity. If, like a fool, I measure it only by notebook pages consumed and flasks dirtied, everything looks fine.

I recall being impressed at one point in my career by a guy down the hall from me, who was working like a man possessed. Every time I went past his lab, he was in there cranking away, looking like a multi-armed Hindu deity with each hand holding an Erlenmeyer flask. Turns out that he was working like this because he was doing almost everything in the longest, most wasteful way possible. No wonder it look so much effort.

This law, in part, comes back to the old advice of "Measure Twice, Cut Once." It's a hard rule to remember, when you've got a box of saws and the wood is just sitting there. But it's worth trying to look through the clouds of sawdust to see if there's any real carpentry going on.

 
Back to Whatever It Is I Do. . .
Coming back to the lab after a few days off presents the same picking-up-the-threads problem as any other job. Just what was I doing, anyway? It was even worse when I was spending all my time synthesizing molecules (now, I spend some time doing that, and the rest of the time sitting in my office, looking at my computer screen with a puzzled expression.)

It took me years to learn that I actually had to write down all the stuff, so I'd be able to remember what it was. That's not just notebook-keeping, although I've never been a shining example of that, either. It's more about what stage things are in, what's coming up next, what the plans are if this doesn't work, and how this batch needs to be split up, and some of this stuff over here needs to be held back because of. . .that sort of thing. That's not the sort of detail that generally goes in a notebook. My problem was that it wasn't the sort of detail I generally put anywhere else, either.

For some reason, I always thought I'd have all this in my head, all the time. And while I'm working in the lab, I do. How could anyone forget? But after a vacation, I was always amazed when I opened up the "Ongoing Lab Work" box in my head, and all this dust would blow out, along with some hungry moths. My first day back always involved a lot of staring at flasks, trying to recall what was in them and why, along with a lot of useful thoughts about what an idiot I was.

It didn't help that I often had my flasks labeled with helpful phrases like "Large Batch," "Second Fraction," "Keep," "Impure," and such. Nothing like those to bring the details rushing back.

Thursday, May 23, 2002
 
A Few Words
I see that some of my comments have spread to investors in Entremed, so let me take a few paragraphs to mention some points. I should write these up in a combination FAQ / disclaimer to deal with these situations.

First off, as it says on the top of the page, I don't speak for my employer. To avoid confusion on that point, I'm not even mentioning them by name, nor will I comment about specific situations that are directly relevant to their business. There are so many things to write about that I don't have to touch on anything sensitive.

So, the fact that I'm talking about Entremed means that, well. . .they aren't directly relevant. They're just another small company with a cancer drug candidate, trying to get it through trials. As you'll notice, I've also written about others in the same category, like Imclone and Sugen. If I held off commenting on companies like these, I might as well not write about anyone.

As for the personal end of things, I own no Entremed stock, nor am I short, nor do I have any option position in them. My policy is that I'll disclose any such holdings I may have in any company I write about. Frankly, anyone who uses this site as an investment tool had better hold onto their hat. The perspective I bring is that of an experienced (and sceptical) scientist, which I believe would be a good weltanschauungfor any pharma/biotech investor to have. But I'm not revealing inside information about anyone or anything, positive or negative.

Finally, there have been some comments about cancer patients and what Entremed's compounds could or could not do for them. That's an argumentum ad misericordiamby proxy, and it's worth just as much as the regular kind. To counteract another Latin tag (De mortius nil nisi bonum,)Voltaire once said that one owes respect to the living; to the dead one owes only the truth.

I believe that that applies to the gravely ill as well. Science deals with the facts, the dirty lowdown, and that's the most valuable currency there is when you're trying to find a treatment for a dread disease. Tumor cells won't listen to analyst reports, or message board posts. They respond only to facts. Right now, it's my considered opinion that those facts say that Entremed's compounds are likely to be inferior to other treatments in development.

The other side of that cold, hard coin is that I can be proven definitively, thoroughly wrong. That's another thing we're good at in science. In this case, I wouldn't mind a bit: I would be very happy indeed if these peptides turn out to be good enough to save lives. But as I see it now, I don't think it's the best place to put your money, or your hopes.

Wednesday, May 22, 2002
 
Now is the Peptide of Our Discontent
Mickey Kaus, in his link to yesterday's post, mentioned that the company I work for seems down on peptides as drugs, and asked his readers to keep that in mind when they read my opinion on endostatin. All I can say is, it isn't just me (or my company.) You won't find much of anyone trying to develop a small protein as a drug. They're just too tempting for a variety of enzymes to tear up; this is a problem that's been known for decades.

Larger proteins, oddly, can have a bit more potential, although not for oral dosing. Depending on how they're folded, they can have a decent half-life in circulation, if you can get them that far (or, failing that, the effects they set off can be reasonably long-lasting.) Insulin and interferon are two examples that come to mind, both of which have to be injected, but work well.

There's been a huge amount of work devoted to making proteins stable enough to be given orally. Usually, the sorts of changes you have to make are also big enough to wipe out the activity you wanted, too. But there are some techniques that can work - attaching a long polyethylene glycol chain is a good one, known to the cognoscenti as "PEGylation." Glaxo SmithKline just signed a deal with a small company that is doing just this sort of thing to insulin. Many schemes have been hatched for encapsulating the proteins in some sort of vehicle that'll sneak them past the gut enzymes, with decidedly mixed success.

And there are ways to get around the digestion problem completely. It turns out that large proteins cross the nasal mucosa into the bloodstream surprisingly well (no, in case you're wondering, cocaine isn't in this category - it's a small molecule.) Several companies are working on this, with an inhaled form of insulin in advanced clinical trials (it's had its problems.)

For small proteins, there are all sorts of ways to modify the peptide bonds to make them less attractive to enzymes (putting in the wrong-handed amino acid, unusual methyl groups, other bonds instead of the usual amino acid amide connection, and so on.) It's a hard living, because many of these changes also get rid of the original protein's activity, and they don't always increase the levels in circulation, either. If you're going to go the peptidomimetic route (many have,) then you need some commitment, because it could take a while.

 
Did He Say What They Said He Said?
I've received some mail pointing out that James Watson denied the "cure cancer in two years" quote which appeared in the 1998 Times article. I was aware of those denials, but (since you have to make a judgment call on these things,) I believe that he probably did say it.

Why? First of all, because it's hard for me to believe that Gina Kolata, the Times reporter, would invent such a doozy of a quote. It's one of the main things that people remember about the article, four years later. It would take nerves of steel (and some other metallic parts) to fabricate that one. Second, Watson has a history of, well, outspokenness. No one I heard at the time had much trouble believing that Watson would have said it. Or that he'd deny it. The incident occurred at a dinner party; I don't know if other witnesses came forward.

I'm also sticking to my interpretation of the Times story as well. Angiogenesis wasn't a new concept when the piece came out. Folkman certainly had been one of the main movers behind it for many years, and his story was well worth telling, but the article centered just as much on the peptides he was working on. Note the link above, which was written at the time of the initial furor. Its whole focus is on the two peptide drugs, and whether they were miracle cures or not. Here's another 1998 story from Time with the same take.

Tuesday, May 21, 2002
 
Hype and Glory
Over at the new home of Kausfiles, Mickey Kaus wondered on Monday about all the news coming out of the ASCO (American Society for Clinical Oncology) meeting. Does it show that the hype in the famous 1998 NY Times front-page story on Judah Folkman and his cancer therapy was actually justified? Does the world owe Gina Kolata (the reporter) an apology?

You won't catch me offering too many opinions on welfare reform over here, so I can't resist weighing in when Mickey Kaus has some on drug discovery. Some background: the ASCO meeting is one of the most Wall Street-ocentric of the medical meetings. It's a forum for late-stage cancer trial results to be presented, and investors watch everything for signs. The headlines from the meeting tend to be out of proportion to the actual news.

Witness the NY Times the other day, saying that Imclone's Erbitux drug "fails" against a placebo. Nothing of the kind! (I seem to have imported some Kausfiles exclamation points.) I'm intensely sceptical of anything Imclone has to say, but these results (as the Times story pointed out about 3/4 of the way through) just failed to show Erbitux working well. Absence of evidence isn't evidence of absence. This was a small study, and the placebo group fared much better than expected, which blew the statistical significance of the Erbitux results. It happens, and that's why you try to run big studies when you can: a larger sample has less chance of showing this sort of jumpiness.

It's true, though, that there's a lot of anti-angiogenic drug news at the meeting this year. But there was a lot last year, and the year before. Angiogenesis has been the hot topic for many years now. Judah Folkman deserves the credit for pushing this idea, and for sticking with it for a long time without much company. But that was well before the Kolata article; by the time it came out, every major drug company (and plenty of minor ones) was on the case, and had been for years. There are a lot of different angiogenesis mechanisms, and a lot of room to work in.

That's why, when I read that article, I smiled to myself at the breathless tone it took about Folkman's peptide drug candidate (a tone that wasn't Folkman's fault.) Because peptides, like his Endostatin, generally make lousy drugs. For one thing, you can almost never give them orally; they have to be injected, like insulin. (The biggest reason is that your gut treats the peptides from a pharmacy exactly like it treats the ones from a hamburger: it digests them, rapidly tearing them down to amino acids.)

And angiogenesis inhibitors, like many of the other new cancer therapies, are probably going to be every-day drugs, which are no fun to inject. It's doubtful that they'll make the cancer disappear completely, and in some cases they'll do well just make it stop growing. If you stop taking the drug, the tumor will probably pick right up where it left off. I can't imagine anyone wanting to find out. (Combinations of the newer drugs with the older cytotoxic ones might deliver the knockout punch, but again, who wants to find out that it didn't? Those will be difficult trials. . .)

Orally active small molecules are the way to go - and I don't say that just because I get paid to discover them. They're cheaper to make, easier to purify, and you can take them with the beverage of your choice. Entremed, the company that licensed Endostatin, is still trying to turn it into a drug (burning through heaps of Bristol-Meyers Squibb money for a few years along the way.) Meanwhile, small molecules targeting angiogenesis are already closer to being approved. I honestly don't see what a difficult, unstable peptide is going to have that these compounds don't.

The person associated with the Kolata article who really deserved to be whacked over the head is James Watson. He grabbed the spotlight with his ill-considered statement that "Judah is going to cure cancer in two years." Well, it's been four years now, and it's not happening. Judah Folkman's concept is already going a long way toward curing cancer, but his compound isn't. And that's the real problem with Kolata's article: angiogenesis wasn't news, and endostatin wasn't news. Drug development is the news, but it's slow, expensive, and doesn't make a snappy above-the-fold very often.

Monday, May 20, 2002
 
Hands Off
There's another aspect to pharmaceutical patenting that you really only find in the US, among major countries: "method of treatment" patents. I don't care for them, myself, but before I explain why, it'll help to see what the usual patents cover.

The traditional drug patent is for composition of matter - you've made some new chemical compound, and you're claiming it as your own. If your new compound is too close to someone else's claims, they can come after you (via the "doctrine of equivalents,") but generally that's not a problem. If it's really new, it's yours if you want it. A footnote for the future: as chemistry advances, we keep having to push into new territory to find patentable material, and some day it's going to be a real problem. For now, finding new stuff is often just an inconvenience, but ask me in twenty years, and I might word things more strongly.

What if you've found something useful, but someone else already owns it? Then you can get a "use patent" - you claim this compound (or class of compounds) for the particular use. If the compound itself - the composition of matter - belongs to someone, then the two of you are in a standoff. They own the compound, but they can't use it. You can use it, but you don't own it. That's the time to have your people contact their people, and hammer something out.

Similarly, if the compound you've found is something that was already known in the literature (or from an expired patent,) then no one can claim composition of matter, and a use patent is the best you can do. It sure beats nothing.

Now for method of treatment claims. These claim the use of some compound (any compound!) that works by some mechanism you've discovered, to treat some disease. That sounds innocuous, but it can spray down a whole field of research. If I'm the first person to discover that blocking the whateverase enzyme is good for treating allergies, say, then I write a patent claiming whatever compounds I've discovered to do it (composition of matter,) the use of those compounds to inhibit whateverase, and the treatment of allergies by using anything that blocks it.That last one is the medical treatment claim. It means that if you go find a compound (a totally different compound,) that does the same thing, then you can patent it until you turn blue. But you can't use it. I've got the medical treatment patented.

The European patent office won't allow those claims, at least not in so many words. They hold that such claims are an unlawful restraint on medical practitioners. There's a tricky technique known as a "Swiss Claim," where you write things up like this: "We claim the process of producing compounds such as Structure I, which are useful for the treatment of allergies through inhibition of whateverase." You didn't claim the treatment per se;you claimed a process of making a compound. But you worked in the whole purpose of making the compounds, and if you've written things in a convoluted enough form, it can be very hard to disentangle the two. A good Swiss claim is virtually a guarantee of a prolonged court fight.

I'd prefer to see the whole business disappear. Medical treatment claims have become more and more popular in recent years, and they're driving everyone in the drug industry nuts. It's turned into a mutually-assured-destruction game: "So, you claim all that stuff! Hah! I claim all this!" If we keep this up, we're going to end up with a medical landscape made up of Balkanized patches, with barbed wire and wasteland in between.

But what to do about it? As these things show up, researchers that wouldn't have thought about writing such claims feel forced to keep up. As long as they're possible, they'll be used. It may take a few years, but I think that we could be heading for some interesting situations if some of the sealed-off treatments look like they could turn into blockbusters. . .

Sunday, May 19, 2002
 
Not As Bad As It Looks
The patent whose illustration I reproduced here the other day is a weird one; I can't take away from that. But in many respects, it's a well-written and reasonable patent, and the way the law is written, I don't see any reason why it shouldn't have been granted.

Some of the key things a patent should show are novelty, disclosure of the best mode of carrying out the invention, and comparison with the prior art. Now, I haven't carried out an exhaustive survey of the butt-kicking literature, but the inventor seems to have taken some time to do all of these. You can contrast that with some of the loser patents that are being granted in what are supposedly more exalted fields. For example, pharmaceuticals. . .

Take a look at those requirements again. Novelty is the easy one, in some ways. These days, you just go on for a paragraph or two about how unprecedented your invention is, contrasting it with the most hapless previous examples you can come up with. Best mode disclosure is a bit more tricky. There's a legal quagmire between this requirement and your right to keep a trade secret, and some truly nasty patent battles have been fought in that swamp. Most of the time, though, you can disclose best mode without too much problem, since the process is still being refined as you write the patent. This lets you show the best way you currently know how to do things, and allows you to reserve later tricky refinements as trade secrets. (When it gets nasty is when there's evidence that these two eras overlapped.)

That brings us to prior art, and here's where the stink of dead fish becomes pronounced. As Greg Aharonian never ceases to point out, technology patents in general do an awful job disclosing prior art. In some cases, the reason for this is pure laziness or stupidity. More oftenm though, the motives are baser. If you just ignore prior art that might invalidate your patent, you can get the thing granted more easily. Then it's an uphill fight for someone who wants to invalidate it - after all, you've got the law on your side until someone proves otherwise. It's doable, but you've raised a barrier that someone will have to think about.

In recent years, there's been a variation on this technique. There are patents that actually disclose what, to an outside observer, would appear to be invalidating prior art - and the patent office grants the thing anyway. This disclosure usually consists of dropping the references into a list, and not dwelling on them in the text. The patent examiners are so overworked that they let a lot of this stuff through.

And if you want to invalidate one of these winners, good luck. Because now the very thing you want to use to show the patent shouldn't have been granted is. . .in the patent. And, legally, has been assumed to have been considered, and found insufficient to deny the application. You're stuck with arguing that the examiner made a mistake, which is generally a losing position.

You've got a better chance of getting one of these through if your examiner is not only overworked, but incompetent. I have it on good authority that some companies will submit the identical application in multiple copies (which is illegal,) waiting to see which examiners get assigned to the cases. Then they'll pick the one that they know from experience is the least demanding or skillful, and withdraw the other applications. I'm proud to say that that one wouldn't have occurred to me.

Friday, May 17, 2002
 
While We're In Update Mode
Another story from this morning was the latest in the Imclone saga. Merck (Germany) has the European rights to the anticancer therapy Erbitux, as everyone learned in the last installment of this soap opera, and they're conducting their own trials. Imclone (and Bristol-Meyers Squibb) have been trying to get them to alter the trial design to provide more data for them to resubmit the drug to the FDA.

But no one's saying just what those alterations were. The New York Times reports that Handelsblatt (the German business daily) has a story that Imclone wanted at least 200 more patients added to the trial. The (unsourced) story goes on to claim that Merck KGgA turned around and asked for comarketing rights in the US, pointing out that Imclone's request was outside the terms of their contract. (Bristol-Meyers Squibb, already co-owner of US marketing rights, would presumably have vetoed that idea.)

What all this means is that the common wisdom back a couple of months ago, that the FDA had agreed to review the data from the German trial as it was then set up, might not have been correct. If everything was agreed on, it's hard to see why Imclone would be asking for what amounts to further delay (enrolling more patients takes time.)

Imclone's record of full disclosure about Erbitux and its development doesn't seem too impressive so far, and this latest episode doesn't change appearances. Something to keep in mind in the coming year as the press releases start appearing, isn't it?

 
Following Up
I'm still adding to my essay on patent problems; I'll try to get that off the ground for Monday. That article won't, unfortunately, be illustrated like the one below! Not that there aren't enough weird patents out there to do the job. . .

For now, I'll update some things that have been recent topics here: Viropharma (see March 19) received a "non-approvable" letter for their antiviral, Pleconaril. The stock promptly lost a chunk of its remaining value, but why anyone would have (a)still been holding it, and (b)been taken by surprise by this action is a mystery. When the FDA advisory committee gives your compound the treatment that Pleconaril got, the non-approvable letter is generally just a matter of time.

Schering-Plough, about whose Clarinex I wrote on May 2, has disclosed some seriously bad news. There is apparently a criminal investigation taking place at their Puerto Rico manufacuring plant. S-P has had some longstanding problems with manufacturing, both there and in New Jersey. As of this morning, it looks like they're going to end up paying the 500 million dollars they set aside for fines coming out of this.

All this has driven their stock still lower, which would increase talk of a takeover. But it's hard to see how that'll happen until this latest investigation gets resolved; that sort of thing really complicates a due-diligance check.

Finally, for those who are interested in the research idea I've been guardedly writing about the last few weeks, things are going along well. Several co-workers are helping out, and we're getting close to having things lined up for some more definitive tests. I'll post updates as the results come in, but I won't be going into too many more details until then. Which, considering that I'm working on that post about intellectual property, makes sense!

Wednesday, May 15, 2002
 
Eliminate the Middleman
There's been a lot of talk recently about problems with the US and European Patent offices. And there are some serious issues to talk about, too.

Maybe tomorrow I'll talk about them! But for now, I pass along US 6,293,874, issued last September, titled "User-Operated Amusement Apparatus for Kicking the User's Buttocks." Have trouble believing this one? The full patent's here.



 
If You've Ever Worked Next to Me, You've Heard This Story Already
There are reports that Mars may have hexavalent chromium compounds in its surface dust, which is already being brought up as a concern for future human exploration. I agree with comments I've seen that this is putting the cart in front of the horse a bit, but it also means that I probably wouldn't be a good candidate for the expedition. I've already had my lifetime's exposure to Cr(VI).

Back in grad school, I had an undergraduate assistant one summer, a guy who was pretty green. I'll refer to him by an altered form of his nickname, henceforth as Toxic Jim. I shouldn't be too hard on him, I guess: I was a summer undergrad in my time, too, and I wasn't a lot of help to anyone, either. But TJ did manage to furnish me with some of my more vivid lab stories in his brief time in my fume hood.

One morning I showed him how to make PCC. That's pyridinium chlorochromate for the non-organic chemists out there, an oxidizing agent that doesn't seem to be used as much as it was 15 or 20 years ago. Even in '85, you could buy it, but the freshly-made stuff was often better. It certainly looked nicer. Like all the Cr(VI) salts, it has a vivid color, in this case a flaming orange. I shouldn't say "flaming;" that's getting ahead of the story. . .

It's not hard to make. You take chromium trioxide, a vicious oxidant in itself which comes as clumpy fine purple crystals, and dissolve it in 6N hydrochloric acid. That's an easy solution to whip up, since it's just concentrated HCl out of the jug cut 1:1 with water. I had Toxic Jim do all this - weighing out the chromium compound, making the HCl. During that part I couldn't resist quoting the ancient adage, which works well in the East Arkansas accent of my youth: "Do like you oughter, add acid to water." Most chemists either remember that one, or they remember the syrupy conc. acids splattering all over their arm when they did it (once!) the other way around.

We set up a three-neck flask with an overhead stirrer to run this in. That's just a motor mounted above the flask, turning a shaft with a paddle on the end of it. Works well for really thick mixtures, which this was supposed to turn into. As things turned out, it was even thicker than planned, for a brief exciting interlude.

In went the HCl, out of a big Erlenmeyer flask, and in went the chromium trioxide. Here's where the wheels began to come off. Instead of a vivid red-orange solution, the stuff got dark and began to thicken. I could tell it was getting hot, too, since you could see the clear wavery solvent vapors coming out of the open necks of the flask. And that was wrong, too - you don't get that so much with water vapor. It's the mark of organic solvent fumes, with their different density and refractive index.

And so it was. TJ had indeed grabbed the wrong Erlenmeyer. Not the one he'd just mixed up the HCl in, but one from another part of the bench that contained ethyl acetate from a big chromatography run the night before. Ethyl acetate is a pretty poor substitute for hydrochloric acid, most of the time, when you stop to think about it.

Then the overhead stirrer began to bog down, which takes a mighty thick mixture to achieve. I hadn't added up what had happened at this point, but I knew that things were going wrong in all directions at once. I pulled the glass hood sash down some more, saying "I think you better stand back -" WHOOOOMPH!

And there it went! The whole reaction went up in a big fireball, which filled a good part of the hood and came roaring out of the gap in the front sash. I felt the heat roll over me, yelled something incoherent, and bolted for the safety shower. I didn't have to run up Toxic Jim's back, either: he was making for the door in championship time. Pulling the chain of the shower dumped a hundred gallons of ice water on me immediately, not that I needed any more waking up.

When I opened my eyes and took inventory, things weren't as bad as I thought. Limbs and appendages all present, head and facial hair still attached - though lightly singed and frizzed - skin not even sunburnt, although it (along with my lab coat) was generously splattered with green. That was what remained of the chromium trioxide. It was now the Cr(III) oxide, having given up three oxidation levels by turning the ethyl acetate into carbon dioxide, most likely. There were a few orange-brown spots of the Cr(VI) stuff, but those were mostly confined to the front of the lab coat, in a vivid line that showed where the hood sash had gotten pulled down to.

My hood wasn't looking its best. There was smoke hanging in the air, although that was getting pulled out. There was a huge stain of the green and brown chromium mixture all over the inside, thickest in the directions of the three open necks of the flask. Which was still intact - if I'd been foolish enough to set this up in a closed system, the whole thing would have gone up as Pyrex shrapnel. Even the ceiling had a line of gunk on it, from the thin gap in the hood sash assembly.

While I was taking this in, wondering what the hell had gone wrong, and wondering what I could possibly do to TJ that was worse than what he'd just gone through, the emergency crews arrived. It was a Saturday morning, but Bob across the hall saw the explosion and immediately dialed 911. In came the fire crews, trying to talk through their breathing apparatus: "Mumph heff deff umphh cafulteff. . " "What?" "We hear there's a casualty up here"

I put my hands on my hips, and gave them the full effect of my green spots, frizzed hair, and soaking wet lab coat: "That would be me."

Tuesday, May 14, 2002
 
After Natural Selection's Through With You
There's an interesting article on aging in the latest issue of Current Biology. The researchers used gene-chip assays, which look at over 13,000 genes simultaneously for signs of up- or down-regulation, in populations of aging fruit flies.

Fruit flies share a rather unnerving number of similar genes with other animals (all the way up to us,) and their short live span makes the attractive for this kind of study. What makes this one stand out is the amount of detail it goes into.

The team checked the flies at different time points, in multiple populations, and under conditions of normal aging and caloric restriction. That last technique - basically, living close to starvation - has been shown in increase life span in many species. There are some people trying it as well (you have to be pretty careful with your nutritional balance, and the question always comes up about how wonderful excess life span can be if you can't eat anything. . .)

This study also controlled for how much the various genes tend to vary. You can see some genes tripling in activity, and it means nothing, because they vary naturally even more than that. Others are so steady that almost any change (up or down) is news.

Gene chips have been all the rage for a few years now, and they're getting more powerful all the time. But not too many people control their experiments with them as well as this group did, which often makes it hard to figure out what the data are telling you. In this case, though, they saw about 800 genes that were definitely associated with age-related changes. Half of those changed whether the flies were calorically restricted or not.

Some of them were things that had already been picked up by other studies. But there are quite a few new ones (enzymes and proteins that inhibit them, proteins involved at the cell nucleus, and others) that no one had fingered before. This paper will be a road map for some time to come for those looking at aging.

And many are, or will be. I think that over the next ten to twenty years, this is a field that could really take off. What use is a longer lifespan if you spend your extra ten (or 20, or 30) years as an eighty-year-old? Let's add those extra years to the twenties, thirties, and forties instead.

This is just the sort of research that probably sends Francis Fukuyama up the wall, to judge from his recent book and op-eds. (There's been a huge pile of commentary in the Blogosphere about all this, which I assume people have seen.) It's true that changing the human life span will probably lead to all sorts of disruptions - but we've done it before. The last hundred years has been a huge experiment in lengthening the average life expectancy, but because it was done by improving mortality rates and nutrition, no one had any room to object. In the same way, no one objects to the long, slow genetic engineering that humans have been doing with their crops and domestic animals. It's just when things get more efficient that the alarm bells start to go off. . .

Sunday, May 12, 2002
 
Back For More
No earthshattering news from the meeting (not, as you could tell from my last post, that I necessarily expected any.) I did make good use of some of the time, though, by taking a stack of scientific literature with me and (for once) actually reading most of it.

Like most researchers, too often I equate photocopying a paper (or, for the more recent years, printing off a copy of the PDF file) with reading it. This was brought home to me again as I made my way through this stack. The papers I'd taken with me are the ones that come closest to the idea that I've been (obliquely) talking about for the last few weeks. I was going over them hoping to pick up some relevant details that could help out in the next experimental tests.

That I did. I'm now convinced that the experiment I ran last week had almost no chance of actually working, and I'm almost equally convinced that I know why. (I generally find my own arguments pretty convincing, which is a mental habit that can be an equally great strength or handicap. You never really know which until it's too late, though. . .)

At any rate, I think that there's a key variable in my experimental setup that I've wrongly estimated. It'll take a few days to rearrange things to put that hypothesis to the test, but that's the next order of business. Of course, if I get everything lined up and things still don't work, I haven't proven anything. But the changes I'm making make logical sense to me (and to my other co-workers who are helping out or following along.) If things don't work this time, at least I'll feel that I've given them every chance to. And I'll be incorporating these changes in the future variations I've spoken of (the ones that, intrinsically, I think have a better chance of working.)

Whenever you change something in your experimental design, there's always a nagging fear that you're unknowingly about to abandon the only conditions that could make things work properly. In this case, the good part is that the original setup I chose is still available. It's the starting point for the new one, and I can (and will) still take data under those conditions as I go on into the new conditions.

Of course, the downside of testing things out this thoroughly is that your original idea is on the chopping block the whole time. Getting all the variables figured out, thinking through just how you want to run things - these could be just sharpening the blade. The nerve-racking thing about science is that we really do prove things. And sometimes we prove ourselves wrong. . .

Tuesday, May 07, 2002
 
Back In A Few
There will be (at best) minimal posting here until Sunday night. I'll be gone the next few days at a meeting, which will take us into the weekend, my traditional (four months now!) time off.

I have to say that I'm not a great fan of scientific meetings. This one is part science, part business, not that that ameliorates things. I believe that most scientific presentations, as a means of imparting information, might as well have been concocted by Beelzebub.

"I've got something really interesting and important to tell you. So I'm going to run it by you once, from fifty feet away, in the dark." Great. There's no time to think about the implications of what you've heard, and no good record of what was said to refer back to. And this is assuming that the presentation was done well. . .when it's a truism among scientists that most of our colleagues couldn't lecture their way out of a sack. Inter caecos regnat luscus,though; the ones who can do it well really make an impression. But even in those cases, I'd still rather read their articles when I want to think about their work.

At any rate, I'll see everyone again Sunday night!

Monday, May 06, 2002
 
Meanwhile, Back at the Chocolate Factory. . .
The attempt today to put one facet of my latest ideas to the test wasn't too encouraging. I didn't get the effect that I was hoping for, but the data suggest some complications that might have intervened.

The next set of experiments is coming up soon, and I'll incorporate what I've learned this time into their design. Next time I try this particular angle, I'm going to do it with several closely related starting materials, in hopes that some of the factors that complicated today's run might clear up with changes in that aspect of the system. If they do, then it's great news. If they don't, then I can rule out some more explanations of why things are going like they are. An ideal experiment is one whose every possible outcome is full of unequivocal meaning. I can't set up one of those, but I can try to make the ones I have cut in as many simultaneous directions as possible.

I've also received an offer of assistance in the form of another analytical technique, which could prove very useful on its own and as a reality check on the others. If any of this stuff starts to work, I'll need all the reality checks I can get.

 
So What's A Worthwhile Problem, Anyway?
My last post naturally leads to that question. I can only speak for my own specialties, organic and medicinal chemistry. An example of really worthwhile problems in the former would be (to pick a few at random): how to form quaternary carbon chiral centers, how to get metal-catalyzed couplings to work more generally and reproducibly, a new inexpensive method to make unnatural amino acids, or a way to turn the nitroaldol reaction into something generally useful.

Examples of worthwhile problems in the latter field would be: how to make good phosphatase inhibitors, how to predict better what sorts of compounds will be absorbed out of the gut into the bloodstream, how to make new things that can substitute for a peptide bond, or how to approach compounds that interfere with protein-DNA interactions.

It's not like no one's worked on these; there are ideas and partial solutions to most of them. But a real advance in any of these areas would be welcomed by plenty of people, and recognized as a significant achievement.

Making lists like that is easy. What about things that have no obvious use? I'm still in favor of those, because the history of science has shown over and over that you can never tell what oddities may turn out to be useful. There's a lot of curiosity-driven research that gets done on projects like these.

So what isn't worth doing? Doing something that's already been done, because everyone's doing it or because you can't think of anything else for one. Doing things that (even if they worked) have already been superseded by techniques available when you started.

And examples of those? Here's where I bring in the fan mail! Things in organic synthetic chemistry that I wouldn't consider worth the effort might include: total syntheses of large natural products that add no new methods to the literature, adding yet another Lewis acid to the long list of the Lewis acids that can be used to, say, form acetals from aldehydes, or similarly coming up with yet another way to dehydrate an aldoxime to a nitrile. But you can pick up chemical journals from the last year and find all these things, and likely worse.

I'll forebear, for now, listing things that I don't think are worth doing in medicinal chemistry, for fear that I'll go to work tomorrow and find that someone wants to do one of them. My point is that many of these dud problems could nonetheless occupy your time, have their high and low points, their challenges and solutions, just like a real research project. If you didn't know better, you'd think you were doing something useful. You could spend nights and weekends on some of these things, and to the untrained eye you'd be getting an awful lot of work done. But to no point.

Of course, one reason I can have this attitude is that I've spent time on such things myself. It's only with time that I've come to see that science is so intrinsically tricky and interesting that almost anything can fill your hours and engage your mind. But isn't it better to find yourself getting interested in something that, someday, someone else might find interesting, too?

 
Anything Worth Doing. . .
There are several types of questions in science. You could plot them on a graph, with axes labled "Important / Trivial," "Hard to Answer / Easy to Answer," to pick two useful distinctions. Note that those don't always correlate as well as you'd think. There have been profound scientific questions that turned out to be surprisingly easy to put to the test, once someone figured out the conceptual framework.

And, more controversially, there are problems that (as far as you can tell) aren't worth the effort it would take to work on them. That's what Peter Medawar meant when he advised working on hard problems, not necessarily just interesting ones. Almost any problem can be interesting, including a lot of trivial time-wasters. It's sorting those out that can be troublesome.

For one thing, sometimes things that look trivial turn out to be important. And science lives on incremental results, and by making connections between things that no one thought were related. But in many cases, you can restate the problem to show why something is worthwhile. Take Fleming and penicillin:

"This stuff landed on my petri dish and killed my bacteria - I'm going to find out what it is."
"Who cares? It's spoiled. Clean it out and get on with your work."
"But something killed off these bacteria, and it looks like this mold may have secreted it. Wouldn't that be useful, to have something that can kill bacteria?"

There's a lot more to the traditional tale of this discovery - we'll come back to that. But it illustrates the point that problems can often be presented in a way that shows why they're worth working on. Of course, you can take work that isn't worth doing and try to present it this way, too (look at some grant applications!), but you can usually spot the seams and stitches that had to be added.

And I can't deny that there have been important results that have been ignored when they first came out. But in most of those cases, they've been ignored because they weren't believed, nd they weren't believed because their (potential) importance wasn't in doubt.

I'm not suggesting that researchers shouldn't follow their own curiosity, or that we should have some sort of central review to tell us what's important and what isn't. You couldn't pay to advocate either of those positions; they're disastrous. But what I'm suggesting is that researchers should sharpen their own instincts, and put their curiosity to the best possible use. More on this as the week goes on.

Friday, May 03, 2002
 
The Nuts and Bolts of A New Idea
Well, Monday will mark the first test of the research ideas that I've been talking about (see the 4/28 and 5/2 posts below.) It's not the perfect experiment that I'd like, partly because it'll be testing one of the less-likely forms of the idea. On the flip side, if this one works, plenty of other stuff probably will, too. I have the starting materials I need ready to go, as well, which comes under the "bird in the hand" principle.

The main uncertainty is still in the control experiments. There's a way that I could get a false positive in this experiment, and there's no way to keep that from happening. It's intrinsic. But there is a way to control for it, leaving out one key factor in a separate experiment. If that run gives me the same result as the "real" one, then I'm in trouble. It'll mean that what looks like a positive result could just be what would happen anyway. I've got several "Plan B"s to go to at that point, other experiments with different starting materials that still might show that the underlying idea could work (just not on the first thing I tried.)

If the results are different in the control versus the real experiment, though, it'll be time to break out the party hats. But I won't know that for a while yet, unfortunately. The complicated part is that I can use a fairly straightforward method to measure how things are going, but it'll only work for the real experiment, not the control. There's a more complex method that'll work for both, so that's what I'll need to do the key head-to-head comparison. It won't be ready for prime time for another week or two; I have some colleagues who are going to work on that for me.

So, Monday's experiment is just a first hurdle. Using the straightforward readout, if the real experiment shows something, that's a necessary (but not sufficient!) piece of evidence. I'll be relieved, but I won't be high-fiving anyone. If it doesn't show anything, though, I'll know to move immediately on to one of those Plan Bs I mentioned.

One of those doesn't deserve that label, actually - it's the system that I think has the best chance of all of them of showing the effect I want. But it requires some chemical synthesis, which is in progress. With any luck, I'll have the necessary compounds made at about the same time my friends in the other hallway get the robust method for comparing the experimental results. When we get that all working at the same time, we'll be ready for some serious moments of truth. Monday's, by comparison, will be a small one. But I'm excited, just the same.

Thursday, May 02, 2002
 
Claritin and Clarinex
I get a lot of Google search hits about those two drugs, so I thought I'd give the public what it wants. I've mentioned that I still hold some Schering-Plough stock (dog though it's been recently,) and I'm about to do my holdings some minor amount of further harm.

That's because, frankly I don't think very much of Clarinex. I've already written (on March 10) about Sepracor and their role in its development. Fitting in with their business plan, Clarinex is another active-metabolite drug idea.

As I've been mentioning in connection with all the acrylamide business, the liver does a fine job ripping up organic compounds. Most of these altered compounds don't do much except go sluicing out the kidneys, but some of them are active. As it happens, Claritin has one main metabolite, and it still has the antihistamine effect that Claritin itself has. (This situation is becoming less frequent, by the way, since the FDA has come more and more to frown on active metabolites in general. Your regulatory path will be simpler now if you don't have any.)

And it's not an exotic transformation, either. For the organic chemists in the audience, it's loss of an ethyl N-carbamate group, down to the NH. Looking at the structure of Claritin, this is the absolute first thing that any competent medicinal chemist would predict as a main metabolite, and so it is.

That means that if you've taken Claritin, you've taken Clarinex. You starting taking it about twenty minutes after you swallowed the Claritin, when that dose started going through the hepatic portal vein and into your liver. It also means that the synthesis of the compound is essentially identical to Claritin, with really only a one-step difference to change the amine.

And, unfortunately, it also means that Clarinex is one of the more blatant me-too drugs out there, this time an internal one. I can't blame Schering, actually. It was clear for years that they'd need something to take up the slack of the Claritin franchise, and there have been some very good shots taken at that in several therapeutic areas. But none of them have paid off yet, and the company decided to do whatever it took to keep a revenue stream coming in. The other choice was virtuous penury, culminating in firing employees who are now occupied, instead, with finding something more useful. It's hard to see that as a better path.

But that still doesn't make Clarinex any better as a drug. I haven't gone over all the clinical data, but I find it hard to imagine that there's any particular advantage over Claritin. And if perchance there is, I find it hard to imagine that it's worth the price disparity versus (generic) Claritin. I may get some feedback setting me straight on this, but it'll have to be pretty convincing to change my mind.

 
Measure Twice, Cut Once
Not much time to post at the moment, between home life and work. If this were in my single days, I'd be at the lab until all hours working on the ideas I spoke of, but I don't think my two small children would care for that (and I'm certain that my wife wouldn't!) I give her updates on what's going on, though (we used to work at the same pharmaceutical company, and she knows the field.) Actually, I even give my 3 1/2 year old son updates: "Daddy, did you use your stir plate today?" "Yes, I did!" "Did you use your hydraulic hammer?" "My what?" "Did you use a backhoe today, Daddy?" "Um. . ."

I'm involved now in experiment design, trying to make sure that I control for all the possible explanations of what could happen. I find it useful to imagine myself explaining this stuff to the most sceptical/hostile people I've encountered in my scientific career. Picturing what questions they'd ask is a good way to come up with control experiments to make the results stronger.

It's frustrating not to immediately run and set something up, but a few days spent at this point could mean a lot. An experiment that looks like it might be big, but could also be explained by something uninteresting, is almost worse than having a negative result. With a little care up front, I can avoid that situation completely.