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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 31, 2002

In Case Anyone's Wondering

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Birth of an Idea

May 30, 2002

Innovation and Its Discontents

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Posted by Derek

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?

Comments (0) + TrackBacks (0) | Category: "Me Too" Drugs

May 28, 2002

Back to Whatever It Is I Do

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Life in the Drug Labs

May 23, 2002

A Few Words

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Cancer

May 22, 2002

Did He Say What They Thought He Said?

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Cancer | Press Coverage

Now Is the Peptide of Our Discontent

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Cancer

May 21, 2002

Hype and Glory

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Cancer | Press Coverage

May 20, 2002

Hands Off

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Patents and IP

May 19, 2002

Not As Bad As It Looks

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Patents and IP

May 15, 2002

Eliminate the Middleman

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Posted by Derek

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.

Comments (0) + TrackBacks (0) | Category: Patents and IP

May 14, 2002

After Natural Selection's Through With You

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Posted by Derek

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. . .

Comments (0) + TrackBacks (0) | Category: Aging and Lifespan

May 12, 2002

Back for More

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Posted by Derek

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. . .

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May 6, 2002

Meanwhile, Back at the Chocolate Factory

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Posted by Derek

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.

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Claritin and Clarinex

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Posted by Derek

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.

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So What's A Worthwhile Problem, Anyway?

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Posted by Derek

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?<

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May 3, 2002

The Nuts and Bolts of a New Idea

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Posted by Derek

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.

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May 2, 2002

Measure Twice, Cut Once

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Posted by Derek

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.

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Anything Worth Doing. . .

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Posted by Derek

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.

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