About this Author
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: Twitter: Dereklowe

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August 31, 2005

More Fun With Impact Factors

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Posted by Derek

Yesterday's post introduced journal Impact Factors to those who haven't had the honor of meeting them yet. Everyone whose livelihood depends on scientific publication, though, already knows them well, since anything that can be measured will be used at performance evaluation time. IFs are a particular obsession in academic research, since publishing papers is one of those things that an aspiring tenure-seeking associate professor is expected to do. (On the priority list, it comes right after hauling down the grant money.)

But that's not what we value in industry. We know about the pecking order of journals, but we just don't get a chance to publish in them as often as academics do. I'd much rather have a paper in Angewande Chemie than in Synthetic Communications (to pick the top and near-bottom of the reasonable organic chemistry journals), but it won't make or break my raise or promotion hopes. Now, having zero patents might do the trick, but that's because patents are a fairly good surrogate for the number of potentially lucrative drug projects you've worked on.

Nope, it's academia that has to live by these things, and there are complaints. On one level, people have pointed out that impact factors may not be measuring what they're supposed to. Here's a broadside in the British Medical Journal, pointing out (among other things) that the individual papers inside a given journal follow a power-law distribution, too. It's glossed over by the assignment of a single impact factor to each journal, but the most-cited 50% of the papers in a given journal can be cited ten times as much as the lesser 50%.

The less interesting papers are getting a free impact ride, while the better ones could have presumably been playing off in a super-impact league of their own, if such a journal existed. The authors also point out that journals covering new fields with a rapidly expanding literature - much of which is also ephemeral - have necessarily inflated IFs. Does it really indicate their quality? (Well now, say the pro-impact people, isn't this just the sort of carping you'd expect from the BMJ, who live in the shadow of the more-prestigious Lancet?)

But there's also the problem of self-citation. As ISI's own data make clear, lousy journals tend to have more of it. (The text of that article seems to spend most of its time trying to deny what its graphs are saying, as far as I can see.) So if you think that the Journal of Pellucidarian Materials Science has an unimpressive impact factor, wait until you see it corrected by stripping out all the citations from the other papers in J. Pelluc. Mat. Sci. If you accept what IFs are supposed to be measuring, you have to conclude that the huge majority of journals are simply not worth bothering with.

On a different level, there's plenty of room to hate the whole idea, regardless of how it's implemented. The number of citations, say such critics, is not necessarily the only (or best) measure of a paper's worth, or the worth of the journal it appears in. (As that link shows, the original papers from both Salk and Sabin on their polio vaccines are on no one's list of high citation rates.)

It is no coincidence, they go on to point out, that the promulgators of this idea make their living by selling journal citation counts. And by conducting interviews with the authors of highly cited papers and with the editors of journals whose impact factors are moving up, and God only knows what else. The whole thing starts to remind one of the Franklin Mint.

Comments (11) + TrackBacks (0) | Category: The Scientific Literature

August 30, 2005

Our Friend the Impact Factor

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Posted by Derek

I had an email asking if scientists in industry care about journal impact factors. It's an interesting question, but it needs to be answered in parts. Unless you deal with academic publishing, the phrase probably doesn't mean much. "Impact factors" are an attempt to quantify what everyone knows empirically: some journals are more prestigious than others. You know how we science types love to quantify stuff.

The whole business comes from the folks at ISI (now owned by Thomson.) They had been publishing the Citation Index for years, which was (and is) a way to find out who had referenced a given paper in the scientific literature after it was published. This can be useful if you want to see if anyone's followed up or commented on an interesting paper (or if you just want to see if anyone's cited your own work.)

And as ISI realized early on, it could also furnish some interesting rankings of "most-cited" papers in a given field. (Here's a recent set of lists from Chemical Abstracts, the big dog in the chemical information world, who got into the citation-counting business themselves.) You could figure out who the most cited authors are, too, although that ISI link won't rank-order them for you. (You have to pay for that data! Or you can look here.) There are lists of the most highly cited institutions, too, naturally.

About ten years ago, they introduced the Impact Factor to do the same thing for scientific journals. That's the number of citations generated by a journal (usually over a multiyear period) divided by the number of papers it published in that time: the average number of cites per paper, in other words.

The publishing community - initially rather worried and sceptical, if my memory serves - has gone completely crazy over the whole idea. Now journals advertise themselves by their impact factors. "Publish here! We're a good journal, really! We have proof!" If you'd like to know what a particular journal's rating is, they'll probably shout it out if it's any good at all. A failure to mention the number, down to three decimal places, is an act that speaks for itself.

Want the whole list? It can be rather hard to come by, unless you're a paying customer of ISI's, but here's a place to start. Those aren't the latest figures, but they'll do. You'll notice that at the top are a bunch of review journals, who publish comparatively few papers but get cited out the wazoo. Among the original-research journals in the top ranks are big kahunas like Cell, Nature, the New England Journal of Medicine, Science, and such. But I find a perverse fascination in browsing the low end of the scale. The Ethiopian Medical Journal? Fertiliser Research? Bovine Practice? Annals of Saudi Medicine? Surely some of these trench-dwellers ceased publication and vanished from sight during the rating period. The list of "0.000" impact factors is particularly alarming, although most of the journals listed are there by some sort of statistical artifact or (I presume) don't really exist. But if no one reads them, how do we know if they're real or not?

In the next installment, we'll look at some problems with the whole idea - there are some - and I'll tell you if we industrial types give a hoot about it or not. . .

Comments (6) + TrackBacks (0) | Category: The Scientific Literature

August 29, 2005


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Posted by Derek

One of the things that came up in regard to that last post was the idea about blood being acidic or alkaline. I don't think that most people outside the medical sciences realize how much effort the human body expends on these matters. Those of us who keep up with these topics could do some good by letting people know how robust this stuff is.

To listen to most quack nutritionists, your body is in perpetual danger of flying apart. This thing is out of balance, that thing over there is running low, all these other things are set totally wrong. You need. . .herbal supplements! Of the kind that I happen to sell! Fix you right up! Of course, if you stop taking them, your physiology might well just start wobbling around again, so you'd better play it safe. . .and it so happens that we offer discounts on a yearly supply. . .

Now, it's not like things can never get out of whack, but a lot of metabolic energy goes into keeping that from happening. Biologists, MDs, and medicinal chemists are always getting surprised at just what sorts of abuse a living system is capable of absorbing without breaking down. Homeostasis is what I'm talking about. That concept applies to a huge number of living processes, but we'll stick with one dear to Kevin Trudeau's alleged heart: acidity and alkalinity.

The pH of the blood is held steady around pH 7.4 by several systems, not all of them well characterized, but all acting at the same time. The amount of carbon dioxide that the lungs exhale (or retain), the actions of the kidneys, and the circulating blood proteins are all involved. (Buy why it's pH 7.4 and not some other value is one of those very good questions that no one has a very good answer for.)

One of the main places that your body can go acidic is in muscle tissue during exercise. That's due largely to the buildup of lactic acid from anaerobic metabolism, and can send the interstitial fluid between muscle cells down to pH 7, much lower than blood gets under the same conditions. (There seems to be something about the capillary wall that excludes the excess acid, which is yet another control mechanism.)

Going alkaline is usually a sign that something's off with your breathing or with your kidneys. (You'd better hope that it's the former, because you can stop hyperventilating a lot easier than you can stop kidney trouble.) In either case, it takes a lot to overload the various pH controls, and if you do manage to - in either direction - you can be headed for serious trouble and even death.

This should illustrate why the "alkalinity causes cancer" theories from the likes of Kevin Trudeau are nonsense. The blood of people who get cancer is at pH 7.4, like everyone else, and that number (if it fluctuates at all) moves around according to whether or not that person just took the stairs, rather than whether they're drinking "coral calcium water" or whatever damn thing. pH changes in your stomach aren't reflected in the blood - if they were, we'd be dead as soon as we smelled lunch.

But all you have to do is Google any combination of "blood" "acid" and/or "alkaline", and you'll step off into a swamp of people who are trying to convince you otherwise. It's a simple, appealing theory, which if it were true it would explain a lot and immediately suggest ideas for treatment. But it's wrong, and it's been known to be wrong for a very long time. The only utility it has is as a prybar to separate people from their money.

Comments (18) + TrackBacks (1) | Category: Snake Oil

Nature Doesn't Care: Latest in a Series

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Posted by Derek

Not only New Orleans, but Gulfport, Biloxi, Mobile. . .here's the Red Cross online donation page.

Comments (0) + TrackBacks (0) | Category: Blink ›

August 28, 2005

Kevin Trudeau's Snake Oil Empire

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Posted by Derek

The time has come to take up the case of Kevin Trudeau. His pernicious book has hit the top of the New York Times best-seller list, a fact that the paper itself seems to find surprising. This 570-page doorstop is an ax job on my industry and my field of research, and accuses my peers and me of complicity in terrible amounts of human suffering. ("The drug industry does not want people to get healthy" is one of his favorite lines.)

How, you wonder, do people like me accomplish such awful things? Why, by denying consumers wonderful all-natural cures for just about everything that could possibly be wrong with them. And how do you find out about these wonders? By forking out for Trudeau's book, naturally. And when you find out that there's hardly a paragraph of specific information in the whole thing, then you can go pay him more money to get access to the untold amounts of crap on his web site. $499, according to the Times, will buy you a lifetime membership. This from a man who says "I changed my priority from making money to positively impacting people."

The medical rationales Trudeau offers are hardly worth even discussing, and make me feel like positively impacting the man with a spiked club. Readers who know some biochemistry might be forgiven if they haven't heard that "If your body is alkaline, you cannot get cancer. . .and if you have cancer, it goes away." I would be interested to hear what on earth he means by a person's body being alkaline - last I heard, my blood was at pH 7.4. But there's really no sense in arguing with the sort of person who can get things like this out with a straight face.

This is someone who spins tales of herbal clinics that cure cancer, every time. Of wonderful all-natural cures that will reverse type I diabetes. Of simple cures for multiple sclerosis, for heart disease. These are not harmless ideas - these are lies that can kill people, and given the number of books Trudeau has sold, they probably have. Perhaps his next book will detail the story of his consciencectomy. No doubt Kevin Trudeau moves around from mansion to mansion, but how he can sleep at night in any of them escapes me.

Update: Longtime reader Don Hertzog sends along this recent demolition of Trudeau in Salon (free registration required.) If you have some time on your hands, the Amazon review pages for the book are worth a look, too - there are over 800 reviews there, and most of them are from some pretty ticked-off customers.

Update 2: Ha!

Comments (32) + TrackBacks (1) | Category: Snake Oil

August 25, 2005

The Painful History of Substance P

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Posted by Derek

I had a question from a reader about Substance P, a peptide that's been known since the 1930s as something that was involved in pain and neurotransmission. Its biological target is the neurokinin receptor subtype NK1, and there's been a huge amount of research on this system over the years, studying its role in the peripheral nerves, the spinal cord, and the brain.

And most of this work pointed to the idea that something that blocked this pathway would be an excellent analgesic. Stimulation of SP-responsive neurons produces sensations of burning pain, for one thing, and injection of the peptide is very unpleasant.) Weirdly, naked mole rats don't use the SP pain pathway, and are impervious to normally painful things like treatment with pure capsaicin. (Capsaicin, the hot pepper active ingredient, causes quick release of SP and the accompanying pain sensations, but ends up depleting it from presynaptic neurons, eventually raising the pain threshold.)

Pain relief is one of those things that some people think has been solved, but it really hasn't been. It's hard to knock down severe pain without knocking out the patient or using something with a high addictive potential. There are plenty of conditions - burn injuries, diabetic neuropathy and cancer come to mind - where a powerful analgesic with fewer side effects would be welcomed with rejoicing.

Several groups took a shot at making antagonists, but there were a lot of wrong turns along the way. For one thing, the NK1 receptors in mice are rather different from the ones in humans, something that was only worked out after many people had been led astray by mouse models of pain. (The good ol' guinea pig, which in spite of its reputation isn't really used much in drug research, turned out to have closer homology to the human receptor.)

And when good compounds were finally developed at Merck and other companies, and were taken into clinical trials for pain relief, an interesting thing happened: they didn't work. Not at all. The title of a review article from a group at Merck (Handbook of Experimental Pharmacology, p. 441, 2004) shows the frustration: "Substance P (NK1) receptor antagonists - analgesics or not?" They go on to say:

"Despite the identification of high affinity and selective substance P (NK1) receptor antagonists and a plethora of preclinical data supporting an analgesic profile of these agents, the outcome from clinical trials has been extremely disappointing with no clear analgesic efficacy being observed in a variety of pain states. This has led the pain community to seriously question the predictability and utility of preclinical pain assays, especially for novel targets."

Indeed it has, and the situation is far from being sorted out, from what I know of it. But Substance P had more life in it. As its distribution (and that of the NK1 receptor) in the brain began to be worked out, people noticed that it was often co-localized with the serotonin system, and these lines of evidence suggested a role in depression. Merck's MK-869 was the first compound to go into the clinic for this purpose.

And it died there, too. Initial results looked promising - check out this glowing report from 1998. But the next year, it was dropped, after failing to work better than placebo under controlled conditions. (That link is well worth reading for those interested in the topic of placebo controls, BTW.) After much searching around, NK1 antagonism was found to be imporatant enough in nausea and emesis for MK-869 to make it as an adjunct to cancer therapy. It's on the market as Emend (aprepitant), selling (as I put it in 2003, about one-fiftieth of what Merck had originally hoped. You have to wonder how long it'll take them to get their money back.

Many other companies have reported development of NK1 ligands, but I don't think that any have reached the market yet - and I don't know what they'll do if they get there. The whole area is an excellent lesson in the crazy complexity of drug target validation and drug discovery, and an interesting thing to consider when you wonder why drugs cost what they do. But we won't have to worry about Merck spending the time and money to learn such things if we sue them until they're crippled, now will we?

Comments (5) + TrackBacks (0) | Category: Drug Industry History | The Central Nervous System

August 24, 2005

Having the Hands

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Posted by Derek

After working so many years in organic chemistry labs, I notice that I have all these little motions and flourishes in my technique. For example, when I'm draining the bottom layer out of a separatory funnel, I always drain it down almost to the bottom, and stop. Then I swirl it around a little bit, because there's always some of the bottom-layer solvent that's still stuck to the sides and hasn't crept down yet. That quick swirl knocks it down, along with any droplets that were holding on to the meniscus at the top. Then I take the stopper out, wiping it edgewise across the ground-glass joint to catch any dripping solvent, and always put it on the side area of my stir plate. Only then do I drain the remainder of the bottom layer. And every time I turn the stopcock off, I automatically reach up with the flask or test tube I'm using and swipe it across the tip of the funnel, to catch the drop that's always hanging there.

I don't usually pay attention to these things in such Proustian detail, but I got to thinking about all the lab habits I've built up in the last 25 years or so (I'm counting back to my undergraduate days.) These things are instant signs, in any field, of someone who's been doing it a long time. They have a set of automatic routines that work and have always worked, and they don't need to think about them any more.

I couldn't tell you, for example, when the last time was that I poured something into the top a sep funnel whose stopcock was left open, although in my first years in the lab I did that a few times (to loud curses.) I'm past all that. Now, I make the advanced mistakes.

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs

August 23, 2005

Outside Reading

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Posted by Derek

A few more links for further reading. . .

Professor Bainbridge wonders about what the Merck verdict says about our jury system. (The quotes he gives from the Wall Street Journal report make me feel like breaking something loud and costly.) There's plenty of comment on the same topic here at Asymmetrical Information as well.

Colby Cosh asks if engineers have become mentally crippled by early exposure to PowerPoint, in light of some disturbing reports from inside NASA. (And an engineer replies that the problem probably comes from the work environment, not the schooling. I don't know whether to be relieved or not. I see an awful lot of the stuff myself, so I hope it isn't taking too great a toll.)

And Medpundit looks back on a Nobel Prize-winning chapter in medicine. But it's not one that a lot of people like to be reminded of. . .

Comments (2) + TrackBacks (0) | Category: General Scientific News

Gritting Our Teeth

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Posted by Derek

I'll tell you a company that's been watching what's happened to Merck and thinking hard about it: Sanofi. Well, OK, everyone in the industry has been looking at Merck's situation and shuddering, but I suspect the people at Sanofi(-Aventis) are especially jumpy. Why? Rimonabant.

Rimonabant, which will come to the market next year (most likely) under the name Acomplia, is one everyone's short list of potential multibillion dollar drugs. It'll be the first new drug treatment for obesity in years, and it's the first one ever with its mechanism of action (antagonism of the CB(1) receptor). It has potential for many sorts of addiction therapy as well. Although there's room to argue about just how effective it is compared to existing therapies, and there's some concern about how many HMOs will pay for it, there's little doubt that it's going to sell like crazy.

And there's the worry. There is absolutely no way that large enough clinical trials could be run on a drug like this to predict everything that might happen when millions of people start taking it. Can't be done. You can get down to a margin of safety that will get you past the FDA, but that isn't enough, now is it? No, if one person out of a hundred thousand has a nasty side effect, that's enough to bring the sky down on your head. And we can't test down to the level of one-per-hundred-thousand effects.

A fine situation, isn't it? This same argument applies to every new drug, naturally, but especially to a groundbreaking compound like rimonabant. That's just what we needed, an incentive not to be first in class with a new drug. What, exactly, are we doing to ourselves?

Comments (3) + TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Diabetes and Obesity

August 22, 2005

Mutual Suspicions

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Posted by Derek

I'm not saying these are all true, or true all the time. But here are three things that industrial pharma researchers tend to believe about academic ones:

1. They talk too darn much. Don't even think about sharing any proprietary material with them, because it'll show up in a PowerPoint show at their next Gordon conference. How'd that get in there?

2. They wouldn't know a real deadline if it crawled up their trouser legs. Just a few weeks, just a few months, just a couple of years more and they'll have it all figured out. Trust 'em.

3. They have no idea of how hard it is to develop a new compound. First compound they make that's under a micromolar IC50, and they think they've just discovered Wonder Drug.

And (fair's fair), here are three things that academic researchers tend to believe about industrial ones:

1. They have so much money that they don't know what to do with it. They waste it in every direction, because they've never had to fight for funding. If they had to write grant applications, they'd faint.

2. They wouldn't know basic research if it bonked them on the head. They think everything has to have a payoff in (at most) six months, so they only discover things that are in front of their noses.

3. They're obsessed with secrecy, which is a convenient way to avoid ever having to write up anything for publication. They seem to think patent applications count for something, when any fool can send one in. Try telling Nature that you're sending in a "provisional publication", details to come later, and see how far that gets you.

Comments (5) + TrackBacks (0) | Category: Academia (vs. Industry)

August 21, 2005

Okay, One More Merck Point

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Posted by Derek

You know, there is one more thing about the Merck case I'd like address. This is brought on partly by the general press coverage of whether Merck knew this or hid that, and partly by an intensely irritating comment to Friday afternoon's post.

You would think, to hear the way some people talk, that no one at Merck ever took Vioxx. That they just launched it onto the market with an evil cackle and a shout of "Caveat emptor", then sat back to watch the money roll in. Actually, employees of Merck very likely took Vioxx at a rate above that of their cohorts in the general population - employee discounts, you know. I've no doubt that this applies to Merck's marketing department, to their clinical development groups, and to their toxicologists. Why shouldn't they take their own company's drug if they're in need of a COX-2 inhibitor?

It's not very far to the conspiracy theories that pop up about cancer, about HIV, about every awful disease you can imagine. "You know," some fool will whisper to you, "that the drug companies really have a cure for it. They're just waiting until more people get sick. In fact, they're probably making sure that as many people get it as possible."

It's difficult for me to express coherently my contempt for that idea. Let me assure you that employees of pharmaceutical companies, and their relatives, and their friends, are potential heirs to every disease that this world offers, just like everyone else. I might add that it's particularly hard to watch someone you know suffer and die from a disease that you've been working for years to treat, but still have nothing to offer for.

So enough of this division between Merck and the rest of the world. Merck is a large company, with tens of thousands of people in it. Many of them took Vioxx. No small number of those people probably worked on it. I'd like to hear how that pulpit-pounding Texas attorney would work them into his world view.

Update: For plenty of good commentary on the legal aspects of the Merck verdict, see Ted Frank's post at Point of Law.

Comments (12) + TrackBacks (0) | Category: Current Events | Press Coverage

No More Merck For A Couple of Days

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Posted by Derek

I'm glad to hear that the punitive damages in the Merck case will be automatically reduced under Texas law. But the jury award will still set a public precedent, which I fear that later juries will be tempted to see and raise. Hey, if the Texas fellow was worth $253 million, who's to say that the next plaintiff isn't worth even more? There may be a tendency to dig deep into the pile of money while it's still there. Ay, what a depressing topic. I hope that everyone who dislikes the drug industry is enjoying this; someone should be.

Comments (1) + TrackBacks (0) | Category: Current Events

August 19, 2005

Judgement Day

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Posted by Derek

A during-the-working day update, and I don't think I've ever done that for good news. Merck has been found liable in the first Vioxx trial. The jury has awarded 24 million dollars in outright damages, and $229 million in punitive damages. (If you'd like a strictly utilitarian, economic response to that award, start by pricing out what $253 million dollars of life insurance will cost - that is, if you can get anyone to not hang up the phone on you.) Merck, of course, is going to appeal.

It shouldn't be any surprise to find out that I think that this is terrible news. While I think Merck really pushed Vioxx too hard, as have the other companies with COX-2 inhibitors, I don't see a way to justify that large an award. This might open the door to a number of such awards, and Merck could end up spending its money fighting for its life rather than trying to bring new drugs to market. Enough of these losses, followed by losses on appeal, could sink the company completely.

I know, I know. They should have thought about that before flogging Vioxx to everyone that could bend their finger joints, right, right. But if every new drug we take to market is going to have a reasonable chance of ruining the company, why bother? And I know the answer to that one, too: "just make sure they're safe." What tiny words "sure" and "safe" are. You wouldn't think that they could cause the trouble that they do.

Comments (18) + TrackBacks (0) | Category: Current Events

August 18, 2005

Everything's Under Control, Right?

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Posted by Derek

One of the odd things about science is that you spend a good amount of time trying to prove that you don't know what you're talking about. At least, if you're doing it right, you should.

Take the first part of a drug discovery project, for instance. Most of them have a "primary assay", which is usually done against a purified protein in vitro, under fairly artificial conditions. Compounds that meet some standard of activity against that target then move on to the secondary assay, which is supposed to be aimed at the same process, but now it's done in living cells. That's a much tougher test. (It's a big leap from pure proteins to cells, about the same size as the leap from cells to whole animals.)

The hope is that the two assays will correlate with each other, but it's never a perfect fit. Generally, what you see is some of the active compounds dropping out for no apparent reason in the cell assay. If your target is in the cytoplasm, then there's always the possibility that these compounds don't penetrate into the cell as well as the others. Or they make it in, but are pumped right back out before they can get anything accomplished. Or perhaps they find some other (even tighter) binding site once they're inside, on some protein unrelated to the readout of your assay. There are always plenty of ways to explain these misfires.

And that's fine, as far as it goes. But if you don't double back and check these things out occasionally, you run the risk of fooling yourself. If your two assays don't correlate very well, it might be that cell penetration is lousing things up, sure - and it might also be that your assays aren't measuring the same thing. Or it could be that your target from the first assay isn't as important as you thought it was. These are the sorts of thing you really ought to be sure about.

So you need to keep yourself honest. Take some of your not-so-good compounds, the ones you'd normally discard after the first cut, and take them on to the cell assay regardless. They'd better not work! Test some of the compounds on a closely related cell line that doesn't have your target in it, if you've got some - is your target really the reason for the activity you're seeing?

Most of the time, you'll find that things are just fine. The inactive compounds really are inactive all the way through. But I've seen the exceptions occur, and more than once. You don't want to wait any longer than necessary to find out that your project is a dud. And worse yet, you really don't want someone else to find out for you. It leads to some of those awkward scenes we'd all rather avoid.

Comments (4) + TrackBacks (0) | Category: Drug Assays

August 17, 2005

No Such Disease

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Posted by Derek

Are we going to "eliminate the suffering and death due to cancer" by 2015, a goal set by the National Cancer Institute? Unfortunately, I greatly doubt it. Will we speed up the timetable, as Senator Arlen Specter has apparently asked, and do it by 2010? Absolutely not, and here's why.

There's a widespread myth at work here: that there's a disease called cancer. Cancer is actually the end result of what are probably hundreds (thousands?) of different diseases. We have confused ourselves by giving them the same category name - it's like the old-style classification of infections as various "fevers." There are many, many ways that a cell can end up with (and maintain) the deranged growth profile that we think of as cancerous, and it's going to take a lot of different treatments to do anything about them. (See this post and this one for some of the consequences of that for the drug industry.)

Look at the situation today. Every type of tumor has specific front-line treatment regimes, and they don't overlap that much. The best agents for some types of cancer are totally useless against some of the others. It's possible that some of those multikinase inhibitors that I was writing about the other day could have a broader spectrum of activity, but even if that pans out, it's likely that different kinase "fingerprints" will be needed for different varieties of tumor.

Actually, there are two myths at work in Senator Specter's question. The other one is that research can be sped up to any degree desired. Although more money is always nice, thanks, there comes a point where it's not sufficient to buy you better results. In the case of the various cancers, it's for sure that there are many, many important details that we don't even know about yet. And, as usual, a good amount of the things that we do already know are going to turn out to be wrong. Time, money, intelligence, luck, and hard work are all going to have to be tossed into the pot in great quantities, and there are no other ingredients that can substitute for any of those.

Comments (10) + TrackBacks (0) | Category: Cancer

August 16, 2005

For Further Enlightenment

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Posted by Derek

A few varied links for your reading pleasure:

Carl Zimmer does a fine job banging the Intelligent Design folks over the head next door at The Loom. And (via Arts and Letters Daily), here's another handy demolition of the whole concept.

Speaking of A&LD, "Michael Blowhard" pens a well-deserved fan letter to them here, while wondeing why the arts haven't taken more notice of the hard sciences than they have.

It looks like I finally have company in the inside-pharma-blogging world: take a look at the Medicine Vault, written by someone on the other side of the aisle in biology. Welcome!

Why would attempting to measure the dipole moment of an electron give anyone the willies? Chad Orzel explains, in a good example of telling people outside the field what some of the big news inside it is.

Comments (0) + TrackBacks (0) | Category: General Scientific News

Experimental News

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Posted by Derek

I set up another run of experiments in my long-running series today. I'm repeating the best results from last time (the previous post in this category), with fresh samples of everything (just to be sure that there wasn't something odd about the last batch, which seemed to work so well.) There's a new type of control in there, too, off in another direction from the ones I've run before. And I've made several new compounds to test, all closely related to the things that seem to have worked.

That's been a big part of the delay. I've exhausted most of the commercially available starting materials by now - as I narrow down to the most promising structures, I find that I have to make a lot of my starting materials myself. Some of them are easy to whip out, but I still have to purify them, and all these things take time. And, of course, none of this is officially what I'm supposed to be doing, so I have to work these things in as I can.

I've also accepted an offer to present the whole idea in a public forum for the first time. Well, an inside-the-company public forum, that is. I've grabbed folks by their shirt collars and scribbled all over their office whiteboards during the last couple of years, but this will be the first time I've put everything together into a real presentation. My submarine project is beginning to surface.

Comments (5) + TrackBacks (0) | Category: Birth of an Idea

August 15, 2005

Out the Door and Over the Edge

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Posted by Derek

Handing a compound over to the clinical development group is usually a reason to celebrate, but there can be times when you don't feel like getting out the party hats. Just as a novel is defined as a lengthy work of narrative fiction that has something wrong with it, a clinical candidate is always defective, too. Rarely does everyone on the team feel that the best compound was picked.

There's nothing necessarily wrong with that situation. Everyone feels that the compound with the best profile in their own specialty should have gone forward, and no one compound can do it all. Applied researchers and engineers the world over know that eventually you just have to get something out the door, rather than sending it around for another round of tweaking. There are always enough surprises waiting in the clinic. You'll never be able to plan for all of them, so you might as well get your compound out there and see what happens.

But sometimes there's a more justifiable reason for unhappiness, which can be summed up in the phrase "making your numbers." Many organizations have targets for how many projects they plan to launch each year, and how many they expect to take on to the clinic. (I wrote about this here in 2002.) What if you feel like your project is being pushed to the next phase just to meet an end-of-the-year target?

This kind of thing definitely happens, and I'm sure that my readers at the larger companies can confirm that. There are several possible outcomes. Sometimes things work out for the best, when it turns out the candidate compound was more ready for the clinic than anyone realized (or when it dies for reasons that no one could have foreseen.) In either of those cases, you're better off having found out.

But there really are times when a project needs a little longer in the oven. My advice in those situations is to fight the good fight, but know when to quit. Most projects are going to die in the clinic, anyway, sad to say, and you'll need to decide for yourself how much capital you want to spend advocating any particular one. Try to position the project as best you can if it has to go. Learn as much as you can from what happens to it in development, and see if that can be applied to a follow-up program. That one should have a better chance.

Of course, if your company is just tossing this over to the clinical side for the sake of doing it, not expecting them to actually develop the candidate, then you might not have a chance to learn much. But if that's what's happening, my advice is to take a look around. Is this a regular part of your company's culture? if it is, perhaps it's time to start looking elsewhere. We waste enough time, money, and effort in this industry without trying to. An outfit that's deliberately throwing stuff away has bigger problems than just your project.

Comments (1) + TrackBacks (0) | Category: Drug Development

August 14, 2005

Blogging About Science Blogging

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Posted by Derek

There seem to be enough science bloggers around now that we're starting to wonder what it is that we're doing, and why. The recent article in The Scientist has started some of this, with its focus on why more scientists don't blog. Living the Scientific Life as well as Chad Orzel at Uncertain Principles have weighed in, among others (and I'd like to thank both of them for the kind words they've said about this site, while I'm at it.)

GrrlScientist, in that first link, points out that the Scientist article seems to miss one of the reasons that scientists blog (or might want to): explaining just what it is that they do. That's an important point - it's a big reason why I started and a big reason why I continue. I had had several experiences over the years where people found out what I did and pumped me for all kinds of information. And it hit me that although few people had any idea about drug discovery, they tended to say "Wow, that sounds like a really neat job" once they did. (It was a big improvement from the usual response you get when you tell people that you're a professional chemist, I can tell you.)

Chad Orzel goes on to note that large numbers of people see science as something that's difficult, boring, and beyond them, so they just tune out. I'm afraid he's right. But I used to explain my experiments to the janitorial staff when I worked late at my first job, which showed me that this didn't have to be the situation. To be sure, none of my explanations started off with the phrase "Consider the Hamiltonian. . .", but none of my conversations with my colleagues start that way, either, not if I can help it.

Instead, we talk about how we're not getting good blood levels with our latest series of compounds, wonder about whether that's because they're not getting absorbed through the gut or are getting cleared from circulation too quickly, and outline some experiments that would tell us one way or another. Now, it's true that we use a lot of verbal and scientific shorthand to discuss these things - a conversation like that could go "See the screening PK yet?" "Yeah, what a rotten AUC. Do we have an i.v. tee-one-half on that stuff yet?" "No, but we could probably get a slot in the next cannulated rat run." And that wouldn't mean much to one of the Uruguayan janitors that used to ask about my work.

But with a few extra minutes to explain what we were trying to do and why, they could appreciate what was going on. And they could see that it wasn't easy, and that we often didn't know why things were happening, and that we had to wait a long time between chances to run around high-fiving each other. Considering how television and movies treat science (which, to be fair, could be the only way to treat it for the purposes of mass entertainment), knowing these things was a real step up.

So when I found out about blogging, I didn't hesitate very long before jumping in. Here was a chance to do just the kind of thing I did when talking to people one-on-one, but for as many visitors as cared to stop by. It sounded like just what I'd been waiting for, and it still is. The pharmaceutical industry has been taking a beating the last few years, some of it (not all!) deserved, and I think there's an ecological niche in the blog world for someone who can talk about it from personal experience.

The majority of my readers, as far as I can tell, are not involved in drug discovery themselves. I certainly enjoy having people from the field reading and commenting, and I try to pitch my posts to both levels at once, as much as possible. But I've never pictured my site being exclusively a peer-to-peer experience. Since I'm in the drug industry, it couldn't very well be, in any case. We drug-industry types obviously can't talk about the specifics of what we're doing, and I don't. (That's why the "Birth of an Idea" posts are so maddeningly vague, and even those don't apply to any specific drug or drug target.) There's just not much chance for blogging to help me out with any current problems in my research, because those problems are all proprietary. It can give me a broader perspective on my industry, which might come in handy, but it's going to do zilch for what's stirring in my fume hood.

(I should note that both of the posts I linked to in the first paragraph put the public-outreach issue in terms of the teaching-intelligent-design debate. More on that another day. . .)

Comments (5) + TrackBacks (0) | Category: Blog Housekeeping

August 11, 2005

Selectivity: One of Those Flexible Concepts

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Posted by Derek

One of the comments to the last post mentioned that a way to provide the benefits of a combination therapy is to make a drug that hits more than one target. For a while there, this idea was a bit out of fashion, but I think it's been making a comeback.

There are a number of multiple-target drugs on the market already, and the list even includes some where this profile was arrived at deliberately. (That was a joke. I think.) Examples of the planned category include Tracleer (bosentan), a dual endothelin receptor antagonist for pulmonary hypertension, rupatadine, a dual histamine/PAF antagonist for allergy (not yet approved in the US, I think), and Cymbalta (duloxetine), an antidepressant which affects both serotonin and noradrenaline reuptake.

Examples of the non-deliberate class include all sorts of drugs marketed before the 1980s or so. (That's about the time that target-based drug design really took over, as opposed to "see what it does in vivo".) In some therapeutic classes, this is the norm - the activities of CNS drugs in general are known to be extraordinarily messy. The antipsychotics, for example, hit so many receptors that it's basically impossible to figure out just how they work. A more recent example is the cardiovascular drug Pletal (cilostazol), which is both a PDE-III inhibitor and an adenosine uptake inhibitor. Other PDE-III inhibitors didn't work nearly as well, so there was clearly something else pitching in. (There may well be something similar at work with Lipitor, to pick a drug that everyone's actually heard of, although no one's quite sure what the extra activity is.)

There are all sorts of other dual-acting drugs being looked at in earlier phases of development. For the most part, they're going after similar receptor subtypes or related enzymes, since that's where you're most likely to get the cross-reactivity. (A good example would be the PPAR alpha-gamma ligands that many companies have been trying to develop for diabetes.) But the biggest area of multiple-action drugs now is cancer.

You might not know it from reading the popular press, though. A lot of reporters are still a generation behind, going on about the new breed of incredibly selective targeted cancer drugs. Problem is, it's turning out that some of those incredibly selective drugs work only on incredibly small numbers of cancer patients, which is not what everyone had in mind. Over the last few years, efforts have shifted to making drugs that hit a slew of potential cancer targets simultaneously, in hopes that this will show more efficacy, and these are just coming to the FDA now.

Many, many cancer targets are from a large family of broadly similar enzymes (the kinases), so getting multiple activities isn't really all that hard. In fact, getting selective kinase inhibitors was the hard part - looking back, had we but known, we all could have probably skipped that step and gone right to the blunderbusses. But the fear was that these compounds would be too toxic (yeah, even for cancer therapy), so selectivity got priority. Now that it turns out that we don't need to be so picky, it's also becoming clear that the multiple-kinase drugs are tolerated a lot better than we thought. You'll see the word "targeted" thrown around when these agents are discussed, but it should have quotes around it.

Comments (7) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Drug Development

August 10, 2005

Another Thing You'd Think Would Be Simple

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Posted by Derek

A little while back, I wrote about combination therapies, and why they're sometimes not pursued. (That question, like so many that begin with "I wonder why they. . .?", has the answer "Money.")

But there are some areas where combinations make sense both medically and financially, and an outstanding one is in antiretroviral therapy. HIV dosing schedules are famously strenuous and complex, and patients (and their insurance companies) are certainly willing to pay for something better. Gilead, about one of whose drugs (Emtriva, emtricitabine) I wrote here, has already combined that one with another drug of theirs (Viread, tenofovir) to make a combination pill sold as Truvada. Now they've been trying to co-formulate that one with Sustiva (efavirenz), from Bristol-Meyers Squibb, to get three agents into one dose.

It's turned out to be harder than it looks. This is their second attempt at getting the combination to show equivalent blood levels to the individual drugs dosed separately, and they still can't get it to work. There are all kinds of reasons why this might be happening - formulation (galenics) is an esoteric science with about as mystic a component as you'll find in the drug industry. Unexpectedly different dissolution rates or effects on each other's solubility, formation of some sort of complex with something else in the gut, competition for the same transport mechanisms across the local area of the gut wall - you could fill up a big sheet of paper with possibilities, and I'm sure that many have been so filled. Gilead isn't saying what they think the problem is, since they have no mandate to satisfy the curiosity of onlookers.

They have said, though, that their next shot is going to be a "bi-layer" formulation, which is about the closest thing to separate dosing that you can do in one pill. Each ingredient will be formulated in the way that suits it best, and the two (completely different) mixtures will be layered one on top of the other and turned into one pill. This is one of the more expensive ways to do it, but it's clearly come to that. Gilead and BMS say that they're going to take three different shots at this technique, and I wish them luck, which is still the most efficacious ingredient in any formulation. Damn stuff is usually on back-order when you really need it, though.

Comments (9) + TrackBacks (0) | Category: Drug Development

August 9, 2005

Differences Between Academia and Industry, Pt. 4

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Posted by Derek

You hear an awful lot about teamwork when you're in industry. (Personally, my fist clenches up whenever I here the phrase "team player", but perhaps that's just me.) But there's a bit of truth in all this talk, and it's something that you generally don't encounter during graduate training.

As a chemistry grad student, you're imbedded in a chemistry department, and most outside groups will either be irrelevant or there to service things for you. Getting along with people outside your immediate sphere is useful, but not so useful that everyone makes the effort. But pharmaceutical companies have a lot of different departments, and they're all pretty much equal, and they are all supposed to get along. You've got your med-chem, your pharmacology, the in vivo group (or groups, who may be stepping on each other's toes), metabolism, PK, toxicology, formulations. . .as a project matures, everybody gets dragged in.

These other folks do not see themselves, to put it mildly, as being put on earth to service the medicinal chemistry group. They are very good at detecting the scent of that attitude, and will adjust theirs accordingly. (Some of them already have filed chemists in the "necessary evil" category.) For the most part, no one is supposed to be able to pull rank on anyone else, so in order to get things done, you'll have to play nicely with others.

Not everyone figures this out. I watched someone once whose technique of speeding up the assay results for his compounds was to march down to the screening lab and demand to know where his procreating numbers were, already. No doubt he thought of himself as a hard-hitting, take-charge kind of guy, but the biologists thought of him, unsurprisingly, as a self-propelled cloaca. His assay submissions automatically got moved to the "think about it until next Tuesday" pile, naturally.

Earlier entries in the series can be found here.

Comments (7) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs

August 8, 2005

Room At the Top?

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Posted by Derek

Tangentially related to that last post is a thought that occurred to me while I was writing my monthly column for Contract Pharma magazine. It's on the place of chemists in a drug company, and in the scientific world in general. And what hit me was this: how many drug companies can you think of that are run by someone who came up through the med-chem department?

The only one I can think of, off the top of my head, is Vertex. (And that's because Joshua Boger left Merck to start his own company, so naturally he's the CEO.) But are there any examples of someone working their way up through the ranks?

Plenty of companies are run by M.D.s and MBAs. You don't see as many plain ol' PhDs. CEOs seem to come up through the clinical side and the marketing organization, but it's rare that one comes from the research side of a big drug company. And very few of that small group come from the chemistry department. Why might this be?

I'd like to think that the Jurgen explanation applies, and that we med-chemists are just too darn clever for top management. Frankly, that may be a little big of the explanation, but it's not enough of it to be useful. For one thing, some (not all) of those top managers are pretty brainy, and for another, I've known plenty of chemists who are dull enough for any job you could name.

I hate to advance this explanation, but perhaps part of the reason is social. There's a particular type of personality that tends to make it to the top of a large organization, and that profile doesn't overlap well with the types you find in research. There's some self-selection involved, too. Someone who makes it to the executive boardroom has most likely devoted most of their energy to getting there, and that's someone who would be unlikely to pursue a chemistry PhD. Why take the slow lane to power, or the scenic detour?

(Note: I'm aware that Margaret Thatcher has a chemistry degree - but it's not a doctorate, and she got out of the field pretty quickly and into politics.)

Comments (20) + TrackBacks (0) | Category: Drug Industry History

August 7, 2005

An Off-Topic Ramble

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Posted by Derek

Note for new readers: I don't talk much about politics on this site, since there are more than enough blogs to cover every political position imaginable. But once in a while we veer off course. . .

The uproar over President Bush's support for "Intelligent Design" seems to have died down a bit. (You can find commentary all over the blog world, naturally - My fellow Corantean Carl Zimmer was, understandably, dismayed. For some cries of distress on the pro-Bush side, try Sissy Willis, Jane Galt, and this roundup at Instapundit.)

I wasn't too thrilled myself. I have no time for the ID folks. I think that the best of them are mistaken, and the worst are flat-out intellectually dishonest. But I wasn't that surprised by Bush's statement, either. It wouldn't surprise me to find out that he doesn't know enough biology to know how silly his support (wishy-washy though it was) makes him sound to people who do.

But I also think that, as a politician, Bush made a back-of-the-envelope calculation that saying this sort of thing wouldn't do him any harm, and (within error bars) it probably hasn't. I'm not sure how much of a slice of the electorate people like me represent (voted for Bush twice, convinced that Intelligent Design is pernicious), but I'll bet it's not too big. And other issues, which frankly - though I hate to admit it - I find to be more pressing, still leave me not regretting my vote in the last election. If Bush goes further in promoting ID teaching, I will of course oppose that in any way I can think of, in the same way I opposed his steel and textile tariffs. That doesn't mean I'm cheerful about the situation, but there's no possible President who wouldn't tick me off about something or another.

I would expect most Presidents to outsource their needs for any knowledge of evolutionary biology, anyway. It's not a job requirement. Now, I know that being smart enough to see problems with Intelligent Design would seem, on the other hand, to be a job requirement, but it depends on what a person turns their attention to. And a review of Presidential history suggests that performance is not well correlated with intelligence, anyway. If anything, the distribution is a bit U-shaped. Dullards like Franklin Pierce and Warren Harding failed, but on the other end of the scale, academicians like Woodrow Wilson failed in different ways.

Aaron Haspel's discussion of "Chet" - friendly, hard-working, well-adjusted, riotously well-paid Chet - is worth reading in this context. And I'll let James Branch Cabell have the last word, in a famous passage from Jurgen, when he meets that fantasy's nearest thing to God:

". . .And of a sudden Jurgen perceived that this Koshchei the Deathless was not particularly intelligent. Then Jurgen wondered why he should ever have expected Koshchei to be intelligent? Koshchei was omnipotent, as men estimate omnipotence: but by what course of reasoning had people come to believe that Koshchei was clever, as men estimate cleverness? The fact that, to the contrary, Koshchei seemed well-meaning, but rather slow of apprehension and a little needlessly fussy, went far toward explaining a host of matters which had long puzzled Jurgen. Cleverness was, of course, the most admirable of all traits: but cleverness was not at the top of things, and never had been."

I'll try to talk a bit about Chets (and George Bushes) as I've experienced them in the drug industry in an upcoming post.

Comments (38) + TrackBacks (0) | Category: General Scientific News | Intelligent Design

August 6, 2005

Even More Worthwhile Stuff

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Posted by Derek

I've finally updated and cleaned up my blogroll over on the left - removed some inactive sites, fixed broken links, and added quite a few others. There may be some folks over there you haven't heard of, so give 'em a try.

On the home front, I'm nearly through adding all my old Lagniappe posts to the archive pages. Next up will be the earlier days of "In the Pipeline", finally categorized for your time-wasting pleasure.

Comments (0) + TrackBacks (0) | Category: Blog Housekeeping

August 4, 2005

The Place to Be

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Posted by Derek

Glenn Reynolds, of Instapundit fame, has some nice things to say about the drug industry in this piece on I appreciate it; we need all the good press we can get these days. Says Glenn:

"The pharmaceutical industry isn't beyond criticism, of course. But I find most of the criticism rather strained, and all of the critics far too slow to give the industry the credit it deserves for the tremendous good it does"

There are some who will say that Reynolds is hardly disinterested, since his wife is responding well to an antiarrythmic medication which she badly needed. I'd respond that this is just the sort of thing we need more of. The more people with reason to like our industry, the better. Those are people that we've helped, who think that they've gotten something worthwhile for their money, who are satisfied with what we've been able to produce. I wish it were harder than it is to find disinterested parties, frankly.

As it is, very few people who've had to deal with Alzheimer's, say, have much reason to feel good about the pharma industry. There are many infectious diseases for which we don't have much to offer. And while some cancers are truly yielding to treatment, many others are just as much of a death sentence as they've always been. The people who encounter those have a right to wonder about what the deal is with all those breakthroughs they read about.

I've said it before, and here it comes again, that the best way for the drug industry to improve its image is to deliver the goods. That's not going to be easy - the disease areas I've named are pretty rough, and the other key ones aren't any better. It's going to cost an insane amount of money and effort to get our good names back.

And while we're at it, we're going to have to make a better case for some of the drugs we're already selling and working on. Glenn's piece is a response to this book, which makes the argument that the industry is spending too much time "treating people who aren't sick". If we're preventing diseases and improving quality of life, and we'd better be, then we need to make people aware of it.

What's left out? Lifestyle drugs - sexual performance, cosmetic enhancement, that sort of thing. They can be profitable, but I think if we spend too much time in those areas, we're going to get hammered on. The grindstone is the place to be.

Comments (2) + TrackBacks (0) | Category: Press Coverage

August 3, 2005

Let's Check This Blank Page, Here

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Posted by Derek

I think that most of the large (and some of the small) drug companies have by now made the switch to electronic lab notebooks. It couldn't have come too soon for me. My merits as a scientist are up for debate, but my virtues as a record keeper are inarguable: I stink.

And have stunk, for some time. Back to graduate school, actually, which is the first time I seriously had to keep a notebook. Looking back at my first-year books by the time I left, I could see the decline in promptness and experimental detail. Man, were those first few months of experiments ever well-documented! Too bad none of them were worth anything, but that's the sort of joke that science plays on us.

My first years in industry were fair to good, but I tended to backslide. Setting up experiments is fun, as chemists know, much more fun than writing them down, and certainly a lot more fun than working them up and purifying the products. So I'd go the post-it-note route - writing down the amounts and a brief structural scribble to remind me, and put that on the appropriate notebook page. To remind me, you know, when I got around to writing it up, which would be Real Soon Now. Need I add that some of these things were as intelligible to me as Hittite tablets by the time that day arrived?

It got to the point at my former job that I once took a lab notebook home to Tennessee over Christmas. That, of course, is a mighty violation of good sense and legal protocol, and if I'd lost the thing, who knows what they would have done to me. Do not try this, if you're still using hard-copy notebooks. But there I was, back at my parent's kitchen table, writing up reductive amination reactions, one after the other.

The electronic notebook has kept me honest. I type much faster than I can write by hand, for one thing, so I actually put a few more details into my experimental procedures. All the analytical data is tied to the procedure, so I can't manage to lose that, either. The structures are all done with chemical drawing software, bless it, which means that you cut, copy, and paste 'em when you're working in a related series of compounds. A far, far superior system. Now I just have to generate some results worthy of it. . .

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs

August 2, 2005

Never Came In Handy. Not Once.

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Posted by Derek

I was trying to think back to the least useful chemistry I ever learned in undergraduate and graduate school, and let me tell you, it's a tough league to play in.

I know, I know, many of you are thinking "Yeah, I hated quantum mechanics, too", but that's not what I'm talking about. Quantum stuff is actually interesting to me, although I am glad to not be obligated to finish any paragraph that begins with "Consider the Hamiltonian. . ." No, I'm thinking of things that were presented as techniques that I'd be using and had better understand and commit to memory.

How about. . .electron spin resonance? ESR was sold to us as a parallel world to NMR, full of its own utility, well worth getting to know. Sheep dip. ESR is interesting and useful to that subset of people who deal with reasonably stable free radicals, but to very few others indeed. I take that point that it's a fine technique for those people, but I'd like to point out that my chances of becoming one of them were never very high. The time and effort I put into learning it could have been spent much more profitably.

"But hold it," says my memory. "You didn't spend any time getting to learn ESR spectroscopy. You read the newspaper during the lectures. You didn't buy the textbook. You only exerted yourself during the hours leading up to the exams, and sometimes not even then. It's no wonder you don't know squat about it."

Er, well, I suppose there's something to that. I recall that the class was divided up into groups of three or four, and assigned regular problem sets to work out and hand in. My group of three became increasingly demotivated as things went on, and by the time of the last problem set, we spent our time complaining about how much we couldn't stand the stuff any more and never got around to solving any of the problems.

Come that Monday morning, I realized that I hadn't put anything together for us to hand in. So I just dug around and found a sheet or two where we'd taken a listless stab at working a problem. That seemed a bit lacking in heft, so I bulked it out with a random handful of paper from a disused notebook, put our names on it, stapled the pile up, and turned it in. There were blank sheets of paper in there; there was a paper towel. The sheets with writing on them often weren't even from the course in question, and many of them were upside down, anyway. What the hey.

Looking back, it's hard to believe I actually did that. My problem set partners found it a bit difficult, too, even at the time: "You did what?" I awaited our grade with interest. A few days later, the professor stopped me on my way out of the class and asked "Do I have your group's problem set?" "Sort of," I responded. "Oh, yes!" came his answer, "that was a messy one, wasn't it?"

Comments (13) + TrackBacks (0) | Category: Graduate School

August 1, 2005

Seven Questions

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Posted by Derek

As a drug discovery project moves along, we synthesize lots of new compounds, test them, and pick the best ones to make in large quantities. Simple, eh? Try your hand, then, at some of these questions, all of which have come up in the course of my career so far:

1. If you're running an experiment in vivo, and your control compound (from a competitor) is a highly active, hard-to-beat standard - how do you interpret your results when you know that this compound has made it to market and is no great shakes in human patients?

2. What do you do when you have to make a large batch of some compound for advanced pre-clinical work, and there's only one person in the whole department who can really get the crucial reaction to work? Do you tell people that you have a good large-scale route, or not?

3. How about a bit earlier in the game - how do you deal with it when you have a high-yielding, clean route to a key intermediate that lots of your people are using, but it uses a reaction that you know, for a fact, that the scale-up group won't touch later on?

4. How do you handle things when your primary biological assay keeps acting up - by factors of five to ten? Do you normalize the numbers to a standard each time and hope for the best, or do you start to doubt the usefulness of the whole assay?

5. For bonus points, how do you tell which numbers you've been getting are closer to the truth - the ones that say your compounds are really active, or the ones that say that they stink?

6. How do you interpret things when the in vivo assay tells you that your compounds have wonderfully long durations of action, but the blood levels tell you that they completely disappeared from circulation long before?

7. What does it mean when your best compound is intolerant of even slight structural changes? Do you just run with it (after all, you only need one compound, right?) Or do you hammer away trying to find something that can be safely modified in order to have a back-up?

Are there right answers? Well, presumably. I know what answers I'd give to some of these, but I make no guarantees that they're the right ones. . .

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