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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: derekb.lowe@gmail.com Twitter: Dereklowe

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April 28, 2005

Speak for Themselves, They Do

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Posted by Derek

I thought about writing a whole post welcoming back my fellow Arkansan, the Ivory-Billed Woodpecker, but decided that not many folks would sit still for that. It does strike me, though, that the bird was rediscovered not that far from where I went to college.

I didn't have much time to hang out in the Cache River Wildlife Refuge, anyway, even if I'd been so inclined. I was living the life of the virtuous chemistry major, which for one semester led me to have all-afternoon lab sections every single day of the week. There's no doubt that I learned something in them, but not all of it was in the official curriculum.

Take one time in a physical chemistry lab, for example. We were doing something that no one in their right mind does in the real world, a determination of molecular weight by boiling point elevation. That's a relic of the sealing-wax era of chemistry, but it's not quite as much of a waste of time as those qualitative organic tests I was railing about the other week. I still wouldn't keep it in a lab course these days, but the way this one was set up, it did have some value.

We were figuring out the molecular weight of benzoic acid by adding increasing amounts of it to a solution (toluene, I seem to recall) and seeing how much the boiling point increased. We then plotted this out, running it through Raoult's Law to get the answer.

Well, of course, we already knew the molecular weight of benzoic acid. But as we took boiling point after boiling point, in a finicky apparatus that splashed boiling solvent over the lowered bulb of our thermometer, we could tell that something was going wrong. We were getting something way over 200, and benzoic acid weighs 122. Hrm. We checked everything again, but the data all looked pretty good. Way over 200. . .about 244, actually.

Then it hit one of us. "Dimer!" he said suddenly. "Benzoic acid forms a dimer, and that weighs twice as much!" We all slapped our foreheads and grinned. But the guys next door to us had put their minds at rest even before we did.

Not that they had the right answer. In fact, their plot showed the molecular weight of the dissolved benzoic acid at 122, right on the nose. Pretty good curve, too, pointed right at the seemingly-correct-but-impossible answer. How did they get there? By taking so many data points that the freaks and throwaways could be assembled, Frankenstein-style, into a zombie plot that gave the answer that they just knew it had to give. Never mind that the other 90% of the data pointed to twice that number - that can't be right. What do the data points know about right answers, anyway?

Comments (6) + TrackBacks (0) | Category: How Not to Do It

April 27, 2005

Experimental Update, For Those Who Care

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Posted by Derek

Well, I got the results of my experiments this afternoon. There might be something there, but I'll have to see the rest of the data in the morning to be a bit more sure. In research, we live for slam-dunk experiments that really prove things, but most of the time we get this could-be might-be stuff.

Most of the reactions did nothing, which was disappointing. Two of them showed what could be a real effect, though, and those two were from the same chemical class. That could be telling me something, or it could be just a coincidence. The analysis of some duplicate runs of the same things will be ready in the morning, and I'll see.

If they repeat, that's probably good news. I'll then simultaneously narrow down and fan out in other directions. That is, I'll set those same reactions up again, and add a few runs that are controlled for against some other variables. On the other hand, if they don't repeat, then I first need to make sure that my wonderful pipetting technique isn't one of the causes, but then I have some other things to try on different systems.

One of the few things I can prove is that not every system I can set up has an equal chance of working - in fact, some of them definitely won't work at all, for reasons that can't be foreseen. Perhaps I've landed on one of these and need to get out into another area - or perhaps I'm just wrong from the start. It's too early, fortunately, to be able to prove that.

UPDATE: Well, all the experiments repeated quite nicely, which is something to be glad of. If I'm wrong, I'm wrong the same way every time. I'm already planning another run of stuff for sometime next week, and I won't inflict the details on everyone until they're finished.

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

April 26, 2005

Knocking Opportunity Costs

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Posted by Derek

I came across the news item that a representative from Ohio (Sherrod Brown, D-13th) has sent a letter to President Bush contesting the White House's recent report on pharmaceutical costs. (A press release of his addressing the same topic is supposed to be available from this list, but all of Representative Brown's links are broken.) Looking at his record, it appears that he's been using my industry as a trampoline for some years now.

There's one part of his complaint that I wanted to address. The over-800-million-dollars-to-develop-a-drug estimate that the Tufts center arrived at is a constant target. (I hate to tell people that it's quite possibly a low estimate.) Rep. Brown specifically complains about the way that this figure includes the opportunity costs associated with the risk of drug development, and he's not the only one. Why, critics ask, should the amount a drug company would have made by investing its research money be included as a cost?

Well, because that's what it is. Most drug development projects don't work, and all the money spent on them goes down the hole. If you're going to risk your cash on one, you need to figure out what you would get if you parked your money in some more reliable investments instead, and you need to realize up front that this is what you're forgoing.

"But I don't do my expenses like that!" goes the cry. Don't you, though? If you have some extra cash around, should you put it in a savings account, the stock market, pay down some principal on your mortgage, or put it all on your lucky number at a roulette table? Depends on the rate of return for each one, and the risk. (This would be a good time to mention that the odds of hitting your roulette number are almost identical to the odds of getting a clinical candidate to market for a central nervous system indication.)

Those first three options don't involve muchrisk , but the last one sure does - and if you decide to go for it, you should realize what it's really costing you: the use of the excess interest on your money, interest which you would have been able to earn. The same consideration applies to the other choices, which is why paying down your mortgage is the equivalent of earning that percentage interest on the cash. An appreciation of opportunity costs would do a lot of people good.

But I have a more direct demonstration, one that I'm prepared to offer to Representative Brown: give me a thousand dollars, Congressman, and in ten years I'll give you a thousand back. If you don't think that this deal is costing you money, I'd love to hear you explain why not - after you've written the check, naturally. How about it?

Comments (8) + TrackBacks (0) | Category: Drug Development

April 25, 2005

What Ails the Germans?

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Posted by Derek

This article from Germany's Deutsche Welle looks at what ever became of the once-mighty German pharmaceutical industry. It's worth a quick look, but not for the reasons the author intended.

For one thing, if Hoechst ever "dominated the industry", as the piece has it, I must have missed it. And Lipitor isn't "one of several home runs" by Pfizer. It was a home run by Warner-Lambert, co-opted by Pfizer after the big risks had already been taken. It's true that Schering AG's "share price on the DAX index dropped 13 percent" since March, but it's worth noting that the DAX as a whole dropped nearly 5% in that period. Bayer, for its part, hasn't completely "focused on over-the-counter drugs like Aspirin+C", but is also trying to climb out of its hole with new cancer and cardiovascular drugs.

And, finally, the article states that many companies outside Germany "have overcome costly drug development and marketing channels (by) merging." What on Earth has Hoechst been doing since about 1990 except merging with everyone that'll have them? And if they've convinced themselves in Germany that mergers are the cure for the drug industry's ills, then the darkest days for the country's pharma sector are still to come.

Comments (0) + TrackBacks (0) | Category: Business and Markets

Live The Stereotype!

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Posted by Derek

Now I know why all the biologists I know are half-sane at best: it's all that pipetting. I set up my experiment today, in a 96-well plate (here's one similar to what I was using, if you don't know the beasts), and spent a good chunk of the afternoon pipetting in a few microliters of this and a few microliters of that. Over and over. A multichannel gizmo (like this one) would have helped, but only in the beginning. Everything else was special-ordered for each well, so this was going to take some time, no matter what.

Still, I'm glad to have finally fulfilled my research destiny. The biologist-holding-a-pipet shot is third in the pantheon of Cheap Scientific Shorthand images. Just ahead of it is Peering Insightfully Into the Microscope, and at number one (as I've written about before) is Looking at a Raised Erlenmeyer With A Thoughtful Expression.

The experiment will run until Wednesday morning. Then it goes to my colleagues downstairs for analysis, and it's possible that I'll start getting results on Wednesday afternoon. Otherwise, I'll just sit around on Thursday and stare at the phone until it rings. That always works.

Comments (6) + TrackBacks (0) | Category: Birth of an Idea

April 24, 2005

The Consolations of Pure Research

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Posted by Derek

I mentioned the other day that I'm getting close to another run of experiments on the research idea I've been messing with for a couple of years now. For those who haven't been following this tedious tale, so far I've had - well, I've had no real success at all. I thought at one point that something might have worked, but it didn't repeat in any detail.

So, why am I coming back for more punishment? Several reasons: for one thing, I can now think of possible confounding variables in the earlier runs that could have rendered them unable to work. (Many of these are addressed in the current experiments.) Second, I still - in the face of a fair amount of evidence, I admit - believe that this whole thing should work. Some roughly similar chemistry has worked for others, and I think that my modifications (which should make the final technique much more broadly useful, I think) aren't big enough to mess up the whole system.

And the third reason is that I enjoy this kind of work very much. It's a luxury to be able to work on your own ideas in industry, outside the bounds of a particular project, that is. (When we're working on inhibitors of XYZ kinase, I'm free, naturally, to have any ideas I want to about inhibitors of XYZ kinase.) Doing this kind of blue-sky side work is a nice change.

I'll know in the next couple of days if my colleagues in the analytical group are ready for me, and the first run of experiments will take a couple of days themselves. Then there's the time it takes to analyze them (on the instruments, that is - once I see the data, I'll know in a couple of minutes if things have worked out or not.)

Every time I come back to this work, I have a clearer idea of what's going on, and a better way to see it. If you keep doing that, you eventually break through. Right?

Comments (3) + TrackBacks (0) | Category: Birth of an Idea

April 21, 2005

The Globalization of Med-Chem

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Posted by Derek

Over the last ten or fifteen years, there seems to have been a real boom in contract synthesis companies. These are small outfits, many of them, anyway, that will make intermediates for you. Send 'em your synthetic route, how much final compound you need, and when you need it by, and they'll send you back a quote. (I also write a column for the trade magazine Contract Pharma, which covers this and the other outsourcing possibilities of the industry.)

This comes in handy when you want to keep your own people busy making new analogs, not diverted to making batches of competitor or reference compounds. And the price you pay for these is often a good deal compared to the price you'd pay to make it in house. (For one thing, the outsourcing company probably doesn't pay its people as much.)

That trend has been reaching its logical conclusion recently, with the entry of suppliers from India and China. Man, are these guys cheap. In many cases, they can underbid pretty much anyone here in the US, and they often do very good work (after all, there's plenty of well-trained scientific labor coming from both of those countries.)

It's gotten to the point that I don't see how the standard make-your-compounds-sir? contract houses are going to stay in business over here. Many of them have already been branching out, looking for some unusual type of chemistry to specialize in (nasty halogenations, high-pressure reactions) or getting into FDA-quality manufacturing for clinical trials, which is something that the Indian and Chinese companies can't yet provide - I think. Others are offering to do medicinal chemistry on an outsourcing basis: Let us develop your lead series! Structure-activity relationships while-u-wait!

Naturally, my nightmare is that that part of the business takes off and becomes a big moneymaker for the US firms. . .at which point it migrates to China and to India. I'm not sure that this is going to happen, or how long it would take, but I can't completely rule it out, either. An awful lot of other technical heavy lifting has migrated over there already, and I'm having trouble coming up with arguments about how we're immune. Perhaps it would do us all good, here in the US-based Big Pharma labs, to find some useful med-chem skills that would be harder to outsource. . .

Comments (10) + TrackBacks (0) | Category: Business and Markets | Drug Development

April 20, 2005

Sneaking Out for an Interview

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Posted by Derek

There was a good question asked in the comments to the previous post on first job interviews: what do you talk about when you work at one company and you're interviewing at another?

Well, I've done that myself, more than once (note to my current co-workers: not in the last few years, folks.) And it can be tricky. But there are some rules that people follow, and if you stay within their bounds you won't cause any trouble. That's not to say that my managers wouldn't have had a cow if they'd seen my old interview slides at the time, but I was at least in the clear legally. Here's how you make sure of that:

First off, it would be best if you could confine your interview talk to work that's been published in the open literature. That stuff is, by definition, completely sterilized from an intellectual property standpoint, and you can yammer on about it all day if you want. The downside is that published work tends to be pretty ancient stuff by the time it shows up in a journal, and you've may have done a lot more interesting things since then. (The other downside is that published projects are almost always failed projects.) Work that's appeared in issued patents is also bulletproof, of course, but it suffers from the same time-lag disadvantages.

Second best is work that's appeared in patent applications. This stuff hasn't been blessed by the patent office yet, so things could always change, but it's at least been disclosed. When you talk about it, you're not giving away anything that couldn't have already been downloaded and read. (Of course, you do have to resist the temptation to add lots of interesting details that don't appear in the application.)

If you've at least filed the applications, then you can still be sort of OK, since they're going to publish in a few months, anyway. This is a case-by-case thing. If the company you're interviewing at is competing with you in that very field, you'd better not give them a head start. But if you're talking antivirals at a company that does nothing but cardiovascular and cancer, you should be able to get away with it. It would be best if you didn't disclose full structures - leave parts of the molecules cut off as big "R" groups and just talk about the parts that make you look like the dynamic medicinal chemist you are.

The worst case is "none of the above." No published work worth talking about, no patent applications, no nothing. I actually did go out and give an interview seminar under those conditions once, and it was an unpleasant experience. I had to talk about ancient stuff from my post-doc, and it was a real challenge convincing people that I knew what was going on in a drug company. I don't recommend trying it.

But I don't recommend spilling the beans in that situation, either. I've seen a job interview talk where it became clear that the speaker was telling us more than he really should have, and we all thought the same thing: he'll do the same thing to us if he gets a job here. No offer.

Comments (3) + TrackBacks (0) | Category: Academia (vs. Industry) | How To Get a Pharma Job | Life in the Drug Labs

April 19, 2005

Getting A Job

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Posted by Derek

I've been seeing quite a few candidate seminars recently, so allow me to pass on some advice to those of you out on the first-job-in-the-drug-industry trail.

First off, some presentation tips: Speak up, if possible. I hear ten too-soft seminars for every too-loud one. Don't give your talk to the screen - either the one on your laptop or the one on the wall. Give it to the people in the room. Look up, turn around, do what you need to do to give them the sense that you're passing information on to them. Find a way to sound somewhere between the extremes of here-is-my-script and gosh-I-don't-remember-this-slide.

As for that information, slides in a scientific presentation should have a medium amount of information on them. A whole slide with one big reaction on it is OK during the introduction, but you'd better fill things out a bit as you move on in the talk. Your audience can tell if you're padding things out.

But don't make the opposite error, putting all your information on one slide in One Big Table. You might think it looks more impressive that way, but it's just irritatingly illegible and uninterpretable. Spread those big data heaps out a bit into coherent piles - put all the aliphatic examples on a slide, followed by the aromatic ones, and so on. You'll find more things to talk about that way, too.

Be honest. If you have to come in with a thin talk, for whatever reason, admit it to yourself and be prepared to admit it in some fashion to your audience. Find some ways to show them that you know more than your slides can illustrate. And don't try to pretend that your results are groundbreaking and exciting, unless they really, really are. Exciting results usually speak for themselves, and your audience will know 'em when they see 'em.

Be prepared for the obvious. If you put a weird reaction up on the screen, someone is going to ask you about the mechanism. If you have some unusual results in a series, someone's going to ask you why you think they came out that way. Be ready with some ideas - it can be fine to not know the answer yet, as long as you've shown that you've thought about what the answer might be. Looking unprepared for down-the-middle pitchs like these will get you crossed off the list very quickly.

And look as if you can learn. No one comes into the drug industry knowing what they really need to know. It comes with experience, and you need to make it clear that you're the sort of person that experience is not wasted on.

That should help. I'll settle for a fee of 10% of your first year's salary, OK?

Comments (3) + TrackBacks (0) | Category: Academia (vs. Industry) | How To Get a Pharma Job

April 18, 2005

The Price of Desperation

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Posted by Derek

Another step down into oblivion: AstraZeneca's Iressa, which was a great hope for them a few years ago, was approved contingent on more studies being completed. As everyone who's been following the story knows, those studies came in a few months ago with terrible news for A-Z and the patients who had been hoping that the drug would help them: no effect on survival, none at all. They pulled the drug from European consideration, and have stopped marketing it here.

Now it appears that another ongoing Iressa trial, a National Cancer Institute study on patients with stable disease after treatment for lung cancer, might be halted based on the negative results of the earlier one. I can see their point, because the data were pretty convincing, in a way that no drug company likes to see. What are the chances that this one will make any difference? Is it ethical, at this point, to continue giving patients the drug?

By the way, does anyone remember, back when Iressa looked like a promising therapy, that the Wall Street Journal (among others) had fits about the FDA's delay in approving it? Here's a piece I wrote about the situation at the time. As it turns out, the less-than-convincing data available back then was about the best that Iressa ever had to offer. If the Journal has offered a follow-up editorial to apologize for pointlessly raising the hopes of cancer patients and wasting their time and money, I've missed it.

And that's the problem that I have, still, with the idea that we should just allow drugs on the market after they've proven safety in Phase I. People get their hopes up. They'll throw their life savings at something if they think that it could help, and it wouldn't surprise me if some folks threw theirs at Iressa. To what end?

Comments (9) + TrackBacks (0) | Category: Cancer

A Smelly Riddle

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Posted by Derek

Here's a chemical puzzle for you: all of us who have worked in an organic chemistry lab can agree, I think, that pyridine reeks to the skies. My descriptive powers aren't up to conveying its smell, because it's really unique - foul, penetrating, and like nothing else but pyridine.

And we'll have no trouble agreeing that thiophenol is a stinker, too. It's one of the prototype stinkers, actually, since it's the main smell of burning rubber. (Imagine that aroma concentrated and ready for use in a bottle, and you've got thiophenol.) Now, what if we take those two structures and combine them?

You'd figure that, say, 2-mercaptopyridine would be impossible to take. But it has no smell whatsoever. (Some of you may be ready to e-mail me about how this compound isn't completely an SH, that it has some thioamide character. But before you do that, recall that thioamides are unbearable, too.) No, this seems to be a case of smells cancelling out at our nasal receptors. For whatever reason, a molecule with the combination of a pyridine nitrogen and an aromatic thiol doesn't set off our sensors.

And that's a good thing, considering what it would be like. Now, I guess you could make a one-molar solution of thiophenol in pyridine, and that would do the trick. I'll bet nothing would cancel out then! Fortunately, I've never come across that reagent combination, and if I ever do, I'll find something else that urgently needs my attention. . .

Comments (6) + TrackBacks (0) | Category: Life in the Drug Labs

April 14, 2005

How Good Is Aricept, Anyway?

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Posted by Derek

Pfizer and Eisai picked up some headlines on the news that their Alzheimer's drug, Aricept (donezipil) showed some effectiveness in delaying the onset of Alzheimer's. That used to be my field of work, although I've got no competing interest in that therapeutic area now. I make that disclaimer up front, because I'm not all that impressed by this new study.

Aricept is a cholinesterase inhibitor, part of the first wave of compounds that were brought in as Alzheimer's therapies. Inhibiting cholinesterase increases the amount of a key neurotransmitter (acetylcholine) that hangs around in the synapse, which should, in theory, lead to stronger signaling between neurons. But this is and always has been a brute-force mechanism, real back-of-the-envelope stuff, which I realized even when I used to work on something pretty similar.

We don't understand neurotransmission well enough to be sure that we're doing much good just by turning up synaptic signaling. To add to the problem, the relevant cholinergic neurons are among those being damaged by Alzheimer's itself, so the drug's therapeutic target is slowly disappearing. That's why the cholinesterase inhibitors are recommended for very early stages of Alzheimer's, and are considered useless for late stages of the disease.

And that's why Pfizer went out as early as possible, out to before patients had even shown signs of Alzheimer's at all. It appears that Aricept therapy helped slow the onset of the disease, among those who developed it at all. Problem is, the effect wasn't large, and after three years any benefit had completely disappeared. The placebo-treated Alzheimer's patients were in the same shape as the ones who had been getting Aricept all along. (Note that Aricept has been studied in non-Alzheimer populations before.)

You wouldn't know all this from a quick look at most of the popular press, though, which went with New Breakthrough headlines like "Drug is First to Delay Onslaught of Alzheimer's." (Science, on the other hand, went with "Study Questions Efficacy of Popular Alzheimer's Treatments", which is more like it.) I'm in the same camp, and it's the same one as the editorial from the issue of the New England Journal of Medicine where the study appeared. Aricept, the journal said, "may offer some benefit, but any such benefit is quite limited and apparently transient" Try turning that into something that'll make you sit past the commercial break. . .

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease

April 13, 2005

Vaccines by the Dozen

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Posted by Derek

After mentioning Jonas Salk, I should also note the recent death of a vaccine wizard, Maurice Hilleman. This Slate article is a good introduction to the man.

Comments (2) + TrackBacks (0) | Category: Blink ›

A Steeplechase of Dead Horses

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Posted by Derek

Health care (and its discontents) seems to be popping up all over the left-of-center blog world this week. (I believe that we have Paul Krugman column in the New York Times to thank for this.)

I don't have the energy reserves at the moment to argue macroeconomic health care issues. And besides, let's be realistic here: my chances of convincing anyone with strongly held views at variance with my own are effectively nil, just as are their chances of convincing me. People with strong opinions argue because it makes them feel better, not because they really plan to convince their opponent. (Undecided types in the middle are another matter, but most of those folks quietly leave the room when the voices get raised.)

What I have noticed, though, are several outbreaks in the comments to those posts of what I'll call the Goozner/Angell Canard: that drugs are found by selfless researchers working with NIH money entrusted to them by the Little Guy, and that said drugs are then snatched from their labs by Big Pharma, who patent the stuff and roll around in the profits like a dog in cut grass. I think I have that worldview about right.

Well, not for the first time (and not for the last, that's for sure), allow me to say that this is a load of manure. I went into table-pounding detail about this issue last fall, and I won't repeat myself. The short course, for anyone who cares: Academic research, although vital, rarely discovers so much as a starting compound for a drug development effort. That's not their job. And developing a drug is a lot harder and more expensive than many people seem to think, and it's getting tougher all the time. That's why we charge so much money. There, that's about as compact as it gets.

Personally, I prefer the weltanschauung of the folks over at Marginal Revolution, but to each his own.

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

Do It Again

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Posted by Derek

This is the 50th anniversary year of the announcement of Jonas Salk's polio vaccine, as you've probably been noticing. There a new book out on the discovery, and plenty of newspaper and magazine articles.

I'll save comment on the vaccine (and Salk himself) for another time. What got me thinking was an incident during the late phases of of the research (which was recounted in a recent article in Smithsonian magazine, taken from the book mentioned above.)

Salk and his team were injecting patients who had already had polio with their vaccine candidates, hoping to show a fresh antibody response. Blood samples were taken after a few days, and the corresponding blood serum was added to a cell culture along with fresh virus and a dye, Phenol Red. If the cells lived - that is, if there were enough antibodies in the serum to inactivate the virus - they would clear the dye color to yellow as the medium became more acidic. If they died, the red color would remain. (This was an assay developed by Julius Youngner. You can see the two colors of Phenol Red here.)

On the morning that the test results were ready for their most promising vaccine candidate, the rack of cell culture tubes showed up completely yellow. There was much celebrating, but Salk finally turned to everyone and said "OK, now let's make sure that we can do it again."

Good for him, I thought when I read that. My fellow researchers will recognize Salk's comment as that of someone who knew his way around a lab. Some of the best scientific advice that you can get is don't trust anything until you've done it at least twice. All kinds of ridiculous stuff happens sporadically, and you'll go crazy if you react to all of it. I've been kicked around like a soccer ball by "N of one" data too many times myself. Nope, don't break out the party hats until the second experiment works, and don't despair until the second one fails.

Comments (5) + TrackBacks (0) | Category: Infectious Diseases

April 7, 2005

An Update

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Posted by Derek

I'd like to thank everyone who's left comments and e-mails. It's all much appreciated. I've been encouraged by those who've told me that they've passed on links and copies of the last post. If it has an effect on someone in time to do some good, I'll be very happy.

I'm still helping to tie up loose ends here, of which there are plenty (and more coming to light each day.) Blogging will resume here sometime next week, probably Tuesday night.

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

April 5, 2005

In Memoriam

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Posted by Derek

I've been unable to post anything the last couple of days. Unfortunately, my brother died on Monday.

His death appears to have been a heart attack, but what really killed him was vodka. My brother was an alcoholic; he had been one for many years. Looking back, he first showed signs of it as an early teenager. It stayed with him, flaring up on and off until over the last ten years, during which drinking had largely destroyed his life.

I wasn't that much help, but I was at least more useful as a brother (helping to get him into rehab for the first time back in 1999) than I was as a medicinal chemist. We don't really understand alcoholism enough to be able to do much about it, and the same goes for almost every other form of addiction. Alcohol's harder than most of them to study because there isn't a specific receptor system that you can point at (as there is for, say, heroin.) Its effects are broad and strong, and for some people, almost impossible to fight.

Needless to say, we don't know why some people can drink and never become alcoholics, while others just seem to slide right down into the pit. Essential questions about the brain and human behavior come up immediately when you start to talk about alcoholism, and no one knows the answers to them yet. I believe that David Foster Wallace defined a harmful addiction as something that offered itself as the solution to the problems that it was causing, and that seems to sum up the tangle of biochemistry and behavior that an alcoholic lives in. Each year, my brother slipped further and further away from the possibility of a normal life.

Eventually, there wasn't much left of the person I grew up with. He died in stages. His memory, his motor skills, his speech and his personality had all been eroded by drinking. Despite his own attempts to break free, despite stays in rehab and AA, despite terrible convulsive bouts of delirium tremens and nearly dying of pancreatitis at least twice, he was never able to find a way out. In the end, he was alone, on a couch, in a littered room that he was unable to summon enough strength to clean.

All I can do is honor his memory, especially the memories of the times before he was a damaged shadow of what I think of as his real self - the days when there was still a real self left. And I can hope to warn others of what could be waiting for them. If any of you reading this think that you might have a problem with alcohol, then you very well might. And the sooner you try to do something about it, the better your chances of succeeding.

Don't wait. Don't end up on that couch. Please.

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April 3, 2005

Don't Talk To Yourself So Much

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Posted by Derek

I've been re-reading Francis Crick's memoir What Mad Pursuit, and this passage struck me:

". . .it is important not to believe too strongly in one's own arguments. This particularly applies to negative arguments, arguments that suggest that a particular approach should certainly not be tried since it is bound to fail. . .While one should certainly try to think which lines are worth pursuing and which are not, it is wise to be very cautious about one's own arguments, especially when the subject is an important one, since then the cost of missing a useful approach is high. . .

Be sensible but don't be too impressed by negative arguments. If at all possible, try it and see what turns up. Theorists almost always dislike this sort of approach."

Right on target. In my field, there is hardly an experiment worth doing that can't be objected to right at the start. Counterexamples abound, theoretical reasons why things won't work out are everywhere. Too sterically hindered, not nucleophilic enough, an interfering functional group somewhere else in the molecule, wrong solvent, wrong catalyst, wrong temperature, wrong everything. If you listen to every one of these objections, even when they're coming from inside your head, you'll never do anything at all. True, you'll never be wrong, but only at the cost of never being right.

This is on my mind tonight, because I'm getting close to a revival of a series of experiments that I've been messing around with for nearly three years now. It's a very interesting idea whose details, painfully, I'm not at liberty to lay out. Not yet. I'm reposting my writings on this work over in the Birth of an Idea category at the right, in case you're interested in seeing what scientific excitement does to a person.

The whole time, I've hardly had the tiniest bit of experimental success, it pains me to say. But I'm back with another variation. Every time I'm more sure that things are going to work. Perhaps, after two years of being quite wrong, I might make the switch to quite right. . .

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