About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
March 28, 2002
After swapping stories, which some of did again at work recently, you wonder how anyone physically survives their academic chemistry training. Chemists usually come out of their degree programs with a stockpile of good yarns, filed under headings like "Idiotic Lab Explosions" and "Maniacs I Have Worked Next To, And Their Life-Threatening Ideas." Your own explosion stories usually start "One time when I was up in the lab at three AM. . ."
I'll pass some of these along every so often, to give folks outside the field an idea. Before doing that, though, I should mention that the litany of explosions drops off dramatically when you get into industry - and no, I don't miss them. The responsible factors are experience, better facilities, not working all hours of the night, and a certain weeding-out of the real hard-core crazies.
I recall one party I went to back in grad school. Several of us from Chemistry were standing around telling ball-of-flame stories, to the great interest of some law students. One of the guys down the hall from me, though, piped up and said "I don't know what y'all are going on about - I've never had an explosion in my life."
Well, the Chemistry Gods listen to you when you say things like that, and they reach for their bottles of laxative. The next morning, my friend was cleaning out a solvent distillation pot. . .and here's where my organic chemistry readership all start to grin. Cleaning out solvent stills is the all-time leading method of starting lab fires in synthetic chemistry, because you tend to distill many solvents from mixtures involving metals like sodium or (God help you) potassium. Bits and chunks of these lively substances tend to hide under layers of sludge as you try to inactivate them, only to jump out and do their thing long after you're sure everything's been quenched.
Which is just what happened that morning. My friend was sure everything was fine, and rinsed the (theoretically) tamed mixture down the sink (which they won't let you do any more, for the most part, but this was back in the mid-80s.) A couple of seconds went by quietly, then there was a muffled "thoongh!" from deep in the pipes - followed at speed by a three-foot geyser of flaming gunk straight up from the sink drain. I heard the shouting, and came down to find him standing wide-eyed in a thin haze of smoke, still holding the flask. "I never should've said that, should I?" were his words. .
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There's an interesting post over at A Dog's Life about the comments that the reviewers of scientific papers make. These comments are (ahem) supposed to be confidential, but good ones do get around.
I don't have enough of those to contribute much to Gregory Hlatky's list, but I do have one that shouldn't be left out (although it's one of those jokes that's largely only funny to chemists.) A famous prize-winning chemist, unnamed by me, was being visited by the second-hand-source of my story. Although getting old, the famous one was still publishing plenty of papers - perhaps more papers than some people wanted to read.
In fact, he'd just had a paper rejected by the Journal of the American Chemical Society, where he was accustomed to publish. "Look at these referee comments!" he said, showing the reviewer's report to my source. "Can you believe they can write things like this?" This fellow's biggest problem wasn't believing it; it was keeping a straight face as he read: "This paper should be substantially reduced. Either that, or it should be completely oxidized."
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March 24, 2002
One of the things that strikes experienced drug-company people is the cyclic nature of the industry. There's the boom-and-bust productivity cycle that's long characterized it, which I've had several chances to remark on. (Doubtless I'll have plenty more.)
But there are others. For example, how long should a drug discovery project take until it recommends something to the clinical development folks? A couple of years? Five years? As long as it darn well takes? Or if you think that's headed in the wrong direction, how about eighteen months? A year? Anyone for nine months? You can find companies that are trying all of these.
What happens, I think, is that a crop of managers get their experience under a given system, and while doing so they note the grievous failures all around them. Of course, there are some occasional winners, but there are always plenty more that never make it: fine projects, worthy ideas that never worked out because they just didn't have enough time (or just dragged on too long and got sidetracked, on the other hand.)
So, when they get the chance to run things, they resolve that they won't make the same mistakes. Nope, we're not having things drag on forever around here any more: you folks have a year to put it in the net, or you do something else. Or, conversely, we're not going to kill off perfectly good projects when they don't hit some arbitrary deadline: you folks keep at it until you get it right this time, OK?
This illustrates a general principle: just because you can screw things up in one direction doesn't mean you can't screw them up in another. It's a Manichean with-us-or-against-us fallacy that trips people up all the time. There's a case to be made both ways, of course, which is why this mistake has been around so long.
You really can run projects too quickly, sending half-baked slapped-together clinical candidates on to Development. And you really can let things drag on too long, pouring money and effort into a sinkhole because, hey, you've come this far already, and if you quit now you're just admitting failure, right? So the reverse approach, whichever one it is, breeds its own crop of should've-worked projects, and the managers in training resolve that they're not going to make those mistakes again. . .
Ideally, you'd split the difference, but that's the hardest way to do it. Alternately cracking the whip and witholding it can breed resentment at the perceived unequal treatment: How come those guys get to keep going when we're under pressure? How come that group got to present that junk as a candidate when they're still making us fix ours? Instead of just hearing one class of complaint, you get the whole spectrum.
Note, of course, that all the choices involve researchers complaining. It wouldn't be research, then, would it?
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March 22, 2002
I've had several letters about chemical colors. One chemist friend points out that for wild colors, the indoles are the way to go. I haven't done too much indole chemistry (which is OK, since they can reek), but he's right about that. You can get all sorts of pinks and purples as side products. The classical indigo pigment is a derivative of this structural class, so it makes sense. Of course, none of the colorful ones are going to be drugs, most likely, since they have lots of weirdly conjugated bonds that make them both colorful and reactive. Not something you'd fork over for at the pharmacy.
Another letter points out that I misstated Carl Sagan's term for the organic goo found in the outer planets (and in my fume hood at work.) It's "tholin", not "thiolin," which removes my objection completely. And it's what I get for doing these things from memory, when I could reach three feet over to the bookshelf and check it out.
The same reader mentions that recent calculations have shown that if someone manages to make 1,3-difluoroazulene, the color should shift from blue to emerald green. That would be worth seeing, but it's still not enough to get me to do serious fluorine chemistry. You can mess things up very thoroughly with some of those fluorination reagents (and I, unfortunately, can tell you what xenon difluoride smells like, so I have no desire to investigate the other possibilities!) For the record, it's not really a bad smell, just not something that should necessarily be smelled. . .
That reminds me of an entry in the Merck Index. I don't have a copy at hand (this time!), but I think it's for something hideous like fluorine oxide. The entry notes "extremely poisonous. . .attacks lungs even in traces. . .peculiar smell." I've always thought that rather evocative. That last observation sounds like someone's last words, frankly.
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March 20, 2002
As I mentioned yesterday, Viropharma's compound Picovir (pleconaril) was turned down unanimously by an FDA panel. This could be the end for an interesting compound that's been kicking around for many years, going back to the days (1990 or so) when Sterling-Winthrop still existed as a drug company.
Kodak took over Sterling in 1988, looking to get into the high-margin drug industry (they already had a chemicals business, the Eastman side of things.) As it turned out, you couldn't have paid a gang of saboteurs to do a worse job running Sterling, and the whole deal was a costly disaster that lasted some six years. The pieces of Sterling were sold off (at a mighty loss) to the French firm Sanofi, among others. During the chaos, some of the Sterling people left to form Viropharma, negotiating with Sanofi for the rights to pleconaril.
It's an interesting compound, with a mechanism that (to my knowledge) isn't shared by any other antiviral candidate. It binds to a site on the surface of the virus, keeping it from infecting cells. Viropharma kept plugging away at it, trying it out for meningitis and respiratory infections, but without notable success.
The last couple of years were a particularly wild ride. If you go back and look at the stock chart, you can see a huge run-up, followed by an equally hair-frizzing decline. What happened was some media reports in December of 1999 convinced various clueless investors that VPHM had, yes, the cure for the common cold. That was indeed what Viropharma had started trying pleconaril against, the meningitis data having proven unimpressive. The compound was far from a miracle cure.
But try telling that to the notorious stock promoter Tokyo Joe. Remember Joe? Viropharma stock was one of his calls during this period, and his people piled into it hugely, followed by a swarm of tag-along momentum players. They had a real fiesta for a while there, but NASDAQ was in all-fiesta mode back then, anyway.
Momentum investing means, of course, buying stocks just because other people are buying them. It's the Bigger-Fool theory in action, and it's always struck me as similar to the way some jackrabbits dart in front of 18-wheel trucks. (This is coming from someone who shorted Imclone at what turned out to be their low point, so I'm no stranger to risk.) In this case, the 18-wheeler appeared in the form of new clinical data showing that pleconaril wasn't particularly effective against colds, which led to the roll-off-the-table section of the stock chart.
I'm happy to say that I was short VPHM when that happened. Of course, I'd shorted them at about 50 and promptly watched the stock jump like it had been hit with a cattle prod, right up over 100, and mighty quickly, too. Swallowing hard, I shorted some more. I just couldn't see the drug working that well based on the clinical data the company had already shown. Meanwhile, Tokyo Joe's people on the stock message boards were already making VPHM out to be the next Pfizer. That's a quote from some guy - another table-pounder kept going on about how you'd have liked to have bought into penicillin in 1940, wouldn't you? Right? Here's the chance of a lifetime, again! Some other maniac saw the compound as basically the savior of the human race. Then the bad news hit. I'd like to have a videotape of me trying to dial my broker right after I saw the stock quote that morning (down 43 5/8 or something like that.) I kept missing the buttons on my phone; it took three tries before I successfully dialed my broker to take my profits.
The data that came out of those studies helped keep the compound from being recommended yesterday. Pleconaril, taken three times a day, starting very early in the course of a cold, reduces the duration of cold symptoms by a day or two. And that's about it, and that's just not enough. That's an awful lot of drug to load your system with for a relatively minor disease, and it would presumably involve spending a fair amount of money that an HMO might not be keen on reimbursing.
Viropharma kept making their case, of course. One point was that dosing with the drug reduced what's descriptively called "virus shedding," which could make you less infectious to others. To the best of my knowledge, no clinical data was ever collected to put that idea to the test, though. They got a big company to buy into the compound, namely Aventis (known to longtime pharmaceutical people by its heritage, as Hoechst-Marion-Merrel Dow-Roussel-Rhone-Poulenc-Rohrer, which sounds like a white-shoe law firm.)
But, in the end, the combination of lackluster efficacy with some extra safety concerns (possible interactions with the menstrual cycle in a few women, for example) doomed the compound. The effects they saw would have meant nothing for a compound that treated, say, pancreatic cancer, which is otherwise a death sentence. But for a cold?
To their credit, you can see that Viropharma realized all this. That's why they started trials on viral meningitis. When that didn't work out, they went to serious respiratory infections. No dice. Finally, they were left with colds. They did the best with what they had, but it wasn't enough.
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March 19, 2002
No longer can I say that the topic of allergenic extraterrestrial life hasn't been taken on in science fiction. Patrick Neilsen Hayden of Electrolite, who is certainly in a professional position to know, passes on the word that the 1999 novel BIOS (by Robert Charles Wilson, reviewed) includes this very idea.
On a related topic, a number of old sf stories made use of the chirality of amino acids and the resulting proteins, with a plot point usually being the possiblity of starvation when trapped in an environment full of the wrong-handed food source. Given that such enantiomeric compounds can have very different properties in the body, I'd think that such an environment would not only be non-nutritious, but extremely toxic.
But are there any such places (stipulating an abudance of life-as-we-know-it in the universe to make it more possible)? That gets right into the question of how we ended up with only L-amino acids (and only D-sugars, which get less attention, undeservedly.)
There are plenty of theories. One thing that most everyone agrees on is that what we see now is a founder's effect - life got started with the series that we know, and stuck with it ever since, across billions of years. (Reminds me of Microsoft.) But was it a pure 50/50 chance at the beginning, or was the deck stacked? For that to happen, you have to have a chiral environment somewhere for it to develop.
Explanations such as seeding by meteorites containing chiral amino acids (or planetary formation from a cloud containing a chiral mix of compounds) just push the question back a bit. Where did those excesses come from? I should note that a paper on the amino acid ratios in the Murchison meteorite was just presented at the same meeting that Jay Manifold has been reporting from over at "A Voyage to Arcturus." Maybe he can give us a report.
For some years, the explanation that was hauled out invoked the weak nuclear force, which is the first place you can find symmetry breaking down in the laws of physics. Trouble is, that's such a small effect on the thermodynamics (if there's an effect at all!) that it's really like sticking with the 50/50 chance.
Another interesting idea was that circularly polarized radiation, potentially from neutron stars, preferentially breaks down one enantiomer of simple molecules over another. This still doesn't give you much of an edge, but it's a lot more compelling explanation that the weak nuclear force.
Last year a theory was proposed that formation of simple biomolecules on rock surfaces (a hot topic in origin-of-life research) might have something to do with it. Calcite seems to absorb different enantiomers on different faces of its crystals, which could have led to local excesses - too local, some say - of one enantiomer. If one of these microenvironments was the first to start things on the road to life, though, that would be all you need. It's still another form of 50/50 chance, depending on what crystal face you pick, but at least (as with polarized radiation) you have a semi-plausible mechanism for generating an excess of one chiral form.
These ideas and others are discussed on this site, but note: that page also brings up an experiment from a few years ago that suggested that magnetic fields could induce chiral chemistry. This result has since been throroughly discredited. No one could ever reproduce it, and it turned out that one of the original graduate students faked the results. Not a smart career move, considering how much interest (and scepticism) the first report got.
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March 10, 2002
Sepracor's really taken a pounding after an FDA "non-approvable" letter for their antihistamine compound. But they haven't been a quiet drug stock to be in, and it isn't a quiet company.
They certainly don't have a quiet business plan, either. As readers who are in the business are well aware, Sepracor doesn't develop any really new drugs. Instead, they look for "improved versions" (pure enantiomers or active metabolites) of existing ones. As the company says:
"In contrast to traditional new drug development, the safety and efficacy of the racemates and parent drugs of Sepracor's pharmaceuticals under development are often well understood before clinical trials begin. Parent drugs have been successfully taken through clinical studies and may have been on the market for years."
Well, yes, but what that leaves unspoken is that someone else did all that. And what it reallyleaves unspoken is that they didn't do it so that Sepracor could cash in with a second-generation compound. Friday's Wall Street Journal article on their stock plunge contained a line about Sepracor helping Schering-Plough develop their successor to Claritin, Clarinex. If you were to ask Schering, they'd probably tell you that Sepracor helped develop that one in much the same way that Blackbeard helped with jewelry shipments. Lilly felt the same way about the single-enantiomer version of Prozac that they ended up licensing.
Both companies were beavering away on these projects when Sepracor showed up with really unwelcome news: They informed Lilly and Schering that they had patent rights for the use of these second-generation compounds. This (as far as one can tell) completely blindsided both companies, who were sure that (as usual) their chemical matter and its uses was covered under their own patents.
Oops. Sepracor had done a more careful job of reading the existing patent claims, it turned out. There was great gritting of teeth at the companies involved (and probably great public flogging of the Legal departments,) but they both went ahead and signed deals. Sepracor got money upfront and a piece of the profits if the drugs made it to market.
They ended up going 1-for-2 on these, but not calmly. The Prozac enantiomer project with Lilly went into the clinic, where it proved, as expected, to be more active. It also proved to be more toxic. Oops. With that one gone, they needed Schering's compound, more than ever. It's finally hitting the market, but not without delays. Schering's problems with the FDA over manufacturing issues have caused Sepracor plenty of trouble. While Schering's stock price felt the pain, Sepracor (with fewer drugs in its portfolio) felt it even more. Clarinex was finally approved last December, and Sepracor went up almost 6% in one day.
They have several other examples of this strategy. The most successful has been licensing the second-generation form of Seldane back to Hoechst (now Aventis), where it's now known to the world as Allegra. So, what went wrongt this time? This compound was an active metabolite of Johnson and Johnson's Hismanal. While that worked with Clarinex, the danger is that active metabolites are new compounds, with new properties all the way. It's not like the single-enantiomer drugs, where at least patients have been getting dosed with the compound already. In this case, there were toxicology problems that Hismanal doesn't seem to have.
And what now for Sepracor? As has been apparent for many years now, their business model is based on a non-renewable resource - incomplete patent coverage. Those loopholes have closed decisively, since everyone now knows what will happen if they aren't. In that way, Sepracor's influence has been a good one on the industry, keeping everyone on their toes.
They've talked over the years about becoming a real, research-driven drug company, but I'll believe it when I see it. That requires costly infrastructure that they don't have, and entails a success rate that (last week's setback notwithstanding) is lower than they're accustomed to. And instead of fishing for drugs from a secluded spot, it would put them right in the big tank with the rest of the sharks.
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