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
January 30, 2009
An analysis of the offer here, from the Dealbook blog at the New York Times. This one leans toward the idea that the whole thing is an attempt to move Genentech's board to accept a deal, rather than go through with a real tender offer. Either way, someone's clearly been reading Delaware securities law (and the original affiliation agreement between the two companies) very closely indeed.
No matter what the intent, not everyone thinks it's it going to work. And as with the Pfizer / Wyeth deal, the cost of insuring Roche's debt have gone up steeply in response to all this.
Meanwhile, at the WSJ Health Blog, they're wondering how this is all going down with Genentech's "brainy, headstrong" scientific staff. Maybe Roche figures there aren't many other places to go? More on this Monday when some of the dust settles.
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I see a fair number of people reading Malcolm Gladwell’s Outliers while I’m commuting. I haven’t read it myself yet, but it seems that a key feature of his case is the “10,000 hour rule”, the idea that many people who are extremely good at a given task have spent at least that long perfecting their skills. (This derives from the work of Anders Ericsson and Herb Simon over the last thirty or forty years).
One of the more perceptive reviews of Gladwell’s book I’ve read is by Michael Nielsen. He brings up the problems that many scientists have had with some of Gladwell’s past work, and according to him, if you weren’t happy with Blink or The Tipping Point, you may well not be happy with this one. (Of course, if you didn’t like those, you probably won’t read this one!) Of course, as a scientist, when you read about something like the ten-thousand-hour rule, the first thing you ask yourself is “Hmm. I wonder if that’s true?” But as Nielsen points out:
There are, of course, many provisos to the 10,000 hour rule. As just one example, to acquire mastery in an area, it’s not enough to just practice for 10,000 hours; the person practicing must constantly strive to get better. Someone who practices without pushing themselves will plateau, no matter how many hours they practice. I suspect many scientists fall afoul of this proviso, putting in enormous hours, but mostly doing administrative or drudge work which doesn’t extend their abilities.
But that said, Nielsen goes on to talk about some scientists who have done great work well before their 10,000 hour mark. These people were working at discontinuities, sudden discoveries that didn’t necessarily build on the past, so they didn’t have as much of a tradition or art to master. A thorough grasp of 19th-century physics didn’t help people much when it came time for quantum mechanics. It wouldn’t be surprising, Nielsen says, if a disproportionate number of great discoveries in science fell into this category.
Now, which category does drug discovery fall into? We have a fair amount of art to be learned and experience to be gained, true. But there’s another factor that confounds things: sheer luck. I think that the fundamental issues of drug design are still so poorly understood that no amount of skill can compensate for them. I’m thinking of difficulties like designing compounds that have good oral absorption or blood-brain barrier penetration – sure, there are guidelines, and there are things that you learn to avoid, but once past those it’s a crap shoot. And then there’s toxicity – you learn pretty quickly not to put known landmine groups into your molecules, but after that, you just have to cross your fingers and hope for the best.
These things also mean that there’s a good amount of work to be done that doesn’t extend a person’s abilities, as the quote above has it. The worst of it is being outsourced these days, the well-known “methyl ethyl butyl futile” stuff, but there’s still a lot of pickaxe work that has to be done in any drug project. It would be a fine thing if ten thousand hours of hard work and practice allowed someone to come in and make nontoxic molecules, but they often have to be discovered by trial and error, and more of the latter.
That said, I take Nielsen’s point about putting in good hours rather than empty ones. As much as possible, I think that we should try to do things that we haven’t done before, learn new skills, and move into untried areas. Try not to get butyl-futiled if you can possibly avoid it; it’s not going to do you much good, personally, to set up another six or eight EDC couplings. There are times that that’s exactly what needs to be done, but don’t set them up just because you can’t think of anything else. This gets back to the point I’ve made about making yourself valuable; anyone can set up amide reactions, unfortunately. Maybe some of the time we spend learning our trade is spent learning how to avoid falling into all the tar pits and time-wasting sinkholes we have.
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January 29, 2009
The research scientists in a drug company often don't mesh well with the marketing people (two cultures, and and all that). For an entertaining look at why this might be the case, try this from BNET Pharma, and just shake your head in amazement. . .
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We’re seeing an example right now of one of the big costs of a drug company acquisition. While the Pfizer / Wyeth deal winds along, with all the regulatory and financial details being slowly worked out, what happens in the R&D organizations?
Well, at Wyeth, I’d imagine that things have slowed down a great deal. No one knows what the future will be like, what parts of the company will stay, and which people will be asked to stay with them. How do you make plans under those conditions? For many people, the project they’re working on is now very much a secondary consideration.
Even outside the personal level, there are a lot of paralyzing influences. The same uncertainties about individual jobs apply to development projects. Some of what Wyeth is working on surely overlaps with what Pfizer’s already doing. So which project goes forward? Not both of a matched set, that’s for sure. There are some projects at both companies that are dead in the water, but no one can be sure which ones, and no one will know for some time to come.
That’s because you can’t really start ironing out these details until the deal goes through. Legally, Pfizer and Wyeth are separate companies, and there are a lot of difficulties involved in sharing information in such depth. Even when that eventually happens, there are going to be plenty of other things to work out. Let’s say that Project Y from Wyeth looks to be in better shape than the corresponding Project Y-Prime from Pfizer, so it goes on through. Fine! But under whose rules does it proceed?
Every company has its own culture about these things – the criteria that are used to recommend a compound to the clinic, the ways those boxes are filled in, the sorts of people who have to sign off on them. A project caught in the middle can stall while all these details are cleared up, losing months (or even a year or two) in the process. You can imagine the disconnects: you guys did check this compound for hERG activity, right? With what assay? And with what cutoff? That’s not the one we use, anyway; we’ll have to run it again, and get that signed off on by. . .hmm, well, by someone, we’ll figure out who’s in charge of that sort of thing soon, about the same time that we figure out who reports to them. Now, about your formulations work. . .you used what, again?
No, all this has a ferocious price, when you measure it in opportunity costs. The people caught up in all this could be doing something much more productive with their time, for sure. This sort of thing doesn’t show up on the books. And the longer the process drags on, the worse it’ll be.
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January 28, 2009
Dennis Overbye had an essay in the science section of the New York Times yesterday, entitled "Elevating Science, Elevating Democracy". That gets across the spirit of it pretty well; it's one of those soaring-rhetoric pieces. It starts off with a gush of at-last-we-have-Obama, but what op-ed in the Times doesn't these days? We're going to be sweeping that stuff into piles and pulling it down out of the trees for months. (Before sending me an e-mail, keep in mind that I'd have a similar reaction no matter whose name was involved; I'm just not a person with high expectations from politicians).
But once he gets past the genuflections, I don't disagree with Overbye's main points. He says that science has a reputation of being totally results-oriented and value-neutral, but wants to point out that there are values involved:
"Those values, among others, are honesty, doubt, respect for evidence, openness, accountability and tolerance and indeed hunger for opposing points of view. These are the unabashedly pragmatic working principles that guide the buzzing, testing, poking, probing, argumentative, gossiping, gadgety, joking, dreaming and tendentious cloud of activity — the writer and biologist Lewis Thomas once likened it to an anthill — that is slowly and thoroughly penetrating every nook and cranny of the world."
We forget what a relatively recent and unusual thing it is, science. In most societies, over most of human history, there hasn't been much time or overhead for such a pursuit. And even when there has, most of the time the idea that you could interrogate Nature and get intelligible, reproducible answers would have seemed insane. Natural phenomena were thought to be either beyond human understanding, under the capricious control of the Gods, or impossible to put to any use. In retrospect, it seems to have taken so painfully long to get to the idea of controlled one-variable-at-a-time experimentation. Even the ancient Greeks, extraordinary in many respects, had a tendency to regard such things as beneath them.
So let's shed the politics and celebrate the qualities that Overbye's highlighting. Run good, strong, experiments. Run them right, think hard about the results, and don't be afraid of what they're telling you. That's what got us to where we are now, and what will take us on from here.
Update: a comment from Cosmic Variance.
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January 27, 2009
You might think that the Pfizer/Wyeth deal means that things are creeping back to normal in the M&A world. But the Wall Street Journal reports that Pfizer is having to pay about 8% for the money it's borrowing, and that the funds are due back in a year. There are also very significant clauses in the deal which make it contingent on Pfizer's bond ratings, etc., and will force the company to shell out if things don't go as planned. There's a 4.5 billion dollar breakup fee, for example, which seems to be about twice the usual contingency.
Meanwhile, Reuters notes that credit default swaps on Pfizer's debt have jumped, reflecting significant uncertainty about whether the whole deal will actually go through. Pfizer's likely to be downgraded even if things go smoothly, so this is going to be expensive from every direction. . .
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A reader reminded me of this paper, which I meant to blog on when it came out last year. The authors looked over the entire Chemical Abstracts Service registry file – in theory, every compound that’s ever been reported in the chemical literature – and asked how many different chemical scaffolds make up the organic chemistry part of the collection. (That ran to a bit over 24 million compounds at the time the paper was written).
You’d expect a power-law (“long tail”) distribution in a data set like this, and that’s just what they found. Among heteroatom-containing scaffolds, the most common 5% were found in about 75% of the compounds. In fact, it was even steeper than that – the most common 0.25% of the heteroatom frameworks made up half the compounds! The flip side of this is that about half of the known scaffolds occur only once, which is about as long a tail as you can get.
That’s almost completely accounted for by (1) the availability of certain starting materials, largely from petroleum and from natural products and (2) the interest in preparing a given framework. Put more crassly, it depends on how much it’ll cost (in time and money), and how much you expect to get back. As the authors put it:
” We believe the presence of this power law is quantitative evidence that the minimization of synthetic cost has been a key factor in shaping the known universe of organic chemistry.”
Tiny variations can send a given scaffold diving off the charts. Think, for example, about the usual steroid framework – there have been a huge number of variations worked on that, since they’re of medical interest and the starting materials are available (thanks, in the early days, to some Mexican yams and their biggest fan). But imagine going in and replacing one or two of those carbon atoms with nitrogens: whoosh, down you go. Many of those frameworks have hardly been touched at all, partly because they’re quite difficult to make. You’d have to have a very good reason to go after them, and that hasn’t presented itself. Meanwhile, the vast numbers of indoles, piperazines, and piperidines in drug molecules help to perpetuate themselves.
The same goes, and even more so, for general compound shapes (heteroatoms or all-carbon). The authors found 836708 different framework shapes, but that breaks down rather sharply: half the compounds are accounted for by 143 frameworks, and the other 836565 make up the other half. I’ll let the authors have the last word:
”It seems plausible to expect that the more often a framework has been used as the basis for a compound, the more likely it is to be used in another compound. If many compounds derived from a framework have already been synthesized, these derivatives can serve as a pool of potential starting materials for further syntheses. The availability of published schemes for making these derivatives, or the existence of these derivatives as commercial chemicals, would then facilitate the construction of more compounds based on the same framework. Of course, not all frameworks are equally likely to become the focus of a high degree of synthetic activity. Some frameworks are intrinsically more interesting than others due to their functional importance (e.g., as a building block in drug design), and this interest will stimulate the synthesis of derivatives. Once this synthetic activity is initiated, it may be amplified over time by a rich-get-richer process. . .”
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January 26, 2009
The Pfizer/Wyeth deal is on, and I would really, really prefer to write about something else this morning. The main thing we can hope for is that the company has decided, just possibly, that its previous takeovers didn’t quite work out the way that they were supposed to on paper, and has resolved to run this one differently. The fact that Wyeth doesn’t have One Huge Drug (the way Warner-Lambert had Lipitor, or Pharmacia-Upjohn had Celebrex), gives me at least a little hope. But, as people were pointed out in the comments to Friday's post, there's no way that you can make this deal work without a lot of layoffs.
What’s frustrating about the way Pfizer’s been going is that I don’t think they’ve necessarily been trying to destroy things. It’s just that they’re so massive that it’s hard for them to pick anything up without crushing it. I could be wrong about that – perhaps there’s an official strategy document somewhere that reads:
“Buy company. Strip of immediately valuable pipeline assets and turn over to Marketing Hordes. Fumble with rest of drug discovery pipeline for a few years while trying to figure out where in the massive scheme of things its parts might fit. Realize that the stuff you bought is going off patent – how time flies! Realize that you have too many sites and too many people – close 'em down, lay 'em off. Realize that, for some reason, you have nothing new ready to sell. Go back to step one. Repeat for as long as there's another drug company.”
If this hasn’t been the plan, it might as well have been. Do it differently this time, guys, if you can. The industry can’t take this stuff forever. If people had internal organs that behaved the way Pfizer has the last ten years, we’d be developing drugs to treat them.
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January 23, 2009
A run of bad accident news today, and all of the same kind. The Chemistry Blog has the story of a fatality in the labs at UCLA. The short and painful details are: inexperienced student, t-butyllithium, flammable clothing, and panic (as in not running toward the safety shower).
This is very sad to hear about, and as with so many lab accidents, one of the saddest parts is how easily it could have been prevented. t-BuLi is, of course, a well-known fire starter, and the student did know about that problem. But one of the keys to working with dangerous substances is to think through what you’ll do if something goes wrong. For a pyrophoric compound, that means knowing where the nearest fire extinguisher and safety shower are. It’s very easy to panic when something goes wrong, but if you’ve rehearsed what to do beforehand, you have a much better chance of doing the right thing in tough circumstances.
I pass this along to the students who read this site, and I’m sure the other experienced lab workers here will agree: always think “OK, what’s the worst thing that can go wrong with this reaction?”, and think about what you’ll do if that happens. Fire? Explosion? Sudden leak of nasty toxic stuff? Think it over. Anyone working in a laboratory should always know where the nearest fire extinguisher is. That is, the nearest appropriate one – if you’ve got a separate Class D model for metal fires, or even just a sand bucket, then when you need it you’re really going to need it. And everyone should know where the nearest safety shower is, be