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August 5, 2004
The State of the State of the Art
This fall will mark my fifteenth year in the drug industry. Looking back at what things were like in late 1989, there's one thing that I find striking above all the others: that very little has changed.
Fifteen years is a pretty long time in the sciences. In a field like molecular biology it's a ridiculous length of time, but their clocks will slow down on them, too: the previous span (from 1974 to 1989) was a much bigger leap for them than the last fifteen years have been. In a mature field like chemistry we don't have such dramatic interludes, but you do see the changes piling up.
But when I started doing drug discovery, it worked like this: you got a chemical lead by random screening, and a bunch of chemists started in on it, changing the structure around to see if they could improve its activity in a set of in vitro assays. The better compounds went into a rodent model of efficacy, and you checked the blood levels of compound to get an idea of its pharmacokinetics. Once you met all the criteria you'd set, you started high-dose toxicology on selected compound in more rodents, then larger animals. And if things held up, you declared a compound to be the winner, and passed it on to the clinical development team (the scale-up chemists had already been having a look at it, to make sure that they could supply enough for longer tox and human trials.)
Sound familiar? That's exactly how we do it now, most of the time. Oh, the compound you started with might have come from a combinatorial chemistry library this time (although odds are that it didn't!) And you might have some help from the molecular modeling folks along the way (but there are plenty of projects where they can't help, and plenty where they only think they can - no offense, guys.) You'll probably have a more assembly-line approach to getting some quick-and-dirty animal dosing for blood levels, too.
But these are minor changes. Are we ever going to do things really differently? Routinely start with an in silico lead compound, say? Build our compounds by mix-and-match fragment assembly instead? Find a way to predict pharmacokinetics, at least a little bit, so we don't have to run everything through mice? Get some serious clues about toxicology, so we can get off the mouse-rat-dog treadmill on the way to human trials?
The cockpit looks pretty much the same as it has for years. All we have are fancier propellers and slightly more responsive rudders. No one has invented the jet engine yet, and I wonder when someone will.
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