I thought that everyone might enjoy a quick trip back to the past with me. In my files, turning a bit yellow around the edges, is a copy of a story from Business Week's May 13, 1991 issue. It's "The Search For Superdrugs: A Union of Biotech and Chemistry May Conquer the Great Killers." Hot stuff, eh? This appears to have been an attempt to introduce BW's readership to the idea of rational drug design, which had been a hot topic for several years at the time. It looks like the people at Vertex were a good source for the reporters:

"Boger (of Vertex) is at the vanguard of a revolutionary approach to drug development. Few drugmakers admit it, but privately their executives say traditional research techniques just don't cut it anymore. The old way - screening thousands of chemical in a hit-or-miss search - is inefficient and wastes time. That's why it can now cost more than $200 million to bring a drug to market."

My first reaction to this is, "Ah, for the good old days, when that's all it cost us." I also note that the one-foot-in-the-grave method of random screening is still very much with us. Vertex's venture-capital pitch back then seems to have been very much into screen-bashing, with the inference that their hot new rational technology would (arrow into the bulls-eye sound effect here) zzzzzZZZISH-thunk right into the target instead.

I also note that the whole point of the paragraph is nonsense. Even back in 1991, the time and effort of random screening contributed at most a few percent to the eventual price tag of a new drug. The last two sentences could just as plausibly read "The old way of installing tires - with compressed air and lug nuts - is inefficient and wastes time. That's why it can now cost more than $30,000 to buy a new SUV." Well, let's press on:

"Boger and others like him are carrying the flag for a new wave of R&D often called "rational drug design." Dozens of these entrepreneurs are consummating the long-awaited combination of biotechnology and chemistry - a union that promises to streamline and enhance drug development and reshape the biotech and pharmaceutical industries. This year, the first "superdrugs" from this marriage will enter human testing. "Everything is coming together," says Brook Byers, a biotechnology venture capitalist. "Chemistry and Biology together will create the drugs of the '90s."

Well, I can't argue with that statement, except by pointing out that Chemistry and Biology together created the drugs of the '70s and '80s, too. (Byers is very much still with us, by the way.) But this naturally leads one to ask: what are these superdrugs from 1991, and where are they today?

One that they mention is an RNAse H inhibitor from Agouron, which was a very neat place to visit in the early 1990s. There's no telling how many journalists went out there to put on goggles and watch models of molecules docking into models of proteins. Then they went back to write their stories and generally made a severe category mistake, thinking that they had been watching actual drug molecules docking into real proteins. While Agouron found some success against HIV protease, the whole RNAse H inhibitor idea has had a tough time of it, although people are still plugging away.

Another drug the article brings up is an glycoprotein IIb/IIIa compound for cardiovascular disease from Genentech. This, I assume, is what eventually turned into sibrafiban (PDF file). Unfortunately, that whole class of drugs didn't work out too well when compared head-to-head against aspirin, and that was pretty much that.

We'll leave aside, for now, the fact that all these folks were trying to compute their way to fame and riches with 1991 hardware, because it's not any easier with the latest 2005 stuff out of the box. Those two examples show you exactly why we're not awash in those wonderful 90's drugs right now. The most important parts of drug development are not yet amenable to a rational approach. We simply don't know enough. If any of the companies developing oral IIb/IIIa ligands thought there was a good chance that they'd lose out to aspirin, of all the cheap competitors, they'd have run away screaming. But they didn't know, and the only way to find out was to spend the money and take the risk. No fancy graphics could have saved them.