(Ir)rational drug design and the history of 20th century science

Here is an excellent overview of the hopes and foibles of "rational" drug design by Brooke Magnanti (Hat tip: Pete Kenny) which touches on several themes and names that would be familiar to those in the field: Ant Nicholls and OpenEye, Dave Weininger and Daylight fingerprints, Barry Werth's "The Billion Dollar Molecule" and Vertex, the inflated hopes of structure-based design, cheminformatics and screening etc. 

Those who are heroic survivors of that period would probably start with looking back with dewey eyes, followed by groans of disappointment. The bottom line in that article and several similar ones is that rational drug design and all that it entails (crystallography and molecular modeling in particular) has clearly not lived up to the hype. It's also clear that the swashbuckling scientists portrayed by Werth in his book for instance were more brilliant than successful. It's a tape of hope and woe that has played before, over and over again in fact.

It's clear that much of the faith in rational drug design until now has had a healthy component of irrational exuberance to it. Looking back at the inflated expectations of the 1980s and early 90s for designing drugs atom by atom, followed by the disappointing failures and massive attrition which rapidly succeeded these expectations, makes me wonder what it was exactly that got everyone into trouble. There was a constellation of factors of course, but the historian of science in me thinks that a major part of at least the psychological (and by extension, organizational) aspects of the issue have to deal with the stupendous successes of twentieth century science in generating a mountain of optimism which skeptics are still trying to chip away at.

It's quite clear that as far as scientific progress goes, the 20th century was the mother of all centuries. Very significant scientific advances (Newton, Maxwell, Darwin, Mendel) had undoubtedly occurred in earlier times, but the sheer rate at which science advanced in the last one hundred years far outstripped scientific progress in all previous centuries. Just consider the roster of both idea-based and tool-based scientific revolutions that we witnessed in the past century: x-rays, the atomic nucleus, relativity, quantum mechanics, nuclear fission, the laws of heredity, the structure of biomolecules, particle physics, lasers, computers, organic synthesis, gene editing...and we are just getting warmed up here.

By the 1980s this amazing collection of scientific gems had reached a crescendo, especially in the biomedical sciences. The rise of recombinant DNA technology, protein structure determination, and improved hardware, software and visualization virtually ensured that scientists started feeling very good indeed about designing drugs to block particular proteins at the molecular level. Philosophically too they were highly primed by the astounding reductionist successes of the past one hundred years. After all reductionism had uncovered the cosmic microwave background radiation from the Big Bang, given us the structure of elemental life proteins like hemoglobin and the photosynthetic complex, split the atom, doubled the number of transistors on a chip in eighteen months and taught us how to copy and paste genes. Designing drugs would be a natural extension, if not a job for graduate students, after all this success.

But what happened instead was that both scientifically and philosophically we ran into a wall. What we found out scientifically was that we still understand only a fraction of the complexity of biological systems that we need to for perturbing them with the fine scalpels of small organic molecules. Philosophically we found out that biological systems are emergent and contingent, so all the reductionist success of the past century is still not enough to understand them. In fact beyond a certain point reductionism would fundamentally put us on the wrong track. The past hundred years made us believers in Moore's Law, but what we got instead was Eroom's Law. Moore's Law is what reduces my running time from 12 mins/mile to 8:30 mins/mile in a year. Eroom's Law is what keeps it from reducing much further. Exponential technological success is not axiomatic and self-fulfilling.

I thus see a very strong influence of the success of twentieth century science in steering the wildly optimistic hopes of drug discovery scientists beginning in the 1980s. Hopefully we are wiser now, but institutional forces and biases still keep us from improving on our failures. As Pete Kenny says in his post for instance, obsession with specific technologies rather than a combined application of several technologies still biases scientists and managers in biotech and pharmaceutical organizations. The rise and ebb (did you just say "rise"?) of economic forces makes the job environment unstable and discourages scientists from pushing bold ideas that promise to break free from reductionist approaches. And much of our science is still based on sloppy theorizing without proper recourse to statistics and controls, not to mention an unbiased look at what the experiments truly are and are not telling us. 

Santayana told us that we are condemned to relive history if we forget it. But when it comes to the promises of rational drug design, what we should do perhaps is to purge our minds of the successes of the 20th century and remember Francis Bacon's exhortation from the 16th century instead: "All depends upon keeping the eye steadily fixed on the facts of nature. For God forbid that we should give out a dream of our own for a pattern of the world."

Image: "Cognition enhancer" (Source: Brooke Magnanti, Garrett Vreeland)