In August, I gave a talk at the Boston ACS meeting about the contribution of academics to molecular modeling. Okay, their lack of contribution to molecular modeling. I might even have had a slide that read, “If all academic research into modeling disappeared tomorrow, it would make no difference… to the drug discovery industry. Discuss.”
How could I have suggested such an outrageous thing? A year ago, I was putting together a talk for Paul Labute’s CCG UGM on the general state of molecular modeling (my “History, Hubris and Greed” talk), and I made a slide which I reused in my Boston ACS talk listing all the things that I had found really useful in my career at OpenEye. Out of a total of nine things, only one was from academia (the Poisson-Boltzmann theory as developed by Barry Honig). Most of them, such as AM1BCC charges, MMFF, came from industry and some (e.g. SMILES) came from government. I found this surprising, considering how little time industry and government scientists get to spend doing novel work. So my Boston talk was essentially a rationalization of the peculiar ineffectiveness of academic research as applied to molecular modeling.
Was I suggesting that academics are lazy or dumb? Of course not. I would, however, draw a parallel with the traders on Wall Street—the thieving bastards who drove the world to an economic precipice only two years ago. Although it’s tempting to think ill of this group, the reality is that they were merely following the incentives laid out for them (public risk and private reward being a really bad idea). Similarly, I think that academics, especially those in the field of drug discovery, have inherited the wrong set of incentives: rather than help build a firm foundation for the field these incentives encourage application of flawed and poorly understood science. Many academics are aware that the incessant need to publish, the endless and often fruitless grant cycles, and the pressures to be monetarily successful have pushed real scientific research onto the back burner. But I think few know how the system got to be this way. Although my explanation is based largely on the history of science in the United States, I think that’s a safe place to start since the U.S. is so scientifically dominant and usually acts as a role model to the rest of the world.
At the end of the nineteenth century there were nine universities in England, and more than two hundred in the United States [Ref #1]. Why the discrepancy? The economy of England was bigger than that of the U.S., yet it had far fewer institutes of higher learning. The reason was simply that in America, anyone could start a university: all you needed was some land (typically granted from the government), some funding from the local rich folk and off you went. In England such things required government coordination, royal patronage, etc. In the U.S., then, so-called “land-grant” universities went up all over the place. Some failed quickly, but some are still with us as major institutions. The point is (as always): where did the money come from? It came, for the most part, from industrialists, typically those who recognized the general social benefit of a university but who also expected some direct benefit by way of technical expertise and research. This was still the case as late as the 1940s. Departments, at least scientific ones, would get the majority of their funding from industrial partners. This led to some spectacular advances in industry. The example I like to spotlight is the development of the fluidized bed catalysis of oil to form petroleum, an effort funded by a consortium of oil companies and led by researchers at MIT. Fluidized bed catalysis probably had the second biggest impact on the Second World War of any American technological invention because it allowed the U.S. to manufacture petroleum more efficiently than Japan or Germany. The next part of the story, of course, revolves around the invention that had the biggest impact: the atomic bomb.
The reason the Manhattan Project has anything to do with the effectiveness of current academic molecular modeling research is that it made politicians realize that science was not something they could ignore. As a consequence of the success of Los Alamos, Truman asked the wholly remarkable Vannevar Bush (who helped build the first computing machine and first proposed the idea of hyperlinks) to work out what science funding should look like after the war. Vannevar understood the incredible leverage that basic research could exert on practical science and wrote a monograph, Science, the Endless Frontier, proselytizing for pure, un-politicized government support for science. His wish was partially granted when the government created the National Science Foundation (NSF). Unfortunately, the government also created the NIH, which became the more powerful institution. The National Institute of Health was (and remains) aimed squarely at health issues, and was (and remains) the creation of political forces. As a consequence, one of the deep-rooted problems in our field is that although the NSF could in theory fund the type of basic research we desperately need, research that would provide the basis for true ‘drug engineering’, this impinges on the territory of the NIH, which has utterly failed to support that mandate. Even today we hear nonsense spewing forth from those who run that organization about “translational” research, which really translates to “just make something work.” It is a classic Catch-22. The basic science that is needed to really transform the field is not funded, in part because the organization that is supposed to perform that role has to answer to political directives.
The final blow to useful academic contribution occurred in 1980 with the Bayh-Dole act. This required universities to make something of the government-funded research they did—i.e., to commercialize it. The story of how Bayh-Dole came about is fascinating. Universities could already patent work that was funded by the government, but there was a patchwork of agencies and procedures. Bayh-Dole not only simplified the process but also shifted the onus from “could patent and commercialize” to “should patent and commercialize”. In my opinion, there has been no more damaging Act of Congress, at least where science is concerned. The way it was sold to the good people up on the Hill was that there were all these patents from research funded by the government and only five percent had actually been licensed. Clearly universities needed some incentives to get off their butts and start helping American Industry (sotto voce: beat the Japanese, who seemed to be taking over industrial leadership). The truth is that most of these patents had been funded by the Department of Defense. And it had always been the case that the military made it really simple for contractors funded by DOD grants to patent and license anything they wanted. There was no barrier; it was just that 95% of the patents weren’t very useful. These facts were never presented to those who voted, fairly overwhelmingly, for Bayh-Dole. Thirty years later, careful examination finds little support for the view that this act helped American productivity [Ref #1], although it has probably reduced that of American science [Ref #2].
With Bayh-Dole we have the complete picture: Funding is heavily weighted towards the practical, not the fundamental. Universities push students and professors to be useful, to make things they can patent and hawk to industry. So what could possibly stop brilliant inventions revolutionizing the field of health care? Well, nothing, really, other than a fundamental misunderstanding of what makes science valuable. Science is about measurement, and the prediction of measurement. The sheer lack of the former and the sheer overabundance of shoddy, over-parameterized, over-hyped examples of the latter defines the state of the field today. Furthermore, because there are now many fewer links between the worlds of academia and industry than there were before the 1940s, academics typically don’t even know what problems industry cares about! I asked a major employer of molecular modelers in pharma how many academic groups they could hire from and expect the new hires to be able to get right to work without additional training. The answer was two. Two out of all the myriad of groups believing they do molecular modeling relevant to the activity of drug discovery.
My suggestions to improve matters come in two flavors: the practical and the impractical. My first impractical wish is that Bayh-Dole be repealed. That isn’t going to happen because we do not elect politicians capable of understanding the nature of science. If only they’d listened to Vannevar! We nearly got the perfect government support of pure science, but reality fell too short. My next impractical suggestion is to cut off all funding for anything to do with molecular modeling, unless it could be considered basic research—and even then only if it were coupled with an experimental component.
Why should industry fund basic research? That is a role for government. Government used to do this, providing long grants that allowed researchers to tackle hard, basic problems. (Talk to the people about to retire in academic departments; they know.) It is, however, entirely reasonable to ask industry to fund “translational” research. Let them decide what needs to be translated, because they—not academics, not politicians—know what the problems are. This is my number one practical suggestion: that private companies shoulder the cost of translational research (provide the incentives) that they used to. True that they effectively would be taxed twice—but I think judicious tax breaks could still make this attractive. My second suggestion is that academics ignore Bayh-Dole. I’ve had a lot of academics tell me they can’t help trying to become millionaires, that Bayh-Dole forces them to act so. This is not true. The operations within universities, the offices of science and technology that seek to patent and to license, are entirely at the mercy of the bench-level scientists. They don’t have the skills to know what is truly novel and what is not: they rely on what the scientists tell them. So. Don’t. Tell them. America was changed forever by the simple civil disobedience of its citizens in the 1960s. What would happen if academics were to rebel—even a little—and stop supporting elements of the system that are ruining science?
Finally, I suggest academia and industry need to talk more directly, exchange ideas, agendas and—most important from the industrial side—data. There are some real problems, both applied and theoretical, that could be addressed. Don’t quote me on this but I might even pay academia to work on problems that would actually have an impact on drug discovery.
In conclusion, academics don’t make much of a difference. They should. I’m not blaming the players, I’m blaming the game. We just have to wake up and realize that it’s really our game.
1: David Mowery, Richard Nelson, Bhaven Sampat, Arvids Ziedonis, “Ivory Tower and Industrial Innovation: University-Industry Technology Transfer Before and After the Bayh-Dole Act” (Stanford Business Books, 2004)
2: Jennifer Washburn: “University, Inc.: The Corporate Corruption of Higher Education” (Basic Books, 2005)