The rise of translational research and the death of organic synthesis (again)?

The journal ACS Neuroscience has an editorial lamenting the shortage of qualified synthetic organic chemists and pharmacologists in the pharmaceutical and biotech industries. The editorial lays much of the blame at the feet of flagging support for these disciplines at the expense of the fad of 'translational research'. It makes the cogent point that historically, accomplished synthetic organic chemists and pharmacologists have been the backbone of the industry; whatever medicinal chemistry and drug design they learnt was picked up on the job. The background and rigor that these scientists brought to their work was invaluable in discovering some of the most important drugs of our time, including ones against cancer, AIDS and heart disease.

The current fascination of applied basic science, i.e., translational science, to funding agencies, due in large part to the perception of a more immediate impact on human health, is a harbinger of its own doom. Strong words? It is clear in the last 10 years that research funding for basic organic chemistry and/or molecular pharmacology is in rapid decline. However, the quality of translational science is only as strong as the basic science training and acumen of its practitioners—this truth is lost in the translational and applied science furor. A training program that instills and trains the “basics” while offering additional research in applied science can be a powerful combination; yet, funding mechanisms for the critical first steps are lacking. 

Historically, the pharmaceutical industry hired the best classically trained synthetic chemists and pharmacologists, and then medicinal chemistry/drug discovery was taught “on the job”. These highly trained and knowledge experts could tackle any problem, and it is this basic training that enabled success against HIV in the 1990s. When the next pandemic arises in the future, we will have lost the in-depth know-how to be effective. Moreover, innovation will diminish.

I have a problem pushing translational research at the expense of basic research myself. As I wrote in a piece for the Lindau Nobel Laureate meeting a few years ago, at least two problems riddle this approach:

The first problem is that history is not really on the side of translational research. Most inventions and practical applications of science and technology which we take for granted have come not from people sitting in a room trying to invent new things but as fortuitous offshoots of curiosity-driven research...For instance, as Nobel Laureates Joseph Goldstein and Michael Brown describe in a Science opinion piece, NIH scientists in the 60s focused on basic questions involving receptors and cancer cells, but this work had an immense impact on drug discovery; as just one glowing example, heart disease-preventing statins which are the world’s best-selling drugs derive directly from Goldstein and Brown’s pioneering work on cholesterol metabolism. Examples also proliferate other disciplines; the Charged-Coupled Device (CCD), lasers, microwaves, computers and the World Wide Web are all fruits of basic and not targeted research. If the history of science teaches us anything, it is that curiosity-driven basic research has paid the highest dividends in terms of practical inventions and advances. 

The second more practical but equally important problem with translational research is that it puts the cart before the horse. First come the ideas; then come the applications. There is nothing fundamentally wrong with trying to build a focused institute to discover a drug, say, for schizophrenia. But doing this when most of the basic neuropharmacology, biochemistry and genetics of schizophrenia are unknown is a great diversion of focus and funds. Before we can apply basic knowledge, let's first make sure that the knowledge exists. Efforts based on incomplete knowledge would only result in a great squandering of manpower, intellectual and financial resources. Such misapplication of resources seems to be the major problem for instance with a new center for drug discovery that the NIH plans to establish. The NIH seeks to channel the newfound data on the human genome to discover new drugs for personalized medicine. This is a laudable goal, but the problem is that we still have miles to go before we truly understand the basic implications of genomic data.

It is only recently that we have started to become aware of the "post-genomic" universe of epigenetics and signal transduction. We have barely started to scratch the surface of the myriad ways in which genomic sequences are massaged and manipulated to produce the complex set of physiological events involved in disease and health. And all this does not even consider the actual workings of proteins and small molecules in mediating key biological events, something which is underlined by genetics but which constitutes a whole new level of emergent complexity. In the absence of all this basic knowledge which is just emerging, how pertinent is it to launch a concerted effort to discover new drugs based on this vastly incomplete knowledge? It would be like trying to construct a skyscraper without fully understanding the properties of bricks and cement.

As an aside, that piece also mentions NIH's NCATS translational research center that has been the brainchild of Francis Collins. It's been five years since that center was set up, and while I know that there are some outstanding scientists working there, I wonder if someone has done a quantitative analysis of how much the work done there has, well, translated into therapeutic developments.

The editorial also has testimonials from leading organic chemists like Phil Baran, E J Corey and Stephen Buchwald who attest to the power of basic science that they discovered in their academic labs, power that they see almost disappearing from today's labs and funding agencies. This basic science which they have pioneered unexpectedly found use in industry. Buchwald's emphasis on C-N cross-coupling reactions is especially noteworthy since it was these kinds of reactions which really transformed drug synthesis and which led to Nobel Prizes for their inventors.

Baran's words are worth noting:

“It is ironic that a field with such an incredible track record for tangible contributions to the betterment of society is under continual attack. Fundamental organic synthesis has been defending its existence since I was a graduate student. If the NIH continues to disproportionally cut funding to this area, progress in the development of medicines will slow down and a vital domestic talent pool will evaporate leaving our population reliant on other countries for the invention of life saving medicines, agrochemicals, and materials.”

Baran is right that fundamental organic synthesis has been defending its existence for the last twenty years or so, but as has been discussed on this blog and in other sources, it's probably because it worked so well that it became a victim of its own success. The NIH is simply not interested in funding more total synthesis for its own sake. To some extent this is a mistake since the training that even a non-novel total synthesis imparts is valuable, but it's also hard to completely blame them. The number of truly novel reactions that have been invented in the last thirty years or so can be counted on one hand, and while chemists like Baran continue to perform incredibly creative feats in the synthesis of complex organic molecules, what they are doing is mostly applying known chemistry in highly imaginative new ways. I have no doubt that they will also invent some new chemistry in the next few years, but how much of it will compare to the fundamental explosion of new reactions and syntheses in the 1960s and 70s? I don't think this blog as well as others have denied the kind of training that synthetic organic chemistry provides, but I have certainly questioned the aura that sometimes continues to surround it (although it has declined in the last few decades) as well as the degree to which the pharmaceutical industry truly needs it.

To some extent the argument is simply about degree. The biggest challenge in most of the pharmaceutical company's postwar history was figuring out the synthesis of important drugs like penicillin, niacin and avermectin. In the era of massive screening of natural products, design wasn't really a major consideration. Contrast this period to today. The general problem of synthesis is now solved, and the major challenge facing today's drug discovery scientists is design. The big question today is not "How do I make this molecule?" but rather "How do I design this molecule within multiple constraints (potency, stability, toxicity etc.) all at the same time?" Multiparameter optimization has replaced synthesis as the holy grail of drug discovery. There are still undoubtedly tough synthetic puzzles that would benefit from creative problem-solving, but nobody thinks these puzzles won't yield to enough manpower or resources or would necessitate the discovery of fundamental new chemical principles. We of course still need top-notch synthetic organic chemists trained by top-notch academic chemists like Corey and Baran, but we equally (or even more) need chemists who are trained in solving such multiparameter design problems. Importantly, the solution to these problems is not going to come only from synthesis but also from other fields like pharmacokinetics, statistics and computer-aided design.

Another major point which I think the editorial does not touch on is the massive layoffs and outsourcing in industry which have bled it dry of deep and hard-won institutional knowledge. Drug discovery is not theoretical physics, and you cannot replenish lost talent and discover new drugs simply by staffing your organization with smart twenty-five year old wunderkinds from Berkeley or Harvard. Twenty or thirty years' experience counts for a hell of a lot in this industry; far from being a fever chill, age is a unique asset in this world. To me, this loss of institutional knowledge is a tragedy that is gargantuan compared to the lack of support for training synthetic organic chemists, and one that may have likely hobbled pharmaceutical chemistry for decades to come, if not longer.

Other than that the editorial gets it right. Too much emphasis on translational research can detract from the kind of rigorous, character-building experience that organic synthesis and classical pharmacology provide. As with many other things we need a bit of both, and some moderation seems to be in order here.