The death of medicinal chemistry?

E. J. Corey's rational methods of chemical synthesis
revolutionized organic chemistry, but they also may have been
responsible for setting off unintended explosions in the medicinal
chemistry job market

Chemjobber points us to a discussion hosted by Michael Gilman, CEO of Padlock Therapeutics, on Reditt in which he laments the fact that medicinal chemistry has now become so commoditized that it's going to be unlikely for wages to rise in that field. Here's what he had to say.

"I would add that, unfortunately, medicinal chemistry is increasingly regarded as a commodity in the life sciences field. And, worse, it's subject to substantial price competition from CROs in Asia. That -- and the ongoing hemorrhaging of jobs from large pharma companies -- is making jobs for bench-level chemists a bit more scarce. I worry, though, because it's the bench-level chemists who grow up and gather the experience to become effective managers of out-sourced chemistry, and I'm concerned that we may be losing that next general of great drug discovery chemists."

I think he's absolutely right and that's partly what has been responsible for the woes of the pharmaceutical and biotech industry over the last few years. But as I noted in the comments section of CJ's blog, the historian of science in me thinks that this is ironically the validation of the field of organic synthesis as a highly developed field whose methods and ideas have now become so standardized that you need very few specialized practitioners to put them into practice. 

I have written about this historical aspect of the field before. The point is that synthesis was undeveloped, virgin territory when scientists like R B Woodward, E J Corey and Carl Djerassi worked in it in the 1950s and 60s. They were spectacularly successful. For instance, when Woodward synthesized complex substances like strychnine (strychnine!) and reserpine, many chemists around the world did not believe that we could actually make molecules as complicated as these. Forget about standardization, even creative chemists found it quite hard to make molecules like nucleic acids and peptides which we take for granted now.

It was a combination of hard work by brilliant individuals like Woodward combined with the amazing proliferation of techniques for structure determination and purification (NMR, crystallography, HPLC etc.) that led to the vast majority of molecules falling under the purview of chemists who were distinctly non-Woodwardian in their abilities and creative reach. Corey especially turned the field into a more or less precisely predictive science that could succumb to rational analysis. In the 1990s and 2000s, with the advent of palladium-catalyzed coupling chemistry, more sophisticated instrumentation and combinatorial chemistry, even callow chemists could make molecules which would have taken their highly capable peers months or years to make in the 60s. As just an example, today in small biotech companies, interns can learn to make in three months the same molecules that bench chemists with PhDs are making. The bench PhDs presumably have better powers of critical thinking and planning, but the gap has still significantly narrowed. The situation may reach a fever pitch with the development of automated methods of synthesis. The bottom line is that synthesis is not longer the stumbling block for the discovery of new drugs; it's largely an understanding of biology and toxicity.

Because organic synthesis and much of medicinal chemistry have now become victims of their own success, tame creatures which can be harnessed into workable products even by modestly trained chemists in India or China, the more traditional scenario as pointed out by Dr. Gilman now involves a few creative and talented medicinal chemists at the top directing the work of a large number of less talented chemists around the world (that's certainly the case at my workplace). From an economic standpoint it makes sense that only these few people at the top command the highest wages and those under them make a more modest living; the average wage has thus been lowered. That's great news for the average bench chemist in Bangalore but not for the ambitious medicinal chemist in Boston. And as Dr. Gilman says, considering the layoffs in pharma and biotech it's also not great news for the field in general.

It's interesting to contemplate how this situation mirrors the situation in computer science, especially concerning the development of the customized code that powers our laptops and workstations; it's precisely why companies like Microsoft and Google can outsource so much of their software development to other countries. Coding has become quite standardized, and while there will always be a small niche demand for novel code, this will be limited to a small fraction at the top who can then shower the rest of the hoi polloi with the fruits of their labors. The vast masses who do coding meanwhile will never make the kind of money which the skill set commanded fifteen years ago. Ditto for med chem. Whenever a discipline becomes too mature it sadly becomes a victim of its own success. That's why it's best to enter a field when the supply is still tight and the low hanging fruit is still ripe for the taking. In the tech sector data science is such a field right now, but you can bet that even the hallowed position of data scientist is not going to stay golden for too long once that skill set too becomes largely automated and standardized.

What, then, will happen to the discipline of medicinal chemistry? The simple truth is that when it comes to cushy positions that pay extremely well, we'll still need medicinal chemists, but only a few. In addition, medicinal chemists will have to shift their focus from synthesis to a much more holistic approach; thus medicinal chemistry, at least as traditionally conceived with a focus on synthesis and rapid access of chemical analogs, will be seeing its demise soon. Most medicinal chemists are still reluctant to think of themselves as anything other than synthetic chemists, but this situation will have to change. Ironically Wikipedia seems to be ahead of the times here since its entry on medicinal chemistry seems to encompass pharmacology, toxicology, structural and chemical biology and computer-aided drug design. It would be a good blueprint for the future.

In particular, medicinal chemistry in its most common practice —focusing on small organic molecules—encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in close combination with chemical biology, enzymology and structural biology, together aiming at the discovery and development of new therapeutic agents. Practically speaking, it involves chemical aspects of identification, and then systematic, thorough synthetic alteration of new chemical entities to make them suitable for therapeutic use. It includes synthetic and computational aspects of the study of existing drugs and agents in development in relation to their bioactivities (biological activities and properties), i.e., understanding their structure-activity relationships (SAR). Pharmaceutical chemistry is focused on quality aspects of medicines and aims to assure fitness for purpose of medicinal products.

To escape the tyranny of the success of synthetic chemistry, the accomplished medicinal chemist of the future will thus likely be someone whose talents are not just limited to synthesis but whose skill set more broadly encompasses molecular design and properties. While synthesis has become standardized, many other disciplines in drug discovery like computer-aided drug design, pharmacology, assay development and toxicology have not. There is still plenty of scope for original breakthroughs and standardization in these unruly areas, and there's even more scope for traditional medicinal chemists to break off chunks of those fields and weave them into the fabric of their own philosophy in novel ways, perhaps by working with these other practioners to incorporate "higher-level" properties like metabolic stability, permeability and clearance into their own early designs. This takes me back to a post I wrote on an article by George Whitesides which argued that chemists should move "beyond the molecule" and toward uses and properties: Whitesides could have been talking about contemporary medicinal chemistry here.

The integration of downstream drug discovery disciplines into the early stages of synthesis and hit and lead discovery will itself be a novel kind of science and art whose details need to be worked out; that art by itself holds promising dividends for adventurous explorers. But the mandate for the 20th century medicinal chemist in the 21st still rings true. Medicinal chemists who can borrow from myriad other disciplines and use that knowledge in their synthetic schemes, thus broadening their expertise beyond the tranquil waters of pure synthesis into the roiling seas of biological complexity will be in far more demand both professionally and financially. Following Darwin, the adage they should adopt is to be the ones who are not the strongest or the quickest synthetically but the ones who are most adaptable and responsive to change. 

For medicinal chemistry to thrive, its very definition will have to change.