The evils of our time

So yesterday over lunch me and some colleagues got into a discussion about why scientific productivity in the pharmaceutical industry has been perilously declining over the last two decades. What happened to the golden 80s when not just the "Merck University" but other companies produced academic-style high quality research and published regularly in the top journals? We hit on some of the usual factors. Maybe readers can think of more.

1. Attack of the MBAs: Sure, we can all benefit from MBAs but in the 80s places like Merck used to be led by people with excellent scientific backgrounds, sometimes exceptional ones. Many were hand-picked from top academic institutions. These days we see mostly lawyers and pure MBAs occupying the top management slots. Not having a scientific background definitely causes them to empathize less with the long hairs.

2. Technology for its own sake: In the 90s many potentially important technologies like HTS and combi chem were introduced. However people have a tendency to worship technology for its own sake and many have fallen in love with these innovations to the extent that they want to use them everywhere and think of them as cures for most important problems. Every technology works best when it occupies its own place in the hierarchy of methodologies and approaches, and where a good understanding of its limitations wisely prevents its over-application. This does not seem to have really happened with things like HTS or combi chem.

3. The passion of the structuralists: At the other end of the science-averse managers are the chemical purists who are so bent on "rules" for generating leadlike and druglike molecules that they have forgotten the original purpose of a drug. The Lipinskians apply Lipinski's rules (which were meant to be guidelines anyway) to the extent that they trump everything else. Lipinski himself never meant these rules to be absolute constraints.

What is remarkable is that we already knew that about 50% of drugs are derived from natural products which are about as un-Lipinskian as you can imagine. In fact many drugs are so un-Lipinskian as to defy imagination. I remember the first time I saw the structure of Metformin, essentially methyl guanidine, and almost fell off my chair. I couldn't have imagined in my wildest dreams that this molecule could be "druglike", let alone of the biggest selling drugs in the world. I will always remember Metformin as the granddaddy of rejoinders to all these rules.

The zealous application of rules means that we forget the only two essential features of any good drug; efficacy and safety, essentially pharmacology. If a drug displays good pharmacology, its structure could resemble a piece of coal for all I know. In the end the pharmacology and toxicity are all that really matter.

4. It's the science stupid: In the 80s there were four Nobel Prize winners on the technical staff of Bell Labs. Now the entire physics division of the iconic research outfit boasts a dozen or so scientists in all. What happened to Bell Labs has happened to most pharmaceutical companies. The high respect that basic science once enjoyed has now been accorded to other things like quarterly profits, CEO careers and the pleasure of stock holders. What is even more lamentable is the apparent mentality that doing good science and making profits are somehow independent of each other; the great pharmaceutical companies in the 80s like Merck clearly proved otherwise.

Part of the drive toward only short term profits and the resulting obsession with mergers and acquisitions has clearly arose from the so-called blockbuster model. If a candidate is not foreseen to be making a billion dollars or more, dump it overboard. Gone are the days when a molecule was pursued as an interesting therapy that would validate some interesting science or biochemical process, irrespective of its projected market value. Again, companies in the past have proved that you can pursue therapeutic molecules for their own sake and still reap healthy profits. Profits seem to be like that electron in the famous double slit experiment; if you don't worry about them, they will come to you. But start obsessing about them too much and you will watch them gradually fade away like that mystical interference pattern.

We ended our discussion wondering what it's going to take in the end for big pharma to start truly investing in academic style basic science? The next public outcry that emerges from drug-resistant strains of TB killing millions because the drugs which could have fought them were never discovered in the current business model? It could be too late then.


  1. All of that is true. You should add one more evil to that pile, dull, cookie cutter scientists (10.1016/j.mehy.2008.11.020)

  2. Since the 1990s, with small biotechs flourishing, big pharma formula seems to either in-licensing biotech products or acquisition them. Perhaps the MBA bosses at BPs prefer these quicker and cheaper approaches to block buster. Is it really so?? While the big pharmas are very thorough in their drug disocovery/development, most of the small biotechs typically cut corners whenever/wherever possible and often push mediocre compounds to clinics. It helps them bringing in more money and that’s their bottom line – keep their investors happy. Eventually though, these inferior products meet the end they deserve – failure past Phase I. In the meantime, a deal has been struck with a big pharma and the few people at the biotechs become rich and the big pharma business bosses have shown “forward progress” by striking few deals like this, but nothing else.

    BTW Metformin isn’t at all in violation of Lipinski’s rules, is it? However, I do agree it is surprisingly orally bioavailable.

  3. It could just be that BigPharma of the 80's and 90's was getting fat on the proverbial low-hanging fruit, the easy and tractable targets/diseases. The profit margins in that era were large enough to support speculative, innovative, and academic-style research groups. Now that the easy stuff has been exhausted, profit margins are plunging, approvals are dwindling, and the firms are forced to take a hard look at what generates value and what does not. It is short-sighted and possibly counterproductive, but can one really blame a senior manager, when cuts must be made, for focusing on the areas where the payoff is uncertain?

  4. I have to agree with AlchemX. To expand on it a little bit, there is very littlel intellectual diversity. In some companies, it is very difficult to get an interview if you are not from certain groups. In others if you don't have a Ph.D. and Post doc in total synthesis, there's no way you are making it in. For example some one with experience in Kinetics and Bioorganic chemistry has no chance of getting an interview. Of course once you get in you are expected to reside in your box. God forbid if you are a synthetic chemist and want to learn some biology. That's not your domain. Just keep making molecules

  5. Good points, all. AlChemX, thanks for the reference about which I will have to say more later.

  6. Please do say more. It is very annoying to see so many new professors get tenure for just cranking out reactions and no real ideas. The students that are coming out are as dull as ever also. Just running one experiment after another without much thought.


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