Having been around the drug discovery industry for as long as I have now, you’d expect me to occasionally have one of those “That’s not how we used to do it” moods. Isn’t that what experienced people in every industry are supposed to do: grumble about the young whippersnappers and how they don’t respect the lessons of the past?

Well, as it turns out, it seems that I might not be getting that privilege. For one thing, there aren’t so many young whippersnappers around the place, for the simple (and ugly) reason that we haven’t been hiring so many of them. Neither has anyone else. This is a big problem, of course, for the people who are in the process of not getting hired. I hear pretty often from chemists who are in graduate school, or are looking to finish up a post-doc, and are asking for advice about how to break into the drug discovery business. (Sometimes they’re asking for advice on what else to do, after finding out that they can’t seem to break in at all.) I don’t have a lot of good stuff to tell them, either.

But this is also a big problem for the companies involved, and I’m not sure if this has been generally realized. I know that I might seem to be confusing cause and effect here, since the reasons that companies aren’t hiring scientists have to do with the other big problems they have. Problems cause further problems, though, and in this case, what we’re ending up with are research departments that are staffed with the same bunch of people year after year. The same ideas get floated around, in many cases, and are met with the same objections from pretty much the same people who objected last time. Psychologically, this isn’t a good situation. If everyone’s already taken the measure of everyone else, the chances for something new happening are diminished.

Back when the Institute for Advanced Study was starting up at Princeton, its founders recognized this very problem. There’s a memo from that time that worried about bringing in a cohort of great minds, all of whom were roughly the same age, and all of whom would get old together. Mathematicians and physicists had long realized how much of the great work in their fields had been done by the younger generations, so this topic came naturally to the IAS administration. Still, while chemistry and drug discovery don’t have that historical record, I think we’re still asking for trouble in the way we’re staffing our departments.

Don’t think that I’m devaluing experience. That’s actually one of the things that makes this work different from theoretical physics. We don’t spend all of our time striking out into the wild unknown, and there’s a lot of value in having been around the drug development racetrack a few times. Filling the labs exclusively with people fresh out of school would be a plan for disaster, while in higher mathematics you could get a lot done that way if you picked up the right people and turned them loose to argue with each other over the whiteboards.

But that said, just because you can mess things up in one direction doesn’t mean that you can’t mess them up in the other. My worry is that aging, inbred drug research departments will suffer from too many of the well-known problems. These include killing off new proposals with some version of “We tried that already, years ago, and it didn’t work,” or by hostility due to the original idea not having come from inside the department in the first place, or — and this is the opposite mistake, which is still sometimes made by the exact same people — by deciding that if this new idea were any good, someone else would have done it first. Right? Are we all in agreement, then, that the way we’ve been doing things for years around here is, in fact, the right way that things should be done? That we’re going to make sure that proposals that suggest otherwise make for uncomfortable discussions and are probably wrong, anyway? Good. What’s next on the meeting agenda?

You see what I’m getting at, and you’ve probably seen behavior much like this yourself. I certainly have, and when I’m in an honest mood, I can admit to having promulgated some of this stuff personally. It’s human nature. I don’t mind giving room to a lot of odd proposals, but (other things being equal) they’ll probably tend to be those odd proposals that don’t undermine my own sense of self-worth. Unfortunately, that doesn’t necessarily correlate with how worthwhile these ideas really are. You have to keep a close eye on this sort of thing; this is one of those times when going on autopilot is not a good plan.

We have enough of a problem with groupthink in this industry as it is. Examples are all too thick on the ground of projects that really shouldn’t have gone as far as they did, but soaked up money because the people doing them had all convinced themselves that everything was going great. The shining example — if “shining” is the right word — would be Pfizer’s Exubera, the inhaled-insulin fiasco from a few years ago. In retrospect, the whole thing looks a bit like Napoleon’s invasion of Russia, but a lot of Pfizerites seemed sure that the nay-sayers were just lacking in vision (and could therefore be safely ignored). I worry that we’re setting ourselves up for more of this sort of thing.

There’s a larger issue behind all this, too. When you think about it, the basic structure of small-molecule drug discovery and development has not changed very much over the years. Screen against a target, validate the hits, do some SAR around them to see which ones are fit for optimization, turn the medicinal chemists loose on them to work on potency, selectivity, PK properties, and so on. Recommend a compound for the clinic, do tox, get a formulation for Phase I, and so on and so on. Now, it’s true that these are all obvious steps, and it’s not like I have any sweeping proposals to change things, but can we look at our success rates and claim that this is all part of a smoothly running optimized process? Not with a straight face.

So perhaps part of the problem is that it’s been all too possible for people to grow old and/or stale in this work, because the work itself has allowed it to happen too easily. And now we get to one of those chicken-and-egg situations. One would assume that anything truly disruptive would have a better chance of coming from people who know the business, but who haven’t been doing it so long to be completely vested (financially and psychologically) in the status quo. If that’s true, though, then these are just the sort of people who are in increasingly short supply.