It’s a Friday in midsummer, so I assume that a fair percentage of the readership is not even around! So I’m not going to do a huge detailed blog post (got one of those coming on Monday, actually). Today I just wanted to go on a bit about a problem that comes with experience in this business, thoughts brought on by some of my own recent day-job work.
It’s very hard at times to walk the line between “experienced” and “jaded”, and I think that that’s because “jaded” is the low-energy state. As everyone who does drug discovery knows, we mostly see projects fail, so psychologically, it’s beneficial not to get too attached to any one idea/molecule/project before it’s cleared some hurdles. The key is to be able to do that in a “Well, let’s see if it works” way and not in a “Yeah, that’s gonna fail” way.
I’ve recently seen some chemical matter, which is reported as binding an interesting target, that I find (gotta be honest) quite ugly. It would be easy to dismiss it out of hand, because I have never seen any compounds that look like that turn out to be useful, but that would also be irresponsible. And yes, this is all the way up to things like rhodanines and other PAINs. My take on those has always been “If you have something better-looking to work on, you’re probably better off working on that”, but for some targets, there is nothing better-looking. So the attitude (in my opinion) has to be “Compounds like this have a poor track record, and need to be approached with caution. But this is what we’ve got. Let’s put this one through the relevant assays – both the project-related ones and the warning-this-is-junk ones – as soon as we can so we can make a call”.
I’ve long tried to approach this problem in that fashion. So far, I have to say, none of the suspicious-looking compounds I’ve put to the test have made the cut. Many of them turned out to be aggregators, redox cyclers, fluorescent interference compounds – all the other classic ways to get false positives. And in a couple of cases, more tractable and potent chemical matter came along to make the issue more moot. But there’s always the possibility that one of these will be real, and the whole drug discovery enterprise makes its living on long shots.
The jadedness problem, of course, extends to more than just chemical matter. After a while, you’ve seen a lot of assays, a lot of instruments, a lot of project ideas and approaches. And since we all see a lot more negative data (and negative results) than positive, the same mental battle has to be fought. To a very good approximation, nothing in drug discovery actually works, if by “works”, you mean “delivers an actual drug”. But if you round off and make that approximation, you’re done.
Is there a limit? Yes, indeed. I draw the line at Huge HR Initiatives That Will Totally Change the Way We Do Business. I am, in fact, willing to stipulate that none of those will in fact change the way we do business. Come to think of it, everything I’ve encountered that actually has totally changed the way that any particular organization did business did so via things like 7:30 AM mandatory site meetings, people arriving at the door holding stacks of folding cardboard boxes, and presentations from HR with an entirely different tone to them. So there’s that!