During a meeting today, some of us were making a decision about whether or not to take a look at a particular series of compounds in some assays. I spoke up, saying "Hey, if we've got 'em, why not? Never talk yourself out of something that's easy to test."
"The voice of pragmatism", said someone else, and I responded "Darn right!" It's a real temptation in this business to think that you know more than you do. The alternative, a realistic appraisal of just how lost you (and everyone else) is, can be a bit disconcerting, and that's why I think people overvalue their expertise. "Those compounds never work," "We did something like that before," "We already know what the answer is" - these are the sounds that people make when they're trying to sound wiser than they probably are.
I have to look out for these tendencies in my own work, too. I've seen enough different sorts of projects that I do have some valuable experience to draw on. But not all of it is valuable all the time, and it's very hard to know when you're being fooled by a false correlation with something that's happened before. I don't know when something is going to be orally active, and I don't know what its blood levels are going to be like. Much as I would like to, I don't know exactly how a given compound binds to its protein target, and neither, in almost every case, does anyone else. I sure can't predict toxicity, either, and it's not for lack of motivation. One of the most valuable things I can take away from all my experience is the willingness to step back and let the results sort themselves out.
Now, there are times when you really shouldn't try something. But those times occur much less frequently than you'd think, and usually for lack of time or resources. But if both of those are available, I'm up for taking a flyer on all kinds of odd stuff. Some of the best things I've ever done looked pretty weird while I was doing them, that's for sure. But I'm at the point in my career where I'm less concerned about looking like a fool, so perhaps my best work is still to come.