I've been speaking my mind publicly for over 20 years, but it's not without risk. I'm not talking about angry or annoyed readers (though there are plenty of them), or threats of lawsuits from people who feel wronged (though there are some!). No, the constant risk on the ropes of the printed word is looking like a complete fool.
It is with a view to revisiting some of the topics on which I was more or less spectacularly wrong, perhaps with a view to redeeming myself a little once the scorched earth war subsides. I will start with something that has been much talked about recently: obesity drugs targeting GLP-1 (including Novo Nordisk's semaglutide (Ozempic/Wegobee), Eli Lilly's tirzepatide (Maunjaro/Zepbound) and their successors targeting related hormones). I have long considered such success extremely unlikely, a view I have frankly expressed to anyone who has asked, and no doubt to many who have not. Any ancestral organism capable of disrupting feeding behavior by affecting a single pathway is surely extinct. Our biochemical ancestors were anything but.
I have been working on several related projects for many years and have solidified that opinion. All attempts to pharmacologically regulate weight without the side effects of (admittedly effective) drugs like amphetamines have failed. After years of failure from various directions, I felt that this might be an insoluble problem, but I am happy to say that I was wrong. GLP-1 therapy is extraordinarily effective and appears to have many other health benefits. The story may become more complicated in the coming years, but the results so far leave no room for doubt.
Another topic where I was too pessimistic is protein structure modeling and prediction. If you had tried to convince me 10 years ago of the incredible power and rapid progress of current modeling systems, I would never have believed it. However, here is a little excuse. As I said before, the proofs back then would have convinced me that we must have made incredible progress in understanding the physics and chemistry of proteins themselves: hydrogen bonding, arrangement of water molecules, entropy and enthalpy compensation, and other arcane topics. No, we have not. We have made incredible progress in computational pattern matching and mimicking the behavior of existing proteins. Never mind the details. If it works, it works.
Similarly, if you had shown me some of the targeted protein degraders currently in development 25 years ago, I would have been seriously confused. That was an era of extreme sensitivity to what constituted desirable molecular properties, and the molecular weights of these compounds alone would have convinced me that they were longshots. Realizing that many of them contained structures similar to thalidomide probably wouldn't have changed my opinion. I grew up reading a lot of old science fiction, so I have a habit of not doubting my future even if amazing news suddenly becomes reality, but these molecular degraders would have certainly been a tough sell.
Sadly, I could be wrong in the other direction as well. I used to absolutely believe that we should have made more progress on Alzheimer's than we do now. This is just one prominent example. Perhaps (I hope) that progress is being offset by continued advances in immuno-oncology and immunology in general. I also hope that some of the areas that seem so intractable right now, like Alzheimer's, might suddenly be opened up, with decades of setbacks and failed trials swept away by something new, like obesity treatment.
But isn't that the hope of biomedical research in general, or all of science? We get it wrong again and again, and painfully wrong, until we finally get it right. And when we finally get it right, we have a new foundation from which to begin the process of getting it right about even more mysteries, toward, as Francis Bacon said so long ago, “making all that is possible come to pass.” And I don't think he's wrong on that point.
