Christopher Walsh passed on earlier this month, and those of us who work in chemical biology owe him quite a debt. In his time at MIT,Harvard, and Dana-Farber he deliberately worked in the borderlands between departments of chemistry, biochemistry, biology, and pharmacology, to the benefit of all concerned. He was one of the pioneers in bringing a “chemist’s sensibility” into many biological topics, and at the same time showed chemists that their field was broader than they knew.
I’ve said many times over the years that molecular biologists have been slowly turning into chemists, whether they realized it or not, and it’s Walsh’s career path (here’s a memoir he wrote in 2010) that helped make that possible. And by “turning into chemists” I mean treating the species in living cells as real molecules rather than as abstractions. What got on my nerves when I took biochemistry as an undergraduate was that too much of it was too abstract and fuzzy: this oval associates with these smaller ovals, and this big curved arrow shows how it turns these small squares into a larger rectangle. Well, no, it actually doesn’t show much of anything. If you’re thinking like a chemist, you’d rather know what’s really happening down at the molecular (and even the atomic) level. What do these things weigh? What shapes do they have? How do they differ along their surfaces in conformational flexibility, in localization of charge, in hydrophobicity, and what are those different regions doing?
The reason biochemistry as a field spent so long in the simple-geometric-shapes mode is of course because these questions were very hard to answer. You could say that this protein associated with that one, and this other one seemed to be needed for this to turn into that, but how all that was happening, well. . .What the field needed was more structural information, for one thing, to start giving these molecules sizes and shapes and to associate these with their functions. Walsh was an early proponent of structural biology, and when he later had the opportunity to merge the departments of biological chemistry and pharmacology at Harvard, he immediately set in hiring X-ray crystallographers and protein NMR spectroscopists. Biomolecules have to be understood as molecules – large, complex molecules, to be sure, but still chemical species that react on the basis of their conformations and charges and the arrangements of their chemical bonds.
Walsh’s career began in the area that was best equipped to start working with these issues around biomolecules, namely enzyme mechanisms. There the problem could often be pared down to the structure and chemistry of a single active site in a larger protein, where in many cases small chemical species were being manipulated by individual amino acid side chains. When you look back on it, these studies (in Walsh’s labs and many others) are where a lot of the gradual merging of chemistry and biology really took place. In order to study enzyme action in detail, you had to be a chemist, but to study enzymes at all you had to be something of a biologist as well. It’s also helped that enzyme inhibition has always been a mainstay of medicinal chemistry and pharmacology, tying all these fields together in common interests. The longstanding research programs in Walsh’s groups on the mechanisms of antibiotics (and of antibiotic resistance) are a perfect example of this.
If you read that memoir linked above, you’ll see how all of these fields work with each other. You have to know the chemical structure of the antibiotic molecule and its structure-activity relationship against its bacterial protein target, and you also have to study in detail the structure of the site it’s binding to on that target. Changes in that structure are one way that resistance is achieved, and the expression of some other pathway or mechanism is another way for the organism to evade the antibiotic’s effects. How are those genes activated? What happens to the rest of the organism when they are? On the other side of the question, how are the natural-product antibiotics biosynthesized in the first place? What enzymes are involved in making them, and how are those regulated and expressed?
You can learn a great deal by digging into these questions, and you’ll need all the tools of stuctural biology, pharmacology, and organic chemistry to do it. As these come together, you get what we now call chemical biology, and Chris Walsh was a big part of how that happened. Respect!
