Where a molecule is affects what it does

In my experience, a large majority of smart and well-trained people (who should know better) don’t have any clear idea of what it’s like inside a cell. I blame this squarely on biochemistry pedagogy, with its unmentioned but implicit linearization of chemical reaction kinetics and tacit assumption that everything can be separated into functioning components and studied separately: we are taught (and have taught, when we were doing that sort of thing) that all molecules always bump into each other in isolated pairs, and have plenty of time and space to associate and dissociate as they wish in their intracellular environment. One that’s fundamentally no different from a test tube of dilute pure molecules we study in the lab. That leads to the supposition that we can infer from laboratory measurements of such pure test cases, where we actually assign numbers to properties of pure dilute macromolecules, what behavior that depends on \(K_D\) or \(K_I\) will be like inside a cell. We assume that because the natural length scales of supramolecular complexes are so much larger than those of chemical reaction and association events, long-range structure has little or no implication for what happens on the scale of the event.

Which is pure bullshit.

Such a premise is tantamount to imagining that the contents of cells are perfectly mixed. If this strikes you as a not-unreasonable modeling assumption, especially for mathematical tractability, I invite you to randomize the contents of some of your cells and see how they do. A blender will do in a pinch.

I haven’t had the pleasure of this rant in a few months, but I was about to start writing about it in the context of Synthetic Biology and wrong-headed notions of design. And I will. But I needed a little jostle to jump-start me. So it is with pleasure that I’m reminded of David Goodsell’s extraordinary work on this subject, by way of a link from BioCurious to “PDB Molecule of the Month: Cholera Toxin”.

If you want to make a positive difference in our lives, by undermining incorrect myths held by biomedical practitioners, send a friend to this stunning work of science and art (be sure to click the three-panel graphic to see it at mind-numbing size). Ask them how much water there is in between those molecules. Ask them how metabolism works, in light of those networks. Ask your biochemistry (or general biology) grad student to point out where they would expect to find the Krebs cycle they draw in simplified circles-and-arrows format on the board in the first week of class—right there, on that map. [It may be a trick question, for that particular picture] Then, while they’re pondering, ask them quickly, “OK. This is easier—how does the information from the genome get from over there, to over here?”

I think that image, along with Dr. Goodsell’s other portfolio on this theme, is probably the most important work of scientific art for this century, and should be plastered up on the wall of any lab that’s doing anything in any setting that involves intracellular molecular dynamics and cellular physiology.

But that’s just me. What do you think?