Bob Lefkowitz: A Life in Science
Mon May 12, 2014
Bob Lefkowitz recently visited Rockefeller University to give a lecture. I’m sad to say that I didn’t know much about him until he was awarded the 2012 Nobel Prize for Chemistry. In grad school I was drawn to DNA and epigenetics and for some reason didn’t gravitate-towards or truly appreciate membrane biology. I remember being somewhat shocked when during a lecture about modeling the brain,Charles Peskinsaid somethign to the effect of “I don’t care whats going on inside the nucleus of the cells except insofar as it affects electric conductivity of the membrane. The nucleus is only there to modulate electrical transmission.” As someone drawn to the elegance and power of genetic regulation I felt that put the cart before the horse but here was a man who wanted to thin-slice the brain and run a full-brain partial-differential equation to explain neural activity. Suffice to say, there is a lot of interesting biology happening at the membrane that I was late to see, and Bob Lefkowitz gave a nice historical overview of his corner of it.
Lefkowitz joined the NIH as a deferral of military service in Vietnam and was trained as pharmacologist/physiologist. He ended up trying to understand the nature and activity of a set of pharmacological agents by purifying the receptor using ligand-based affinity reagents and after over a decade of painstaking work he was able to identify several different classes of receptor. In his wry style, he showed a slide of three different purified receptors and panned “this figure brings back many memories… most of them painful.” The isolation of the beta adrenergic receptor led to a series of advances to understand the biology of the receptor: reconstitution of the receptor in a simplified assay using cells lacking beta-adrenergic receptor (cow erythrocytes, I believe); hybrid receptors to identify the regions that could activate; discovery that the receptor was modified by phosphorylation and the identification of the regulatory kinases; the discovery of the arrestin proteins that bind and response to the phosphorylated receptor.
Bob’s talk was a delight. He walked through the major conceptual advances in membrane physiology and his role in it. He highlighted the several times where he faced hostility to his views (the “receptor” model, the similarity with rhodopsin), and brought us up the current research where he is employing a combination of crystallographic and cryo-EM techniques to look at receptor-b’arrestin complexes.
These historical talks, when given by someone with a long, high view of the field are always wonderful and highlight the way in which science can be difficult in practice both labor-wise and social-wise, while also demonstrating the beauty of how the incremental steps of knowledge begin to build up a powerful conceptual edifice, in this case for receptor signaling. As Bob mentioned, the majority of drug targets hit transmembrane receptors and understanding how their shape responds to binding ligand has immense practical implications for drug design. He did mention how the paradigm for ligand binding has changed with the realization that different ligands can confer unique downstream signaling profiles when hitting the same receptor. Understanding the means by which particular conformers with favorable signaling profiles are stabilized in is an area of intense pharmacological interest.
Well done, Professor; thanks for the visit.