Whence Evolutionary Pharmacology

June 25, 2012

The idea of evolutionary pharmacology extends back to my graduate days in the lab of Stuart Schreiber, in particular insights stemming from the unexpected reaction of yeast cells to therapeutic drugs. These insights led to varied hypotheses regarding the complexity and conservation of cellular drug responses, or modes d’action, to quote the inimitable 19th French physiologist Claude Bernard.

In my first first-author paper, I showed that drug responses – resistance or hypersensitivity – of naturally recombinant yeast strains are genetically complex, i.e., modified by two or more genes. In other words, “fungal pharmacogenetics” was born. (The original Chemistry & Biology cover image for this paper is reproduced above, and was designed by my good friend Ben de Bivort).

That initial publication was extended a year later by a genetic linkage study that I published in collaboration with Leonid Kruglyak’s lab. I identified nucleotide polymorphisms that broadly modify “drug overdose” in yeast cells, including substitution of a deeply conserved proline residue of an inorganic phosphate transporter protein PHO84 that confers resistance to polyphenolic uncouplers of oxidative phosphorylation. My collaboration with the Kruglyak lab continues to this day, and we are currently preparing a manuscript describing the application of the X-QTL method to identifying psychoactive drug overdose genetic determinants in yeast.

In parallel with those quantitative genetic analyses, I undertook a yeast cell growth-based high-throughput screen to identify novel chemical modifiers of the TOR kinase inhibitor rapamycin. In an email that I dashed off in 2004 to Prof. David Rubinsztein at the University of Cambridge, I proposed a collaboration to see if any of the Small-Molecule Enhancers of the cytostatic effects of Rapamycin, or SMERs, which I had identified in a primary screen in yeast were active in secondary assays of autophagy in metazoa. The rationale was simple: rapamycin induces autophagy, so a subset of SMERs may induce autophagy, too. As fate would have it, Prof. Rubinsztein responded favorably to my invitation to collaborate, and in 2007 we published a paper describing three SMERs, and analogs thereof, that were effective in a Drosophila melanogaster (fruit fly) model of neurodegeneration.

We still don’t know the molecular targets of those SMERs. But last year Paul Greengard’s lab at Rockefeller University independently showed that SMER28, which is commercially available, promotes clearance of amyloid-b in mammalian cells by a mechanism that depends on autophagy. When a Nobel laureate replicates your findings, it’s a good day in Academia…