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Professor of Biology and Biological Engineering, Caltech PubMed lester ha INSTITUTION AND LOCATION DEGREE (if appl) YEAR(s) FIELD OF STUDY Harvard College, Cambridge MA A.B. 1966 Chemistry and Physics The Rockefeller University, New York NY Ph.D. 1971 Biophysics Institut Pasteur, Paris Postdoc 1971-73 Neurobiologie Moléculaire

I continue to collaborate, on other projects, with Loren Looger’s renowned biosensor engineering lab at the HHMI Janelia Research Campus, Ashburn VA. Genetically encoded, intracellular live-cell fluorescent sensors for nicotine, other drugs, and intracellular messengers represent a natural next step in my continuing efforts to analyze drug effects on nervous systems. My career synthesizes concepts from biophysics, pharmacology, physical chemistry, organic chemistry, molecular biology, neuroscience, thermodynamics, and (unusual for a neuroscientist) pharmacokinetics. This application partially studies intracellular events; for 20 yr, I served as PI for an NIH grant, “Intracellular Messengers, Biophysical Studies”. The ideas also center on trafficking of membrane proteins; this was a major focus of my 15-yr NIH grant, “Neurotransmitter transporters, Biophysical Studies”. The concepts and intuitions continue to serve in my activities.

I understand signaling by drugs at receptors, channels, and transporters fairly well. I continue contributions to this topic across the scale from single atoms, to single molecules, to single cells, to single microcircuits, to behaving mice. I continue to work along the time scale ranging from 3 x 10-6 s to 1.2 x 106 s (three microseconds to two weeks). I helped to originate the concept that heterologous expression can be used to discover more selective drugs (1988).

My unique background is apparent in several ways. I am the only person who has served as both President of the Biophysical Society and as a member of NIMH National Council; who has written invited reviews for the Annual Review of Biophysics, the Annual Review of Pharmacology and Toxicology, the Annual Review of Physiology, and the Annual Review of Neuroscience; who received both the Cole Award in Membrane Biophysics from the Biophysical Society and the Fuller Award in Neuropharmacology from ASPET.

I’ve introduced several innovative techniques. This is a superset of the contributions in in (C). In reverse chronological order, I helped to invent genetically encoded drug sensors for inside-out pharmacology (2019), zero-mode waveguides for studying ion channel stoichiometry (2012), fluorescent unnatural amino acids (2009), fluorescent protein knock-in mice for measuring receptor and transporter density (2002, 2007), hypersensitive knock-in mice for defining the actions of receptors (2001, 2004, 2008), engineered Cys-loop receptors for what we now call “pharmacogenetics” (2002), unnatural amino acids for probing channel and receptor structure-function (1995-present), planar patch clamping at Axon Instruments (2004), expression cloning of channels, transporters, and receptors (1983-1992), the pCLAMP electrophysiology programs (1985), light flashes for activating and blocking ion channels (1977-1985), light-activated cyclic nucleotides (1985), and voltage-jump relaxations for probing receptor kinetics (1975).