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Developing New Physical Tools to Study Molecules and Cells

Research Summary

Adam Cohen develops tools to visualize bioelectric phenomena: firing of neurons, electrical pacing in the heart, and even electrical spiking in bacteria. The electric field in lipid membranes pulls on charged components of molecules, changing the conformations of proteins and regulating transport of ions. The Cohen lab has engineered proteins to convert bioelectric fields into flashes of fluorescence, which are readily observed in a microscope.

We develop new physical tools to study molecules and cells, and we apply these tools to make new measurements. We combine nanofabrication, optics, microfluidics, electronics, and biochemistry to generate data, and we apply statistics and physical modeling to understand the data. At the moment, our main project is to develop tools to visualize electrical activity in cells. We dream of peering into the brain of a fish or a mouse and watching the neurons light up as they fire.

As a step toward realizing this dream, we developed a protein-based fluorescent indicator of membrane voltage. In the wild, microbial rhodopsin proteins convert solar energy into changes in transmembrane voltage. This voltage provides energy and information for the organism. Microbial rhodopsin proteins have recently attracted much attention as a means to gain optical control over membrane potential in neurons and cardiac cells. We engineered microbial rhodopsins to run in reverse: they convert changes in membrane potential into a readily detectable optical signal. When expressed in a neuron or a cardiac myocyte, these voltage-indicating proteins convert electrical action potentials into visible flashes of fluorescence. We made movies of action potential propagation in primary neuronal cultures, in neurons and cardiomyocytes derived from human induced pluripotent stem cells, in zebrafish embryos, and in live mice. We combined rhodopsin-based voltage indicators with channelrhodopsin-based neuronal actuators to create an all-optical electrophysiology system. We developed computational techniques to map electrical propagation in neurons at effective frames rates up to 100,000 frames per second.

Figure: All-optical electrophysiology in a cultured neuron.

The genes, imaging systems, and analysis software enable studies of electrical dynamics in cells, tissues, and organisms with an information content and throughput that greatly exceed the capabilities of electrode-based devices. We are applying these tools to screen drugs in stem cell–based models of neuropsychiatric and cardiac disease.

Other projects in the lab include development of nanofabricated devices for trapping and studying single biomolecules in free solution, studies on optical spectroscopy in highly contorted electromagnetic fields, experiments on magnetically sensitive photochemical reactions, and studies of the mechanochemistry of biological hydrogels.

Some of this research is supported in part by grants from the National Institutes of Health, Office of Naval Research, National Science Foundation, Gordon and Betty Moore Foundation, Dreyfus Foundation, and the Sloan Foundation. 

As of March 11, 2016

Scientist Profile

Harvard University
Biophysics, Neuroscience