Optogenetics: Studying Proteins from Single-celled Algae to Illuminate the Mysteries of the Brain
Abstract of the lecture
My path to Kyoto began at Harvard, in the 1980s, where I first planned to focus on writing, as my calling and career. I found myself derailed by science however, becoming captivated by new principles emerging from biology and engineering. After completion of my M.D., Ph.D. and psychiatry training at Stanford (where I continue to treat patients), I launched a laboratory effort in Stanford’s Bioengineering Department, and began to build new classes of tools for studying the brain, seeking to find new answers—or at the very least, to find ways to ask new questions. New ways to ask questions are needed; our brains are biological objects, organs built from cells and blood; but in psychiatric illness, the organ itself is not damaged in a way we can see or understand now, in the way we can for a broken leg or a weakened heart.
One of the first technologies I developed, optogenetics, involves putting genes from ancient forms of bacteria and from green algae, into specific brain cells of mammals. A strange thing to do—but with a certain logic, for the microbial genes we borrowed in this way directed the production of proteins that turn light into electricity—and electricity is the fundamental language of the brain. These channelrhodopsin proteins are light-gated ion channels that enable algae to seek light conditions suitable for photosynthesis; we have been able to discover principles of function by solving the protein structures and by redesigning for altered ion selectivity, kinetics, and spectral properties. These discoveries not only revealed basic principles governing operation of light-gated ion channels for algal behavior, but also enabled the creation of new proteins for illuminating animal behavior. As a result, we can now flash laser light (delivered through thin fiberoptics deep into the brain) to turn neurons on or off, and observe the effects on behavior.
As a result of this work, we know now which cells and connections across the brain actually control key behaviors of pleasure, reward, social interaction, and motivation to meet challenges, as well as (on the negative side) symptoms of anxiety, depression and fear. This optogenetic technology has taken hold throughout neuroscience and now enables us to test precise cellular basis for behavior by controlling the brain’s circuitry.