Controlling the Brain with Light

Every day as a practicing psychiatrist, I confront my field’s limitations. Despite the noble efforts of clinicians and researchers, our limited insight into the roots of psychiatric disease hinders the search for cures and contributes to the stigmatization of this enormous problem, the leading cause worldwide of years lost to death or disability. Clearly, we need new answers in psychiatry. But as philosopher of science Karl Popper might have said, before we can find the answers, we need the power to ask new questions. In other words, we need new technology.

Developing appropriate techniques is difficult, however, because the mammalian brain is beyond compare in its complexity. It is an intricate system in which tens of billions of intertwined neurons—with multitudinous distinct characteristics and wiring patterns—exchange precisely timed, millisecond-scale electrical signals and a rich diversity of biochemical messengers. Because of that complexity, neuroscientists lack a deep grasp of what the brain is really doing—of how specific activity patterns within specific brain cells ultimately give rise to thoughts, memories, sensations and feelings. By extension, we also do not know how the brain’s physical failures produce distinct psychiatric disorders such as depression or schizophrenia. The ruling paradigm of psychiatric disorders—casting them in terms of chemical imbalances and altered levels of neurotransmitters—does not do justice to the brain’s high-speed electrical neural circuitry. Psychiatric treatments are thus essentially serendipitous: helpful for many but rarely illuminating.

Little wonder, then, that in a 1979 Scientific American article, Nobel laureate Francis Crick suggested that the major challenge facing neuroscience was the need to control one type of cell in the brain while leaving others unaltered. Electrical stimuli cannot meet this challenge, because electrodes are too crude a tool: they stimulate all the cells at their insertion site without distinguishing between different cell types, and their signals also cannot turn neurons off with precision. Crick later speculated in lectures that light could serve as a control tool because it could be delivered in precisely timed pulses in a range of colors and locations, but at the time no one had any idea about how specific cells could be made to respond to light.

Meanwhile, in a realm of biology as distant from the study of the mammalian brain as might seem possible, researchers were working on microorganisms that would only much later turn out to be relevant. At least 40 years ago biologists knew that some microorganisms produce proteins that directly regulate the flow of electric charge across their membranes in response to visible light. These proteins, which are produced by a characteristic set of “opsin” genes, help to extract energy and information from the light in the microbes’ environments. In 1971 Walther Stoeckenius and Dieter Oesterhelt, both then at the University of California, San Francisco, discovered that one of these proteins, bacteriorhodopsin, acts as a single-component ion pump that can be briefly activated by photons of green light—a remarkable all-in-one molecular machine. Later identification of other members of this family of proteins—the halorhodopsins in 1977 and the channelrhodopsins in 2002—continued this original theme from 1971 of single-gene, all-in-one control.

In 20/20 hindsight, the solution to Crick’s challenge—a strategy to dramatically advance brain research—was therefore available in principle even before he articulated it. Yet it took more than 30 years for the concepts to come together in the new technology of optogenetics.

Optogenetics is the combination of genetics and optics to control well-defined events within any specific cells of living tissue (not just those of the nervous system). It includes the discovery and insertion into cells of genes that confer light responsiveness; it also includes the associated technologies for delivering light into the brain, directing the light’s effect to genes and cells of interest, and assessing readouts, or effects of this optical control. What excites neuroscientists about optogenetics is that it provides control over defined events within defined cell types at defined times—a level of precision that is not only fundamentally new but most likely crucial to biological understanding.

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