In 1979 Francis Crick, famed co-discoverer of DNA’s structure, published an article in Scientific American that set out a wish list of techniques needed to fundamentally improve understanding of the way the brain processes information. High on his wish list was a method of gaining control over specific classes of neurons while, he wrote, “leaving the others more or less unaltered.”
Over the past few years Crick’s vision for targeting neurons has begun to materialize thanks to a sophisticated combination of fiber optics and genetic engineering. The advent of what is known as optogenetics has even captured popular attention because of its ability to alter animal behavior—one research group demonstrated how light piped into a mouse’s brain can drive it to turn endlessly in circles. Such feats have inspired much public comment, including a joke made by comedian Jay Leno in 2006 about the prospect for an optogenetically controlled fly pestering George W. Bush.
Controlling a subordinate or a spouse with a souped-up laser pointer may be essential for science-fiction dystopia and late-night humor, but in reality optogenetics has emerged as the most important new technology for providing insight into the numbingly complex circuitry of the mammalian brain. It has already furnished clues as to how neural miswiring underlies neurological and mental disorders, including Parkinson’s disease and schizophrenia.
A seminal event that sparked widespread neuroscience interest came in 2005, when Karl Deisseroth and his colleagues at Stanford University and at the Max Planck Institute for Biophysics in Frankfurt demonstrated how a virus could be used to deliver a light-sensitive gene called channelrhodopsin-2 into specific sets of mammalian neurons. Once equipped with the gene (taken from pond algae), the neurons fired when exposed to light pulses. A box on Crick’s list could be checked off: this experiment and ones that were soon to follow showed how it would be possible to trigger or extinguish selected neurons, and not their neighbors, in just a few milliseconds, the speed at which they normally fire. Hundreds of laboratories worldwide have since adopted Deisseroth’s technique.
A 38-year-old psychiatrist by training who still sees patients once a week, Deisseroth entered the field of bioengineering because of his frustration over the inadequate tools available to research and treat mental illness and neurodegenerative disorders. “I have conducted many brain-stimulation treatments in psychiatry that suffered greatly from a lack of precision. You can stimulate certain cells that you want to target, but you also stimulate all of the wrong cells as well,” he says. Instead of just observing the effects from a drug or an implanted electrode, optogenetics brings researchers closer to the fundamental causes of a behavior.
Since 2005 Deisseroth’s laboratory—at times in collaboration with leading neuroscience groups—has assembled a powerful tool kit based on channelrhodopsin-2 and other so-called opsins. By adjusting the opening or closing of channels in cell membranes, opsins can switch neurons on or turn them off. Molecular legerdemain can also manipulate just a subset of one type of neuron or control a circuit between groups of selected neurons in, say, the limbic system and others in the cortex. Deisseroth has also refined methods for delivering the opsin genes, typically by inserting into a virus both opsin genes and DNA to turn on those genes.
To activate the opsins, Deisseroth’s lab has attached laser diodes to tiny fiber-optic cables that reach the brain’s innermost structures. Along with the optical fibers, electrodes are implanted that record when neurons fire. “In the past year what’s happened is that these techniques have gone from being something interesting and useful in limited applications to something generalizable to any cell or question in biology,” Deisseroth says.
Most compelling, however, are experiments that have demonstrated te relevance of optogenetics to both basic science and medicine. At the Society for Neuroscience meeting in Chicago last October, Michael Häusser of University College London reported on an optogenetics experiment that showed how 100 neurons could trigger a memory stored in a much larger ensemble of about 100,000 neurons, suggesting how the technique may be used to understand memory formation.
Last spring Deisseroth’s group published an optogenetics study that helped to elucidate the workings of deep-brain stimulation, which uses electrodes implanted deep in the brain to alleviate the abnormal movements of Parkinson’s disease. The experiment called into question the leading theory of how the technology works—activation of an area called the subthalamic nucleus. Instead the electrodes appear to exert their effects on nerve fibers that reach the subthalamic nucleus from the motor cortex and perhaps other areas. The finding has already led to a better understanding of how to deploy deep-brain electrodes. Given its fine-tuned specificity, optoelectronics might eventually replace deep-brain stimulation.
Although optogenetic control of human behavior may be years away, Deisseroth comments that the longer-range implications of the technology must be considered: “I’m not writing ethics papers, but I think about these issues every day, what it might mean to gain understanding and control over what is a desire, what is a need, what is hope.”
Note: this story was originally printed with the title "A Light in the Brain"