Stopped at a red light on his drive home from work, Karl Deisseroth contemplates one of his patients, a woman with depression so entrenched that she had been unresponsive to drugs and electroshock therapy for years. The red turns to green and Deisseroth accelerates, navigating roads and intersections with one part of his mind while another part considers a very different set of pathways that also can be regulated by a system of lights. In his lab at Stanford University’s Clark Center, Deisseroth is developing a remarkable way to switch brain cells off and on by exposing them to targeted green, yellow, or blue flashes. With that ability, he is learning how to regulate the flow of information in the brain.
Deisseroth’s technique, known broadly as optogenetics, could bring new hope to his most desperate patients. In a series of provocative experiments, he has already cured the symptoms of psychiatric disease in mice. Optogenetics also shows promise for defeating drug addiction. When Deisseroth exposed a set of test mice to cocaine and then flipped a switch, pulsing bright yellow light into their brains, the expected rush of euphoria—the prelude to addiction—was instantly blocked. Almost miraculously, they were immune to the cocaine high; the mice left the drug den as uninterested as if they had never been exposed.
Today, those breakthroughs have been demonstrated in only a small number of test animals. But as Deisseroth pulls into his driveway he is optimistic about what tomorrow’s work could bring: Human applications, and the relief they could deliver, may not be far off.
For all its complexity, the brain in some ways is a surprisingly simple device. Neurons switch off and on, causing signals to stop or go. Using optogenetics, Deisseroth can do that switching himself. He inserts light-sensitive proteins into brain cells. Those proteins let him turn a set of cells on or off just by shining the right kind of laser beam at the cells.
That in turn makes it possible to highlight the exact neural pathways involved in the various forms of psychiatric disease. A disruption of one particular pathway, for instance, might cause anxiety. To test the possibility, Deisseroth engineers an animal with light-sensitive proteins in the brain cells lying along the suspected pathway. Then he illuminates those cells with a laser. If the animal begins cowering in a corner, he knows he is in the right place. And as Deisseroth and his colleagues illuminate more neural pathways, other researchers will be able to design increasingly targeted drugs and minimally invasive brain implants to treat psychiatric disease.
Optogenetics originally emerged from Bio-X, a multidisciplinary project spearheaded in part by Stephen Chu, then a Stanford physicist and now the U.S. Secretary of Energy. Bio-X takes some of Stanford’s best engineers, computer scientists, physicists, chemists, and clinicians and throws them together in the Clark Center, where an open, glass-clad structure makes communication unavoidable. Deisseroth, whose beat-up jeans and T-shirt practically define the universal academic wardrobe, proved a natural at working across disciplines. Over the past decade, his omnivorous quest has filtered far beyond Bio-X into a thousand institutions around the world.
Although his Bio-X work involves esoteric genetics and animal experiments, Deisseroth has never forgotten the human needs that motivated him in the first place. He still divides his time between his basement lab and the psychiatry patients who desperately need his research to pay off.
Psychiatry’s Core Dilemma
Karl Deisseroth was 27 when he first brushed past the curtains of the psychiatry ward at Palo Alto’s VA hospital in northern California. It was 1998 and he had just completed his first two years of Stanford Medical School, where he had earned a Ph.D. in brain cell physiology, exploring the electrical language of neuron communication. As part of his medical training, he was required to complete a rotation in psychiatry—a hazy specialty, he felt, much less compelling than the brain surgery that was his career goal.
Several patients in the ward lay in narrow beds lined up before him, awaiting a treatment called electroconvulsive therapy (ECT). After the anesthesiologist on duty put them under, the attending psychiatrist placed pads on the patients’ temples and walked from bed to bed, pressing a small button on each person’s control box, sending volts of electricity into their brains. Their bodies tensed and their brains rattled with seizures for a full minute. The recipients risked losing large swaths of memory, but if things went well, the current would reset their neurons, purging their depression and providing months of relief.
From that experience, Deisseroth determined that he would spend his life solving a core puzzle of psychiatric disease: A brain could appear undamaged, with no dead tissue or anatomical deformities, yet something could be so wrong it destroyed patients’ lives. Perhaps because the damage was invisible, the available therapies were shockingly crude. ect was lifesaving but usually temporary; although it was likely that just a small set of cells caused the patient’s troubles, the shock jolted neurons throughout the brain. Psychoactive drugs, targeting general brain regions and cell types, were too broad as well. And scientists were so uncertain about what chemical imbalances impacted which neural circuits that one-third of people with major depression did not respond to drugs at all.
Deisseroth pondered the problem through a subsequent psychiatry residency, where he oversaw more than 200 ECT procedures over four years. Then, in 2004, he became a principal investigator at Stanford and was given his own lab. As a clinician treating patients, his arsenal was limited. But with his scientific imagination roaming free and a brand-new lab sparkling with empty chairs and beakers to fill, he began to envision elegant new strategies. One stood out: a concept first suggested by Francis Crick, the legendary genetics and consciousness researcher.
Crick’s idea was that light, with its unparalleled speed and precision, could be the ideal tool for controlling neurons and mapping the brain. “The idea of an energy interface instead of a physical interface to work with the brain was what was so exciting,” Deisseroth says. He thought creating a light-sensitive brain was probably impossible, but then an idea floated up: What about tapping the power of light-sensitive microbes, single-celled creatures that drift in water, turning toward or away from the sun to regulate energy intake? Such brainless creatures rely on signals from light-sensitive proteins called opsins. When sunlight hits the opsin, it instantly sends an electric signal through the microbe’s cell membrane, telling the tiny critter which way to turn in relation to the sun.
Deisseroth wondered if he could insert these opsins into targeted mammalian brain cells in order to make them light-sensitive too. If so, he could learn to control their behavior using light. Shining light into the brain could then become the tool Crick imagined, providing a way to control neurons without electric shocks or slow-acting, unfocused drugs.