As a psychiatrist, Stanford University's Karl Deisseroth treats patients with depression, schizophrenia, and other serious mental health disorders. But early in his career he bumped up against the limitations of the field. Brain disorders are chronic, hard to treat, and sometimes fatal. Drugs often don't help.
"We just don't understand them," Deisseroth says of mental illness and other brain disorders like Parkinson's disease. He believes the prevailing view of brain disease as resulting from a chemical imbalance restricts our understanding and, instead, views electricity as the syntax of the brain's internal language. "Right now, we're treating the brain like neurotransmitter soup. That's a very limiting view and it's why drugs fail in many cases. They don't speak the language of the brain."
To understand that language, scientists need to study how groups of neurons talk to each other using electricity. But until now, there have been no tools precise enough to get at this fundamental problem in neuroscience. So Deisseroth—who is also a bioengineer and a neuroscientist—made his own tools. Along the way he developed a new field, with technology so unusual it needed a new name: optogenetics.
Optogenetic approaches take light-activated molecular switches from nature, add them to neurons, and then try to decipher the language of the brain. For example, a flash of blue light switches brain cells on—so they send a signal to other neurons—while a flash of yellow light turns them off. These colorful tools promise to provide deep insights into how the brain works—and what goes wrong with specific neural circuits during illness. "The goal is to march through the disease circuitry and understand how the dynamics of neurons talking to each other is broken, and how that can be tweaked to correct the disorder," explains Deisseroth.
This new approach was made possible by an unlikely ally—pond scum. Certain species of algae produce a light-sensitive surface protein, called channelrhodopsin, that acts as a valve. Blue light opens the valve, letting positive ions into the cell. Serendipitously, this influx happens to correspond to how mammalian neurons are triggered to fire. In 2005, after reaching across traditional scientific boundaries to the algae-biology field, Deisseroth discovered that he could smuggle channelrhodopsin into neurons and get them to fire exactly when he wanted in response to light. Further, he engineered the channelrhodopsin gene to be expressed only in specific types of neurons. With this technique, Deisseroth can control which populations of brain cells respond to light. He found that switching those cells on then becomes as simple as slipping a thin optical fiber into the brain and pulsing blue light through it. Later, Deisseroth harnessed a similar protein from salt lake bacteria that, when inserted into neurons, acts as an off switch when exposed to yellow light. Together, the two switches offer unprecedented control over the brains of lab animals.
In a series of experiments in 2007, Deisseroth and his collaborators added the on-off switches to neurons in the mouse hypothalamus that control wakefulness. A flip of the switch then awakens the mouse—and provides insight into the sleeping disorder narcolepsy.
In 2009, Deisseroth published several papers that explore arrhythmias in the brain's electrical activity and provide insights into autism, schizophrenia, Parkinson's disease, and addiction. In one set of papers published in Nature, Deisseroth and colleagues showed that a certain type of neuron controls high-level information flow in the brain. This information flow shows up on electrical graphs as so-called gamma waves. In autism, the rhythm of gamma waves appears to be askew, while in schizophrenia, there are too few of the particular type of neuron that produces gamma waves. By identifying the neurons that control gamma waves, Deisseroth has opened a new frontier in understanding those two illnesses.
In a second set of papers published in Science, Deisseroth and colleagues controlled circuitry involving dopamine neurons deep in the brain. These neurons are thought to play a major role in controlling movements (and are lost in Parkinson's disease) and also are important in reinforcing behaviors that feel good. Deisseroth found that, in animals with Parkinson's disease symptoms, he was able to optically track down and stimulate the precise cellular components needed to correct the disease symptoms. In a separate study, he found that only certain high-frequency rhythms in the dopamine neurons, triggered by light, made mice appear to feel good—encouraging them to stay in the area of their enclosure where they received the feel-good pulses. The experiments suggest that people with depression and who are unable to feel enjoyment might have dopamine circuits that are out of rhythm.
Because of the vast potential of optogenetics, Deisseroth is actively courting advice from bioethicists and philosophers. "We want to make sure the ethical issues are addressed," he says. "What does 'desire' or 'want' mean if we can stimulate those feelings with a flash of light?"
Deisseroth has shared his optogenetics tools with hundreds of labs around the world that are conducting wide-ranging brain studies and has helped these other scientists to launch optogenetics projects of their own. Insights made possible by optogenetics may guide new therapies and provide relief for the millions of people with brain disorders. "From a clinical standpoint, this could be wonderful," says Deisseroth. But most importantly, he adds, breakthroughs made possible by optogenetics are providing insight into the many functions of complex biological circuitry.
