Dr. Deisseroth is also the D.H. Chen Professor of Bioengineering and of Psychiatry at Stanford University. He was an HHMI early career scientist from 2009 to 2014.
"If you asked 100 psychiatrists if we know enough about the brain to devise truly specific treatments," says Karl Deisseroth, "all 100 would probably say no." That's why Deisseroth, a practicing psychiatrist himself, is working to elucidate the detailed form and function of the brain's neural circuitry.
He describes the timing and relationships of electrical activity within specific populations of neurons as the "syntax of the brain's internal language." And he has developed ways to study how groups of neurons influence each other using fast and specific electrical signals. He's also using the techniques to explore how that circuitry goes awry in disorders such as depression, anxiety, and Parkinson's disease. Along the way, he's founded a new field of bioengineering and neuroscience called optogenetics and devised a way to "see through" the brain with unprecedented completeness in a new approach called CLARITY.
Starting his own lab at Stanford University in 2004, Deisseroth decided to tackle a high-risk project. Scientists knew that some algae make a protein that opens a gate in cell membranes when the protein absorbs light. Deisseroth wanted to try slipping the gene for that light-sensitive protein into specific neurons and then use the gate-opening properties to stimulate or inhibit neurons with millisecond-quick flashes of light delivered through hair-thin optical fibers.
His team finally succeeded in modulating behavior in freely moving mammals by controlling specific activity patterns in defined neurons. Deisseroth calls the approach optogenetics. After early progress in 2005, he recalls a "huge moment" in 2007 when his group was able to compel unrestrained and sleeping mice to wake up, by using (through a custom-designed fiberoptic interface) certain well-defined patterns of pulsed light to control a specific kind of neuron in the hypothalamus. Then in 2009 they published a series of discoveries and advances for controlling behavior by targeting light and optical control tools in versatile ways, applicable to virtually any type of cell across the brain.
Deisseroth, who became an HHMI early career scientist in 2009, has shared optogenetics methods and tools with thousands of other laboratories and has trained many other scientists in his lab. An avalanche of discovery has ensued. The findings are already helping explain how to optimally place electrodes to stimulate the brain in diseases like Parkinson's and major depression, for example. Between 2011 and 2013, Deisseroth also showed that regions of the brain associated with anxiety and depression actually also include anti-anxiety and antidepression circuits, operating side-by-side with the more negative pathways. That means, he says, that those disorders may involve a shift in the natural balance between the opposing circuits. These results suggest how tweaking these pathways may treat the illnesses.
Optogenetics alone could have been a career-crowning achievement, but Deisseroth followed up with another major advance—from a project so risky that he enlisted only those people in his lab with enough prior success that their careers wouldn't be set back by a failure. His idea: make an intact, transparent brain with all of its internal structure and wiring visible and accessible.
The team started by building a framework, or skeleton, within the neurons by using a structural protein called keratin, then supporting the brain with an external hydrogel—an exoskeleton. "We got so good at building the exoskeleton that we realized the internal one wasn't needed," he says. Stabilizing the brain made it possible to dissolve away the brain's opaque fat, which bends and scatters light and obscures scientists' views of the deep tissues. The result is a transparent, intact brain where researchers can chart long-distance connections between neurons and probe the fine details of individual cells with standard molecular biology tools like antibodies or DNA probes.
Deisseroth calls the approach CLARITY. He has also shared its tools with hundreds of other neuroscientists. Some researchers are even using it to study other organs, like the lung, liver, and pancreas. In his own lab, Deisseroth's team has recently used CLARITY to build brain-wide maps of cells that make dopamine, the chemical messenger associated with reward and pleasure. They visualized, for example, deep within the intact brain a small scattering of these cells separate from the main populations of dopamine neurons, embedded within the dorsal raphe (a brain region best known for making another neurotransmitter, serotonin). Optogenetic tools will help researchers define the causal importance of specific populations of dopamine neurons like these that are visualized and mapped with CLARITY.
Deisseroth's primary goal is to help the research community understand as much as possible about key principles of brain circuitry. Perhaps along the way, such knowledge might be harnessed to create better treatments for brain disorders. "The brain is a complicated place, and will take a long time to sort out," he says. "But in the last four years, the increment in understanding has been thrilling."