Why you should care

Dr. Karl Deisseroth’s work in optogenetics may open a door to treatments for depression, Parkinson’s and even cocaine addiction. No wonder the words “Nobel Prize” keep coming up. 

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Karl Deisseroth was leafing through his notes at the nurse’s station in the Palo Alto VA Hospital’s psychiatric unit in 1998, when a patient burst into the room and began screaming at him. The patient’s speech was jumbled and delusional — a classic symptom of schizoaffective disorder. But Deisseroth wasn’t scared. He was enthralled.

“I felt the pain and the suffering,” said Deisseroth, now a professor of bioengineering and psychiatry at Stanford University. “I was struck by the depth of the mystery that was facing me — that someone could be sitting there with an intact brain, yet his reality was so different from mine.”

Deisseroth was starting clinical rotations as part of a joint program MD-PhD program at Stanford. He had just finished his doctorate in neuroscience and planned to specialize in neurosurgery. But his psychiatric rotation had “completely transformed” him. He was overcome with the desire to help the mentally ill and understand the mechanisms that give rise to psychiatric disorders. It wasn’t enough to examine neurons in a dish, as he had done for his PhD research. Since behaviors arise from complex networks of neurons, he wanted to study the whole brain — but there were almost no techniques for doing so. Tools like functional MRI were too slow and imprecise to investigate the brain effectively.

So Deisseroth developed two game-changing techniques. The first, optogenetics, uses light to control specific neurons, a technique used by scientists for years — but without success. Researchers used it to switch off depression- and OCD-like symptoms, drug addiction and other neuropsychiatric conditions in mice. Some have applied it to other organs, allowing blind mice to perceive light, for example. For now, optogenetics is primarily a research tool, but Deisseroth hopes to see optogenetic-derived therapies in the clinic within a decade. Meanwhile, he has developed a new technique called CLARITY that renders entire brains transparent so scientists can study their wiring in 3-D. Both techniques can help scientists establish causal links between brain circuitry and disease symptoms, which could lead to highly targeted, effective therapies.

Someone could be sitting there with an intact brain, yet his reality was so different from mine.

 

Deisseroth has won international recognition for developing optogenetics, which other scientists have hailed as “revolutionary.” Physicist Leonard Mlodinaw thinks “a Nobel Prize isn’t far off.”

Boyish and soft-spoken, Deisseroth, 42, has been studying behavior since childhood, when he developed a fascination with people. His father, a hematologist-oncologist, was also a professor whose faculty appointments took Deisseroth, his mother and two sisters to Boston, Maryland, California and Texas. He learned to enjoy meeting new people and developed a knack for engaging them in long, in-depth conversations.

The experience also made Deisseroth more open to new ways of thinking. “He takes his drive to do clinical good and an engineer’s flair for innovation and brings them together,” said neuroanatomist Richard Tsien, under whom Deisseroth earned his PhD. As a Stanford student, Deisseroth shared his ideas for studying the whole brain with researchers from diverse fields. During his residency, he met Edward Boyden, a doctoral student with a strong engineering background. The two began brainstorming ways to manipulate individual neurons.

One idea was to use light to control neuronal firing, which is triggered by the flow of ions through protein channels in the neuron cell membrane. Both researchers knew of similar proteins, called opsins, which open in response to light to allow ions in and out of cells. If they could engineer neurons to express opsins, they could activate or inhibit them with the flip of a light switch — in theory. Until that point, scientists had struggled to get opsins into mammalian neurons.

Both his techniques can help scientists establish causal links between brain circuitry and disease symptoms.

Deisseroth opened his own lab at Stanford in 2004 to focus on this challenging task. Other groups had used opsins from closely related species. But their biological pathways were highly complex, so the opsins had to be delivered as part of a package that included many different proteins — meaning more opportunities for error. But Deisseroth had a counterintuitive idea: to use opsins from algae, a more distantly related but much simpler organism. “It would be risky, but we thought it was worth a try,” he said.

The risk paid off. A year later, his group reported that they had inserted opsins from algae into neurons grown in a dish. In 2008 the researchers got the technique to work in a mouse. The animal expressed opsins in the brain region that regulates locomotion, where a fiber optic implant delivered light from a laser. Turning on the laser made the mouse begin walking in a circle. Switching it off stopped it in its tracks. “It was exhilarating,” Deisseroth said.

Deisseroth’s new CLARITY technique renders entire brains transparent so scientists can study their wiring in 3-D.

Now that optogenetics can be used in animals — mice and monkeys so far — scientists have been studying how toggling brain circuits affects disease symptoms. In June, Deisseroth’s team saw that shining light on the brain region associated with motivation and reward caused mice with depression-like symptoms to act more like healthy mice. Turning off the light reversed the effect. Deisseroth’s group and others have also used optogenetics to induce and relieve OCD- and Parkinson’s disease-like symptoms, seizures and even cocaine addiction.

Current medications for these conditions act on neurotransmitters found throughout the brain, causing a wide range of side effects. Companies are using optogenetics to reveal which circuits are responsible for disease symptoms so they can design drugs that specifically target them and minimize side effects.

With optogenetics already revolutionizing research on brain activity, Deisseroth set his sights on brain structure. Current techniques typically involve slicing the brain into thin sections, imaging them with a microscope and stacking the images together, often imprecisely.

Instead, Deisseroth wanted to make the brain transparent by extracting the fatty molecules, or lipids, in brain cells, which are impermeable to light. But when other groups had tried removing lipids, the brain turned into a “soggy, soupy” mess, Deisseroth said.

So he and his lab thought about how to build a structure that would hold up even without lipids. They settled on a material called hydrogel, which could also fix proteins, DNA and other structures in place so they could be tagged with fluorescent molecules. Immersing the brain in hydrogel solution caused the material to form a sturdy mesh around it. A special detergent could wash away the lipids, leaving the brain transparent.

The new technique, CLARITY, has already begun shedding light on brain disorders. The team reported in April that the neurons in the brain tissue of a patient with autism curved inward, rather than branching out like the neurons in typical brains — a pattern that would have been impossible to confirm with brain slices alone.

Today more than a thousand labs use optogenetics, and Deisseroth trains visiting researchers in the techniques — on top of running his own lab, mentoring students, seeing patients, and raising four kids. “It’s a complicated life, but I enjoy it,” he said.

Next up, Deisseroth wants to design a way to visualize activity that integrates optogenetics and CLARITY. The technique could be even more revolutionary than the last two. “I think he’ll continue to surprise us,” said Feng Zhang, one of Deisseroth’s former graduate students. “Who knows what Karl has cooking in his tech kitchen?”

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