The Trickiest Brain Exploration of All

Karl Deisseroth developed astounding technologies that light up the brain and render it transparent. Yet some of his most compelling breakthroughs still come from listening to patients.

The patient—he says I can call him Pablo—wants to leave his job and find a new one. For a 30-something tech worker in Palo Alto, his story’s not uncommon: the position was all right, but now he wants out. Pablo, his eyes downcast toward a spot near his feet throughout the appointment, says he wants a job “that feels fulfilling.” His no longer passes muster. Friends and colleagues are leaving at rates of cryptocurrency-inspired curvature. Pablo plans to stick around for the time being. He brushes a mop of hair back from his forehead, its thickness matching his beard, over and over. “They pay me a lot for what I do,” Pablo says, “but all I’m doing is going into work and cashing checks.” He’s good at what he does, he explains. Since everyone else jumped ship, he promised his manager he wouldn’t start looking elsewhere for another few weeks. Beneath the disaffect, he’s conscientious.

Pablo is an autistic patient of Karl Deisseroth, professor of bioengineering and psychiatry at Stanford University. Deisseroth, 46, led the inventions of two of the past decade’s most remarkable technologies for seeing into the brain. But even those techniques reveal only so much about how the brain works — and, ultimately how he can better do what he has intended to do his entire career: help people with conditions such as depression and autism. To crack the code, he still must also do the slow, painstaking, analog work of regularly listening to patients.

Deisseroth has seen Pablo in his practice for about a decade, which has attuned Deisseroth’s ear to Pablo’s subtleties. Pablo might meet Deisseroth’s eyes a couple of times per session, but only while describing his daily routines. He’s been feeling a little depressed because of work. Not the worst he’s ever felt, but still: no desire to get up and out of the house. On the bright side, Pablo can’t dwell on it much, because one of his neighbors, a co-worker, would be banging on his door to carpool regardless.

Deisseroth asks whether Pablo’s been keeping up with friends (he has — in fact Pablo’s helping one finance a funeral), how he’s been sleeping (very well, eight to nine hours), how he relaxes (walking, audiobooks), and whether he’s taking his prescriptions.

Deisseroth’s pace and pauses, his two-step of ask and answer, are kind. His voice is deep and consistent, fit for a fireside or public radio. Like a host, he elicits stories that he returns to, sometimes years later, in his research and in his clinical practice.

Deisseroth asks Pablo about his weekends. Pablo moves in his seat, extends his arms broadly, clasps them behind his head, widens them like a strung bow. This is a movement he repeats with vigor.

To what extent are autism, depression, and other mental disorders rooted in or the causes of abnormal wiring in the brain?

Pablo begins telling a story. Every weekend he gets in his car. It’s usually a Saturday morning. He sets a route to the animal shelter. Sometimes he turns back for home before he makes it there. Other times he arrives but doesn’t go inside. He just sits in his car. He can’t bring himself to go inside. He drives home, and repeats this the following weekend.

Based on the information Deisseroth teases out, this eventually becomes clear to me:

Pablo is single. He has never had a romantic relationship. His closest companion, a focal presence in his life, was a cat he once owned. He cared very deeply for that cat, and when it passed away, Pablo experienced a punctuating loss. This loss bred an aversion to potential future loss, a feeling that seems now to contain Pablo. When he parks outside the animal shelter he does not open the car door. But he imagines it. Imagines approaching the shelter, anticipation bubbling, a new possibility for joy with a new cat. But he has an equal proximity to past griefs, some inner voice thinks. He imagines scrutinizing each whiskered face, a mortal face, which would inevitably go the way of his old cat.

His old cat.

Instead he remains in the car and after some time goes home.

Pablo finishes his story and I feel sad. To be more specific, I’d say I feel a pang in my body, a loose, dissociated ache. Whether it’s more of a figurative or physical reaction, or both, it’s hard to say. We all can recall what it’s like to feel betrayed by anticipation. Who doesn’t have a cemetery of unfulfilled wants?

What Karl Deisseroth would ask is: What lit up in my brain, which cells coughed to life during Pablo’s cat story? How are emotions mapped throughout a brain — where do feelings, like our empathy for Pablo, or Pablo’s fear of future loss, take root? Why does his story produce a pang in my brain? These questions of the origin and the biological purpose of emotion drew Deisseroth to this field and to patients like Pablo. They sharpened his interest in autism, and kept him around the clinic, despite an astonishing career made famous by those two inventions that are driving a new wave of neuroscience.

The first of those enormous breakthroughs was optogenetics. Nearly a decade ago, Deisseroth and some of his graduate students, including future CRISPR pioneer Feng Zhang, developed a technique for genetically engineering cells so they could be turned on or off by flashes of light. That lets scientists study, with unmatched precision, what individual neurons and circuitry do — and how they go awry in brain disorders.

You might say optogenetics renders the workings of the brain more transparent, except that would steal the thunder of the thing Deisseroth developed next. It’s a technology known as Clarity, and it makes it possible to take brains (or other organs) donated for research and drain them of opaque materials, like lipids, and replace them with a transparent “hydrogel” that preserves the intricate structure of the organ. Clarity lets scientists study the brain in three-dimensional detail: local circuit wiring, neuronal connections, subcellular structures, and the chemical interplay of neurotransmitters can all be revealed. It’s a big opening for psychiatrists like Deisseroth who have long wondered: to what extent are autism, depression, and other mental disorders rooted in (or themselves the causes of) abnormal wiring or patterns of connectivity in the brain?

Clarity reveals local circuit wiring, neuronal connections, subcellular structures, and the chemical interplay of neurotransmitters.

Deisseroth’s patients are like many of the big questions he’s trying to answer: they don’t lend themselves to easy answers or simple explanations. In his office he tells me that he’s only accepting patients with depression or autism so he can focus on those conditions more intently. While scientists have identified genes associated with both disorders, and some therapies work to certain extents in certain people, variations in individual expression are vast. There’s no easy way to diagnose them, no lab test or scan. There’s more that we don’t know than what we do know. Every patient Deisseroth encounters is like a cipher, a lengthy hangman of consonants. A different kind of examination, or perspective, is required to even attempt to treat them.

To get inside their heads, Deisseroth needs to understand their stories. He is a devoted reader (attributed in part to a childhood hardly marked by television) and a fiction writer, and he inspects patients’ minds the way a reader inspects a protagonist’s. He is very sensitive about how his patients deal with, and comprehend, their own symptoms.

For instance:

One time, several years after he began seeing Pablo, Deisseroth asked Pablo why he avoided eye contact. Deisseroth asked him if he felt shy. Pablo said he didn’t. Deisseroth asked if he made Pablo feel uncomfortable. Pablo denied that as well. Eventually, Pablo revealed that when talking or explaining something, maintaining eye contact and then having to process his listener’s reactions amounted to an overwhelming added task to juggle. “It felt like too much stimulus for him,” Deisseroth said.

Social interaction is such a hard thing for humans to master — it requires a certain rhythm, anticipation of another’s moves, execution of one’s own. “It’s like a dance,” Deisseroth says. His mention of rhythm reminded me of Pablo’s laugh: Pablo tended to inject laughter before he said something funny, rather than in time with it. That’s a little different from laughing at one’s own jokes (which I am an expert at, I’m afraid); instead it seemed as though Pablo anticipated a humorous reaction, ideally, from what he’d say, and then rushed to it. Like shuffling the sequence of expected events, Deisseroth noted.

That set off a spark of insight in Deisseroth. Pablo’s lack of eye contact fit with the information-overload theory, previously suggested by UCSF’s John Rubenstein, that individuals with autism feel their speech disrupted by extra sensory and processing information. And that took Deisseroth back to the bench. In 2011 Nature published a study out of Deisseroth’s lab that showed ordinary mice can be made to develop autism-type behavioral deficiencies by stimulating certain nerve cells. Then last year, Deisseroth’s lab went further. Lab members conducted two experiments on hyperactive mice using optogenetics: in the first, they used light to stimulate an inhibitory neuron in the prefrontal cortex. In the second, the lab used light to dampen an excitatory neuron. Both experiments resulted in less hyperactive, more sociable mice who spent as much time schmoozing new mice as controls.

Deisseroth intends to further investigate neural circuits implicated in autism. Last November, his lab published a paper in Cell on the brain’s mechanism for attention. After witnessing how various neurons speak to one other during a behavioral state, Deisseroth discovered that circuits that modulate brain behavior do not perform in a binary fashion (either “on” or “off”). Instead they have a sort of gradualism, secreting molecules that render excitatory or inhibitory firing more likely or less likely depending on environment. Little by little, this kind of work is demystifying why people with autism have issues with sensory integration issues and sociability. It’s also a step toward understanding the mechanisms of different states of consciousness.

Pablo has never had a romantic relationship. However, there was a time when he decided to give it a shot, with encouragement from Deisseroth and a psychologist. Normally Deisseroth wouldn’t have angled this sort of nudge. But Pablo had told Deisseroth and his psychologist about an old female friend visiting one weekend from out of town. It seemed she may have harbored feelings. While nothing ever came of that girl or that weekend, given Pablo’s clouded description, Deisseroth figured a romantic relationship might be something Pablo could want.

So with Deisseroth and his psychologist’s support, Pablo cast his net. He set up online dating profiles. He went on dates with women.

His attempt at finding love was not successful. He tried for about a year. Deisseroth described it as a difficult time for Pablo, which sounds like an understatement.

This kind of work is demystifying autism. It’s also a step toward understanding the mechanisms of consciousness.

Pablo started working out that year. He’d walk into Deisseroth’s office all burly, chest-forward, Dwayne Johnson. He bought a leather jacket. He shaved his beard.

But after a year, he handed it all back. He told Deisseroth that a romantic relationship was not something he felt he actually craved or needed. He felt content and sufficient without it.

What, on a chemical or cellular level, is different from most people in an individual who feels disinclined toward love? What biology translates to that awareness, I ask Deisseroth. He likes the question and turns it around: what causes someone to crave intimacy if they’ve never experienced its reward before?

“It’s all a connected ecosystem,” Deisseroth tells me, referring to his first, second, and third acts: physician, writer, scientist. “It all relates to feelings. Where they come from. What are feelings?” There are feelings with a clear biological or evolutionary basis, like sexual attraction or pair bonding. But what, he asks, about those whose origins remain a mystery?

For example, he says, one day I go to the beach and I sit down and look out at the ocean. I feel calm. I watch the waves crash. I am moved by it. Something wells up in me: a feeling, most certainly. But why do I feel it? What could be its evolutionary basis? And if someone can’t relate to that feeling, what’s the mechanism to explain that?

When he sits down to write and studies the watermarks patients have left with their stories, Deisseroth thinks about this last bit. What elicited that first pang in us when we heard about Pablo’s cat? What’s the pang’s point? What’s its odd beauty? A recognition of yourself in something, or better yet someone, else? A shared human story?

Or maybe it’s a sense that things, people, are more entangled than they seem, with connections that are brief but unmistakable, like the spark of a synapse.

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