Discoveries by Deisseroth and his two co-recipients regarding microbial light-activated molecules led to his development of a way to manipulate selected neurons in living animals to observe changes in their behavior.
September 24, 2021 - By Bruce Goldman
Decades of high-risk research, driven by a combination of curiosity and passion, have earned neuroscientist and bioengineer Karl Deisseroth, MD, PhD, one of the most respected science prizes in the world.
Deisseroth, professor of psychiatry and behavioral sciences and of bioengineering at Stanford, has been named a co-recipient of this year’s Lasker Basic Medical Research Award.
The award, sponsored by the New York City-based Lasker Foundation, is given annually to honor visionaries whose insight and perseverance have led to dramatic advances with practical medical potential.
Deisseroth, the D. H. Chen Professor and a Howard Hughes Medical Institute investigator, shares the $300,000 award with Peter Hegemann, PhD, professor of biophysics at Humboldt University of Berlin, and Dieter Oesterhelt, PhD, emeritus group leader at the Max Planck Institute of Biochemistry in Martinsried, Germany.
The foundation’s official citation of the award credits the three researchers “for the discovery of light-sensitive microbial proteins that can activate or deactivate individual brain cells, leading to the development of optogenetics and revolutionizing neuroscience.”
“Karl Deisseroth’s astounding imagination has traversed disparate disciplines, including genetics, optics, structural biology and virology to spark the creation of optogenetics,” said Lloyd Minor, MD, dean of the Stanford School of Medicine. “This game-changing technology has transformed neuroscience, allowing researchers to better understand our brains’ intricate wiring and to develop interventions that address diseases of the brain and mental health conditions.”
Deisseroth devoted more than 15 years of his career to the development and promulgation of the technique, which has immeasurably improved scientists’ ability to probe the neural basis of sensation, cognition, decision and action. He identified new kinds of light-activated proteins from microbes, deciphered their high-resolution structures at the level of individual atoms, and discovered how these structures give rise to amazing properties of ion flow in response to light. He spearheaded discoveries of ways to position these proteins on the surfaces of specific neurons so they could be independently activated or inhibited in a fraction of a second by pulses of laser light. He also designed a method of delivering those light pulses via fine fiber-optic cables surgically implanted in the brains of living animals, making it possible to watch their behavior change at the flip of a switch.
“It was clear early on that optogenetics would have a transformative effect on neuroscience,” said Liqun Luo, PhD, a professor of biology at Stanford. Luo, the Ann and Bill Swindells Professor, collaborates frequently with Deisseroth. Principles of Neurobiology, a college textbook Luo wrote, contains an entire section on optogenetics.
“He’s very thoughtful,” Luo said. “He doesn’t speak a lot. When he speaks, each sentence means more than that of an average person.”
'A fire burning'
Robert Malenka, MD, PhD, the Pritzker Professor of Psychiatry and Behavioral Sciences and deputy director of the Wu Tsai Neurosciences Institute at Stanford, in whose laboratory Deisseroth spent a lot of time early in his career, jokingly calls Deisseroth a “surfer dude.”
“He’s extremely relaxed and calm,” Malenka said. “He’s rarely dressed in anything but a T-shirt — untucked — and blue jeans. But underneath that, there’s a fire burning.”
A practicing psychiatrist as well as a basic scientist, Deisseroth has treated many patients suffering from severe, debilitating mental disorders such as autism, schizophrenia and depression. His goal is to find a way to end their suffering.
“Psychiatry has a long way to go,” he said. “We’ve lacked the tools to tease apart the component circuits that make up a working brain and examine their functions, one by one.”
In the absence of such tools, it’s tough to learn with any precision how the brain works, and even tougher to learn what’s wrong with a brain that isn’t working so well.
Before the advent of optogenetics, most brain studies relied on electrodes or drugs. Electrodes work fast, but they stimulate in a nonspecific way, igniting many different nerve-cell types in many different circuits. And while electrodes can activate neurons, they can’t as precisely inhibit them, which is critical to studying brain function.
Drugs can selectively activate or inhibit neurons, but not necessarily the ones of interest. Plus, they diffuse widely and can’t be mopped up quickly, making them lousy on/off switches.
But optogenetics lets neuroscientists selectively inhibit or activate exactly the cells they’re interested in.
A major milestone along the way to realizing this capability was Oesterhelt’s isolation of a light-activated protein, or opsin, in a one-celled creature, Halobacterium salinurum, in 1971, the year Deisseroth was born. Oesterhelt showed that this opsin and similar ones can respond to light by pumping ions, electrically charged particles, through the membrane in which it sits.
Hegemann, who was Oesterhelt’s PhD student, later identified an opsin gene from algae. He was able to insert the gene into frog eggs and study the electrical activity of the encoded opsin molecules, showing that they could transmit current across the membranes of the eggs, as well as those of cultured mammalian kidney cells. And he discovered additional opsins.
Deisseroth took these discoveries to the next level, making major discoveries of his own along the way.
Native of Boston
Born in Boston, Deisseroth has an older sister and a younger sister. His father was a physician and professor, and his mother was a high school chemistry teacher. An avid reader of prose, poetry and science, he initially dreamed of becoming a writer. He was also blessed with an extraordinary memory, often remarked upon by his peers today.
In 1988, Deisseroth enrolled at Harvard University, where he became increasingly interested in how the mind works and, ultimately, how biomolecules beget conscious sensation, cognition and action. After graduating summa cum laude with a bachelor’s degree in biochemical sciences, he entered Stanford’s MD-PhD program. He earned a PhD in neuroscience in 1998 and medical degree in 2000. It wasn’t until his final year as a medical student that a clinical rotation in psychiatry piqued his interest in that discipline.
“Psychiatry was full of mystery,” Deisseroth said. “I realized how intriguing it was, how great the need was and how well it fit with what I could do.”
He took up a Stanford residency in psychiatry, spending long hours in the psychiatric ward — and acquiring experiences and insights that served as a basis for Projections, his recently published book about his efforts to understand mental disorders from the perspective of the patient, doctor and scientist. On nights and weekends, he moonlighted as a postdoctoral scholar in Malenka’s lab. There, Deisseroth learned how to bioengineer viruses to deliver genes of interest to mammalian cells.
“I said, ‘Karl, do whatever you want,’” Malenka said. “He’s in a league by himself now. He’s like the Michael Jordan or the Tom Brady or the Roger Federer of neuroscience. He works amazingly hard. You don’t become the best in the world if you don’t work very hard. Just being smart isn’t enough.”
‘Incredible intelligence, creativity and ingenuity’
In July 2004, Deisseroth, straight out of his residency, was able to set up his own laboratory with resources that Alan Schatzberg, MD, the Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences (who was then chair of psychiatry and behavioral sciences), and Scott Delp, PhD, the James H. Clark Professor in the School of Engineering (who was then chair of bioengineering), helped direct to him.
“Although he’s not somebody who touts himself, Karl displays incredible intelligence, creativity and ingenuity,” Schatzberg said. “He’s a phenomenal scientist. But he’s also a good person and a good doc. He’s doing this research because he believes it will help psychiatric patients get their lives back.”
Ensconced in his new lab, Deisseroth and a pair of graduate students engineered a harmless virus to deliver an opsin gene to neurons grown in culture dishes and, with pulses of laser light, get the neurons to fire at will. In 2005, Deisseroth, now an assistant professor of psychiatry and behavioral sciences and of bioengineering, published the first paper in Nature Neuroscience describing how this initial step worked. He became an associate professor in 2009, associate chair of bioengineering in 2010, and a full professor in 2012. (The Department of Bioengineering is jointly managed by the School of Medicine and School of Engineering.) In 2014, he was named a Howard Hughes Medical Institute investigator.
Throughout, he continued his rapid development of optogenetics. He explored the molecular structure of opsins, learned more about how they worked, engineered them to yield new properties and discovered new ones. With further tinkering, he was able to manipulate neurons not only in a dish but in living animals and observe how their behavior changed. This feat involved discovering how to place optical fibers in animals’ brains for light delivery in order to control specific cell types both safely and precisely.
The technology caught fire. In December 2010, the peer-reviewed journal Nature Methods named optogenetics the journal’s “method of the year.” That same month, Science magazine kicked off a roundup of 10 “insights of the decade” with a nod to Deisseroth.
He has trained hundreds, perhaps thousands, of scientists from all over the world in optogenetic techniques, from the basics to the most recent advances.
At first, scientists had trouble getting his innovation to work.
“There was an adaption barrier,” Deisseroth said. Initially, few neuroscientists possessed the technical skills and broad knowledge base required to master the technology. So Deisseroth set up a free workshop two floors above his lab to teach people how to succeed with it.
Optogenetics now a standard tool of neuroscience
Today, optogenetics is a standard tool of neuroscience. Researchers around the world are using it to study learning, memory, perception, motivation, mood and appetite, and to pinpoint the neural-circuit glitches responsible for Parkinson’s disease, epilepsy, schizophrenia, autism, anxiety, depression, addiction, aggression and more.
“There isn’t a neuroscience lab in the world that doesn’t use it,” Malenka said.
Deisseroth has co-authored nearly 400 peer-reviewed journal papers and won scores of previous awards. He is the director of undergraduate education in Stanford’s Department of Bioengineering.
“I don’t know how he manages his time,” Luo said.
Living on campus with his wife, associate professor of neurology and neurological sciences Michelle Monje, MD, PhD, Deisseroth somehow finds time to raise four young kids — ages 13, 11, 8 and 5 — packing their lunches and getting them to school. He also has a 24-year-old son in medical school.
Somehow he found time to write a book. And he runs a bustling lab.
What does he look for in a prospective student or postdoc? “To truly love and be intrigued and excited about what you’re doing,” he said.
To what does Deisseroth himself attribute his success? “Curiosity,” he said. That’s the living philosophy of his lab. “We don’t want to do things that would get done anyway,” he said. “We want to build a telescope to see a part of the sky nobody has ever seen.”
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