#191 – Revolutionizing our understanding of mental illness with optogenetics | Karl Deisseroth M.D., Ph.D.

Karl Deisseroth is a world-renowned clinical psychiatrist, neuroscientist, and author of Projections: A Story of Human Emotions. In the episode, Karl explains his unique career path that led to the development of optogenetics—a revolutionary technique that uses specialized light-sensitive ion channels to precisely control the activity of select populations of neurons. Karl provides a concise overview of how optogenetics works and how it can be used to better understand mental illness, to identify the neurons responsible for specific behaviors, and to guide development of new treatments. Karl uses his experience as a practicing psychiatrist to provide deep insights into depression, anxiety, autism, and personality disorders and explains the role of optogenetics in mapping out brain regions responsible for common mental health afflictions. 

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We discuss:

• Karl’s journey through medical school and interest in the brain [5:00];
• A profound medical school experience that changed Karl’s career path to psychiatry [17:30];
• Karl’s commitment to research and challenges overcome early in his career [27:00];
• The state of psychiatry and mental health therapies when Karl started his lab in 2004 [33:15]; 
• Neuroscience 101: fundamentals of neuroanatomy and neurophysiology [38:15]; 
• Traditional techniques for identifying the brain regions involved in specific behaviors [47:15];  
• Intro to optogenetics and how to get a gene into a neuron [51:15];
• How viruses helped make optogenetics possible [1:01:45];
• How optogenetics was used to investigate the effects of dopamine neurons [1:15:45];
• Appreciating the power of optogenetics [1:22:00];
• Investigating and treating anxiety with optogenetics [1:26:45];
• Autism and autism-related anxiety, and the potential of optogenetics in treating autism [1:38:00];
• Optogenetics as a powerful tool for the discovery and creation of medical treatments [1:45:00];
• Karl’s inspiration to write his book, Projections [1:48:00];
• Mania and bipolar disorder: evolutionary basis, symptoms, and the high prevalence in North America [1:52:45];
• Depression: evolutionary basis and insights from optogenetics [2:03:15];
• The effects of trauma early in life [2:18:45]; and
• More.

*Notes from intro

• Karl is a former classmate of Peter’s from Stanford, where he received his MD and PhD
• He completed his clinical training in psychiatry, and he also did a postdoctoral fellowship there at Stanford during the same period of time
• He’s currently a professor of psychiatry and behavioral sciences and bioengineering at Stanford
• Over the past 16 years, Karl’s lab has focused on combining neuroscience and bioengineering to create a set of revolutionary tools
  • This has done something for the first time ever in neuroscience, which is basically to allow the use of genetic engineering to input light sensitive channels into very specific neurons
    • In fact, into any neuron that they choose to put these into
  • This then allows Karl and his team, and others who have been able to follow in his footsteps, to use photons, that is to say to use light, to turn on and turn off very selective neurons
  • This is something that was absolutely impossible until about a decade ago.
• This tool is referred to as optogenetics
  • As its name suggests it’s opto, it’s light
  • It’s genetics, it uses this genetic engineering tool to put these channels, these light sensitive channels, into neurons
  • This has opened up a field of neurobiology that basically has allowed investigators like Karl to ask questions that have never been asked or answered before
• The discussion today will go into how Karl and his team came up with these unbelievable ideas, how they refine the tools, and what they’ve learned as a result of doing this
• This work has not gone unnoticed in the scientific community; Karl has won virtually every scientific award out there
  • Just this month, he was awarded the very prestigious Lasker award for his optogenetic light activated molecular research
    • Now it’s worth pointing out, to those who might not be aware, that about 50% of Lasker winners go on to win the Nobel prize 
• This episode will discuss not just about his background and how it led him to these discoveries in his chosen career path, but it will also dive into some of the deeper questions about mental illness
  • Remember, Karl is a practicing psychiatrist, and it’s his interest in the human condition that really guides his research
  • This episode will dive quite deep into depression, anxiety, autism
  • It will touch briefly on some personality disorders
  • But truthfully, this episode ran out time after two and a half hours; and the discussion only made it through about half of the material that Peter wanted to talk about
  • So it’s safe to say that Karl will absolutely be back on this podcast because there’s still so much to talk about
• The other thing to be aware of, before this discussion begins, is that Karl has recently written a remarkable book called Projections
  • This is a book that Peter has mentioned in the podcast; he’s read it twice
  • Karl’s ability to write is perhaps only rivaled by his ability to conduct Nobel prize-worthy science
  • He’s a remarkable writer, and you don’t need to be afraid of this book being written by such an esteemed scientist; it reads like a piece of poetry
  • It really is a remarkable book and a remarkable journey into not just his personal journey, but also into the eye of mental illness

Karl’s journey through medical school and interest in the brain [5:00]

•  Karl was in the MD PhD program when Peter met him
  • They didn’t start at the same time but finished at the same time
  • The reason Peter knew him, even on their first day of surgery was because Karl had done his PhD in the same lab as 2 of Peter’s friends
• All kids that go to med school are pretty bright, but the MD PhD students were in a class of their own
  • Peter suspects it was even harder to get into the MD PhD program than it was just the straight MD program
• Karl did his undergrad in biochemical sciences at Harvard; they didn’t call it biochemistry
  • They didn’t call it a major either; it was a concentration; he concentrated in biochemical sciences
  • He had a lot of other interests; all of his friends were physicists, theoretical physicists; so he was exposed to some pretty unusual stuff for a biochemist
• He knew he wanted to go into medicine pretty early on because he was interested in the brain early on
• He wanted to understand the brain at the level of cells
  • But he was also interested in the most high-level aspects of brain function, so he thought he needed to talk to human beings
  • He needed some access to the human brain
• He found that interesting because he was interested in emotion and the ability to express feelings through words
• Further, he was torn; he liked writing and literature and the use of words, and he liked cells and biology
  • He wanted to somehow fuse them, and it seemed that medical school was the way to go because he could work with the human brain
• He could have just gone to medical school, but he was also selected into this very, very advanced program that was incredibly selective, the MSTP program, the medical science training program
  • This tells Peter that Karl knew he wanted to do research beyond just clinical medicine
  • Yes, and the nice thing about the MSTP is it lets one delay in making a commitment, so he could keep both threads alive
  • Then there’s a beautiful synergy that can happen too, and certainly happened with him, that he realized, “Oh wait, I don’t have to make this decision.” It actually is good to keep both threads alive in his work and his life
  • It’s a pretty special program in the United States; there are efforts along these lines in Europe and other countries, but it’s not nearly as institutionalized as it is here
• Peter recalls there were maybe 6 or 8 MSTP students in their class at Stanford
  • He always felt like they  had the most pressure on them; there was this expectation from both the clinical and research side
  • An expectation that they would go on to be great doctors
  • On the research side, they had the opportunity to do their PhD with a Nobel laureate or exceptional scientist
  • There was also this expectation that they would lead the charge scientifically
  • Of the MSTP students in their class, Peter thinks Karl is the only one that ended up doing clinical training 
    • The others didn’t end up doing a residency; they either went purely into academic research or into industry

Neurosurgery, Karl’s first clinical rotation

• In med school Peter remembers Karl was “pretty hell bent on neurosurgery” 
• That was the goal; because he wanted access to the human brain, and who among the different clinical specialties has that access? 
  • It seemed to him that neurosurgeons had it all
  • If one were to build an interface with the brain, if one wanted to both communicate with a person as they were expressing feelings and emotions, and to understand at the level of cells what was going on, who could do that but a neurosurgeon, was my reasoning
  • The neurosurgeons, his colleagues and friends, are amazing people, brilliant, and he saw no reason not to pursue that
• Neurosurgery was the first rotation that he selected in the second 2 years of medical school
  • Even before surgery, he did neurosurgery, which was kind of interesting just coming in there with no general surgical training
  •  That’s how certain he was
• Peter had a similar experience where he was absolutely, positively, sure of what he wanted to focus on, pediatric oncology
  • In his case, he had a less pleasant experience than Karl
  • He did not enjoy his time in pediatrics largely because he felt like he didn’t fit in
• He thinks so much of the clinical rotations in the medical school experience, is a function of how well one fits in with the residents of that specialty
  • He didn’t feel like he fit in with the pediatricians
    • They didn’t laugh at his jokes
    • They thought he was probably a little too obnoxious, that he spent too much time imitating Dr. Evil and Fat Bastard, pretending to eat the babies
  • The whole thing just didn’t go well; it was a disaster
  • Then his next rotation was general surgery where he connected, and even though he had no desire whatsoever to go into surgery, that became an overnight love
• Peter thinks its highly unusual that Karl would do a neurosurgery rotation so early in his training
  • That’s usually something one does in the fourth year, not the third year
• When Peter did general surgery at Hopkins, he did one month of neurosurgery as a rotation
  • He never had an interest in neurosurgery, but he didn’t have a choice about this rotation
  • During that month, he fell in love with it
  • In fact, he spoke to the program director at Hopkins and said, “Would it be ridiculous for me to try to transfer into neurosurgery?” 
    • That’s how much he enjoyed it
    • The director said, “I can absolutely get you in, but it won’t be at Hopkins. Hopkins is the most competitive neurosurgery program in the country. We only take three people. It’s already full. You’re not going to get in here, but I can get you to another program.” 
    • And Peter actually contemplated it for about a month
  • He can see the appeal of it; there was something about cutting open the dura and operating on the brain; it’s a surprisingly simple organ in that sense
• Karl notes, at one level it is an organ, but it would be unfair to say that all that neurosurgeons get to do is think about it as an organ
  • They do have to think about that, the blood supply and whether the cells are receiving enough oxygen and glucose
  • They also get to think about high level concepts
• In his neurosurgery rotation, there was a patient who had a little bit of thalamic infarct as a result of the surgery, and a little bit of loss of tissue in the thalamus
  • The patient had a neglect syndrome
  • He spent a lot of time working with the patient afterward characterizing exactly how this worked
  • He asked the patient to draw a clock, and the patient drew just half of a clock; it was a classical thing, but amazing to see with one’s own eyes talking to another person
  • And the patient said, “The clock looks fine,” but it was a half a clock
  • That certainly didn’t diminish his interest in neurosurgery at all
  • At the one level, there were problems which clearly needed to be better 
    • Aspects of neurosurgery, as with every clinical specialty needed to improve, needed to reduce consequences like that
  • Yet at the same time, it was incredibly interesting as well
• He loved the operating room
• He love the suturing, although he wasn’t as good as Peter 
• But he was good enough and particularly because it was so early, he thinks that the promise was there
  • It would’ve worked out; it still had a magic about it
  • When the dura is exposed, yes, it’s an organ, but there’s a spirituality to that

“To know that you’re actually looking at the storehouse of a human being’s thoughts and feelings and everything about them, all encapsulated in this collection of cells. It’s quite an amazing thing.” – Karl Deisseroth

• So he had no negativity at all

• He did notice that neurosurgeons didn’t get a lot of free time; there was not a lot of philosophizing
  • It’s a 7-year progression
  • He talked to all the neurosurgery residents, and he noted a steady decline in willingness to philosophize as their progress through the residency continued
    • This could almost be plotted linearly on a graph
    • With all due credit to them, it’s the nature of the system they’re in that they don’t necessarily have all the time they would like to think deeply, although they certainly are very bright and thoughtful, and they certainly could
  • He noted that here are people who maybe don’t have the freedom to do everything he would like, and that was in the back of his mind
• Peter thinks back to the 3 people in his class that were assigned neurosurgery
  • These were 3 ridiculously smart guys, and one would think, “Well, they’re in neurosurgery, so how interested are they going to be in their year of general surgery?” 
    • But they were every bit the exceptional interns that the categoricals were, the ones who were going to go into general surgery
  • One of the experiences that stands out from his month of general surgery in his internship was an awake procedure they did on a patient
    • So under local anesthetic, the brain was opened, and the patient while wide awake was being probed in an effort to determine certain symptoms and to see what part of the brain could be lesioned in order to ameliorate these symptoms
    • He thinks for anybody to see that in real life with their own eyes, even once, it’s really hard to believe what’s happening
    • First of all, the brain is not some sensory organ—The fact that the patient can be awake while a surgeon is probing into the brain, and it’s firing an electrical impulse into one area or another; to see how it changes this part of the visual field… “that was magic”
• Karl felt very strongly after his neuroscience rotation; it was all systems go after that
  • Surprisingly, the neurosurgeons at Stanford liked him okay after that too
  • He got very positive feedback from them; they wanted him to come back and do an internship
  • He was happy with that; it was where he was headed; but things changed

A profound medical school experience that changed Karl’s career path to psychiatry [17:30]

• There are a set of mandatory rotations medical students have to do, neurosurgery is not one of them

{end of show notes preview}

Karl Deisseroth M.D., Ph.D.

Karl Deisseroth is the D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University, and Investigator of the Howard Hughes Medical Institute. He received his undergraduate degree from Harvard, his PhD from Stanford, and his MD from Stanford. He also completed postdoctoral training, medical internship, and adult psychiatry residency at Stanford, and he is board-certified by the American Board of Psychiatry and Neurology. He continues as a practicing psychiatrist at Stanford with specialization in affective disorders and autism-spectrum disease, employing medications along with neural stimulation.

Over the last sixteen years, his laboratory created and developed optogenetics, hydrogel-tissue chemistry (beginning with CLARITY), and a broad range of enabling methods. He also has employed his technologies to discover the neural cell types and connections that cause adaptive and maladaptive behaviors, and has disseminated the technologies to thousands of laboratories around the world.

He is also an inpatient/outpatient attending physician in the Department of Psychiatry and Behavioral Sciences at Stanford.  His clinical work focuses on treatment-resistant depression and autism-spectrum disease using medications and high-speed neural stimulation.

Among other honors, Deisseroth was the sole recipient for optogenetics of the 2010 Koetser Prize, the 2010 Nakasone Prize, the 2011 Alden Spencer Prize, the 2013 Richard Lounsbery Prize, the 2014 Dickson Prize in Science, the 2015 Keio Prize, the 2015 Lurie Prize, the 2015 Albany Prize, the 2015 Dickson Prize in Medicine, the 2017 Redelsheimer Prize, the 2017 Fresenius Prize, the 2017 NOMIS Distinguished Scientist Award, the 2018 Eisenberg Prize, the 2018 Kyoto Prize, and the 2020 Heineken Prize in Medicine from the Royal Netherlands Academy of Arts and Sciences. For his discoveries, Deisseroth has also received the Perl Prize (2012), the BRAIN prize (2013), the Pasarow Prize (2013), the Breakthrough Prize (2015) the BBVA Award (2016), the Massry Prize (2016) and the Harvey Prize from the Technion/Israel (2017). He was selected a Howard Hughes Medical Institute Investigator in 2013, and was elected to the US National Academy of Medicine in 2010, to the US National Academy of Sciences in 2012, and to the US National Academy of Engineering in 2019. [Stanford Profiles]