- Welcome to Healthy Minds.

I'm Dr. Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one, do not suffer in silence.

With help, there is hope.

(piano music) Today we continue a conversation with Dr. Karl Deisseroth where we discuss new technologies that are helping us better understand the brain and develop new treatments for psychiatric conditions.

(piano music) One of the things that you speak about in the book that I found very striking, and it's an example of how the clinical informs the science, is in your interactions with a person who has autism and experiences what many people with autism experience, which is difficulty making eye contact and speaking with that person and getting a sense of why he does that.

What's the reason for that?

And I'd like you to speak a little bit about what you learned speaking to the person and then how that relates to some of the neuroscience.

- Yeah.

Well, for someone who has worked hard to develop both the scientific side and the medical side of his life, this conversation with the patient was a really important moment of convergence of the different sides of life.

This was a patient who had autism, but was verbal.

So able to communicate, was able to tell me and discuss, to some extent, the symptoms and the inner experiences.

Which is not true of everybody with autism, as you know.

And so this patient was interestingly positioned on the spectrum.

Severe enough to be debilitated, but verbal enough to communicate accurately, which was an incredible opportunity.

My patient, someone who I was helping.

Many people, although we don't have medicines for autism, we can help the comorbid symptoms, including anxiety, that these people experience.

And so, as the psychiatrist, I was helping to treat the anxiety.

This was a young man who had very severe anxiety, particularly in social and work situations.

Social interactions are very anxiety-provoking if you fundamentally have trouble understanding and keeping up with all the dynamics.

And this patient also had other symptoms of autism, including a very profound eye contact avoidance.

And this is a common feature in autism.

It's very striking to see.

There's not just a incidental looking somewhere else, but also quite a market avoidance when eye contact is made, a immediate flickering away of the eyes as well.

As if it's aversive in some way.

And this was a patient I was able to talk to about this.

And for all the time taken in the course of going through MD, PhD, residency training, post doctoral work, this is sort of a double duty of training and all that.

And sometimes you don't always get the feedback that this was a good course to take, this was valuable.

But in this moment, it was quite a remarkable thing.

I was able to talk to this human being and ask, "At this moment, when you make this eye contact and look away immediately, what's really going on?

Are you afraid?"

I was able to ask the patient.

And he said, "No, not afraid."

So this was a patient who had every reason to be afraid.

Very powerful anxiety, which I was treating, but it wasn't fear, it wasn't anxiety.

But I was able to probe deeper, just communicating with this human being.

It was my patient.

And he said after some back and forth, what we were able to to establish was that it was a sense of being overwhelmed.

Not fear, but too much.

Too much information coming through the eye channel of communication and that the vastness and the speed of all that information was too much, he knew it was too much, felt it to be too much and that was the aversive, fundamental quality of the eye contact.

The being overwhelmed with information.

Okay, so not many patients would be positioned well enough on the spectrum to have such a precise discussion about this.

And the amazing thing was that this was over some years of work with optogenetics, this was a concept that we were able to map quite well onto precise and causal neural circuit processes with the over-excitability, the easily triggered nature of cells in certain parts of the brain.

Actually, which is a feature of autism as a number of clinical studies, including EEG can suggest.

This over-excitability indeed can limit the information carrying capacity of cells in the frontal cortex, for example.

And this is something that we could measure precisely in bits per second, that the over-excitability that causes social dysfunction, also places limits on the information carrying capacity in cells in this frontal cortex part of the brain.

And so bringing these disparate concepts together, a human being's internal experience, just articulable enough with precise and causal information processing established in homologous circuits in mammals.

This convergence was an example and became the focus of one of these human stories in "Projections".

It's one example, there are others, there's eating disorders, there's mania, there's depression, there's grief and bereavement, dementia.

And this is a, I think for the world, for the community, for the public to share, to appreciate, that we're now at a point where these mysterious and complex altered human interstates, we can now talk about them with precision and causality.

- And that by having a conversation and listening carefully to what the person says, that could help lead to the science that can ultimately help that person and others, which is tremendous.

- Exactly.

Yeah and there was no way.

Again, I feel gratitude to my former self who put in the time, the difficult times of internship and residency and all that to make it happen because it was not 100% clear that such a convergence would happen.

And I give my tip of the hat to all the people out there working hard at this convergence.

So many people working at the interface of medicine and science and working to raise awareness, working to raise support.

That convergence is where the ideas come from.

And I'm grateful to everybody who's working at that interface.

- I agree with you and grateful to the people who have such passion for doing this work.

One of the things that you speak about in the book, is the importance of, for want of a better phrase, ideas coming from the bottom up, instead of all of the having a large RFP saying, "This is what you need to do."

And I'd like you to speak a little bit about that in terms of science moving forward and how your science moved forward as a result of that.

- This is a really important point.

It certainly was not first shown with optogenetics.

Although optogenetics is a great example of it.

It's a recurrent theme in the march of science.

Is that the big ideas, the things that truly change the landscape of what we can do, of our understanding, are very often not planned.

Are not part of an ordered process of saying, "Here's a disease that we must understand.

Therefore, we will devote some large amount of money and a large amount of human resources to this specific disease and we'll work to understand it."

That that can happen, but very, very powerfully, the big changes in our capabilities, in our understanding, very often come from completely unexpected directions.

And optogenetics is an example.

These microbial opsins, these beautiful biomolecules that turn light into electricity.

As I mentioned earlier, these were studied for many decades.

And actually, you have to go back to the mid 1800s and a Russian botanist named Andrei Famintsyn who was just studying algae in a dish, he'd collected algae from a freshwater river, the Neva River near his laboratory near St. Petersburg.

And he noticed when he was able to shine light on one side of the dish, there was a fast movement of these single celled algae, which have flagella, so they can swim through the water.

The algae moved to an optimal level of light very quickly.

So this was plant behavior studied by a botanist more than 150 years ago.

And that curiosity-driven exploration of natural world.

And then later the work beginning in the 1970s, understanding these proteins.

And then later the work we did to look at the structure of these proteins and how they work.

Basic science from unexpected directions turned out to be the key leverage needed.

And so it's something important for all of us, as members of society, people who care about the progress of human understanding and of medicine, we have to realize this.

That even if one's central goal is medicine, is alleviating human suffering, supporting the pure, basic understanding of nature and curiosity about oddities of nature.

Elegant, natural things that don't have any obvious purpose.

This can be the most important thing that we do.

And that is a story that we tell to the public, we tell to leaders of society.

Everybody listening now, it's an important story.

And one that again, optogenetics is not the first example of this, there's many others, but it's a very clear one.

- Yeah.

I think you're making an important point that basic research can make such a big difference.

And we don't know where it's gonna go often, but it often does result in the clinical advances that change people's lives.

I wanna ask you about another area of work that you've developed, which is CLARITY.

Tell us what that is and how you developed that.

- Well, this came into being about seven or eight years after the first optogenetics experiments.

And by this point, between 2010 and 2013, optogenetics was working really well, all around the world people were using it.

People were understanding which kinds of cells were important in sensations, cognitions, in actions, in health and disease.

But there was still a level of mystery because we didn't know the precise connectivity.

We didn't know the wiring of the cells that we were working with.

And we knew where they were, where their cell bodies, the main central part of the cell with the nucleus and the DNA.

But we didn't have a clear sense of all their outgoing connections, how they were wired up.

And that was really valuable.

There were ways to access that sort of question.

You can inject cell filling tracers and you can slice the brain into innumerable, very thin slices to look at those labeled molecules as they go through the outgoing connections of the cell, the axon.

That's incredibly laborious.

You lose a lot of information as you make these slices.

Still, you had to slice it because the brain is not transparent.

The brain is opaque.

It's not that it has pigment that's absorbing light.

There's very little color in the brain, but rather it scatters light.

And scattering is what happens at the interface of water and lipid photon, a light particle, will bounce off in a random direction when it meets an interface of fat and water.

And the brain is the most incredible jumble of fat and water interfaces that you could possibly imagine.

Every neuron is coated with a layer of lipid, of varying thickness, of various compositions.

And if you try to go more than a couple hundred microns, if you try to go these tiny fractions of a millimeter, very quickly, you lose all resolution of the light because all of the light particles are bouncing off in random directions and you can't see deep in the brain.

That's why you have to cut these very thin slices.

So, what we did was figure out a way to keep the brain intact and make it completely transparent so you could see all the way through it.

See the connections of the labeled cells, see where the axon goes.

Does it branch?

Does it connect to two different regions?

And that was really powerful because the very same cells that one was controlling, optogenetically and seeing the behaviors, the actions, you also could understand the connectivity of these cells more deeply.

So this hydrogel tissue chemistry, the first form of it, we called CLARITY.

That was in 2013.

Now another form we developed called STARmap, we can look at, not just the protein, not just a few RNA molecules, but we can look at the transcriptome.

All the RNAs, all the expressed genes in each cell, as it's still within its intact, local environment.

And so this is a way of bringing structure, the physicality of the brain, and layering that onto the causal information that optogenetics gives.

And so we can see structure and function together at the same time.

- With all of these technical advancements to study the brain, where do you see this going?

What do you expect in five years, 10 years, 20 years from now, what will we know that we don't know yet?

And what will that mean for people living with various psychiatric conditions?

- One thing that that getting to this deep understanding of the cells that are involved will bring, is understanding and treatment.

Understanding comes from knowing the components deeply and what they do.

It's like a circuit wiring diagram, understanding how a computer works.

You need to know how it's wired up and you need to know what the parts are.

Each capacitor, each transistor.

You know the parts, you know how they're connected, and you know their function.

That's very important.

Basic understanding, but that also gives you tools for an intervention.

If you know all the genes that are expressed, all the proteins, all the little biomolecules that are made by a cell that you know, is causal in a disease symptom, like anxiety.

That gives incredible leverage because then you can look for targets, molecular targets that may set that cell apart a bit or a lot from its neighbors, and maybe a protein that a drug combined to.

Like a G-protein coupled receptor that is expressed more in one kind of cell than another kind of cell in a brain region.

Now you're armed with causal knowledge, you know that cell matters.

And now anchored in that causal knowledge, that gives a very firm foundation for developing new treatments.

So the future is bright for treatments based on causality, but also the basic science of the brain.

At heart, although I'm a psychiatrist, I care very deeply about just the beauty of the brain itself.

How does it work?

How does it achieve the amazing things it does?

And your question, what's the next five years gonna bring, next 10 years?

What we're doing now and many other groups around the world, we're taking a very whole brain.

We're taking a complete view of the vertebrate brain in action as neurons are firing away doing their jobs, but we're maintaining single cell resolution.

We're maintaining track of all the individual cells that are present and firing away in this intact system.

We're observing this activity.

We're controlling this activity at single cell resolution in the intact functioning brain of mammals and other vertebrates like fish.

And the question is, what are the principles?

How does this dynamical system, as we call it, this incredibly interconnected network of active elements, how does it control itself?

How does it shift toward one decision or one state, one mode of being or another?

It's gotta have principles.

And maybe there's a bunch of little tricks, but there's gonna be some big tricks too.

There are gonna be some big principles that govern how the whole thing works as a unit, as a system, that might strike to the very heart of some of the most interesting questions in neuroscience.

I'll give you one example and this one really bridges, almost philosophy and science at the same time.

And it has to do with the nature of the self, what we consider as ourself.

If you think about it, the self, we take it for granted.

I'm myself.

I have a body, I have some motivations.

I have some thoughts and memories.

But it's actually not obvious if you think about it a little more.

How do I choose what parts of me are considered myself and what parts are not?

It's not so trivial and it matters a lot and it matters clinically.

In psychiatry, as you know, there's this state called dissociation, where parts of what's normally considered the self are no longer considered the self.

And this shows up in PTSD, shows up in the dissociative disorders.

Borderline personality, shows up in trauma.

More than 70% of people experiencing severe trauma will dissociate or develop a dissociative state.

Can show up in drug use, PCP, ketamine.

It can show up in epilepsy.

So dissociation, you have this separation of the body where it's no longer considered part of the self anymore.

The person is aware of sensations coming into the body.

It's not numb.

It's not on anesthesia, but it doesn't matter because it's not considered part of the self.

And this can be a debilitating state.

Well, using brain-wide intact brain methods, we've been able to come to a causal understanding of what dissociation actually is.

And a year ago we published a paper using optogenetics and other methods where we were able to show, both in mouse and in human, how this separation of the self happens.

There's activity patterns that become forced out of synchrony in one part of the brain and another part of the brain.

And so two parts of the brain can never be active at the same time.

They can't form a unified representation.

And so they're both active, neither part is unconscious or asleep, but they can't come together and form a unified representation of the self.

And so this is an example.

It seems hard to believe that we could get to this state, but here we are, we actually are able to do rigorous and causal experiments in mouse and human on these very high level concepts.

But anchored in this rigorous cellular level of understanding.

- In many ways, people say, we look at the high percentage of people that experience depression, anxiety, other illnesses, schizophrenia, bipolar disorder and all of these disorders.

And why do so many people have this?

On the other side of the coin, given how complicated the brain is, the question may be, why doesn't everybody have something?

Because there's so much there that could go awry.

I'm wondering, given your perspective, how you would respond to that question.

- Well, I think, the short answer is sure.

Everybody has something.

And I came to psychiatry, I'd been fortunate.

I hadn't myself suffered a severe mental illness, but I wanted to help the people who were experiencing it.

And I was very interested in it, but actually, I discovered a lot about myself while writing the book, writing "Projections".

And it was only when the book was complete, it was almost as if I'd completed a decade long period of psychoanalysis because taking a step back at the completed book, I saw some themes that I didn't quite realize about myself until I'd written the book.

And I talk about this a little bit in the epilogue of the book.

And yeah, everybody's got some unusual things going on in their brains.

And it takes sometimes a little thought, a little introspection, or a lot, to sort that out.

But that's the beauty of humanity, right?

This is the incredible diversity that we have.

Sometimes it works well in the moment, sometimes it doesn't.

But in a way, this is also a major theme of the book, is we should cherish those differences.

Even those that don't necessarily work so well in the moment.

Fully acknowledging the discomfort, the suffering, the disability that happens.

The diversity of the human family is, including in our internal states and the inner reaches of our minds, is one of the most interesting and uplifting aspects of who we are as a family.

- Karl, optogenetics is used in scientific research.

What potential is there in terms of actual clinical care for people with this technique?

- Optogenetics is primarily a discovery tool.

This is how we will achieve understanding of the brain.

And once we get to that level of understanding, any kind of treatment will become more powerful.

Whether it's a medication that for the first time is specific for the cells that are truly causal in a symptom, grounded in the knowledge that optogenetics brings.

Or a brain stimulation treatment.

Again, guided now for the first time by causal understanding.

Which cells, which connections actually matter.

This is the future where we have a deep understanding that optogenetics has brought us and that's informed every kind of therapy.

Now that said, just this year, my friend and colleague and collaborator Botond Roska, in Switzerland, he completed an optogenetic study in people.

He took blind people, and he was able to make a blind person able to see again, to reach for objects on a table accurately that were not visible before to this person with retinal degeneration.

He put one of the microbial opsins into the retina using genetic tricks of this human being and was able to bring site to the blind.

And so that's the kind of thing that it can work in people.

For psychiatry, I see optogenetics as a powerful tool for understanding and all treatments will become more solidly grounded in what actually matters.

- I agree with what you're saying and having the opportunity to help people who are experiencing difficulty is just so extraordinary.

As you know, as I know, it makes such a big difference in people's lives.

Karl, I wanna thank you for all that you do.

The extraordinary research, the clinical work, and all that you're going to do moving forward to move the field forward, to help so many people.

And I want thank you for joining us today to share these extraordinary perspectives.

- Thank you.

Thank you for taking the time.

And I wanna, again, thank all my patients and all my colleagues and students and everybody who's contributed to supporting the work.

Including all the wonderful work that you do along those lines.

And I'm very grateful.

- Thank you.

- Thank you.

(uplifting music) - [Jeffery] Do not suffer in silence.

With help, there is hope This program is brought to you in part by the American Psychiatric Association Foundation, The Bank of America Charitable Gift Fund, and the John & Polly Sparks Foundation.

Remember, with help, there is hope.

(uplifting music)