- [Jeff] 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.

(gentle music) - [Announcer] Today on "Healthy Minds".

- And I remember recently being at a scientific meeting where they're describing the methods and they say using standard optogenetic techniques, which again is an amazing sentence if you go back just a few years.

- We now using optogenetics, we know the precise patterns of activity that can cause, or turn off these sensations, cognitions and actions, and we can see how they can go awry in disease models.

And so everything from anxiety to depression, obsessive compulsive disorder, the circuits involved in schizophrenia, and circuits involved in autism.

All of these have now been studied with this millisecond precision of light and the cellular resolution that optogenetics provides.

- [Announcer] That's today on "Healthy Minds".

- [Jeff] 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.

(gentle music) It sounds like science fiction, but it's actually science.

Today, I speak with Dr. Karl Deisseroth, about a number of new technologies that are creating tremendous advances in our understanding of the brain, and potentially treatment of psychiatric conditions.

(gentle music) Karl, thank you for joining us today.

3,000 miles apart, but it's the next best thing to being there.

- Great to see you.

Yeah, we're getting used to that.

I wish I could be there, but hopefully soon.

- Absolutely.

So I wanna jump in and talk about your book "Projections: A Story of Human Emotions."

And I wanna ask you, what was it like for you to write a book where you really brought together your clinical experience, your research endeavors and also personal perspectives?

What was it like for you to write the book?

- Well, I had always wanted to be a writer that was my first and greatest passion.

So it was almost therapeutic if you will, coming full circle on the course of a big part of my life.

I'd always loved words.

I'd loved playing words, and thinking about how they made me feel and made others feel.

But then I got interested in science and medicine, and that the years of all those wonderful discoveries, the scientific work sort of caught me up.

But then coming back to it, coming back to the writing was an incredible experience because I remembered how much I loved it and it became almost addictive each day.

I would look forward to it.

I'd think about the right words to use in the book.

And then the whole time thinking about how I could communicate with the public to share the excitement of what was going on in science, but also share these very hard experiences, the internal worlds of patients with psychiatric illness, making that something that was communicable to the public in a helpful way.

So it was quite a journey.

And in the end it was really thrilling.

- One of the areas of the science that you speak about is optogenetics.

So in many ways, optogenetics sounds like science fiction, but it now is real science.

Tell us about optogenetics.

- Optogenetics is one of the sparks that made this moment in time happen, which was this conjunction of our understanding of our inner worlds with the external progress in neuroscience.

And what epigenetics is, it's a way of using light to probe the inner workings of the brain, but with a twist, it's not the way you normally think about using light.

We think about light as a way of bringing in information, bringing in concepts, ideas, thoughts, images into our brains.

Optogenetics does the opposite.

It uses light as a tool to control things, to make things happen.

And this is different.

It's extremely powerful.

And I'll explain why.

Inside the brain, we have a real, a beautiful complexity of interconnected cells, almost a 100 billion neurons in the human brain.

Each of them making 10,000 or more synapses with other cells, connections with other neurons, and they're all intertwined.

And the cells that do things that are completely different are right next to each other.

And they're all electrical in nature.

So if you put in an electrode, and you stimulate one spot of the brain, you're gonna stimulate all the cells that may have totally different jobs, doing completely different things, even opposing each other.

And that makes it very hard to understand in the brain, as you know, what's actually making the things happen.

What are sensations, cognitions, and actions?

How are they elicited?

How can they go wrong?

Very hard to understand what actually matters, what makes things happen.

With optogenetics we use a trick.

We make some cells respond to light.

Now, normally none of the cells respond to light deep in the brain.

There's no light in there anyway, but that's a great situation if one wanted to confer light sensitivity onto some cells, but not others, because then you have a way of achieving specificity of control.

If you could turn some cells on with light or turn some cells off with light, that would be incredibly powerful.

Of course, how do you do that?

Is the question.

And it turned out the way to do it, that was practical was, seems almost, as you say, science fiction like, is to go to microbes, single-celled algae, archaebacteria, ancient forms of life, and take genes, little bits of DNA that encode biomolecules very special biomolecules called microbial opsins.

These turn transduces, as we say, light into electricity.

These little proteins receive a photon of light and allow ions charged particles to pass across the membrane of a cell, that's electricity, bioelectricity if you will.

And that singular job, this turning of a photon into the passage of ions allows us to use light to turn neurons on or off.

And that's the essence of optogenetics.

Seems unlikely to work, but turns out it does.

And first experiment now, 2004 was the first experiment in July.

And now it's been more than 17 years, and thousands of laboratories around the world are using it for discoveries.

- What led you to come up with that idea?

How did you realize to put these things together?

- Well, a lot of people were trying.

This was the kind of thing that, science is an exciting and unpredictable journey.

And the irony is that the microbial opsins were very well known.

They were understood for a long time to exist.

They'd been discovered in 1971 by a couple scientists at the University of California, San Francisco, Dieter Oesterhelt and Walther Stoeckenius.

And at the same time, you had a thread of neuroscientists, including Francis Crick of DNA structure fame had been saying, "In neuroscience, we need ways to turn cells on or off selectively."

And Crick in 1999, he even suggested that light would be a good way to do it, but he had absolutely idea how to do this.

He wrote in a paper in the proceedings of the Royal Society in 1999 that light would be a great way to do it, but this seems farfetched.

He said, "The irony is," This was 1999 that he wrote that.

We would do that first experiment five years later in 2004.

But the microbial opsins had been known since 1971.

It was just seemed so unlikely to work that you would be able to take these genes from these microbes all the way across the tree of life, put them into sensitive, delicate, intricate cells in the mammalian brain and have them work robustly, efficiently, well, have them be adversely and generalizable strategy.

So the first experiment showed it was, that it might work.

It was just in a dish.

And then it took us about five years of hard work engineering, figuring out how to put all the pieces together, along the way we worked hard to understand these proteins a lot more deeply, and that helped us engineer them, turn them into new forms that made them more potent, more effective.

We used crystallography the same sort of tool that Crick used to unlock the double helix structure of DNA to unlock the structure of these proteins, these channelrhodopsins, a very potent form of these.

And we were able to see how they work, how they allow charged particles to flow across the membrane, and that let us change them into new and powerful configurations.

And so it was a lot of beautiful, basic science understanding the proteins themselves.

And at the end of the day, we achieved what Crick had asked for which is we could turn on or off individual kinds of cells or even single cells within freely behaving complex mammals.

- And you could turn them on or off instantaneously by turning on or off the light and see the reaction- - Exactly.

- For the laboratory animal?

And you've mentioned that it's used by thousands of labs.

And I remember recently being at a scientific meeting where they're describing the methods and they say using standard optogenetic techniques, which again is an amazing sentence, if you go back just a few years.

- That's right.

- Tell us about some of the types of discoveries that are being made using optogenetics.

- Yeah, this is one of the most gratifying things has been helping other people use the techniques and we've had, we've sent the DNA, the clones as we call them to all over thousands of laboratories around the world.

And many thousands of papers have been published, but we've also done work in our own lab using these methods.

Everything you can imagine has now been studied.

Primary survival drives the motivations that are so powerful in animals, and that can go wrong in psychiatric disease, aggression, parenting, hunger, thirst, social interaction, motivation to overcome a challenge, all these basic functions of survival for the animal brain.

We now using optogenetics, we know the precise patterns of activity that can cause, or turn off these sensations, cognitions, and actions, and we can see how they can go awry in disease models.

And so everything from anxiety to depression, obsessive compulsive disorder, the circuits involved in schizophrenia and circuits involved in autism.

All of these have now been studied with this millisecond precision of light and the cellular resolution that optogenetics provides.

It's a little quite remarkable, but also a little disturbing to have a free moving mammal, our cousins across the tree of life, like a mouse or a rat.

And to see as you play in a precise pattern of activity to precisely to find cells, to see a complex behavior instantly put in place, or specifically suppressed, a hungry animal no longer caring about food or a not hungry animal becoming ravenous, same thing with thirsts, same thing with aggression, violent behavior, or very simple things, simple actions like turning left or turning right.

Finally, with neuroscience with studying the brain, we have this material causal understanding of which connections which cells can cause or suppress these complex action patterns.

But it's a little eerie too.

And it raises very interesting, philosophical and even, a consideration of ethical issues.

- It is extraordinary to think about the fact that in our complicated brains, in our complicated behaviors turning on or off a few cells through their connections could have such an effect on behaviors and thoughts.

- That's right.

And this is as you well know, there have been very vigorous debates over the nature of the causes for actions, they're vigorous and contentious arguments over genes versus culture, for example, in the causes of violence, very powerful debates on the nature of free will and personal responsibility.

And in many ways, a lot of, although optgenetics doesn't answer the fundamental philosophical questions.

Those of course, are things that we as a human family still have to struggle with.

What is very clear is that adding or removing a few blips of electoral activity in a few very well defined cells can, and does instantaneously change the actions chosen by an animal, reshapes their priorities, reshapes the choices that are made in the moment, and that can no longer be denied.

We know this with incredible precision.

And so it's an important state for us to be in.

We know exactly how many cells can be involved and how many blips of activity in those cells.

- In many ways, it sort of shows that the nature nurture question really both are important.

The actual physical cells genetically there, and also environment that has an impact on those cells.

- Certainly true.

And the fact that there is a structural and a cellular basis to them, doesn't point the arrow of causality or blame, however you like to look at it on either nature or nurture.

The cells and the connections are created by genes and developments, but also are reshaped by experience and plasticity.

So both are important, but now material at the elemental level of cells and their connections, we can understand causality.

- We often think of science as informing clinical care, but you make the point that in many ways, your work as a clinician has helped inform your thoughts about the science.

And I'd like you to speak a little bit about that.

- So I'm a psychiatrist, as you know, you and I share a lot of the same motivations.

We are deep down trying to understand mental illness and try to work on ways to alleviate this vast source of human suffering.

And I am a general adult psychiatrist.

I still treat patients both in the clinic and with inpatient work I have.

Despite everything going on it's I keep returning to it.

It matters so much to me.

It's something that admittedly, when I've spent a little time away, a few months away, and I come back to the inpatient work, it can be a little nerve wracking, 'cause I haven't been there for a few months, but then it's immediately, it recharges me with motivation, with energy.

I remember what brought me here.

And I remember the need, the human need that's there.

It's so enthralling and disturbing and it's both sad and frustrating, but also very interesting.

Psychiatric disease has so many of these qualities, all mixed in together.

And this is something that's guided me over decades is how can we come to a deeper understanding of these states?

And understanding comes first.

Optogenetics is a wonderful tool for understanding, and that's this nice synergy I can work in the laboratory, and then I can talk to a human being the next day who's suffering from crippling anxiety.

And I can talk about the concrete, physical material elements that we now know cause each of the fundamental elements of anxiety, because we've shown this in the laboratory at connection from point A to point B causing the respiratory rate changes of anxiety.

Another connection causing the negative internal subjective state.

Another connection causing the behavioral avoidance of anxiety, avoiding risky environments.

And this is incredibly helpful for the patients.

They have this interstate that's been crushing, been debilitating that nobody understands.

It's hard to explain and I can tell them materially.

I now know at this fundamental level, and I can share, and we're talking about it as scientists.

We now know that this is very physical, very real, precisely definable rigorously studyable.

And this is incredibly helpful for the patients and for their families.

And this is what I hope.

Understanding is so much of it in psychiatry, just as in years past, it was for cancer and for other realms of the human condition that were poorly understood, stigmatized.

Now, it's very clear that with psychiatry, the convergence of the science and the medicine together is, brings a lot of hope for the future, and the patients feel it.

And that matters a great deal to me.

- Yeah, I think with the example of anxiety that you give explaining that, first of all, no one decides they wanna be anxious.

This is, just as nobody decides they wanna have cancer.

It is something that physically is occurring and understanding that gives people in some ways more control over their anxiety or other symptoms that they may have.

- That's right.

Yeah, and this is, the patients tell me this, and it's not that we're, our job is by no means done, but we've cracked open the door.

And this is a theme in the book that I return to with each story that the "Projections" as a collection of stories about human experiences in these altered states.

And the central focus on the human beings, but I try to show the promise and the power of the science and how it brings hope for the future.

- 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, this was a, for someone who has worked hard to develop both the scientific side and the medical side of his life, this patient, 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.

This is a common feature in autism.

It's very striking to see.

There's not just a incidental looking somewhere else, but also a quite a marked avoidance when eye contact is made a immediate flickering away of the eyes as well as if it's aversive in some way.

And so, 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?

What, 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.

He was my patient.

And he said after some back and forth, what we were able to establish was that it was a sense of being overwhelmed, not fear, but 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 this, 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 the 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, 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 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, caring 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 and 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 I think for the world, for the community, for the public to share it.

(gentle music) - Join us again next time when we continue this wonderful conversation with Dr. Deisseroth.

Remember with help, there is hope.

(gentle music) Do not suffer for in silence with help there is hope.

(gentle music) - [Announcer] 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.

(gentle music)