How the Brain Works, Curing Blindness & How to Navigate a Career Path | Dr. E.J. Chichilnisky

Welcome to the Huberman Lab podcast where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. E.J. chichelniski. Dr. E.J. chichelniski is a professor of neurosurgery, ophthalmology and neuroscience at Stanford University. He is one of the world's leading researchers trust trying to understand how we see the world around us, that is how visual perception occurs and then applying that information directly to the design of neural prostheses, literally robotic eyes that can allow blind people to see once again. Today's discussion is a very important one for anyone who wants to understand how their brain works. Indeed, EJ spells out in very clear terms exactly how the world around us is encoded by the neurons, the nerve cells within our brain enclosed order to create these elaborate visual images that we essentially see within our minds. And with that understanding, he explains how that can be applied to engineer specific robotic AI and machine learning devices that can allow human brains not only to see once again in the blind, but also to perceive things that typical human brains can't. And indeed for memory to be enhanced and for cognition to be enhanced. This is the direction that neuroscience is going and. And in the course of today's discussion, we have the opportunity to learn from the world expert in these topics where the science is now and where it is headed. During today's discussion, we also get heavily into the topic of how to select one's professional and personal path. And indeed you'll learn from Dr. Chichelniski that he has a somewhat unusual path both into science and through science. So for those of you that believe that everyone that's highly accomplished in their career always knew exactly what they wanted.

To do at every stage, you, you will soon learn that that is absolutely not the case with ej.

He describes wandering through three different graduate programs, taking several years off from school in order to dance.

Yes, you heard that correctly.

To dance. And how that wandering and indeed dancing helped him decide exactly what he wanted to do with his professional life and exactly what specific problems to try and tackle in the realm of neuroscience and medicine. It's a discussion that I'm certain that everybody, scientist or no, young or old, can benefit from and can apply the specific tool that EJ describes in their own life and pursuits. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating and sleep tracking capacity. Now, I've spoken many times before on this and other podcasts about the fact that sleep is the foundation of mental health, physical health and performance. Now, one of the key aspects to getting a great night's sleep is to control the temperature of your sleeping environment. And that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about 1 to 3 degrees. And in order to wake up in the morning feeling refreshed, your body temperature actually has to increase by about 1 to 3 degrees. 8 Sleep makes it extremely easy to control the temperature of your sleeping environment at the beginning, middle and throughout the night and when you wake up in the morning. I I've been sleeping on an eight Sleep mattress cover for nearly three years now and it has dramatically improved my sleep. If you'd like to try Eight Sleep, you can go to eightsleep.comhuberman to save $150 off their Pod 3 cover. Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU and Australia. Again, that's eightsleep.comhuberman Today's episode is also brought to us by Roka. Roka makes eyeglasses and sunglasses that are of the absolute highest quality. I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly under different conditions. Roka understands this and designed all of their eyeglasses and sunglasses with the biology of the visual system in mind. Now, Roka eyeglasses and sunglasses were initially developed for use in sport and as a consequence you can wear them without them slipping off your face while running or cycling, and they're extremely lightweight. Roka eyeglasses and sunglasses are also designed with a new technology called Floatfit, which I really like because it makes their eyeglasses and sunglasses fit perfectly and they don't move around even when I'm active. So if I'm running and I'm wearing my glasses, they stay on my face most of the time. I don't even remember they're on my face because they're so lightweight. You can also use them while cycling or for other activities. So if you'd like to try Roka glasses? Go to ROKA. That's R-O-K-A.com and enter the code HUBERMAN to save 20% off your first order. Again, that's R-O- K-A.com and enter the code Huberman.

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Today's episode is also brought to us by BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out online. I've been going to therapy for well over 30 years. Initially, I didn't have a choice. It was a condition of being allowed.

To stay in school.

But pretty soon I realized that therapy is extremely valuable. In fact, I consider doing regular therapy just as important as getting regular exercise, including cardiovascular exercise and resistance training, which of course, I also do every week. The reason I know therapy is so valuable is that it's if you can find a therapist with whom you can develop a really good rapport, you not only get terrific support for some of the challenges in your life, but you also can derive tremendous insights from that therapy. Insights that can allow you to better not just your emotional life and your relationship life, but of course, also the relationship to yourself and to your professional life, to all sorts of career goals. In fact, I see therapy as one of the key components for meshing together all aspects of one's life and being able to really direct one's focus and attention to toward what really matters. If you'd like to try BetterHelp, go to betterhelp.comhuberman to get 10% off your first month. Again, that's betterhelp.comhuberman and now for my discussion with Dr. E.J. chicholniski.

Dr. E.J. chICHOLNISKI, welcome.

Good to see you.

For the audience, we are friends. We go way back. EJ has been a few years or more ahead of me in the science game. And the best way to describe you and your work, EJ is you're an astronaut. You go places no one else has been willing to go before. You develop new technologies in order to do that. All with the bold mission of trying to understand how the nervous system, which of course includes the brain works and how to make it better with engineering. So today we are going to get into all of that. But. But just to start off and get everybody on the same page, maybe we could just take a moment and talk about the brain and nervous system and what it consists of that allows it to do all the sorts of things that we're going to get into, like see things in our environment and respond to those Things in our environment. So at risk of throwing too much at you right out the gate, what's your one to five minute version of how the brain works?

Oh, I don't have a one to five minute version of how the brain works, but I can tell you how I think vision is initiated in the brain. And you and I go back a long way, so we have a lot of common understanding about this. But I'll narrate it from scratch if that makes sense. Vision is initiated in the retina of the eye, which is a sheet of neural tissue at the rear of the eye that captures the light that is incident on the eye, that comes in through the eye, transforms that light into electrical signals, processes those electrical signals in interesting ways and changes them up, and then sends that visual information to the brain where it is used to bring about our sense of vision. And you asked me about the one to five minute version, how the brain works. I don't know. But I do know that the brain receives all these patterns of electrical activity coming out of these nerve cells in the retina and somehow assembles that into our visual experience, Whether that be responding to things coming at us, or our circadian rhythms that govern our sleep and behavior, or identifying objects for prey, or avoiding predators, or appreciating beauty. And what we know is that the brain receives a fantastically complex set of signals from the retina and puts that all together into our visual experience. And we are very visual creatures, obviously. So I think that's a big part of how the brain works, because so much of what we do revolves around vision, revolves around how the brain puts together these signals coming out of the retina. And I would love to understand how that works. At the moment, I don't. And what we're trying to do is get a really complete understanding of how that begins in the retina and then how we can restore it in those who have lost sight.

Why focus on this issue in the retina, this thin set of layers of neurons that line the back of the eye? Why explore vision there? I mean, obviously there are centers within the brain that of course contain neurons, nerve cells that are involved in vision, if one wants to understand visual perception. And I agree, by the way, that visual perception is one of the most dominant forces in the quality and experience of our life. Why focus on the retina? Why not focus on the visual cortex or the visual thalamus? What's so special about the retina?

Well, we have to focus on all of it, because understanding the retina won't give us A full understanding of how all this works. Obvious. And if you don't have your visual cortex and visual thalamus, you won't see. But if you don't have your retina, you also won't see. You won't even have a chance to see. So I focus on the retina because I enjoy the possibility that we can really understand a piece of the nervous system. In my lifetime, in our lifetimes, we can understand it so well that we can build it, replace it, restore its function. That's farther off in the central regions of the brain. It's going to be quite a bit harder. I find satisfaction in really understanding something so well that I can write down in a mathematical formula what it's doing, that I can test my hypotheses up and down. And yes, we really get how this little machine works, and that I can engineer devices to replace the function of that circuit when it's lost. That, to me, is just deeply satisfying. But there also is a really fundamental role for people who want to go and do more exploratory work in the visual brain, as you mentioned, in the visual cortex and the thalamus and other places. Because ultimately those retinal signals won't lead to anything if those areas aren't putting it all together to govern our perception and ultimately our behavior.

So let's talk about the retina in its full beauty and detail. Three layers of cells that line the back of the eye like a pie crust somehow take light that comes into the eye. The lens focuses that light. If it doesn't do that well, we put lenses in front of our eyes, such as contact lenses or spectacles, and somehow takes that light and transforms it, as you said, into neural signals and processes that within the retina. So let's take a deep dive into the retina and do so with the understanding, at least. My understanding is that in part, thanks to your work and the work of others, this is perhaps the best understood piece of the brain.

Yes, I think it's a solid argument that it's the best understood piece of the brain. And we'll turn back to that in a minute. So the retina begins with a sheet of cells called the photoreceptor cells that are highly specialized. These are cells that essentially don't exist anywhere else in the brain. And what they do is transform light energy into electrical signals in neurons. Very specialized, very demanding cells. They require a lot of maintenance, and they die relatively easily, which is what gives rise to some of the forms of blindness. Those are the. You might Call them pixel detectors. They're tiny cells called photoreceptors that each one captures light from a particular location in the world. That sheet of cells has done that initial transduction process where light is converted into neural signals that the brain can then begin to work with. The second layer is responsible for processing, adjusting, changing, mixing and matching, comparing signals in different neurons. Many complex operations that we're still trying to understand. And consists of dozens of distinct cell types that extract features, if you will, of the visual world from the elementary pixels represented in the photoreceptor cells. So that second layer is receiving the input from that sheet of photoreceptors and picking stuff out of it. The third layer of cells is the so called retinal ganglion cells. That's the only term that I'd like to probably will come up repeatedly in this conversation. So for your viewers and listeners, these retinal ganglion cells are the ones who are responsible for taking the signals that are there in the retina and sending them to the brain so that the process of vision can begin. They are the messengers, if you will, from the retina to the brain. The retinal ganglion cells, and There are about 20 different types in humans, are again feature extractors. They pick out different bits and pieces of the visual scene and send interesting stuff to the brain, trying to leave out the uninteresting stuff. And the 20 or so cell types all pick out different types of information from the visual scene. You can sort of think of them as Photoshop filters. Each cell type in the retina, again, about 20 different ganglion cell types. Each type represents the full scene, the entire visual world, but picks out different features, such as some cells pick out spatial detail, tiny little points of light almost. Some cells pick out and signal information about things that are moving in the visual world. Some cells pick out information that's been captured about different wavelengths from the photoreceptor cells and thereby giving us our sensations of color and probably more things in those 20 different ganglion cell types that we don't fully understand. The result then is that the retina has this sort of a representation of the visual world, but it has 20 different representations, not one. It's not one picture that comes out of the retina and gets sent to the brain. No, no, no. It's 20 different pictures. And you can think of maybe as 20 different Photoshopped pictures, but one of them has the edges highlighted, one of them has the colors highlighted, one of them has movement encoded in it. And these somehow these filters Send the information to many different targets in the brain, and then our brain puts it all together, and then we have a cohesive sense of the visual world, which is the remarkable feature that we really don't understand.

Amazing. Is it fair for those that don't work with Photoshop to think about these different Photoshop filters, perhaps as different movies of the visual world? One movie contains the outlines of objects and people and things. Another movie is showing the motion of blobs in the environment, meaning whatever's moving in the environment is kind of just represented as blobs. Another movie is just the color in the environment, another movie. And then all of those what I'm calling movies are sent into the brain, and then the brain somehow combines those in ways that allow us to see each other and see cars and objects and recognize faces. Is that one way to think about it?

That's exactly how I think about it. Maybe it's a better way to say it.

No, I like the Photoshop filter analogy. For those that don't work with Photoshop, I just think that the movie analogy might. Might be a decent alternative.

How the retina works is an example. We think of how all sensory systems work. There's an initial representation in a specialized cell type that is responsible for and capable of extracting physical features from the world. And then neural circuits in the brain use that information in different ways to grab stuff out of the visual world. In the auditory system, there's the sound world is represented also in specialized cells that capture sound energy and transduce that into neural signals. And then subsequent stages of processing in the auditory system pick out different features.

Of our auditory world, like the frequency, how high or how low a tone is, the direction it's coming from.

Right. The movement of it, how loud it is. Different features are extracted. So we think the visual system is just an example of how the external world is represented in our brain. And of course, in some sense, a philosophical approach to the brain is really saying, well, there's the sensory world and then there's the actions we take. And there's almost nothing else that we really know other than those two things. How the sensory world comes in and then finally it results in our action. That's what our brain is about, because vision is so important for people. I find it absolutely compelling and fascinating. I mean, as an example, as you know. Well, many people study rodents to understand how different aspects of the brain work. And, you know, rodents are interesting animals and do all sorts of really cool things, but they interact with the world differently than we do they? In a lot of ways, they sense by smelling, they identify objects by smelling, and they navigate with their whiskers. To a large extent, we don't do any of that. You don't navigate with your whiskers. At least I don't think you do. You don't recognize me when I walk in the room by my smell. No. You use vision for all that. And we humans use vision. So it's a really fundamental aspect of who we are as biological creatures.

I wonder if, just for sake of entertainment, we could think about how the human retina, and therefore vision in our species, differs a little bit from some extreme examples of vision in other species. Not to make this a comparative or zoological exploration, but just to really illustrate the fact that the specific cell types within our retinas create a visual representation of the outside world that can be, and often is very different from that of other species. For instance, or at least my understanding is that the mantis shrimp sees, I don't know, 60 to 100 different variations of each color that we are essentially blind to because their photoreceptors can detect very subtle differences in red, for instance, long wavelengths of light. What most people refer to as red pit vipers can sense heat emissions essentially with their eyes, but also other organs, and on and on. I raise this because I think the human neural retina is such an incredible example of extracting features from the visual world that then we recreate. But I think it's also worth reminding everyone and ourselves that it's not a complete representation of what's out there. Like, there's a lot in light that we don't see because our neural retina just can't turn it into electrical signals. Right.

Do you want to give some examples.

Of what we can't see? And if any particular examples from the animal kingdom delight you, feel free to throw those out.

Well, one thing you mentioned, color. We experience a rich sensation of color when we look at the world and say, wow, I see all these colors. That's immediate and that's just how we talk about it. But in fact, we have very little information about color. Color is a very high dimensional, complex thing, or wavelength, I should say. Wavelength information really is about how much energy there is in the light around us at different wavelengths. We only have three sort of snapshots of that in our retinas with the three different types of photoreceptor cells that are sensitive to different wavelength, different bands of the wavelength spectrum. Three is not a lot, as you just said. Other creatures have many More ways of capturing wavelength information. And one way you can verify for yourself that we just have three is to realize that if you look at your tv, there are only three primaries on your tv. There's a red, there's a green, there's a blue. That's it. And from those three primaries, the entire richness of the experience on your TV set is composed. So with just those three things, you basically are able to create any human visual sensation. Well, the mantis shrimp would be like, that's nothing. There's so much more stuff out there that's not represented on this tv. If you could speak to the mantis shrimp. Another thing we. We maybe don't see, another example of a difference in the animal kingdom is so again, taking rodents as an example. One of the. One of the things that rodents have to do is to not be hunted by birds that are coming down toward them. And so it appears that there are cells in the retina that are. Seem to be quite sensitive to looming, to something dark that's getting bigger, like a shadow coming from a bird coming down at you. We don't know for sure that this is exactly what causes animals to avoid being eaten by birds, but there's interesting evidence in that direction that's not really a big thing for us, for humans, as far as I know, we're not typically hunted by huge birds. So that's not a thing we need. And I think that's where it comes back to where you were headed, if I understand right, which is we occupy different biological niches, we and the mantis shrimp and the rodents. And our visual systems reflect that we have different stuff that we're looking for in our visual environment than other creatures are. And so our eyes are different. And that's one of the reasons that we emphasize work on the human retina, as opposed to certain other animal species that would be less clearly relevant to the visual experience you and I have.

So let's talk about these incredible experiments that your laboratory has been doing for several decades now. I've had the privilege of sitting in on some of these experiments, and they are very involved, um, to say the least. If you could just walk us through one of these experiments, I think the audience would appreciate understanding what goes into, quote, unquote, trying to understand what's going on in the electrical activity of these specific retinal cell types, the retinal ganglion cells in particular. You know, what does this look like? You know, you're in your laboratory at Stanford and you get a phone call. Someone says, I Got a retina. What happens next?

We scramble like crazy. We drop everything we're doing, cancel all our appointments, and get ourselves ready for 48 hours of nonstop work down in the lab getting as much data as we possibly can from the retina. The most exciting example of what you just said is when we get a human retina. When, for example, there's a donor who has died and the retina is available for research, we jump at that opportunity.

How soon after the person is deceased do you need to get the eye globe, the eyeball, in order to get the retina in a condition that would allow you to record electrical signals from it?

A few minutes, so you're waiting in the hospital. The way we typically get these eyes is from brain dead individuals. So people who are legally and medically dead, but their hearts are still pumping and therefore their retinas are still alive and functioning when those individuals are used. The bodies of those individuals are used for organ donations. We can benefit from that organ donation setup that organ distribution centers do to save many people's lives and also to promote research. So we sometimes get those retinas and that begins the experiment for us.

I'm going to ask for a few more details here, just to put the picture in people's minds and not to be gruesome. I just really want people to understand what's involved here.

So you'll get a call.

We've got a patient who is soon to be deceased. They've consented to giving their eye globes, their eyeballs, for research so that you can study the human retina. Is it you who goes over and takes the eyes out? Does somebody do that or hand them to you in a bucket of ice? I'm sorry if I'm making people queasy at all, but this is, folks, how one goes about trying to understand how the human brain works.

Absolutely. And this is also how you go about donating your heart so that you can save somebody else's life who needs a heart transplant. The same incredible organizations that do the harvesting of the tissue for us. Their primary goal is to do that for organ donations to save lives. They save lives every day. These people are incredible. Donor Network west is one of those organizations, the one that we work with. They're really amazing. So their technicians or a retinal surgeon will take the eye out, give it to myself or somebody from my lab who will bring it back to the lab, and we have a way to keep the eye alive and functioning. Just the eye by itself.

Is this always at Stanford or do you sometimes travel elsewhere, local hospitals, up.

To an hour away.

So then you drive them back.

We drive them back. It's the Retina express. And when, when we're bringing back the Retina Express, it's again, it's all hands on deck. In our lab, we are scrambling, setting up all of our equipment, getting everything ready. You've been at experiments, they're intense and they really are, really are 48 hour marathons of incredible activity by really dedicated individuals. So we, we might get those eyes sometimes again at 2 in the morning. That's common. And from that 2 in the morning time, it begins the experiment. So we bring the eyes back, we open them up and we, we have access to the rear of the eye, which is what the, where the retina is. It's a thin sheet of neural tissue at the back part of the eye. We hemisect the eye, cut it in half so that we can see the back. It's like half of a globe, if you will. And then we put in relaxing cuts and lay it out flat so we can see what we're working with. Then we take little segments of retina out in the subsequent 48 hours, cut them out, maybe a 3 by 3 millimeter piece of the retina, a little chunk of retinal tissue, and bring it into an electrophysiology recording and stimulation apparatus that allows us to interact with, with it. And we do two types of experiments with that. So this electrophysiological recording and stimulation apparatus is very custom built by our physics collaborators who have developed high end equipment. It allows us to record and stimulate through 512 channels simultaneously at very high density. This is pretty high end stuff in terms of technology for interrogating and manipulating the electrical signals in the retina. That's what we specialize in in my lab.

Could I just ask a question about this device? I've seen it before, it's very small, as you mentioned, you're recording from a few millimeters square of the retina from this recently deceased patient. It looks a little bit like a bed of nails, tiny little microwires all arranged very closely to one another. You got the retina laying down on top of it. And that bed of nails can extract, meaning, record the electrical signals that are coming out of the retinal ganglion cells.

That's right.

And the retina is still alive. So you are in a position to shine light on it and essentially make it behave in the same way it would if it were still lining the back of a healthy alive person.

That is the Beauty of these experiments. So, because we can keep the retina alive and happy, and because the retinal ganglion cells, the cells that are the ones that message the visual information to the brain, are on the surface, we can put them right next to the electrodes, and we can record their electrical activity. In other words, we record the signal that those cells would have sent to the brain if they were still in the living person. And at the same time, as you said, we can focus an image that we create on a computer display onto the retina. So we're treating the retina, if you will, as a little electronic circuit, which it almost is, honestly delivering light to the photoreceptor cells so that they are electrically excited and then recording the electrical activity that the retina is sending out, if you will, that allows us to study how the retina works normally. What we also do with that same electrical apparatus is turn around and pass current through those electrodes in order to see if we can activate those ganglion cells directly with no light, just electrodes. Why do we do that? We do that because it allows us to design future methods of restoring vision by electrical stimulation of the retina, which we'll probably talk about in a few minutes.

I'd like to take a brief moment and thank one of our sponsors, and that's AG1. AG1 is a vitamin, mineral, probiotic drink that also contains adaptogenic. I started taking AG1 way back in 2012. The reason I started taking it and the reason I still take it every day is that it ensures that I meet all of my quotas for vitamins and minerals, and it ensures that I get enough prebiotic and probiotic to support gut health. Now, gut health is something that over the last 10 years, we realized is not just important for the health of our gut, but also for our immune system and for the production of neurotransmitters and neuromodulators, things like dopamine and serotonin. In other words, gut health is critical for proper brain functioning. Now, of course, I strive to consume healthy whole foods for the majority of my nutritional intake every single day. But there are a number of things in AG1, including specific micronutrients that are hard to get from whole foods, or at least in sufficient quantities. So AG1 allows me to get the vitamins and minerals that I need, probiotics, prebiotics, the adaptogens, and critical micronutrients. So anytime somebody asks me if they were to take just one supplement, what that supplement should be, I tell them, AG1 because AG1 supports so many different systems within the body that are involved in mental health, physical health, and performance. To try AG1, go to drink ag1.comhuberman and you'll get a year supply of vitamin D3K2, and five free travel packs of AG1. Again, that's drinkag1.comhuberman let's take this moment to talk a little bit about cell types.

So you mentioned there are about 20 different types of these retinal ganglion cells, what we may refer to, in brief, as RGCs. So retinal ganglion cells, RGCs, same thing. And as you mentioned, these cover the entire retina. So that if each cell type is extracting a different set of features from the visual world, motion, color, specific colors, et cetera, that essentially no location in the world around us fails to be represented by these cells. Put differently, these cells are looking everywhere.

Each cell type is looking everywhere.

Each cell type is looking everywhere. So that if movement occurs in any region of our visual world, we are in a position to detect it. But maybe we could talk a little.

Bit about cell types.

Cell types is such an important theme in the field of neuroscience and indeed in all of biology, but it's actually not something we have talked about very much on this podcast before, either in solo episodes or in guest episodes. I don't have any specific reason for that. We've talked about brain areas, prefrontal cortex, basal ganglia, anterior meticulous cortex, and on and on. We've talked about neural circuits, but we've never really talked about cell types. So the ganglion cells.

Brother, you let me down. No talking about cell types.

Well, but that's why you're here.

That's why I'm here.

That's why you're here.

Tell us about cell types.

How do you figure out if you.

Have a cell type?

How do you know if it's a cell type? Or is it the shape? Is it how it responds? How do you know if you have a cell type?

What's this about?

Now, you want to just put in the back of this question, or rather in the back of people's minds, that this issue of cell types is not just an issue pertinent to the retina. This is an issue that is critical to understanding how the brain works.

Absolutely.

It's critical to understanding consciousness. I know a lot of people like, what is consciousness? Right. We're not going there just yet. But what are cell types? How do you determine if you have a cell type? And why is this so important to Understanding how the brain works.

Yeah, I mean, as you said, as far as we understand, every single brain circuit is full of very distinct cell types. Those cell types are distinguished by their genetic expression, their shapes and sizes, which other cells they do contact and which cells they don't contact, where they send their information to in other parts of the brain and what they represent. And as far as we know, this is true throughout the brain, and it's true in the retina. The different ganglion cell types, retinal ganglion cell types, about 20 of them, each of which is looking at the whole visual scene, extracts different stuff. This cell type one extracts one thing, cell type two extracts something else. But they all represent the entire visual scene. But those cell types we know from lots of beautiful work that you're closely connected to and some of which you've done. Those cell types have different morphology, different shapes and sizes, different patterns of gene expression, different targets in the brain. They send their outputs to different places in the brain. So really, to study the retina without understanding cell types, you're kind of lost right away. You have to know what's going on with the cell types. Otherwise you can't make sense of this retinal signal. The way we identify them in two ways under different, for different purposes, the basic way we identify the different cell types is their function, because we study their function, we study how they respond to light images, and we can clearly separate them out. And in fact, it's a simple thing to say, but it's really true. Our 512 electrode array technology, which you've seen in our lab and stuff that we developed with collaborators about 20 years ago, was crucial for this, because with that 512 electrode technology, we could see many cells of each type, and we could clearly parse them apart from one another. Previous studies working on one cell at a time, had great difficulty doing that. So with our technology, with 512 electrodes, we record hundreds of cells simultaneously. We say, oh, there's 20 of these, there are 50 of those, there's 26 of those, and here they are. And we can just set them in different bins and say, okay, this is what's present in this retina, just what the information is they're extracting. There's another purpose, again, referring forward to the neuroengineering aspect. We need to identify the cell types not just based on what visual information they carry, but based on their electrical features, properties, electrical properties of the cell cells. As you know, neurons are electrical cells. They fundamentally receive and transmit electrical information. And the way that they do that has a distinctive electrical signature that turns out to be super important for developing devices to restore vision.

Could you explain how you determine what a given cell type does, its electrical properties? Let's just draw a mental image for people. The retina is taken out of this deceased individual, put down on this bed of nails of electrodes. Those electrodes can detect electrical signals within the ganglion cells. You are able to shine light onto the retina and see how the retinal ganglion cells respond, meaning what electrical signals they would transmit to the brain if they were still connected to a brain. They're not connected to a brain in the experiment.

They're sitting there, but they're trying.

But they're trying. I could imagine playing those cells a movie of, I don't know, a checkerboard going where every square on the checkerboard goes from white to black to gray could do that. I could play a cartoon. I could show it. This year's Academy award winner for best picture. How do you decide what to show the retina? This is a human being's retina, after all. Presumably, it looked at things that are relevant to human beings until that person died. But how do you determine cell type, electrical signals, if you don't know what specific things to show it? I mean, you're going to show it. I don't know, Disney movies. What do you show it?

So what we show now reflects the fact that we've built up a lot of information, and our work stands on the shoulders of many scientists who have studied the retina for decades to figure out what different cell types respond to. And we know that certain cell types respond primarily to increments of light. When light gets brighter than it was. So a change from a certain brightness to a higher brightness, this particular cell type fires. Another cell type fires or sends spikes to the brain when it gets darker. Some cell types respond primarily to large targets in the visual world. Other cell types respond better to small targets in the visual world. Some cell types respond to different wavelengths of light that we can identify. There exist certain cell types that are still poorly understood, that respond to movement. So we can tailor visual stimuli to types that we kind of already know about because of much preceding research. That's not actually how we do it in our experiments, for the most part. Instead, we use a very unbiased, flickering checkerboard pattern, as it turns out, which is a really unbiased way to sample many cells simultaneously, so that in a half hour of electrical recording from a retina, we can Figure out what all the 512 or so cells are that we're recording and know all of their types. And the way we do that is to play essentially random garbage TV snow, type image to the retina for a period of time and determine which bits of brightening or darkening or movement or whatever in that random garbage activated this particular cell by looking at average across the half hour recording and saying, oh, it looks like this cell was always firing when it became bright in this region of the screen. That must be an on cell sensitive to light in this region of the screen, and so on. So we have sophisticated, efficient ways of doing it. But it all comes back to these basic things about what features in the visual world tend to cause a given cell to send a signal to the brain.

Yeah, that makes a lot of sense. So you take essentially what you called random garbage snow, white, black and gray pixels on a screen, the retina views that. And then the cells in the retina will respond every once in a while with an electrical potential. They'll fire, as we say, spike, sometimes called. And then you take sort of a forensic approach a bit later, you look back in time and you say, you know, what was the arrangement of pixels in this random garbage right before this cell fired an electrical potential? That's right, a spike. And then from that you can reconstruct the preferred stimulus. The you can say, oh, this cell and cells around it seem to like motion of things going in a particular direction, for instance. And how do you know that the cell doesn't also like a bunch of other stuff that you didn't pick up on using this random garbage?

Yeah, two things. First, let me just say for the record, we don't record from these cells that signal motion in particular directions. They are an elusive cell type that is best understood in rodents and other creatures and not well understood. And the primate as you, you know, although some people are discovering potential cells of that type now and have. Have recently discovered them.

Okay, so let's say cells that respond to small, like spots that are red, you know, that go from dim red to bright red, right? Yeah.

So we can go through that colored TV snow and pick out the cells that responded to a transition of the kind you described from darker to lighter or from greener to redder or something like that. Cells tend to respond to transitions in the visual scene rather than static imagery. And so we can pick that stuff out. But you ask the question, well, gee, is the TV snow going to capture everything about what these cells are doing? That's a really important Question that I want to just mention more quite likely not. That's a scientific instrument. It's an unbiased way to sample a whole bunch of cells. You know, first cut, look at, you know, generally speaking, what are they up to? But that doesn't mean we've really captured their role in natural visual perception. Because actually you don't go through the world perceiving visual snow. You go through the world perceiving objects and meals and mates and targets and all these things, right? So the study of how the retina responds to more naturalistic visual stimuli in my lab and in many other labs around the world is really get getting off the ground now. And I would say we have limited understanding. I would say we know that our simple laboratory experiments with the TV snow don't capture the whole story. There's more. There are about 20 different cell types in the retina. We have basic characterizations of seven of them, if you count a certain way. We know that there are another 15 or so lurking right behind the curtain that we've started to sample. We don't know what naturalistic targets they respond to in the visual life of the animal. That's work that's underway. Exciting, interesting work, because this we know that they got to be there for something. One way to think of it, I'm pretty sure you think of it this way too, is that the retina is a highly evolved organ with a lot of evolutionary pressure for it to be efficient, to have a small optic nerve sending to the brain. It's probably the case that there's no accidental stuff sitting around in the retina that's vestigial and sending information to the brain. It's probably the case that those signals are all doing something important for our visual behavior, for our well being, for our sleep, all sorts of stuff. And the field is still trying to figure that out. These are the big mysteries, I think, in terms of the retina. What are those signals exactly in all those different cell types? What different behaviors and aspects of our life do they control?

What is the wildest cell type you've ever encountered? Like what did it do? What did it respond to? That's what I mean when I say wildest. It sells retinal ganglion cells that respond to increasingly red portions of the visual scene or decreasingly green portions of the visual scene. Like, okay, cool, that seems cool. Get some, you know, around the time of Christmas, that that's useful and it's useful on other days of the year as well. But, you know, given that the retina Is indeed the best understood piece of the brain. And given that you have 20 cell types, 20 isn't 20 million. It's, you know, it seems tractable. Probably gets on understanding it in its entirety. Or understanding them in their entirety. Excuse me, one would like to know, like, what stuff are we paying attention to at the level of the retina? I mean, are there like spiral cells that like spiral stuff in the environment? Are there cells that like emojis, like what's going on in there? You spend a lot of time doing this?

We do. We spend a lot of time.

After all, you give up two nights sleep, which is kind of incredible, by the way. I'll just do a little. Take a moment here and just say, you know, for a guy that's been doing this for this long, with these sleepless nights, you look pretty good. You look pretty rested.

I tend to go home. I go home before the graduate students do.

Oh, they stay up.

They stay up.

You used to stay up?

I used to stay up until my mid-40s. I was in there doing the all nighter type things.

Got it.

And maybe you can help me figure out my sleep patterns better.

Yeah, we can talk about that.

This episode. We talk about how to pull all.

Nighters and still survive. Done plenty of those. But yeah, lots at stake here. There's a human retina, meaning a human gave up their eyeballs to. For this experiment after they died, of course. You've got many people on this. These sorts of experiments are very expensive. A lot of fancy equipment, a lot of salaries to try and figure this stuff out. This is the chief mission of the National Eye Institute. There's a lot of tax dollars. This is, in my opinion, as important as the space program. Probably more important, in my opinion, restoring vision to the blind, obviously. So what are you finding in there?

Yep. And we have the privilege of being on the front lines of that. Funded by the National Eye Institute and other institutions to be out there figuring out what's going on in this human retina. I'm with you on that. So I'll tell you how we go about it. These days there are about seven cell types that we understand pretty well what they're doing. They're not complicated. They just have different properties. Color, size, this kind of thing, Temporal properties, their timing of their signals. Those seven cell types we understand pretty well. But we're trying to really nail down the details. Why? Because of neuroengineering for vision restoration. Then there's another, I'm going to say 15 or so the anatomists the people who study the shapes and sizes of the cells have long known that there were more cell types lurking in the retinal circuitry, but their function has not been known. And because we didn't have many recordings from them, we didn't have electrical recordings in response to light that would tell us what they naturally do. We've actually had a breakthrough in the last few years led by a senior researcher in my lab named Alexandra Kling, who has figured out that there's another 15 or so cell types lurking in those recordings, that if we look more carefully, they're there and they have crazy properties. And so the crazy properties I can tell you about have to do with the spatial region of the visual world that they respond to. The well known cell types that you know and I know from the textbooks kind of respond to a circular spot in the visual world. If there's light in this little circular area, they'll fire a spike. If there's no light there, they don't care. Well, okay, some cells is not quite circular. Some cells respond to the light that's there and the difference from the light that's around it. So if it's brighter than the light that's nearby, then you, you get a big response. The new cell types are more puzzling than that. Some of them respond to three or four blobs in the visual world. That's kind of strange, unexpected, definitely unexpected based on the textbooks. And the newest ones are weirder yet. Some of them, their visual response profiles, that is the region of the visual world that they are sensitive to light in, almost has a spidery shape, almost like the dendrites of a cell, like the processes of a cell. And some of them have blobby light sensitivity. They're sensitive to light increments here and decrements there and increments here and decrements there and some blue light over here and blue light over here. We don't understand these cells. To be clear, the seven that we understand reasonably well are not trying to just pin down and really nail for vision restoration the sort of first cut at cell type specific vision restoration. Those ones don't have these weird properties. They're a little simpler to understand. But we're just working out all the details of the timing of the responses and all that. These new ones, we don't know what's going on with them, so we're doing experiments. Those seven cell types constitute maybe 70% of all the neurons that send visual information from the eye to the brain. So we think it's A really solid target for vision restoration to work with the simple ones. And so when I say that I think that the retina is the best understood circuit in the nervous system. I'm talking about those seven cell types, which we know a lot about, what they do. We really do know a lot. It's not done, but we know a lot. I'm not talking about the other 15 cell types which are a minority of the population, but seem to be doing very strange and surprising things that are yet to be determined. So it's a mix. We know some really good stuff. And then there's really some deep mysteries out there about these other cell types.

So we've been talking a lot about.

How to understand the signals that the retina is sending the brain. And I know your lab has done incredible work in this arena and figured out a number of the different signals as you described. Some of the features that the different cell types are extracting just a moment ago. These blobs of different colors, et cetera. What good is this to the everyday person? In addition to wanting to understand how we see, what sorts of medical applications can this provide in terms of potentially restoring vision to the blind? But perhaps even larger theme is this notion of neuroengineering, taking this information and creating devices that can help us help our nervous system function better, maybe even function at supraphysiological levels. I know there's a lot of interest in this these days, in part due to neural link, because Elon's out there, front facing, very vocal about his vision of the, no pun intended, of chips being implanted in people's brains that would allow them to be in conversation with 100 people at the same time, just by hearing those voices in the head, maybe filtering things out so it doesn't sound like a clamor of 100 different voices, perhaps giving people super memory. I mean, sky's the limit. No one really knows where this is all headed. You're working in what we call a very constrained system where it has specific properties that you're trying to understand. And once you understand those, you can start to think about real applications of what's possible. Could you create a visual system that.

Can extract more color features from the.

World that no other human can see? Can you restore pattern vision to somebody.

Who is essentially blind and dependent on.

A cane or a dog, or, God forbid, can't even leave their house because they can't see anything at all? Where is this headed? What is the information useful for? And perhaps we should frame that first within the Medical rehabilitative context of repairing or restoring vision rather, and then get into the more kind of sci fi type neuroengineering stuff.

Absolutely, yeah. This really is my passion these days, turning that corner, continuing to figure out the mysteries in the retina, but also saying, wait a second, we actually know quite a lot about this. Shouldn't this be the first place that we can solve problems like restoring vision, restoring function, or augmenting our function? I think it should be. The concept of how to do this is straightforward and not invented by us in any way. And that is the following. One of the major sources of blindness in the Western world is loss of the photoreceptor cells that capture light. Macular degeneration and retinitis pigmentosa are two well known ailments that give rise to vision loss. The vision loss is because the cells that capture light in the first place that we talked about earlier die off. You're no longer sensitive to light, and then you're blind. The concept is that you may be able to bypass those early sections of the retina that capture the light and process the signals, and instead build an electronic implant that connects up directly to the retinal ganglion cells. And this electronic implant would do the following. It would capture the light using a camera, which is relatively easy. It would process the visual information in a manner similar to the way that the retina normally does, as similar as possible. And then it would electrically activate the retinal ganglion cells by passing current and causing the ganglion cells to fire the spikes and send those spikes to the brain. And if we do this really well, we can essentially replace those first two layers of the retina and piggyback on to the third layer and say, okay, we're just jumping right into that third layer. We're going to force those ganglion cells to send reasonable visual signals to the brain. And then the brain is going to think it got a natural visual signal and proceed accordingly. That's the concept. This is not our idea. People have had this concept for decades, and some people have even started to make it work in human patients. And what I mean by that is implanting electrodes on the retina, stimulating and causing people who have been profoundly blind for decades to see visual sensations, blobs and streaks of light in their visual world that are reproducible.

So that's happening now.

That's happened.

People who were at once blind are able to see objects, are able to.

See crude blobs and flashes of light.

In ways that allow them to navigate their world a little bit.

A little bit. Avoid a coffee table, maybe, or at least see a bright window in a dark wall and be able to point to that bright window or the bright doorway, a dark wall, something like that. So it's a glass half full, half empty story that I want to turn. That I'd like to turn attention to in this conversation because I think it's very exciting. Yes. You can see stuff by artificially, electrically stimulating the ganglion cells. And you can see stuff that actually helps you interact with your world a tiny little bit. So great. That's the glass half full. The glass half empty is. It's nothing remotely resembling what we understand as naturalistic vision, where we see fine spatial detail and color and objects and can navigate complex environments and all that stuff. No chance. You can't do anything remotely like that. And you can see that there's a bright doorway over that way and turn toward it, which is a helpful step in your human experience.