A light switch for neurons - Ed Boyden

[Music] [Applause]

Think about your day for a second: you woke up, felt fresh air in your face as you walked out the door, encountered new colleagues, had great discussions, and felt in awe when you found something new. But I bet there's something that you didn't think about today; something so close to home that you probably don't think about it very often at all.

And that's that all those sensations, feelings, decisions, and actions are mediated by the computer in your head called your brain. Now, the brain may not look like much from the outside: a couple pounds of pinkish-gray flesh, amorphous; but the last 100 years of neuroscience have allowed us to zoom in on the brain and to see the intricacy of what lies within. And they've told us that this brain is an incredibly complicated circuit made out of hundreds of billions of cells called neurons.

Now, unlike a human-designed computer where there's a fairly small number of different parts, we know how they work because we humans design them. The brain is made out of thousands of different kinds of cell, maybe tens of thousands. They come in different shapes, they're made out of different molecules, and they project and connect to different brain regions. They also change in different ways in different disease states.

Just to make it concrete, there's a class of cells, a fairly small cell, an inhibitory cell, that quiets its neighbors. It's one of the cells that seem to be atrophied in disorders like schizophrenia, called the basket cell. This cell is one of the thousands of kinds of cell that we are learning about; new ones are being discovered every day.

As just a second example, these paramal cells, large cells that can span a significant fraction of the brain, they're excitatory, and these are some of the cells that might be overactive in disorders such as epilepsy. Every one of these cells is an incredible electrical device. They receive inputs from thousands of upstream partners and compute their own electrical outputs, which then, if they pass a certain threshold, will go to thousands of downstream partners.

This process, which takes just, you know, a millisecond or so, happens thousands of times a minute in every one of your 100 billion cells as long as you live and think and feel. So how are we going to figure out what this circuit does? Ideally, we could go through this circuit and turn these different kinds of cells on and off and see whether we could figure out which ones contribute to certain functions and which ones go wrong in certain pathologies.

If we could activate cells, we can see what powers they can unleash, what they can initiate and sustain. If we can turn them off, then we could try and figure out what they're necessary for. And that's the story I'm going to tell you about today—an odyssey where we've gone through over the last 11 years through an attempt to find ways of turning circuits and cells and parts and pathways of the brain on and off, both to understand the science and also to confront some of the issues that face us all as humans.

Now, before I tell you about the technology, the bad news is that a significant fraction of us in this room, if we live long enough, will encounter perhaps a brain disorder. Already, a billion people have had some kind of brain disorder that incapacitates them. The numbers don't do it justice, though. These disorders—schizophrenia, Alzheimer's, depression, addiction—they not only steal away our time to live; they change who we are. They take our identity and change our emotions.

In the 20th century, there was some hope that was generated through the development of pharmaceuticals for treating brain disorders. And while many drugs have been developed that can alleviate symptoms of brain disorders, practically none of them can be considered to be a cure. In part, that's because, if you think about it, we're bathing the brain in a chemical. This elaborate circuit made out of thousands of different kinds of cell is being bathed in a substance; that's also why perhaps most of the drugs—not all—on the market can present some kind of serious side effect, too.

Now, some people have gotten some solace from electrical stimulators that are implanted in the brain. For Parkinson's Disease, these implants have indeed been able to bring some kind of remedy to people with certain kinds of disorders. But electricity also will go in all directions—the path of least resistance—which is kind of where that phrase, in part, comes from. It also will affect normal circuits as well as the abnormal ones that you want to fix.

So again, we're sent back to the idea of ultra control: could we dial in information precisely where we want it to go? When I started in neuroscience 11 years ago, I had trained as an electrical engineer and a physicist. The first thing I thought about was, well, if these neurons are electrical devices, all we need to do is to find some way of driving those electrical changes at a distance.

If we could turn on the electricity in one cell but not its neighbors, that would give us the tool we need to activate and shut down these different cells to figure out what they do and how they contribute to the networks in which they're embedded. It would also allow us to have the ultra-precise control we need in order to fix the circuit computations that have gone awry.

Now how are we going to do that? Well, there are many molecules that exist in nature which are able to convert light into electricity. You can think of them as little proteins that are like solar cells. If we install these molecules in neurons somehow, then these neurons would become electrically drivable with light, and their neighbors, which don't have this molecule, would not.

There's one other magic trick you need to make this all happen, and that's to get light into the brain. The brain doesn't feel pain; you can put in optical fibers connected to lasers that you can use to activate, in animal models for example in preclinical studies, these neurons and to see what they do.

So how do we do this? Around 2004, in collaboration with Gernhge and Carl Dieth, this vision came to fruition. There's a certain alga that swims in the wild, and it needs to navigate towards light in order to photosynthesize optimally. It senses light with a little eye spot, which works not unlike how our eye works. In its membrane, or its boundary, it contains little proteins that indeed can convert light into electricity.

So these molecules are called channel opsins, and each of these proteins acts just like that solar cell that I told you about. When blue light hits it, it opens up a little hole and allows charge particles to enter the eye spot. That allows this eye spot to have an electrical signal, just like a solar cell charging up a battery. So what we need to do is to take these molecules and somehow install them in neurons.

Because it's a protein, it's encoded for in the DNA of this organism, so all we got to do is take that DNA, put it into a gene therapy vector like a virus, and put it into neurons. It turned out that this was a very productive time in gene therapy, and lots of viruses were coming along, so this turned out to be fairly simple to do.

Early in the morning, one day in the summer of 2004, we gave it a try, and it worked on the first try. You take this DNA and you put it into the neuron; the neuron uses its natural protein-making machinery to fabricate these little light-sensitive proteins and install them all over the cell—like putting solar panels on a roof. The next thing you know, you have a neuron which can be activated with light.

So this is very powerful. One of the tricks you have to do is to figure out how to deliver these genes to the cells that you want and not all the other neighbors, right? You can tweak the viruses so they hit just some cells and not others, and there are genetic tricks you can play in order to get light-activated cells.

This field has now come to be known as optogenetics, and just as one example of the kind of thing you can do, you can take a complex network and use one of these viruses to deliver the gene just to one kind of cell in this dense network. Then when you shine light on the entire network, just that cell type will be activated.

So for example, let's consider that basket cell I told you about earlier—the one that's atrophied in schizophrenia and the one that is inhibitory. If we can deliver that gene into these cells and they're not being altered by the expression of the gene, of course, then flash blue light over the entire brain network. Just these cells are going to be driven, and when the light turns off, these cells go back to normal.

So there don't seem to be adverse events to that. Not only can we use this to study what these cells do, what their power is in computing in the brain, but you can also use this to try and figure out, well, maybe we could jazz up the activity of these cells if indeed they're atrophied.

Now, I want to tell you a couple short stories about how we're using this, both at the scientific, clinical, and preclinical levels. One of the questions that we've confronted is what are the signals in the brain that mediate the sensation of reward? Because if you could find those, those would be some of the signals that can drive learning.

Right? The brain will do more of whatever got that reward. Also, these are signals that go awry in disorders such as addiction. So if we could figure out which cells they are, we can maybe find new targets for which drugs can be designed or screened against, or maybe places where electrodes could be put in for people who have very severe disabilities.

So to do that, we came up with a very simple paradigm in collaboration with the Filla group where one side of this little box, if the animal goes there, the animal gets a pulse of light. We're to make different cells in the brain sensitive to light; so if these cells can mediate reward, the animal should go there more and more. And so that's what happens.

This animal is going to go to the right-hand side and poke its nose there, and it gets a flash of blue light every time it does that, and it'll do that hundreds and hundreds of times. These are the dopamine neurons, which some of you may have heard about as some of the pleasure centers in the brain.

Now we've shown that a brief activation of these is enough indeed to drive learning. Now we can generalize the idea: instead of one point in the brain, we can devise devices that span the brain that can deliver light into three-dimensional patterns—arrays of optical fibers, each coupled to its own independent miniature light source.

Then we can try to do things in vivo that have only been done to date in a dish—like high-quality screening throughout the entire brain for the signals that can cause certain things to happen or that could be good clinical targets for treating brain disorders.

One story I want to tell you about is how can we find targets for treating post-traumatic stress disorder—a form of uncontrolled anxiety and fear. One of the things that we did was to adopt a very classical model of fear. This goes back to the Pavlovian days, and it's called Pavlovian fear conditioning, where a tone ends with a brief shock. The shock isn't painful, but it's a little annoying.

Over time, in this case a mouse, which is a good animal model commonly used in such experiments, learns to fear the tone. The animal reacts by freezing, sort of like a deer in the headlights. Now the question is: what targets in the brain can we find that allow us to overcome this fear?

So what we do is play that tone again after it's been associated with fear, but we activate targets in the brain—different ones—using that optical fiber I told you about on the previous slide in order to try and figure out which targets can cause the brain to overcome that memory of fear.

This brief video shows you one of these targets that we're working on now. This is an area in the prefrontal cortex, a region where we can use cognition to try and overcome aversive emotional states. The animal's going to hear a tone, and the flash of light occurred there. There’s no audio on this, but you can see the animals freezing.

This tone used to mean bad news, and there's a little clock in the lower left-hand corner so you can see that this animal is about 2 minutes into this. Now this next clip is just 8 minutes later, and the same tone is going to play, and the light's going to flash again. Okay, there it goes, right?

Now you can see just 10 minutes into the experiment that we've equipped the brain by photoactivating this area to overcome the expression of this fear memory. Now, over the last couple of years, we've gone back to the tree of life because we wanted to find ways to turn circuits in the brain off. If we could do that, this could be extremely powerful.

If you can delete cells just for a few milliseconds, seconds, you can figure out what necessary role they play in the circuits of which they're embedded. We've now surveyed organisms from all over the tree of life, every kingdom of life except for animals. We see differently, and we found all sorts of molecules called halo opsins and archaeropsins that respond to green and yellow light, and they do the opposite thing of the molecule I told you about before—the blue light activator, channel opsin.

Let’s give an example of where we think this is going to go. Consider, for example, a condition like epilepsy, where the brain is overactive. Now, if drugs fail in epileptic treatment, one of the strategies is to remove part of the brain. But that's obviously irreversible and there could be side effects.

What if we could just turn off that brain for the brief amount of time until the seizure dies away and cause the brain to be restored to its initial state? Sort of like a dynamical system that's being coaxed down into a stable state. This animation just tries to explain this concept where we made these cells sensitive to being turned off with light, and we beam light in just for the time it takes to shut down a seizure.

We're hoping to be able to turn it on, and so we don't have data to show you in this front, but we're very excited about this. Now I want to close with one story which we think is another possibility, which is that maybe these molecules, if you can do ultra-precise control, could be used in the brain itself to make a new kind of prosthetic—an optical prosthetic.

I've already told you that electrical stimulators are not uncommon; about 75,000 people have Parkinson's deep brain stimulators implanted, and maybe 100,000 people have cochlear implants which allow them to hear. There's another thing, which you've got to get these genes into cells. New hope in gene therapy has been developed because there are viruses like the adeno-associated virus, which probably most of us in this room have, and it doesn't have any symptoms.

These have been used in hundreds of patients to deliver genes into the brain or the body, and so far, there have not been serious adverse events associated with the virus. There's one last alpha in the room: the proteins themselves, which come from algae and bacteria and fungi and all over the tree of life.

Most of us don't have fungi or algae in our brain, so what is our brain going to do if we put that in? Are the cells going to tolerate it? Will the immune system react? It's early days; these have not been done in humans yet, but we're working on a variety of studies to try and examine this. So far, we haven't seen overt reactions of any severity to these molecules or to the illumination of the brain with light.

So it's early days up front, but we're excited about it. I want to close with one story, which we think could potentially be a clinical application. Now, there are many forms of blindness where the photoreceptors—our light sensors that are in the back of our eye—are gone, and the retina, of course, is a complex structure. Let's zoom in on it here so we can kind of see it in more detail.

The photoreceptor cells are shown here at the top, and then the signals that are detected by the photoreceptors are transformed through various computations until finally, that layer of cells at the bottom—the ganglion cells—relay the information to the brain where we see that as perception.

In many forms of blindness, like retinitis pigmentosa or macular degeneration, the photoreceptor cells have atrophied or been destroyed. Now, how could you repair this? It's not even clear that a drug could cause this to be restored, because there's nothing for the drug to bind to. On the other hand, light can still get into the eye, right? The eye is still transparent, and you can get light in.

So what if we could just take these channel opsins and other molecules and install them on some of these other spared cells and convert them into little cameras? Because there's so many of these cells in the eye, potentially, they could be very high-resolution cameras. So this is some work that we're doing. It's being both led by one of our collaborators, Alan Hoeger at USC, and being sought to be commercialized by a startup company, EOS Neuroscience, which is funded by the NIH.

What you see here is a mouse trying to solve a maze. It's a six-arm maze, and there's a bit of water in the maze to motivate the mouse to move, where he'll just sit there. The goal, of course, of this maze is to get out of the water and go to a little platform that's under the lit top port. Now, mice are smart, so this mouse solves the maze eventually, but he does a brute-force search.

He's swimming down every avenue until he finally gets to the platform. So he's not using vision to do it. These different mice are different mutations that recapitulate different kinds of blindness that affect humans. We're being careful and trying to look at these different models so we with a generalized approach.

So how are we going to solve this? Well, we're going to do exactly what we outlined in the previous slide: we're going to take these blue light photosensors and install them onto a layer of cells in the middle of the retina in the back of the eye and convert them into a camera, just like installing solar cells all over those neurons to make them light sensitive. Light is converted to electricity on them.

So this mouse was blind a couple weeks before this experiment and received one dose of this photosensitive molecule in a virus. Now you can see the animal can indeed avoid walls and go to the platform and make cognitive use of its eyes again. To point out the power of this: these animals are able to get to that platform just as fast as animals that have seen their entire life.

So this preclinical study I think bodes hope for the kinds of things we're hoping to do in the future. To close, I want to point out that we're also exploring new business models for this new field of neurotechnology. We're developing these tools, but we share them freely with hundreds of groups all over the world so people can study and try to treat different disorders.

Our hope is that by figuring out brain circuits at a level of abstraction that lets us repair them and engineer them, we can take some of these intractable disorders that I told you about earlier—practically none of which are cured—and in the 21st century, make them history. Thank you.

So some of the stuff is a little dense, but the implications of being able to control seizures or epilepsy with light instead of drugs, and being able to target this specifically is a first step. The second thing that I think I heard you say is you can now control the brain in two colors, like an on/off switch.

That's right, which makes every impulse going through the brain a binary code, right? Yeah. So with blue light, we can drive information in this form of a one, and by turning things off, it's more like zero. Our hope is to eventually build co-brain co-processors that work with the brain so we can augment functions in people with disabilities.

In theory, that means that as a mouse feels, smells, hears, touches, you can model it out as a string of ones and zeros. Sure, yeah, we're hoping to use this as a way of testing what neural codes can drive certain behaviors, certain thoughts, and certain feelings, and use that to understand more about the brain.

Does that mean that someday you could download memories and maybe upload them? Well, it's something we're starting to work on very hard. Yeah, we're now working on some work where we're trying to tile the brain with recording elements too, so we can record information and then drive information back in—sort of computing what the brain needs in order to augment its information processing.

Well, that might change a couple of things. Thank you. [Applause]