Nobel Prize in Medicine 2026 Explained: Optogenetics (EP 61)

How do you prove what a brain cell actually does? The 2026 Nobel Prize in Medicine celebrates a remarkable answer: give cells a light-sensitive protein, then switch their activity on or off with light. In Episode 61 of From First Principles, Lester Nare and Krishna Choudhary explain optogenetics from the ground up and trace the discoveries of Peter Hegemann, Georg Nagel and Karl Deisseroth. We follow the story from algae swimming toward light to channelrhodopsins, precisely controlled neurons, and experiments probing memory, reward and behavior. Then we explore heart-brain connections, early attempts to restore vision, and what these experiments can and cannot tell us. CHAPTERS 00:00 The discovery that put brain cells under light control 02:34 Hello Internet 03:28 2026 Medicine Nobel and optogenetics 05:38 Understanding the brain 08:42 From correlation to causation 18:13 Controlling neurons with light 21:25 Early optogenetics and the chARGe system 24:17 Light-sensitive microbial proteins 26:26 Algae and phototaxis 31:42 Discovering channelrhodopsins 34:42 Nagel and light-gated ion channels 40:55 Controlling mammalian neurons 50:19 Expanding the optogenetic toolkit 56:10 Neural circuits and behavior 59:02 Memory, reward and reinforcement 1:02:53 Heart rhythm and emotion 1:04:02 Beyond the brain and toward medical treatments 1:06:56 Implications and limits 1:09:10 Closing and Nobel week RESEARCH & FURTHER READING Full paper list: https://ffppod.com/episodes/ep61 Nobel Prize announcement and background: https://www.nobelprize.org/prizes/medicine/2026/summary/ Optical control of neurons: https://doi.org/10.1038/nn1525 Memory recall in mice: https://doi.org/10.1038/nature11028 Partial visual recovery: https://doi.org/10.1038/s41591-021-01351-4 EDITORIAL NOTES On-screen clarifications are included at these timestamps: 13:46 The Jennifer Aniston neuron was recorded in human patients. Selective firing alone did not establish that it causes recognition. 30:34 Vertebrate rhodopsin is a GPCR. In rods and cones, light closes cGMP-gated channels and causes hyperpolarization. 35:12 Xenopus oocytes are immature frog egg cells, not embryos. 39:52 Calcium entry triggers neurotransmitter release; neurotransmitters carry the signal across the synapse. ChR2 conducts several positive ions, not just calcium. 52:17 Halorhodopsin is a light-driven chloride pump, not a channel. 1:03:18 The heart-pacing study expressed ChRmine in mouse heart muscle cells, not neurons. Animal studies and early clinical results are distinguished from established treatments. WATCH & LISTEN Watch this episode: https://youtu.be/PKAYqhy8xf8 Our Nobel predictions: https://open.spotify.com/episode/4xuoH7WhM5svq8vEJPL3Ce Support: https://ffppod.com/donate Contact: https://ffppod.com/contact Follow @FFPPod. Breaking down science news so it makes sense to curious people everywhere.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

  Hello, everybody.

• 0:02Lester Nare?

  Okay, here we go.

• 0:03Speaker 00

  Nice to see you all here. Very welcome to Nobel Forum for the announcement of this year's Nobel Prize.

• 0:11Krishna Choudhary?

  It's the same guys last year.

• 0:12Lester Nare?

  The same guys last year.

• 0:13Speaker 00

  My name is Thomas Perlmann. I'm the Secretary General of the Nobel Assembly and the Nobel Committee. I will first read the announcement in Swedish and immediately followed in English. And we will then present the background to the prize and open up for questions.

• 0:35Speaker 00

  Nobel-församlingen vid Karolinska Institutet har idag beslutat att Nobelpriset i fysiologi eller medicin år 2026 ska delas lika mellan Carl Diceroth, Peter Hegeman och Georg Nagel.

• 0:54Lester Nare?

  Oh, wait, wait, wait, bro. Carl Diceroth, Peter Hegeman and... Bro, I called it. The first two, bro, I called it. This is so good. I called it. This is so good. Optogenetics. What did I say? Optogenetics. What did I say?

• 1:08Lester Nare?

  That's crazy. Maybe a year late. Yeah.

• 1:12Lester Nare?

  That's good.

• 1:13Speaker 00

  jointly to Carl Diceroth, Peter Hegeman and Georg Nagel.

• 1:20Lester Nare?

  Georg Nagel? So not Miesenberg? Yes. And not... Yes.

• 1:28Lester Nare?

  The other MIT guy, Ed Boyden. Yeah, yeah, yeah, yeah. Okay, interesting. Okay, we're gonna, we're gonna dig into this and we will be diving deep finally. Yeah. On optogenetics.

• 1:40Lester Nare?

  Pond Algae, two biophysicists in Germany and a psychiatrist at Stanford. Together, they gave biology a light switch, a protein that opens the moment light hits it. Chlamydamonus swims toward light. Nagel and Hegeman found its sensor, channel rhodopsin. Blue light opens the channel, ions rush in, and the cell gets an electrical signal. In 2005, Diceroth put that gene into neurons. A flash of blue light and the neuron fires on command. By 2007, it worked in living mice. Today, it's how neuroscientists map the circuits behind memory, emotion, and behavior. And it's being tested to restore sight.

• 2:25Lester Nare?

  This is from First Principles, and this is the 2026 Nobel Prize in Physiology or Medicine.

• 2:34Lester Nare?

  Hello, internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD and predictor of the future, Krishna Choudhary. We are here for the first of our three-part Nobel Prize special. And we're talking about medicine and physiology today. First, we want to thank all of you who voted in our Instagram poll. Thirty-four percent of you got it right. Well done.

• 3:02Krishna Choudhary?

  Yeah, something like 500-plus people voted. And I was actually very surprised at how few people voted something else.

• 3:09Lester Nare?

  Yeah.

• 3:09Krishna Choudhary?

  People have a lot of faith in us. That's crazy.

• 3:13Lester Nare?

  So again, thank you all so much for those votes. We are going to talk about the science from the ground up today as always. And this will be for the Nobel Prize in Medicine from First Principles.

• 3:28Krishna Choudhary?

  That's right. The Nobel Assembly at Karolinska Institute has awarded the 2026 Nobel Prize in Physiology or Medicine jointly to Carl Diceroth at the Howard Hughes Institute of Medicine and Stanford University, Peter Hegeman at the Humboldt University of Berlin, and Georg Nagel at the University of Wurzburg in Germany for their discoveries concerning light gated ion channels and optogenetics. This is a prize that I have been calling since last year. It didn't go last year. I recycled the prediction this year and voila, it's here. So that's two years in a row that I've gotten something right. What makes this prize particularly interesting is that it represents a remarkable convergence of fields.

• 4:13Krishna Choudhary?

  We've got biophysics, molecular biology, microbial physiology, genetics, electrical engineering, neuroscience, and they're all coming together to solve one of the most fundamental problems in biology, which is namely, how do you establish a causal relationship? A causality between single cells and their activities in the brain or in neural tissue, and as we'll see in other parts of the body, and the behavior of the entire organism? That's a crazy link to go from a single cell all the way to behavior. Okay? And that is the central question that this technology is trying to answer. This is also a great example of how fundamental discoveries are seemingly coming from obscure

• 4:57Krishna Choudhary?

  biological systems, and they can totally transform medicine. And this, as always, the Nobel Committee puts out like artwork. And this is the particular artwork that is their flagship sort of thing that they're putting out to the press. It depicts a woman who's playing chess. There's a light switch that goes into a particular neuron in her brain, and it's got something to do with chess behavior. By the end, we should be able to understand everything about this image.

• 5:24Lester Nare?

  It's giving Queen's Gambit.

• 5:26Krishna Choudhary?

  Yes.

• 5:27Lester Nare?

  But I think also this dovetails with what we talked about with the Golden Goose Awards, where where you start and where you end are, you know, can be, there can be a large gap in between those two spaces. And I think this is going to be an interesting additional proof point to that idea about basic research and then ultimately clinical type outcomes.

• 5:45Krishna Choudhary?

  Yeah, yeah, yeah. This is, this is a flagship example of exactly that. It's pretty amazing. So the whole point of neuroscience, right, is to understand the brain. These are some famous author quotations about the brain. The Nobel Institute in their press release quotes Virginia Woolf with her quote, "My own brain to me is the most unaccountable of machinery, always buzzing, humming, soaring, roaring, driving, and then buried in mud. And why? What is the passion for?" They quote that one. I brought up two more that I quite like. The second one is from Arthur Conan Doyle, the author of Sherlock Holmes. Sherlock Holmes says, "I am a brain, Watson. The rest of me is a mere appendix." Which is quite interesting for him to say all the way back then, that really the brain

• 6:29Krishna Choudhary?

  is the thing that creates the self, the illusion of reality, everything around us. Finally, Maya Angelou, this one's quite funny. "The brain is wonderful. It starts working the minute you're born and never stops until you get up to speak in public." I quite like that last quote by Maya Angelou because Senator John Kennedy, who's very famously funny, he adopted it on the floor of the Senate and said, "The brain is an incredible organ. It starts working when you're born and then it stops working when you get elected to Congress."

• 7:03Krishna Choudhary?

  It was, it was one of those highlight videos of like all the funny things he says. But it's really quite amazing, right? How can this organ that only weighs 1.3 kilograms, like if you put your hands like this, that is about how big your brain is if you put your hands together like this. And that 1.3 kilograms of fat and neural tissue, that holds childhood memories, daydreams, creativity, it gives us joy, love, jealousy, all of the emotions. It also controls the pace of heartbeats, the rhythm of breathing, the sleep cycle. Literally, everything that has to do with being alive is controlled by 1.3 kilograms that are in your skull.

• 7:44Krishna Choudhary?

  And to give you a sense of how complex this problem is, this is a cubic millimeter of the mouse's visual cortex. This is by the Allen Brain Institute. They're part of the Microns Project. They took a cubic millimeter of the mouse visual cortex, sliced it up, and then stained it, and you can now trace the hundreds of thousands of neurons that are in that one cubic millimeter. Each of those neurons can be traced using machine learning to like stitch everything together. And you can see the, the amazing diversity of the cells there.

• 8:22Lester Nare?

  Yeah.

• 8:23Krishna Choudhary?

  There's 500 million synapses in this one cubic millimeter. And the length of axons is four kilometers worth of axons, like neural fiber, in this one cubic millimeter. Now, that's a cubic millimeter of the mouse brain. For the human brain, the whole human brain, that's 100 billion neurons, 500 trillion synapses. So the question is, if we want to study this thing, how do we establish causality?

• 8:48Lester Nare?

  Yeah, right.

• 8:49Krishna Choudhary?

  Right? Because in, for most of the 20th century, neuroscience was fundamentally an observational science. Okay? You observe what the neuron is doing and you try to correlate it to behavior. And researchers could record electrical activity of neurons. They could stimulate brain regions using electrodes. They could lesion particular structures. And this gives you a good sense of what is going on. But these methods have significant limitations.

• 9:15Lester Nare?

  I can imagine, because part of it's like you have to wait for the things to do what you're looking them to do and then hope and then track.

• 9:21Krishna Choudhary?

  Yeah.

• 9:22Lester Nare?

  And it's not quite...

• 9:24Krishna Choudhary?

  It's not quite like a two-way street of information. It's a one-way street of information. And it's done amazing things, right? Like, consider electrophysiological recordings. So here, you take an electrode. You can either put it in the vicinity of the cell, or sometimes you can use a patch clamp and go inside the cell and see what the voltage is across the membrane from the inside to the outside. Neurons fundamentally use the transport of ions to create a kind of electricity that they use to talk. And that's how you get these very, very fast responses. Now, with electrophysiology, you can learn a lot about how action potentials propagate from one end of the neuron to the other, how neurons aggregate information. Like, if a bunch of neurons are talking to the single neuron, how do you actually get this particular neuron to fire?

• 10:08Krishna Choudhary?

  Turns out, there's ions that are coming in that change the membrane potential, right? Because if you dump a bunch of positive ions on the inside, then that's going to change the electrical environment. That electrical environment is then going to change the proteins that are nearby, which is going to let in more ions. That's going to let in more ions. You have this kind of runaway effect that creates action potentials. All of this was discovered using electrophysiology, meaning electrodes going into the physiology for us to measure precisely what the electrical environment is around a neuron or even inside of a neuron, right? Amazing stuff.

• 10:44Lester Nare?

  Yes.

• 10:44Krishna Choudhary?

  Several Nobel Prizes have happened because of this, okay? But you reach a kind of ceiling on the kinds of science that you can do.

• 10:51Lester Nare?

  Right.

• 10:52Krishna Choudhary?

  Because suppose, for example, you're recording from a neuron in the hippocampus while the animal is learning a spatial task. This was very famously awarded the 2014 Nobel Prize in Medicine and Physiology for the discovery of place cells and grid cells in the hippocampus and in the entorhinal cortex. And there, on the lower right, is my first paper that was in Nature. I was a minor author in there. But the point of that paper was that, you know, originally, it had been thought that these place cells in the hippocampus only respond to place. But the paper from my own command's lab that I was a part of, it showed that actually those same place cells can respond to visual cues.

• 11:34Krishna Choudhary?

  Only visual cues, no behavior, right? So now, you have a relationship between place and this activity, the neuron's activity. But now, we've just shown that, you know, visual cues are enough to elicit the same cells to do the same kind of firing pattern that you see when the animal is moving around, right?

• 11:55Lester Nare?

  I remember we covered this briefly, and it was very popular because people, it was the concept was like very surprising for people.

• 12:02Krishna Choudhary?

  Yeah, yeah, because they thought that, you know, place cells are place cells, and that's it. They respond to place. Well, it turns out, no. There's multimodal inputs that come in that are actually creating the activity of this particular neuron. And I just want to shout out one author of that particular paper, Shonali Dingra. She was one of the first authors. She recently passed away. She was a huge mentor for me. She was a postdoc when I was a graduate student. And a lot of the scientists that I became was because of her. So, you know, in memory of Shonali, I'd like to dedicate this whole episode because she was a huge influence in my life as a scientist. The point of that paper was correlation doesn't establish causation, right? The place does not establish why this particular place cell is firing. And perhaps even the name place cell

• 12:46Krishna Choudhary?

  might not be that good of a name. It might be a multimodal sensory cell in the hippocampus.

• 12:52Lester Nare?

  And so, the idea being, we've been doing this observational science, which has given us a lot of advances. But we can't necessarily jump all the way to the conclusion that we can define causation just using that one-way street that we've been using thus far.

• 13:07Krishna Choudhary?

  Exactly, yeah. And so, you might say, okay, well, let's try to establish causation by stimulating the neuron electrically, right? You've got an electrode in there. Why don't I just pump electricity? The problem there is electrical stimulation is spatially imprecise. You've got an electrode, right? Unless it's targeting a single cell, then maybe you can make that cell fire. But then, it's only going to be that cell, right? And how many cells are you going to try to elicit some kind of behavior? Oftentimes, behavior depends on networks of cells, not just a single cell. Although, you can get lucky sometimes. There's the very famous Jennifer Aniston cell that responds only to when, like, the animal was shown a picture of Jennifer Aniston. And it was literally called the Jennifer Aniston cell.

• 13:52Krishna Choudhary?

  But they got extremely lucky somehow, right? Where it's like, they showed exactly the right actress, and then they elicited a response. So, fine, there's causality. But then, most of behavior is because of networks of cells, right? And sure, the electrical stimulation that you're putting an electrode in, that's going to cause some kind of activity. But it's going to be spatially imprecise. If it's outside the cell, that those electrons are going to leak everywhere because of the fluids in the brain, the Navier-Stokes equation. Come back again. And so, you're not going to get a nice one-way street. The resulting behavior could be caused by the neuron around there, or it could be caused by single neurons somewhere else that are connected to some other part of the brain that is doing all of this nonsense.

• 14:37Lester Nare?

  This reminds me of the discussion around precision we talked about when we looked at histotripsy versus other ultrasound therapies in terms of using thermal ablation, which has more of a spread impact.

• 14:49Krishna Choudhary?

  Yeah, because again, the brain is conductive in heat. It's also conductive in electricity.

• 14:53Lester Nare?

  Versus having some more mechanistic approach. So, the precision really matters here, especially when you talk about the brain.

• 14:58Krishna Choudhary?

  Yes, exactly. Because single neurons can elicit crazy stuff, right? The other option you have is pharmacology. Pharmacology, meaning like you inject some kind of receptor agonist or antagonist, and then you try to like block some type of receptor that blocks the neuron's activity. But again, same thing. There's a problem, right? Because you inject something that's going to spread around because of diffusion. You're not sure whether you targeted that specific circuit or not. The other problem with pharmacology is the response time is quite slow.

• 15:30Lester Nare?

  Right.

• 15:31Krishna Choudhary?

  You're relying on diffusion. So, you're injecting something. That thing has to spread, go to the neurons. Neurons are fast.

• 15:37Lester Nare?

  Right.

• 15:38Krishna Choudhary?

  So, we've got to find a different way to do this, right? Now, genetic approaches offer a way to get specific, right? Because you can target specific neurons because you can be like, well, the perimonal neurons in layer three have this specific type of genetic expression. And if I can hone in on that, then I can like turn it on or off. But that's not really reversible, one thing, right? Once you turn it on, it's kind of hard to take out that kind of stuff. And the brain also has time to compensate, reorganize, develop alternate pathways. So, again, not great.

• 16:16Lester Nare?

  We're trying to get to a place where we can create a two-way street where there's a very well-understood, discrete control on our input into the system that does not have this like combinatorial effect in other ways that is unintended. So, we can isolate, saying, we only touched this thing, and it only had this sort of next step outcome. And that way, we can start to really probe with an understanding that when we look for causation, we know that we didn't input more than we need. We didn't put too many ingredients into the recipe.

• 16:47Krishna Choudhary?

  Exactly, exactly. Which, we just changed one thing, okay? So, there are three things that we need for this perfect ideal technique, okay? Here are the three things. First, we need genetic specificity, right? We need to be able to target specific types of neurons in a very specific location. Second, we need temporal precision, meaning timing needs to be extremely fast. There, you see the electrical signature of an action potential recorded with electrophysiology. One of the great things with electrodes is that you can record like at 40 kilohertz, so 40,000 data points per second. So, that's 40 data points in a single millisecond, right? In a thousandth of a second, you'll get 40 data points. So, you can really look at the waveform

• 17:31Krishna Choudhary?

  and see what the waveform of an action potential looks like. You can see that the width of an action potential is like a millisecond. It's right, so we need whatever tool we're developing to be extremely fast. And the second, and the third, actually. I couldn't find a visual for it, so I just used the Uno reverse card.

• 17:49Lester Nare?

  Uno reverse.

• 17:49Krishna Choudhary?

  But you want it to be experimentally reversible.

• 17:54Lester Nare?

  Right.

• 17:54Krishna Choudhary?

  You want the ability to switch the neural activity on and off repeatedly, right? Because then you want, that's how you really establish causation. You turn it on, something happens. Well, is that because you turned something else on? Or if you turn this off, do I recover the old behavior?

• 18:08Lester Nare?

  Right, do you go back to baseline?

• 18:10Krishna Choudhary?

  Exactly, yeah. And one of the people who dreamed about this more precise tool to explore the brain was Francis Crick, the Nobel Prize winner in 1962 for the DNA double helix. He, you know, he discovered the double helix in 1953, and then decades later, he started investigating human consciousness. He became obsessed with this idea about what is consciousness. And in order to do that, he wanted some kind of tool that would help him, you know, activate individual neurons in a living brain, okay? And in...

• 18:47Lester Nare?

  Ambitious.

• 18:47Krishna Choudhary?

  It is quite ambitious. And he said it was quite ambitious. And in 1999, he wrote this article where he forecasted that maybe we could use light. He said, light would be ideal, right? If we could somehow manipulate nerve cells and get them to react to light, that might give us the genetic specificity because we can maybe only target certain neurons. It could give us the temporal specificity because light, you can turn on and off at an arbitrarily, you know, fast time regime. And also reversibility, because I can turn light on and off. And he admits in that paper, it's like a perspective paper. And he admits that the idea sounds very far-fetched, but perhaps not impossible, okay?

• 19:31Lester Nare?

  Perhaps.

• 19:32Krishna Choudhary?

  Perhaps not impossible. And that vision of the future is what this Nobel Prize is about.

• 19:38Lester Nare?

  So good.

• 19:39Krishna Choudhary?

  The new field of optogenetics. It was the Nature Method of the Year in 2010. It's been all over scientific journals. Using light, researchers are now able to switch individual neural circuits on and off. They can bring memories to life. They can create feelings. They can drive behaviors. They can study the types of neurons that are involved in psychiatric and neurological disorders. Optogenetics is, I mean, fundamentally transforming our understanding of the brain. And every year, countless papers come out using this technique.

• 20:12Lester Nare?

  It's the hammer of the toolbox of neuroscience in the modern, and the context of being a very, a tool with a lot of uses.

• 20:20Krishna Choudhary?

  Exactly, yeah. So, how do we get there, right? How do we get here?

• 20:24Lester Nare?

  Yeah.

• 20:24Krishna Choudhary?

  The idea of using light to manipulate biological systems was already known. This might be a good time to talk about a particular individual. Miesenbach.

• 20:34Lester Nare?

  Miesenbach.

• 20:35Krishna Choudhary?

  Gero Miesenbach. In his Wikipedia article, it says, "Miesenbach is known as the founder of optogenetics." Well, this is a bit awkward. This is why I originally thought he might be the third.

• 20:50Lester Nare?

  Yeah.

• 20:50Krishna Choudhary?

  Right? They gave it to Nagel instead, and we'll see why. Funny thing, I was watching the whole press conference right after they announced. The very first question was, "Why was Miesenbach not awarded?" I'm sure, I'm sure the guy knows him or something and was like, "Yo, what's going on?"

• 21:09Krishna Choudhary?

  So, the, the response was, "Well, we're writing a forward description about the scientific justification, and we do not comment on why someone got it or not." And then, and then the follow-up was, "If there were four recipients, would Miesenbach have gotten it?" And the guy was like, "Mate."

• 21:25Lester Nare?

  Come on.

• 21:25Krishna Choudhary?

  Come on. All right, let's go to the next question.

• 21:27Lester Nare?

  Next question.

• 21:28Krishna Choudhary?

  Yeah. So here's what Miesenbach was known for. He developed this thing called a charge system. It utilized this multi-gene strategy to co-express three distinct proteins from the Drosophila visual cascade. Drosophila is the fruit fly. He took proteins from that visual cascade and he expressed that in neurons. And he, crucially, this, he expressed this in mammalian neurons. The problem is the following, though. Okay? If you look at Figure A, and this is the paper that came out in 2002 where he did this. It's already kind of optogenetic-y in mammalian neurons already. But the problem is, in Part A, that's the response of this neuron. So,

• 22:12Krishna Choudhary?

  the light turns on when the gray bar ends. Look at the response time of this thing. The scale bar down there, that's not milliseconds.

• 22:21Lester Nare?

  Yeah.

• 22:21Krishna Choudhary?

  That's seconds.

• 22:22Lester Nare?

  Yep.

• 22:22Krishna Choudhary?

  Okay? This is on the order of thousands of times the time scale of a neuron. We want things at the millisecond time scale. This is happening at seconds. So this is good, right? You can turn on neurons and turn off neurons, but you don't get the temporal precision. Furthermore, you get a lot of variability. On the right-hand side, you're seeing the gray is when the light was off, and then it's turned on. Sometimes, the response is very quick, half a second to a second. Sometimes it's very, very long, all the way to 10, 10 seconds later. Right? It took a long time for all of this to, to accumulate and then that neuron to turn on in Panel B.

• 22:59Lester Nare?

  And, and so this is the, it's like a diet version of ultimately what happened. And in terms of, it didn't have the precision from a time perspective. It didn't also have for the reversibility piece. It wasn't quite,

• 23:10Krishna Choudhary?

  Yeah.

• 23:10Lester Nare?

  you know, what it needed to be.

• 23:12Krishna Choudhary?

  Exactly, yeah. Because if, if you take this long to turn something on, then like, when you turn it off, presumably it's going to take very long time to turn off as well, right? And the other thing, it required three proteins to go in. It also required cofactors, which are like things that bind to the protein to enable, like, there's all these working parts that are going in to create it. It's the first time, though. It's 2002, so this is very early.

• 23:35Lester Nare?

  Yeah, it's quite early.

• 23:35Krishna Choudhary?

  And that's why he, he's been given many awards. It's not the Nobel this time.

• 23:40Lester Nare?

  No, it's so tough.

• 23:41Krishna Choudhary?

  That is tough.

• 23:41Lester Nare?

  That's tough.

• 23:42Krishna Choudhary?

  That is tough. And so the challenge now is to create a light control that is genetically targetable, and it's fast to operate at that time scale of neural computation.

• 23:54Lester Nare?

  At this point, we, it was, you're saying there's a chance. We now knew.

• 23:58Krishna Choudhary?

  We now knew there's a chance, but we got to find the right tool, right? We want a single protein to do the job. We don't want these three different proteins. Plus, I need to inject cofactors. So that means like, in order to keep this thing going, I need to keep injecting cofactors, right, that are going to help this protein out. It's, it's not, it's not great, right? And the solution comes from a very unexpected source: microbial photoreceptors. So to really understand optogenetics, we need to understand how certain microorganisms detect light. Okay, the relevant proteins belong to a broader family called microbial rhodopsins. These are proteins that have a, a nice architecture that lets them absorb light in some kind of retinal chromophore. That's like a central

• 24:43Krishna Choudhary?

  chemical, you can imagine, on the inside of this protein that absorbs light,

• 24:50Krishna Choudhary?

  transforms that energy into a kind of kinetics that makes the outer protein change shape. And then that outer protein changing shape is going to create some kind of activity in the cell. The historical foundation of this is I'll, is, um, from Halophilic archaeon, halophilic bacteria,

• 25:11Krishna Choudhary?

  by Dieter Osterheld. In 1971, he publishes this paper that shows a pump. It's a photon-mediated pump, meaning,

• 25:22Krishna Choudhary?

  there's a pump on the membrane that takes in light and then uses that energy to pump protons one way or the other.

• 25:29Lester Nare?

  Across, across the membrane.

• 25:30Krishna Choudhary?

  Across the membrane. So we're getting close.

• 25:32Lester Nare?

  Okay.

• 25:32Krishna Choudhary?

  We're getting to a, a protein that takes in light energy and then uses that to pump ions. In this case, it's just protons, right?

• 25:40Lester Nare?

  Okay.

• 25:40Krishna Choudhary?

  H plus ions.

• 25:41Lester Nare?

  Okay.

• 25:42Krishna Choudhary?

  Now, this is great, but this is a pump. A pump, meaning like, one single photon is coming in. That's going to cause one ion to move, right? Like, that work is getting transformed. What we'd really want is one photon to come in. That opens a kind of gate. And then whatever ion concentration is already present, let's say there's a lot of some kind of ion, sodium, potassium, calcium on one side, less on the other side. There's already a gradient. All we want to do is open the dam.

• 26:12Lester Nare?

  Instead of it being a toll booth with cars where each car has to stop, we want a drawbridge where multiple boats can go by because the drawbridge gets open.

• 26:20Krishna Choudhary?

  Yeah, yeah. And it's all because there's more boats on this side, so they're just like trying to leave.

• 26:23Lester Nare?

  Yep.

• 26:24Krishna Choudhary?

  Right? That's what we'd like.

• 26:25Lester Nare?

  Yeah, right.

• 26:26Krishna Choudhary?

  So, let's consider the unicellular green algae, Clamiidomonas Reinhardtii. I always have a hard time with these taxonomical names. They're obsessed with Latin, the biologists. But in any case, this is a green unicellular algae. And like other photosynthetic organisms, it needs to detect light. Right? Because it depends on light to actually like, live and eat. And so it's got a little eye of some kind. It's not the eye that we have where we can like make images, but it's certainly got something that is receptive to light. Okay? It's got an eye spot. And that eye spot senses light and it creates phototaxis. For example, you put it in a Petri dish.

• 27:12Krishna Choudhary?

  We've got light on one side, dark on the other side. You'll see all the algae migrate towards the light side. So there's got to be some kind of sensitivity in there that is making them sense the light is in this direction, I'm going to swim in this direction.

• 27:23Lester Nare?

  This is where my food is, we're going to go there.

• 27:25Krishna Choudhary?

  Exactly. It's got two flagella that allow it to swim, and it possesses this kind of light sensing architecture that can tell the flagella which way to swim. Quick aside, as I was doing research on this stuff, people use this algae for all different sorts of stuff. This is the Shoji Takeuchi Research Group at the University of Tokyo. They're making little tiny machines that are propelled by these algae. Like, the algae get trapped in these baskets. And then, and then the flagellar motion, like, creates pinwheels and like movement in some sense. I just thought that was kind of cool, that people are like, doing this. I'm sure there are plenty of use cases, right, for this kind of stuff. I just thought it was kind of cool. So, the point is, researchers have been studying this algae for well over a century

• 28:09Krishna Choudhary?

  because it's really, really cool. The fact that a unicellular organism can respond to light that, just from a fundamental biology perspective.

• 28:18Lester Nare?

  There's so many different questions and experiments you'd want to do with that, knowing that that's there.

• 28:22Krishna Choudhary?

  Exactly. Now, the quest to uncover the molecular mechanism underlying this phototactic behavior, that takes a turn when Peter Hegeman, our first Nobel laureate that we're going to talk about, he recently graduated with his PhD from Dieter Osterheld's lab at the Max Planck Institute. The, the guy who did the first proton pump.

• 28:42Lester Nare?

  Yep.

• 28:42Krishna Choudhary?

  Okay?

• 28:42Lester Nare?

  Yep.

• 28:42Krishna Choudhary?

  So, graduated with a PhD from that lab. He joins the laboratory of Kenneth Foster in Syracuse University.

• 28:49Lester Nare?

  The lineage thing is always so interesting.

• 28:51Krishna Choudhary?

  It is.

• 28:51Lester Nare?

  When we talk about the story, because it really does kind of matter.

• 28:54Krishna Choudhary?

  It really does matter, right? He, he, he goes to get his PhD from the guy who

• 28:58Lester Nare?

  The guy.

• 28:59Krishna Choudhary?

  is, is the, the premier guy for bacterial phototaxis. And then, he starts worrying about, okay, this eukaryote, this algae, how does it do it? He wants to understand the biophysical basis for these photos receptor currents. And in 1991 and in 1996, he comes out with these papers that show The photoreceptor currents in wall deficient algae mutants. So there you you've got like a pipette that kinda is stuck to the algae. And from that now you can record the activity of the algae and you can see like, how fast is the light response? And look at the time scale on that light response.

• 29:38Lester Nare?

  That's what we're talking about.

• 29:38Krishna Choudhary?

  That's one millisecond.

• 29:39Lester Nare?

  That's what we're talking about.

• 29:40Krishna Choudhary?

  That's what we're talking about, okay? Immediately when you see that, you go, nice.

• 29:45Lester Nare?

  We got him.

• 29:46Krishna Choudhary?

  We got him, right? This is in 1996. Hegeman comes out with this paper.

• 29:50Lester Nare?

  Okay.

• 29:51Krishna Choudhary?

  Now, this one millisecond time scale, it's hard to reconcile this with what we normally know about rhodopsins. For example, the vertebrate rhodopsin, the visual rhodopsin that's in our rods and cones in our eye, here's how it works. There's the opsin, which is the optical element, the the protein that has the optical ability to to take in light. That thing is coupled to a G protein receptor. So it's called a G protein coupled receptor. And the signaling happens in a cascade.

• 30:28Lester Nare?

  Okay.

• 30:29Krishna Choudhary?

  Okay, so the light absorption initiates some kind of biochemical signaling cascade that ultimately then regulates a cyclic GMP gated ion channel that then causes depolarization to then give us the sensation of light.

• 30:44Lester Nare?

  And so this is a multi-stage process where light is an instigator and now three other downstream steps.

• 30:51Krishna Choudhary?

  Yeah, and then there's an ion channel.

• 30:53Lester Nare?

  Then there's an ion channel that the drawbridge opens.

• 30:55Krishna Choudhary?

  Yeah.

• 30:55Lester Nare?

  And there's like these two intermediate steps.

• 30:57Krishna Choudhary?

  Exactly. Now presumably this is not going to be that fast, though.

• 31:01Lester Nare?

  Right.

• 31:01Krishna Choudhary?

  Right?

• 31:01Lester Nare?

  Because there's there's a lot going on.

• 31:03Krishna Choudhary?

  There's a lot going on there in between. And so there's gonna it's gonna take time, not that much time, but not a millisecond, right? A millisecond is telling you that the left part, the opsin part, which is the light detector and the ion channel part are somehow a single entity.

• 31:22Lester Nare?

  So I think I get what you're saying. By the fact that we could see that this was happening at a response time that was at millisecond time scales, there is some other relationship between the opsin and the ion channel that we're not seeing that is not necessarily related to this G protein.

• 31:35Krishna Choudhary?

  Yeah.

• 31:36Lester Nare?

  And cascade that that was the starting point.

• 31:40Krishna Choudhary?

  Exactly.

• 31:40Lester Nare?

  Okay.

• 31:41Krishna Choudhary?

  That's the point, right? So in the early 2000s, Hegeman and his colleagues, they start investigating what is the molecular basis for that phototaxis, okay? In the 90s, he's established that this thing is fast. The 2000s, he gets his own lab and he's like, I'm gonna go after it. Okay, I'm gonna see what exactly is happening. Now, traditional biochemical approaches, they're difficult because these proteins are present in very low abundance. They're only in the eye spot and even then it's not a lot of them. And it's difficult to purify in the traditional sense. So the research team pursues a different molecular approach using genes. They want to identify candidate genes. And one thing that they piggybacked on

• 32:22Krishna Choudhary?

  is the fact that the blue, the algae's expressed sequence tag database, this is by Asamizu and other authors in 2000, they had already published the sequence tag database for this algae. Okay, so the genetic data is now available for people to try and access.

• 32:46Lester Nare?

  And they didn't need to create that from scratch.

• 32:48Krishna Choudhary?

  Exactly.

• 32:49Lester Nare?

  So they were be able to piggyback again.

• 32:52Krishna Choudhary?

  Science is interdisciplinary, right? Only three people got the Nobel Prize, but there there are multiple people that are involved in this research, right? And it wouldn't have happened without the entire community going after this problem. I wanted to make that clear. So in the early 2000s, three research groups, one led by Peter Hegeman, but another one by John Spuditch and then Toshio Takahashi, they independently identified the DNA sequences that encode for these proteins. What they look for is a protein that looks kind of like the rod protein in our eyes. And that's exactly what they find. On the left is our vertebrate rhodopsin, right? This is the stuff that's in our rods. And on the right hand side is the protein structure of what they found.

• 33:35Krishna Choudhary?

  You can see that there's immediate similarities, right? All these alpha helices that are clustered around a central chromophore, right? And so what they can look for is analogs. You already know the the sequence over here from the Human Genome Project and all that other stuff. And then you can look for homologues in the algae.

• 33:56Lester Nare?

  And so we already had this database that was done previously. We know how it works in the humans and we're basically saying, okay, in this database, what looks like the thing that we have on the human side?

• 34:05Krishna Choudhary?

  Exactly.

• 34:06Lester Nare?

  And as a way to identify where to do the work, where to start, like instead of doing a blind, like starting and

• 34:12Krishna Choudhary?

  Yeah.

• 34:12Lester Nare?

  Where do you begin?

• 34:12Krishna Choudhary?

  What do you even look for, right? The genetic sequence is massive.

• 34:15Lester Nare?

  Right.

• 34:16Krishna Choudhary?

  So from this, they identified two segments of DNA. They call it channel opsin one and channel opsin two. These are then put into the genetic databank. And now these are like maybe the thing that is creating the photo ability of these algae, right? The idea that these guys can maybe let the algae respond to light. Okay, the decisive functional breakthrough emerges when Peter Hegeman contacts George Nagel. Georg Nagel, I should say. Georg Nagel, strong electrophysiological expertise in studying ion channels and pumps. He has already used his expertise with

• 35:01Krishna Choudhary?

  pumps to look at how the the original, you know, the proton pumps that I was telling you about from Dieter?

• 35:08Lester Nare?

  Yeah.

• 35:09Krishna Choudhary?

  He put these inside the Xenopus levis usites, which are frog embryos.

• 35:14Lester Nare?

  Okay.

• 35:15Krishna Choudhary?

  Effectively. And he had figured out that these are proton pumps. That's how we know that they're proton pumps. This is the guy who did it. He genetically engineered frog embryos to express that particular protein and then you can actually characterize that this is a light driven proton pump. So he's already got expertise in doing this. So Peter Hegeman goes to him and he's like, look, I got these two pieces of DNA.

• 35:36Lester Nare?

  Yep.

• 35:37Krishna Choudhary?

  Chop one and chop two. And I want you to express them and study their function. In 2002, Georg Nagel, Ernest Bamberg and Peter Hegeman and their colleagues, they publish this seminal paper. This is the first of several papers that we're gonna go through that earns them the Nobel Prize. Channel rhodopsin one, a light gated proton channel in green algae. This is in Science, shout out AAAS.

• 36:02Lester Nare?

  Yes.

• 36:03Krishna Choudhary?

  So he showed that green light illumination can induce inward photocurrents that are primarily carried by protons. This is again, still protons. This thing is opening up. And if there's a gradient of protons, this thing is gonna let protons in, okay? Somehow the the algae maintains a gradient of protons. That's for another story.

• 36:22Lester Nare?

  Okay.

• 36:22Krishna Choudhary?

  But if there's already a gradient of protons, there's more protons on one side than the other. You open up this dam, the protons are gonna go through.

• 36:29Lester Nare?

  And not just a single one this time. It's gonna have the flow of multiple.

• 36:32Krishna Choudhary?

  Yes, exactly. It doesn't need light to do work. It's just opening up a dam.

• 36:36Lester Nare?

  Yep.

• 36:36Krishna Choudhary?

  Right? And this biophysical fingerprint provides the first direct evidence of light gated ion channels.

• 36:43Lester Nare?

  Okay.

• 36:44Krishna Choudhary?

  And this is the first time we got a formal designation, channel rhodopsin one. Okay, because now we've established that this is the protein that's doing it. This is amazing already, right? This thing can function as a light activated ion channel.

• 36:55Lester Nare?

  Yeah, yeah, yeah.

• 36:56Krishna Choudhary?

  It's already amazing.

• 36:57Lester Nare?

  Yeah, yeah, yeah.

• 36:57Krishna Choudhary?

  But it's not the complete story because the electrical response isn't particularly spectacular and it's doing protons, right? We would like something that messes around with sodium, potassium ions, things like that.

• 37:15Lester Nare?

  The things that are in the brain.

• 37:17Krishna Choudhary?

  In the brain, right? The stuff that the neurons use. Neurons don't use protons. Mitochondria use protons, but I want to turn on a whole cell.

• 37:24Lester Nare?

  This is cool. We we want to go to the the big leagues.

• 37:27Krishna Choudhary?

  Yeah, yeah. And so the next year, subsequent landmark paper by Nagel and his colleagues, channel rhodopsin two. This is the second piece of CDNA that they had identified. This is a directly light gated cat ion selective membrane channel. That word cat ion selective is massive here.

• 37:44Lester Nare?

  Okay.

• 37:45Krishna Choudhary?

  Cat ions are positively charged ions. This is a general purpose ion channel. You give it sodium, it'll let in sodium. You give it potassium, it will let in potassium, okay?

• 37:56Lester Nare?

  This is a big deal.

• 37:57Krishna Choudhary?

  This is a big deal.

• 37:58Lester Nare?

  This is a big deal.

• 37:59Krishna Choudhary?

  Right, this is the second protein channel rhodopsin two. And the other thing that I want to show you, this is again, he used the usite embryos to do this. In panel B, what you're seeing is the response time of this guy, right? Immediately it turns on and it actually plateaus. It's not like it turns on and then goes to baseline. The plateau, it still keeps producing a current. Even when you keep it on for a whole second, right? So the illumination is directly opened by this ion conducting pathway.

• 38:31Lester Nare?

  Good.

• 38:32Krishna Choudhary?

  And it's fundamentally different from the conventional G protein coupled stuff that we have in our eye because now this is directly light gated.

• 38:39Lester Nare?

  Yes.

• 38:39Krishna Choudhary?

  So this is a protein that absorbs light and then immediately just turns on. There's no intermediary.

• 38:44Lester Nare?

  There's no, none of those two steps that we talked about earlier. This is more that direct relationship.

• 38:50Krishna Choudhary?

  Yes, yeah.

• 38:51Lester Nare?

  From the initial image.

• 38:52Krishna Choudhary?

  Exactly, and that's why we're getting that really fast time scale of work.

• 38:56Lester Nare?

  Okay, okay, okay.

• 38:58Krishna Choudhary?

  This was an amazing paper that was out in Proceedings of National Academy of Sciences. And the researchers immediately recognized a potentially much broader implication. If this protein is expressed in an unrelated cell and if that cell could then be made to be electrically electrically responsive to light, then you can use it to control cells in general.

• 39:21Lester Nare?

  Yeah, right.

• 39:22Krishna Choudhary?

  Right?

• 39:22Lester Nare?

  Right, it's a platform.

• 39:23Krishna Choudhary?

  And in that work, the last line is actually quite amazing. This is the last line of their paper in 2003. Additionally, we have shown that expression of channel rhodopsin two in usites or mammalian cells may be used as a powerful tool to increase cytoplasmic calcium two plus concentration. Or to depolarize the cell membrane simply by illumination.

• 39:45Lester Nare?

  That's so crazy.

• 39:46Krishna Choudhary?

  Right? So you are literally mimicking synapses in some sense. Like when a bunch of neurons synapse onto a particular neuron, they release calcium 2 plus ions. And then those calcium 2 plus ions go inside, or they release a bunch of neurotransmitters. That induces the calcium 2 plus ions to go inside the cell, depolarize the cell and create an action potential. Here, you're opening up the calcium 2 plus ions, the channel, and the calcium 2 plus ion goes in, depolarizes the cell membrane simply by illumination.

• 40:15Lester Nare?

  We now have this understanding of this like cellular channel of communication that we can then now use to go back to our two way street. We could always read.

• 40:26Krishna Choudhary?

  Yeah.

• 40:27Lester Nare?

  We were trying to figure out what language, how can we write with those three elements? We talked about at the beginning.

• 40:32Krishna Choudhary?

  Yep.

• 40:33Lester Nare?

  The time responsiveness, the experimental reproducibility. And there was a third one that's escaping me.

• 40:38Krishna Choudhary?

  Reversibility, time and genetics specificity.

• 40:42Lester Nare?

  And we kind of have now hit.

• 40:43Krishna Choudhary?

  Yeah, we've hit them all.

• 40:44Lester Nare?

  All three of those in that 2003 paper.

• 40:47Krishna Choudhary?

  Yes, exactly.

• 40:49Lester Nare?

  Yeah.

• 40:49Krishna Choudhary?

  Yeah. And so now the next step is how do we go from a microbial ion channel to now optical control of neurons? Right? You said that that could work.

• 40:57Lester Nare?

  Right.

• 40:57Krishna Choudhary?

  But now we need to make this kind of a general purpose thing. Right? How do we, how do we do it for like anything?

• 41:03Lester Nare?

  It theoretically could work.

• 41:04Krishna Choudhary?

  Yes, that's what they said, 2003.

• 41:06Lester Nare?

  Theoretically.

• 41:07Krishna Choudhary?

  So let's talk about neurons just in general, real quick. Neurons are electrically excitable cells. They work with ion channels that open and close and let in sodium and potassium. Now crucially, these things are voltage gated ion channels. Here's what I mean by that. The protein in its native state is closed. And now let's say I get a bunch of calcium 2 plus coming in because of either channelrhodopsin or because synapses put in a bunch of neurotransmitters. And then now that leads to a bunch of calcium 2 plus coming in. That's going to change the voltage across the cell. Right? If you change the voltage across the cell, you've got an electrical force, an electrical field. And that literally changes the shape. So it's a voltage gated ion channel

• 41:52Krishna Choudhary?

  because it's an ion channel that turns on or off depending on the voltage. And if I can control the voltage by letting in calcium 2 plus ions, then I can control these voltage gated ion channels. And that is going to create my action potential that goes from one place to the other. Right? The key question now is whether the relatively small photo current that is produced by the channelrhodopsin is enough to trigger all of the rest.

• 42:16Lester Nare?

  Right, right.

• 42:17Krishna Choudhary?

  Right? Because usually the synapses, they dump a bunch of neurotransmitters, a bunch of calcium 2 plus goes in. And then that causes the membrane potential to change that causes this cascade effect. Can channelrhodopsin do this?

• 42:27Lester Nare?

  Right, across this.

• 42:29Krishna Choudhary?

  Yeah, yeah, yeah. Can it, can it trigger the?

• 42:31Lester Nare?

  The runaway cascade.

• 42:33Krishna Choudhary?

  Cascade, right? It's, you can imagine neurons are like in this unstable equilibrium of like an inverted pendulum.

• 42:38Lester Nare?

  Okay.

• 42:38Krishna Choudhary?

  And it needs a kind of kick.

• 42:39Lester Nare?

  Yeah.

• 42:40Krishna Choudhary?

  To like go down and, and fire.

• 42:42Lester Nare?

  Yep.

• 42:42Krishna Choudhary?

  Right? But is the channelrhodopsin kick enough?

• 42:45Lester Nare?

  To have it?

• 42:45Krishna Choudhary?

  Right? That's the question.

• 42:47Lester Nare?

  That's a great visual.

• 42:47Krishna Choudhary?

  So in 2005, Ed Boyden, Feng Zhang, George Nagel, and Ernst Bangberg and Carl Deisseroth, they publish one of the field's defining papers. This thing has like 5,000 citations by now. It's in Nature Neuroscience, Millisecond Timescale Genetically Targeted Optical Control of Neural Activity. And this is where we get all three.

• 43:10Lester Nare?

  This is the translation now to, from the algae now neurons.

• 43:15Krishna Choudhary?

  Yeah. This paper demonstrates that you can take channelrhodopsin and you can express it in mammalian neurons and use that to trigger action potentials with millisecond time scale precision. So I want to talk about those two second authors. Okay, Carl Deisseroth is on the left. He's the one who won the prize. Ed Boyden was a PhD student at the time. He kind of was at the start of this whole thing. He did a lot of the work and he hasn't gotten the prize. He's at MIT right now. There's going to be a lot of drama out there about why he didn't get it. The third guy Feng Zhang, this is the second time that he's. Because the first time we talked about was CRISPR.

• 43:56Lester Nare?

  Oh, that's right.

• 43:56Krishna Choudhary?

  That's the same Feng Zhang. He's the same guy who, who, who used CRISPR to finally, to finally create a type of programmable genetic scissor in mammalian cells. Remember, we had the whole drama between Berkeley and MIT. Berkeley was Jennifer Doudna. This is the MIT guy who has the patent.

• 44:17Lester Nare?

  I don't know.

• 44:19Krishna Choudhary?

  And this is the second time.

• 44:20Lester Nare?

  That's tough.

• 44:21Krishna Choudhary?

  It's tough, bro. It's crazy that he, he's been at the forefront of both CRISPR and optogenetics.

• 44:27Lester Nare?

  That's actually pretty crazy, like.

• 44:28Krishna Choudhary?

  Yeah, I mean, the guy's a beast.

• 44:29Lester Nare?

  Yeah, that's, yeah, okay.

• 44:31Krishna Choudhary?

  So, but, but you know, MIT Broad Institute just getting shafted.

• 44:36Lester Nare?

  I played the fifth.

• 44:37Krishna Choudhary?

  Yeah.

• 44:37Lester Nare?

  You know who didn't get shafted last year? Princeton.

• 44:40Krishna Choudhary?

  Yeah, that's right. And perhaps coming, coming this year, tomorrow or the day after. In any case, so here's what the experiment was. It was conceptually quite simple, but it's technically very, very important. This is a Nobel Prize committee reproduction of some of their work. They took hippocampal neurons in a Petri dish. So from the hippocampus, mammalian hippocampus, they expressed channelrhodopsin in those hippocampal neurons and showed that the hippocampus can actually affect the, the firing of the neurons. The light can actually affect the firing of the neurons. Also, with suitable illumination, the depolarization can be controlled, like the amount of depolarization can be controlled, right?

• 45:25Krishna Choudhary?

  The intensity of the light will tell you sort of how much firing happens.

• 45:31Lester Nare?

  You turn the volume dial to 11, the depolarization has, is, is at a discrete point that's similar to that volume 11. You turn it to five, it looks like. So you now have a granularity of control where the intensity of light actually drives the level, like how the depolarization.

• 45:49Krishna Choudhary?

  Yeah.

• 45:50Lester Nare?

  Happens.

• 45:50Krishna Choudhary?

  Yeah.

• 45:51Lester Nare?

  Which then gives you more degrees of movement when you're trying to.

• 45:55Krishna Choudhary?

  Exactly.

• 45:55Lester Nare?

  Do this, okay.

• 45:56Krishna Choudhary?

  Yeah. And you can, you can get reliable spiking frequency of tens of hertz, which is on the order of what, you know, normal neurons would do in a brain. Now, this is extraordinary because one, it shows the molecular machinery that was discovered in the green algae. You can now express it inside mammalian neurons.

• 46:12Lester Nare?

  Yep.

• 46:14Krishna Choudhary?

  The protein is genetically encoded. So once you put the gene into the neuron, the cell can produce the light sensitive channel by itself.

• 46:21Lester Nare?

  You don't need to keep pumping stuff in.

• 46:23Krishna Choudhary?

  Exactly. It'll just make the channelrhodopsin on its own. And the channelrhodopsin will go and be expressed on the membrane because the cell kind of knows what to do with it.

• 46:31Lester Nare?

  This is quite nice.

• 46:31Krishna Choudhary?

  In some sense, right? And the other thing is the chromophore that's in the middle of this whole thing. The protein surrounds, it's a bunch of alpha helices that surround a chromophore that is the actual thing that absorbs the light. That chromophore, retinal, is naturally found in mammalian tissue at exactly the right concentration. So you don't need to keep pumping this cofactor into it. Right?

• 46:56Lester Nare?

  Like we talked about earlier. Uh huh. There's, there's an abundance of the source material.

• 47:01Krishna Choudhary?

  Exactly. So all you have to do is somehow figure out how to encode the gene and express that gene.

• 47:05Lester Nare?

  That's.

• 47:06Krishna Choudhary?

  That's all you gotta do.

• 47:07Lester Nare?

  Okay.

• 47:07Krishna Choudhary?

  Right?

• 47:07Lester Nare?

  That's a big deal.

• 47:08Krishna Choudhary?

  The other thing, that third thing, is reversible. Yes, the stimulation is reversible. So on the left hand side, we're seeing the thing turn on for a particular amount of time in the blue. Boom, boom, boom, boom, boom. It fires. You turn it off, goes back, doesn't fire. On the right hand side, we actually see the other neurons that are not related to the specific one. Other neurons can actually stop firing because this particular neuron that started firing is maybe inhibiting that one.

• 47:36Lester Nare?

  Yep, yep.

• 47:37Krishna Choudhary?

  Right? So you can have second order effects and actually start looking at how do networks behave?

• 47:42Lester Nare?

  This is, yeah, now we can, yeah, exactly.

• 47:44Krishna Choudhary?

  You can be like, well, this neuron was definitely affected by this one, but I never expressed channelrhodopsin in this one. So it's got to be tied together as part of the same network. Right? And that same year, so this was in 2005, that very same year, paper after paper about channelrhodopsin. Deisseroth's was the first one. But that same year, we've got independent studies published within a year that confirms the efficacy of channelrhodopsin in controlling the activity of hippocampal neurons. That's Lee et al. in 2005. Lee is in Stefan Herlitz's lab at Case Western. We also have motor activity in the embryonic chick spinal, spinal cord, also by Lee.

• 48:27Krishna Choudhary?

  Behavior in C. elegans, which is huge. C. elegans is the model organism for so much developmental studies. And reinforcement learning in Drosophila by Schroll.

• 48:38Krishna Choudhary?

  So we're seeing this being applied to different types of organisms, living organisms, right? It's happening.

• 48:45Lester Nare?

  This is, and this is what we talk about when you say, you know, the idea is that, you know, usually get a Nobel, you wanna see all the labs have, all the universities have a lab that is doing work in this area. You're seeing multiple unlocks from some fundamental discovery point, you know, and then usually you'll then wanna see like how it then has positive impact.

• 49:12Krishna Choudhary?

  Yeah.

• 49:12Lester Nare?

  At some endpoint, but at first it has to be something that starts to spread.

• 49:16Krishna Choudhary?

  Yeah.

• 49:17Lester Nare?

  And becomes a fundamental basis for some area of study.

• 49:19Krishna Choudhary?

  Yeah, yeah. And Dyseroth's lab really took that to the max because he's the first guy who had, he had Ed Boyden, he had Feng Zhang. He, he kind of got lucky in being at Stanford and having these amazing scientists, you know, who are postdocs and grad students at the time. So now the term optogenetics captures the central idea of this technique, right? You're combining genetic targeting with optimal control, with optical control, right? The genetics provides that specificity.

• 49:48Lester Nare?

  Which is such a not like as, for me, it just seems so unintuitive or non-intuitive that you would be able to have genetic control via light.

• 49:57Krishna Choudhary?

  Yeah.

• 49:58Lester Nare?

  And then not only that, but then you could use it specifically for this idea of controlling ion channels.

• 50:03Krishna Choudhary?

  Yeah.

• 50:04Lester Nare?

  By which you could then now have a two-way street to better understand like neural activity. That connecting what's happening at the micro level of biology to the end behavior, human behavior that we.

• 50:19Krishna Choudhary?

  Well, we haven't gotten to behavior yet.

• 50:21Lester Nare?

  But like, that's the idea, like, that's where we're going.

• 50:23Krishna Choudhary?

  That's where we're going, yeah.

• 50:24Lester Nare?

  Is so, I'm like, it's already so crazy.

• 50:27Krishna Choudhary?

  Yeah, it's already so crazy and.

• 50:28Lester Nare?

  We haven't even gotten to the second piece.

• 50:30Krishna Choudhary?

  Yeah, yeah. The, the second piece is now we wanna make this thing better, both in terms of genetic specificity and the general use case.

• 50:37Lester Nare?

  Yeah.

• 50:37Krishna Choudhary?

  And in terms of, we wanna make the, the channel rhodopsin itself better, okay?

• 50:41Lester Nare?

  Okay.

• 50:41Krishna Choudhary?

  So the first piece is, how do we, how do we express this in living organisms at a general level? Like suppose I wanna target this particular neuron, right? How do I do that? Well, I can set up a viral vector, or I can create transgenic animals. And that's what these papers did. This was in 2006 by Beetall, Ishizuka, and Zhang. These are the three papers that I highlighted. Specifically what you do is you create a viral vector, a kind of genetic element that has a part that recognizes a specific type of neuron, and another part that has the genetics for channel rhodopsin. This thing goes into the specific neuron that it recognizes, and then that specific neuron, because it has the

• 51:24Krishna Choudhary?

  other part, the channel rhodopsin part, that's gonna, it's gonna express channel rhodopsin. And now I can very specifically target those neurons. The beauty of this approach is that the light itself is not specific, right? I'm lighting up the entire tissue, but only the neurons that I targeted genetically are the ones that have the ability to actually respond to the light, right?

• 51:46Lester Nare?

  It's the, this delivery mechanism that allows a singular outside light source, but then targeted internal activation.

• 51:53Krishna Choudhary?

  Yeah. And that becomes super important in some of the later studies that we're gonna see. Now, the next thing we wanna do is also make channel rhodopsin a bit more general, because right now it's cation specific, right? It's positive ions. Positive ions mean that the neuron is going to fire, because it's going to create the correct type of voltage to make that runaway effect. What if I wanna silence the neurons? Then I need cholinergic activation, meaning like chlorine ions, negative ions need to go through, so that the voltage becomes opposite and it shuts off the neuron. So Feng Zhang comes out with this paper, Multimodal Fast Optical Interrogation of Neural Circuits, again with

• 52:35Krishna Choudhary?

  Carl Dyseroth in 2007. And this is where he introduces the chlorine version.

• 52:41Lester Nare?

  They were going off in the 2000s.

• 52:43Krishna Choudhary?

  They were going off, Dyseroth's lab.

• 52:44Lester Nare?

  They were going off.

• 52:45Krishna Choudhary?

  Yeah, this is two years later.

• 52:46Lester Nare?

  Yeah, that's the reason I feel like 2007.

• 52:50Krishna Choudhary?

  Yeah, which means that they had already, like, by the time that they had published 2005.

• 52:53Lester Nare?

  Right.

• 52:53Krishna Choudhary?

  They were already in on this.

• 52:54Lester Nare?

  Right, right.

• 52:55Krishna Choudhary?

  And they're like, this is clearly what's next. And over there you can see the, the cation version, you turn it on, boom, lots of spiking. The, the chlorine version, there's a lot of spiking, you turn it on, spiking stops.

• 53:08Lester Nare?

  So good.

• 53:09Krishna Choudhary?

  Right? Amazing. And so this, that was halorodopsin, which is, it's a microbial light-driven chlorine pump that they've now used for this exact purpose.

• 53:22Krishna Choudhary?

  Right? And now, the last thing that Dyseroth's lab did, that, I mean, it's not the last thing, but the last thing in terms of increasing the efficacy of this stuff, is they developed cheetah, that's the, what we're seeing over here, ultra-fast optogenetic control in 2010. On the left-hand side, what you're seeing is normal channel rhodopsin, okay? You see the, the little blue ticks?

• 53:46Lester Nare?

  Yep.

• 53:46Krishna Choudhary?

  That shows when channel rhodopsin went on. And you can see that, you know, there's a bunch of spikes, but there's extra spikes. You don't just get one spike. You get extra spikes, and then there's kind of a trailing off of the membrane potential, because like, the thing depolarizes, but then it kinda just stays, because maybe the, the channel rhodopsin itself has a kind of relaxation time, right? That it opens really quickly, so that's good, but I wanna be very, very precise.

• 54:14Lester Nare?

  And, and so this is where we're seeing that kind of like that, that little hill here on the, on the left in the top charts, but we basically effectively only wanna have a spike with as minimal amount of drop off as possible.

• 54:25Krishna Choudhary?

  Yes. I, I don't want a prolonged depolarization. I wanna boom, and then I want you to turn off. And that's cheetah on the right-hand side.

• 54:31Lester Nare?

  Yeah, you can see.

• 54:32Krishna Choudhary?

  You see? Same time scale.

• 54:33Lester Nare?

  Yeah.

• 54:34Krishna Choudhary?

  But now I'm affecting single spikes.

• 54:36Lester Nare?

  Yeah.

• 54:38Krishna Choudhary?

  Isn't that insane?

• 54:39Lester Nare?

  Yeah, with no prolonged, yeah. And it's, it's also, this is all just.

• 54:43Krishna Choudhary?

  Right? It's amazing. And then on the lower, you can see that like, sometimes the, the cell gets, the, the channel rhodopsin gets tired.

• 54:50Lester Nare?

  Yeah.

• 54:51Krishna Choudhary?

  And you get missed spikes, because it's been firing for so much, sometimes it gets tired, the cell gets tired. With cheetah, because it's so precise, you can just go.

• 55:00Lester Nare?

  Yep.

• 55:01Krishna Choudhary?

  It's like a metronome. You don't miss any spikes, right? This is the kind of stuff that is required to really now dig in to how neurons are working, right? These faster variants allow more precise control of high-frequency neurons, if we wanna do that. It's made possible the production of sustained changes in neural activity. It's, it's, it's huge, right? So the evolution of channel rhodopsin, like, there's a larger point about the nature of technological breakthroughs in biology.

• 55:30Lester Nare?

  Yeah.

• 55:30Krishna Choudhary?

  You start with something and you just make, keep getting better and better, because you start seeing the efficacy of the tool, and you start honing in on exactly what you want for each use case.

• 55:41Lester Nare?

  And, and it is a tool, and then different people are gonna use that tool for different purposes. And then ultimately, you know, we, we, we get this better understanding because, like everything, like humanity in general, like we, we've just continued to make better tools, which have allowed us to then have better outcomes, because we better understand the world around us at an increasingly large scale and increasingly small scale.

• 56:07Krishna Choudhary?

  Yeah. Absolutely incredible.

• 56:09Lester Nare?

  This, this, this is good.

• 56:11Krishna Choudhary?

  Yeah. We've gotten, we've gone to single neurons.

• 56:13Lester Nare?

  Yes.

• 56:13Krishna Choudhary?

  Now let's do circuits.

• 56:14Lester Nare?

  Yes.

• 56:15Krishna Choudhary?

  Okay? So this is what makes optogenetics particularly powerful for dissecting human circuits, for dissecting neural circuits, I should say. So here, in this paper, this is in 2007, what they're showing is an optical neural interface. Here, they're expressing it in a living mouse. They've used that viral vector type thing to target the part of the cortex that controls the whiskers, the mouse. We're trying to go from now neural circuits to behavior. This is the link. This is the paper that links the two. The idea is, if

• 56:58Krishna Choudhary?

  I, if I target the rodent motor system that is involved with the whisker deflection, can I make the whiskers deflect? The whiskers are how a lot of rodents, you know, sense their environment. If I turn these neurons on, can the whiskers deflect? That's a behavior response. This is the first time that this happens, okay? In 2007. And now at last, we finally have Francis Crick's theoretical vision.

• 57:22Lester Nare?

  Yeah.

• 57:23Krishna Choudhary?

  Right? Scientists can now control specific genetically ordained neurons in an alert animal using only light.

• 57:36Krishna Choudhary?

  Right, an alert, awake behaving animal using light.

• 57:40Lester Nare?

  I plead the fifth, but and we've talked about this so many times and every time we talk about it, I have the same reaction because I we're just so we're so brilliant and I think we're able to do things that part of the benefit of talking through this amount of detail is again, going to the specificity of, well, how is it that you know what's going on in the brain like, like, you know, or like, you know, science is not a black box.

• 58:04Krishna Choudhary?

  Yeah.

• 58:05Lester Nare?

  Right. And you can literally trace the lineage of this.

• 58:08Krishna Choudhary?

  Yeah.

• 58:09Lester Nare?

  Uh, and it start, you know, it kind of starts with Crick's kind of far fetched.

• 58:13Krishna Choudhary?

  Yeah, he said it's far fetched.

• 58:15Lester Nare?

  At the time.

• 58:15Krishna Choudhary?

  Yeah.

• 58:16Lester Nare?

  Um, but I know we still have a little bit more to go, but I just, this is so, the behavior piece is so interesting because it's a little bit, it's like different than the biological piece in terms of there's a, there is a huge leap here.

• 58:31Krishna Choudhary?

  Yeah.

• 58:31Lester Nare?

  Uh, to go to behavior and ascribing.

• 58:34Krishna Choudhary?

  Yeah.

• 58:35Lester Nare?

  The behavior to a very particular underlying change.

• 58:38Krishna Choudhary?

  Yeah, it's causality.

• 58:39Lester Nare?

  Right, it's that causality point and it, you want to be very sure.

• 58:43Krishna Choudhary?

  Yeah.

• 58:44Lester Nare?

  When you're saying that's what's happening.

• 58:45Krishna Choudhary?

  Mm hmm. And this tool lets you, lets you say that.

• 58:48Lester Nare?

  Very sure.

• 58:49Krishna Choudhary?

  It offers a way to selectively manipulate specific populations.

• 58:52Lester Nare?

  Yeah, yeah.

• 58:53Krishna Choudhary?

  So I'm going to just real quick, go through some of the work that has come about in optogenetics.

• 58:58Lester Nare?

  Yep.

• 58:58Krishna Choudhary?

  There's obviously a huge repertoire of work that we cannot get to.

• 59:01Lester Nare?

  Yep.

• 59:02Krishna Choudhary?

  Perhaps another episode that is based on, you know, what optogenetics has, has given us, but a few that I'll go into. Um, first one, Ilana Witten, Carl Diceroth and colleagues. Ilana Witten is Ed Witten's daughter.

• 59:16Lester Nare?

  Oh.

• 59:17Krishna Choudhary?

  Who's now at Princeton University.

• 59:18Lester Nare?

  Okay.

• 59:19Krishna Choudhary?

  She's a professor there.

• 59:20Lester Nare?

  Okay.

• 59:20Krishna Choudhary?

  In this particular paper, she used optogenetic approaches to investigate reward-related circuitry and dissected the role of cholinergic neurons that make up only 1% of the local neurons. Turns out they play a very specific and significant role in modulating driving behavior and like addictive behavior, like in this particular case, cocaine conditioning.

• 59:46Lester Nare?

  Okay.

• 59:46Krishna Choudhary?

  Right? So we can, we can now start targeting specific neurons and be like, yeah, this is actually involved in the kind of addiction and things like that, right? Um, you can also do optical manipulation of hippocampal circuits for learning and memory. This one's pretty crazy. One profound application is the search for the memory engram, which is the physical cellular substrate for encoding a specific memory. Like I've got a specific memory that lives somewhere in the brain, right? Very famously, Tsusumu Tonegawa, who is a Nobel Prize winner in his own right, in 1987 for the discovery of genetic principles underlying antibody diversity. He's seeking his second Nobel by searching for the memory engram.

• 1:00:31Lester Nare?

  Good on you. Good on you.

• 1:00:32Krishna Choudhary?

  Yep. He's, he's trying. What he wants to find is the cellular basis for like stored memories.

• 1:00:38Lester Nare?

  Yeah.

• 1:00:38Krishna Choudhary?

  Okay. In 2012, he published a paper with Liu and colleagues. It's a landmark paper in Nature that demonstrates optogenetic activation of a neural ensemble. It's associated with a particular experience that triggers the expression of fear. Okay, this is pretty crazy.

• 1:00:57Lester Nare?

  Yeah.

• 1:00:58Krishna Choudhary?

  This is pretty crazy. It's a striking demonstration of the possibility of like manipulating memory-related neural representations. Obviously, a lot of weird implications, also a lot of clinical implications.

• 1:01:11Lester Nare?

  For sure.

• 1:01:11Krishna Choudhary?

  For example, with PTSD, things like that, right? So it is worth being precise about what these experiments established, though. Like, you're activating a neural ensemble, you've targeted a bunch of neurons and you've activated them using this channelrhodopsin trick. Now, that does not mean that a complete, fully formed memory is literally stored in that population. Okay? Because memory is a weird thing. It depends on distributed networks, specific synaptic modifications, other brain networks that you might not have targeted. What this optogenetics tool is making possible is a causal test that, yeah, this particular set of neurons elicits a behavioral response.

• 1:01:49Lester Nare?

  Mm hmm.

• 1:01:49Krishna Choudhary?

  Okay? So I do want to make that distinction.

• 1:01:51Lester Nare?

  It's actually an important one, yeah.

• 1:01:52Krishna Choudhary?

  Yeah. And then finally, the last one I'll talk about is a causal link between manipulating dopaminergic activity and prediction and reward and the error from that prediction. Like I predict something, if I get it, that's good. If I don't get it, that's bad. The brain fundamentally is a kind of predicting machine, right?

• 1:02:14Lester Nare?

  Oh, are you saying we're just the next token prediction machine?

• 1:02:16Krishna Choudhary?

  Yeah, exactly. Well, this, well, this particular paper kind of says that. And actually, the model of prediction error is corroborated by some of these optogenetic experiments where what you can do is specifically target these dopaminergic neurons, make them fire when errors happen or when the prediction comes true and see how the circuit adapts, right? So you can literally now causally test this model of prediction and error in this neural circuit.

• 1:02:50Lester Nare?

  Mm hmm. That's very nice.

• 1:02:51Krishna Choudhary?

  You can study much more complicated behavior. Diceroth, for example, has gone even beyond neuroscience.

• 1:02:57Lester Nare?

  Okay.

• 1:02:58Krishna Choudhary?

  Okay. Diceroth has demonstrated that the heart rhythm can affect our emotions because he's developed another type of extrasensitive opsin called kermine. I think it's channelrhodopsin mean, and that thing is so sensitive that you can put it deep within the body and it'll still respond to the light, right? So you can stick it in the heart, in the, in the neural circuitry in the heart that controls heart rhythm. And now you can shine light on it through the muscles and everything.

• 1:03:27Lester Nare?

  Oh, that's, that's really, yeah.

• 1:03:28Krishna Choudhary?

  And then the heart is going to now start beating faster and that has an effect on the brain in terms of anxiety. Right? It used to be thought that, no, the brain is doing the anxiety part down.

• 1:03:38Lester Nare?

  Right, right.

• 1:03:39Krishna Choudhary?

  But actually, there's something going up as well. It's a two-way street.

• 1:03:42Lester Nare?

  It's, it's, it's starting to sound like that street in, uh, in, uh, Hollywood where it's like six, it's a circular six entryway.

• 1:03:50Krishna Choudhary?

  Yeah. Oh, yeah, yeah. In Beverly Hills.

• 1:03:52Lester Nare?

  Beverly Hills.

• 1:03:53Krishna Choudhary?

  Yeah, yeah.

• 1:03:53Lester Nare?

  In Beverly Hills.

• 1:03:54Krishna Choudhary?

  That was the worst stop sign in LA.

• 1:03:56Lester Nare?

  Yeah, yeah.

• 1:03:56Krishna Choudhary?

  Yeah, exactly. I mean, the, the body is a complicated thing, right?

• 1:04:00Lester Nare?

  Hundred percent.

• 1:04:01Krishna Choudhary?

  Um, optogenetics is most closely associated with neuroscience, but it's got a much broader significance. As we just showed, it's, it can be used to talk about the heart. Light-sensitive proteins can be engineered to regulate intracellular signaling pathways inside the cell. They can be used to control light-sensitive systems like Ro family GTPases, which are another set of cytoskeletal proteins that like can make the cell move and contort. In development biology, light-sensitive tools can be used to investigate how, you know, spatially localized tissue becomes what they are as the animal grows up, right? You've got a ball of tissue. How does this know to become the head and this become the tail?

• 1:04:46Lester Nare?

  We talk about it all the time.

• 1:04:47Krishna Choudhary?

  We talk about that all the time. That's a, that's a problem that can be used, that optogenetics can be used for. So it's, it's huge, right?

• 1:04:54Lester Nare?

  Yeah.

• 1:04:55Krishna Choudhary?

  And finally, um, there is hope for new medical treatments. I mean, beyond just the fundamentals of understanding how the brain works.

• 1:05:02Lester Nare?

  Yeah.

• 1:05:03Krishna Choudhary?

  Right? That is going to clearly give us a better understanding about depression, anxiety, PTSD, Alzheimer's, dementia, Parkinson's, you name it, right? At the end of the day, understanding the brain at a fundamental level is going to give us insights into all of these.

• 1:05:19Lester Nare?

  You name it.

• 1:05:20Krishna Choudhary?

  Ailments, right?

• 1:05:21Lester Nare?

  Yeah.

• 1:05:21Krishna Choudhary?

  Because fundamental science, I think, happens first. But in a very direct sense, it's also used as the first step towards an optogenetics treatment for blindness. So there's ongoing clinical trials that are happening to restore vision in people who have become blind due to retinitis pigmentosa. It's a disease that destroys the rods and cones. Here, they've interest, they've inserted channelrhodopsin-like proteins into the eye of a blind person. Those neurons then express.

• 1:05:55Lester Nare?

  Yep.

• 1:05:56Krishna Choudhary?

  Channelrhodopsin. And now the person has regained some kind of vision. This is a paper that shows like special glasses that emit light into the person's eye and then that person is able to discern and grasp objects, someone who was, you know, previously blind.

• 1:06:13Lester Nare?

  That's, I mean, again, it is, both things are now concurrently happening, which is the expansion of the basic and fundamental research across, you know, all of the areas of the human body, not just the brain. But we are in the clinical trial phase for applied, you know, clinical or medical outcomes

• 1:06:34Krishna Choudhary?

  Yeah.

• 1:06:35Lester Nare?

  that are impacting people's real lived experience.

• 1:06:38Krishna Choudhary?

  Yeah.

• 1:06:40Lester Nare?

  And like, obviously, we're human beings, our eyesight is so, such a core part of what, how we experience the world.

• 1:06:46Krishna Choudhary?

  Exactly.

• 1:06:46Lester Nare?

  If you have a very like effective way to restore that for people, what's not to love?

• 1:06:52Krishna Choudhary?

  What's not to love, right? And when we predicted, when we predicted optogenetics, there were a lot of comments that were saying that this is going to clearly lead to zombies and mind control. Now, I'd like to brace that type of speculation. I don't think optogenetics is going to lead to zombies because I don't think, you know, we're going to get viral vectors in our brain anytime soon. On the other hand, the more we understand about the brain, the more nefarious applications can become.

• 1:07:23Lester Nare?

  Yeah.

• 1:07:23Krishna Choudhary?

  So, you know, there is some concern here that, like the memory engrams, right?

• 1:07:28Lester Nare?

  Yeah.

• 1:07:28Krishna Choudhary?

  Clearly, of course, it's going to be used for PTSD and clinical approaches to understanding trauma and maybe eliminating trauma, past trauma of an individual. That would be the dream. But at the same time, you know, with the advent of tools like Neuralink and AI compounding on the tools like Neuralink, you can imagine a world where things get very scary.

• 1:07:54Lester Nare?

  Yeah.

• 1:07:54Krishna Choudhary?

  Right? We've, we've discussed on this podcast several brain machine interfaces, like the reading inner thoughts.

• 1:08:01Lester Nare?

  Yep. That was a good, that was a good one.

• 1:08:03Krishna Choudhary?

  Yeah. So, you know, putting this in the context of all of the neuroscience that we've looked at, it's both something that gives us hope because optogenetics is an incredible tool that is going to let us understand very nitty gritty causal links between brain neural circuits and behavior and perhaps even maybe consciousness. That was another question that was asked during the Nobel press conference. And the person said, well, not yet, but maybe in the future. Maybe in the future, right? We'll get some idea. But at the same time, you know, we have to be vigilant of all of the other weird things that could happen because we learn more and more about the brain. Because the brain is really the organ that makes us us.

• 1:08:45Lester Nare?

  Yeah.

• 1:08:45Krishna Choudhary?

  And if we lose control of that, if we lose sovereignty over the brain, who are we in some sense, right?

• 1:08:52Lester Nare?

  Right.

• 1:08:53Krishna Choudhary?

  So, I, I mean, I've been calling optogenetics for a while, even before this podcast.

• 1:08:59Lester Nare?

  Yeah, yeah, yeah.

• 1:09:00Krishna Choudhary?

  So, the first year that we did this podcast, I said optogenetics. I recycled this year and I got it right.

• 1:09:05Lester Nare?

  And so, everyone who, anyone who said, oh, but you recycled, it's because it was correct.

• 1:09:09Krishna Choudhary?

  Yeah. Sometimes, sometimes you gotta recycle.

• 1:09:14Lester Nare?

  We have a lot of great previous episodes as well that touch on a variety of, of different areas in neuroscience. And it's, again, it's interesting how these things all connect. The Mylan sheath stuff we talked about, about how it then create the degradation of that and then the repair in order to have these action potentials and these ion channels continue to be able to operate. We did a whole deep episodes on that. This was, I think the, the Nobel Prize of Medicine deep dive last year and this year are two of my favorites because I think it's, um, sometimes for other subjects, it's hard for people to get how it relates to themselves. And this one feels very, can feel very personal. So, we are going to keep this tight today. We will be back again tomorrow, early morning,

• 1:09:58Lester Nare?

  for one of the favorites, which is going to be the Physics Nobel. For those of you who are joining us for the first time, welcome to the best science show on the planet. You can follow us on all of our socials at FFP Pod, as well as check out our episodes and all of the research papers that we covered in this episode. If you want to actually take a look at them, you can go to FFP Pod dot com. Each one of our episodes always catalogs all of the research papers we cover. And if you would like to watch, we're available on YouTube, all the podcast networks to listen as well. We appreciate you, as always, my favorite week of the year.

• 1:10:36Krishna Choudhary?

  Mm hmm. Nobel Prize week, baby.

• 1:10:38Lester Nare?

  How are you feeling about already being on the board after day one?

• 1:10:41Krishna Choudhary?

  I, I'm, I'm so happy because now there's no pressure for like physics and chem, you know?

• 1:10:46Lester Nare?

  Yeah, I've already done it.

• 1:10:48Krishna Choudhary?

  I already did it, yeah.

• 1:10:48Lester Nare?

  I already done it. Maybe we'll get Princeton on the board tomorrow, we'll see. My name is Asenara, joined as always by my co-host and our resident PhD and the oracle, Krishna, the oracle, Choudhary. We will see you all tomorrow for the Physics Nobel Prize.