Optogenetics: Controlling Your Genes with Light

my eyeballs and hits everything. I know. I that's actually that was a question of mine, like earlier about you know, could you just shine a light in somebody's eyeballs and make this work? And I that's probably the future, but who knows. It's not the it's not the present. Should fortunately know? So um soon enough, Chuck though, soon enough. Just hang on another fifty years. Okay. So we're talking today about opti genetics. And if that word doesn't sound

at all familiar, don't worry. It's only been around for honestly fifteen years. It's like the cutting edge in um manipulating the function of brain cells to make them do what you want to do or to study brain pathways to see which ones are responsible for what. And it's really really difficult to get across in the details. But it's one of those really interesting science tech things that

the broad Strokes are like really understandable, you know. Yeah, I mean you're literally one day, hopefully well I don't know about hopefully, but possibly going to be able to turn on and turn off uh neural cells. Yeah, after we have modified them, right, so we can control them. Yeah, and modify them genetically. That's a big, big key here, yes,

So but this is really important. Ed put this together for us, and he makes a really good point like if you read you know, kind of um cutting edge side tech articles about this stuff, it sounds like we're right there, like we're about to start, you know, flipping on and off neural neural circuits and humans any day. We're not. We are way far away from that. We're still figuring out like the ethical and legal implications of even beginning to try that. Yeah. I think the writers

like that get they get really excitable about stuff. They're like fruit flies are so boring, and they're like we could do this, and just think we could do this and this, and it's like maybe one day, many many years from now, but maybe not even yeah, because of that whole moral and legal and ethical implications of it. But I think, um, I think there are probably plenty of people out there who are, like, my depression is severe enough that I'm fine with the moral and ethical

implications of this. I just want this to to fix things for me, because it could conceivably someday. But we say that just to say, like, what we're talking about is on the front tier of science. Although some of the research that's been conducted has been successful, but it's just been conducted in things like mice and fish and fruit flies. Poor little well, we'll put a pin in that one, not literally, but well maybe yeah, poor little

fruit flies done some things to fruit flies. So here's the thing, right, the human brain is pretty complex as far as organs go. You compared to your spleen, your spleen is just gonna slink away and be like, there's no comparison here. I just produced bile, you know. So the brain is far more complicated than the spleen, which everybody, everybody knows. And the reason it's so complicated because there's so many specialized cells inside that brain. Neurons, right, Neurons

are just one tie put brains out. Yeah, and you know, we've talked about the brain a lot over the years on this show, and we always kind of come back to the same thing, which is as much as we've learned, which has been a ton, there's still a lot of shrugging in the room. Yeah for sure. Jeez, I don't know. I mean, but when you look at the hundred billion neurons and the quadrillion synapsies, yeah, thousand trillion, that's you know, give it, I'm giving humans a break here that we

haven't figured all of this out at this point. We haven't. And then you look at the brain it's just I mean, you look AT's just a big, gross, lumpy, gray mess. Yeah, it's like it's like a spleen on steroids. I know, Like, who even wants to get in that thing to begin with? People who like making squishy sounds at their finger. It should be shiny and sparkly, and god, you gotta stop doing that. It is a little sparkly though, if you think about it, like it's shiny because it's got it's

coated and it's bathed in cerebro spinal fluid. Remember, Yeah, I guess I've never seen a picture of the brain when it's really donuts thing. I didn't know it's so exciting looking, so so okay, So the brain is extremely complex, and we figured out some stuff about it. Um. Mainly what we figured out starting back in the nineteenth century that all of these connections, these thousand trillions and napses UM that that allow neurons to communicate with one another

and carry like an impulse through the brain. All that is based on electricity chemical electricity right to where there's a difference in the concentration of different types of ion, say like calcium in potassium in the cell, so that when it reaches a certain concentration, it actually generates an electrical impulse, and then that impulse can be translated or transferred to another neuron, and then that neuron may send that electrical impulse on and on and on until it

finally reaches its destination where suddenly you're you're flooded in dopamine and you're feeling pretty good because you just try to crispy cream that was fresh and hot right off of the line. Yeah, So like when you hear people say, or us say, like when your neurons are firing, that's literally what's going on. They are tiny little electrical charges. Uh, we can call them action potentials, and they measure them in tiny little Miller volts. It's adorable, it is. They

have little bow ties on and short pants. Yeah, but there's little tiny electrical triggers that go off constantly, right, right, so, or they don't go off, which which also has um in effect as well. Right, So, like you can have something firing firing and firing and that stops firing and you're suddenly not feeling pain any longer, which is great. So you want to have them on and off. But it all is based on electricity. And we figured this out thanks to a guy named Chuck. Are you talking

about Luis gi Galvani? Ye, yes i am. And you know that famous experiment with frog legs where you can take dismembered frog legs and sprinkled salt on them and they'll start twitching or whatever. Those are always creepy. Well, this same guy figured out that you could introduce electricity into the brains of frogs and you can make the frog legs kind of twitch and hop in the in the brain of a dead frog. So it shows pretty clearly that electricity is what move makes the brain move,

and that the brain is what makes the legs move. Right. And then later on there was a guy named m Robert's Bartholow. Boy, this guy, did you look up this experiment? I did pretty pretty pretty bad. Yeah. So there was a woman named Mary Rafferty who had an ulcer on her brain, which ended up resulting in a literal hole in her skull. So her brain was exposed, and Robert's Bartholow, I guess, was like, well, well, perfect, this is just what I've been waiting for, is access to a human brain.

So let me see if I can stimulate these neurons by looking at with needles her brain, and see what happens when I stimulate that with electricity. And he kept it super low voltage at first and noticed some things like wow, when I poke here, her arm moves right. He's like, does anyone have a question, But he ramped that electricity up at higher voltage, looking for what he called a more decided reaction, and he well, he argued afterwards that he did not cause her death, but she

had a seizure. She went into a coma and she died. Right, So the kind of the sticking point here is and he was censured by the A M A. But nothing really happened was that he was experimenting on a human being, but not with the aim of curing anything that was wrong with her. No. He even said in the study that he produced that anyone who tried to replicate this would be would be UM conducting like a criminal experiment. It may be criminal. Redo it. Yeah, I'm good, right,

I'm all good, but just don't do this again. But what's what was interesting to me is like it wasn't until six that we started to um, like the scientific community started to enforce informed consent after the Nazi atrocities of World War two. UM, And this guy was was carrying this experiment and I think in eighteen seventy four.

But even at the time, so in his defense, people weren't about informed consent, and there were like the ethics of scientific experiments weren't nearly as pronounced and structured as they are today. And yet his experiment was still denounced, like everybody could see that on some level that hadn't been like elucidated, yet he had violated something which is actually like the life of a person, like something's bothering me,

but I can't quite put my finger on it. Oh well, now he's hit me with the electric needles in my fingers, going exactly where he wanted to. Oh boy, the am A actually banned human experimentation if it was not for the purposes of saving a human life after this very good stuff. So what we figured out though from Galvani and um barth Bartho, Yeah, he's got a tough one, a tough last thing, Um and others who showed that electricity is the currency that moves messages around the brain.

Um that you can actually stimulate the brain with electricity to go around its internal drives and externally make it do things right. But the problem is is like if you're using the society of the brain, it's really clumsy. It really like an electrical impulse is really tough to

keep localized. So if you're trying to just kind of see what one particular type of neuron does, well, t s for you because you're electrically going to stimulate a whole bunch of neurons in the neighborhood and it's not a very um a fine tuned way of studying how the brain works. And again, it's really important that we understand what regions of the brain are responsible for what.

So if we're just kind of trying to see what regions are responsible for raising your arm, we might hit those neurons with electric needles, but we might also like kick the leg out too. That just kind of it's not as precise as it needs to be. Do you want to uh use this repeated metaphor? It was a fine metaphor, but it was a mixed metaphor, and the first one really didn't work. Yeah, let's just go ahead and say it, because it does get a little bit

more credible as the metaphor develops. But I agree this first one was a little rough. But just just take this metaphor, put in your pocket, everybody, and smoke it with some salt. I don't even know what that means. So imagine a neighborhood or a city, if you will, with all the people, let's say New York City and people everywhere moving around. These are your neural uh, this is your neural network. Everyone's going places. They're taking subways

to run busses or driving cards, are walking. Some of them have that have no conscience or in a horse and buggy in Central Park and it's not trade to the giant. He just stole it. And Uh, electrical stimulation, which is something that deep brain stimulation we've talked about on the show, with something we currently are doing and

are able to do just very imprecisely. So, Uh, that electrical stimulation is like trying to learn about people only driving Ferraris through New York City by setting a city block on fire. That's where it loses me because it doesn't make any sense. I just said, shocking entire city block. Sure, I guess so, Yeah, that would have made more sense, right. Yeah. I saw another analogy on you know how we always say when you can't understand something, go to like the

kids science website. Sure, I found one called Frontiers for Young Minds, and they were explaining up to Janet's and they basically put it similarly saying, if you wanted to study the movement of track Affrick in the city, Um, but you wanted to see like like you were saying, how ferrari Um car drivers drive. Um, you want to

be able to tell everybody when to drive. But the problem is if you're using an electrical stimulation that doesn't just tell Ferrari drivers when to drive and tells everybody in the city you want to start to start driving, and everyone starts driving, So it doesn't tell you anything about just the Ferrari drivers. Yeah, that makes sense. And by the way, Ferrari, you chucking me in Ferrari each for all this buzz Ferrari marketing. Ferrari, I would just

like to drive one once. That'd be fun. Don't don't set your slights higher than that, chuck. See if we can get a free one Ferrari, just stress me out. We'll sell it on Craigslist. I'm gonna park a Ferrari in my driveway backwards. You back it in? Oh goodness. Uh so should we take a break now that we have a nice little set up in hand. Sure, all right, let's take a break, and we're gonna talk about potassium and calcium and color dye right for this shock. Alright.

So people figured out pretty quickly that yes, electrical impulses will make parts of the brain work, but it's not very precise. We need a more precise way to study the different parts of the brain to see what's going on where at any given time. That's right, and enter Lawrence Cohen in the nineteen seventies, Leonard Cohen's brother. No it could be uh no, No, I was so disappointed. I thought, wow, that's amazing. All the genius in one family. Yeah,

it's a lot of genius. Uh And in nineteen eighty it was further developed by man named Roger CN, Leonard Cohen's one time stage manager. Okay, it was waiting on that is it c N? Is it c N d N? I don't know? T S I E N anytime your name starts with T S I seen one of those is silent. Yeah, but I think they together make a D sound. Oh really, I think so? In what language? Chinese, Mandarin, maybe Cantonese, one of those two. Okay, oh god, I feel like I'm drowning. It's okay, grab hold of me, thanks.

Uh So what they did was they worked on um this synthetic die UM, like I said, coming in the seventies, refined in the eighties by Roger T and Roger you already yeah, you already talked about in the intro about the action potential in a neuron that's created that little electrical charges. It's not like it's plugged into something. It's created by concentrations of potassium and calcium shifting around right right.

So what they figured out, what Um, Lawrence and Roger figured out is that you can actually introduce the synthetic die so that the dye is produced or triggered or it becomes a parent once calcium ion concentration reaches a

certain point. And if you know that a calcium ion concentration will trigger this action potential, this electrical impulse in the neuron, if the neuron suddenly is glowing or has this dye colored dye that's showing up under a microscope, you know that that neuron is just fired because the

calcium concentration changed enough for that die to become a parent. Yeah, it's like the very easy way to say this is scientists basically said, you know when someone uh metaphorically turns on a light and that neuron that'd be great an actual light turned on. Yeah, this is very similar to that for sure, And it's still was a little it's a little clunky, um because well, I'm not fully under I don't fully understand why it's a little clink. I think it's that maybe you can't control it. It's just

you can witness it. I think is the issue with it. Well, if we're going to further that metaphor, it's really giant to escate fast to this point, but go ahead. The next step would be, uh, you want to learn about these Ferrari drivers in New York City, So you just paint and inside and the entire city block instead of shocking it with electricity or setting it on fire. But any car that's driving on that city plot city block is gonna it's gonna glow or it's gonna move through

the paint. So you're gonna get car track. Sure, you're gonna get glow paint all over every car. You still are not just targeting the Ferrari. But it's better the metaphor. Sure, that's right, much better, but it's still not precise enough. And I think where it's lacking is that you, yes, you can see now what neuron has just gone off, but you can't make the neuron go off. But but um,

Lawrence and Roger gave future researchers an idea. They're like, wait a minute, we're onto something here, like being able to to to see when a neuron has gone off. That is a great idea. Let's figure out how to do that but also make neurons go off. And to do this they turn to our friends in the sea for help. Yeah, this is really interesting, and this is where um genetics come into play, because it is it

is important to point out that neurons are basically the same. Uh. They all contain basically the same genetic information even but it's that mystery of the differences switching these genes on and off, and why would one be switched on when

another switched off. That's sort of like what makes them unique among each other, right, right, So, like if you have a human cell, especially like say a stem cell or whatever, but any cell has all of the your genetic blueprint, and it's just depending on what genes are on or off that determines what kind of cell it is and what it's responsible for doing. You know. So maybe it's like a retinal cell and it detects light, or maybe it's a cardiac cell and it it makes

up heart muscle. All of them have the same DNA, the same genetic blueprint, but some of those genes are gonna be turned off, some are gonna be turned on. And the same is true for neural cells. To right, you have neural cells that are responsible for releasing dopamine. You have neural cells that are responsible for sensing temperature. Um. You have all these different neural cells, and all of them are roughly the same kind of cell, but they

have different genes turned on and off. And once you know that, and once you can differentiate between one gene and another, you've just taken your first step towards genetically manipulating these different genes, you know, and understanding Ferrari drivers exactly. So you brought us to the sea, and I jumped it right back out again, and now we are back at the sea like the manatee. That's right. But here this is where it gets super super cool. Uh. And

it sounds like it's confusing, but it's really not. It's really pretty simple still. Um. There are genes in mother nature that respond to light, and then there are proteins that emit light when they're triggered by something. Flores Yeah, I like to say glow. In fact, if you'll look here, I scratched out fluoresce every single time as you did glow. That's a lot of work you put into those, just a lot easier to say glow. I think people get it a lot better than Fluoresce. I watched Coming to

America the other day of Man Soul. Glow is so hilarious. It still holds up. That movie is even better than I remember. Actually it's great. Yeah, it's when we go back to a lot. Like I knew Eddie Murphy was a charmer, but dude, that guy is one charming human being. Yeah, all the all the barbershop stuff is just so classic. It's great, but all of it like it really, it's just a great, great movie. You know, they're sequeling that thing.

They've been shooting it in Atlanta. Sequeling or rebooting sequel Oh good? So uh. I mean, I think the the easiest way to go about a sequel is what they're doing, which is now King of Zamunda. Eddie Murphy has a son who wants to find his love. Yeah, but I think everyone's back, like our Cineo's back. Sure they Oh, I'm not gonna be mean good. They found him in great spirits and he was eager to work. He said, yeah, that's a great idea. I can fit it into my skin.

Then he went, whoo, who did you see the Grammy's the other day. I don't usually watch those either, but I happened to see the entire thing, and um, I didn't know that you were kidnapped and it was it was like um mel Gibson and um oh conspiracy theory. I was tied to a wheelchair and my eyes were taped open. So you watched all of it? Huh? Yeah, But I haven't watched all the Grammy since I was like thirteen, Bro, I haven't either. It was really something.

It's like a marathon or an ultrathon really, but um, Tyler the Cree eat or did like a live thing and it was amazing. Dude. I've never heard a single second of any of his songs or really him perform or anything, but um, I like that guy. Now, Yeah, he's great. And you know I listened to that early. I can't even remember the acronym, but his sort of hip hop collective band that they all started out of that,

like Frank Ocean came out of that. Tyler the Creator and a bunch of other guys whoa what's it called? Oh what was it? Do you know? Odd Future? And then it had another like five or six words after that Odd Future was the shortened version. Good stuff, very good stuff. Thanks to Josh T for swooping in and that uh that the first Frank Ocean album was is amazing. I've not heard that either. Oh man, it's so good Channel Orange. I think I'm always confused by rappers who

who just have normal names. Uh Frank Ocean. Yeah, he's kind of a singer, crooner type. I mean he does Okay, all right, now that makes sense. Yeah, he's he's awesome. So cheeze. That's how it happens. We're in the sea. We're in the ocean. The Grammys are over right. We have found genes that respond uh to light and also proteins and other organisms that emit light when triggered. I'll let you walk people through what those two things are. But the point is they said, we've got the two

components to make this happen. We can build we can control jenes turning on a light, and we can also see what happens when something responds to the light. We just need to be able to get these two things from two different organisms into one thing that we can control exactly exactly, And that's the entire basis of optogenetics. Um. I think you did a fine job of explaining it. Well, I didn't know if you want to talk literally about the jellyfish, and well sure so if you don't mind, no,

it's great. So the algae, like green algae, has something called an eye so it's like a single cell organism, right, yeah, And it has an eyehole which is light sensitive. It's a light sensitive area on the cell. And when sunlight hits that eyehole, it triggers the tail of the algae to start moving towards the sunlight so that that single cell algae can can maximize its exposure to sunlight as

much as possible. All right, So that's one half. You got the thing that sees light and reacts to it, right, And again, all this stuff has to do with ion channels. That has to do with the concentration of minerals inside and outside of these the cell in these channels, right, and that's what triggers this movement. That's what triggers the electrical impulse. That's the basis of all life apparently, are the movement of minerals inside and outside of cell membranes

triggering electrical impulses. That's life in that bizarre So then with jellyfish they have a similar thing too. We're not exactly sure why they fluoresce, but say like a predator comes up and they sense like a predator's coming, it might trigger a chain inge in their eye on concentration, which triggers a protein that fluoresces to be produced. So

the jellyfish starts to glow. And these are two separate things, but like you were saying, at some point, I think in two thousand five, a team led by Carl dis roth Um published a paper that said, hey, man, we could take this algae light sensitive gene, and we can take this jellyfish fluorescent gene and put them together, and then take that so that one triggers the other, and like kind of this rubics QB way, so that if you shine light on this one gene, it will trigger

the production of this fluorescence. And we can if we can just figure out how to take that gene combination and put it into another organism that doesn't have either, then we could shine a light on the organism and make the cells in that organism glow. And now finally, finally, just the ferraris would start to move when we signaled for them to move. We don't have to set a city block on fire. We don't have to code everything and glowing paint. We can just signal to the ferraris.

Can you believe this? It's it's astounding that that they figured out not only like in theory, how to do this, but they have actually, over the last fifteen years, been successful in doing it. It seems like something that if someone was describing, they would just be laughed out of a room and say, yeah, that's great. Take this jellyfish things alogy thing, put him together, shove it in a fruit fly, up at fruit flies, but and then shine a light on his face and make him rob a bank.

I think that's I think that's how that's the ultimate goal. Really, it's unbelievable. It really is chuck, all right. So the fruit fly is a great little candidate because we've been working with fruit flies for a long long time. When it comes to genetics, they also um we share like jeans in gene sequences that are so closely matched that when we find a like a novel gene in a fruit fly, we go look at the human genome and just try to find its match, and it usually matches.

That's how closely related we are of human genetic diseases are also found in fruit flies. This all seems made up, am I being? Maybe this is gonna come out April first? Maybe? Oh uh, So the fruit fly is a great little candidate for all those reasons, and for one other reason is we can actually, uh, we don't need to cut a fruit fly's head open to see its brain. We

can see that little guy's brain through a microscope. That's pretty great, Which is a pretty good way to analyze something just by letting it do its do its thing, you know, especially as far as the fruit flies concerned. Oh sure, it's like, yeah, just just hold me down, that's fine, Just don't cut my head off. Yeah, but you're setting people up to think it's all of mine and roses. Yeah, it gets pretty bad. That's when you

pull a ruck out from under him. Shock. So what's happening though, is they're putting that stuff in the fruit fly. And then what you do is you have to breed like the next generation. I think I don't think it would work on that one, would it? Um? No, But but you can very easily cultivate like a fruit fly colony that is now genetically modified. Just throw some throwing in a cage with some martinis and a little bit of Sinatra classics. So this is what they did, and

it was successful. And so this gave them the ability to do two things to map out where all these neurons are, which was the first kind of big part of this problem. And the second thing they could do is actually activate these neurons with light. Right, So, now, like one of the first things they experimented on, are you ready to pull the rug out from people? Sure?

One of the first fruit fly experiments that they conducted, and I shouldn't say one of the first, but one of the big ones was that, um, they they genetically modified fruit flies whose neurons responsible for their escape reflex, which is when their legs tense up and their wings tents up and they just fly away when they sense danger. These were now genetically modified with an algae and jellyfish combination,

uh gene sequence, that's right. So they shine a light on the fruit flies, and the fruit flies sprung away, and they said, that's pretty great, but makes sense. It's entirely possible that we just scared him with the light. How could we possibly figure out if the actual neurons are being activated optogenetically. Right. And in the movie scene, you just hear a voice on the other side of a desk of some scientists eating Chinese food out of a box. He goes, no, you cut their heads off

and they still live for a little while. That's funny. You should do that, I imagine instead um, Robert what's his name like scratching the chalkboards slowly with yeah, with his idea about cutting their heads off. They could probably cheat it both ways because just like Mike the headless chicken, had a lot of brain left when they cut his head off, so too with the fruit fly. There are genes um or neurons i should say, associated with the escape reflects that are not just located in the fruit

fly's head. So they cut the fruit flies heads off because, like you said, or like the guy who eating Chinese food said, um, the fruit fly will still be able to fly around and move around for a little while without a head. So they cut the heads off, and then they shine the light into the thorax where some of these neurons are, and sure enough the fruit flies sprung away and flew into the air headless, zombie like. But they did it specifically because those neurons were reacting

to light. So they successfully showed that you can control the behavior of a once living organism by shining a light on it, once you genetically modified it's it's neurons with these proteins. Yeah, I wanted to know a little bit more about that second part. I'm sure I did a lot of other controls, but my first instinct was how close was this light? Did it feel like the air move when they put it in front of it,

or was it you know, distance. But you know, they're scientists, I'm sure Rodney and his Chinese food, I'm sure a lot of other great suggestions for everybody. Right. The other questions are did they mash the heads with their thumbs to make sure there was no way that they were getting any light info? Al Right, I feel like we should take another break because what we've described as almost a miracle, but like, what good does that do us? Great question, and well we'll talk about what good it

could do us write after this. Okay, So the fruit fly experiment that was that was pretty huge, and it wasn't It didn't just end with fruit flies, like we said, They've successfully experimented with mice, with fish, um worms, worms yep, and all of these are they they use these UM these types of of um ion channels or ion pumps called dopsins or opsins, it's specifically rhodopsins. They respond to light, they're stimulated by light. UM. But they've figured out how

to insert different ones in the different genes and UM. Eventually, what they're thinking is that if we can figure out how to use these in humans, we will be able to do all manner of things, some of which we've already successfully demonstrated on on things like mice and fruit flies, not just to get a human to jump using our escape reflex, but things like UM. Treating depression is a

big one. Well, yeah, that's sort of one of the the huge potential benefits here is what if we could really control the really release of dopamine and someone's brain and when people suffer from depression and they're having a hard time getting their dopamine reactions to occur naturally instead of putting them on pills, which you know, a pill doesn't just affect the cells uh that it needs to. That's why they have a whole list of side effects

because they affect everything. UM. They're like, maybe we can get so specific that we can literally turn on those cells with light, give someone a dopamine hit that will take seconds instead of weeks and weeks of being on medication that may or may not work and may or may not have devastating side effects. Yeah, and you just hit the nail on the head that the effect will

take seconds. Um. That's one of the really big um advantages of optogenetics is it's light controlled, and we have really great lights that can turn on and off very very quickly, like um lasers connected to fiber optics is one way that they have figured out how to deliver this. I saw it's cute, heartbreaking picture of a mouse with like this kind of plastic helmet on the side of its head, and coming out of it was a single

fiber optic cable. Remember those fiber optic kind of brushes that had like a light source of the bottom, and like the brush itself was just this beautiful, colorful thing. I love those. I went and looked through like Google images pictures of those and it's just like, God, these

are so pretty. So they had one of those fiber optic little fibers coming out of the mouse's head and the mouse is just this little dirt looking at the camera like what um, But they can they can connect the end of that fiber optic cable to a laser and it will deliver that light source too inside the mouse's brain. The problem is that there's um all sorts of brain damage that you can create by inserting even like a really tiny fiber optic fiber into the brain

of something. But it is one way to do it now. UM. What they're working on also is, like I said, those Rhodopson's UM. One of the one of the ones they're looking at is like red shifted towards the red end of the spectrum, which means that you can use something like infrared light, which is absorbed more deeply into the body, as an external light source. So you just shine like an infrared light through the skull and then that will

um will activate the neurons in the brain too. So I don't remember exactly how we started on this, but there's there's stuff that we're starting to figure out from these mouse models, UM, including things like treating depression. Oh yeah, how precise it is, How precise the delivery of light is, which is really really important because the timing of neurons um and the the triggering them in the the cascade of events that it sets off is extremely precisely time.

So you can't just use like a flashlight and expect to treat depression. You would have to be able to time it in the way that the brain is supposed to be doing it in the first place. Yeah, what I wonder is if in the future, and first of all, you've got to get past all the ethical hurdles of gene therapy to begin with, which are many um and complex. So let's say we do get through all that, and let's say we get FDA approval to start therapies like this.

What kind of what does that look like? Because if it happens in seconds, does do you make an appointment and go to a a a specialist who does this light therapy or is this something that you do You have a device that you're in control of, right, so, like it would probably follow a model like deep brain stimulation what you mentioned earlier, where you have electrodes and planted in your brain that are doing basically the same thing, but a lot less precise and a lot more clumsy.

But they're electrically stimulating neurons say that released dopamine to treat depression. I don't know if we're doing that yet, but there's definitely deep brain stimulation. But do you go

to a place to have that done? You have like a pacemaker like device connected via wire from your sin, and then the devices like under your skin in your chest, but it's being controlled by a computer, Like you have an onboard computer on you on you right, But what I'm saying is you don't like carry around a button, No, it's under your skin. So how would this work? Then?

I would guess the same way that we would figure out exactly from studying opto genetically these neurons that glow when when they go off, So we'll figure out the brain pathways in the regions responsible for things like depression and all that. We would figure out what this standard normal pattern is and then to recreate it and then the computer would regulate it when needed in the brain.

Well that makes a little more sense, But I mean just that kind of stuff, like just that alone shows you how far we are from actually doing this in humans, Like we have no idea what the normal pattern in the brain is for like um, the like normal serotonin release for you know, a normal mood. But it also raises these other questions to Chuck where it's like, Okay, if we figure that out and we figure out how to um, how to how to replicate that, why stop there?

Like why not just make everybody happier than we are normally? Yeah, which brings in the whole free will debate which has been around since the dawn of time, And it also UM and ED does a great job of kind of wrapping it up and pointing out that kind of makes you think about things like if we are we just a bag of cells that can be uh manipulated by a flashing light? Like, uh, is that where you're saying is yes, we are? Like is that what happiness is? Like?

You think happiness is seeing your dog when you get home from work and getting those licks. But if those are just synapsies firing, that's a very I mean, that's scientifically what's going on, but it is a very cold and humane way to look at things. I think I disagree with that. I think it's just a that's a better understanding of what's going on, But I don't think it undermines the happiness you're experiencing. I think for a lot of people it might well, yeah, I mean I

it's not like I can't see how it wouldn't. But to me, it's like, no, I mean, you're still experiencing happiness. The happiness is still important to you. Happiness is still the point of life. This is just understanding the mechanism that we experience happiness by. That's true. And I have seen you around dogs and you constantly are just saying, I'm a bag of neurons firing at once. It's like Francis Crick, the guy who co discovered DNA. He had

a book in the seventies called The Astonishing Hypothesis. I know we've talked about it before, but he had this famous quote where he said, you're nothing but a pack of neurons. And I mean, like, to me, it's that's a really good way of maintaining a positive outlook on things. It's like, no matter how bad things get, it's just neurotransmitters in your head that are going haywire or that

are doing right. Well, that's that's when. That's that's the reason to do all this is to regain control over it and it's not functioning correctly, and then making things even better than they are normally Naturally, there's no written law that says if we figure out how to make ourselves happier, that we shouldn't do that. As a matter of fact, basically every moral code there is says we should do that. If we can be happier, let's figure

out how to be happier. Yeah. I think the other thing it makes me think about, slippery slope wise, is, um, will people cease to do the things that they do to make them happy if they can simply touch a

button to do so? Yeah, that's called wire heading. And that's actually a big problem with artificial intelligence is um they're saying, like, Okay, if we train artificial intelligence to do something based on a reward, the artificial intelligence just gonna go figure out how to go right to the reward.

But it's not. It's going to circumvent that um. And that's that's a great question too, where if we start to become like digital consciousness right where we migrate online and we should at our bodies and our consciousness just exists in digital form, then all that stuff will be available to us. And it does make you think like, okay, if if our existence is just digital, there's no purpose to it except to experience pleasure. Is there anything wrong

with just sitting around experiencing pleasure all the time? Or do we need more than that? I don't know. That's a that's a next next level question if you ask me. Yeah, I mean it kind of do you ever see wall e yes? Sort of like that there could be the future, Like why go out and take a walk if you're feeling down to get some sunshine on your face? If you can just press a button to do the same thing. Yeah, And like in that movie, it's it's like there's well,

there's something inherently wrong with that. But I don't know, man, because like if you think about it, when you go outside and you get a walk, you feel better, you feel like more positive if you can get that without doing the walk. To you, if you can get everything from a walk without having to go on a walk, do you still need to go on a walk? Will including like the benefits to your health and body? Yes?

If you could get every single scrap of benefit that you can get from a walk digitally or somehow without actually going on a walk, do you need to go on a walk? I say yes, but you and I are different. No, No, I'm with you. I still say yes as well, but I can't. I can't explain why. Okay, yeah, yeah, I'm not just like this full transhumanist guy. I definitely have questions about the whole thing too. I think you just built some bond water on the carpet that's never

gonna come out. I'm gonna stop it up with a fa breeze dryer sheet. Remember that, Remember when when kids? You saw kids do that at the dorms. Yeah, I don't know if kids had fabrize dryer sheets when I was in college, they didn't exist yet, Okay. Or you mean to just like the bounce sheets? Yes, oh sure, Yeah, yeah I've seen I've seen those old tricks. It's hilarious. Okay, Well, you got anything else about opt to genetics? No, it's

pretty pretty fascinating stuff. Yeah, we'll see where it goes, agreed. Actually, probably won't see where it goes in our life time. But I don't know, man. I suspect that while we're alive, things are going to change quite a bit. We'll live to see a lot of this stuff. I'm gonna check in with you in in thirty five years, we'll be sitting across the desk from me. Still, when we get commemorated into the Podcasting Hall of Fame, you're on that,

aren't you. You're gonna stroll into that room wearing your your VR headset, pressing your little dopamine button right talking about how great life is, right, just wire headed to the Guild's right. So if you want to know more about optogenetics, well go start reading about It's pretty interesting stuff. And since I said that it's time for listener mail, listener mail, I think it was me who goofed up

on the postal going Postal EPP. When I think off handedly, when they were talking about the Californo Commission about how much money we spent, I think it's a tex stollar money. Yeah, like a dope because we've covered the U. S. Postal service and we know that that is not the case. And this is from Peter among many others. Hey guys, want to start off by saying how much I love the show. You always do a great job researching the subjects you talk about. However, I knew, however, I got

a small bone to pick. In your recent episode Why Postal Employees Go Postal, you talked about how the US Postal Service spent four million tax dollars on the Joseph Californo Commission. While Congress does still control the USPS budget, it receives no funding from them at all, and has not since the early nineteen eighties. The USPS operates solely on the money they make from stamps and packages zero tax dollars. Anyway, thanks for the amazing content. May you

keep doing so for many years to come. That is from Peter and many many others. And by the way, we heard from a lot of people, uh, postal employees or people whose family was are or were in the Postal Service, and we got a range of things from you guys are crazy, my post office is great, there's no toxic environment, to people saying oh, they're absolutely is a very toxic environment. Yeah, like it's even worse than

you guys said. Yeah, So I think for the people that wrote in that said that was not the case, then I am very happy that you work in a great place that has a great environment. But it seems like there is a range. They're right, that's the nicest way to say it. Yeah. Uh, well that was Peter, right, Peter, Thanks a lot, Peter. That was a very nice way to put it. And if you want to get in touch with us like Peter did, you can go and send us an email. Send it off to stuff podcast

at iHeart radio dot com. Stuff you Should Know is a production of iHeart Radios. How stuff works for more podcasts for my heart Radio because at the iHeart Radio app, Apple podcasts are wherever you listen to your favorite shows.