February 11, 2020 • 45 mins
What if a genetic brain disease could be turned off simply by flashing a light in your eyes? What if your depression could be cured that way? Sounds amazingly wonderful, true, but what if your behavior could be controlled that way too?
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Episode Transcript
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Speaker 1 (00:01):
Welcome to Stuff You should know, a production of I
Heart Radios How Stuff Works. Hey, and welcome to the podcast.
I'm Josh Clark. There's Charles W. Chuck Bryant, and there's
guest producer Josh T over there, Josh T Josh Tizzy.
(00:21):
That's his new nickname. Okay, Josh nodding, goodhead, Yep, he knows,
he knows the score. How you doing, man? Oh, I've
had better days and weeks. But you know, if only
there was a la ed light, someone could blink in
my eyeballs and hits everything. I know. I that's actually
(00:41):
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
(01:04):
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
(01:24):
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
(01:46):
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
(02:09):
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
(02:32):
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.
(02:52):
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
(03:13):
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
(03:38):
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
(03:59):
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
(04:19):
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,
(04:40):
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,
(05:02):
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
(05:24):
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
(05:47):
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,
(06:10):
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,
(06:34):
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
(06:56):
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
(07:17):
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
(07:38):
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
(07:58):
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
(08:19):
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
(08:41):
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,
(09:03):
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.
(09:24):
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
(09:45):
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
(10:09):
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
(10:29):
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
(10:49):
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
(11:11):
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
(11:33):
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
(11:56):
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
(12:18):
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,
(12:41):
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,
(13:02):
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
(13:25):
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.
(13:50):
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.
(14:20):
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.
(14:45):
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
(15:07):
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
(15:32):
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
(15:52):
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
(16:16):
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,
(16:38):
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
(16:58):
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
(17:20):
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,
(17:46):
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
(18:08):
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
(18:28):
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
(18:48):
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,
(19:09):
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.
(19:31):
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
(19:53):
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,
(20:18):
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
(20:40):
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
(21:01):
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,
(21:24):
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.
(21:45):
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
(22:07):
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
(22:29):
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
(22:50):
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
(23:14):
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
(23:35):
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
(23:56):
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
(24:17):
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
(24:39):
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,
(25:01):
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
(25:23):
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,
(25:46):
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
(26:09):
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
(26:31):
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
(26:52):
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?
(27:16):
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,
(27:37):
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
(27:57):
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
(28:21):
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?
(28:42):
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.
(29:03):
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.
(29:24):
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
(29:47):
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
(30:08):
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
(30:29):
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
(30:49):
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,
(31:13):
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
(31:33):
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
(32:01):
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,
(32:26):
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,
(32:47):
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
(33:12):
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
(33:34):
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
(33:57):
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.
(34:18):
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
(34:40):
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
(35:03):
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
(35:26):
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
(35:46):
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.
(36:10):
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,
(36:31):
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
(36:54):
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,
(37:15):
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
(37:38):
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
(38:01):
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
(38:23):
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
(38:43):
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
(39:05):
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
(39:27):
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
(39:48):
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
(40:09):
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
(40:33):
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
(40:53):
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
(41:14):
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,
(41:37):
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
(41:58):
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
(42:21):
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
(42:42):
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,
(43:03):
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
(43:24):
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,
(43:49):
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
(44:11):
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
(44:32):
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
(44:52):
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
(45:13):
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
(45:33):
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.
Welcome to Stuff You should know, a production of I
Heart Radios How Stuff Works. Hey, and welcome to the podcast.
I'm Josh Clark. There's Charles W. Chuck Bryant, and there's
guest producer Josh T over there, Josh T Josh Tizzy.
(00:21):
That's his new nickname. Okay, Josh nodding, goodhead, Yep, he knows,
he knows the score. How you doing, man? Oh, I've
had better days and weeks. But you know, if only
there was a la ed light, someone could blink in
my eyeballs and hits everything. I know. I that's actually
(00:41):
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
(01:04):
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
(01:24):
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
(01:46):
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
(02:09):
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
(02:32):
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.
(02:52):
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
(03:13):
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
(03:38):
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
(03:59):
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
(04:19):
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,
(04:40):
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,
(05:02):
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
(05:24):
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
(05:47):
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,
(06:10):
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,
(06:34):
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
(06:56):
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
(07:17):
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
(07:38):
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
(07:58):
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
(08:19):
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
(08:41):
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,
(09:03):
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.
(09:24):
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
(09:45):
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
(10:09):
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
(10:29):
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
(10:49):
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
(11:11):
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
(11:33):
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
(11:56):
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
(12:18):
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,
(12:41):
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,
(13:02):
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
(13:25):
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.
(13:50):
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.
(14:20):
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.
(14:45):
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
(15:07):
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
(15:32):
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
(15:52):
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
(16:16):
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,
(16:38):
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
(16:58):
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
(17:20):
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,
(17:46):
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
(18:08):
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
(18:28):
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
(18:48):
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,
(19:09):
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.
(19:31):
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
(19:53):
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,
(20:18):
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
(20:40):
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
(21:01):
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,
(21:24):
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.
(21:45):
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
(22:07):
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
(22:29):
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
(22:50):
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
(23:14):
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
(23:35):
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
(23:56):
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
(24:17):
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
(24:39):
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,
(25:01):
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
(25:23):
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,
(25:46):
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
(26:09):
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
(26:31):
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
(26:52):
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?
(27:16):
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,
(27:37):
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
(27:57):
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
(28:21):
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?
(28:42):
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.
(29:03):
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.
(29:24):
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
(29:47):
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
(30:08):
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
(30:29):
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
(30:49):
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,
(31:13):
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
(31:33):
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
(32:01):
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,
(32:26):
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,
(32:47):
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
(33:12):
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
(33:34):
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
(33:57):
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.
(34:18):
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
(34:40):
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
(35:03):
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
(35:26):
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
(35:46):
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.
(36:10):
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,
(36:31):
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
(36:54):
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,
(37:15):
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
(37:38):
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
(38:01):
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
(38:23):
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
(38:43):
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
(39:05):
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
(39:27):
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
(39:48):
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
(40:09):
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
(40:33):
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
(40:53):
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
(41:14):
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,
(41:37):
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
(41:58):
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
(42:21):
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
(42:42):
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,
(43:03):
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
(43:24):
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,
(43:49):
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
(44:11):
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
(44:32):
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
(44:52):
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
(45:13):
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
(45:33):
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.
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Josh Clark
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