WEBVTT

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Steve Ramirez:
My first year of grad school,

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I found myself in my bedroom

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eating lots of Ben & Jerry's

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watching some trashy TV

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and maybe, maybe listening
to Taylor Swift.

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I had just gone through a breakup.

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(Laughter)

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So for the longest time, all I would do

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is recall the memory of this
person over and over again,

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wishing that I could get
rid of that gut-wrenching,

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visceral "blah" feeling.

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Now, as it turns out,
I'm a neuroscientist,

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so I knew that the memory of that person

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and the awful, emotional undertones
that color in that memory,

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are largely mediated
by separate brain systems.

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And so I thought, what if we could
go into the brain

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and edit out that nauseating feeling

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but while keeping the memory
of that person intact?

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Then I realized, maybe
that's a little bit lofty for now.

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So what if we could start off
by going into the brain

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and just finding a single
memory to begin with?

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Could we jump-start
that memory back to life,

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maybe even play with the contents
of that memory?

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All that said, there is one person
in the entire world right now

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that I really hope is not
watching this talk.

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(Laughter)

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So, there is a catch.
There is a catch.

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These ideas probably remind
you of "Total Recall,"

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"Eternal Sunshine of the Spotless Mind,"

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or of "Inception."

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But the movie stars that we work with

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are the celebrities of the lab.

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Xu Liu: Test mice.

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(Laughter)

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As neuroscientists,
we work in the lab with mice

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trying to understand how memory works.

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And today, we hope
to convince you that now

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we are actually able to activate
a memory in the brain

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at the speed of light.

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To do this, there's only two simple
steps to follow.

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First, you find and label
a memory in the brain,

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and then you activate it with a switch.

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As simple as that.

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(Laughter)

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SR: Are you convinced?

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So, turns out finding a memory
in the brain isn't all that easy.

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XL: Indeed. This is way more
difficult than, let's say,

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finding a needle in a haystack,

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because at least, you know,
the needle is still something

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you can physically put your fingers on.

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But memory is not.

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And also, there's way
more cells in your brain

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than the number of straws
in a typical haystack.

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So yeah, this task does
seem to be daunting.

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But luckily, we got help
from the brain itself.

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It turned out that all we need
to do is basically

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to let the brain form a memory,

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and then the brain will tell us
which cells are involved

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in that particular memory.

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SR: So what was going on in my brain

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while I was recalling the memory of an ex?

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If you were to just completely
ignore human ethics for a second

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and slice up my brain right now,

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you would see that there
was an amazing number

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of brain regions that were active
while recalling that memory.

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Now one brain region
that would be robustly active

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in particular is called the hippocampus,

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which for decades
has been implicated in processing

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the kinds of memories
that we hold near and dear,

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which also makes it
an ideal target to go into

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and to try and find and maybe
reactivate a memory.

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XL: When you zoom in into the hippocampus,

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of course you will see lots of cells,

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but we are able to find
which cells are involved

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in a particular memory,

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because whenever a cell is active,

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like when it's forming a memory,

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it will also leave a footprint
that will later allow us to know

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these cells are recently active.

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SR: So the same way
that building lights at night

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let you know that somebody's probably
working there at any given moment,

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in a very real sense, there
are biological sensors

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within a cell that are turned on

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only when that cell was just working.

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They're sort of biological
windows that light up

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to let us know that that cell
was just active.

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XL: So we clipped part of this sensor,

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and attached that to a switch
to control the cells,

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and we packed this switch
into an engineered virus

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and injected that into the brain
of the mice.

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So whenever a memory is being formed,

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any active cells for that memory

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will also have this switch installed.

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SR: So here is what the hippocampus
looks like

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after forming a fear memory, for example.

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The sea of blue that you see here

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are densely packed brain cells,

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but the green brain cells,

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the green brain cells
are the ones that are holding on

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to a specific fear memory.

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So you are looking at the crystallization

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of the fleeting formation of fear.

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You're actually looking
at the cross-section

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of a memory right now.

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XL: Now, for the switch
we have been talking about,

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ideally, the switch
has to act really fast.

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It shouldn't take minutes
or hours to work.

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It should act at the speed
of the brain, in milliseconds.

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SR: So what do you think, Xu?

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Could we use, let's say,
pharmacological drugs

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to activate or inactivate brain cells?

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XL: Nah. Drugs are pretty messy.
They spread everywhere.

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And also it takes them
forever to act on cells.

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So it will not allow us
to control a memory in real time.

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So Steve, how about let's zap
the brain with electricity?

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SR: So electricity is pretty fast,

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but we probably wouldn't
be able to target it

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to just the specific cells
that hold onto a memory,

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and we'd probably fry the brain.

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XL: Oh. That's true.
So it looks like, hmm,

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indeed we need to find a better way

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to impact the brain at the speed of light.

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SR: So it just so happens that light
travels at the speed of light.

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So maybe we could activate
or inactivate memories

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by just using light -

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XL: That's pretty fast.

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SR: - and because normally brain cells

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don't respond to pulses of light,

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so those that would respond
to pulses of light

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are those that contain
a light-sensitive switch.

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Now to do that, first we need
to trick brain cells

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to respond to laser beams.

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XL: Yep. You heard it right.

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We are trying to shoot lasers
into the brain.

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(Laughter)

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SR: And the technique that lets us do that
is optogenetics.

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Optogenetics gave us this
light switch that we can use

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to turn brain cells on or off,

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and the name of that switch
is channelrhodopsin,

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seen here as these green dots
attached to this brain cell.

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You can think of channelrhodopsin
as a sort of light-sensitive switch

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that can be artificially
installed in brain cells

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so that now we can use that switch

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to activate or inactivate the brain
cell simply by clicking it,

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and in this case we click it on
with pulses of light.

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XL: So we attach this light-sensitive
switch of channelrhodopsin

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to the sensor we've been talking about

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and inject this into the brain.

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So whenever a memory is being formed,

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any active cell for that particular memory

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will also have this light-sensitive switch
installed in it

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so that we can control these cells

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by the flipping of a laser
just like this one you see.

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SR: So let's put all of this
to the test now.

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What we can do is we can take our mice

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and then we can put them in a box
that looks exactly like this one,

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and then we can give them
a very mild foot shock

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so that they form a fear
memory of this box.

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They learn that something
bad happened here.

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Now with our system,
the cells that are active

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in the hippocampus
in the making of this memory,

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only those cells will now
contain channelrhodopsin.

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XL: When you are as small as a mouse,

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it feels as if the whole
world is trying to get you.

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So your best response of defense

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is trying to be undetected.

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Whenever a mouse is in fear,

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it will show this very typical behavior

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by staying at one corner of the box,

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trying to not move any part of its body,

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and this posture is called freezing.

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So if a mouse remembers that something
bad happened in this box,

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and when we put them
back into the same box,

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it will basically show freezing

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because it doesn't want to be detected

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by any potential threats in this box.

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SR: So you can think of freezing as,

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you're walking down the street
minding your own business,

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and then out of nowhere
you almost run into

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an ex-girlfriend or ex-boyfriend,

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and now those terrifying two seconds

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where you start thinking,
"What do I do? Do I say hi?

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Do I shake their hand?
Do I turn around and run away?

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Do I sit here and pretend
like I don't exist?"

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Those kinds of fleeting thoughts
that physically incapacitate you,

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that temporarily give you
that deer-in-headlights look.

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XL: However, if you put the mouse
in a completely different new box,

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like the next one,

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it will not be afraid of this box

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because there's no reason that it
will be afraid of this new environment.

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But what if we put
the mouse in this new box

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but at the same time,
we activate the fear memory

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using lasers just like we did before?

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Are we going to bring back the fear memory

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for the first box into this
completely new environment?

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SR: All right,
and here's the million-dollar experiment.

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Now to bring back to life
the memory of that day,

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I remember that the Red Sox had just won,

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it was a green spring day,

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perfect for going up and down the river

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and then maybe going to the North End

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to get some cannolis, #justsaying.

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Now Xu and I, on the other hand,

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were in a completely windowless black room

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not making any ocular movement
that even remotely resembles an eye blink

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because our eyes were fixed
onto a computer screen.

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We were looking at this mouse
here trying to activate a memory

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for the first time using our technique.

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XL: And this is what we saw.

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When we first put the mouse into this box,

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it's exploring, sniffing
around, walking around,

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minding its own business,

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because actually by nature,

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mice are pretty curious animals.

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They want to know,
what's going on in this new box?

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It's interesting.

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But the moment we turned on the laser,
like you see now,

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all of a sudden the mouse
entered this freezing mode.

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It stayed here and tried not to move
any part of its body.

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Clearly it's freezing.

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So indeed, it looks like
we are able to bring back

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the fear memory for the first box

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in this completely new environment.

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While watching this, Steve and I

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are as shocked as the mouse itself.

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(Laughter)

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So after the experiment,
the two of us just left the room

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without saying anything.

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After a kind of long,
awkward period of time,

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Steve broke the silence.

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SR: "Did that just work?"

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XL: "Yes," I said. "Indeed it worked!"

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We're really excited about this.

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And then we published our findings

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in the journal Nature.

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Ever since the publication of our work,

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we've been receiving numerous comments

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from all over the Internet.

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Maybe we can take a look at some of those.

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SR: So the first thing
that you'll notice is that people have

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really strong opinions
about this kind of work.

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Now I happen to completely
agree with the optimism

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of this first quote,

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because on a scale
of zero to Morgan Freeman's voice,

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it happens to be
one of the most evocative accolades

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that I've heard come our way.

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(Laughter)

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But as you'll see, it's not
the only opinion that's out there.

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XL: Indeed, if we take
a look at the second one,

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I think we can all agree that it's, meh,

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probably not as positive.

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But this also reminds us that,

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although we are still working with mice,

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it's probably a good idea
to start thinking and discussing

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about the possible ethical ramifications

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of memory control.

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SR: Now, in the spirit of the third quote,

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we want to tell you about a recent project

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that we've been working on in lab
that we've called Project Inception.

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So we reasoned that
now that we can reactivate a memory,

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what if we do so but then
begin to tinker with that memory?

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Could we possibly even
turn it into a false memory?

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XL: So all memory
is sophisticated and dynamic,

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but if just for simplicity,
let's imagine memory

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as a movie clip.

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So far what we've told you
is basically we can control

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this "play" button of the clip

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so that we can play this video clip
any time, anywhere.

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But is there a possibility
that we can actually get

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inside the brain and edit this movie clip

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so that we can make it
different from the original?

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Yes we can.

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Turned out that all we need
to do is basically

00:11:46.509 --> 00:11:50.679
reactivate a memory
using lasers just like we did before,

00:11:50.699 --> 00:11:54.118
but at the same time,
if we present new information

00:11:54.138 --> 00:11:58.092
and allow this new information
to incorporate into this old memory,

00:11:58.112 --> 00:12:00.530
this will change the memory.

00:12:00.550 --> 00:12:04.193
It's sort of like making a remix tape.

00:12:04.213 --> 00:12:07.051
SR: So how do we do this?

00:12:07.071 --> 00:12:09.278
Rather than finding
a fear memory in the brain,

00:12:09.278 --> 00:12:10.984
we can start by taking our animals,

00:12:10.984 --> 00:12:13.987
and let's say we put them in a blue box
like this blue box here

00:12:13.987 --> 00:12:16.625
and we find the brain cells
that represent that blue box

00:12:16.625 --> 00:12:18.854
and we trick them to respond
to pulses of light

00:12:18.854 --> 00:12:20.445
exactly like we had said before.

00:12:20.445 --> 00:12:23.119
Now the next day, we can take
our animals and place them

00:12:23.119 --> 00:12:25.508
in a red box that they've never
experienced before.

00:12:25.508 --> 00:12:27.727
We can shoot light
into the brain to reactivate

00:12:27.727 --> 00:12:29.303
the memory of the blue box.

00:12:29.323 --> 00:12:30.748
So what would happen here if,

00:12:30.748 --> 00:12:33.476
while the animal is recalling
the memory of the blue box,

00:12:33.476 --> 00:12:35.584
we gave it a couple of mild foot shocks?

00:12:35.604 --> 00:12:38.277
So here we're trying to artificially
make an association

00:12:38.297 --> 00:12:40.192
between the memory of the blue box

00:12:40.212 --> 00:12:41.695
and the foot shocks themselves.

00:12:41.715 --> 00:12:43.474
We're just trying to connect the two.

00:12:43.494 --> 00:12:45.017
So to test if we had done so,

00:12:45.037 --> 00:12:46.695
we can take our animals once again

00:12:46.695 --> 00:12:48.461
and place them back in the blue box.

00:12:48.461 --> 00:12:51.169
Again, we had just reactivated
the memory of the blue box

00:12:51.169 --> 00:12:53.530
while the animal got a couple
of mild foot shocks,

00:12:53.530 --> 00:12:55.566
and now the animal suddenly freezes.

00:12:55.586 --> 00:12:58.920
It's as though it's recalling being
mildly shocked in this environment

00:12:58.944 --> 00:13:01.770
even though that never actually happened.

00:13:01.790 --> 00:13:03.632
So it formed a false memory,

00:13:03.652 --> 00:13:05.681
because it's falsely
fearing an environment

00:13:05.701 --> 00:13:07.035
where, technically speaking,

00:13:07.059 --> 00:13:09.246
nothing bad actually happened to it.

00:13:09.266 --> 00:13:11.699
XL: So, so far we are only talking about

00:13:11.719 --> 00:13:14.065
this light-controlled "on" switch.

00:13:14.085 --> 00:13:17.353
In fact, we also have
a light-controlled "off" switch,

00:13:17.373 --> 00:13:19.433
and it's very easy to imagine

00:13:19.453 --> 00:13:22.059
that by installing this
light-controlled "off" switch,

00:13:22.080 --> 00:13:26.264
we can also turn off a memory,
any time, anywhere.

00:13:27.519 --> 00:13:29.713
So everything
we've been talking about today

00:13:29.733 --> 00:13:34.390
is based on this philosophically
charged principle of neuroscience

00:13:34.410 --> 00:13:38.508
that the mind, with its seemingly
mysterious properties,

00:13:38.528 --> 00:13:42.153
is actually made of physical stuff
that we can tinker with.

00:13:42.173 --> 00:13:43.628
SR: And for me personally,

00:13:43.648 --> 00:13:45.410
I see a world where we can reactivate

00:13:45.434 --> 00:13:47.325
any kind of memory that we'd like.

00:13:47.345 --> 00:13:50.623
I also see a world where we can
erase unwanted memories.

00:13:50.643 --> 00:13:52.834
Now, I even see a world
where editing memories

00:13:52.858 --> 00:13:54.098
is something of a reality,

00:13:54.118 --> 00:13:56.463
because we're living in a time
where it's possible

00:13:56.463 --> 00:13:58.872
to pluck questions from the tree
of science fiction

00:13:58.872 --> 00:14:00.908
and to ground them
in experimental reality.

00:14:00.908 --> 00:14:02.461
XL: Nowadays, people in the lab

00:14:02.461 --> 00:14:04.717
and people in other groups
all over the world

00:14:04.737 --> 00:14:08.534
are using similar methods
to activate or edit memories,

00:14:08.554 --> 00:14:12.375
whether that's old or new,
positive or negative,

00:14:12.395 --> 00:14:15.047
all sorts of memories
so that we can understand

00:14:15.067 --> 00:14:16.911
how memory works.

00:14:16.931 --> 00:14:18.695
SR: For example, one group in our lab

00:14:18.715 --> 00:14:21.480
was able to find the brain cells
that make up a fear memory

00:14:21.501 --> 00:14:24.388
and converted them into
a pleasurable memory, just like that.

00:14:24.388 --> 00:14:27.530
That's exactly what I mean about editing
these kinds of processes.

00:14:27.530 --> 00:14:29.752
Now one dude in lab
was even able to reactivate

00:14:29.752 --> 00:14:31.553
memories of female mice in male mice,

00:14:31.553 --> 00:14:34.478
which rumor has it
is a pleasurable experience.

00:14:34.498 --> 00:14:38.595
XL: Indeed, we are living
in a very exciting moment

00:14:38.615 --> 00:14:42.400
where science doesn't have
any arbitrary speed limits

00:14:42.420 --> 00:14:45.587
but is only bound by our own imagination.

00:14:45.607 --> 00:14:47.734
SR: And finally,
what do we make of all this?

00:14:47.754 --> 00:14:49.705
How do we push this technology forward?

00:14:49.725 --> 00:14:51.916
These are the questions
that should not remain

00:14:51.940 --> 00:14:53.217
just inside the lab,

00:14:53.237 --> 00:14:55.790
and so one goal of today's talk
was to bring everybody

00:14:55.810 --> 00:14:58.191
up to speed with the kind
of stuff that's possible

00:14:58.215 --> 00:14:59.492
in modern neuroscience,

00:14:59.512 --> 00:15:01.002
but now, just as importantly,

00:15:01.022 --> 00:15:04.334
to actively engage everybody
in this conversation.

00:15:04.354 --> 00:15:07.164
So let's think together as a team
about what this all means

00:15:07.188 --> 00:15:09.137
and where we can and should go from here,

00:15:09.157 --> 00:15:11.235
because Xu and I think we all have

00:15:11.255 --> 00:15:13.771
some really big decisions ahead of us.

00:15:13.791 --> 00:15:14.934
Thank you.
XL: Thank you.

00:15:14.958 --> 00:15:17.079
(Applause)