0:00:00.000,0:00:01.000
Steve Ramirez: My first year of grad school,

0:00:01.000,0:00:03.000
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.

0:00:11.000,0:00:12.000
I had just gone through a breakup.

0:00:12.000,0:00:14.000
(Laughter)

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So for the longest time, all I would do

0:00:16.000,0:00:20.000
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,

0:00:33.000,0:00:35.000
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.

0:00:45.000,0:00:48.000
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

0:01:30.000,0:01:33.000
we are actually able to activate a memory in the brain

0:01:33.000,0:01:36.000
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?

0:01:51.000,0:01:55.000
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,

0:01:57.000,0:02:00.000
finding a needle in a haystack,

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

0:02:02.000,0:02:05.000
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

0:02:10.000,0:02:15.000
than the number of straws in a typical haystack.

0:02:15.000,0:02:18.000
So yeah, this task does seem to be daunting.

0:02:18.000,0:02:22.000
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

0:02:34.000,0:02:36.000
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

0:02:42.000,0:02:45.000
of brain regions that were active while recalling that memory.

0:02:45.000,0:02:48.000
Now one brain region that would be robustly active

0:02:48.000,0:02:50.000
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,

0:03:12.000,0:03:14.000
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

0:03:22.000,0:03:25.000
let you know that somebody's probably working there at any given moment,

0:03:25.000,0:03:29.000
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

0:04:03.000,0:04:05.000
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

0:04:09.000,0:04:11.000
to a specific fear memory.

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So you are looking at the crystallization

0:04:13.000,0:04:15.000
of the fleeting formation of fear.

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You're actually looking at the cross-section of a memory right now.

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

0:04:21.000,0:04:24.000
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?

0:04:32.000,0:04:35.000
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.

0:04:41.000,0:04:44.000
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.

0:04:48.000,0:04:52.000
So Steve, how about let's zap the brain with electricity?

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SR: So electricity is pretty fast,

0:04:54.000,0:04:56.000
but we probably wouldn't be able to target it

0:04:56.000,0:04:58.000
to just the specific cells that hold onto a memory,

0:04:58.000,0:05:00.000
and we'd probably fry the brain.

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

0:05:03.000,0:05:06.000
indeed we need to find a better way

0:05:06.000,0:05:09.000
to impact the brain at the speed of light.

0:05:09.000,0:05:14.000
SR: So it just so happens that light travels at the speed of light.

0:05:14.000,0:05:18.000
So maybe we could activate or inactive memories

0:05:18.000,0:05:19.000
by just using light --

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XL: That's pretty fast.

0:05:21.000,0:05:23.000
SR: -- and because normally brain cells

0:05:23.000,0:05:24.000
don't respond to pulses of light,

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so those that would respond to pulses of light

0:05:26.000,0:05:29.000
are those that contain a light-sensitive switch.

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

0:05:31.000,0:05:32.000
to respond to laser beams.

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XL: Yep. You heard it right.

0:05:33.000,0:05:35.000
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

0:05:44.000,0:05:45.000
to turn brain cells on or off,

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and the name of that switch is channelrhodopsin,

0:05:48.000,0:05:50.000
seen here as these green dots attached to this brain cell.

0:05:50.000,0:05:53.000
You can think of channelrhodopsin as a sort of light-sensitive switch

0:05:53.000,0:05:56.000
that can be artificially installed in brain cells

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so that now we can use that switch

0:05:58.000,0:06:01.000
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

0:06:09.000,0:06:12.000
and inject this into the brain.

0:06:12.000,0:06:15.000
So whenever a memory is being formed,

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any active cell for that particular memory

0:06:17.000,0:06:21.000
will also have this light-sensitive switch installed in it

0:06:21.000,0:06:23.000
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 box here,

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and then we can give them a very mild foot shock

0:06:38.000,0:06:40.000
so that they form a fear memory of this box.

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They learn that something bad happened here.

0:06:42.000,0:06:44.000
Now with our system, the cells that are active

0:06:44.000,0:06:47.000
in the hippocampus in the making of this memory,

0:06:47.000,0:06:50.000
only those cells will now contain channelrhodopsin.

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XL: When you are as small as a mouse,

0:06:53.000,0:06:56.000
it feels as if the whole world is trying to get you.

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So your best response of defense

0:06:58.000,0:07:01.000
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

0:07:04.000,0:07:06.000
by staying at one corner of the box,

0:07:06.000,0:07:09.000
trying to not move any part of its body,

0:07:09.000,0:07:12.000
and this posture is called freezing.

0:07:12.000,0:07:17.000
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,

0:07:19.000,0:07:21.000
it will basically show freezing

0:07:21.000,0:07:23.000
because it doesn't want to be detected

0:07:23.000,0:07:26.000
by any potential threats in this box.

0:07:26.000,0:07:28.000
SR: So you can think of freezing as,

0:07:28.000,0:07:30.000
you're walking down the street minding your own business,

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and then out of nowhere you almost run into

0:07:31.000,0:07:34.000
an ex-girlfriend or ex-boyfriend,

0:07:34.000,0:07:36.000
and now those terrifying two seconds

0:07:36.000,0:07:38.000
where you start thinking, "What do I do? Do I say hi?

0:07:38.000,0:07:39.000
Do I shake their hand? Do I turn around and run away?

0:07:39.000,0:07:41.000
Do I sit here and pretend like I don't exist?"

0:07:41.000,0:07:44.000
Those kinds of fleeting thoughts that physically incapacitate you,

0:07:44.000,0:07:47.000
that temporarily give you that deer-in-headlights look.

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

0:07:50.000,0:07:53.000
new box, like the next one,

0:07:53.000,0:07:56.000
it will not be afraid of this box

0:07:56.000,0:08:00.000
because there's no reason that it will be afraid of this new environment.

0:08:00.000,0:08:03.000
But what if we put the mouse in this new box

0:08:03.000,0:08:07.000
but at the same time, we activate the fear memory

0:08:07.000,0:08:10.000
using lasers just like we did before?

0:08:10.000,0:08:13.000
Are we going to bring back the fear memory

0:08:13.000,0:08:17.000
for the first box into this completely new environment?

0:08:17.000,0:08:19.000
SR: All right, and here's the million-dollar experiment.

0:08:19.000,0:08:22.000
Now to bring back to life the memory of that day,

0:08:22.000,0:08:24.000
I remember that the Red Sox had just won,

0:08:24.000,0:08:26.000
it was a green spring day,

0:08:26.000,0:08:28.000
perfect for going up and down the river

0:08:28.000,0:08:31.000
and then maybe going to the North End

0:08:31.000,0:08:33.000
to get some cannolis, #justsaying.

0:08:33.000,0:08:36.000
Now Xu and I, on the other hand,

0:08:36.000,0:08:39.000
were in a completely windowless black room

0:08:39.000,0:08:42.000
not making any ocular movement that even remotely resembles an eye blink

0:08:42.000,0:08:45.000
because our eyes were fixed onto a computer screen.

0:08:45.000,0:08:47.000
We were looking at this mouse here trying to activate a memory

0:08:47.000,0:08:49.000
for the first time using our technique.

0:08:49.000,0:08:52.000
XL: And this is what we saw.

0:08:52.000,0:08:54.000
When we first put the mouse into this box,

0:08:54.000,0:08:57.000
it's exploring, sniffing around, walking around,

0:08:57.000,0:08:59.000
minding its own business,

0:08:59.000,0:09:01.000
because actually by nature,

0:09:01.000,0:09:03.000
mice are pretty curious animals.

0:09:03.000,0:09:05.000
They want to know, what's going on in this new box?

0:09:05.000,0:09:07.000
It's interesting.

0:09:07.000,0:09:10.000
But the moment we turned on the laser, like you see now,

0:09:10.000,0:09:13.000
all of a sudden the mouse entered this freezing mode.

0:09:13.000,0:09:18.000
It stayed here and tried not to move any part of its body.

0:09:18.000,0:09:19.000
Clearly it's freezing.

0:09:19.000,0:09:22.000
So indeed, it looks like we are able to bring back

0:09:22.000,0:09:24.000
the fear memory for the first box

0:09:24.000,0:09:27.000
in this completely new environment.

0:09:27.000,0:09:29.000
While watching this, Steve and I

0:09:29.000,0:09:32.000
are as shocked as the mouse itself.

0:09:32.000,0:09:33.000
(Laughter)

0:09:33.000,0:09:36.000
So after the experiment, the two of us just left the room

0:09:36.000,0:09:38.000
without saying anything.

0:09:38.000,0:09:41.000
After a kind of long, awkward period of time,

0:09:41.000,0:09:43.000
Steve broke the silence.

0:09:43.000,0:09:46.000
SR: "Did that just work?"

0:09:46.000,0:09:49.000
XL: "Yes," I said. "Indeed it worked!"

0:09:49.000,0:09:51.000
We're really excited about this.

0:09:51.000,0:09:53.000
And then we published our findings

0:09:53.000,0:09:55.000
in the journal Nature.

0:09:55.000,0:09:58.000
Ever since the publication of our work,

0:09:58.000,0:10:00.000
we've been receiving numerous comments

0:10:00.000,0:10:02.000
from all over the Internet.

0:10:02.000,0:10:06.000
Maybe we can take a look at some of those.

0:10:06.000,0:10:08.000
["OMGGGGG FINALLY... so much more to come, virtual reality, neural manipulation, visual dream emulation... neural coding, 'writing and re-writing of memories', mental illnesses. Ahhh the future is awesome"]

0:10:08.000,0:10:10.000
SR: So the first thing that you'll notice is that people

0:10:10.000,0:10:13.000
have really strong opinions about this kind of work.

0:10:13.000,0:10:16.000
Now I happen to completely agree with the optimism

0:10:16.000,0:10:17.000
of this first quote,

0:10:17.000,0:10:19.000
because on a scale of zero to Morgan Freeman's voice,

0:10:19.000,0:10:22.000
it happens to be one of the most evocative accolades

0:10:22.000,0:10:23.000
that I've heard come our way.

0:10:23.000,0:10:25.000
(Laughter)

0:10:25.000,0:10:27.000
But as you'll see, it's not the only opinion that's out there.

0:10:27.000,0:10:29.000
["This scares the hell out of me... What if they could do that easily in humans in a couple of years?! OH MY GOD WE'RE DOOMED"]

0:10:29.000,0:10:31.000
XL: Indeed, if we take a look at the second one,

0:10:31.000,0:10:33.000
I think we can all agree that it's, meh,

0:10:33.000,0:10:35.000
probably not as positive.

0:10:35.000,0:10:37.000
But this also reminds us that,

0:10:37.000,0:10:40.000
although we are still working with mice,

0:10:40.000,0:10:43.000
it's probably a good idea to start thinking and discussing

0:10:43.000,0:10:46.000
about the possible ethical ramifications

0:10:46.000,0:10:48.000
of memory control.

0:10:48.000,0:10:50.000
SR: Now, in the spirit of the third quote,

0:10:50.000,0:10:52.000
we want to tell you about a recent project that we've been

0:10:52.000,0:10:55.000
working on in lab that we've called Project Inception.

0:10:55.000,0:10:58.000
["They should make a movie about this. Where they plant ideas into peoples minds, so they can control them for their own personal gain. We'll call it: Inception."]

0:10:58.000,0:11:02.000
So we reasoned that now that we can reactivate a memory,

0:11:02.000,0:11:05.000
what if we do so but then begin to tinker with that memory?

0:11:05.000,0:11:08.000
Could we possibly even turn it into a false memory?

0:11:08.000,0:11:12.000
XL: So all memory is sophisticated and dynamic,

0:11:12.000,0:11:15.000
but if just for simplicity, let's imagine memory

0:11:15.000,0:11:16.000
as a movie clip.

0:11:16.000,0:11:19.000
So far what we've told you is basically we can control

0:11:19.000,0:11:21.000
this "play" button of the clip

0:11:21.000,0:11:25.000
so that we can play this video clip any time, anywhere.

0:11:25.000,0:11:28.000
But is there a possibility that we can actually get

0:11:28.000,0:11:31.000
inside the brain and edit this movie clip

0:11:31.000,0:11:34.000
so that we can make it different from the original?

0:11:34.000,0:11:36.000
Yes we can.

0:11:36.000,0:11:38.000
Turned out that all we need to do is basically

0:11:38.000,0:11:42.000
reactivate a memory using lasers just like we did before,

0:11:42.000,0:11:46.000
but at the same time, if we present new information

0:11:46.000,0:11:50.000
and allow this new information to incorporate into this old memory,

0:11:50.000,0:11:52.000
this will change the memory.

0:11:52.000,0:11:56.000
It's sort of like making a remix tape.

0:11:56.000,0:11:59.000
SR: So how do we do this?

0:11:59.000,0:12:01.000
Rather than finding a fear memory in the brain,

0:12:01.000,0:12:02.000
we can start by taking our animals,

0:12:02.000,0:12:05.000
and let's say we put them in a blue box like this blue box here

0:12:05.000,0:12:08.000
and we find the brain cells that represent that blue box

0:12:08.000,0:12:10.000
and we trick them to respond to pulses of light

0:12:10.000,0:12:12.000
exactly like we had said before.

0:12:12.000,0:12:14.000
Now the next day, we can take our animals and place them

0:12:14.000,0:12:17.000
in a red box that they've never experienced before.

0:12:17.000,0:12:19.000
We can shoot light into the brain to reactivate

0:12:19.000,0:12:21.000
the memory of the blue box.

0:12:21.000,0:12:23.000
So what would happen here if, while the animal

0:12:23.000,0:12:24.000
is recalling the memory of the blue box,

0:12:24.000,0:12:27.000
we gave it a couple of mild foot shocks?

0:12:27.000,0:12:30.000
So here we're trying to artificially make an association

0:12:30.000,0:12:32.000
between the memory of the blue box

0:12:32.000,0:12:33.000
and the foot shocks themselves.

0:12:33.000,0:12:35.000
We're just trying to connect the two.

0:12:35.000,0:12:37.000
So to test if we had done so,

0:12:37.000,0:12:38.000
we can take our animals once again

0:12:38.000,0:12:40.000
and place them back in the blue box.

0:12:40.000,0:12:43.000
Again, we had just reactivated the memory of the blue box

0:12:43.000,0:12:45.000
while the animal got a couple of mild foot shocks,

0:12:45.000,0:12:47.000
and now the animal suddenly freezes.

0:12:47.000,0:12:50.000
It's as though it's recalling being mildly shocked in this environment

0:12:50.000,0:12:53.000
even though that never actually happened.

0:12:53.000,0:12:55.000
So it formed a false memory,

0:12:55.000,0:12:57.000
because it's falsely fearing an environment

0:12:57.000,0:12:58.000
where, technically speaking,

0:12:58.000,0:13:01.000
nothing bad actually happened to it.

0:13:01.000,0:13:03.000
XL: So, so far we are only talking about

0:13:03.000,0:13:06.000
this light-controlled "on" switch.

0:13:06.000,0:13:09.000
In fact, we also have a light-controlled "off" switch,

0:13:09.000,0:13:11.000
and it's very easy to imagine that

0:13:11.000,0:13:13.000
by installing this light-controlled "off" switch,

0:13:13.000,0:13:19.000
we can also turn off a memory, any time, anywhere.

0:13:19.000,0:13:21.000
So everything we've been talking about today

0:13:21.000,0:13:26.000
is based on this philosophically charged principle of neuroscience

0:13:26.000,0:13:30.000
that the mind, with its seemingly mysterious properties,

0:13:30.000,0:13:34.000
is actually made of physical stuff that we can tinker with.

0:13:34.000,0:13:35.000
SR: And for me personally,

0:13:35.000,0:13:37.000
I see a world where we can reactivate

0:13:37.000,0:13:39.000
any kind of memory that we'd like.

0:13:39.000,0:13:42.000
I also see a world where we can erase unwanted memories.

0:13:42.000,0:13:44.000
Now, I even see a world where editing memories

0:13:44.000,0:13:46.000
is something of a reality,

0:13:46.000,0:13:47.000
because we're living in a time where it's possible

0:13:47.000,0:13:50.000
to pluck questions from the tree of science fiction

0:13:50.000,0:13:52.000
and to ground them in experimental reality.

0:13:52.000,0:13:54.000
XL: Nowadays, people in the lab

0:13:54.000,0:13:56.000
and people in other groups all over the world

0:13:56.000,0:14:00.000
are using similar methods to activate or edit memories,

0:14:00.000,0:14:04.000
whether that's old or new, positive or negative,

0:14:04.000,0:14:07.000
all sorts of memories so that we can understand

0:14:07.000,0:14:08.000
how memory works.

0:14:08.000,0:14:10.000
SR: For example, one group in our lab

0:14:10.000,0:14:13.000
was able to find the brain cells that make up a fear memory

0:14:13.000,0:14:16.000
and converted them into a pleasurable memory, just like that.

0:14:16.000,0:14:19.000
That's exactly what I mean about editing these kinds of processes.

0:14:19.000,0:14:21.000
Now one dude in lab was even able to reactivate

0:14:21.000,0:14:23.000
memories of female mice in male mice,

0:14:23.000,0:14:26.000
which rumor has it is a pleasurable experience.

0:14:26.000,0:14:30.000
XL: Indeed, we are living in a very exciting moment

0:14:30.000,0:14:34.000
where science doesn't have any arbitrary speed limits

0:14:34.000,0:14:37.000
but is only bound by our own imagination.

0:14:37.000,0:14:39.000
SR: And finally, what do we make of all this?

0:14:39.000,0:14:41.000
How do we push this technology forward?

0:14:41.000,0:14:43.000
These are the questions that should not remain

0:14:43.000,0:14:45.000
just inside the lab,

0:14:45.000,0:14:47.000
and so one goal of today's talk was to bring everybody

0:14:47.000,0:14:50.000
up to speed with the kind of stuff that's possible

0:14:50.000,0:14:51.000
in modern neuroscience,

0:14:51.000,0:14:53.000
but now, just as importantly,

0:14:53.000,0:14:56.000
to actively engage everybody in this conversation.

0:14:56.000,0:14:58.000
So let's think together as a team about what this all means

0:14:58.000,0:15:01.000
and where we can and should go from here,

0:15:01.000,0:15:03.000
because Xu and I think we all have

0:15:03.000,0:15:05.000
some really big decisions ahead of us.

0:15:05.000,0:15:06.000
Thank you.[br]XL: Thank you.

0:15:06.000,0:15:08.000
(Applause)