How to pronounce "mild"

Steve Ramirez: My first year of grad school,

I found myself in my bedroom

eating lots of Ben & Jerry's

watching some trashy TV

and maybe, maybe listening to Taylor Swift.

I had just gone through a breakup.

(Laughter)

So for the longest time, all I would do

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

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

visceral "blah" feeling.

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

so I knew that the memory of that person

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

are largely mediated by separate brain systems.

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

and edit out that nauseating feeling

but while keeping the memory of that person intact?

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

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

and just finding a single memory to begin with?

Could we jump-start that memory back to life,

maybe even play with the contents of that memory?

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

that I really hope is not watching this talk.

(Laughter)

So there is a catch. There is a catch.

These ideas probably remind you of "Total Recall,"

"Eternal Sunshine of the Spotless Mind,"

or of "Inception."

But the movie stars that we work with

are the celebrities of the lab.

Xu Liu: Test mice.

(Laughter)

As neuroscientists, we work in the lab with mice

trying to understand how memory works.

And today, we hope to convince you that now

we are actually able to activate a memory in the brain

at the speed of light.

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

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

and then you activate it with a switch.

As simple as that.

(Laughter)

SR: Are you convinced?

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

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

finding a needle in a haystack,

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

you can physically put your fingers on.

But memory is not.

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

than the number of straws in a typical haystack.

So yeah, this task does seem to be daunting.

But luckily, we got help from the brain itself.

It turned out that all we need to do is basically

to let the brain form a memory,

and then the brain will tell us which cells are involved

in that particular memory.

SR: So what was going on in my brain

while I was recalling the memory of an ex?

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

and slice up my brain right now,

you would see that there was an amazing number

of brain regions that were active while recalling that memory.

Now one brain region that would be robustly active

in particular is called the hippocampus,

which for decades has been implicated in processing

the kinds of memories that we hold near and dear,

which also makes it an ideal target to go into

and to try and find and maybe reactivate a memory.

XL: When you zoom in into the hippocampus,

of course you will see lots of cells,

but we are able to find which cells are involved

in a particular memory,

because whenever a cell is active,

like when it's forming a memory,

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

these cells are recently active.

SR: So the same way that building lights at night

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

in a very real sense, there are biological sensors

within a cell that are turned on

only when that cell was just working.

They're sort of biological windows that light up

to let us know that that cell was just active.

XL: So we clipped part of this sensor,

and attached that to a switch to control the cells,

and we packed this switch into an engineered virus

and injected that into the brain of the mice.

So whenever a memory is being formed,

any active cells for that memory

will also have this switch installed.

SR: So here is what the hippocampus looks like

after forming a fear memory, for example.

The sea of blue that you see here

are densely packed brain cells,

but the green brain cells,

the green brain cells are the ones that are holding on

to a specific fear memory.

So you are looking at the crystallization

of the fleeting formation of fear.

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

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

ideally, the switch has to act really fast.

It shouldn't take minutes or hours to work.

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

SR: So what do you think, Xu?

Could we use, let's say, pharmacological drugs

to activate or inactivate brain cells?

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

And also it takes them forever to act on cells.

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

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

SR: So electricity is pretty fast,

but we probably wouldn't be able to target it

to just the specific cells that hold onto a memory,

and we'd probably fry the brain.

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

indeed we need to find a better way

to impact the brain at the speed of light.

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

So maybe we could activate or inactive memories

by just using light --

XL: That's pretty fast.

SR: -- and because normally brain cells

don't respond to pulses of light,

so those that would respond to pulses of light

are those that contain a light-sensitive switch.

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

to respond to laser beams.

XL: Yep. You heard it right.

We are trying to shoot lasers into the brain.

(Laughter)

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

Optogenetics gave us this light switch that we can use

to turn brain cells on or off,

and the name of that switch is channelrhodopsin,

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

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

that can be artificially installed in brain cells

so that now we can use that switch

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

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

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

to the sensor we've been talking about

and inject this into the brain.

So whenever a memory is being formed,

any active cell for that particular memory

will also have this light-sensitive switch installed in it

so that we can control these cells

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

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

What we can do is we can take our mice

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

and then we can give them a very mild foot shock

so that they form a fear memory of this box.

They learn that something bad happened here.

Now with our system, the cells that are active

in the hippocampus in the making of this memory,

only those cells will now contain channelrhodopsin.

XL: When you are as small as a mouse,

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

So your best response of defense

is trying to be undetected.

Whenever a mouse is in fear,

it will show this very typical behavior

by staying at one corner of the box,

trying to not move any part of its body,

and this posture is called freezing.

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

and when we put them back into the same box,

it will basically show freezing

because it doesn't want to be detected

by any potential threats in this box.

SR: So you can think of freezing as,

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

and then out of nowhere you almost run into

an ex-girlfriend or ex-boyfriend,

and now those terrifying two seconds

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

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

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

Those kinds of fleeting thoughts that physically incapacitate you,

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

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

new box, like the next one,

it will not be afraid of this box

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

But what if we put the mouse in this new box

but at the same time, we activate the fear memory

using lasers just like we did before?

Are we going to bring back the fear memory

for the first box into this completely new environment?

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

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

I remember that the Red Sox had just won,

it was a green spring day,

perfect for going up and down the river

and then maybe going to the North End

to get some cannolis, #justsaying.

Now Xu and I, on the other hand,

were in a completely windowless black room

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

because our eyes were fixed onto a computer screen.

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

for the first time using our technique.

XL: And this is what we saw.

When we first put the mouse into this box,

it's exploring, sniffing around, walking around,

minding its own business,

because actually by nature,

mice are pretty curious animals.

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

It's interesting.

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

all of a sudden the mouse entered this freezing mode.

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

Clearly it's freezing.

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

the fear memory for the first box

in this completely new environment.

While watching this, Steve and I

are as shocked as the mouse itself.

(Laughter)

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

without saying anything.

After a kind of long, awkward period of time,

Steve broke the silence.

SR: "Did that just work?"

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

We're really excited about this.

And then we published our findings

in the journal Nature.

Ever since the publication of our work,

we've been receiving numerous comments

from all over the Internet.

Maybe we can take a look at some of those.

["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"]

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

have really strong opinions about this kind of work.

Now I happen to completely agree with the optimism

of this first quote,

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

it happens to be one of the most evocative accolades

that I've heard come our way.

(Laughter)

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

["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"]

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

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

probably not as positive.

But this also reminds us that,

although we are still working with mice,

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

about the possible ethical ramifications

of memory control.

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

we want to tell you about a recent project that we've been

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

["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."]

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

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

Could we possibly even turn it into a false memory?

XL: So all memory is sophisticated and dynamic,

but if just for simplicity, let's imagine memory

as a movie clip.

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

this "play" button of the clip

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

But is there a possibility that we can actually get

inside the brain and edit this movie clip

so that we can make it different from the original?

Yes we can.

Turned out that all we need to do is basically

reactivate a memory using lasers just like we did before,

but at the same time, if we present new information

and allow this new information to incorporate into this old memory,

this will change the memory.

It's sort of like making a remix tape.

SR: So how do we do this?

Rather than finding a fear memory in the brain,

we can start by taking our animals,

and let's say we put them in a blue box like this blue box here

and we find the brain cells that represent that blue box

and we trick them to respond to pulses of light

exactly like we had said before.

Now the next day, we can take our animals and place them

in a red box that they've never experienced before.

We can shoot light into the brain to reactivate

the memory of the blue box.

So what would happen here if, while the animal

is recalling the memory of the blue box,

we gave it a couple of mild foot shocks?

So here we're trying to artificially make an association

between the memory of the blue box

and the foot shocks themselves.

We're just trying to connect the two.

So to test if we had done so,

we can take our animals once again

and place them back in the blue box.

Again, we had just reactivated the memory of the blue box

while the animal got a couple of mild foot shocks,

and now the animal suddenly freezes.

It's as though it's recalling being mildly shocked in this environment

even though that never actually happened.

So it formed a false memory,

because it's falsely fearing an environment

where, technically speaking,

nothing bad actually happened to it.

XL: So, so far we are only talking about

this light-controlled "on" switch.

In fact, we also have a light-controlled "off" switch,

and it's very easy to imagine that

by installing this light-controlled "off" switch,

we can also turn off a memory, any time, anywhere.

So everything we've been talking about today

is based on this philosophically charged principle of neuroscience

that the mind, with its seemingly mysterious properties,

is actually made of physical stuff that we can tinker with.

SR: And for me personally,

I see a world where we can reactivate

any kind of memory that we'd like.

I also see a world where we can erase unwanted memories.

Now, I even see a world where editing memories

is something of a reality,

because we're living in a time where it's possible

to pluck questions from the tree of science fiction

and to ground them in experimental reality.

XL: Nowadays, people in the lab

and people in other groups all over the world

are using similar methods to activate or edit memories,

whether that's old or new, positive or negative,

all sorts of memories so that we can understand

how memory works.

SR: For example, one group in our lab

was able to find the brain cells that make up a fear memory

and converted them into a pleasurable memory, just like that.

That's exactly what I mean about editing these kinds of processes.

Now one dude in lab was even able to reactivate

memories of female mice in male mice,

which rumor has it is a pleasurable experience.

XL: Indeed, we are living in a very exciting moment

where science doesn't have any arbitrary speed limits

but is only bound by our own imagination.

SR: And finally, what do we make of all this?

How do we push this technology forward?

These are the questions that should not remain

just inside the lab,

and so one goal of today's talk was to bring everybody

up to speed with the kind of stuff that's possible

in modern neuroscience,

but now, just as importantly,

to actively engage everybody in this conversation.

So let's think together as a team about what this all means

and where we can and should go from here,

because Xu and I think we all have

some really big decisions ahead of us.

Thank you. XL: Thank you.

(Applause)