A light switch for neurons Ed Boyden

your day for a second you woke up felt

fresh air in your face as you walked out

the door

encountered new colleagues and had great

discussions and felt in awe and you

found something new but I bet there’s

something that you didn’t think about

today something so close to home that

you probably don’t think about it very

often at all and that’s what all those

sensations feelings decisions and

actions are mediated by the computer in

your head called your brain now the

brain may not look like much from the

outside a couple pounds of pinkish gray

flesh amorphous but the last 100 years

of neuroscience have allowed us to zoom

in on the brain and to see the intricacy

of what lies are then and they told us

that this brain is an incredibly

complicated circuit made out of hundreds

of billions of cells called neurons now

unlike a human designed computer where

there’s a fairly small number different

parts we know how they work because we

humans design them the brain is made of

thousands of different kinds of cell

maybe tens of thousands they come in

different shapes they’re made out of

different molecules and they project and

connect to different brain regions and

they also change different ways in

different disease states let’s make it

concrete there’s a class of cells fairly

small cell I’m an inhibitory cell that

quiets its neighbors it’s one of the

cells that seem to be atrophied in

disorders like schizophrenia called the

basket stop and this cell is one of the

thousands of kinds of cell that we are

learning about new ones being discovered

every day as just a second example these

parental cells large cells they can span

a cific infraction the brain they’re

excitatory and these are some of the

cells that might be over active and

disorders such as epilepsy every one of

these cells is an incredible electrical

device they receive inputs from

thousands of upstream partners and

compute their own electrical outputs

which then if they pass a certain

threshold will go to thousands of

downstream partners and this process

which takes just you know a millisecond

or so happens thousands of times a

minute and every one of your hundred

billion cells as long as you live and

think and feel so how we’re gonna figure

out what this circuit does ideally we

could go through this circuit and turn

these different kinds of

on and off and see whether we could

figure out which ones contributed to

certain functions and which ones go

wrong in certain pathologies we could

activate cells or to see what powers

they can unleash what they can initiate

and sustain if we can turn them off then

we could try and figure out they’re

necessary for and that’s the story I’m

going to tell you about today and

honestly where we’ve gone through over

the last 11 years through an attempt to

find ways of turning circuits and cells

and parts and pathways of the brain on

and off both to understand the science

and also to confront some of the issues

that face us all as humans now before I

tell you the technology the bad news is

that a significant fraction of us in

this room if we live long enough will

encounter perhaps a brain disorder

already a billion people have had some

kind of brain disorder incapacitate stun

and the numbers don’t do it justice

though these disorders schizophrenia

Alzheimer’s depression addiction they

not only steal away our time to live

they change who we are they take our

identity and change our emotions and

change who we are as people now in the

20th century there was some hope that

was generated through the development of

pharmaceuticals for treating brain

disorders and while many drugs have been

developed that can alleviate symptoms of

brain disorders practically none of them

can be considered to be cured and in

part that’s because if you think about

it we’re bathing the brain in a chemical

this elaborate circuit made out of

thousand different kinds of cell is

being bathed in a substance that’s also

why perhaps most of the drugs is not all

in the market can present some kind of

serious side effect to now some people

have gotten some solace from electrical

stimulators that are implant in the

brain and for Parkinson’s disease

cochlear implants these have indeed been

able to bring some kind of remedy to

people with certain kinds of disorder

but electricity also will go in all

directions the path of least resistance

which is kind of where that phrase in

part comes from

and it also will affect normal circuits

as well as the abnormal ones that you

want to fix so again

weird sent back to the idea of ultra

precise control could we dial in

information precisely where we want it

to go so when I started in neuroscience

well

years ago I had trained it as an

electrical engineer and a physicist and

the first thing I thought about was well

if these neurons or electrical devices

all we need to do is to find some way of

driving those electrical changes at a

distance if we could turn on electricity

in one cell but not its neighbors that

would give us the toll we need to

activate and shut down these different

cells here what they do and have the

contribute to the networks in which

they’re embedded and also it allow us to

have the ultra precise control we need

in order to fix the circuit computations

that have gone awry now how are gonna do

that well there many molecules that

exist in nature

which are able to convert light and

electricity you can think of them as

little proteins that are like solar

cells if we install these molecules in

neurons somehow then these neurons would

become electrically drivable with light

and their neighbors which don’t have

this molecule would not there’s one

other magic trick you need to make this

all happen and that’s the only got light

into the brain and to do that the brain

doesn’t feel pain you can put taking

advantage of all the effort that’s gone

into the internet and telecommunications

and so on optical fibers connected to

lasers that you can use to activate in a

neural models for example in preclinical

studies these neurons and to see what

they do so how do we do this we’re on

2004 in collaboration with beard

Nagaland Carl dice Roth this vision came

to fruition there’s a certain alga that

swims in the wild and it needs to

navigate towards light in order to

photosynthesize optimally and it senses

light with a little eye spot which works

not unlike how our eye works in its

membrane or the boundary it contains

little proteins that indeed can convert

light into electricity so these

molecules are called channelrhodopsins

and each of these proteins acts just

like that solar cell that I told you

about when blue light hits it it opens

have a little hole and allows charged

particles to enter the eye spot and that

allows this eye spot to have an

electrical signal just like a solar cell

charging up a battery so what we need to

do is to take these molecules and

somehow install them in neurons and

because it’s a protein it’s encoded for

in the DNA of this organism so all I got

to do is take that DNA put into a gene

therapy vector like a virus and put it

into neurons so it turned out that this

was a very productive try

in gene therapy and lots of viruses are

coming along so this turn out to be

fairly simple to do and early in the

morning one day in the summer of 2004 we

gave it a try and it worked on the first

try

you take this DNA and you put into the

neuron the neuron uses its natural

protein making machinery to fabricate

these little light-sensitive proteins

and install them all over the cell like

putting solar panels on a roof and the

next thing you know you have a neuron

which can be activated with light so

this is very powerful one of the tricks

you have to do is to figure out how to

deliver these genes to the cells that

you want and not all the other neighbors

right and you can do that you can tweak

the viruses so they hit just some cells

and not others

and there’s other genetic tricks you can

play in order to get light activated

cells this field has now come to be

known as optogenetics and this is one

example of the kind of thing you can do

you can take a complex network use one

these viruses deliver the gene just to

one kind of cell in this dense Network

and then when you shine light on the

entire network just that cell type will

be activated so for example that sort of

cancer that basket saw I told you about

earlier the one that’s after feeding

schizophrenia and the one that is

inhibitory if we can deliver that gene

to these cells and they’re not being

altered by the expression of the gene of

course and then flash blue light over

the entire brain Network just these

cells are going to be driven and when

the light turns off these cells go back

to normal so there don’t seem to be

adverse events that I only can use this

a study what these cells do what their

power is in computing in the brain but

you can also use this to try and figure

out well maybe we could jazz up the

activity these cells have indeed their

atrophied now I don’t tell you a couple

short stories about how we’re using this

both of the scientific clinical and

preclinical levels one of the questions

that we’ve confronted is what are the

signals in the brain that mediate the

sensation of reward because it could

find those those would be some of the

signals that can drive learning right

the brain will do more whatever got that

reward and also these are signals that

go awry in disorders such as addiction

so if we could figure out what cells

they are we can maybe find new targets

for which drugs can be designed or

screened against or maybe places where

electrodes could be put in for people

who have very severe disability so to do

that we even with a very simple paradigm

in collaboration with the Fiorello group

where one side of this little box if the

animal goes there they all gets a pulse

of light and we’re to make different

cells in the brain sensitive

so if these cells can mediate reward the

animal should go there more and more and

so that’s what happens this animals

gonna go to the right-hand side

and poke his nose there and gets a flash

of blue light every times it does that

and he’ll do that hundreds and hundreds

of times these are the dopamine neurons

which some of you may have heard about

into some of the pleasure centers in the

brain now we’ve shown that a brief

activation of these is enough indeed to

drive learning now we can generalize the

idea instead of one point in the brain

we can devise devices that span the

brain that can deliver light into

three-dimensional patterns arrays of

optical fibers each couple to its own

independent miniature light source and

then we can try to do things in vivo

that have only been done to date in a

dish like high-throughput screening

throughout the entire brain for the

signals that can cause certain things to

happen or that could be good clinical

targets for treating brain disorders and

one sterile I talked about is how can we

find targets for treating post-traumatic

stress disorder a form of uncontrolled

anxiety and fear and one of the things

that we did was to adopt a very

classical model of fear this goes back

you know back to the Pavlovian days and

it’s called Pavlovian fear conditioning

where a tone ends the brief shock shock

isn’t painful but it’s little annoying

and over time in this case the mouse

which is a good animal model commonly

used in such experiments the animal

learns to fear the tone the animal

reacts by freezing sort like a deer in

headlights now the question is what

targets the brain can we find that allow

us to overcome this fear so what we do

is you play that tone again after it’s

been associated with fear but we

activate targets the brain different

ones using that optical fiber a I told

you about in the previous slide in order

to try and ferret which targets can

cause the brain to overcome that memory

of fear and so this brief video shows

you one of these targets that were

working on now this is an area in the

prefrontal cortex a region where we can

use cognition to try and overcome

adversity of emotional states and then I

was going to hear a tone and the flash

of light occurred there there’s no audio

in this but you can see the animals

freezing this tone used to mean bad news

and there’s a little clock in the lower

left hand corner so you can see that

this animal is about two minutes into

this and now this next clip is just

eight minutes later and the same tones

gonna play in the lights gonna flash

again okay there it goes right now and

now you can see just ten minutes into

the experiment that we’ve equipped the

brain by photoactive in this area to

overcome the

rushon of the sphere memory now over the

last couple years we’ve gone back to the

Tree of Life because we wanted to find

ways to turn circuits in the brain off

if we could do that this could be

extremely powerful if you can delete

cells just for a few milliseconds of

seconds you can figure out what

necessary role they play in the circuits

in which they’re embedded and we’ve now

surveyed organisms from all over the

Tree of Life every kingdom of life

except for animals we seek slept one

differently and we found all sorts of

molecules they’re called halorhodopsin

dark gray Dobson to respond to green and

yellow light and they do the opposite

thing of the molecule I told you about

before the blue light activator general

Dobson let’s give an example of where we

think this is going to go consider for

example a condition like epilepsy where

the brain is overactive now if drugs

fail an epileptic treatment one of the

strategies is to remove part of the

brain that’s obviously irreversible and

there could be side effects what if we

could just turn off that brain for the

brief amount of time until the seizure

dies away and cause the brain to be

restored res initial state sort like a

dynamical system that’s being coaxed

down into a stable state this animation

is tries to explain this concept where

we made these cells sensitive to being

turned off with light and we beam light

in and just for the time it takes to

shut down a seizure we’re hoping to be

able to turn it off and so we don’t have

data to show you in this front but we’re

very excited about this now I want to

close on one story which we think is

another possibility which is that maybe

these molecules if you can do ultra

precise control to be used in the brain

itself to make a new kind of prosthetic

an optical prosthetic I already told you

that electrical stimulators are not in

common seventy-five thousand people have

Parkinson’s deep brain stimulators

implanted maybe a hundred thousand

people have cochlear implants which will

allow them to hear there’s another thing

which it’s got to get these genes into

cells and new hope and gene therapy has

been developed because there are viruses

like the add no source and virus which

probably most of us around this room

have and it doesn’t have any symptoms

which have been used in hundreds of

patients

delivered genes into the brain of the

body and so far there have not been

serious adverse events associated with

the virus there’s one last alpha in the

room the proteins themselves which come

from algae and bacteria and funguses and

all over the Tree of Life most of us

don’t have funguses or algae in our

brain so what is their brain gonna do if

we put that in how this cell is gonna

tolerate it

well the immune system react and it’s

early days these are not been done in

humans yet but we’re in a variety of

studies

to try and examine this and so far we

haven’t seen overt reactions of any

severity to these molecules or to these

the illumination of the brain with light

so it’s early days yet front we’re

excited about it I want to close in one

story which we think could potentially

be a clinical application now there many

forms of blindness where their

photoreceptors our light sensors that

are in the back of our eye are gone and

the retina of course is a complex

structure let’s zoom in on it here so

you can see it in more detail the

photoreceptor cells are shown here at

the top and then the signals that are

detected by the photoreceptors are

transformed through various computations

until finally that layer cells at the

bottom the ganglion cells relay the

information to the brain where we see

that as perception in many forms of

blindness they recognise pigmentosa or

macular degeneration the photoreceptor

cells have atrophied or been destroyed

now how could you repair this it’s not

even clear that a drug could cause this

to be restored because there’s nothing

for the drug to bind to other hand like

you still get into the eye right the eye

is still transparent and you can get

light in so what if we could just take

these general drops and other molecules

and install them on some of these other

spared cells and convert them into

little cameras and because there’s so

many of these cells in the eye but

initially it could be very

high-resolution cameras so this is some

work that we’re doing that’s being both

led by one of our collaborators Alan hor

saga at USC and being sought to be

commercialized by a startup company your

stereo science which is funded by the

NIH and what you see here is a mouse

trying to solve a maze as the six arm

maze and as a bit of water in the maze

to motivate the mouse to move where

he’ll just sit there and the goal of

course of this maze is to get out of the

water and go to a little platform that’s

under the ellipse top port now mice are

smart this mouse solve the maze

eventually but he does a brute force

search he’s swimming down every Avenue

until he finally gets to the platform so

he’s not using vision to do it these

different mice are different mutations

that recapitulate different kinds of

blindness that that affect humans and

sort of being careful and trying to look

at these different models so we come

with a generalized approach so how are

gonna solve this well we’re gonna do

exactly like line the previous slide

we’re gonna take these blue light photo

sensors and install them onto a layer of

cells in the middle of the retina in the

back of the eye and convert them into a

camera just like installing solar cells

all over those neurons

make them light-sensitive flightless

converts electricity on them so this

mouse was blind a couple weeks before

this experiment and received one dose of

this photosensitive molecule and a virus

and now you can see the animal can

indeed avoid walls and go to this little

platform and make cognitive use of its

eyes again and to point out the power of

this these animals are able to get to

that platform just as fast as animals

have seen their entire life so this

preclinical study I think bodes hope for

the kinds of things we’re hoping to do

in the future to close I want to point

out that we’re also exploring new

business models for this new field of

neuro technology we’re developing these

tools but we share them freely with

hundreds of groups all over the world so

people can study and try to treat

different disorders and our hope is that

by figuring out brain circuits at a

level of abstraction that lets us repair

them and engineer them we can take some

of these intractable disorders that I

told you about earlier practically none

of which are cured and the 21st century

make them history thank you

so some of the stuff is a little dense

but the implications of being able to

control seizures or epilepsy with light

instead of drugs and being able to

target those specifically is the first

step the second thing that I think I

heard you say is you can now control the

brain in two colors mm-hmm like an

on/off switch that’s right which makes

every impulse going through the brain a

binary code right yeah so with blue

light we can drive information in this

form of a one and by turning things off

it’s more or less a zero so our hope is

to eventually build brain coprocessors

that work with the brain so we can

augment functions in people with

disabilities and in theory that means

that as a mouse feels smells hears

touches you can model it out as a string

of ones and zeros sure yeah we’re hoping

that use this as a way of testing what

neural codes can drive certain behaviors

and certain thoughts and certain

feelings I’ve used that to understand

more about the brain does that mean that

someday you could download memories and

maybe upload them well it’s something

we’re starting to work on very hard yeah

we’re we’re now working on some work

where we’re trying to tile the brain

with recording elements to so we can

record information and then drive

information back in serve computing what

the brain needs in order to augment its

information processing that might change

a couple of things thank you thank you