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