A map of the brain Allan Jones
humans have long held a fascination for
the human brain we charted we’ve
described it we’ve drawn it we’ve mapped
it now just like the physical maps of
our world that have been highly
influenced by technology think Google
Maps think GPS the same thing is
happening for brain mapping true
transformation so let’s take a look at
the brain most people when they first
look at a fresh human brain is it
doesn’t look like what you’re typically
looking at when someone shows you a
brain typically what you’re looking at
is a fixed brain it’s gray and this
outer layer this is the vasculature
which is incredible around the human
brain this is the blood vessels 20% of
the oxygen coming from your lungs 20% of
the blood pumped from your heart is
servicing this one organ that’s
basically if you hold two fifths
together it’s just slightly larger than
the two fists scientists sort of in the
end of the 20th century learned that
they could track blood flow to map
non-invasively where activity was going
on in the human brain so for example
they can see in the back part of the
brain which is just turning around there
there’s the cerebellum that’s keeping
you upright right now it’s keeping me
standing it’s involved in coordinated
movement on the side here this is the
temporal cortex this is the area where
primary auditory processing so you’re
hearing my words you’re sending it up
into higher language processing centers
towards the front of the brain is the
place in which all of the dis sort of
more complex thought decision-making is
the last two mature sort of a late
adulthood this is where all your
decision-making processes are going on
it’s the place where you were deciding
right now you probably aren’t going to
order the steak for dinner so if you
take a deeper look at the brain one of
the things if you look at it in
cross-section what you can see is that
you can’t really see a whole lot of
structure there but there’s actually a
lot of structure there it’s cells and
it’s wires all wired together so about a
hundred years ago some scientists
invented its
that would stain cells and that shown
here in the very light blue you can see
areas where neuronal cell bodies are
being stained and what you can see is
this very non-uniform you see a lot more
structure there’s the outer part of that
brain are the is the neocortex it’s one
sort of continuous processing unit if
you will but you could also see things
underneath there as well and all of
these blank areas are the areas in which
the wires are running through they’re
probably less cell dense so there’s
about 86 billion neurons in our brain
and as you can see they’re very non
uniformly distributed and how they’re
distributed really contributes to their
underlying function and of course as I
mentioned before since we can now start
to map brain function we can start to
tie these into the individual cells so
let’s take a deeper look let’s look at
neurons so as I mentioned there are 86
billion neurons there are also these
smaller cells as you’ll see these are
support cells astrocytes glia and the
nerves themselves are the ones who are
receiving input they’re storing it
they’re processing it each neuron is
connected via synapses to up to 10,000
other neurons in your brain and each
neuron itself is largely unique then
unique character of both individual
neurons and neurons within a collection
of the brain are driven by fundamental
properties of their underlying
biochemistry these are proteins they’re
proteins that are controlling things
like ion channel movement they’re
controlling who nervous system cells
partner up with and they’re controlling
basically everything that the nervous
system has to do so if we zoom in to
even deeper level all of those proteins
are encoded by our genomes we each have
23 pairs of chromosomes we get one from
mom one from dad and on these
chromosomes are roughly 25,000 genes
they’re encoded in the DNA and the
nature of a given cell driving its
underlying biochemistry is dictated by
which of these 25,000 genes are turned
on and at what level they’re turned on
and so our project is seeking to look at
this readout understanding which of
these 25,000 genes is turn
so in order to undertake such a project
we obviously need brains so we sent our
lab technician out we were seeking
normal human brains what we actually
start with is a medical examiner’s
office this is a place where the dead
are brought in we are seeking normal
human brains there’s a lot of criteria
by which we’re selecting these brains we
want to make sure that we have normal
human between the ages of 20 to 60 they
died somewhat natural death with no
injury to the brain no history of
psychiatric disease no drugs on board we
do a toxicology workup and we we’re very
careful about the brains that we do take
we’re also selecting for brains in which
we can get the tissue we can get consent
to take the tissue within 24 hours of
time of death because what we’re trying
to measure the RNA which is the readout
from our genes is a very labile and so
so we have to move very quickly one side
note on the collection of brains because
of the way that we collect and because
we’re requiring consent we actually have
a lot more male brains than female
brains males are much more likely to die
accidental death in the prime of their
life and men are much more likely to
have their significant other spouse give
consent than the other way around so the
first thing that we do at the site of
collection is we collect what’s called
an mr this is magnetic resonance imaging
MRI it’s a standard template by which
we’re going to hang the rest of this
data so we collect this mr and you can
think of this as our satellite view for
our map the next thing we do is we
collect what’s called the diffuse and
tensor imaging this maps the large
cabling in the brain and again you can
think of this is almost mapping our
interstate highways if you will the
brain is removed from the skull and then
it sliced into 1 centimeter slices and
those are frozen solid and they’re
shipped to Seattle and in Seattle we
take these this is a whole human
hemisphere and we put them into it’s
basically a glorified meat slicer
there’s a blade here that’s going to cut
across this section of the tissue and
transfer it to a microscope slide we’re
going to then apply one of those stains
to it and we scan it and then what we
get is our first
rapping so this is where our experts
come in and they make basic anatomica
sign mminton siddur this state
boundaries if you wear those pretty
broad outlines from this we’re able to
then fragment that brain into further
pieces which then we can put on a
smaller cryostat and this is a showing
this here is frozen tissue and it’s
being cut this is 20 microns thin so
this is about a baby hairs with remember
it’s frozen and so you can see here
old-fashioned technology of a paintbrush
being applied would take a microscope
slide and we very carefully melt onto
this slide this will then go into a
robot that’s going to apply one of those
stains to it okay and our anatomist are
going to go in and take a deeper look at
this so again this is what they can see
under the microscope you can see
collections and configurations of large
and small cells and clusters and various
places and from their expertise they
understand where to make these
assignments and they can make basically
what’s a reference outlets this is a
more detailed map our scientists then
use this to go back to another piece of
that tissue and do what’s called laser
scanning microdissection so the
technician takes the instructions they
scribe along a place there and then the
laser actually cuts you can see the blue
dot there cutting and that tissue falls
off you can see on the microscope slide
here that’s what’s happening in real
time there’s a container underneath
that’s collecting that tissue we take
that tissue we purify the RNA out of it
using some basic technology and then we
put a fluorescent tag on it
we take that tagged material and we put
it on to something called a microarray
now this may look like a bunch of dots
to you but each one of these individual
dots is actually a unique piece of the
human genome that we spotted down on
glass this has roughly 60,000 elements
on it so we repeatedly measure various
genes of the 25,000 genes in the genome
and when we take a sample and we
hybridize it to it we get a unique
fingerprint if you will
quantitatively of what genes are turned
on in that sample now we do this over
and over again this process for any
given brain were taking over a thousand
samples for each brain this area shown
here is an area called the hippocampus
it’s a
than learning and memory and it
contributes to about 70 samples of those
thousand samples so each sample gives us
about fifty thousand data points with
repeat measurements a thousand samples
so roughly we have 50 million data
points for a given human brain we’ve
done right now to human brains worth of
data we’ve put all of that together into
one thing and I’ll show you what that
synthesis looks like basically a large
data set of information that’s all
freely available to any scientist around
the world they don’t even have to log in
to come use this pool - data find
interesting things out with us so here’s
the modalities that we put together
you’ll start to recognize these things
from what we’ve collected before here’s
the M R it provides the framework
there’s an operator side on the right
that allows you to turn it allows you to
zoom in it allows you to highlight
individual structures but most
importantly we’re now mapping into this
anatomic framework which is a common
framework for people to understand where
our genes are turned on so the red
levels are where a gene is turned on to
a great degree Green is this sort of
cool areas where it’s not turned on and
each gene gives us a fingerprint and
remember that we’ve assayed all the
25,000 genes in the genome and have all
that data available so what can
scientists learn about this data and
we’re just starting to look at this data
ourselves there’s some basic things that
you would want to understand - great
examples are drugs Prozac and wellbutrin
these are commonly prescribed
antidepressants now remember we’re a
saying genes genes send the instructions
to make proteins proteins are targets
for drugs so drugs bind to proteins and
either turn them off etc so if you want
to understand the action of drugs you
want to understand how they’re acting in
the ways you want them to and also in
the ways you don’t want them to and the
side effect profile etc you want to see
where those genes are turned on and for
the first time we can actually do that
we can do that in multiple individuals
since we’ve a say - so now we can look
throughout the brain we can see this
unique fingerprint and we get
confirmation we get confirmation that
indeed the gene is
for something like prozac in
serotonergic structures things that are
already known to be affected but we get
to see the whole thing we also get to
see areas that no one has ever looked at
before and we see these genes turned on
there is this interesting side effects
it could be one other thing you can do
was such a thing is you can because it’s
a it’s a pattern matching exercise
because there’s a unique fingerprint we
can actually scan through the entire
genome and find other proteins that show
a similar fingerprint so if you’re in
drug discovery for example you can go
through an entire listing of what the
genome has on offer to find perhaps
better drug targets and optimize most of
you are probably familiar with
genome-wide Association studies in the
form of people covering in the news
saying scientists have recently
discovered the gene or genes which
affect X and so these kinds of studies
are routinely published by scientists
and they’re great and they analyze large
populations they look at their entire
genomes and they try to find hotspots of
activity that are that are linked
causally to genes but what you get out
of such an exercise is simply a list of
genes it tells you the what but it
doesn’t tell you the where and so it’s
very important for those researchers
that we’ve created this resource now
they can come in and they can start to
get clues about activity they can start
to look at common pathways other things
that they simply haven’t been able to do
before
so I think this audience in particular
can understand the importance of
individuality and I think every human we
all have different genetic backgrounds
we all have lived separate lives but the
fact is our genomes are greater than 99%
similar we’re very very similar at the
genetic level and what we’re finding is
actually even at the brain biochemical
level we are quite similar and so this
shows it’s not 99% but it’s roughly 90
percent correspondence at a reasonable
cutoff so everything in the cloud is
sort of roughly correlated and then we
find some outliers some things that lie
beyond the cloud and those genes are
interesting but they’re very subtle so
I think it’s just an important message
to take home today that even though we
celebrate all of our differences we are
quite similar even at the brain level
and one of those differences look like
this is an example of a study that we
did to follow up and see what exactly
those differences were and they’re quite
subtle these are things where genes are
turned on in an individual cell type
these are two genes that we found that
as good examples one is called ghrelin
it’s involved in early developmental
cues discs one is a gene that’s deleted
in schizophrenia
these aren’t schizophrenic individuals
but they do show some population
variations and so what you’re looking at
here in donor 1 and donor 4 which are
the exceptions to the other two that
genes are being turned on at a very
specific subset of cells it’s this dark
purple precipitate within the cell
that’s telling us a gene is turned on
there whether or not that’s due to the
individual’s genetic background or their
experiences we don’t know those kinds of
studies require much larger populations
so I’m going to leave you with a final
note about the complexity of the brain
and how much more we have to go I think
these resources are incredibly valuable
they give researchers a handle on where
to go but we’ve only looked at a handful
of individuals at this point we’ve
certainly going to be looking at more
I’ll just close by saying that that the
the tools are there and this is truly an
unexplored undiscovered continent this
is the the new frontier if you will and
so for those who are undaunted but
humbled by the complexity of the brain
the future awaits thanks