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