How to pronounce "outsides"

Sleep.

It's something we spend about a third of our lives doing,

but do any of us really understand what it's all about?

Two thousand years ago, Galen,

one of the most prominent medical researchers

of the ancient world,

proposed that while we're awake,

our brain's motive force, its juice,

would flow out to all the other parts of the body,

animating them but leaving the brain all dried up,

and he thought that when we sleep,

all this moisture that filled the rest of the body

would come rushing back,

rehydrating the brain

and refreshing the mind.

Now, that sounds completely ridiculous to us now,

but Galen was simply trying to explain

something about sleep

that we all deal with every day.

See, we all know based on our own experience

that when you sleep, it clears your mind,

and when you don't sleep,

it leaves your mind murky.

But while we know a great deal more about sleep now

than when Galen was around,

we still haven't understood why it is that sleep,

of all of our activities, has this incredible

restorative function for the mind.

So today I want to tell you about

some recent research

that may shed new light on this question.

We've found that sleep may actually be

a kind of elegant design solution

to some of the brain's most basic needs,

a unique way that the brain

meets the high demands and the narrow margins

that set it apart from all the other organs of the body.

So almost all the biology that we observe

can be thought of as a series of problems

and their corresponding solutions,

and the first problem that every organ must solve

is a continuous supply of nutrients to fuel

all those cells of the body.

In the brain, that is especially critical;

its intense electrical activity uses up

a quarter of the body's entire energy supply,

even though the brain accounts

for only about two percent of the body's mass.

So the circulatory system

solves the nutrient delivery problem

by sending blood vessels to supply nutrients

and oxygen to every corner of our body.

You can actually see it in this video here.

Here, we're imaging blood vessels

in the brain of a living mouse.

The blood vessels form a complex network

that fills the entire brain volume.

They start at the surface of the brain,

and then they dive down into the tissue itself,

and as they spread out, they supply nutrients

and oxygen to each and every cell in the brain.

Now, just as every cell requires

nutrients to fuel it,

every cell also produces waste as a byproduct,

and the clearance of that waste

is the second basic problem

that each organ has to solve.

This diagram shows the body's lymphatic system,

which has evolved to meet this need.

It's a second parallel network of vessels

that extends throughout the body.

It takes up proteins and other waste

from the spaces between the cells,

it collects them, and then dumps them into the blood

so they can be disposed of.

But if you look really closely at this diagram,

you'll see something

that doesn't make a lot of sense.

So if we were to zoom into this guy's head,

one of the things that you would see there

is that there are no lymphatic vessels in the brain.

But that doesn't make a lot of sense, does it?

I mean, the brain is this intensely active organ

that produces a correspondingly large amount of waste

that must be efficiently cleared.

And yet, it lacks lymphatic vessels, which means that

the approach that the rest of the body takes

to clearing away its waste

won't work in the brain.

So how, then, does the brain solve

its waste clearance problem?

Well, that seemingly mundane question

is where our group first jumped into this story,

and what we found

as we dove down into the brain,

down among the neurons and the blood vessels,

was that the brain's solution

to the problem of waste clearance,

it was really unexpected.

It was ingenious,

but it was also beautiful.

Let me tell you about what we found.

So the brain has this large pool

of clean, clear fluid called cerebrospinal fluid.

We call it the CSF.

The CSF fills the space that surrounds the brain,

and wastes from inside the brain

make their way out to the CSF,

which gets dumped, along with the waste, into the blood.

So in that way, it sounds a lot like

the lymphatic system, doesn't it?

But what's interesting is that the fluid and the waste

from inside the brain,

they don't just percolate their way randomly

out to these pools of CSF.

Instead, there is a specialized network of plumbing

that organizes and facilitates this process.

You can see that in these videos.

Here, we're again imaging into the brain

of living mice.

The frame on your left shows

what's happening at the brain's surface,

and the frame on your right shows

what's happening down below the surface of the brain

within the tissue itself.

We've labeled the blood vessels in red,

and the CSF that's surrounding the brain

will be in green.

Now, what was surprising to us

was that the fluid on the outside of the brain,

it didn't stay on the outside.

Instead, the CSF was pumped back into

and through the brain

along the outsides of the blood vessels,

and as it flushed down into the brain

along the outsides of these vessels,

it was actually helping to clear away,

to clean the waste from the spaces

between the brain's cells.

If you think about it,

using the outsides of these blood vessels like this

is a really clever design solution,

because the brain is enclosed

in a rigid skull

and it's packed full of cells,

so there is no extra space inside it

for a whole second set of vessels like the lymphatic system.

Yet the blood vessels,

they extend from the surface of the brain

down to reach every single cell in the brain,

which means that fluid

that's traveling along the outsides of these vessels

can gain easy access to the entire brain's volume,

so it's actually this really clever way

to repurpose one set of vessels, the blood vessels,

to take over and replace the function

of a second set of vessels, the lymphatic vessels,

to make it so you don't need them.

And what's amazing is that no other organ

takes quite this approach

to clearing away the waste from between its cells.

This is a solution that is entirely unique to the brain.

But our most surprising finding

was that all of this,

everything I just told you about,

with all this fluid rushing through the brain,

it's only happening in the sleeping brain.

Here, the video on the left

shows how much of the CSF is moving

through the brain of a living mouse while it's awake.

It's almost nothing.

Yet in the same animal,

if we wait just a little while until it's gone to sleep,

what we see is that the CSF

is rushing through the brain,

and we discovered that at the same time

when the brain goes to sleep,

the brain cells themselves seem to shrink,

opening up spaces in between them,

allowing fluid to rush through

and allowing waste to be cleared out.

So it seems that Galen may actually have been

sort of on the right track when he wrote about

fluid rushing through the brain

when sleep came on.

Our own research, now it's 2,000 years later,

suggests that what's happening is that

when the brain is awake

and is at its most busy,

it puts off clearing away the waste

from the spaces between its cells until later,

and then, when it goes to sleep

and doesn't have to be as busy,

it shifts into a kind of cleaning mode

to clear away the waste

from the spaces between its cells,

the waste that's accumulated throughout the day.

So it's actually a little bit like how you or I,

we put off our household chores during the work week

when we don't have time to get to it,

and then we play catch up on all the cleaning that we have to do

when the weekend rolls around.

Now, I've just talked a lot about waste clearance,

but I haven't been very specific

about the kinds of waste

that the brain needs to be clearing

during sleep in order to stay healthy.

The waste product that these recent studies

focused most on is amyloid-beta,

which is a protein that's made in the brain all the time.

My brain's making amyloid-beta right now,

and so is yours.

But in patients with Alzheimer's disease,

amyloid-beta builds up and aggregates

in the spaces between the brain's cells,

instead of being cleared away like it's supposed to be,

and it's this buildup of amyloid-beta

that's thought to be one of the key steps

in the development of that terrible disease.

So we measured how fast amyloid-beta is cleared

from the brain when it's awake

versus when it's asleep,

and we found that indeed,

the clearance of amyloid-beta

is much more rapid from the sleeping brain.

So if sleep, then,

is part of the brain's solution

to the problem of waste clearance,

then this may dramatically change how we think

about the relationship between sleep,

amyloid-beta, and Alzheimer's disease.

A series of recent clinical studies

suggest that among patients

who haven't yet developed Alzheimer's disease,

worsening sleep quality and sleep duration

are associated with a greater amount

of amyloid-beta building up in the brain,

and while it's important to point out

that these studies don't prove

that lack of sleep or poor sleep

cause Alzheimer's disease,

they do suggest that the failure of the brain

to keep its house clean

by clearing away waste like amyloid-beta

may contribute to the development

of conditions like Alzheimer's.

So what this new research tells us, then,

is that the one thing that all of you

already knew about sleep,

that even Galen understood about sleep,

that it refreshes and clears the mind,

may actually be a big part

of what sleep is all about.

See, you and I, we go to sleep

every single night,

but our brains, they never rest.

While our body is still

and our mind is off walking in dreams somewhere,

the elegant machinery of the brain

is quietly hard at work

cleaning and maintaining

this unimaginably complex machine.

Like our housework,

it's a dirty and a thankless job,

but it's also important.

In your house, if you stop cleaning your kitchen

for a month,

your home will become completely unlivable

very quickly.

But in the brain, the consequences

of falling behind may be much greater

than the embarrassment of dirty countertops,

because when it comes to cleaning the brain,

it is the very health and function

of the mind and the body that's at stake,

which is why understanding these

very basic housekeeping functions of the brain today

may be critical for preventing and treating

diseases of the mind tomorrow.

Thank you.

(Applause)