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Sleep.

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

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

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Two thousand years ago, Galen,

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one of the most prominent medical researchers

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of the ancient world,

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proposed that while we're awake,

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our brain's motive force, its juice,

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

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animating them but leaving the brain all dried up,

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and he thought that when we sleep,

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all this moisture that filled the rest of the body

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would come rushing back,

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rehydrating the brain

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and refreshing the mind.

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Now, that sounds completely ridiculous to us now,

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but Galen was simply trying to explain

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something about sleep

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that we all deal with every day.

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See, we all know based on our own experience

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that when you sleep, it clears your mind,

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and when you don't sleep,

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it leaves your mind murky.

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But while we know a great deal more about sleep now

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than when Galen was around,

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

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of all of our activities, has this incredible

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restorative function for the mind.

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So today I want to tell you about

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some recent research

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that may shed new light on this question.

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We've found that sleep may actually be

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a kind of elegant design solution

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to some of the brain's most basic needs,

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a unique way that the brain

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meets the high demands and the narrow margins

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

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So almost all the biology that we observe

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can be thought of as a series of problems

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and their corresponding solutions,

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and the first problem that every organ must solve

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is a continuous supply of nutrients to fuel

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all those cells of the body.

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In the brain, that is especially critical;

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its intense electrical activity uses up

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a quarter of the body's entire energy supply,

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even though the brain accounts

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

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So the circulatory system

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solves the nutrient delivery problem

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by sending blood vessels to supply nutrients

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and oxygen to every corner of our body.

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You can actually see it in this video here.

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Here, we're imaging blood vessels

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in the brain of a living mouse.

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The blood vessels form a complex network

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that fills the entire brain volume.

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They start at the surface of the brain,

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and then they dive down into the tissue itself,

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and as they spread out, they supply nutrients

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and oxygen to each and every cell in the brain.

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Now, just as every cell requires

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nutrients to fuel it,

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every cell also produces waste as a byproduct,

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and the clearance of that waste

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is the second basic problem

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that each organ has to solve.

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This diagram shows the body's lymphatic system,

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which has evolved to meet this need.

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It's a second parallel network of vessels

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that extends throughout the body.

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It takes up proteins and other waste

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from the spaces between the cells,

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it collects them, and then dumps them into the blood

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so they can be disposed of.

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But if you look really closely at this diagram,

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you'll see something

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that doesn't make a lot of sense.

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

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one of the things that you would see there

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is that there are no lymphatic vessels in the brain.

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

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I mean, the brain is this intensely active organ

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that produces a correspondingly
large amount of waste

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that must be efficiently cleared.

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And yet, it lacks lymphatic vessels, which means that

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the approach that the rest of the body takes

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to clearing away its waste

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won't work in the brain.

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So how, then, does the brain solve

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its waste clearance problem?

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Well, that seemingly mundane question

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is where our group first jumped into this story,

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and what we found

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as we dove down into the brain,

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down among the neurons and the blood vessels,

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was that the brain's solution

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to the problem of waste clearance,

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it was really unexpected.

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It was ingenious,

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but it was also beautiful.

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Let me tell you about what we found.

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So the brain has this large pool

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of clean, clear fluid called cerebrospinal fluid.

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We call it the CSF.

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The CSF fills the space that surrounds the brain,

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and wastes from inside the brain

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make their way out to the CSF,

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

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So in that way, it sounds a lot like

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the lymphatic system, doesn't it?

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

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from inside the brain,

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they don't just percolate their way randomly

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out to these pools of CSF.

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Instead, there is a specialized network of plumbing

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that organizes and facilitates this process.

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You can see that in these videos.

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Here, we're again imaging into the brain

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of living mice.

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The frame on your left shows

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what's happening at the brain's surface,

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and the frame on your right shows

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what's happening down below the surface of the brain

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within the tissue itself.

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We've labeled the blood vessels in red,

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and the CSF that's surrounding the brain

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will be in green.

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Now, what was surprising to us

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was that the fluid on the outside of the brain,

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it didn't stay on the outside.

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Instead, the CSF was pumped back into

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and through the brain

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along the outsides of the blood vessels,

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and as it flushed down into the brain

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along the outsides of these vessels,

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it was actually helping to clear away,

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to clean the waste from the spaces

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between the brain's cells.

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If you think about it,

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using the outsides of these blood vessels like this

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is a really clever design solution,

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because the brain is enclosed

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in a rigid skull

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and it's packed full of cells,

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so there is no extra space inside it

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

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Yet the blood vessels,

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they extend from the surface of the brain

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down to reach every single cell in the brain,

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which means that fluid

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that's traveling along the outsides of these vessels

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

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so it's actually this really clever way

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to repurpose one set of vessels, the blood vessels,

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to take over and replace the function

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of a second set of vessels, the lymphatic vessels,

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to make it so you don't need them.

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And what's amazing is that no other organ

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takes quite this approach

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to clearing away the waste from between its cells.

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

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But our most surprising finding

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was that all of this,

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everything I just told you about,

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with all this fluid rushing through the brain,

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it's only happening in the sleeping brain.

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Here, the video on the left

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shows how much of the CSF is moving

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

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It's almost nothing.

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Yet in the same animal,

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

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what we see is that the CSF

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is rushing through the brain,

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and we discovered that at the same time

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when the brain goes to sleep,

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the brain cells themselves seem to shrink,

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opening up spaces in between them,

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allowing fluid to rush through

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and allowing waste to be cleared out.

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So it seems that Galen may actually have been

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sort of on the right track when he wrote about

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fluid rushing through the brain

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when sleep came on.

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

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suggests that what's happening is that

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when the brain is awake

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and is at its most busy,

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it puts off clearing away the waste

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from the spaces between its cells until later,

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and then, when it goes to sleep

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and doesn't have to be as busy,

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it shifts into a kind of cleaning mode

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to clear away the waste

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from the spaces between its cells,

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the waste that's accumulated throughout the day.

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

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we put off our household chores during the work week

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

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

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when the weekend rolls around.

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

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but I haven't been very specific

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about the kinds of waste

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that the brain needs to be clearing

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during sleep in order to stay healthy.

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The waste product that these recent studies

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focused most on is amyloid-beta,

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

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My brain's making amyloid-beta right now,

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and so is yours.

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But in patients with Alzheimer's disease,

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amyloid-beta builds up and aggregates

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in the spaces between the brain's cells,

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

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and it's this buildup of amyloid-beta

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that's thought to be one of the key steps

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in the development of that terrible disease.

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So we measured how fast amyloid-beta is cleared

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from the brain when it's awake

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versus when it's asleep,

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and we found that indeed,

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the clearance of amyloid-beta

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is much more rapid from the sleeping brain.

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So if sleep, then,

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is part of the brain's solution

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to the problem of waste clearance,

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then this may dramatically change how we think

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about the relationship between sleep,

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amyloid-beta, and Alzheimer's disease.

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A series of recent clinical studies

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suggest that among patients

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who haven't yet developed Alzheimer's disease,

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worsening sleep quality and sleep duration

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are associated with a greater amount

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of amyloid-beta building up in the brain,

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and while it's important to point out

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that these studies don't prove

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that lack of sleep or poor sleep

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cause Alzheimer's disease,

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they do suggest that the failure of the brain

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to keep its house clean

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by clearing away waste like amyloid-beta

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may contribute to the development

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of conditions like Alzheimer's.

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So what this new research tells us, then,

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is that the one thing that all of you

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already knew about sleep,

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that even Galen understood about sleep,

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that it refreshes and clears the mind,

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may actually be a big part

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of what sleep is all about.

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See, you and I, we go to sleep

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every single night,

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but our brains, they never rest.

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While our body is still

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and our mind is off walking in dreams somewhere,

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the elegant machinery of the brain

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is quietly hard at work

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cleaning and maintaining

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this unimaginably complex machine.

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Like our housework,

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it's a dirty and a thankless job,

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but it's also important.

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In your house, if you stop cleaning your kitchen

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for a month,

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your home will become completely unlivable

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very quickly.

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But in the brain, the consequences

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of falling behind may be much greater

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than the embarrassment of dirty countertops,

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because when it comes to cleaning the brain,

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it is the very health and function

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

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which is why understanding these

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very basic housekeeping functions of the brain today

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may be critical for preventing and treating

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diseases of the mind tomorrow.

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Thank you.

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(Applause)