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.