A New Way to See the Brain

  • By Ari Daniel
  • Posted 08.27.15
  • NOVA

Scientists at MIT have embedded slices of brain in the absorbent material found in diapers, which swells four to five times its normal size. And when they look at the expanded result using an ordinary light microscope, they see an unprecedented view of nerve fibers, cells, and proteins. It’s the deepest look into the brain we’ve ever had.

Running Time: 05:28


Ari: Sometimes all you’ve got is a crazy idea and a lot of ambition.

Tillberg: I had this feeling from very early in this project that there is a way to make this work—don’t know what it is yet, but there is a way.

Chen: It’s kind of like a wild dream—it’s not something that you would intuitively expect to work.

Ari: People told these guys they were wasting their time. That they should do something productive. But they just dug in further. Now, before I tell you what their crazy idea was, first let me say that Tillberg and Chen study the brain.

Tillberg: The brain is extremely complex—so complex that we don’t necessarily even know what we’re looking for.

Boyden: The brain is like a circuit made out of cells called neurons. In a cubic millimeter of your brain, those cells will have about a billion connections between them doing some fraction of a trillion things per second with millisecond timescale precision.

Ari: For Boyden and his students, the brain is a vast and largely uncharted three-dimensional expanse. 

Boyden: So we want to get what you might call the wiring diagram of the brain. But not just the wiring—all the molecules along those wires and at those connections.

Ari: Sure, we’ve got ways to map and image the brain already, but they’ve all got their limitations. MRI’s reveal brain activity but across large swaths, so zooming in on the neural nanoscale to see connectivity—forget it. Electron microscopes give incredible detail, but you can’t label different structures with different colors. So you can’t discern the 3D configuration of molecules and connections. The light microscope actually provides gorgeous images of brain slices, but there’s a limit to how much you can see.

Tillberg: There’s an analogy to this where if you zoom into a digital photograph, you can see smaller things. At some point you get to a limit where you can see individual pixels. And if you keep on magnifying it, you’re not gonna see any more information about what was in that scene.

Ari: Same thing with a light microscope—zoom in past the size limit—into a synapse where two nerves meet, say—and you get a blur. But what if you could somehow zoom past that limit? And this is where we get to that crazy idea: inflating the brain itself.

Boyden: We’ve been thinking about ways that you might be able to physically magnify the brain. Could you actually blow it up and make it bigger?

Ari: And then look at it with the same old light microscope. But how do you enlarge a brain, while keeping all of the nanostructure in place that you want to look at?

Chen: Just to think that you could preserve all that complexity while basically destroying your sample—that’s what’s crazy about it.

Ari: So here’s the DIY version of how to actually do this in five somewhat simplified steps. And keep in mind, this approach took months to develop.

Chen: First, we take a brain of, let’s say, a mouse, and we fix it with formaldehyde and that just locks down all the molecules. It’s kind of like taking a snapshot.

Ari: Step two—use the lab equivalent of a deli slicer to shave off a slice of brain. Step three, add fluorescent dye. Step four, embed that slice in a material that swells in size. That material—sodium polyacrylate. Better known as the stuff in diapers that absorbs just an obscene amount of water. Step five—and this is the really counterintuitive one—digest away the brain. That prevents the tissue from tearing. Now all you’re left with is the dye embedded in the diaper material.

Tillberg: So you can think of that like taking a three-dimensional fluorescent cast.

Ari: And then the cast is expanded by washing it in water.

Tillberg: That’s it.

Ari: In other words, this is your brain on diapers. Or, actually, this is your mouse’s brain on diapers. Regardless, the result—once you place this cast, expanded four or five-fold, under a light microscope—is just astounding.

A spray of neurons interlocking in three dimensions, bundles of axons coursing in all directions. Zoom further in to see actual proteins. All in color. This is the three-dimensional weave of the brain itself.

This took months to figure out. And when Fei Chen and Paul Tillberg finally succeeded in doing this crazy thing—in magnifying a slice of brain tissue and then peering at it—well, there’s nothing quite like seeing something that no one’s ever seen before.

Chen: You know, we had started this experiment pretty late at night, and we didn’t really expect it to work.

Tillberg: And we watched in the microscope as it began to expand.

Chen: We were like, “Oh my god, it’s working.”

Tillberg: We were so excited about it when we saw that it was starting to work that we stayed up the whole night, watching this thing every hour because we just wanted to see every single detail in this process. Went out and had breakfast and showed it to Ed.

Chen: Four months later, we would basically have the technology fully developed.

Ari: They’re calling it expansion microscopy. Back then the expansion took several hours. Now it takes like five minutes. And it’s already being used in labs around the world—to map the brain and beyond.

Boyden: One of our hopes is that you could actually hunt down very rare things in a tissue—to find the stem cell that generates a tumor, to pinpoint where a virus is as it moves from cell to cell, what causes Alzheimer’s, what causes an epileptic state to develop.

What I most feel is a sense of possibility.

Ari: The possibility of coming right up to the edge of what is known and seeing past it.



Narrated, Written, & Produced by
Ari Daniel
Ari Daniel
Animation Assistance
Sam Stulin
Original Footage
© WGBH Educational Foundation 2015


Additional Imagery and Animation
Ed Boyden and the McGovern Institute for Brain Research at MIT
Fei Chen, Paul Tillberg & Ed Boyden
Thomas Deerinck
Flickr/MR McGill
Tom Lentz
Jeff Lichtman
Daniel Margulies, Max Planck Institute for Human Cognitive and Brain Sciences
Inga Popesko
Crean Quaner (www.neuronize.de)
Ron Schott
Tamily Weissman/Livet et al, Nature 2007
Wikimedia Commons/MethoxyRoxy


(main image: colorful brain image)
Fei Chen, Paul Tillberg & Ed Boyden

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