The quest to understand the brain:

IMES Core Faculty Kwanghun Chung wants to—quite literally—shed more light on the brain, to help unlock the mysteries of neurodevelopmental and neurodegenerative disorders, like autism, schizophrenia, Alzheimer’s and Parkinson’s.

“We want to see inside, right? That has been the dream of biologists. We want to see inside the brain to really understand the pathology,” he says. “But it’s very challenging. The fat—the lipid bilayer—acts as a scattering material that blocks penetration of light. If you remove the fat, the tissue becomes transparent. But if you only do that, tissue collapses.”

For a century, this perplexing lipid/light issue has stood squarely in the way of research. Experiments with fat solvents and structural proteins such as keratin didn’t yield positive results. And cutting-edge tools, such as genomic sequencing and MRI, provided only pieces of the neural puzzle—rich molecular details without spatial information, or global images with resolution limitations.

As the only chemical engineer in the Deisseroth Lab at Stanford, Chung (then a postdoctoral fellow) came up with an idea that excited Principal Investigator Karl Deisseroth: use a polymer hydrogel to transform intact dead brain tissue into an optically transparent, permeable, structurally sound hybrid. Once lipids were removed, the physically girded tissue-hybrid could be probed, viewed and phenotyped, allowing scientists to witness the molecular architecture of the brain in high-resolution. (See visualizations.)

The novel technique known as CLARITY (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging / Immunostaining / in situ-hybridization-compatible Tissue hYdrogel) illuminates molecular details in their native spatial relationship, including neural circuitry, biomolecules and subcellular morphology—providing that long-desired “snapshot” of the brain, says Chung.

“It was quite straightforward to me, because, as a chemical engineer, I was very aware of polymers. Hydrogel was the first hydrogen material I picked and it worked.”

Eager to share and “scale up” the technique, Chung joined MIT in 2013 to start the Chung Lab, which offers a CLARITY training course for scientists, and hopes to unveil offshoot technologies.

“The original approach was designed for a small mouse brain. But the human brain is 2,000 times larger and 5 times more myelinated (fat-encrusted),” Chung says. “So we have new techniques—not published yet: hopefully soon—that are easy to use and don’t require special equipment . . . One thing I am very excited about (is) a new way of transporting molecule probes. Things that could take several months before can be done within a day. That really speeds up the entire process.”

In addition to heading up Chung Lab, Chung is an assistant professor with IMES and ChemE, as well as a principal investigator with the Picower Institute for Learning and Memory. His interdepartmental reach helps him recruit an interdisciplinary research team, including chemical engineers, neuroscientists, mechanical engineers, and a programming expert. The result: a stimulating pluralism.

“I think my lab is a mixture of excitement and confusion. And that’s a positive thing . . . That can only happen because I’m at MIT. Just interacting with these many communities helps move our research in the right direction.”

Ultimately Chung says he wants to develop techniques that can empower the neuroscience community to accelerate neuroresearch and discovery.

“It’s a lot of responsibility and also a lot of pressure. The economic and societal cost of neurological disorders like Alzheimer’s is huge: there is an urgent need to find new therapeutic approaches. To do that, we need to understand better how the brain works. And doesn’t work. How are human neurons connected with each other? What kind of pathological molecules are expressed? How are they distributed and how do they interact with different types of cells—immune cells and neurons? With all the amazing tools we have, they are not enough. We need more.

“The brain is such a big part of our life; it basically governs everything. I just want to understand.”