Researchers use 'brain-on-a-chip' to revolutionize fight against deadly encephalitis viruses

A transparent chip no larger than a stick of gum is helping scientists at the University of Tennessee Health Science Center, an R1 research institution, transform the way researchers study the human brain and develop treatments for some of the world's deadliest viruses.

Colleen Jonsson, Ph.D., Harriet S. Van Vleet Chair of Excellence in Virology and director of UT Health Science Center's Regional Biocontainment Laboratory and Institute for the Study of Host Pathogen Systems, is leading a groundbreaking project using a human brain-on-a-chip system to study how lethal encephalitis viruses infect the brain and how to stop them. Working alongside her doctoral student, Walter Reichard, she is pushing forward a new frontier in non-animal research.

Venezuelan and Eastern equine encephalitis viruses (VEEV and EEEV) cause rare but devastating infections that can result in fatal brain inflammation, particularly in children and older adults. "The brain is extremely well protected, and these viruses can still find a way in," Dr. Jonsson said.

Traditionally, scientists have relied on mouse models to study these pathogens. Dr. Jonsson's lab is testing a revolutionary alternative: a miniature, three-dimensional system that replicates the function of the human brain. The brain-on-a-chip technology represents what the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) are calling the future of non-animal research, or "NAMs," new-approach methods.

"This is novel technology to advance biological and therapeutic discovery," Dr. Jonsson said. "The human brain chip allows us to do testing in humans. Whereas otherwise, we're limited to doing our preclinical research with mice."

Reichard has spent months refining the system consisting of two microscopic channels separated by a porous membrane. One channel contains human vascular cells that line blood vessels; the other holds key cell types that make up the brain's structure and immune defenses. Fluid flows continuously through the system, mimicking blood circulation and creating a tight barrier between the two chambers. That barrier, just like the real blood-brain barrier, carefully filters what can and cannot enter the "brain."

"The virus we study is able to sneak through this barrier and get into the brain," Dr. Jonsson said. "The chip recapitulates this tight barrier between our brain and our body. It's a 3D representation of the brain."

The living human cells used in the model are commercially obtained from de-identified deceased adult donors, allowing researchers to observe infections and drug responses under conditions far closer to human biology than traditional animal models.

While the system shows extraordinary promise, Dr. Jonsson emphasizes that the research is still at early stages. "This is exploratory research to determine the ability of the human brain chip to bridge the gap from mouse to human," she said.

She doesn't yet call it superior to animal models, but she believes it could dramatically accelerate translation to human medicine. "I don't know if we'll ever get rid of animal models," she said, "but having human cells to look at how our drug is working gives us better insight into translation." And while the system isn't cheaper, she said, its precision makes it valuable. "It gets us right to whether or not the drug could be effective for humans."

Early tests in the Jonsson lab have been promising. The team has already shown that antiviral drug candidates developed in collaboration with Bernd Meibohm, Ph.D., distinguished professor and associate dean for Research at the UT Health Science Center College of Pharmacy, and Jennifer Golden, Ph.D., associate director of the Medicinal Chemistry Center at the University of Wisconsin, can protect mice from encephalitic virus infection. Now, they are using the brain-on-a-chip to see whether those same drugs inhibit viral replication in human brain tissue.

"We can see antiviral efficacy in this chip," Dr. Jonsson said, referring to a recent proof-of-concept experiment using one compound called Badger 49. "This is a really promising series of antivirals that treat encephalitic infections."

The potential applications extend far beyond encephalitis research. "This technology could be used for Alzheimer's drugs, Parkinson's, even brain cancer," Dr. Jonsson said. "The system is being used elsewhere in the country for different applications, but when we started, we were a little ahead of the game."

Reichard finds the system thrilling from a research standpoint. "When we got our first data, we were instantly brainstorming all the things we could do next," he said. "There was a lot of excitement."

Provided by University of Tennessee at Knoxville