Toxicity's New Foe: Brain-on-a-Chip

Primary Investigator: Yeoheung Yun

Testing animals is expensive, time-consuming and doesn’t always accurately reflect what happens in human beings. Yeoheung Yun of North Carolina Agricultural and Technical State University is working to replace animal tests for deadly toxins with a human brain on a chip.

“We want to screen for toxicity, but we cannot depend on animals because it takes forever,” says Yun, Graduate Program Director of NC A&T’s Bio-Engineering Program. And lab dishes full of cells, even human cells, don’t tell researchers much because they don’t function like a complete organ.

That’s especially true for researchers studying the brain, which is not only complex, but has its own defense against toxins and pathogens called the blood-brain barrier. This barrier, made using the endothelial cells that line capillaries, brain cells and cells known as pericytes, is dynamic. It’s not easy to reproduce in a lab dish.

Mini-brains might do it, however. “We want to develop a platform which can recapitulate the neurovascular system of our brain,” Yun says. “We develop it using stem cell technology to make a 3-dimensional system you can call a brain on a chip.”

The immediate need is to test poison gases that might be used in conflict. One of the most concerning is sarin, an organophosphate pesticide perhaps best known because it was used in attacks in 1994 and 1995 by the Japanese extremist group Aum Shinrikyo. Twenty people died in those attacks.

Yun, working with a grant organized by the Minority Serving Institutions Science, Technology, Engineering and Mathematics Research and Development Consortium (MSRDC), is collaborating with RTI International to plan is to screen various organophosphates.

“These gases immediately penetrate and affect the brain system. We want to score which ones penetrate fast, and once they are past the blood-brain barrier, how fast they can kill neurons,” he said.

To make the mini-brains, Yun’s lab and colleagues at NC A&T are using a specialized type of stem cell called an induced pluripotent stem cell. These iPS cells, made from ordinary skin or other cells, are genetically manipulated to make them behave as if they were embryonic stem cells. They’re taken back to the “master” stem cell stage, when they have the power to morph into any tissue or organ type. 

They are retrained to differentiate into various types of brain cells. With the right coaxing and conditions, they form into little organoids that include the various nerve cells that make brain, as well as blood vessels.

“The next step is to see if we can reverse the toxicity,” Yun said.

The mini-brains can be used for many purposes other than toxicity screening. “We are getting patient-derived cells from patients with diseases,” Yun said. For example, a skin call taken from a patient with Alzheimer’s disease can be used to grow a mini-brain genetically identical to the patient’s brain. That mini-brain could then be used for personalized testing.

“You can do so many things,” Yun said.