Using a Jell-O-like substance and stem cells to create a structure that mimics human brain tissue, scientists in Wisconsin have offered a glimpse at how we may one day test the safety of both pharmaceutical drugs and commercial compounds.
"We're mimicking a lot of the interactions that are known to be important for developing brain tissue," said Michael Schwartz, an assistant scientist in biomedical engineering at the University of Wisconsin-Madison and the co-lead author of the study published Monday in the journal Proceedings of the National Academy of Sciences. The segments of tissue the researchers made were about 5 millimeters in diameter, visible to the naked eye.
The study, a collaboration by researchers from UW and the Morgridge Institute for Research, including stem cell pioneer James Thomson, begins to address a key challenge long faced by drug companies: Devising ways to test the effects of medications on living human brain tissue.
The ways of determining whether a compound will harm the brain are far from perfect. Compounds can be tested on brain cells growing in a lab dish. But that's not the same as testing the effect on three-dimensional brain tissue, which has different cells working together.
For now, the only way to get regulatory approval of chemicals is to test them on multiple generations of rodent: a group of rats, their offspring and the sometime even offspring's offspring.
"It can require large numbers of animals and cost $1 million just to test one drug," said Schwartz, whose co-lead author for the study was Zhonggang Hou, who had worked for the Morgridge Institute and now works at Harvard University.
Even then, rats and humans differ enough that the tests are limited in their ability to detect threats to the human brain. A test using rats alone may be only 40% successful in picking up toxins to the human brain. Even tests using rats and other animal species achieve only an estimated 60% to 70% success.
The issue is a key one in drug development. Toxicity is a major reason why drugs fail, a problem that reflects the limitations of using animals to model for humans.
The new method described in Monday's study used what are called hydrogels, which look like colorless Jell-O. Scientists seeded the hydrogels with neuroprogenitor cells, very early forms of brain cells. The neuroprogenitors were derived from human embryonic stem cells.
These early neural cells developed into neurons and glial cells. The scientists also added immune and blood vessel cells for the brain separately. Schwartz expressed surprise at how quickly the hydrogel and stem cells began to form tissue that mimics fetal brain tissue.
"Within a week you start to see pretty pronounced three-dimensional structure," he said, explaining that the cells and hydrogel continued to develop up to 21 days.
Schwartz cautioned that the tissue they constructed "does not capture the full complexity of the human brain," but did create a good model of the cellular interactions that are important in brain development.
However, the scientists also developed their own predictive model for testing both safe and unsafe compounds on the brain tissue model. This method recognized chemicals that would be safe and unsafe based on their genetic signatures.
There are now roughly a dozen confirmed toxins harmful to the developing fetal brain and about 200 that are harmful to the adult brain. In a test involving five known toxins and five safe chemicals, the new model got nine out of 10 correct.
One of the difficulties in simulating brain tissue is creating a way to deliver nutrients or toxins through the vessels in the tissue. Schwartz said the Wisconsin scientists are collaborating with colleagues at the Massachusetts Institute of Technology to address this problem.
By Mark Johnson
Sept. 21, 2015