Brain-Like Organoids Enable New Insights into Autism

Researchers in Salt Lake City have grown sesame seed-sized, brain-like organoids that are providing insights into the causes of autism and other neural diseases. Published recently in Nature Communications, the University of Utah Health (U of U Health)-led study sheds light on the cellular and molecular causes of symptoms associated with autism.

Scientists have long searched for suitable models for the human brain. Lab-grown organoids are not new, but previous versions did not develop in a reproduceable way, making experiments difficult to interpret.

“We used to think it would be too difficult to model the organization of cells in the brain,” says Alex Shcheglovitov, PhD, assistant professor of neurobiology at U of U Health. “But these organoids self-organize. Within a few months, we see layers of cells that are reminiscent of the cerebral cortex in the human brain.”

Shcheglovitov’s team used an innovative process to investigate effects of a genetic abnormality associated with autism spectrum disorder and human brain development. They found that organoids engineered to have lower levels of the gene, called SHANK3, had distinct features.

Even though the autism organoid model appeared normal, some cells did not function properly. The neurons were hyperactive, firing more often in response to stimuli, and other signs indicated neurons may not efficiently pass along signals to other neurons. Specific molecular pathways that cause cells to adhere to one another were also disrupted.

These findings are helping to uncover the cellular and molecular causes of symptoms associated with autism, the authors say. They also demonstrate that the lab-grown organoids will be valuable for gaining a better understanding of the brain, how it develops, and what goes wrong during disease.

“One goal is to use brain organoids to test drugs or other interventions to reverse or treat disorders,” says Jan Kubanek, PhD, a co-author on the study and an assistant professor of biomedical engineering at University of Utah.

To create an improved organoid, Shcheglovitov’s team took cues from how the brain develops normally. The researchers prompted human stem cells to become neuroepithelial cells, a specific stem cell type that forms self-organized structures, called neural rosettes, in a dish. Over the course of months, these structures coalesced into spheres and increased in size and complexity at a rate similar to the developing brain in a growing fetus.

After five months in the lab, the organoids were reminiscent of “one wrinkle of a human brain” at 15 to 19 weeks post-conception, Shcheglovitov says. The structures contained an array of neural and other cell types found in the cerebral cortex, the outermost layer of the brain involved in language, emotion, reasoning, and other high-level mental processes.

Like a human embryo, organoids self-organized in a predictable fashion, forming neural networks that pulsated with oscillatory electrical rhythms and generated diverse electrical signals characteristic of a variety of different kinds of mature brain cells. “These organoids had patterns of electrophysiological activity that resembled actual activity in the brain. I didn’t expect that,” Kubanek says. “This new approach models most major cell types and in functionally meaningful ways.”

Shcheglovitov explains that these organoids, which more reliably reflect intricate structures in the cortex, will allow scientists to study how specific types of cells in the brain arise and work together to perform more complex functions.

“We’re beginning to understand how complex neural structures in the human brain arise from simple progenitors,” says Yueqi Wang, PhD, a former graduate student in Shcheglovitov’s lab. “And we’re able to measure disease-related phenotypes using 3D organoids that are derived from stem cells containing genetic mutations.” He adds that using the organoids, researchers will be able to better investigate what happens at the earliest stages of neurological conditions, before symptoms develop.