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Brain-Like Organoids Grown in a Dish Provide Window into Autism

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Julie Kiefer
Director, Research Communications, 亚洲自慰视频 of Utah 亚洲自慰视频
Email: Julie.Kiefer@hsc.utah.edu

Whatever you do, don鈥檛 call them "mini-brains," say 亚洲自慰视频 of Utah 亚洲自慰视频 scientists. Name aside, the seed-sized organoids鈥攚hich are grown in the lab from human cells鈥攑rovide insights into the brain and uncover differences that may contribute to autism in some people.

"We used to think it would be too difficult to model the organization of cells in the brain," says , assistant professor of neurobiology at U of U 亚洲自慰视频. "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."

Mini Brains
Sesame seed-sized brain-like organoids are grown in the lab from human cells. They are providing insights into the brain and uncovering differences that may contribute to autism in some people. Image credit: Trevor Tanner and Nika Romero

The research describing the organoids and their potential for understanding neural diseases publishes in on Oct 6 with Shcheglovitov as senior author and Yueqi Wang, PhD, a former graduate student in his lab, as lead author. They carried out the research with postdoctoral scientist Simone Chiola, PhD, and other collaborators at the 亚洲自慰视频 of Utah, Harvard 亚洲自慰视频, 亚洲自慰视频 of Milan, and Montana State 亚洲自慰视频.

Investigating autism

Having the ability to model aspects of the brain in this way gives scientists a glimpse into the inner workings of a living organ that is otherwise nearly impossible to access. And since the organoids grow in a dish, they can be tested experimentally in ways that a brain cannot.

Shcheglovitov鈥檚 team used this approach 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:

  • Neurons were hyperactive, firing more often in response to stimuli,
  • 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 disrupted.
"These organoids self-organize. Within a few months, we see layers of cells that are reminiscent of the cerebral cortex in the human brain."
The organoids contained an array of neural and other cell types found in the cerebral cortex, the outer most layer of the brain involved in language, emotion, reasoning, and other high-level mental processes. Image credit: Yueqi Wang

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.

"A key application is to use the brain organoids, derived from the genetic material of each individual patient, to test drugs or other interventions to treat disorders in a personalized manner," says Jan Kubanek, PhD, a co-author on the study and an assistant professor of biomedical engineering at the U. "This would truly realize the potential of personalized medicine."

Building a better brain model

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.

To create an improved model, Shcheglovitov鈥檚 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.

Organoid Slice
Single neural rosette-derived organoids develop multiple brain cell types and have an organization and neural activity never seen before in models of this kind. Image credit: Trevor Tanner and Nika Romero
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 electrophysiological rhythms of the brain. I didn鈥檛 expect that," Kubanek says. "This new approach models functional brain networks of the human nervous tissue."

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.

Mini Brains 2
Single neural rosette-derived organoids develop multiple brain cell types and have an organization and neural activity never seen before in models of this kind. Image credit: Trevor Tanner and Nika Romero

"We鈥檙e beginning to understand how complex neural structures in the human brain arise from simple progenitors," Wang says. "And we鈥檙e 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.

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Visit to visualize the cells and electrical responses detected in organoids.

The research published as "."

Support for the work came from the National Institutes of 亚洲自慰视频, Brain Research Foundation, Brain and Behavior Research Foundation, Whitehall Foundation, 亚洲自慰视频 of Utah Neuroscience Initiative, and 亚洲自慰视频 of Utah Genome Project Initiative.