Brain-like organ research has revealed a new window in autism

Scientists at the University of Utah Health Center say the seed-sized organs were grown from human cells in the lab — providing insight into the brain and revealing differences
that may lead to autism in some people.
"We used to think that it was too difficult to simulate the tissue of cells in the brain," said Dr.
Alex Shcheglovitov, an assistant professor of neurobiology at
Harvard's School of Health.
"But these organoids organize themselves
.
After a few months, we will be able to see a layer of cells similar to the human cerebral cortex
.
”

The study, which describes organoids and their potential in understanding neurological disorders, will be published today (October 6) in the journal Nature Communications, with Shcheglovitov as senior author and Dr.
Yueqi Wang, a former graduate student in his lab, as lead author
.
They conducted the study
with postdoctoral scientist Dr.
Simone Chiola and other collaborators at the University of Utah, Harvard, Milan and Montana State University.

The ability to model all aspects of the brain in this way gives scientists a glimpse into the inner workings of living organs, which would otherwise be nearly impossible to access
.
Since organoids are grown in a Petri dish, they can be experimentally tested
in ways that the brain cannot.

Shcheglovitov's team used an innovative approach to study the effects
of a genetic abnormality associated with autism spectrum disorders and human brain development.
They found that engineered organoids have lower levels of this gene, called SHANK3, with unique characteristics
.

Although the autistic organ model looks normal, some cells are not working properly:

• Neurons are hyperactive and respond more frequently to stimuli,

• Other indications that neurons may not be able to effectively transmit signals to other neurons,

• The specific molecular pathways that cause cells to adhere to each other are disrupted
  .
  

According to the authors, these findings help shed light on the cellular and molecular causes
of autism-related symptoms.
They also demonstrated that lab-grown organoids are valuable
for better understanding the brain, how it develops, and what happens during disease.
"One goal is to use brain organs to test drugs or other interventions that reverse or treat disease," said Dr.
Jan Kubanek, one of the study's co-authors and an assistant professor at
the American School of Biomedical Engineering.
A single neural rosette-derived organoid develops multiple brain cell types and has tissue and neural activity
that has never been seen in such models.
Dr.
Simone Chiola selected radial structures
called neural rosettes formed from human stem cells.
After a few months, these structures became globular organs
that mimic all aspects of the human brain.

Scientists have long been looking for models
that fit the human brain.
Lab-grown organoids are not new, but previous versions have not developed in a replicable way, which makes experiments difficult to explain
.
To create an improved model, Shcheglovitov's team took cues
from the normal development of the brain.
The researchers prompted human stem cells to become neuroepithelial cells, a special type of stem cell that can form self-organizing structures called neural rosettes in a dish
.
Over the course of a few months, these structures combine into spheres whose size and complexity grow at a rate similar to the brain development
of a growing fetus.

Shcheglovitov said that after spending 5 months in the lab, the organoids were reminiscent of "a wrinkle in the human brain" 15 to 19 weeks after pregnancy
.
These structures contain a series of nerve cells and other types of cells found in the cerebral cortex, the outermost layer of the brain involved in language, emotion, reasoning, and other higher-level mental processes
.
Just like human embryos, organoids organize themselves in a predictable way, forming neural networks that pulsate with oscillating electrical rhythms and produce different electrical signals that are characteristic
of various different types of mature brain cells.

"The pattern of electrophysiological activity of these organoids is similar
to the actual activity in the brain.
I didn't expect that," Kubanek said
.
"This new method mimics most of the major cell types
in a functionally meaningful way.
"

Shcheglovitov explained that these organoids, which more reliably reflect the complex structure of the cerebral cortex, will enable scientists to study how specific types of cells in the brain are produced and how they work together to perform more complex functions
.

"We are beginning to understand how the complex neural structures in the human brain evolved from simple ancestors," Wang said
.
"We were able to use 3D organoids derived from stem cells containing genetic mutations to measure disease-related phenotypes
.
" By using organoids, he added, researchers will be able to better study the early stages of neurological disease, what happens
before symptoms appear.

References:

Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes