UC San Diego Research: Embryonic Brain Size Indicates Autism Severity
Some children with profound autism experience lifelong difficulties with social, language and cognitive skills, and even lack the ability to speak. Others experience more mild symptoms that improve with time.
The disparity in outcomes has been a mystery to scientists, until now. A new study, published in Molecular Autism by researchers at University of California San Diego, is the first to shed light on the matter. Among its findings: The biological basis for these two subtypes of autism spectrum disorder develops in the first weeks and months of embryonic development.
Researchers used inducible pluripotent stem cells (iPSCs) derived from blood samples of 10 toddlers with autism and six neurotypical “controls” of the same age. Able to be reprogrammed into any kind of human cell, they used the iPSCs to create brain cortical organoids (BCOs) — models of the brain’s cortex during the first weeks of embryonic development. The veritable “mini brains” grown from the stem cells of toddlers with autism grew far larger — roughly 40% — than those of neurotypical controls, demonstrating the growth that apparently occurred during each child’s embryonic development.
“We found the larger the embryonic BCO size, the more severe the child’s later autism social symptoms,” said UC San Diego’s Eric Courchesne, the study’s lead researcher and Co-Director of the Autism Center of Excellence in the neuroscience department. “Toddlers who had profound autism, which is the most severe type of autism, had the largest BCO overgrowth during embryonic development. Those with mild autism social symptoms had only mild overgrowth.”
In remarkable parallel, the more overgrowth a BCO demonstrated, the more overgrowth was found in social regions of the profound autism child’s brain and the lower the child’s attention to social stimuli. These differences were clear when compared against norms of hundreds and thousands of toddlers studied by the UC San Diego Autism Center of Excellence. What’s more, BCOs from toddlers with profound autism grew too fast as well as too big.
“The bigger the brain, the better isn’t necessarily true,” agreed Alysson Muotri, Ph.D., director of the Sanford Stem Cell Institute’s Integrated Space Stem Cell Orbital Research Center at the university. Muotri and Courchesne collaborated on the study, with Muotri contributing his proprietary BCO-development protocol that he recently shared via publication in Nature Protocols, as well as his expertise in BCO measurement.
Because the most important symptoms of profound autism and mild autism are experienced in the social affective and communication domains, but to different degrees of severity, “the differences in the embryonic origins of these two subtypes of autism urgently need to be understood,” Courchesne said. “That understanding can only come from studies like ours, which reveals the underlying neurobiological causes of their social challenges and when they begin.”
One potential cause of BCO overgrowth was identified by study collaborator Mirian A.F. Hayashi, Ph.D., professor of pharmacology at the Federal University of São Paulo in Brazil, and her Ph.D. student João Nani. They discovered that the protein/enzyme NDEL1, which regulates growth of the embryonic brain, was reduced in BCOs of those with autism. The lower the expression, the more enlarged the BCOs grew.
“Determining that NDEL1 was not functioning properly was a key discovery,” Muotri said.
Courchesne, Muotri and Hayashi now hope to pinpoint additional molecular causes of brain overgrowth in autism — discoveries that could lead to the development of therapies that ease social and intellectual functioning for those with the condition.