Summary: Fetal brain overgrowth may help explain why autism varies so dramatically in children. A UC San Diego team grew brain cortical organoids from toddlers and found that larger organoid size and faster prenatal-like growth correlated with more severe social and language symptoms. These results point to embryonic origins of two autism subtypes and could inform earlier detection and new therapeutic approaches.
Key Facts:
- Brain cortical organoids derived from toddlers with autism were about 40% larger than organoids from neurotypical toddlers.
- Greater embryonic-like brain growth correlated with more severe social, language and cognitive deficits.
- Organoids from all children with autism grew roughly three times faster than those from neurotypical controls.
Source: UCSD
Autism spectrum disorder (ASD) ranges from mild presentations that improve over time to profound forms that involve lifelong developmental, social and communication challenges. Until now, the biological origins that produce these markedly different outcomes have been unclear. A new study from the University of California San Diego, published in Molecular Autism, provides evidence that the biological differences underlying two autism subtypes emerge during embryonic brain development.
Researchers reprogrammed blood-derived stem cells collected from 10 toddlers (ages 1–4) with idiopathic autism into brain cortical organoids (BCOs) that model early fetal cortex development. For comparison, they generated BCOs from six neurotypical toddlers. Hundreds of organoids were produced per participant across two independent experimental batches (2021 and 2022), allowing robust measurement of size, growth and cellular features.
The cortex—the brain’s outer gray matter that supports thinking, language, memory and social processing—showed a clear difference in these organoid models. Across both batches, BCOs derived from toddlers with autism were significantly larger than controls, by roughly 39–41% on average. Moreover, the rate of growth during early organoid development was accelerated in ASD-derived BCOs, nearly three times faster than neurotypical organoids.
Importantly, organoid size and growth were linked to clinical outcomes. Toddlers whose BCOs were the largest and grew the fastest later showed the most severe social and language impairments, lower social attention and reduced cognitive and language IQ. These children also had larger brain volumes in MRI scans and atypical enlargement of brain regions involved in social, language and sensory processing. In cell-level analyses, the largest ASD organoids displayed accelerated neurogenesis, suggesting excess neuron formation during early development.
The investigators identified two embryonic BCO subtypes that align with clinical trajectories: one with pronounced organoid enlargement, rapid growth and accelerated neurogenesis corresponding to profound autism with severe and persistent social deficits; and another with milder enlargement and more moderate clinical features. Molecular assays highlighted the activity of Ndel1, a regulator of the cell cycle and neurogenesis, which correlated strongly with organoid growth and size.
“Bigger is not always better,” said Alysson Muotri, Ph.D., co-lead of the study and director at the Sanford Stem Cell Institute Integrated Space Stem Cell Orbital Research Center. The findings support the long-standing hypothesis that at least some forms of autism begin prenatally and involve dysregulated cell proliferation and early overproduction of neurons.
Co-leader Eric Courchesne, Ph.D., emphasized the study’s unique approach: pairing detailed clinical data—including symptom severity, IQ and MRI measures—with patient-derived embryonic-stage organoids to link prenatal-like biological processes with later behavioral outcomes. Together, the results suggest measurable embryonic origins for divergent autism trajectories and point toward targets for future intervention research that could modify early developmental processes to improve long-term social and cognitive outcomes.
The study lists multiple co-authors and acknowledges funding from the National Institute of Deafness and Communication Disorders, the National Institutes of Health, the California Institute for Regenerative Medicine and the Hartwell Foundation. The authors thank the families who contributed toddlers’ cells for organoid generation.
Conflicts of interest: Muotri is a co-founder and equity holder in TISMOO, a company focused on genetic analysis and human brain organogenesis for neurodevelopmental disorders; this arrangement was reviewed and approved by UC San Diego. Eichler serves on a scientific advisory board for Variant Bio, Inc. Other authors report no conflicts.
About this autism and neurodevelopment research news
Author: Danielle Lewis
Source: UCSD
Contact: Danielle Lewis – UCSD
Image: Image credited to Neuroscience News
Original Research: Open access. “Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms” by Alysson Muotri et al. Molecular Autism
Abstract
Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms
Background
Social affect and communication impairments define autism, but severity varies: some toddlers improve and develop functional language and social skills, while others exhibit persistent, profound deficits requiring long-term care. The biological origins that drive these divergent developmental paths have been unclear.
Methods
The team analyzed 4,910 embryonic-stage brain cortical organoids from 10 toddlers with ASD and 6 neurotypical controls (averaging 196 organoids per subject). Two independent experimental batches (2021 and 2022) assessed replicability. BCO size and growth were measured between one and two months of development, neurogenesis markers were quantified at two months, and molecular activity of Ndel1 was evaluated due to its role in cell cycle control and neurogenesis.
Results
BCOs from ASD toddlers were significantly larger (39–41% increase) across both batches. Organoid size strongly correlated with later social symptom severity (r = 0.719 and r = 0.873 in the two batches). ASD organoids exhibited accelerated growth rates—nearly three times that of controls—with the most enlarged organoids showing accelerated neurogenesis. Ndel1 activity correlated with organoid growth and size. Two embryonic subtypes emerged: one with marked overgrowth and severe clinical features, and a second with milder enlargement and less severe clinical differences.
Limitations
Larger and more diverse samples of toddler-derived BCOs and clinical profiles may reveal additional embryonic subtypes and refine associations.
Conclusions
The study indicates that by embryogenesis the biological divergence leading to profound versus mild autism is already present and measurable. Dysregulated cell proliferation, accelerated neurogenesis and increased early brain growth are linked to later social, language and cognitive impairments, and to atypical development of social and language brain regions.