Summary: Brain overgrowth in utero may explain the varying severity of autism in children. Researchers used brain organoids from toddlers to show that larger brain growth correlated with more severe autism symptoms. The findings could lead to prenatal identification and potential therapies for autism.
Key Facts:
- Brain organoids from autistic toddlers were 40% larger than those from neurotypical children.
- Larger brain growth in utero was linked to more severe social and language deficits.
- All children with autism showed faster brain organoid growth than neurotypical peers.
Source: UCSD
Some children with autism experience profound, lifelong difficulties like developmental delay, social struggles and even the inability 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 develops in utero.
Researchers used blood-based stem cells from 10 toddlers, ages 1 through 4, with idiopathic autism (in which no single-gene cause was identified) to create brain cortical organoids (BCOs), or models of the fetal cortex. They also created BCOs from six neurotypical toddlers.
Often referred to as gray matter, the cortex lines the outside of the brain. It holds tens of billions of nerve cells and is responsible for essential functions like consciousness, thinking, reasoning, learning, memory, emotions and sensory functions.
Among their findings: The BCOs of toddlers with autism were significantly larger — roughly 40 percent — than those of neurotypical controls, according to two rounds of study performed in different years (2021 and 2022). Each round involved the creation of hundreds of organoids from each patient.
The researchers also found that abnormal BCO growth in toddlers with autism correlated with their disease presentation. The larger a toddler’s BCO size, the more severe their social and language symptoms were later in life, and the larger their brain structure on MRI.
Toddlers with excessively enlarged BCOs showed greater-than-typical volume in social, language and sensory brain areas when compared to neurotypical peers.
“The bigger the brain, the better isn’t necessarily true,” said Alysson Muotri, Ph.D., director of the Sanford Stem Cell Institute (SSCI) Integrated Space Stem Cell Orbital Research Center at the university.
The SSCI is directed by Catriona Jamieson, M.D., Ph.D., a leading physician-scientist in cancer stem cell biology whose research explores the fundamental question of how space alters cancer progression.
“We found that in the brain organoids from toddlers with profound autism, there are more cells and sometimes more neurons — and that’s not always for the best,” added Muotri, who is also a professor in the Departments of Pediatrics and Cellular and Molecular Medicine at the UC San Diego School of Medicine.
What’s more, the BCOs of all children with autism, regardless of severity, grew roughly three times faster than those of neurotypical children. Some of the largest brain organoids — from children with the most severe, persistent cases of autism — also saw the accelerated formation of neurons.
The more severe a toddler’s autism, the quicker their BCO grew — sometimes to the point of developing an excess of neurons.
Eric Courchesne, Ph.D., a professor in the School of Medicine’s Department of Neurosciences who co-led the research with Muotri, called the study “one of a kind.” Matching data on children with autism — including their IQs, symptom severity and imaging like MRIs — with their corresponding BCOs or similar stem cell-derived models makes an incredible amount of sense, he said. But oddly enough, such research hadn’t been undertaken ahead of their work.
“The core symptoms of autism are social affective and communication problems,” said Courchesne, who also serves as co-director of the UC San Diego Autism Center of Excellence.
“We need to understand the underlying neurobiological causes of those challenges and when they begin. We are the first to design an autism stem cell study of this specific and central question.”
It’s long been assumed that autism, a complex pool of progressive disorders, begins prenatally and involves multiple stages and processes.
While no two people with autism are like — just as no two neurotypical people are — those with the neurodevelopmental condition can generally be grouped into two categories: those who have severe social struggles and require lifelong care, and may even be nonverbal, and those who have a milder version of the condition who eventually develop good language skills and social relationships.
Scientists haven’t been able to ascertain why at least two groups of individuals with autism exist. They also haven’t been able to prenatally identify children with autism, let alone predict how severe their condition might be.
Now that Courchesne and Muotri have established that brain overgrowth begins in the womb, they hope to pinpoint its cause, in a bid to develop a therapy that might ease intellectual and social functioning for those with the condition.
Co-authors of the study include Vani Taluja, Sanaz Nazari, Caitlin M. Aamodt, Karen Pierce, Kuaikuai Duan, Sunny Stophaeros, Linda Lopez, Cynthia Carter Barnes, Jaden Troxel, Kathleen Campbell, Tianyun Wang, Kendra Hoekzema, Evan E. Eichler, Joao V. Nani, Wirla Pontes, Sandra Sanchez Sanchez, Michael V. Lombardo and Janaina S. de Souza.
Funding: This work was supported by grants from the National Institute of Deafness and Communication Disorders, the National Institutes of Health, the California Institute for Regenerative Medicine and the Hartwell Foundation. We thank the parents of the toddlers in San Diego whose stem cells were reprogrammed to BCOs.
Note: Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis, focusing on therapeutic applications customized for autism spectrum disorders and other neurological disorders origin genetics.
The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.
Eichler is a scientific advisory board member of Variant Bio, Inc.
The other authors have no conflicts of interest to declare.
About this autism and neurodevelopment research news
Author: Danielle Lewis
Source: UCSD
Contact: Danielle Lewis – UCSD
Image: The image is 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 affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with “profound” autism have persistently low social, language and cognitive skills and require lifelong care.
The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.
Methods
Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls.
In a 2022 batch, we tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers.
BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions.
Results
At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms.
Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs.
Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions.
Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences.
Limitations
Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes.
Conclusions
By embryogenesis, the biological bases of two subtypes of ASD social and brain development—profound autism and mild autism—are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth.
The larger the embryonic BCO size in ASD, the more severe the toddler’s social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.
