Researchers have discovered that despite a wide range of genetic differences, autism-linked variants converge on shared biological processes during brain development, offering new insights into the complex condition. A large-scale study utilizing brain organoids – miniature, lab-grown human brains – revealed that while initial effects of individual genetic variants differ, they ultimately disrupt similar key processes related to neuron maturation and brain function. This finding strengthens the idea that diverse genetic causes can lead to common underlying mechanisms in autism spectrum disorder.
The study, published last month in Nature, provides compelling evidence for this convergence, according to experts in the field. “Proposing something is not the same as demonstrating it,” commented Jürgen Knoblich, professor of synthetic biology at the Medical University of Vienna. The research represents a significant step forward in understanding the biological basis of autism and could pave the way for more targeted therapeutic interventions.
The investigation, led by Daniel Geschwind, professor of human genetics, neurology and psychiatry at the University of California, Los Angeles, is notable for its scale. Geschwind explained that “The number of lines, the number of variants, the amount of replication—this has never been done before.” Researchers created cortical brain organoids from stem cells derived from 55 individuals with autism, including those with idiopathic autism (where the genetic cause is unknown) and those carrying one of eight known autism-linked genetic variants. These organoids were then monitored for approximately 100 days to observe developmental changes.
How Genetic Variants Converge in Brain Development
Early in development, each genetic variant impacted the organoids in a unique way. Though, over time, the researchers observed a consistent pattern: disruption of common molecular pathways crucial for neuronal differentiation, synapse formation and chromatin remodeling – the process controlling gene expression. A core network of genes emerged as a central regulator, influencing downstream changes associated with autism. Lowering the activity of genes within this network demonstrably affected other genes, suggesting a key control mechanism.
Interestingly, organoids derived from individuals with idiopathic autism did not exhibit the same convergent changes, likely due to the more subtle genetic effects in these cases, and the relatively small sample size. Geschwind and his team are currently expanding their research to include more participants with idiopathic autism and additional genetic variants to address this limitation.
Brain Organoids: A Powerful Tool for Autism Research
Brain organoids have grow increasingly valuable tools for studying neurodevelopmental disorders, offering a human-relevant model that overcomes limitations of traditional animal studies. As noted in a review in ScienceDirect, these organoids can replicate key aspects of human brain development, generating diverse cell types found in the developing brain. Previous research, including studies from Knoblich’s group, has utilized brain organoids to investigate the effects of specific autism-linked variants, but this study uniquely considered the broader genetic background.
However, researchers acknowledge limitations. The current study focused on cortical organoids, primarily composed of excitatory neurons, and lacked the inclusion of inhibitory neurons (interneurons). Knoblich cautioned that the balance between excitatory and inhibitory neurons is critical in autism, and omitting these cells may indicate some important biological mechanisms were not fully captured.
Future Directions and Potential Therapeutic Targets
Despite these limitations, the study is viewed as a significant advancement. Kristiina Tammimies, associate professor of medical genetics at the Karolinska Institutet, described the work as “a great compilation of work,” highlighting its confirmation of long-suspected neurodevelopmental processes. A key finding is that the distinct effects of autism-linked variants early in development ultimately converge on shared biological changes, a stage that has been less studied until now.
Looking ahead, Geschwind and his team plan to collect detailed molecular, cellular, and electrophysiological data from the brain organoids. They hope to identify specific subsets of changes that could serve as biomarkers for screening potential therapies. “We don’t expect that everything is going to converge on the same cell type or the same process, but we hope to identify subsets where one can observe a refined convergence,” Geschwind stated.
This research underscores the complexity of autism spectrum disorder, but also offers a promising path toward identifying shared biological mechanisms and, developing more effective treatments. Further investigation into these convergent pathways will be crucial for translating these findings into clinical benefits.
Disclaimer: This article provides informational content about medical research and should not be considered medical advice. Please consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
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