With a revolutionary combination of organoids and genetics, scientists can now comprehensively test the effects of multiple mutations in human brain organoids, identifying vulnerable cell types and gene regulatory networks-the foundation for treating autism spectrum disorder. This achievement provides an unprecedented and innovative approach to understanding one of the most complex human brain diseases and offers hope for clinical research. The results were published on the 13th in the journal *Nature*.
For development, the human brain relies on a unique process to build an intricate network of layers and connections in the cortex. This process also makes humans more susceptible to neurodevelopmental disorders-many high-risk genes for autism spectrum disorders are closely related to cortical development. To unlock the "black box" of autism research, the Institute for Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences and ETH Zurich have jointly developed a technology to screen key transcriptional regulatory genes in autism. This technology is considered to mark the beginning of an era of complex, efficient, and convenient gene screening in human tissues.
In the newly developed system called "CHOOSE," each cell in the brain organoid carries at most one specific gene mutation. Researchers can track the effects of each mutation at the single-cell level and map the developmental trajectory of each cell.
This high-throughput method can systematically inactivate a range of pathogenic genes, and as organoids carrying these mutations grow, the impact of each mutation on development can be analyzed.
Researchers used this technique to understand the common molecular mechanisms underlying autism-causing genes. Collaborating with clinicians, they generated human brain organoids from stem cell samples of two patients. Both patients had mutations in the same gene that causes autism. The generated organoids exhibited significant developmental defects associated with specific cell types. This new technology provides scientists and clinicians with a powerful and precisely controlled high-throughput screening tool that can significantly reduce analysis time and provide valuable information for understanding disease mechanisms and ultimately curing the disease.
Compared to other species, the human brain clearly possesses unique characteristics, including the potential for brain diseases. However, it is precisely this uniqueness that limits the use of animal models in medical research on the human brain. Take autism as an example: although clinical studies have shown a causal relationship between various gene mutations and autism, scientists still do not understand how these mutations lead to brain defects. Now, with the binding system described in this article, we have gained entirely new insights into the pathology of autism, and the versatility and transferability of this new system may also be applicable to other complex brain disorders.
