Human models for human diseases: how pluripotent stem cell derived brain organoids can help us understand and treat diffuse hemispheric glioma

The precise orchestration of neurodevelopment and epigenetic regulation is essential for normal brain development with devastating consequences if disrupted, leading to neurological diseases and cancer. For diseases such as paediatric high grade gliomas (pHGG), the epigenetic driver mutation in Histone 3.3 contorts the fate of developing cells in the brain, resulting in poor outcomes for most children and adolescents with this disease. The complexity of diseases such as pHGG is reflected in the intricacy of the development of human cortical structures and their subsequent neural functions; it is our cortex that significantly delineates us from all other mammalian species. This complexity cannot be modelled adequately in systems other than human. Indeed, there are thousands more neurons with a thousand-fold increase in surface area of the human brain in comparison to the mouse cortex. Approaches to study the human developing brain are therefore required to understand the complexities of human cortical structures. Here, we describe the neurodevelopmental trajectories and epigenetic regulation of human cortex development. We then report how investigators study the human cortex, how it can be recapitulated in 3D brain organoids, and why this is important for modelling disease. We focus on the lethal childhood brain cancer H3G34-mutated Diffuse Hemispheric Glioma (DHG), a sub-type of pHGG arising in the cortex of adolescents, as an exemplar for modelling a difficult-to-treat disease in 3D brain organoids. Finally, we provide a perspective on the current shift from research using animals to New Approach Methodologies (NAMs) and why 3D brain organoids offer opportunities for the future of pre-clinical validation.