Functional Genomics of Human Brain Development Cluster
Lead Research Organisation:
King's College London
Department Name: Developmental Neurobiology
Abstract
Neurodevelopmental conditions like autism, attention deficit hyperactivity disorder (ADHD), epilepsy, and intellectual disability affect millions of children worldwide. These conditions are highly complex, and their causes remain elusive. Recent technological advances have revealed that genetics play a crucial role in these disorders. However, we still need to understand how specific gene variations disrupt the development of the human brain and lead to alterations that disrupt the lives of affected individuals. Our goal is to unlock the secrets behind neurodevelopmental disorders and find ways to help affected children and their families lead better lives.
Our team of scientists will be using brain organoids, three-dimensional "avatars" of the human brain grown in the lab from human stem cells, to study the developing brain in a more accurate and detailed way. These organoids mimic some of the cellular complexity of the human brain better than previous methods, allowing us to study how genes influence brain development and function. We will initially focus on the cerebral cortex, a critical brain region responsible for higher functions like planning and memory. By studying brain organoids containing different types of brain cells, we aim to discover the role of specific genes associated with neurodevelopmental disorders. This research will help us identify the causes of these conditions and pave the way for developing targeted treatments.
One significant challenge is that brain organoids created in different labs can vary, affecting the reliability of the research. To overcome this, we will create a standardised platform for generating brain organoids, ensuring consistency and reproducibility across multiple research centres in the UK. We will also use cutting-edge technologies like single-cell genomics, imaging, and electrophysiology to analyse brain organoids and unravel the intricate pathways contributing to human brain development in health and disease. We will also investigate how different people's genetic backgrounds influence these disorders, ensuring our findings are representative and applicable to diverse populations.
We will bring together scientists from eight institutions in the UK and worldwide. Team members from these institutions are already collaborating by sharing resources and data. By developing this platform, we can extend these interactions and combine their expertise to share our findings and resources nationally. This approach will multiply our collective capacity to investigate the molecular mechanisms regulating brain development and their dysregulation in disease. We will accelerate the ability of other researchers to carry out investigations using brain organoids through dedicated training, sharing of protocols, and outreach programs in which we will interact with researchers and the general community, facilitating effective knowledge-sharing across multiple groups of individuals.
In summary, this collaboration will accelerate our understanding of the biology underlying human brain development and the role that specific gene changes play in acquiring a neurodevelopmental condition. We envision that this knowledge will ultimately help identify new ways to improve the lives of children and families affected by these conditions.
Our team of scientists will be using brain organoids, three-dimensional "avatars" of the human brain grown in the lab from human stem cells, to study the developing brain in a more accurate and detailed way. These organoids mimic some of the cellular complexity of the human brain better than previous methods, allowing us to study how genes influence brain development and function. We will initially focus on the cerebral cortex, a critical brain region responsible for higher functions like planning and memory. By studying brain organoids containing different types of brain cells, we aim to discover the role of specific genes associated with neurodevelopmental disorders. This research will help us identify the causes of these conditions and pave the way for developing targeted treatments.
One significant challenge is that brain organoids created in different labs can vary, affecting the reliability of the research. To overcome this, we will create a standardised platform for generating brain organoids, ensuring consistency and reproducibility across multiple research centres in the UK. We will also use cutting-edge technologies like single-cell genomics, imaging, and electrophysiology to analyse brain organoids and unravel the intricate pathways contributing to human brain development in health and disease. We will also investigate how different people's genetic backgrounds influence these disorders, ensuring our findings are representative and applicable to diverse populations.
We will bring together scientists from eight institutions in the UK and worldwide. Team members from these institutions are already collaborating by sharing resources and data. By developing this platform, we can extend these interactions and combine their expertise to share our findings and resources nationally. This approach will multiply our collective capacity to investigate the molecular mechanisms regulating brain development and their dysregulation in disease. We will accelerate the ability of other researchers to carry out investigations using brain organoids through dedicated training, sharing of protocols, and outreach programs in which we will interact with researchers and the general community, facilitating effective knowledge-sharing across multiple groups of individuals.
In summary, this collaboration will accelerate our understanding of the biology underlying human brain development and the role that specific gene changes play in acquiring a neurodevelopmental condition. We envision that this knowledge will ultimately help identify new ways to improve the lives of children and families affected by these conditions.
Technical Summary
Recent technological advances are beginning to shed light on the genetic bases of many brain disorders, including epilepsy, autism, intellectual disability, and schizophrenia. Gene associations are often cross-diagnostic, raising essential questions about why different phenotypes emerge from similar mutations. The field has evolved to a point where the identification of risk genes is highly reliable, particularly for highly penetrant rare mutations. However, the challenge remains to elucidate how genetic variation disrupts human brain development and causes these conditions.
We aim to accelerate our understanding of the mechanisms through which gene variation leads to neurodevelopmental disorders. To this end, we will establish a platform to engineer next-gen brain organoids that closely mimic human brain tissue and develop for extended periods, thereby facilitating the emergence of functional networks in vitro. We will initially focus on the cerebral cortex because functional genomic studies have revealed that gene variation linked to neurodevelopmental disorders is most significantly associated with specific cell types of this brain region. Leveraging our knowledge of brain patterning mechanisms, we will produce cortical organoids containing the necessary diversity of cortical cell types.
We will use genome editing to investigate the role of disease-associated genes in human cortical development. We will generate cortical organoids from induced pluripotent stem cells carrying highly penetrant mutations strongly linked to neurodevelopmental conditions. We will then use a multimodal approach to analyse the development of cortical organoids, including single-cell genomics, imaging, electrophysiological, and computational tools. This approach will reveal changes in gene expression, gene regulatory networks, and neural activity associated with specific mutations, allowing us to delineate causal pathways contributing to disease.
We aim to accelerate our understanding of the mechanisms through which gene variation leads to neurodevelopmental disorders. To this end, we will establish a platform to engineer next-gen brain organoids that closely mimic human brain tissue and develop for extended periods, thereby facilitating the emergence of functional networks in vitro. We will initially focus on the cerebral cortex because functional genomic studies have revealed that gene variation linked to neurodevelopmental disorders is most significantly associated with specific cell types of this brain region. Leveraging our knowledge of brain patterning mechanisms, we will produce cortical organoids containing the necessary diversity of cortical cell types.
We will use genome editing to investigate the role of disease-associated genes in human cortical development. We will generate cortical organoids from induced pluripotent stem cells carrying highly penetrant mutations strongly linked to neurodevelopmental conditions. We will then use a multimodal approach to analyse the development of cortical organoids, including single-cell genomics, imaging, electrophysiological, and computational tools. This approach will reveal changes in gene expression, gene regulatory networks, and neural activity associated with specific mutations, allowing us to delineate causal pathways contributing to disease.
