The human brain contains around 100 billion neurons. Their genesis, development and degeneration are all governed by underlying gene regulatory networks (GRNs). These fundamental biological processes represent a nexus where basic and translational neurobiology converge; the same processes that orchestrate normal neuronal development, maturation and death are those that malfunction in neurodevelopmental and neurodegenerative disorders. We aim to identify these networks and uncover how they vary across individuals, thereby causing errors of neurodevelopment or susceptibility to neurodegeneration. This overarching goal is as much about developing a basic understanding of how neuronal phenotype emerges from interactions among the genes of the network as it is about translating this understanding into identification of novel therapeutic targets. All of our work is guided by a credo that understanding basic biological mechanisms and identifying targets for therapeutic intervention are inextricably intertwined. To implement this vision, we work collaboratively with basic, clinical and translational neuroscientists, molecular biologists, stem cell biologists and computational biologists.
This mission can be broken down into three overlapping phases, First, we need to define the networks. We do this by using induced pluripotent stem cells (iPSCs) to examine neuronal development and degeneration on specific genetic backgrounds (our disease focus is increasingly on ASD and Alzheimer’s Disease). We use a variety of genomic tools to harvest transcriptional and epigenetic data and then interrogate these data to infer the interactions among the genes and to define how the network topology changes during neuronal development and neuronal death. Second, we need to attribute changes in network topology to specific genes. This we do by using genome editing to introduce specific genetic changes and then reanalysing the network topology. Third, we use a range of genetic and small molecule manipulations to target specific pathways inferred from the network analyses. Our hope is to identify candidate pathways and genes that may represent novel therapeutic targets to delay, abrogate or rescue aberrant neuronal development or degeneration.
As well as this systems approach, we also focus on transcription factors that are known regulators of neurodevelopment and neurodegeneration. Much of our attention has been focussed on REST, a key transcriptional regulator, that we have shown plays a critical role in embryonic neurogenesis and in maintaining adult neuronal phenotype. Furthermore, REST is a critical component in mediating cell death in Huntington’s Disease and potentially in rescuing cell death in Alzheimer’s disease.
We are part of a broad consortium of scientists at Oxford under the ARUK Drug Development Institute that will expedite rapid translation of our findings to develop target-enabling packages including assays, screens, probe compounds and other reagents for target development.
