Rick Livesey MB BChir PhD, Wellcome Trust Senior Investigator, Reader in Molecular Neuroscience and Member of the Department of Biochemistry.
Development, evolution and degeneration of the brain
Can we model human brain development and disease in the lab? The human cerebral cortex, the thinking, decision-making, largest part of our brain, sets us apart from other animals – and poses a challenge for biomedical researchers. Animal models cannot capture the spectrum of characteristics of the human cerebral cortex in development or disease, and so our research uses human cells in tissue culture.
Our methods for differentiating human pluripotent stem cells – via cortical stem cells – into cortical neurons allows us to study neurons and the neural circuits they make, starting from living patients’ cells. We are studying how the human cerebral cortex develops and how that differs from other animals, and how variations in development lead to disease.
We also apply these approaches to study neurodegeneration in dementia, particularly Alzheimer’s disease. Using stem cells from patients with genetic forms of Alzheimer’s disease, we have modelled the disease pathogenesis in neurons in culture. We use these systems to understand how Alzheimer’s disease starts and progresses in the brain, and to test the efficacy of potential therapeutic strategies.
• Otani T et al. (2016) 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. Cell Stem Cell 18(4): 467-80.
• Kirwan P et al. (2015) Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro. Development 142(18): 3178–3187.
• Moore S et al. (2015) APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons. Cell Reports 11(5): 689–696.
• Saurat N et al. (2013) Dicer is required for neural stem cell multipotency and lineage progression during cerebral cortex development. Neural Dev. 8:14.
• Shi Y, Kirwan P, Smith J, Robinson HP and Livesey FJ (2012) Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature Neuroscience, 15, 477-486
• Shi Y, Kirwan P, Smith J, Maclean G, Orkin SH and Livesey FJ (2012) A human stem cell model of early Alzheimerâ€™s disease pathology in Down syndrome.Science Translational Medicine, 124ra29
• Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A and Livesey FJ (2010) Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc National Academy of Science USA, 107, 15957-15962.