Johns Hopkins School of Medicine

While cells are generally perceived as fundamental units of biology, their intrinsic variation, heterogeneity, and diversity of responses are widely ignored or unintentionally masked using aggregate experimental designs. With the advent of technologies to probe the physiological, transcriptional, and genomic states of individual cells, there has been an increased appreciation of the extent and contribution of cell-to-cell variation to both steady state cellular functions and to the population-level responses during cell state transitions. The increasing resolution of these assays enables exploration into how cell-cell variation contributes to cellular population composition dynamics, the diversity of cellular responses and transitions during critical processes such as differentiation, and importantly, how disease-associated mutations may alter or exploit cellular heterogeneity.

Nowhere, perhaps, is cellular heterogeneity more relevant than in the brain. The mammalian central nervous system (CNS) is dependent on a remarkable diversity of cell types and cell states for its proper development and function. CNS heterogeneity manifests across many abstract levels including the establishment and maintenance of a large diversity of discrete cell types, their integration into the complex circuitry of the nervous system, and the integration of signals from their physical environment with intrinsic properties such as physiological state or neurotransmitter:receptor composition to evoke specific responses. Transcriptional analysis of single cells/neurons in the CNS provides an additive proxy output signal (gene expression) to explore cell-cell variation and identify co-varying modules of genes that can be correlated with specific properties such as cell type, spatial position, or developmental stage. By understanding how specific cellular properties relate to distinct cellular phenotypes in the CNS, we begin to understand such key processes as neuronal plasticity, regulation of neuronal circuitry, developmental fate specification, and the impact of disease-associated mutations on proper organization and function of the mammalian brain.

Our lab is focused on the role of cellular context-specific variation in the development, organization, and function of the mammalian nervous system. We examine single cell heterogeneity as it pertains to 1) the characterization and annotation of cellular diversity in the mammalian CNS and ENS, 2) the phenotypic diversity in population-level responses to stimuli or insults, 3) the effect of genetic variation on cellular diversity in steady state and disease conditions, and 4) the reconstruction and modulation of cellular state transitions in development and disease.