May 3, 2018
10:30 AM - 12:00 PM
Speaker: Ronald Germain
National Institutes of Health
Title: "Combining Imaging and Cell-based Systems Analysis to Develop a Deep Understanding of Immunity"
Recent advances in genomic, flow cytometric, and imaging technologies have increasingly emphasized highly multiplexed examination of biological systems at the single cell level. Our dynamic and static imaging methods, including newly devised highly multiplex 3D methods, have begun to provide a comprehensive spatiotemporal understanding of immune system operation in situ. A key theme that has emerged from this work is the role of fine grained levels of tissue organization in producing efficient adaptive immune responses from an inherently inefficient, sparse system. Our studies have also revealed that several paradigmatic views of cell behavior are not accurate when examined in vivo, while studies of innate immune myeloid cells have provided new insights into regulation of inflammatory tissue damage. At the system biology level, RNA-seq as well as mass-spectrometric examination of cell state (CyTOF analysis) have led to the putative definition of an increasingly large number of cell subsets, approaching the ‘snowflake’ paradigm of every cell being unique. In this lecture, I will discuss some of the key issues pertaining to the origin of variation in RNA and protein expression among what appear to be members of a single cell subset (e.g., TCR transgenic, naïve, resting CD8+ T cells), how such variation affects cellular responses to stimulation, and how predictable, functional biology emerges in an organism with cells, especially rare members of the adaptive immune system, occupying diverse microstates at any given time. Issues to be discussed include: (i) whether cells respond in an ‘instantaneous’ manner dependent on momentary microstate or integrate signals over time as the state changes to decrease the heterogeneity of response, (ii) whether clustering algorithms applied to RNA-seq data reveal stable differentiated subsets of cells or transient fluctuation in sets of co-regulated genes, and (iii) whether individual cells with multiple receptors whose expression varies in time respond with full integration of multiple signals or if biology emerges from the sum of distinct behaviors of individual cells.
This research was supported by the Intramural Research Program of NIAID, NIH.