Micro - and Nanoscale Tools for "Bottom Up" Profiling of Interacting Cellular Systems
Research in the Shalek Lab is directed towards the development and application of new technologies that will facilitate understanding of how cells collectively perform systems-level functions in healthy and diseased states. With respect to technology development, we are leveraging recent advances in nanotechnology and biological chemistry to establish a host of core, cross-disciplinary platforms that will collectively enable us to extensively profile and precisely control cells and their interactions within the context of complex systems. Examples include: (1) a portable, low-cost, sample-efficient, and massively-parallel microwell-based single-cell RNA-Seq platform called Seq-Well, which may prove transformative for global diagnostic and therapeutic applications; (2) experimental and computational platforms for linking the cellular transcriptome with additional informative metadata – e.g., mass, protein abundance, lineage, T cell receptor usage, genetic state, infection status, and more; and, (3) strategies for sequencing pairs of cells and deconstructing how cellular interactions alter individual cellular phenotypes. With respect to biological applications, we are focusing on how cellular heterogeneity and cell-to-cell communication drive ensemble-level decision-making in the human immune system, with an emphasis on “two-body” interactions (e.g., host cell-virus interactions, innate immune control of adaptive immunity, tumor infiltration by immune cells). Representative projects include: (1) identifying dendritic cell response states, enriched in HIV-1 Elite Controllers, that have superior antiviral functionality and can be rationally induced for therapeutic and prophylactic purposes; (2) building an atlas of the healthy human gut, and studying deviations induced by inflammatory bowel disease; and, (3) defining the cellular microenvironment of melanomas, pancreatic cancers, and cerebrospinal fluid from patients with brain metastases to explore the intra- (e.g., cancerous cell subpopulations) and intercellular interactions (e.g., tumor-tumor infiltration lymphocyte) that impact cancer progression and evolution under therapy. Ultimately, we aspire not only to provide broadly applicable experimental tools, but also to help transform the way in which the community thinks about single cells, cell-cell interactions, diseased cellular states, and therapeutics so as to create a new paradigm for understanding and designing systems-level behaviors in the human body.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.