Research in the Shalek Lab is directed towards the creation and implementation of new technologies to understand how cells collectively perform systems-level functions in healthy and diseased states. To examine the rules that govern ensemble cellular behaviors, we employ a comprehensive, five-step approach: first, we identify the fundamental elements that comprise our systems; second, we decipher the salient characteristics that differentiate each element; third, we explore how environmental signals impact the molecular computations each element makes; fourth, we examine how direct interactions between elements influence each other; and, finally, we investigate how the foregoing factors cooperatively drive ensemble phenomena. At each step, as we face technical limitations and pressing biological needs, we develop and apply innovative methodologies to empower a deeper, more mechanistic inquiry. Our technology development leverages recent advances in genomics, chemical biology, and nanotechnology to establish cross-disciplinary platforms for in-depth profiling and precise manipulation of cells and their interactions. Examples include microdevices for massively-parallel single-cell genomics, strategies for simultaneously measuring diverse cellular variables, microfluidic tools for controlling the cellular microenvironment, and approaches for engineering and profiling cell-cell interactions. Our biological applications focus on the roles of cellular heterogeneity and cell-to-cell communication in driving immune responses. Current studies examine how: innate and adaptive immune cells coordinate balanced responses to environmental changes; host cell-pathogen interactions evolve across time and tissues during HIV-1 and M. Tuberculosis infection; and, tumor cells evade immune responses. Overall, our goal is to realize broadly-applicable experimental and computational platforms to uncover common cellular motifs that inform healthy and diseased immune responses. Using this information, we aim to help transform how the community thinks about single cells, cell-cell interactions, diseased tissues and processes, and therapeutics to create a new paradigm for understanding and designing systems-level multicellular behaviors.   SELECTED PUBLICATIONS Gierahn, T.#, Wadsworth II, M.H. #, Hughes, T.K. #, Bryson, B.D., Butler, A., Satija, R., Fortune, S., Love, J.C.*, and Shalek, A.K.*, “Seq-Well: A Portable, Low-cost Platform for Single-Cell RNA-Seq of Low-Input Samples,” Nature Meth., 14, 395 (2017). Tirosh, I. #, Izar, B. #, Prakadan, S.M., Wadsworth II, M.H., Tracy, D., Trombetta, J.J., Rotem, A., Rodman, C., Lian, C., Murphy, G., Fallahi-Sichani, M., Dutton-Regester, K., Lin, J.R., Cohen, O., Shah, P., Lu, D., Genshaft, A., Hughes, T.K., Ziegler, C.G.K., Kazer, S.W., Gaillard, A., Kolb, K.E., Villani, A.C., Johannessen, C.M., Andreev, A.Y., van Allen, E.M., Bertagnolli, M., Sorger, P.K., Sullivan, R.J., Flaherty, K.T., Frederick, D.T., Jané-Valbuena, J., Yoon, C.*, Rozenblatt-Rosen, O.*, Shalek, A.K.*, Regev, A.*, and Garraway, L.*, “Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq,” Science, 352, 189 (2016). Macosko, E.Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I., Bialas, A.R., Kamitaki, N., Martersteck, E.M., Trombetta, J.J., Weitz, D.A., Sanes, J.R., Shalek, A.K., Regev, A., and McCarroll, S.A., “Genome-wide expression profiling of thousands of individual cells using nanoliter droplets,” Cell, 161, 1202 (2015). Shalek, A.K.#, Satija, R.#, Shuga, J.#, Trombetta, J.J., Lu, D., Gennert, D., Chen, P., Gertner, R.S., Gaublomme, J.T., Yosef, N., Schwartz, S., Fowler, B., Weaver, S., Wang, J., Wang, X., Ding, R., Raychowdhury, R., Friedman, N., Hacohen, N., Park, H.*, May, A.P.*, and Regev, A.*, “Large-Scale Single-Cell RNA-Seq Reveals Strategies for Regulating Cell-to-Cell Dynamic Variability through Paracrine Signaling,” Nature, 510, 363 (2014). Shalek, A.K.#, Satija, R.#, Adiconis, X., Gertner, R.S., Gaublomme, J.T., Raychowdhury, R., Schwartz, S., Yosef, N., Malboeuf, C., Lu, D., Trombetta, J.J., Gennert, D., Gnirke, A., Goren, A., Hacohen, N., Levin, J.Z., Park, H., and Regev, A., “Single-Cell Transcriptomics Reveals Bimodality in Expression and Splicing in Immune Cells,” Nature, 498, 236 (2013). Yosef, N.#, Shalek, A.K.#, Gaublomme, J.T.#, Jin, H., Lee, Y., Awasthi, A., Wu, C., Karwacz, K., Xiao, S., Jorgolli, M., Gennert, D., Satija, R., Shakya, A., Lu, D.Y., Trombetta, J.J., Pillai, M., Ratcliffe, P.J., Coleman, M.L., Bix, M., Tantin, D., Hongkun Park, H., Kuchroo, V.K., and Regev, A., “Dynamic Regulatory Network Controlling Th17 Cell Differentiation,” Nature, 496, 461 (2013). A full list of Professor Shalek’s publications can be found on his website.