Alex K. Shalek
Institute for Medical Engineering & Science and Department of Chemistry, MIT
Ragon Institute/ Broad Institute/ HMS/ MGH
Development and application of new technologies that facilitate understanding of how immune cells collectively perform systems-level functions in health and disease.
The interdisciplinary research in the Shalek Lab aims to create and implement new approaches to elucidate cellular and molecular features that inform tissue-level function and dysfunction across the spectrum of human health and disease. This encompasses both the development of broadly enabling technologies as well as their application to characterize, model, and rationally control complex multicellular systems. With respect to technology development, we couple genomics, chemical biology, and nanotechnology to establish accessible, broadly-applicable cross-disciplinary platforms that enable us and others to profile and control cells and their interactions within complex multicellular systems. In addition to sharing this toolbox to empower mechanistic scientific inquiry across the global research community, we are applying it to uncover principles that inform ensemble immune responses within tissues, focusing on the roles of cellular heterogeneity and cell-to-cell communication. Current studies seek to methodically dissect human disease to understand links between cellular features and clinical observations, including how: immune cells coordinate balanced responses to environmental changes with tissue-resident cells; host cell-pathogen interactions evolve across time and tissues during HIV-1 and M. Tuberculosis infection; and, tumor cells evade homeostatic immune activity. From these collective observations, we aim to construct generalizable models of how disease alters tissue homeostasis and function on the cellular level that can be tested to aid in the design of therapeutic and prophylactic interventions to improve human health. Overall, we hope that our work not only provides broadly-applicable experimental and computational tools to advance many avenues of scientific study, but also transforms how the community thinks about leveraging human disease as natural perturbations to the human immune system.
Tirosh, I.#, Izar, B.#, Prakadan, S.M., Wadsworth II, M.H., Tracy, D., Trombetta, J.J., Lu, D., Rotem, A., Lian, C., Murphy, G., Cohen, O., van Allen, E., Bertagnolli, M., Genshaft, A., Hughes, T.K., Ziegler, C.G.K., Kazer, S.W., Gaillard, A., Kolb, K.E., 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).
Patel, A.P.*, Tirosh, I*, Trombetta, J.J., Shalek, A.K., Gillespie, S.M., Wakimoto, H., Cahill, D.P., Nahed, B.V., Curry, W.T., Martuza, R.L., Louis, D.N., Rosenblatt-Rosen, O., Suvà, M.L., Regev, A., and Bernstein, B.E., “Single Cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma,” Science, 344, 1396 (2014).
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).
Massachusetts Institute of Technology
Cambridge, MA 02139