Jeffrey Moffitt is an Assistant Professor in the Department of Microbiology at Harvard Medical School and the Program in Cellular Molecular Medicine at Boston Children’s Hospital, as well as an Associate Member of the Broad Institute. His research focuses on the development of spatially resolved transcriptomic tools and their application to questions at the microbe-host interface in mammals.
Jeff received his PhD from the University of California Berkeley in Physics working with Dr. Carlos Bustamante, where he developed novel methods to understand enzyme mechanism by measuring the Angstrom-scale movements of single molecules in real time. He then moved to Harvard University where he conducted postdoctoral research in the laboratory of Dr. Xiaowei Zhuang. In the Zhuang laboratory, Jeff developed methods to fluorescently label RNA molecules at the transcriptome-scale and leveraged these tools to demonstrate that the bacterial transcriptome is spatially organized. In parallel, he co-developed multiplexed-error robust fluorescence in situ hybridization (MERFISH), a transcriptome-scale single-RNA-molecule imaging technique capable of imaging and identifying thousands of RNA molecules within single cells in intact tissue samples. He demonstrated that this new measurement capability can define gene regulatory networks, map the intracellular organization of the transcriptome, and define and map cell types within tissues such as the brain. Jeff started his own laboratory in 2018, where he continues to develop new extensions of MERFISH and to apply these techniques to understand the spatial organization of commensal microbial communities, the role this organization plays on microbe-microbe and microbe-host interactions, and the role of the cellular organization of host tissues in the response to microbial perturbations. Recognizing the potential of his research, Jeffrey was named a Pew Biomedical Research Scholar in 2019.
Abstract: Creating Molecular Atlases of Tissues by Imaging the Transcriptome
The behavior of tissues arises from the complex interactions of a diversity of cell types and states, whose intricate spatial organization within tissues shapes the interactions of these cells and ultimately the function of the tissue. Single-cell techniques, such as single-cell RNA sequencing, have demonstrated a remarkable ability to discover, characterize, and catalog a diverse array of cell types from a range of tissues, yet these methods provide limited insight into the essential spatial structure of these tissues. By contrast, image-based approaches to single-cell transcriptomics represent an exciting new complement to single-cell RNA sequencing methods, as they preserve this essential spatial context by quantifying RNA expression within single cells in intact tissues via direct single-molecule imaging.
I will describe the development and performance of multiplexed error robust single-molecule fluorescence in situ hybridization (MERFISH)—a leading image-based approach to single-cell transcriptomics capable of identifying and quantifying hundreds to ten thousand different RNAs simultaneously in single fixed cells within a range of tissues. MERFISH leverages combinatorial labeling and readout of error tolerant barcodes to identify RNAs with high fidelity, detection efficiency, and single-molecule sensitivity across large expression ranges. In turn, these spatially resolved, single-cell transcriptomic measurements provide the ability to create molecularly defined atlases of tissues. I will highlight several applications of these novel measurements that illustrate the potential for tissue atlases to provide new insights into a range of biological questions.