Cell Circuits and Complex Tissues

The vast number and variety of activities our cells need to undertake to maintain health rely on finely tuned circuits involving multiple genes and molecules. Deciphering the genetic and molecular basis of circuits inside cells is critical to understand the impact of genetic variations on these circuits. How do molecules within cells function to perform their functions? How do malfunctions in genes and cells cause or exacerbate disease? Our goal is to develop a comprehensive and quantitative analysis of cell circuits that will enable researchers to better understand disease and develop effective new treatments.

The Cell Circuits Program is a community focused on systematically defining the genetic and molecular circuits in a wide range of cell types. Brought together through a weekly seminar series, the CCP’s collaborative community is devoted to tackling this challenging but essential biological problem. The CCP also hosts external visitors to learn experimental and computational methods as part of the activities of the NHGRI Center for Cell Circuits.

Under the direction of Broad core faculty member Nir Hacohen, CCP labs collaborate within the program and across the Broad and affiliated labs to map cell circuitry by charting the molecular and genetic connections in human cell types. To help create these comprehensive "wiring diagrams," CCP labs also develop and employ new systematic genome-wide approaches to interrogate the structure and function of each circuit. In particular, CCP labs combine an iterative cycle of measurements, or observations, of cellular responses on a genomic scale, computational modeling, or inference, of the circuits that explain those responses, and massive perturbations of these components, followed by profiling, to test and refine those models.

Among the key areas of work in the CCP:

Genetic and molecular analysis of cellular circuits. Our researchers are focused on revealing the molecular mechanisms that drive cell circuits, and how genetic information can be interpreted in the context of cell circuits.
Application to key cells types and responses. CCP labs focus deeply on key cell types, as both driving biological problems for method development and to demonstrate the value and insight gained by cell circuits research. Among the key systems are primary immune cells, like dendritic cells and T cells, stem cell differentiation, and reprogramming.
Technology and computational development. CCP labs build experimental and computational tools to measure and perturb cells, and help disseminate them to the broader community. They also develop computational tools, including expertise in machine learning and AI.
Relation to human genetic variation. CCP scientists are also key contributors to the Broad’s Variant to Function initiative, which aims to scale up efforts to understand the impact of the more than 60,000 disease-linked genetic variants identified to date. Cell circuitry provides a natural testing ground, where natural genetic variation can be used to shine light on the function of circuits, while simultaneously revealing the impact of particular variants in the cellular context. CCP scientists have demonstrated this in immune cell systems, and continue to develop tools that will also help to accelerate the V2F effort.

CCP scientists have benefitted greatly from the Klarman Cell Observatory. The methods, tools, and projects that the Klarman Cell Observatory pursued in its first five years, spanning single cell genomics and cellular circuitry, have empowered CCP labs in their studies across all their areas. Examples include applications of CRISPR screens, especially Perturb-seq, and a project on the cellular characterization of blood cell types. As the KCO now turned to the study of circuits at the level of integrated tissues rather than individual cells, it remains a key hub of activity and cross fertilization with the CCP.