Probing Intercell Variability Using Bulk Measurements

The measurement of noise is critical when assessing the design and function of synthetic biological systems. Cell-to-cell variability can be quantified experimentally using single-cell measurement techniques such as flow cytometry and fluorescent microscopy. However, these approaches are costly and impractical for high-throughput parallelized experiments, which are frequently conducted using plate-reader devices. In this paper we describe reporter systems that allow estimation of the cell-to-cell variability in a biological system's output using only measurements of a cell culture's bulk properties. We analyze one potential implementation of such a system that is based upon a fluorescent protein FRET reporter pair, finding that with typical parameters from the literature it is able to reliably estimate variability. We also briefly describe an alternate implementation based upon an activating sRNA circuit. The feasible region of parameter values for which the reporter system can function is assessed, and the dependence of its performance on both extrinsic and intrinsic noise is investigated. Experimental realization of these constructs can yield novel reporter systems that allow measurement of a synthetic gene circuit's output, as well as the intrapopulation variability of this output, at little added cost.