Project Summary: MIRA Title: Dynamics and evolution of synthetic and natural gene regulatory networks Tissues or microbial cell populations can consist of millions of cells, each of which contains billions of molecules. Central among these molecules, DNA stores information in protein-coding genes, but also in noncoding, gene-regulatory regions. Gene products binding to such regions form complex gene regulatory networks that influence the behavior of individual cells and thereby cell populations. Changes in DNA sequence can alter these networks, making cell populations better adapted in various environments, contributing to genetic evolution. Yet, to learn how gene networks control cell populations, we must understand how network dynamics and stochasticity affects cells and thereby cell populations. Answering these questions should help us understand the behavior and evolution of cell populations, which are the bases of cancer progression and microbial drug resistance. To attack this problem, we have developed computational models of natural regulatory networks to understand how they modulate nongenetic diversity in cell populations. We have also designed synthetic gene networks to control the variability of protein expression in yeast and mammalian cells. Now we plan to connect these research directions, using synthetic gene networks to generate specific gene expression patterns in space and time that serve as signals for natural gene networks, studying the subsequent effects on cell population behavior and evolution by computational modeling and experimental evolution. Overall, these studies will shed light on how complex networks enable control across scales of space and time in biology, from molecules to cells. Addressing these questions will teach us how to control evolving cell populations, which is relevant for understanding, predicting and possibly preventing cancer and microbial resistance.