CAREER: Predictive Understanding and Control of Embryonic Developmental Programs

University Of California-Berkeley, Berkeley CA

Investigators

Abstract

How does a single cell develop into a multicellular organism? As a cell divides, its progeny read the program encoded in their DNA and adopt distinct fates, such as muscle, liver, and brain cells. The decisions that cells make during development are not so much based on which genes to express, but rather on when, where, and how to express them. The central goal of this project is to establish the experimental and theoretical infrastructure for a predictive understanding of cellular decision-making in the developing embryo of the fruit fly Drosophila melanogaster, the hydrogen atom of developmental biology. Although theoretical models currently predict gene expression from DNA regulatory sequences, the field lacks technology to test these model predictions by precisely measuring gene-expression dynamics in single cells of a living embryo. Additionally, previous models of development mainly focused on predicting gene expression from complex endogenous DNA regulatory sequences with a plethora of binding sites for activators and repressors, yielding complex theoretical models with multiple unknown parameters. These research efforts will be complemented with new undergraduate and graduate courses aimed at breaching the divide between biology and physics. The PI will actively introduce pre-college students and undergraduates to research, with particular emphasis on underrepresented minorities. Specifically, the PI will (i) create new hands-on modules to introduce students at UC Berkeley and nearby schools and community colleges to real-world problems in physical biology, and (ii) commit significant lab resources to mentoring undergraduates during the summer and the academic year. The proposed investigations will make progress toward reaching this predictive understanding of development by (i) developing a suite of novel technologies to test theoretical predictions by quantifying developmental decisions in real time in single cells of a living embryo, and (ii) using synthetic biology to isolate developmental decisions into simple and quantitatively tractable units that can be systematically queried, both theoretically and experimentally, in terms of their regulatory parameters. As an initial case study, these enabling technologies and precisely engineered flies will be used to uncover the governing equations that dictate how activators create the gene expression boundaries that segment the embryo. These investigations will set the stage for uncovering the governing rules behind the creation of more complex gene expression patterns such as stripes, and will make it possible to apply these approaches in other animals.