From single cells to microbial consortia: bridging the gaps between synthetic circuit design and emerging dynamics of heterogeneous populations

Introduction

A key turning point in the evolution of life was the transition from single-cell to multicellular organisms and the optimization of fitness via division of labour and specialization. Similarly, microorganisms have evolved equivalent strategies by forming communities or consortia.

Division of Labour in Microbial Populations

Division of labour in isogenic microbial populations is often implemented by mechanisms that create or act upon population heterogeneity to diversify functionality. Rational design in synthetic biology, on the other hand, is focused on the engineering of gene circuits with deterministically predictable functionality within single cells.

Challenges in Synthetic Biology

While synthetic biology has certainly come a long way, predictable functionality of circuits in growing microbial populations still remains elusive or limited to tightly constrained operating conditions.

Project Objectives

We will develop novel mathematical methods to characterize and control the dynamics of synthetic gene circuits within growing microbial populations. Our objectives include:

1. Developing a modelling framework and novel computational methods that account for:

   • Stochasticity of single-cell processes
   • Consequences of heterogeneity for population dynamics

2. Coupling single-cell stochastic processes to state-dependent population processes such as growth or selection.

3. Developing methods for:

   • Parameter inference
   • Experimental design
   • Control for such models

Expected Outcomes

This will enable the construction of models that can be used to design synthetic circuits that function as specified within growing populations. Additionally, these models can be deployed to regulate single-cell processes such that desirable dynamics emerge at the scale of populations and consortia.

Application in Bioproduction

We will apply the methodology for bioproduction problems in which proteins that are hard to fold need to be produced. Overproducing such proteins impairs cellular growth, which creates couplings between single-cell and population processes and raises the need for feedback control in production.