Gaining an understanding of the cellular processes underlying bacterial growth is crucial for fundamental research in biology as well as for applications in biotechnology, health, and environmental technology. Growth laws have been formulated that relate growth rate to the macromolecular composition of the cell, reflecting cellular resource allocation. These results, however, do not consider variability across an isogenic population. New experimental technologies have been developed to monitor growth and gene expression at the single-cell level, opening the path to the exploration of the origins of variability in growth phenotypes. So far, these technological breakthroughs have been exploited only in part, in studies of cellular resource allocation at an average population level. Appropriate mathematical models and methods to relate single-cell resource allocation with the emergence of growth variability in a population are missing.
The ARBOREAL project aims at developing a new mathematical framework for the analysis of growth variability from single-cell data, by combining structured branching processes with models of resource allocation at the single-cell level. We will obtain a new class of stochastic individual-based models, called Branching Resource allocation Processes (BRP), that will enable investigation of the variability of growth phenotypes in a proliferating microbial population in terms of the variability of physiological and cell division processes. Driven as a reference case-study by our own datasets from microfluidics experiments, comprising single-cell measurements of growth and expression levels of ribosomes and enzymes in Escherichia coli carbon and energy metabolism, the development of the BRP framework will entail modelling, analysis, inference and application objectives.
Starting from existing resource allocation models, we will develop multi-scale models relating single-cell resource allocation with growth variability. The first level will consist of molecular processes taking place in individual cells, while the second level will account for the growth of the cellular population, via cellular division. These hierarchical models will be analyzed by means of analytical and simulation methods. We will study dynamics and long-term behaviour of BRPs and the propagation of variability of intracellular processes to growth phenotypes across lineages. We will next develop inference tools for the reconstruction of BRP models from parallel single-cell growth and gene expression data. We will then apply this framework to our datasets to investigate the relation between single-cell resource allocation and growth variability in E. coli.
The scientific coordinator of ARBOREAL, Aline Marguet, is an applied mathematician, with an expertise on branching processes and mathematical biology. The project is conducted by an interdisciplinary scientific team, including experts in mathematical modelling and statistical inference, computational biology and microbiology.
ARBOREAL is an ambitious, interdisciplinary research project, bringing together concepts and competences from applied mathematics (probability theory and statistics) and microbial systems biology. It addresses difficult and timely problems at the interface of these disciplines, with contributions on both the biological and the mathematical side. ARBOREAL is expected to have a substantial impact on the modelling approaches adopted by the community for the study of single-cell processes in bacterial populations, opening the path to an in-depth exploration of the emergence of variability in bacterial populations, and a foreseen long-term impact in biotechnology (design of bioproduction processes) and health (antibiotics resistance).
