Lundi 13 juin 2022


Organisme intervenant (ou équipe pour les séminaires internes)
Theoretical Biophysics Group, Humboldt University, Berlin
Nom intervenant
Ana Bulović
Modelling of stress and growth in E. coli

Bacterial hosts, and Escherichia coli in particular, are used extensively for the production of industrial recombinant protein. The stress induced in the cells by this procedure is systemic - it introduces radical changes in the finely tuned system of mRNA and protein expression. Due to the complex and interwoven nature of the bacterial cell, it is no simple thing to understand the type and extent of these changes. This thesis deals with the problem of understanding and modeling such stress conditions, in which the entire cellular state is grossly affected.
I have attempted to tackle this problem in a number of ways. I first model and analyze the regulatory mechanisms involved in the cellular response to the stress provoked by recombinant protein expression, and show that, despite its apparent complexity, it has some unexpected and "simple" properties. Afterwards I shift the emphasis from regulation to cellular investment of resources. Since bioproduction is resource-wise very costly, it is reasonable to expect that many stress effects are due to the shifts in resource investment brought on by the genetic modification of the bacterium. For this purpose, I develop and calibrate a steady-state whole-cell model of E. coli. It is implemented in Resource Balance Analysis, a modeling framework able to realistically represent the cost of cellular events and account for a number of constraints under which cells operate - those of energy, efficiency and space - which lead to resource-related cellular decisions. This models shows good predictive power and because of its scope, level of detail and ease of manipulation, it can be used to assist experimental design in bioproduction. Lastly, I create a model whose purpose is to test whether the regulation of the bioproduction-induced stress responses can be explained by the tendency of the cell to implement resource strategies optimal for growth. For this purpose, I develop a simple time-resolved model of the heat shock response which takes into account the cellular constraints of energy, efficiency and space. I show that the obtained response to stress under the assumption of parsimonious resource allocation closely resembles one determined by experiment. The conclusions drawn from the three modeling approaches show that integrating the idea of resource allocation into cell models can help shed light on many regulatory events and adaptations taking place during bioproduction, and the tools developed in this thesis can help optimize the process of recombinant protein expression in Escherichia coli.


Salle de réunion 142, bâtiment 210
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