Novel column generation-based optimization approach for poly-pathway kinetic model applied to CHO cell culture

Erika Hagrot; Hildur Æsa Oddsdóttir; Meeri Mäkinen; Anders Forsgren; Véronique Chotteau

doi:10.1016/j.mec.2018.e00083

Novel column generation-based optimization approach for poly-pathway kinetic model applied to CHO cell culture

Metab Eng Commun. 2018 Dec 25:8:e00083. doi: 10.1016/j.mec.2018.e00083. eCollection 2019 Jun.

Authors

Erika Hagrot^{1

2}, Hildur Æsa Oddsdóttir³, Meeri Mäkinen^{1

2}, Anders Forsgren³, Véronique Chotteau^{1

2

4}

Affiliations

¹ Cell Technology Group, Department of Industrial Biotechnology/Bioprocess Design, School of Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.
² AdBIOPRO, VINNOVA Competence Centre for Advanced Bioproduction by Continuous Processing, Sweden.
³ Department of Mathematics, Division of Optimization and Systems Theory, KTH Royal Institute of Technology, Stockholm, Sweden.
⁴ WCPR, Wallenberg Centre for Protein Research, Sweden.

Abstract

Mathematical modelling can provide precious tools for bioprocess simulation, prediction, control and optimization of mammalian cell-based cultures. In this paper we present a novel method to generate kinetic models of such cultures, rendering complex metabolic networks in a poly-pathway kinetic model. The model is based on subsets of elementary flux modes (EFMs) to generate macro-reactions. Thanks to our column generation-based optimization algorithm, the experimental data are used to identify the EFMs, which are relevant to the data. Here the systematic enumeration of all the EFMs is eliminated and a network including a large number of reactions can be considered. In particular, the poly-pathway model can simulate multiple metabolic behaviors in response to changes in the culture conditions. We apply the method to a network of 126 metabolic reactions describing cultures of antibody-producing Chinese hamster ovary cells, and generate a poly-pathway model that simulates multiple experimental conditions obtained in response to variations in amino acid availability. A good fit between simulated and experimental data is obtained, rendering the variations in the growth, product, and metabolite uptake/secretion rates. The intracellular reaction fluxes simulated by the model are explored, linking variations in metabolic behavior to adaptations of the intracellular metabolism.

Keywords: Amino acid; Chinese hamster ovary cell; Column generation; Elementary flux mode; Kinetic modelling; Metabolic flux analysis; Optimization; Poly-pathway model.