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Novel column generation-based optimization approach for poly-pathway kinetic model applied to CHO cell culture
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Industrial Biotechnology. AdBIOPRO, VINNOVA Competence Centre for Advanced Bioproduction by Continuous Processing, Sweden. (Cell Technology Group)
KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Industrial Biotechnology. AdBIOPRO, VINNOVA Competence Centre for Advanced Bioproduction by Continuous Processing, Sweden. (Cell Technology Group)
KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory.ORCID iD: 0000-0002-6252-7815
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2019 (English)In: Metabolic Engineering Communications, ISSN 2214-0301, Vol. 8, article id e00083Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 8, article id e00083
Keywords [en]
Amino acid, Chinese hamster ovary cell, Column generation, Elementary flux mode, Kinetic modelling, Metabolic flux analysis, Optimization, Poly-pathway model
National Category
Bioinformatics (Computational Biology)
Identifiers
URN: urn:nbn:se:kth:diva-246415DOI: 10.1016/j.mec.2018.e00083ISI: 2-s2.0-85061356952OAI: oai:DiVA.org:kth-246415DiVA, id: diva2:1301460
Note

QC 20190402

Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-10-04Bibliographically approved

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Hagrot, ErikaForsgren, Anders

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