Quantitative Analysis of Metabolic and Regulatory Networks of Cellular Systems

For a better understanding of cell growth and product formation in animal cell culture, comprehensive quantitative data sets are collected over the cultivation process [1-3]. These data can give insight into the morphology of cells, their growth state, and their metabolism. Virus infected cells are adding another dimension to the complexity of the bioprocess. Here, virus replication can dramatically affect cell growth and metabolism depending on cell line and virus strain. Additionally, infection conditions, multiplicity of infection, quasi-species character of virus populations, and accumulation of defective interfering virus particles can lead to a multidimensional dynamic network where mathematical models can help to simulate and explain the observed experimental findings.

The cellular network:

Cell physiology - Cell size, cell count, cell cycle, apoptosis...

Intracellular metabolites - Nucleotides, glycolytic intermediates, TCA intermediates, hexosamine pathway...

Extracellular metabolites - Substrates (pyruvate, glucose, amino acids, oxygen), inhibitors, Products (lactate, ammonia, virus)

Enzyme activities - intracellular enzyme activity, Virus, Virus titer, intracellular virus replication, defective interfering particles

Fig. 1 Extracellular (orange and yellow) and intracellular (red) metabolites build together with enzyme kinetics the metabolic cell network. Viral infections can affect the cell network on multiple levels depending on cell line and virus type. — **Fig. 1** Extracellular (orange and yellow) and intracellular (red) metabolites build together with enzyme kinetics the metabolic cell network. Viral infections can affect the cell network on multiple levels depending on cell line and virus type.

© MPI Magdeburg (BPE)

**Fig. 1** Extracellular (orange and yellow) and intracellular (red) metabolites build together with enzyme kinetics the metabolic cell network. Viral infections can affect the cell network on multiple levels depending on cell line and virus type.

© MPI Magdeburg (BPE)

References

Janke, R.; Genzel, Y.; Wahl, A.; Reichl, U.: Measurement of Key Metabolic Enzyme Activities in Mammalian Cells Using Rapid and Sensitive Microplate-Based Assays. Biotechnology and Bioengineering 107 (3), pp. 566 - 581 (2010)

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Schulze-Horsel, J.; Schulze, M.; Agalaridis, G.; Genzel, Y.; Reichl, U.: Infection dynamics and virus-induced apoptosis in cell culture-based influenza vaccine production – flow cytometry and mathematical modeling. Vaccine 27 (20), pp. 2712 - 2722 (2009)

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Ritter, J. B.; Genzel, Y.; Reichl, U.: High-performance anion-exchange chromatography using on-line electrolytic eluent generation for the determination of more than 25 intermediates from energy metabolism of mammalian cells in culture. Journal of Chromatography B 843 (2), pp. 216 - 226 (2006)

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Genzel, Y.; König, S.; Reichl, U.: Amino acid analysis in mammalian cell culture media containing serum and high glucose concentrations by anion exchange chromatography and integrated pulsed amperometric detection. Analytical Biochemistry 335, pp. 119 - 125 (2004)

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