Dataset Information

Dynamic Modeling of CHO Cell Metabolism Using the Hybrid Cybernetic Approach With a Novel Elementary Mode Analysis Strategy.

ABSTRACT: Chinese hamster ovary (CHO) cell culture has a major importance on the production of biopharmaceuticals, including recombinant therapeutic proteins such as monoclonal antibodies (MAb). Mathematical modeling of biological systems can successfully assess metabolism complexity while providing logical and systematic methods for relevant genetic target and culture parameter identification toward cell growth and productivity improvements. Most modeling approaches on CHO cells have been performed under stationary constraints, and only a few dynamic models have been presented on simplified reaction sets, due to substantial overparameterization problems. The hybrid cybernetic modeling (HCM) approach has been recently used to describe the dynamic behavior by incorporating regulation between different metabolic states by elementary mode participation control, with sets of equations evaluated by objective functions. However, as metabolic networks evaluated are constructed toward a genomic scale, and cell compartmentalization is considered, identification of the active set becomes more difficult as EM number exponentially grows. Thus, the development of robust approaches for EM active set selection and analysis with smaller computational requirements is required to impulse the use of cybernetic modeling on larger up to genome-scale networks. In this report, a novel elementary mode selection strategy, based on a polar representation of the convex solution space is presented and coupled to a cybernetic approach to model the dynamic physiologic and metabolic behavior of CHO-S cell cultures. The proposed Polar Space Yield Analysis (PSYA) was compared to other reported elementary mode selection approaches derived from Common Metabolic Objective Analysis (CMOA) used in Flux Balance Analysis (FBA), Yield Space Analysis (YSA), and Lumped Yield Space Analysis (LYSA). For this purpose, exponential growth phase dynamic metabolic models were calculated using kinetic rate equations based on previously modeled growth parameters. Finally, complete culture dynamic metabolic flux models were constructed using the HCM approach with selected elementary mode sets. The yield space elementary mode- and the polar space elementary mode- hybrid cybernetic models presented the best fits and performances. Also, a flux reaction perturbation prediction approach based on the polar yield solution space resulted useful for metabolic network flux distribution capability analysis and identification of potential genetic modifications targets.

SUBMITTER: Martinez JA

PROVIDER: S-EPMC7174696 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dynamic Modeling of CHO Cell Metabolism Using the Hybrid Cybernetic Approach With a Novel Elementary Mode Analysis Strategy.

Martínez Juan A JA Bulté Dubhe B DB Contreras Martha A MA Palomares Laura A LA Ramírez Octavio T OT

Frontiers in bioengineering and biotechnology 20200415

Chinese hamster ovary (CHO) cell culture has a major importance on the production of biopharmaceuticals, including recombinant therapeutic proteins such as monoclonal antibodies (MAb). Mathematical modeling of biological systems can successfully assess metabolism complexity while providing logical and systematic methods for relevant genetic target and culture parameter identification toward cell growth and productivity improvements. Most modeling approaches on CHO cells have been performed under ...[more]

PMID: 32351947

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Project description:Decision-making is a high-level cognitive process based on cognitive processes like perception, attention, and memory. Real-life situations require series of decisions to be made, with each decision depending on previous feedback from a potentially changing environment. To gain a better understanding of the underlying processes of dynamic decision-making, we applied the method of cognitive modeling on a complex rule-based category learning task. Here, participants first needed to identify the conjunction of two rules that defined a target category and later adapt to a reversal of feedback contingencies. We developed an ACT-R model for the core aspects of this dynamic decision-making task. An important aim of our model was that it provides a general account of how such tasks are solved and, with minor changes, is applicable to other stimulus materials. The model was implemented as a mixture of an exemplar-based and a rule-based approach which incorporates perceptual-motor and metacognitive aspects as well. The model solves the categorization task by first trying out one-feature strategies and then, as a result of repeated negative feedback, switching to two-feature strategies. Overall, this model solves the task in a similar way as participants do, including generally successful initial learning as well as reversal learning after the change of feedback contingencies. Moreover, the fact that not all participants were successful in the two learning phases is also reflected in the modeling data. However, we found a larger variance and a lower overall performance of the modeling data as compared to the human data which may relate to perceptual preferences or additional knowledge and rules applied by the participants. In a next step, these aspects could be implemented in the model for a better overall fit. In view of the large interindividual differences in decision performance between participants, additional information about the underlying cognitive processes from behavioral, psychobiological and neurophysiological data may help to optimize future applications of this model such that it can be transferred to other domains of comparable dynamic decision tasks.

Project description:Introduction: Hybrid modeling combining First-Principles with machine learning is becoming a pivotal methodology for Biopharma 4.0 enactment. Chinese Hamster Ovary (CHO) cells, being the workhorse for industrial glycoproteins production, have been the object of several hybrid modeling studies. Most previous studies pursued a shallow hybrid modeling approach based on three-layered Feedforward Neural Networks (FFNNs) combined with macroscopic material balance equations. Only recently, the hybrid modeling field is incorporating deep learning into its framework with significant gains in descriptive and predictive power. Methods: This study compares, for the first time, deep and shallow hybrid modeling in a CHO process development context. Data of 24 fed-batch cultivations of a CHO-K1 cell line expressing a target glycoprotein, comprising 30 measured state variables over time, were used to compare both methodologies. Hybrid models with varying FFNN depths (3-5 layers) were systematically compared using two training methodologies. The classical training is based on the Levenberg-Marquardt algorithm, indirect sensitivity equations and cross-validation. The deep learning is based on the Adaptive Moment Estimation Method (ADAM), stochastic regularization and semidirect sensitivity equations. Results and conclusion: The results point to a systematic generalization improvement of deep hybrid models over shallow hybrid models. Overall, the training and testing errors decreased by 14.0% and 23.6% respectively when applying the deep methodology. The Central Processing Unit (CPU) time for training the deep hybrid model increased by 31.6% mainly due to the higher FFNN complexity. The final deep hybrid model is shown to predict the dynamics of the 30 state variables within the error bounds in every test experiment. Notably, the deep hybrid model could predict the metabolic shifts in key metabolites (e.g., lactate, ammonium, glutamine and glutamate) in the test experiments. We expect deep hybrid modeling to accelerate the deployment of high-fidelity digital twins in the biopharma sector in the near future.

Dataset Information

Dynamic Modeling of CHO Cell Metabolism Using the Hybrid Cybernetic Approach With a Novel Elementary Mode Analysis Strategy.

Publications

Dynamic Modeling of CHO Cell Metabolism Using the Hybrid Cybernetic Approach With a Novel Elementary Mode Analysis Strategy.

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