A Multi-Scale Model of the Whole Human Body based on Dynamic Parsimonious Flux Balance Analysis

Toroghi, Masood Khaksar; Cluett, William R.; Mahadevan, Radhakrishnan

doi:10.1016/j.ifacol.2016.07.319

Cited by 17 publications

(14 citation statements)

References 16 publications

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“…The computational efficiency of the integration algorithm has been shown in our previous study [5]. Also, the applications of the modelling framework have been demonstrated to biomarker identification and blood alcohol concentration prediction in our previous studies [5,6]. In both studies, a single objective function has been used in the parsimonious flux…”

Section: Methodsmentioning

confidence: 92%

“…Research has shown that in the majority of metabolic models that are based on the constraint-based modelling approach, a single function of the living organism has been considered in the simulation analysis [5,6]. In other words, in the analysis, a single objective function is solved at a time [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…In this paper, we have presented a new computational approach to include multiple functions of the human hepatocyte cells in the whole body metabolism framework. The algorithm is an extension of our previous study, presenting a multi-scale whole body metabolic model [5]. The computational efficiency of the integration algorithm has been demonstrated using several in silico studies.…”

Section: Introductionmentioning

confidence: 99%

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A Multi-Scale Modelling Framework of the Whole Human Body Based on Multi-Objective Functions

Khaksar

Cluett

Mahadevan

2018

Preprint

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Constraint-based multi-scale metabolic models are powerful tools to study complex biological systems like the human body, and to develop new treatment strategies for human diseases. They capture different scales of the system under study and provide the opportunity of understanding the interaction between multiple scales. In this paper, we have used our previously developed multi-scale whole body metabolism framework to establish a new approach to include multiple objectives of the human cells in computational analysis. The model has 3555 ordinary differential equations (ODEs) integrated with a genome-scale model of the hepatocyte, including 1826 biochemical reactions. The model has been solved for 74 objective functions simultaneously.Simulation results show that the integration algorithm has promise with respect to convergence, computational efficiency and response to perturbation. The results suggest that this method holds significant potential for the simulation of the range of metabolic phenotypes for mammalian cells where there are multiple objectives.

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Section: Methodsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Multi-Scale Modelling Framework of the Whole Human Body Based on Multi-Objective Functions

Khaksar

Cluett

Mahadevan

2018

Preprint

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“…We chose to use the significant components as features instead of performing feature selection on the whole-body fluxes as the main question was the assessment of the dWBM model sensitivity towards glucose and insulin challenges and the subsequent whole-body metabolic shift. Furthermore, the activated reaction fluxes in each time step are among many possible solutions in the AOS space and cannot be used as conclusive evidence of the disrupted metabolic pathways in T1D and healthy models, even though pFBA considerably reduces the AOS space (Toroghi et al, 2016). We addressed the question of disrupted metabolic pathways in T1D by performing FVA in T1D and healthy models and using all solution vectors of the AOS as a basis for comparison.…”

Section: Tolerance Testsmentioning

confidence: 99%

“…Therefore, in each time step, the solution of the linear program can be distant from the previous solution, which compromises the smoothness of dynamical simulations in large-scale metabolic models. We addressed this issue by i) performing pFBA 39 in each time step to obtain a reduced AOS space as previously suggested (Toroghi et al, 2016);…”

Section: The Simulation Algorithm Cronicsmentioning

confidence: 99%

Pan-organ model integration of metabolic and regulatory processes in type 1 diabetes

Guebila

Thiele

2019

Preprint

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Type 1 diabetes mellitus (T1D) is a systemic disease triggered by a local autoimmune inflammatory reaction in insulin-producing cells that disrupts the glucose-insulin-glucagon system and induces organ-wide, long-term effects on glycolytic and nonglycolytic processes.Mathematical modeling of the whole-body regulatory bihormonal system has helped to identify intervention points to ensure better control of T1D but was limited to a coarse-grained representation of metabolism. To extend the depiction of T1D, we developed a whole-body model using a novel integrative modeling framework that links organ-specific regulation and metabolism. The developed framework allowed the correct prediction of disrupted metabolic processes in T1D, highlighted pathophysiological processes common with neurodegenerative disorders, and suggested calcium channel blockers as potential adjuvants for diabetes control. Additionally, the model predicted the occurrence of insulin-dependent rewiring of interorgan crosstalk. Moreover, a simulation of a population of virtual patients allowed an assessment of the impact of inter and intraindividual variability on insulin treatment and the implications for clinical outcomes. In particular, GLUT4 was suggested as a potential pharmacogenomic regulator of intraindividual insulin efficacy. Taken together, the organ-resolved, dynamic model may pave the way for a better understanding of human pathology and model-based design of precise allopathic strategies.Therefore, systematic analyses of disrupted metabolic processes beyond glycolysis in T1D require extended approaches. To better capture metabolism, we used an whole-body organresolved reconstruction of human metabolism (WBM reconstruction) (Thiele et al., 2018), which was built using the comprehensive, but generic human metabolic reconstruction (Brunk et al., 2018). The male WBM reconstruction includes the comprehensively known metabolic pathways for 20 organs, two sex organs, and six blood cells, which are anatomically accurately interconnected. Through the integration of condition-specific information, aka constraints, such as diet, gene expression, or physiological parameters, the WBM reconstruction can be converted into a personalized, condition-specific WBM model . Consequently, the male WBM model enables the simulation of carbohydrate disorders and the investigation of their impact on nonglycolytic pathways. Thereby, the WBM reconstruction provides a complete picture of organ-resolved human metabolism. However, addressing the disease dynamics and patient responses to insulin requires the modeling of metabolic pathways and nonmetabolic processes as well as insulin receptor binding, signal transduction, and internalization of receptors. Recently, multiscale, multialgorithm, whole-organism dynamic models in biology, primarily models of microbiology (Bauer and Thiele, 2018; Bauer et al., 2017; Covert et al., 2008; Karr et al., 2012), plant physiology (Grafahrend-Belau et al., 2013), human physiology and xenobiotic metabolism (Cordes et al., 2018; Gueb...

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Adaption of Generic Metabolic Models to Specific Cell Lines for Improved Modeling of Biopharmaceutical Production and Prediction of Processes

Calmels

Joshi

Lewis

et al. 2019

Cell Culture Engineering

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A Multi-Scale Model of the Whole Human Body based on Dynamic Parsimonious Flux Balance Analysis

Cited by 17 publications

References 16 publications

A Multi-Scale Modelling Framework of the Whole Human Body Based on Multi-Objective Functions

A Multi-Scale Modelling Framework of the Whole Human Body Based on Multi-Objective Functions

Pan-organ model integration of metabolic and regulatory processes in type 1 diabetes

Adaption of Generic Metabolic Models to Specific Cell Lines for Improved Modeling of Biopharmaceutical Production and Prediction of Processes

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