Abstract
When realistic mathematical models of whole body metabolism eventually become available, they are likely to add entirely new dimensions to the understanding of the integrated physiological function of the organism, in particular the mechanisms governing the regulation of transitions between different physiological states, like fed-fasted, exercise-rest and normal-diseased. So far the strategy for whole body modelling has primarily been a bottom-up approach where the central problem is an apparently insurmountable barrier of complexity involved in defining and optimising the huge number of parameters. Here we follow a top-down strategy and present a complete mathematical framework for realistic whole body model development. The approach proposed is modular and hierarchical and whole body metabolism is taken as the top level. Next are the organs, where the sum of the contributions from the individual organs must equal the top level metabolism. This hierarchy can be extended to lower levels of organisation, i.e. clusters of cells, individual cells, organelle and individual pathways. Exploiting this hierarchy, metabolism at each level forms an absolute constraint on the contributions from lower level. Importantly, these constraints can in many ways be defined experimentally through mass balance and flux data. Furthermore, the constrained approach allows the lower level models to be developed independently and subsequently adapted to the whole body model. The paper describes the process of whole body modelling in practical terms, centred on a mathematical framework, devised to allow whole-body models of any complexity to be developed. Furthermore, an example of sub-model incorporation in the whole-body framework is illustrated by adapting an existing erythrocyte model to the whole body constraints. Finally, we illustrate the operation of the system by including two sets of whole-body data from humans, reflecting two different physiological states.
Highlights
The development of mathematical models that can describe the overall metabolism of a human will be a milestone for biosimulation but is likely to add completely new dimensions to the understanding of the dynamics of the integrated metabolic and physiological function in health and disease.The human and other mammalian organisms are naturally compartmentalised, composed of a number of organs with specialised physiological and metabolic functions
When realistic mathematical models of whole body metabolism eventually become available, they are likely to add entirely new dimensions to the understanding of the integrated physiological function of the organism, in particular the mechanisms governing the regulation of transitions between different physiological states, like fed-fasted, exercise-rest and normal-diseased
The approach proposed is modular and hierarchical and whole body metabolism is taken as the top level
Summary
The development of mathematical models that can describe the overall metabolism of a human will be a milestone for biosimulation but is likely to add completely new dimensions to the understanding of the dynamics of the integrated metabolic and physiological function in health and disease. The modelling strategy developed in this communication, exploits the natural compartmentation into organs to facilitate parameter estimation: The integrated function of each individual organ can in principle be studied in vivo by applying the Fick principle [40] by multiplying arterio-venous concentration differences with blood flow across the organ This experimental approach has been applied extensively in the study of organ physiology in the past and more recently to study of brain energy metabolism as well as muscle-brain interactions providing data on the global metabolism of the human brain in vivo [41,42,43] at a time resolution of less than five seconds [44]. The mathematical tools for adapting specific organ models as modules of the whole-body model are presented
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