Milestones of the Modeling of Human Physiology

An overview of about 70-year research efforts in area of mathematical modeling of human physiology is provided.The overview has two goals:(1)to recognize the main advantages and causes of disadvantages or disappointments;(2)to distinguish the most promising approach for creating future models.Until recently,efforts in the modeling of quantitative physiology were concentrated on the solving of three main types of tasks:(1)how to establish the input-output dynamic characteristics of a given isolated organ or isolated anatomical-functional system(AFS);(2)how to create a computer-based simulator of physiological complex systems(PCM)containing many organs and AFSs;and(3)how to create multi-scale models capable of simulating and explaining causalities in organs,AFSs,PCMs,and in the entire organism in terms that will allow using such models for simulating pathological scenarios(the“Physiome”project)too.The critical analysis of the modeling experience and recent physiological concepts convinced us that the platform provided by the paradigm of physiological super-systems(PPS)looks like the most promising platform for further modeling.PPS causally combines activities of specific intracellular mechanisms(self-tunable but of limited capacities)with their extracellular enhancers.The enhancement appears due to the increase of nutrients incomes toward cells affected because of low energy and inadequate chemical composition of cytoplasm.Every enhancer has its activator chemicals released by the affected cells.In fact,PPS,indicating causal relationships between cellscale and upper-scales(in organs,AFSs,PCMs)physiological activities,is the single platform for future models.They must definitely describe when and how the bottom-to-up information flows do appear and how is the organism-scale adaptation activated against destructive trends in cells.

The Optimal Coexistence of Cells:How Could Human Cells Create The Integrative Physiology

A general view of human physiology is proposed.Each of 220 cell types must provide its intimate functions despite occasional or chronic obstacles created by other cells.The physiological mechanisms are independently emerged and evolutionarily saved due to their ability to provide optimal-like coexistence of cells on a background of destructive challenges of external/internal environments.In certain limits,both cells and organs are adaptive.The cell has accumulated both passive adaptation mechanisms mainly parallel working in the biochemistry,and active physiological mechanisms fighting for the optimal cell metabolism.Its rate depends on the cell type and current phase into the cell cycle.The adaptive properties of organs and their functional systems have resulted from the cells’adaptivity.The impaired cells(under energy lack and/or contaminated cytoplasm)produce adaptation factors acting both in the cell and at multiple organism-scales.Multicellular mechanisms,enhancing the cell fight for energy balance,creating the due cytoplasm for optimizing metabolism,force the most physiological characteristics,including the mean arterial pressure to fluctuate or shift.The view is a basis for re-thinking the concept of the socalled physiological norm and fundamental mechanisms of age-associated pathologies,in particular,hypertension.

Several Theoretical and Applied Problems of Human Extreme Physi­ology:Mathematical Modeling

Human cardiovascular system(CVS)and hemodynamics are critically sensitive to essential alterations of mechanical inertial forces in directions of head-legs(+Gz)or legs-head(-Gz).Typically,such alterations appear during pilotage maneuvers of modern high maneuverable airspace vehicles(HMAV).The vulnerability of pilots or passengers of HMAV to these altering forces depends on their three main characteristics:amplitude,dynamics,and duration.Special protections,proposed to minimize this vulnerability,should be improved in parallel with the increasing of these hazardous characteristics of HMAVs.Empiric testing of novel protection methods and tools is both expensive and hazardous.Therefore computer simulations are encouraged.Autonomic software(AS)for simulating and theoretical investigating of the main dynamic responses of human CVS to altering Gz is developed.AS is based on a system of quantitative mathematical models(QMM)consisting of about 1300 differential and algebraic equations.QMM describes the dynamics of both CVS(the cardiac pump function,baroreceptor control of parameters of cardiovascular net presented by means of lumped parameter vascular compartments)and non-biological variables(inertial forces,and used protections).The main function of AS is to provide physiologist-researcher by visualizations of calculated additional data concerning characteristics of both external and internal environments under high sustained accelerations and short-time microgravity.Additionally,AS can be useful as an educational tool able to show both researchers and young pilots the main hemodynamic effects caused by accelerations and acute weightlessness with and without use of different protection tools and technics.In this case,AS does help users to optimize training process aimed to ensure optimal-like human tolerance to the altered physical environment.Main physiological events appearing under different scenarios of accelerations and microgravity have been tested.

Modeling of Mechanisms Providing the Overall Control of Human Circulation

Multiple humoral and nervous mechanisms,each influencing the cardiovascular system(CVS)with its specific dynamics and power,had been evolutionarily saved both in animals and in human organisms.Most of such mechanisms are considered to be controllers of CVS’s function,but there is no concept clearly explaining the interaction of global and local controllers in intact human organisms under physiological or pathological conditions.Methodological and ethical constraints create practically insuperable obstacles while experiments on animals mainly concern artificial situations with certain switched-of mechanisms.Currently,mathematical modeling and computer simulations provide the most promising way for expanding and deepening our understanding of regulators’interactions.As most of CVS’s models describe only partial control mechanisms,a special model(SM)capable of simulating every combination of control mechanisms is encouraged.This paper has three goals:i)to argue the uncial modeling concept and its physiological basis,ii)to describe SM,and iii)to give basic information about SM’s test research.SM describes human hemodynamics,which is under influence of arterial baroreceptor reflexes,peripheral chemoreceptor reflexes,central(cRAS)and local(lRAS)renin-angiotensin systems,local ischemia,and autoregulation of total brain flow.SM,performed in form of special software(SS),is tested under specific endogenous and/or exogenous alterations.The physiologist using SS can easily construct the desirable configuration of regulator mechanisms,their actual state,and scenarios of computer experiments.Tests illustrated the adequateness of SM,are the first step of SM’s research.Nuances of the interaction of modeled regulator mechanisms have to be illustrated in special publications.