A conceptual review on systems biology in health and diseases: from biological networks to modern therapeutics

Human physiology is an ensemble of various biological processes spanning from intracellular molecular interactions to the whole body phenotypic response. Systems biology endures to decipher these multi-scale biological networks and bridge the link between genotype to phenotype. The structure and dynamic properties of these networks are responsible for controlling and deciding the phenotypic state of a cell. Several cells and various tissues coordinate together to generate an organ level response which further regulates the ultimate physiological state. The overall network embeds a hierarchical regulatory structure, which when unusually perturbed can lead to undesirable physiological state termed as disease. Here, we treat a disease diagnosis problem analogous to a fault diagnosis problem in engineering systems. Accordingly we review the application of engineering methodologies to address human diseases from systems biological perspective. The review highlights potential networks and modeling approaches used for analyzing human diseases. The application of such analysis is illustrated in the case of cancer and diabetes. We put forth a concept of cell-to-human framework comprising of five modules (data mining, networking, modeling, experimental and validation) for addressing human physiology and diseases based on a paradigm of system level analysis. The review overtly emphasizes on the importance of multi-scale biological networks and subsequent modeling and analysis for drug target identification and designing efficient therapies.     

The power of fitness in mammals: perceptions from the African slipstream

Evolutionary physiology is the emerging physiological discipline. Unlike environmental physiology or ecophysiology, whose definitions have long been made quite clear, evolutionary physiology has a broader scope of objectives, and its definition lacks a concise treatise. This paper presents the argument that the lack of a common definition of evolutionary physiology is retarding the unification of the mechanistic and amechanistic physiological sciences, a multidisciplinary obligation crucial for a holistic understanding of a physiological basis of fitness. The divide between mechanistic "how" questions, devoted primarily to homeostasis, and evolutionary "why" questions, concerned with understanding phenotypic and genotypic physiological variation, remains broad and is currently not conducive to synergy in the physiological disciplines. Unification may be facilitated, however, by embracing a common currency of measurement and analysis. A likely candidate is the cascade of energy from the environment to offspring and the evolution of physiological form and function, including homeostasis, associated with power management. This currency approach seeks to identify an energetic basis of fitness, namely, whether or how the evolution of life-history traits is influenced by energetic constraints and/or trade-offs.     

Integrated analysis of metabolic phenotypes in Saccharomyces cerevisiae

Background  

The yeast Saccharomyces cerevisiae is an important microorganism for both industrial processes and scientific research. Consequently, there have been extensive efforts to characterize its cellular processes. In order to fully understand the relationship between yeast's genome and its physiology, the stockpiles of diverse biological data sets that describe its cellular components and phenotypic behavior must be integrated at the genome-scale. Genome-scale metabolic networks have been reconstructed for several microorganisms, including S. cerevisiae, and the properties of these networks have been successfully analyzed using a variety of constraint-based methods. Phenotypic phase plane analysis is a constraint-based method which provides a global view of how optimal growth rates are affected by changes in two environmental variables such as a carbon and an oxygen uptake rate. Some applications of phenotypic phase plane analysis include the study of optimal growth rates and of network capaCity and function.     

Physics and the canalization of morphogenesis: a grand challenge in organismal biology

Morphogenesis takes place against a background of organism-to-organism and environmental variation. Therefore, fundamental questions in the study of morphogenesis include: How are the mechanical processes of tissue movement and deformation affected by that variability, and in turn, how do the mechanic of the system modulate phenotypic variation? We highlight a few key factors, including environmental temperature, embryo size and environmental chemistry that might perturb the mechanics of morphogenesis in natural populations. Then we discuss several ways in which mechanics-including feedback from mechanical cues-might influence intra-specific variation in morphogenesis. To understand morphogenesis it will be necessary to consider whole-organism, environment and evolutionary scales because these larger scales present the challenges that developmental mechanisms have evolved to cope with. Studying the variation organisms express and the variation organisms experience will aid in deciphering the causes of birth defects.     

Pattern and process: evidence for the evolution of photosynthetic traits in natural populations

The patterns of interspecific variation identified by comparative studies provide valuable hypotheses about the role of physiological traits in evolutionary adaptation. This review covers tests of these hypotheses for photosynthetic traits that have used a microevolutionary perspective to characterize physiological variation among and within populations. Studies of physiological differentiation among populations show that evolutionary divergence in photosynthetic traits is common within species, and has a pattern that supports many adaptive hypotheses. These among-population studies imply that selection has influenced photosynthetic traits in some way, but they are not designed to identify the traits targeted by selection or the environmental agents that cause selection. Analyses of genetic and phenotypic variation within populations address these questions. Studies that have quantified genetic variation within populations show that levels of heritable variation can be adequate for evolutionary change in photosynthetic traits. Other studies have measured phenotypic selection for these traits by analyzing how the variation within populations is correlated with fitness. This work has shown that selection for photosynthetic traits may often operate indirectly via correlations with other traits, and emphasizes the importance of viewing the phenotype as an integrated function of growth, morphology, life-history and physiology. We also outline some methodological problems that may be encountered for ecophysiological traits by these types of studies, provide some potential solutions, and discuss future directions for the field of plant evolutionary ecophysiology.     

Variation in the link between oxygen consumption and ATP production,and its relevance for animal performance

It is often assumed that an animal''s metabolic rate can be estimated through measuring the whole-organism oxygen consumption rate. However, oxygen consumption alone is unlikely to be a sufficient marker of energy metabolism in many situations. This is due to the inherent variability in the link between oxidation and phosphorylation; that is, the amount of adenosine triphosphate (ATP) generated per molecule of oxygen consumed by mitochondria (P/O ratio). In this article, we describe how the P/O ratio can vary within and among individuals, and in response to a number of environmental parameters, including diet and temperature. As the P/O ratio affects the efficiency of cellular energy production, its variability may have significant consequences for animal performance, such as growth rate and reproductive output. We explore the adaptive significance of such variability and hypothesize that while a reduction in the P/O ratio is energetically costly, it may be associated with advantages in terms of somatic maintenance through reduced production of reactive oxygen species. Finally, we discuss how considering variation in mitochondrial efficiency, together with whole-organism oxygen consumption, can permit a better understanding of the relationship between energy metabolism and life history for studies in evolutionary ecology.     

Phenotypic plasticity for life history traits in Drosophila melanogaster. II. Epigenetic mechanisms and the scaling of variances

Abstract We manipulated developmental time and dry weight at eclosion in 15 genotypes of Drosophila melanogaster by growing the larvae in 9 environments defined by 3 yeast concentrations at 3 temperatures. We observed how the genetic and various environmental components of phenotypic variation scaled with the mean values of the traits. Temperature, yeast, within-environmental factors and genotype influenced the genotypic and environmental standard deviations of the two traits in patterns that point to very different modes of physiological and developmental action of these factors. Since different factors affected the environmental and genetic components of the phenotypic variation either in parallel or inversely, we conclude that environmental heterogeneity may have small or large effects on evolutionary rates depending on which factors cause the heterogeneity. The analysis also suggests that the scaling of variances with the mean is not as trivial as is often assumed when coefficients of variation are computed to “standardize” variation.     

A reductionist approach to dissecting grain weight and yield in wheat

Grain yield is a highly polygenic trait that is influenced by the environment and integrates events throughout the life cycle of a plant. In wheat, the major grain yield components often present compensatory effects among them, which alongside the polyploid nature of wheat,makes their genetic and physiological study challenging. We propose a reductionist and systematic approach as an initial step to understand the gene networks regulating each individual yield component. Here, we focus on grain weight and discuss the importance of examining individual subcomponents, not only to help in their genetic dissection, but also to inform our mechanistic understanding of how they interrelate. This knowledge should allow the development of novel combinations, across homoeologs and between complementary modes of action, thereby advancing towards a more integrated strategy for yield improvement. We argue that this will break barriers in terms of phenotypic variation,enhance our understanding of the physiology of yield, and potentially deliver improved on-farm yield.     

Is the whole more than the sum of its parts? Evolutionary trade-offs between burst and sustained locomotion in lacertid lizards

Trade-offs arise when two functional traits impose conflicting demands on the same design trait. Consequently, excellence in one comes at the cost of performance in the other. One of the most widely studied performance trade-offs is the one between sprint speed and endurance. Although biochemical, physiological and (bio)mechanical correlates of either locomotor trait conflict with each other, results at the whole-organism level are mixed. Here, we test whether burst (speed, acceleration) and sustained locomotion (stamina) trade off at both the isolated muscle and whole-organism level among 17 species of lacertid lizards. In addition, we test for a mechanical link between the organismal and muscular (power output, fatigue resistance) performance traits. We find weak evidence for a trade-off between burst and sustained locomotion at the whole-organism level; however, there is a significant trade-off between muscle power output and fatigue resistance in the isolated muscle level. Variation in whole-animal sprint speed can be convincingly explained by variation in muscular power output. The variation in locomotor stamina at the whole-organism level does not relate to the variation in muscle fatigue resistance, suggesting that whole-organism stamina depends not only on muscle contractile performance but probably also on the performance of the circulatory and respiratory systems.     

Biomechanics of the lung parenchyma: critical roles of collagen and mechanical forces.

The biomechanical properties of connective tissues play fundamental roles in how mechanical interactions of the body with its environment produce physical forces at the cellular level. It is now recognized that mechanical interactions between cells and the extracellular matrix (ECM) have major regulatory effects on cellular physiology and cell-cycle kinetics that can lead to the reorganization and remodeling of the ECM. The connective tissues are composed of cells and the ECM, which includes water and a variety of biological macromolecules. The macromolecules that are most important in determining the mechanical properties of these tissues are collagen, elastin, and proteoglycans. Among these macromolecules, the most abundant and perhaps most critical for structural integrity is collagen. In this review, we examine how mechanical forces affect the physiological functioning of the lung parenchyma, with special emphasis on the role of collagen. First, we overview the composition of the connective tissue of the lung and their complex structural organization. We then describe how mechanical properties of the parenchyma arise from its composition as well as from the architectural organization of the connective tissue. We argue that, because collagen is the most important load-bearing component of the parenchymal connective tissue, it is also critical in determining the homeostasis and cellular responses to injury. Finally, we overview the interactions between the parenchymal collagen network and cellular remodeling and speculate how mechanotransduction might contribute to disease propagation and the development of small- and large-scale heterogeneities with implications to impaired lung function in emphysema.     

Sources of Variation in Physiological Phenotypes and Their Evolutionary Significance

We offer the thesis that environmental physiologists and evolutionarybiologists can find fertile common ground in the study of howindividual variation in physiological phenotypes originatesand develops. The sources of such individual variation are oftencomplex; the consequences affect how natural selection willact on a suite of traits, of which some may seem, at first glance,far removed from the usual domain of environmental physiology.We illustrate our thesis in two ways. First, we offer two examplesdrawn from studies of thermal tolerance in the poeciliid fishHeterandria formosa. We show how fitness variation can be acomplex function of the gestational temperature and thermaltolerance and how these effects can produce environmentallyinduced variation among populations in thermal tolerance thatmimics a pattern of adaptive variation. Second, we review twocase studies that illuminate how environmental effects on amultivariate phenotype can channel the action of natural selection.The phenotypic plasticity of male life history in Poecilia latipinnain response to temperature embraces a spectrum of traits; theeffects of each one upon fitness will influence the abilityof selection to mold the response of any one of them to temperature.The phenotypic covariances in thermal tolerance and life-historytraits in Heterandria formosa differ slightly between populationsfrom different parts of the species range, apparently becauseof differences between them in thermal sensitivity; this differenceinsures that the multivariate nature of selection will be correspondinglydifferent in those different populations.     

Phenotypic convergence along a gradient of predation risk

A long-standing question in ecology is whether phenotypic plasticity, rather than selection per se, is responsible for phenotypic variation among populations. Plasticity can increase or decrease variation, but most previous studies have been limited to single populations, single traits and a small number of environments assessed using univariate reaction norms. Here, examining two genetically distinct populations of Daphnia pulex with different predation histories, we quantified predator-induced plasticity among 11 traits along a fine-scale gradient of predation risk by a predator (Chaoborus) common to both populations. We test the hypothesis that plasticity can be responsible for convergence in phenotypes among different populations by experimentally characterizing multivariate reaction norms with phenotypic trajectory analysis (PTA). Univariate analyses showed that all genotypes increased age and size at maturity, and invested in defensive spikes (neckteeth), but failed to quantitatively describe whole-organism response. In contrast, PTA quantified and qualified the phenotypic strategy the organism mobilized against the selection pressure. We demonstrate, at the whole-organism level, that the two populations occupy different areas of phenotypic space in the absence of predation but converge in phenotypic space as predation threat increases.     

The other side of phenotypic plasticity: a developmental system that generates an invariant phenotype despite environmental variation

Understanding how the environment impacts development is of central interest in developmental and evolutionary biology. On the one hand, we would like to understand how the environment induces phenotypic changes (the study of phenotypic plasticity). On the other hand, we may ask how a development system maintains a stable and precise phenotypic output despite the presence of environmental variation. We study such developmental robustness to environmental variation using vulval cell fate patterning in the nematode Caenorhabditis elegans as a study system. Here we review both mechanistic and evolutionary aspects of these studies, focusing on recently obtained experimental results. First, we present evidence indicating that vulval formation is under stabilizing selection. Second, we discusss quantitative data on the precision and variability in the output of the vulval developmental system in different environments and different genetic backgrounds. Third, we illustrate how environmental and genetic variation modulate the cellular and molecular processes underlying the formation of the vulva. Fourth, we discuss the evolutionary significance of environmental sensitivity of this developmental system.     

Integrating GIS-based environmental data into evolutionary biology

Many evolutionary processes are influenced by environmental variation over space and time, including genetic divergence among populations, speciation and evolutionary change in morphology, physiology and behaviour. Yet, evolutionary biologists have generally not taken advantage of the extensive environmental data available from geographic information systems (GIS). For example, studies of phylogeography, speciation and character evolution often ignore or use only crude proxies for environmental variation (e.g. latitude and distance between populations). Here, we describe how the integration of GIS-based environmental data, along with new spatial tools, can transform evolutionary studies and reveal new insights into the ecological causes of evolutionary patterns.     

Exposure to elevated temperature and Pco(2) reduces respiration rate and energy status in the periwinkle Littorina littorea

In the future, marine organisms will face the challenge of coping with multiple environmental changes associated with increased levels of atmospheric Pco(2), such as ocean warming and acidification. To predict how organisms may or may not meet these challenges, an in-depth understanding of the physiological and biochemical mechanisms underpinning organismal responses to climate change is needed. Here, we investigate the effects of elevated Pco(2) and temperature on the whole-organism and cellular physiology of the periwinkle Littorina littorea. Metabolic rates (measured as respiration rates), adenylate energy nucleotide concentrations and indexes, and end-product metabolite concentrations were measured. Compared with values for control conditions, snails decreased their respiration rate by 31% in response to elevated Pco(2) and by 15% in response to a combination of increased Pco(2) and temperature. Decreased respiration rates were associated with metabolic reduction and an increase in end-product metabolites in acidified treatments, indicating an increased reliance on anaerobic metabolism. There was also an interactive effect of elevated Pco(2) and temperature on total adenylate nucleotides, which was apparently compensated for by the maintenance of adenylate energy charge via AMP deaminase activity. Our findings suggest that marine intertidal organisms are likely to exhibit complex physiological responses to future environmental drivers, with likely negative effects on growth, population dynamics, and, ultimately, ecosystem processes.     

Hormone signaling in evolution and development: a non-model system approach

Cooption and modularity are informative concepts in evolutionary developmental biology. Genes function within complex networks that act as modules in development. These modules can then be coopted in various functional and evolutionary contexts. Hormonal signaling, the main focus of this review, has a modular character. By regulating the activities of genes, proteins and other cellular molecules, a hormonal signal can have major effects on physiological and ontogenetic processes within and across tissues over a wide spatial and temporal scale. Because of this property, we argue that hormones are frequently involved in the coordination of life history transitions (LHTs) and their evolution (LHE). Finally, we promote the usefulness of a comparative, non-model system approach towards understanding how hormones function and guide development and evolution, highlighting thyroid hormone function in echinoids as an example.     

Parameters in dynamic models of complex traits are containers of missing heritability

Polymorphisms identified in genome-wide association studies of human traits rarely explain more than a small proportion of the heritable variation, and improving this situation within the current paradigm appears daunting. Given a well-validated dynamic model of a complex physiological trait, a substantial part of the underlying genetic variation must manifest as variation in model parameters. These parameters are themselves phenotypic traits. By linking whole-cell phenotypic variation to genetic variation in a computational model of a single heart cell, incorporating genotype-to-parameter maps, we show that genome-wide association studies on parameters reveal much more genetic variation than when using higher-level cellular phenotypes. The results suggest that letting such studies be guided by computational physiology may facilitate a causal understanding of the genotype-to-phenotype map of complex traits, with strong implications for the development of phenomics technology.     

The ecological effect of phenotypic plasticity — Analyzing complex interaction networks (COIN) with agent-based models

Analyzing complex dynamics of ecological systems is complicated by two important facts: First, phenotypic plasticity allows individual organisms to adapt their reaction norms in terms of morphology, anatomy, physiology and behavior to changing local environmental conditions and trophic relationships. Secondly, individual reactions and ecological dynamics are often determined by indirect interactions through reaction chains and networks involving feedback processes.

We present an agent-based modeling framework which allows to represent and analyze ecological systems that include phenotypic changes in individual performances and indirect interactions within heterogeneous and temporal changing environments. We denote this structure of interacting components as COmplex Interaction Network (COIN).

Three examples illustrate the potential of the system to analyze complex ecological processes that incorporate changing phenotypes on the individual level:

• A model on fish population dynamics of roach (Rutilus rutilus) leads to a differentiation in fish length resulting in a conspicuous distribution that influences reproduction capability and thus indirectly the fitness.

• Modeling the reproduction phase of the passerine bird Erithacus rubecula (European Robin) illustrates variation in the behavior of higher organisms in dependence of environmental factors. Changes in reproduction success and in the proportion of different activities are the results.

• The morphological reaction of plants to changes in fundamental environmental parameters is illustrated by the black alder (Alnus glutinosa) model. Specification of physiological processes and the interaction structure on the level of modules allow to represent the reaction to changes in irradiance and temperature accurately.

Applying the COIN-approach, individual plasticity emerges as a structural and functional implication in a self-organized manner. The examples illustrate the potential to integrate existing approaches to represent detailed and complex traits for higher order organisms and to combine ecological and evolutionary aspects.