Articulo De Anatomia

Systems biology in heart diseases

G E Louridas, I E Kanonidis, and K G Lourida

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Abstract

Systems biology based on integrative computational analysis and high technology is in a position to construct networks, to study the interactions between molecular components and to develop models of cardiac function and anatomy. Clinical cardiology gets an integrated picture of parameters that are addressed to ventricular and vessel mechanics, cardiac metabolism and electrical activation. The achievement of clinical objectives is based on the interaction between modern technology and clinical phenotype. In this review the need for more sophisticated realization of the structure and function of the cardiovascular system is emphasized while the incorporation of the systems biology concept in predicting clinical phenotypes is a promising strategy that optimize diagnosis and treatment in cardiovascular disease.

Keywords: systems biology, cardiac models, network biology, clinical phenotypes

In the latter part of the last century, biology was driven by reductionist concepts that concerned with information originating from the interactions of genes and molecules. A novel conceptual idea developed over the last few years with the purpose of understanding biological processes which were not explained fully by the properties of genes and molecules. Both evolutionary theories over many decades and systems biology recently have transformed the consensus of biology.

Systems biology (SB) is a new discipline which tries to explain the biological phenomenon not only with delineation of the function of genes and molecules but by reconstructing biochemical supramolecular networks that represent various cellular functions. Systems biology concern with biochemical networks is focused on their functional status and on the nature of the links connecting the molecules of the network1. This concept considers the biological networks as 'systems' of cooperating and interacting components with complex behaviors.

This novel approach is transforming the way of thinking in research, biology and disease. Network modeling could explain cardiovascular metabolism and thus design new diagnostic and therapeutic tools. Also the SB perspective could help to predict and treat complex diseases such as heart failure, metabolic syndrome and diabetes mellitus.

Biological components and systems analysis

In the second half of the previous century after the discovery of the DNA construction, attention focused on explaining the cellular function and the chemical composition of isolated biological components (gene, protein, pathways). This reductionist tendency was increased with the advent of genomics and proteomics. The DNA sequences in a large number of organisms are known but their function at the moment is incomplete. The proteomic technology is important in predicting the activation of some particular genes but remains still in its infancy.

The recent advent of integrative analysis of the different gene products, the new experimental technologies, and in particular the notion that the cells are organized in systems has forced biologists to give special attention to the systems properties. This shift of focus from individual cellular components to systems properties and tissue organization is an inexorable process that eventually would apply to the study of tissue and organ functions. The appearance of novel systems properties in cellular, tissue or organ level, are considered properties emerging from the complex metabolic and regulatory networks of tissues and organs and are not properties of distinct cellular components.

There is a hierarchical coordination that in steps or levels involves genes, genetic products, cellular functions, tissues and organs. There is not a simple relationship between genes but rich biological networks that transform genetic potential into phenotypic reality. The coordinated function at each level between the different components produces a kind of circuit. The term "genetic circuit" was used to designate a collection of different gene products executing a particular cellular function1. Genetic circuits are responsible for information processing, metabolism, cellular function and evolution. Therefore the integrated functions of many genetic circuits form the basic material for cellular function and tissue as well as organ coordinated operation.

In a similar way with the molecular biology and the complex metabolic and regulatory networks, the scientific pursuit can extend to tissue and organ functional coordination in the different levels of the hierarchical ladder. The advances in bioinformatics and clinical phenotype make plausible this kind of research and application2–4.

The proceeding steps of systems biology

The process leading to the emergence of SB is a new paradigm of holistic decoding of biological systems function and consists of four principal steps1: a) Enumeration of biological components participating in the process including the plurality of –omics (Genome, Transcriptome, Proteome, Metabolome). b) Interaction diagrams between these biological components are depicted and the constructed cellular networks are demonstrated. Such examples of biological networks are gene and proteomic networks, immunological networks, and metabolomic and disease networks. c) Reconstructed networks are analyzed and the biological functions are predicted. d) The above emerging models should predict experimental outcomes and explore the phenotypic space.

The universal theories of networks by Barabasi et al emphasized that the cell functional organization is based on biological similar networks that comply with universal laws ruling complex systems5–7.

It is likely that the SB from the level of genome-cell exploration would advance to the broader field of an organismic concept. This broader field of SB from the networks of cellular interactions would be directed to the diverse phenotypic space of tissues and organs. The previous mentioned hierarchical thinking starts from the DNA and continues to the systemic two-dimensional genome-scale stoichiometric matrix. The hierarchical structure extends from introns, exones, alleles and other components of DNA scale, through a network of chemical reactions, modules and pathways, to tissue functional organization and organ cooperation.

The cardiovascular (CV) disorders have the highest mortality rates in the world, change the quality of life and increase the economic burden of the society. Therefore there is great significance to understand the cellular

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