Systems biology

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An illustration of the systems approach to biology Genomics GTL Pictorial Program.jpg
An illustration of the systems approach to biology

Systems biology is the computational and mathematical analysis and modeling of complex biological systems. It is a biology-based interdisciplinary field of study that focuses on complex interactions within biological systems, using a holistic approach (holism instead of the more traditional reductionism) to biological research. [1]

Particularly from the year 2000 onwards, the concept has been used widely in biology in a variety of contexts. The Human Genome Project is an example of applied systems thinking in biology which has led to new, collaborative ways of working on problems in the biological field of genetics. [2] One of the aims of systems biology is to model and discover emergent properties, properties of cells, tissues and organisms functioning as a system whose theoretical description is only possible using techniques of systems biology. [1] [3] These typically involve metabolic networks or cell signaling networks. [1] [4]

Overview

Systems biology can be considered from a number of different aspects.

As a field of study, particularly, the study of the interactions between the components of biological systems, and how these interactions give rise to the function and behavior of that system (for example, the enzymes and metabolites in a metabolic pathway or the heart beats). [5] [6] [7]

As a paradigm, systems biology is usually defined in antithesis to the so-called reductionist paradigm (biological organisation), although it is consistent with the scientific method. The distinction between the two paradigms is referred to in these quotations: "the reductionist approach has successfully identified most of the components and many of the interactions but, unfortunately, offers no convincing concepts or methods to understand how system properties emerge ... the pluralism of causes and effects in biological networks is better addressed by observing, through quantitative measures, multiple components simultaneously and by rigorous data integration with mathematical models." (Sauer et al.) [8] "Systems biology ... is about putting together rather than taking apart, integration rather than reduction. It requires that we develop ways of thinking about integration that are as rigorous as our reductionist programmes, but different. ... It means changing our philosophy, in the full sense of the term." (Denis Noble) [7]

As a series of operational protocols used for performing research, namely a cycle composed of theory, analytic or computational modelling to propose specific testable hypotheses about a biological system, experimental validation, and then using the newly acquired quantitative description of cells or cell processes to refine the computational model or theory. [9] Since the objective is a model of the interactions in a system, the experimental techniques that most suit systems biology are those that are system-wide and attempt to be as complete as possible. Therefore, transcriptomics, metabolomics, proteomics and high-throughput techniques are used to collect quantitative data for the construction and validation of models. [10]

As the application of dynamical systems theory to molecular biology. Indeed, the focus on the dynamics of the studied systems is the main conceptual difference between systems biology and bioinformatics. [11]

As a socioscientific phenomenon defined by the strategy of pursuing integration of complex data about the interactions in biological systems from diverse experimental sources using interdisciplinary tools and personnel. [12]

History

Although the concept of a systems view of cellular function has been well understood since at least the 1930s, [13] technological limitations made it difficult to make systems wide measurements. The advent of microarray technology in the 1990s opened up an entire new visa for studying cells at the systems level. In 2000, the Institute for Systems Biology was established in Seattle in an effort to lure "computational" type people who it was felt were not attracted to the academic settings of the university. The institute did not have a clear definition of what the field actually was: roughly bringing together people from diverse fields to use computers to holistically study biology in new ways. [14] A Department of Systems Biology at Harvard Medical School was launched in 2003. [15] In 2006 it was predicted that the buzz generated by the "very fashionable" new concept would cause all the major universities to need a systems biology department, thus that there would be careers available for graduates with a modicum of ability in computer programming and biology. [14] In 2006 the National Science Foundation put forward a challenge to build a mathematical model of the whole cell.[ citation needed ] In 2012 the first whole-cell model of Mycoplasma genitalium was achieved by the Karr Laboratory at the Mount Sinai School of Medicine in New York. The whole-cell model is able to predict viability of M. genitalium cells in response to genetic mutations. [16]

An earlier precursor of systems biology, as a distinct discipline, may have been by systems theorist Mihajlo Mesarovic in 1966 with an international symposium at the Case Institute of Technology in Cleveland, Ohio, titled Systems Theory and Biology. Mesarovic predicted that perhaps in the future there would be such a thing as "systems biology". [17] [18] Other early precursors that focused on the view that biology should be analyzed as a system, rather than a simple collection of parts, were Metabolic Control Analysis, developed by Henrik Kacser and Jim Burns [19] later thoroughly revised, [20] and Reinhart Heinrich and Tom Rapoport, [21] and Biochemical Systems Theory developed by Michael Savageau [22] [23] [24]

According to Robert Rosen in the 1960s, holistic biology had become passé by the early 20th century, as more empirical science dominated by molecular chemistry had become popular. [18] Echoing him forty years later in 2006 Kling writes that the success of molecular biology throughout the 20th century had suppressed holistic computational methods. [14] By 2011 the National Institutes of Health had made grant money available to support over ten systems biology centers in the United States, [25] but by 2012 Hunter writes that systems biology still has someway to go to achieve its full potential. Nonetheless, proponents hoped that it might once prove more useful in the future. [26]

Shows trends in systems biology research by presenting the number of articles out of the top 30 cited systems biology papers during that time which include a specific topic SystemsBiologyTrendsInMostCitedResearch.PNG
Shows trends in systems biology research by presenting the number of articles out of the top 30 cited systems biology papers during that time which include a specific topic

An important milestone in the development of systems biology has become the international project Physiome.[ citation needed ]

Associated disciplines

Overview of signal transduction pathways Signal transduction pathways.svg
Overview of signal transduction pathways

According to the interpretation of systems biology as using large data sets using interdisciplinary tools, a typical application is metabolomics, which is the complete set of all the metabolic products, metabolites, in the system at the organism, cell, or tissue level. [28]

Items that may be a computer database include: phenomics, organismal variation in phenotype as it changes during its life span; genomics, organismal deoxyribonucleic acid (DNA) sequence, including intra-organismal cell specific variation. (i.e., telomere length variation); epigenomics/epigenetics, organismal and corresponding cell specific transcriptomic regulating factors not empirically coded in the genomic sequence. (i.e., DNA methylation, Histone acetylation and deacetylation, etc.); transcriptomics, organismal, tissue or whole cell gene expression measurements by DNA microarrays or serial analysis of gene expression; interferomics, organismal, tissue, or cell-level transcript correcting factors (i.e., RNA interference), proteomics, organismal, tissue, or cell level measurements of proteins and peptides via two-dimensional gel electrophoresis, mass spectrometry or multi-dimensional protein identification techniques (advanced HPLC systems coupled with mass spectrometry). Sub disciplines include phosphoproteomics, glycoproteomics and other methods to detect chemically modified proteins; glycomics, organismal, tissue, or cell-level measurements of carbohydrates; lipidomics, organismal, tissue, or cell level measurements of lipids.[ citation needed ]

The molecular interactions within the cell are also studied, this is called interactomics. [29] A discipline in this field of study is protein–protein interactions, although interactomics includes the interactions of other molecules.[ citation needed ] Neuroelectrodynamics, where the computer's or a brain's computing function as a dynamic system is studied along with its (bio)physical mechanisms; [30] and fluxomics, measurements of the rates of metabolic reactions in a biological system (cell, tissue, or organism). [28]

In approaching a systems biology problem there are two main approaches. These are the top down and bottom up approach. The top down approach takes as much of the system into account as possible and relies largely on experimental results. The RNA-Seq technique is an example of an experimental top down approach. Conversely, the bottom up approach is used to create detailed models while also incorporating experimental data. An example of the bottom up approach is the use of circuit models to describe a simple gene network. [31]

Various technologies utilized to capture dynamic changes in mRNA, proteins, and post-translational modifications. Mechanobiology, forces and physical properties at all scales, their interplay with other regulatory mechanisms; [32] biosemiotics, analysis of the system of sign relations of an organism or other biosystems; Physiomics, a systematic study of physiome in biology.

Cancer systems biology is an example of the systems biology approach, which can be distinguished by the specific object of study (tumorigenesis and treatment of cancer). It works with the specific data (patient samples, high-throughput data with particular attention to characterizing cancer genome in patient tumour samples) and tools (immortalized cancer cell lines, mouse models of tumorigenesis, xenograft models, high-throughput sequencing methods, siRNA-based gene knocking down high-throughput screenings, computational modeling of the consequences of somatic mutations and genome instability). [33] The long-term objective of the systems biology of cancer is ability to better diagnose cancer, classify it and better predict the outcome of a suggested treatment, which is a basis for personalized cancer medicine and virtual cancer patient in more distant prospective. Significant efforts in computational systems biology of cancer have been made in creating realistic multi-scale in silico models of various tumours. [34]

The systems biology approach often involves the development of mechanistic models, such as the reconstruction of dynamic systems from the quantitative properties of their elementary building blocks. [35] [36] [37] [38] For instance, a cellular network can be modelled mathematically using methods coming from chemical kinetics [39] and control theory. Due to the large number of parameters, variables and constraints in cellular networks, numerical and computational techniques are often used (e.g., flux balance analysis). [37] [39]

Bioinformatics and data analysis

Other aspects of computer science, informatics, and statistics are also used in systems biology. These include new forms of computational models, such as the use of process calculi to model biological processes (notable approaches include stochastic π-calculus, BioAmbients, Beta Binders, BioPEPA, and Brane calculus) and constraint-based modeling; integration of information from the literature, using techniques of information extraction and text mining; [40] development of online databases and repositories for sharing data and models, approaches to database integration and software interoperability via loose coupling of software, websites and databases, or commercial suits; network-based approaches for analyzing high dimensional genomic data sets. For example, weighted correlation network analysis is often used for identifying clusters (referred to as modules), modeling the relationship between clusters, calculating fuzzy measures of cluster (module) membership, identifying intramodular hubs, and for studying cluster preservation in other data sets; pathway-based methods for omics data analysis, e.g. approaches to identify and score pathways with differential activity of their gene, protein, or metabolite members. [41] Much of the analysis of genomic data sets also include identifying correlations. Additionally, as much of the information comes from different fields, the development of syntactically and semantically sound ways of representing biological models is needed. [42]

Creating biological models

A simple three protein negative feedback loop modeled with mass action kinetic differential equations. Each protein interaction is described by a Michaelis-Menten reaction. Toy Biological Model.jpg
A simple three protein negative feedback loop modeled with mass action kinetic differential equations. Each protein interaction is described by a Michaelis–Menten reaction.

Researchers begin by choosing a biological pathway and diagramming all of the protein, gene, and/or metabolic pathways. After determining all of the interactions, mass action kinetics or enzyme kinetic rate laws are used to describe the speed of the reactions in the system. Using mass-conservation, the differential equations for the biological system can be constructed. Experiments or parameter fitting can be done to determine the parameter values to use in the differential equations. [44] These parameter values will be the various kinetic constants required to fully describe the model. This model determines the behavior of species in biological systems and bring new insight to the specific activities of system. Sometimes it is not possible to gather all reaction rates of a system. Unknown reaction rates are determined by simulating the model of known parameters and target behavior which provides possible parameter values. [45] [43]

The use of constraint-based reconstruction and analysis (COBRA) methods has become popular among systems biologists to simulate and predict the metabolic phenotypes, using genome-scale models. One of the methods is the flux balance analysis (FBA) approach, by which one can study the biochemical networks and analyze the flow of metabolites through a particular metabolic network, by optimizing the objective function of interest (e.g. maximizing biomass production to predict growth). [46]

Plot of Concentrations vs time for the simple three protein negative feedback loop. All parameters are set to either 0 or 1 for initial conditions. The reaction is allowed to proceed until it hits equilibrium. This plot is of the change in each protein over time. Toy Model Plot.jpg
Plot of Concentrations vs time for the simple three protein negative feedback loop. All parameters are set to either 0 or 1 for initial conditions. The reaction is allowed to proceed until it hits equilibrium. This plot is of the change in each protein over time.

See also

Related Research Articles

<span class="mw-page-title-main">Bioinformatics</span> Computational analysis of large, complex sets of biological data

Bioinformatics is an interdisciplinary field of science that develops methods and software tools for understanding biological data, especially when the data sets are large and complex. Bioinformatics uses biology, chemistry, physics, computer science, computer programming, information engineering, mathematics and statistics to analyze and interpret biological data. The subsequent process of analyzing and interpreting data is referred to as computational biology.

<i>In vitro</i> Latin term meaning outside a natural biological environment

In vitro studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and its subdisciplines are traditionally done in labware such as test tubes, flasks, Petri dishes, and microtiter plates. Studies conducted using components of an organism that have been isolated from their usual biological surroundings permit a more detailed or more convenient analysis than can be done with whole organisms; however, results obtained from in vitro experiments may not fully or accurately predict the effects on a whole organism. In contrast to in vitro experiments, in vivo studies are those conducted in living organisms, including humans, known as clinical trials, and whole plants.

<span class="mw-page-title-main">Proteomics</span> Large-scale study of proteins

Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In addition, other kinds of proteins include antibodies that protect an organism from infection, and hormones that send important signals throughout the body.

<span class="mw-page-title-main">Computational biology</span> Branch of biology

Computational biology refers to the use of data analysis, mathematical modeling and computational simulations to understand biological systems and relationships. An intersection of computer science, biology, and big data, the field also has foundations in applied mathematics, chemistry, and genetics. It differs from biological computing, a subfield of computer science and engineering which uses bioengineering to build computers.

<span class="mw-page-title-main">Gene regulatory network</span> Collection of molecular regulators

A generegulatory network (GRN) is a collection of molecular regulators that interact with each other and with other substances in the cell to govern the gene expression levels of mRNA and proteins which, in turn, determine the function of the cell. GRN also play a central role in morphogenesis, the creation of body structures, which in turn is central to evolutionary developmental biology (evo-devo).

In computational biology, gene prediction or gene finding refers to the process of identifying the regions of genomic DNA that encode genes. This includes protein-coding genes as well as RNA genes, but may also include prediction of other functional elements such as regulatory regions. Gene finding is one of the first and most important steps in understanding the genome of a species once it has been sequenced.

<span class="mw-page-title-main">Mathematical and theoretical biology</span> Branch of biology

Mathematical and theoretical biology, or biomathematics, is a branch of biology which employs theoretical analysis, mathematical models and abstractions of living organisms to investigate the principles that govern the structure, development and behavior of the systems, as opposed to experimental biology which deals with the conduction of experiments to test scientific theories. The field is sometimes called mathematical biology or biomathematics to stress the mathematical side, or theoretical biology to stress the biological side. Theoretical biology focuses more on the development of theoretical principles for biology while mathematical biology focuses on the use of mathematical tools to study biological systems, even though the two terms are sometimes interchanged.

<span class="mw-page-title-main">Synthetic biology</span> Interdisciplinary branch of biology and engineering

Synthetic biology (SynBio) is a multidisciplinary field of science that focuses on living systems and organisms, and it applies engineering principles to develop new biological parts, devices, and systems or to redesign existing systems found in nature.

Modelling biological systems is a significant task of systems biology and mathematical biology. Computational systems biology aims to develop and use efficient algorithms, data structures, visualization and communication tools with the goal of computer modelling of biological systems. It involves the use of computer simulations of biological systems, including cellular subsystems, to both analyze and visualize the complex connections of these cellular processes.

<span class="mw-page-title-main">Protein–protein interaction</span> Physical interactions and constructions between multiple proteins

Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and the hydrophobic effect. Many are physical contacts with molecular associations between chains that occur in a cell or in a living organism in a specific biomolecular context.

<span class="mw-page-title-main">Metabolic network modelling</span> Form of biological modelling

Metabolic network modelling, also known as metabolic network reconstruction or metabolic pathway analysis, allows for an in-depth insight into the molecular mechanisms of a particular organism. In particular, these models correlate the genome with molecular physiology. A reconstruction breaks down metabolic pathways into their respective reactions and enzymes, and analyzes them within the perspective of the entire network. In simplified terms, a reconstruction collects all of the relevant metabolic information of an organism and compiles it in a mathematical model. Validation and analysis of reconstructions can allow identification of key features of metabolism such as growth yield, resource distribution, network robustness, and gene essentiality. This knowledge can then be applied to create novel biotechnology.

<span class="mw-page-title-main">Flux balance analysis</span>

Flux balance analysis (FBA) is a mathematical method for simulating metabolism in genome-scale reconstructions of metabolic networks. In comparison to traditional methods of modeling, FBA is less intensive in terms of the input data required for constructing the model. Simulations performed using FBA are computationally inexpensive and can calculate steady-state metabolic fluxes for large models in a few seconds on modern personal computers. The related method of metabolic pathway analysis seeks to find and list all possible pathways between metabolites.

Systems immunology is a research field under systems biology that uses mathematical approaches and computational methods to examine the interactions within cellular and molecular networks of the immune system. The immune system has been thoroughly analyzed as regards to its components and function by using a "reductionist" approach, but its overall function can't be easily predicted by studying the characteristics of its isolated components because they strongly rely on the interactions among these numerous constituents. It focuses on in silico experiments rather than in vivo.

<span class="mw-page-title-main">Biological network inference</span>

Biological network inference is the process of making inferences and predictions about biological networks. By using these networks to analyze patterns in biological systems, such as food-webs, we can visualize the nature and strength of these interactions between species, DNA, proteins, and more.

Fluxomics describes the various approaches that seek to determine the rates of metabolic reactions within a biological entity. While metabolomics can provide instantaneous information on the metabolites in a biological sample, metabolism is a dynamic process. The significance of fluxomics is that metabolic fluxes determine the cellular phenotype. It has the added advantage of being based on the metabolome which has fewer components than the genome or proteome.

<span class="mw-page-title-main">Biological network</span> Method of representing systems

A biological network is a method of representing systems as complex sets of binary interactions or relations between various biological entities. In general, networks or graphs are used to capture relationships between entities or objects. A typical graphing representation consists of a set of nodes connected by edges.

<span class="mw-page-title-main">Cellular model</span>

A cellular model is a mathematical model of aspects of a biological cell, for the purposes of in silico research.

Cancer systems biology encompasses the application of systems biology approaches to cancer research, in order to study the disease as a complex adaptive system with emerging properties at multiple biological scales. Cancer systems biology represents the application of systems biology approaches to the analysis of how the intracellular networks of normal cells are perturbed during carcinogenesis to develop effective predictive models that can assist scientists and clinicians in the validations of new therapies and drugs. Tumours are characterized by genomic and epigenetic instability that alters the functions of many different molecules and networks in a single cell as well as altering the interactions with the local environment. Cancer systems biology approaches, therefore, are based on the use of computational and mathematical methods to decipher the complexity in tumorigenesis as well as cancer heterogeneity.

The human interactome is the set of protein–protein interactions that occur in human cells. The sequencing of reference genomes, in particular the Human Genome Project, has revolutionized human genetics, molecular biology, and clinical medicine. Genome-wide association study results have led to the association of genes with most Mendelian disorders, and over 140 000 germline mutations have been associated with at least one genetic disease. However, it became apparent that inherent to these studies is an emphasis on clinical outcome rather than a comprehensive understanding of human disease; indeed to date the most significant contributions of GWAS have been restricted to the “low-hanging fruit” of direct single mutation disorders, prompting a systems biology approach to genomic analysis. The connection between genotype and phenotype remain elusive, especially in the context of multigenic complex traits and cancer. To assign functional context to genotypic changes, much of recent research efforts have been devoted to the mapping of the networks formed by interactions of cellular and genetic components in humans, as well as how these networks are altered by genetic and somatic disease.

Machine learning in bioinformatics is the application of machine learning algorithms to bioinformatics, including genomics, proteomics, microarrays, systems biology, evolution, and text mining.

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