Systems biology

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An illustration of the systems approach to biology

Systems biology is the

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

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

metabolites in a metabolic pathway or the heart beats).[5][6][7]

As a

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

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

Michael Savageau[22][23][24]

According to

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. From 1992 to 2013 database development articles increased. Articles about algorithms have fluctuated but remained fairly steady. Network properties articles and software development articles have remained low but experienced an increased about halfway through the time period 1992-2013. The articles on metabolic flux analysis decreased from 1992 to 2013. In 1992 algorithms, equations, modeling and simulation articles were most cited. In 2012 the most cited were database development articles.
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[27]

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

Associated disciplines

Overview of signal transduction pathways

According to the interpretation of systems biology as using large data sets using interdisciplinary tools, a typical application is

metabolites, in the system at the organism, cell, or tissue level.[28]

Items that may be a computer database include:

lipids.[citation needed
]

The molecular interactions within the cell are also studied, this is called

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.

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

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,

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.[43]

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.

See also

References

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Further reading

External links

Look up systems biology in Wiktionary, the free dictionary.
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