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Systems biology is the computational and mathematical analysis and modeling of complex
biological system A biological system is a complex network which connects several biologically relevant entities. Biological organization spans several scales and are determined based different structures depending on what the system is. Examples of biological syst ...
s. It is a
biology Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary ...
-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. 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 Systems thinking is a way of making sense of the complexity of the world by looking at it in terms of wholes and relationships rather than by splitting it down into its parts. It has been used as a way of exploring and developing effective actio ...
in biology which has led to new, collaborative ways of working on problems in the biological field of genetics. One of the aims of systems biology is to model and discover emergent properties, properties of cells, tissues and
organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells ( cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and fu ...
s functioning as a
system A system is a group of interacting or interrelated elements that act according to a set of rules to form a unified whole. A system, surrounded and influenced by its environment, is described by its boundaries, structure and purpose and express ...
whose theoretical description is only possible using techniques of systems biology. These typically involve
metabolic networks A metabolic network is the complete set of metabolic and physical processes that determine the physiological and biochemical properties of a cell. As such, these networks comprise the chemical reactions of metabolism, the metabolic pathways, as w ...
or
cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
networks.


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 In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...
or the heart beats). 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 scientific method is an empirical method for acquiring knowledge that has characterized the development of science since at least the 17th century (with notable practitioners in previous centuries; see the article history of scientifi ...
. 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.'') "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) As a series of operational
protocol Protocol may refer to: Sociology and politics * Protocol (politics), a formal agreement between nation states * Protocol (diplomacy), the etiquette of diplomacy and affairs of state * Etiquette, a code of personal behavior Science and technology ...
s used for performing research, namely a cycle composed of theory,
analytic Generally speaking, analytic (from el, ἀναλυτικός, ''analytikos'') refers to the "having the ability to analyze" or "division into elements or principles". Analytic or analytical can also have the following meanings: Chemistry * ...
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. 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. As the application of dynamical systems theory to
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and phys ...
. Indeed, the focus on the dynamics of the studied systems is the main conceptual difference between systems biology and
bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
. 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.


History

Systems biology was begun as a new field of science around 2000, when 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. A Department of Systems Biology at Harvard Medical School was launched in 2003. 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. In 2006 the
National Science Foundation The National Science Foundation (NSF) is an independent agency of the United States government that supports fundamental research and education in all the non-medical fields of science and engineering. Its medical counterpart is the National ...
put forward a challenge to build a mathematical model of the whole cell. 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. 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 Cleveland ( ), officially the City of Cleveland, is a city in the United States, U.S. U.S. state, state of Ohio and the county seat of Cuyahoga County, Ohio, Cuyahoga County. Located in the northeastern part of the state, it is situated along ...
, Ohio, titled ''Systems Theory and Biology''. Mesarovic predicted that perhaps in the future there would be such as thing as "systems biology". 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 later thoroughly revised, and Reinhart Heinrich and
Tom Rapoport Tom Abraham Rapoport (born June 17, 1947) is a German-American cell biologist who studies protein transport in cells. Currently, he is a professor at Harvard Medical School and a Howard Hughes Medical Institute investigator. Born in Cincinnati, OH ...
, and Biochemical Systems Theory developed by Michael Savageau 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. Echoing him forty years later in 2006 Kling writes that the success of
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and phys ...
throughout the 20th century had suppressed holistic computational methods. By 2011 the
National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the lat ...
had made grant money available to support over ten systems biology centers in the United States, but by 2012 Hunter writes that systems biology had not lived up to the hype, having promised more than it achieved, which had caused it to become a somewhat minor field with few practical applications. Nonetheless, proponents hoped that it might once prove more useful in the future. An important milestone in the development of systems biology has become the international project
Physiome The physiome of an individual's or species' physiological state is the description of its functional behavior. The physiome describes the physiological dynamics of the normal intact organism and is built upon information and structure (genome, prote ...
.


Associated disciplines

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. Items that may be a computer database include: phenomics, organismal variation in
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...
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 In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
, 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 Two-dimensional gel electrophoresis, abbreviated as 2-DE or 2-D electrophoresis, is a form of gel electrophoresis commonly used to analyze proteins. Mixtures of proteins are separated by two properties in two dimensions on 2D gels. 2-DE was first ...
, mass spectrometry or multi-dimensional protein identification techniques (advanced HPLC systems coupled with mass spectrometry). Sub disciplines include
phosphoproteomics Phosphoproteomics is a branch of proteomics that identifies, catalogs, and characterizes proteins containing a phosphate group as a posttranslational modification. Phosphorylation is a key reversible modification that regulates protein function, s ...
, glycoproteomics and other methods to detect chemically modified proteins; glycomics, organismal, tissue, or cell-level measurements of
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...
s; lipidomics, organismal, tissue, or cell level measurements of
lipids Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
. The molecular interactions within the cell are also studied, this is called interactomics. A discipline in this field of study is protein-protein interactions, although interactomics includes the interactions of other molecules. Neuroelectrodynamics, where the computer's or a brain's computing function as a dynamic system is studied along with its (bio)physical mechanisms; and fluxomics, measurements of the rates of metabolic reactions in a biological system (cell, tissue, or organism). 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. 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; biosemiotics, analysis of the system of sign relations of an organism or other biosystems;
Physiomics Physiomics is a systematic study of physiome in biology. Physiomics employs bioinformatics to construct networks of physiological features that are associated with genes, proteins and their networks. A few of the methods for determining individual ...
, a systematic study of
physiome The physiome of an individual's or species' physiological state is the description of its functional behavior. The physiome describes the physiological dynamics of the normal intact organism and is built upon information and structure (genome, prote ...
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 Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or ane ...
). 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. The systems biology approach often involves the development of
mechanistic The mechanical philosophy is a form of natural philosophy which compares the universe to a large-scale mechanism (i.e. a machine). The mechanical philosophy is associated with the scientific revolution of early modern Europe. One of the first expo ...
models, such as the reconstruction of dynamic systems from the quantitative properties of their elementary building blocks. For instance, a cellular network can be modelled mathematically using methods coming from
chemical kinetics Chemical kinetics, also known as reaction kinetics, is the branch of physical chemistry that is concerned with understanding the rates of chemical reactions. It is to be contrasted with chemical thermodynamics, which deals with the direction in ...
and
control theory Control theory is a field of mathematics that deals with the control system, control of dynamical systems in engineered processes and machines. The objective is to develop a model or algorithm governing the application of system inputs to drive ...
. 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).


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; 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 Weighted correlation network analysis, also known as weighted gene co-expression network analysis (WGCNA), is a widely used data mining method especially for studying biological networks based on pairwise correlations between variables. While it ...
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. 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.


Creating biological models

Researchers begin by choosing a biological pathway and diagramming all of the protein interactions. After determining all of the interactions of the proteins, mass action kinetics is utilized to describe the speed of the reactions in the system. Mass action kinetics will provide differential equations to model the biological system as a mathematical model in which experiments can determine the parameter values to use in the
differential equation In mathematics, a differential equation is an equation that relates one or more unknown functions and their derivatives. In applications, the functions generally represent physical quantities, the derivatives represent their rates of change, ...
s. These parameter values will be the reaction rates of each proteins interaction in the system. This model determines the behavior of certain proteins in biological systems and bring new insight to the specific activities of individual proteins. 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. 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 maximizing the object of interest.


See also

* Biological computation * BioSystems (journal) * Computational biology * Exposome * Interactome * List of omics topics in biology *
living systems Living systems are open self-organizing life forms that interact with their environment. These systems are maintained by flows of information, energy and matter. In the last few decades, some scientists have proposed that a general living sys ...
* Metabolic network modelling * Modelling biological systems * Molecular pathological epidemiology * Network biology *
Network medicine Network medicine is the application of network science towards identifying, preventing, and treating diseases. This field focuses on using network topology and network dynamics towards identifying diseases and developing medical drugs. Biological ...
* * Synthetic biology * Systems biomedicine * Systems immunology * Systems medicine * TIARA (database)


References


Further reading

* * * * provides a comparative review of three books: * * * *


External links

*
Biological Systems in bio-physics-wiki
{{DEFAULTSORT:Systems Biology Bioinformatics Computational fields of study