Systems biology

Systems biology is a relatively new biological study field that focuses on the systematic study of complex interactions in biological systems, thus using a new perspective (integration intead of reduction) to study them. Particularly from 2000 onwards, the term is used widely in the biosciences, and in a variety of contexts. Because the scientific method has been used primarily toward reductionism, one of the goals of systems biology is to discover new emergent properties that may arise from the systemic view used by this discipline in order to understand better the entirety of processes that happen in a biological system.

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Overview

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

• Some sources discuss systems biology 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)^[1][2].

• Other sources consider systems biology as a paradigm, usually defined in antithesis to the so-called reductionist paradigm, although fully 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" Science^[3]

"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^[4]

• Still other sources view systems biology in terms of the operational protocols used for performing research, namely a cycle composed of theory, 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.^[5][6]. 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.

• Finally, some sources see it 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.

This variety of viewpoints is illustrative of the fact that systems biology refers to a cluster of peripherally overlapping concepts rather than a single well-delineated field. However the term has widespread currency and popularity as of 2007, with chairs and institutes of systems biology proliferating worldwide.

History

Systems biology finds its roots in:

• the quantitative modelling of enzyme kinetics, a discipline that flourished between 1900 and 1970,
• the simulations developed to study neurophysiology, and
• control theory, and cybernetics.

One of the theorists who can be seen as a precursor of systems biology is Ludwig von Bertalanffy with his general systems theory. One of the first numerical simulations in biology was published in 1952 by the British neurophysiologists and nobel prize winners Alan Lloyd Hodgkin and Andrew Fielding Huxley, who constructed a mathematical model that explained the action potential propagating along the axon of a neuronal cell^[7]. Their model described a cellular function emerging from the interaction between two different molecular components, a potassium and a sodium channels, and can therefore be seen as the beginning of computational systems biology^[8]. In 1960, Denis Noble developed the first computer model of the heart pacemacker ^[9].

The 1960s and 1970s saw the development of several approaches to study complex molecular systems, such as the Metabolic Control Analysis and the biochemical systems theory. The successes of molecular biology throughout the 1980s, coupled with a skepticism toward theoretical biology, that then promised more than it achieved, caused the quantitative modelling of biological processes to become a somewhat minor field.

However the birth of functional genomics in the 1990s meant that large quantities of high quality data became available, while the computing power exploded, making more realistic models possible. In 1997, the group of Masaru Tomita published the first quantitative model of the metabolism of a whole (hypothetical) cell.

Around the year 2000, when Institutes of Systems Biology were established in Seattle and Tokyo, systems biology emerged as a movement in its own right, spurred on by the completion of various genome projects, the large increase in data from the omics (e.g. genomics and proteomics) and the accompanying advances in high-throughput experiments and bioinformatics. Since then, various research institutes dedicated to systems biology have been developed. As of summer 2006, due to a shortage of people in systems biology^[10] several doctoral training centres in systems biology have been established in many parts of the world.

Techniques associated with systems biology

According to the interpretation of System Biology as the ability to obtain, integrate and analyze complex data from multiple experimental sources using interdisciplinary tools, some typical technology platforms are:

• Transcriptomics: whole cell or tissue gene expression measurements by DNA microarrays or SAGE
• Proteomics: complete identification of proteins and protein expression patterns of a cell or tissue through two-dimensional gel electrophoresis and 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.
• Metabolomics: identification and measurement of all small-molecules metabolites within a cell or tissue
• Glycomics: identification of the entirety of all carbohydrates in a cell or tissue.

In addition to the identification and quantification of the above given molecules further techniques analyze the dynamics and interactions within a cell. This includes:

• Interactomics which is used mostly in the context of protein-protein interaction but in theory encompasses interactions between all molecules within a cell
• Fluxomics, which deals with the dynamic changes of molecules within a cell over time
• Biomics: systems analysis of the biome.

The investigations are frequently combined with large scale perturbation methods, including gene-based (RNAi, mis-expression of wild type and mutant genes) and chemical approaches using small molecule libraries. Robots and automated sensors enable such large-scale experimentation and data acquisition. These technologies are still emerging and many face problems that the larger the quantity of data produced, the lower the quality. A wide variety of quantitative scientists (computational biologists, statisticians, mathematicians, computer scientists, engineers, and physicists) are working to improve the quality of these approaches and to create, refine, and retest the models to accurately reflect observations.

The investigations of a single level of biological organization (such as those listed above) are usually referred to as Systematic Systems Biology. Other areas of Systems Biology includes Integrative Systems Biology, which seeks to integrate different types of information to advance the understanding the biological whole, and Dynamic Systems Biology, which aims to uncover how the biological whole changes over time (during evolution, for example, the onset of disease or in response to a perturbation). Functional Genomics may also be considered a sub-field of Systems Biology.

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^[11][12]. For instance, a cellular network can be modelled mathematically using methods coming from chemical kinetics and control theory. Due to the large number of parameters, variables and constraints in cellular networks, numerical and computational techniques are often used. Other aspects of computer science and informatics are also used in systems biology. These include new forms of computational model, such as the use of process calculi to model biological processes, the integration of information from the literature, using techniques of information extraction and text mining, the development of online databases and repositories for sharing data and models (such as BioModels Database), approaches to database integration and software interoperability via loose coupling of software, websites and databases (such as Gaggle [1]), and the development of syntactically and semantically sound ways of representing biological models, such as the Systems Biology Markup Language.

See also

• Artificial life
• Biological systems engineering
• Biomedical cybernetics
• Biostatistics
• Computational Biology
• Computational systems biology
• Computer simulation
• Gene regulatory network
• List of omics topics in biology
• List of publications in biology#Systems biology
• List of Systems Biology Research Groups
• Metabolic network modelling
• Model
• Model checking and systems biology
• Network Theory of Aging
• Regulome
• Synthetic biology
• Systems Biology Markup Language
• SBO
• Systems ecology
• Systems immunology
• Systems theory

Bibliography

Books

• H Kitano (editor). Foundations of Systems Biology. MIT Press: 2001. ISBN 0-262-11266-3
• CP Fall, E Marland, J Wagner and JJ Tyson (Editors). "Computational Cell Biology." Springer Verlag: 2002 ISBN 0-387-95369-8
• G Bock and JA Goode (eds).In Silico" Simulation of Biological Processes, Novartis Foundation Symposium 247. John Wiley & Sons: 2002. ISBN 0-470-84480-9
• E Klipp, R Herwig, A Kowald, C Wierling, and H Lehrach. Systems Biology in Practice. Wiley-VCH: 2005. ISBN 3-527-31078-9
• L. Alberghina and H. Westerhoff (Editors) – Systems Biology: Definitions and Perspectives, Topics in Current Genetics 13, Springer Verlag (2005), ISBN 13: 978-3540229681
• A Kriete, R Eils. Computational Systems Biology., Elsevier - Academic Press: 2005. ISBN 0-12-088786-X
• K. Sneppen and G. Zocchi, (2005) Physics in Molecular Biology, Cambridge University Press, ISBN 0-521-84419-3
• D. Noble, The Music of life. Biology beyond the genome Oxford University Press 2006. ISBN-10: 0199295735, ISBN-13: 978-0199295739
• Z. Szallasi, J. Stelling, and V.Periwal (eds.) System Modeling in Cellular Biology: From Concepts to Nuts and Bolts (Hardcover), MIT Press: 2006, ISBN 0-262-19548-8
• B Palsson, Systems Biology - Properties of Reconstructed Networks. Cambridge University Press: 2006. ISBN 978-0-521-85903-5
• K Kaneko. Life: An Introduction to Complex Systems Biology. Springer: 2006. ISBN 3540326669
• U Alon. An Introduction to Systems Biology: Design Principles of Biological Circuits. CRC Press: 2006. ISBN 1-58488-642-0 - emphasis on Network Biology (For a comparative review of Alon, Kaneko and Palsson see^[13] )

Articles

• M. Tomita, Hashimoto K, Takahashi K, Shimizu T, Matsuzaki Y, Miyoshi F, Saito K, Tanida S, Yugi K, Venter JC, Hutchison CA. E-CELL: Software Environment for Whole Cell Simulation. Genome Inform Ser Workshop Genome Inform. 1997;8:147-155. [2]
• ScienceMag.org - Special Issue: Systems Biology, Science, Vol 295, No 5560, March 1, 2002
• Marc Vidal and Eileen E. M. Furlong. Nature Reviews Genetics 2004 From OMICS to systems biology
• Marc Facciotti, Richard Bonneau, Leroy Hood and Nitin Baliga. Current Genomics 2004 Systems Biology Experimental Design - Considerations for Building Predictive Gene Regulatory Network Models for Prokaryotic Systems
• Katia Basso, Adam A Margolin, Gustavo Stolovitzky, Ulf Klein, Riccardo Dalla-Favera, Andrea Califano, (2005) "Reverse engineering of regulatory networks in human B cells". Nat Genet;37(4):382-90
• Mario Jardon Systems Biology: An Overview - a review from the Science Creative Quarterly, 2005
• Johnjoe McFadden, Guardian.co.uk - 'The unselfish gene: The new biology is reasserting the primacy of the whole organism - the individual - over the behaviour of isolated genes', The Guardian (May 6, 2005)
• WTEC Panel Report on International Research and Development in Systems Biology (2005)
• E. Werner, "The Future and Limits of Systems Biology", Science STKE 2005, pe16 (2005).
• Francis J. Doyle and Jörg Stelling, "Systems interface biology" J. R. Soc. Interface Vol 3, No 10 2006
• Kahlem, P. and Birney E. (2006). "Dry work in a wet world: computation in systems biology." Mol Syst Biol 2: 40.
• E. Werner, "All systems go", "Nature" vol 446, pp 493-494, March 29, 2007. (Review of three books (Alon, Kaneko, and Palsson) on systems biology.)
• Santiago Schnell, Ramon Grima, Philip K. Maini, "Multiscale Modeling in Biology", American Scientist, Vol 95, pages 134-142, March-April 2007.
• TS Gardner, D di Bernardo, D Lorenz and JJ Collins. "Inferring genetic networks and identifying compound of action via expression profiling." Science 301: 102-105 (2003).

References

1. ^ Snoep J.L. and Westerhoff H.V.; Alberghina L. and Westerhoff H.V. (Eds.) (2005.). "From isolation to integration, a systems biology approach for building the Silicon Cell". Systems Biology: Definitions and Perspectives: p7, Springer-Verlag. 
2. ^ Systems Biology - the 21st Century Science.
3. ^ Sauer, U. et al. "Getting Closer to the Whole Picture" Science (journal) 316 550 17 April 2007
4. ^ Denis Noble The Music of Life Oxford University Press (2006) p21
5. ^ Systems Biology: Modelling, Simulation and Experimental Validation.
6. ^ Kholodenko B.N., Bruggeman F.J., Sauro H.M.; Alberghina L. and Westerhoff H.V.(Eds.) (2005.). "Mechanistic and modular approaches to modeling and inference of cellular regulatory networks". Systems Biology: Definitions and Perspectives: p143, Springer-Verlag. 
7. ^ Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol, 117: 500-544.
8. ^ Le Novere (2007) The long journey to a Systems Biology of neuronal function. BMC Systems Biology, 1: 28
9. ^ Noble D (1960) Cardiac action and pacemaker potentials based on the Hodgkin-Huxley equations. Nature, 188: 495-497.
10. ^ Working the Systems.
11. ^ Gardner, TS; di Bernardo D, Lorenz D and Collins JJ (04 Jul 2003). "Inferring genetic networks and identifying compound of action via expression profiling". Science 301: 102-1005. PMID 12843395.
12. ^ di Bernardo, D; Thompson MJ, Gardner TS, Chobot SE, Eastwood EL, Wojtovich AP, Elliot SJ, Schaus SE and Collins JJ (Mar 2005). "Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks". Nature Biotechnology 23: 377-383. PMID 15765094.
13. ^ Werner, E., "All systems go"., Naturevol 446, pp 493-494, March 29, 2007.