Systems biology

As an academic discipline, systems biology aims to explain, predict and control the functions, properties and behaviors of biological systems--assemblages of interrelated, dynamically interacting, coordinated and hierarchically organized components. Developing models, including quantitative models, systems biologists try to achieve those aims in part through analyses of experimentally derived data about the interacting components. They work to develop realistic representations of biological systems that can allow predictions of their properties, functions and behavior in response to given stimuli and given sets of conditions. They use sophisticated mathematical, statistical and computational tools in diverse modeling approaches, in network analyses, in computer simulations, in design and building synthetic networks and models; and, iteratively, incorporating data derived from systems-analysis-inspired further experimentation. They try to accomplish their aims in part:

• by studying the interrelations (structural, organizational) and interactions (dynamical, coordinated) among various components of a biological system (e.g., gene and protein interactions involved in metabolic pathways or cell signaling);

• by organizing and analyzing those components in terms of abstractions such as modules, circuits and networks, feedback and feedforward loops, hierarchies, robustness, complexity, and emergence; and,

• by design, construction and testing of synthetic networks.

Systems biologists expect progress in the field to yield understanding of biological systems-as-a-whole suitable for applications in ecology, ethology, medicine, agriculture, business, and technology--and to some extent it has already done so. Some systems biologists consider the discipline critical to further progress in biology.

In the late 20th and early 21st century, the study of biological systems has greatly expanded as the result of major advances in molecular biology, including sequencing of genomes and developments in genetic engineering, and the developments of technologies for generating massive amounts of data on the structure and organization of the cell--all fueled by increasing interest by mathematicians, computer scientists, physicists, chemists, and engineers, among other non-biological scientists, in applying the principles and methods of their sciences to the understanding of adaptive biological complexity.

No definition or succinct description can capture the breadth and depth of the interdisciplinary enterprise of systems biology. Indeed, historian and philosopher of science Evelyn Fox Keller argues that “so far, ‘systems biology’ is a concept waiting for definition". This article elaborates on the above description of the discipline.

On the Nature of Biological "Systems"

A 'system' in biology comprises any interconnected, interacting and coordinated assemblage of biological components or elements. For example, the vertebrate body system consists of an assemblage of interacting organs, among other components. Each component or element in a biological system interacts in some way(s) with one or more co-components or co-elements in the system--a dynamical assemblage of components. For example, in the system constituting a cell, proteins interact with genes, metabolites and other elements. Systems exhibit behavior or behaviors characteristic of the system-as-a-whole, or subsystem-as-a-whole (see below), and not shared to any degree, or to any major degree, with any of its components (so-called emergent behaviors). A tree fruits, for example, because its dynamically interacting components enable it to, but no component of a tree can.

Subsystems consist of smaller (less complex) systems embedded in a larger (more complex) system, and constitute at least part of the components or elements of the larger system. Whether a systems biologist treats a given assemblage of components or elements as a subsystem or as a system depends on the 'level' at which she focuses her attention. If she focuses her research at the level of a whole vertebrate organism, for example, she treats its organs as subsystems. If she focuses her research at the level of the heart, she treats the heart's interacting assemblage of components as a system, recognizing that the heart system remains a component or element of a larger system (e.g., the circulatory system).

Even the larger systems, e.g., the vertebrate body system, function as components or elements of even larger systems, a species of vertebrates, say, where individual members of the species interact with each other, as components, to generate a set of behaviors or properties characteristic of the species but not of the individual members of the species. The flocking behavior of birds illustrates a species behavior--technically the behavior of a deme--that one bird cannot accomplish.

For purposes of trying to understand biological systems, systems biologists need not treat the components or elements of a system (or subsystem) exclusively as discrete or concrete objects or entities (e.g., molecules, organelles, cells, etc.), but may also treat them as abstracted concepts of organizational collections or activity patterns of those objects or entities, admitting of study by advanced mathematical, computational and statistical tools. Those include such concepts as circuits, networks and modules, more about which will follow below. Such concepts have a way of appearing less abstract or hypothetical as biologists more fully define them in terms of structure and coordinated dynamical interactions; predict systems behavior from them using quantitative models; and relate them functionally in the the larger systems embedding them.

Biological system behaviors typically perform one or more evolution-informed functions, so unravelling the evolutionary history of a biological system contributes importantly in fully understanding it.

Examples of biological systems (subsystems) include:

• ecosystems (e.g., a forest)
• species (e.g., Homo sapiens)
• demes (e.g., a local population of a species)
• organisms (e.g., humans; bacteria)
• organs (e.g., brain; the vascular endothelium)
• cells (e.g., epithelial cell)
• metabolic pathways (e.g., glycolysis)
• genes (e.g., protein blueprints)
• gene complexes (e.g., co-expressing genes)
• genomes (e.g., the entire complement of DNA in an organism, as the ’mouse genome')
  

History of Systems Biology

Knowledge of the historical path(s) leading to a modern scientific program offers a perspective that contributes heuristically to an understanding of the nature of the program, in particular, its goals and its methodologies. So for systems biology. In part, the facilitation to understanding results from the different focuses and approaches different historians have in writing about the same topic.

The Evolution of Molecular Biology into Systems Biology

Westerhoff and Palsson introduce the school of thought “…that systems biology of the living cell has its origin in the expansion of molecular biology to genome-wide analyses.” They point out, however, that molecular biology has an earlier history of systems thinking, in particular in the elucidation of numerous molecular regulatory circuits and of their contribution to the logic of the cell. They see technologic advances that have permitted rapid collection of large data sets (so-called high-throughput technologies mapping the genome) as upping the scale of that research “…enabling us [molecular biologists] to view the genome as the ‘system’ to study.”

They describe two separate pathways of enquiry that they see as having merged into modern systems biology of the cell.

They see one root as the advances in molecular biology that ultimately “…led to efforts toward genome-scale model building to analyze the systems properties of cellular function”: recognition of DNA as the genetic material, identifying the structure of DNA, recombinant technology, automated determination of DNA base sequences, and high-throughput technologies yielding the sequences of entire genomes.

They discuss as a second, parallel root the development of non-equilibrium thermodynamics, a predictive mathematical theory for describing the behavior of systems that transfer energy from one place to another or convert energy from one form to another in processes the move towards an irreversible state of stability characterized by randomness or disorder—for biological systems, death. Since living systems produce order and maintain a state of non-randomness they must carry out processes that keep them in a condition far from the equilibrium of randomness, which they achieve by transforming energy (and matter and information) taken in from the environment. The non-closed biological system produces order at the expense of the environment it opens to, which environment becomes more disordered.

Westerhoff and Palsson describe advances in the development of non-equilibrium thermodynamics as presaging molecular and cellular systems biology through ‘quantitative’ integration of system components and through the discovery of principles connecting molecular mechanisms and system behaviors. Westerhoff and Alberghina ask of systems biology: “Did we know it all along?”

Some Important Historical Milestones Leading to the Development of Systems Biology

Anthony Trewavas, a scientist conducting research in the molecular and systems biology of plant cells, emphasizes the following aspects of the history of systems biology (see references cited in Trewavas article):

• How Rene Descartes’ formulation of reductionism—the concept that one could explain the properties/functions/behaviors of complex objects/events by reducing them into their parts and studying the properties/functions/behaviors of the parts to explain/predict the properties/functions/behaviors of the whole—led biologists at first to the unwarranted assumption that one could explain a complex biological system's behavior from the behavior of its subsystems;

• How reductionism played hand-in-hand with the mechanistic view of reality, leading biologists to view systems as predetermined complex machines, like clocks;

• How reaction against the reductionist-mechanistic view led to a holistic view of biological systems consistent with Aristotle’s dictum that adding together the values of the parts does not result in the value of the whole—substitute ‘concatenating’ or ‘joining’ for ‘adding’, and ‘function” or ‘behavior’ for ‘value’.;

• How experiments revealed that the averaged behavior of a population did not apply to individual members of the population, however homogeneous the population appeared, complementing experiments revealing non-machine-like toleration of large variability among kindred organisms, organs and cells with respect to behavior and function—each manifesting a so-called norm of reaction that overlapped among individuals;

• How a system’s organization of subsystems itself exerts a level of control and constraint over the range of behaviors available to the subsystems in isolation;

• How a system’s subsystems exist in hierarchies, where the properties of a subsystem emerge from the dynamic interactions of subsystems at lower levels of the hierarchy;

• How subsystems at lower levels of hierarchy exhibit more variability and how their behavior exhibits more order within the system than without—the higher level emergent properties orchestrate and constrain the behavior of the subsystems generating that emergence;

• How Karl Ludwig von Bertalanffy [b. 1901, d. 1972] recognized that all systems share “…the common property of being composed of interlinked components, in which case they might share similarities in detailed structure and control design”;

• How Michael Polyani [b. 1891, d. 1976] recognized that adjacent levels of a system’s subsystems constrain each other and that upper level behaviors require the lower level behaviors;

• How psychologist and polymath Donald T. Campbell [b, 1916, d. 1996] coined the term “downward causation” to describe higher system level constraints on lower levels, as in constraints on gene expression by higher level subsystems—a prelude to understanding ‘emergent’ systems as having properties or behaviors that “make a difference”, i.e., have causal properties;

• How the work of Claude Bernard, Walter Cannon, and Norbert Weiner established the importance of negative feedback for maintaining stability within large systems, leading to subsequent demonstration of negative feedback at the molecular level;

• How the identification of feed-forward mechanisms led to advances in understanding the features characterizing the design of systems control mechanisms.

Growth of Publications Relating Systems Biology

The historical pace of research in systems biology greatly accelerated at the beginning of the 21st century. The figure below shows the exponential growth of publications relating to or discussing systems biology in the decade 1996-2006. The data points derive from the National Library of Medicine's PubMed database, and likely underestimate annual "systems biology" publication rates by not including articles in journals in many non-biological disciplines that apply to the subject. [[Image:Growth_sysbio_pubs.jpg|thumb|400px|center|Growth in papers on systems biology.]}

[…more to come…]

Modeling in Systems Biology

For systems biologists, modeling serves as the key to unlocking the system of interest, whether a cell, a species, or an ecosystem.

Reminding us of the story of the six blind men investigating a different part of an elephant and coming up with six different descriptions of the animal, James Haefner wrote:

One failure of the blind men was to ignore the relations between objects. A seventh man, one sensitive to the importance of testing alternative models, might have said: “Hmmm, ‘tree’, ‘snake’, ‘fan’, ‘spear’, ‘wall’, ‘rope’: It’s a single, big thing with columnar supports and appendages at the ends.” The blind men, especially, need a systems approach, and with respect to the scientific unknown, we are all blind.

To understand a key systems approach, one must know something about model building, or simply, modeling, especially computer-based quantitative modeling. Models represent (re-present) reality in an abstract form, such as a diagram, a rule, a theory, a graph, a formula, a set of equations, a computer program. Systems biologists use numerous different quantitative mathematical models as keys to understanding biological systems—their logic, say—and as keys to predicting and controlling their behavior.

Quantitative models of biological systems potentially serve these main functions:

• They allow management of data sets of structures and interactions too large and complex for the human mind to manage without the “exo-cortex” computer-based quantitative representation;

• They participate in an iterative process whereby experimental data inspires a model and the model suggests the need for further experimental research the results of which inspire changes in the model, which repeats the cycle;

• By failing to fully account for the targeted behavior of the system:

• they raise the possibility of the existence of unknown subsystems of the system that require further experimental work, and may give direction to that further research;

• they inspire refinements of the model to account for the gaps;

• They provide an satisfying and usable ‘explanation’ of the system—an explanation of its properties, functions and behaviors in quantitative terms of its coordinated, dynamically interacting, hierarchically arranged components;

• They enable ‘control’ of the system—the ability to induce a desired behavior or propensity with the appropriate manipulation;

• They enable ‘prediction’ of the behavior of the system—predicting how it will respond to a given set of circumstances, especially predicting novel behaviors of the system.

Despite the large datasets available for many biological systems, especially cell systems, they still fall short in quantity and quality for realizing the full potential of quantitative modeling in applying advanced methodologies for statistical analyses, testing of hypotheses, and estimating the values of equation constants and independent variables. Wellstead et al. note the “enormous challenges to bio-sensing for systems biology” that lie ahead.

Some Examples of Familiar Models

The examples below facilitate learning about modeling heuristically.

A road map of an urban complex: For a given level of detail, a road map represents (re-presents, or models) the structure of the system of roads in a region of land at a given point in time, using the language of graphic illustration. In network parlance, cities and other points of interest (e.g., parks, lakes) serve as nodes and the connections between nodes serve as edges, some of which may indicate one-way connections only. Using the road map, one can control the system of roads in the sense that one can exploit the information to get from one place (node) to another, and predict how long it will take to get there. The level of detail may not allow determination of the grades of the roads (steepness) or the degrees of curviness or the position of side roads or new roads added since the date of the map.

Systems biologists use maps, for example, to model the structure and interrelationships among biochemical molecules in cellular subsystems, such as the subsystems that convert glucose to usable energy and to other biochemical molecules (e.g., glycogen).

A chemical formula: Anyone reading this far knows H2O as a model (representation) for the substance, water. As such it has many uses, in particular in modeling chemical reactions. Other models of water, such as HOH, or

provide additional information for particular purposes.

A computer-based flight simulator: For a given level of detail, a computer-based flight simulator represents the multi-subsystem of a flight vehicle system (e.g., airplane), including its control characteristics, and the environment in which the flight vehicle must interact with in order to function stably and exhibit its system behavior of taking off, flying to destination, and landing. The representation (model) uses the languages of engineering, mathematics, computer programs, and dynamical graphics, among others to enable control of the system and to predict its behavior in response to a given set of environmental conditions for comparison with the response to those conditions in real flight—testing the goodness of fit of the model.

Systems biologists use computer-based simulators, for example, to predict the behavior of the human heart in response to drugs.

Newton’s equations: For macroscopic mechanical systems, Newton’s equations represent, or model, the behavior of bodies of mass in motion, allowing predictions of the trajectories of moving masses, including the masses comprising the solar system; allowing calculation of the strength of the mutual attraction of masses and the contribution of each of two masses to that attraction; enabling explanation of macroscopic properties of gases and liquids (e.g., pressure, temperature) from the average effects of microscopic particles interacting in conformity with Newton’s equations; and, enabling engineers to construct vehicles for transporting humans to the moon and back.

Systems biologists use mathematical expressions, often more complex than Newton’s equations, based on empirical data and theoretical principles, in numerous ways to model the behavior of biological systems at all hierarchical levels. See below.

Examples of Modeling in Systems Biology

Introductory remarks here…

Darwin’s theory of evolution by means of natural and sexual selection: Darwin’s theory, stated conceptually in words, and its 20th century amplification, stated genetically/molecularly often in quantitative terms, represents, or models, the behavior of nature in creating species and varieties sufficiently adapted to their environment to survive long enough to reproduce and care for their offspring and kin. The theory enables understanding of an enormous range of behaviors of animals, plants, unicellular organisms, and cellular and subcellular systems, and has explanatory and predictive value in every biological discipline, and many non-biological disciplines.

Evolutionary principles permeate the discipline of systems biology and have led to the emerging discipline of “evolutionary system biology” A case in point: Determining whether natural selection operating at the molecular level has forged the structure of molecular networks may enhance understanding of their underlying design principles and thereby facilitate design of better predictive models.

Human Walking and Running: In the human organism, walking and running emerge as system behaviors (no subsystem itself walks or runs). The energy cost to the system of those locomotor behaviors defines a property of the system applicable to those behaviors. The energy cost owes to the appropriate forces the system must generate to support itself against gravity and to swing the locomoting limbs to achieve forward motion. Researchers have found that the rate at which the system produces those forces—shorthanded simply to ‘force production’—correlates with the system’s energy cost of locomotion. Thus, if one could develop a mathematical model that predicts force production from readily determined values of variables related to anatomy (e.g., limb length) and motion (e.g., forward speed), that model could then predict the system property of energy cost of locomotion.

Based on the findings of earlier studies, Harvard anthropologist Herman Pontzer developed a mathematical model—viz., an equation—that justified force production as a function of three variables: the rate of muscular force production in the vertical direction, the rate of muscular force production in the horizontal direction, and the rate of muscular force production required to swing the limbs. From empirical data, knowledge of trigonometry and physics (force mechanics) and of muscle physiology, he identified measureable anatomical and motor variables--length and proportion of limbs, speed, frequency of stride, and angle of excursion--that allowed estimation of those required three force variables. Following earlier studies that linked force production with cost of locomotion, he generated the model--the equation--he hoped to predict the latter from the former. He found that the model well predicted the observed cost of locomotion, somewhat better for running than walking.

[...discuss implications and refinements of the model to demonstrate power of modeling...]

[...Work in progress…More examples to come...]

Systems biology, emergent behaviour and the 'new vitalism'

In terms of cell biology , a type of 'vitalism' can be recognized in contemporary molecular biology, for example in the proposal that some high level features of organisms, perhaps including even life itself, are examples of emergent processes which cannot be accurately described simply by understanding each of the chemical processes which occur in the cell in isolation from all the others ; When individual chemical processes form interconnected feedback cycles which produce products perpetuating these cycles rather than unconnected products, they can form systems with properties that the reactions, taken individually, lack . Such emergent processes have been recognised as, for example, contributing to subcellular morphology , developmental biology , metabolic networks , proteomics and indeed in purely physical systems as well as biological systems . At a higher level, emergent processes are a widespread concept in cellular neuroscience and in cognitive science . At a still higher level, emergent properties are recognised for example in the behaviour of ant colonies and the concept of swarm intelligence,; they have been simulated in artificial systems , and parallels have been drawn with human societies .

History

[...incorporate in above "history" section...]

In 1952, the British neurophysiologists and nobel prize winners Alan Lloyd Hodgkin and Andrew Fielding Huxley constructed a mathematical model of the action potential - the fundamental mechanism underlying communication between nerve cells, expressing it as the consequence of a dynamic interaction between interdependent ionic conductances of the cell membrane. In 1960, Denis Noble developed the first computer model of a beating heart. Systems biologists invoke these pioneering pieces of work as illustrative of the systems biology project. The possibility of performing systems biology increased around the year 2000 with the completion of various genome projects and the proliferation of genomic and proteomic data, and the accompanying advances in experimental methodology.

The experimental procedures available during the 20th century necessitated 'one protein at a time' projects which have been the mainstay of molecular biology since its inception. Some biologists and biochemists believe that this approach of individual biomolecules has fostered a reductionist perspective, and that it is just the first step toward an understanding of the overall (integrated) life process, which can only be properly addressed from a systems biology perspective.

Approaches

There are two major and complementary focuses in systems biology:

• Quantitative Systems Biology - otherwise known as "systems biology measurement", it focuses on measuring and monitoring biological systems on the system level.
• Systems Biology Modeling - focuses on mapping, explaining and predicting systemic biological processes and events through the building of computational and visualization models.

Quantitative systems biology

This subfield is concerned with quantifying molecular reponses in a biological system to a given perturbation.

Some typical technology platforms are:

• Gene expression measurement through DNA microarrays and SAGE
• Protein levels through two-dimensional gel electrophoresis and mass spectrometry, including phosphoproteomics and other methods to detect chemically modified proteins.
• metabolomics for small-molecule metabolites
• glycomics for sugars

These are frequently combined with large scale perturbation methods, including gene-based (RNAi, misexpression 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 until the predicted behavior accurately reflects the phenotype seen.

Systems biology modeling

[...incorporate in above "modelling" section...]

Using knowledge from molecular biology, the systems biologist can causally model the biological system of interest and propose hypotheses that explain a system's behavior. These hypotheses can then be confirmed and be used as a basis for a mathematically model of the system. The difference between the two modeling approaches is that causal models are used to explain the effects of a biological perturbations while mathematical models are used to predict how different perturbations in the system's environment affect the system.

== Applications== Many predictions concerning the impact of genomics on health care have been proposed. For example, the development of novel therapeutics and the introduction of personalised treatments are conjectured and may become reality as a small number of biotechnology companies are using this cell-biology driven approach to the development of therapeutics. However, these predictions rely upon our ability to understand and quantify the roles that specific genes possess in the context of human and pathogen physiologies. The ultimate goal of systems biology is to derive the prerequisite knowledge and tools. Even with today's resources and expertise, this goal is distant.

International conferences

• International Conference on Complex Systems
• International Conference on Systems Biology, 2006

Tools for systems biology

• Systems Biology Markup Language - developed by the Computational Neurobiology group at the European Bioinformatics Institute
• PSIbase Database structural interactome map of all proteins
• SimTK
• Gaggle
• Genevestigator
• Systems Biology Workbench
• Systems Biology Markup Language
• The CellML language
• The little b Modeling Language
• Copasi (Version 4 of Gepasi)
• E-Cell System
• StochSim
• Virtual Cell
• JigCell (John Tyson Lab)
• Python Simulator for Cellular Systems
• Ingenuity Pathways Analysis
• SAVI Signaling Analysis and Visualization
• JSim
• BioNetGen
• SBML-PET Systems Biology Markup Language based Parameter Estimation Tool
• BIOREL web-based resource for quantitative estimation of the gene network bias in relation to available database information about gene activity/function/properties/associations/interactions

Bibliography

Books

• Kitano H (editor) Foundations of Systems Biology. MIT Press: 2001. ISBN 0-262-11266-3
• 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
• Klipp E, Herwig R, Kowald A, Wierling C, Lehrach H (2005) Systems Biology in Practice. Wiley-VCH: ISBN 3-527-31078-9
• Palsson B (2006) Systems Biology - Properties of Reconstructed Networks. Cambridge University Press: 2006. ISBN 9780521859035
• Szallasi Z, Stelling J, Periwal V (eds). System Modelling in Cellular Biology: From Concept to Nuts and Bolt. A Bradford Book, The MIT Press: 2006. ISBN 0-262-19548-8 [4 SECTIONS; 17 CHAPTERS; 36 CONTRIBUTORS]

Articles

• Vidal M, Furlong EEM (2004) Nature Reviews Genetics From OMICS to systems biology

• Werner E (2005) The future and limits of systems biology, Science STKE pe16 (2005).

• ScienceMag.org - Special Issue: Systems Biology, Science, Vol 295, No 5560, March 1, 2002
• Nature - Molecular Systems Biology
• Systems Biology: An Overview - a review from the Science Creative Quarterly
• 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', Johnjoe McFadden, The Guardian (May 6, 2005)
• Trewavas AJ (2006) A brief history of systems biology: "Every object that biology studies is a system of systems." Francois Jacob (1974). Plant Cell 18:2420-30 Fulltext or PDF need access rights

External links

• BioChemWeb.org - The Virtual Library of Biochemistry and Cell Biology: A Guide to Biochemistry, Molecular Biology & Cell Biology on the Web
• Systems Biology Portal - administered by the Systems Biology Institute
• Community for Interactomics - Systems Biology Wiki
• Systems Biology Medicine Symposium 2006 - View webcasts (in Real Player or Windows Media Player) of a symposium on research and applications of systems approaches in Medicine

See also

• Gene regulatory network
• Metabolic network modelling
• Model
• Computer simulation
• Important publications in systems biology
• Systems ecology
• Regulome
• Biomedical cybernetics
• Artificial life