Systems biology
sation), although fully consistent with the scientic
An illustration of the systems approach to biology
Systems biology is the computational and mathematical
modeling of complex biological systems. An emerg-
ing engineering approach applied to biological scien-
tic research, systems biology is a biology-based inter-
disciplinary eld of study that focuses on complex
interactions within biological systems, using a holis-
tic approach (holism instead of the more traditional
reductionism) to biological research. Particularly from
year 2000 onwards, the concept has been used widely
in the biosciences in a variety of contexts. For exam-
ple, the Human Genome Project is an example of applied
systems thinking in biology which has led to new, col-
laborative ways of working on problems in the biological
eld of genetics.[1] One of the outreaching aims of sys-
tems biology is to model and discover emergent proper-
ties, properties of cells, tissues and organisms functioning
as a system whose theoretical description is only possible
using techniques which fall under the remit of systems bi-
ology. These typically involve metabolic networks or cell
signaling networks.[2]
1 Overview
Systems biology can be considered from a number of dif-
ferent aspects:
As a eld 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 path-
way).[3][4]
As a paradigm, usually dened in antithesis to the
so-called reductionist paradigm (biological organi-
1
method. The distinction between the two paradigms
is referred to in these quotations:
The reductionist approach has successfully
identied most of the components and many
of the interactions but, unfortunately, oers no
convincing concepts or methods to understand
how system properties emerge...the pluralism of
causes and eects in biological networks is bet-
ter addressed by observing, through quantitative
measures, multiple components simultaneously
and by rigorous data integration with mathe-
matical models (Sauer et al.).[5]
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 rigor-
ous as our reductionist programmes, but dier-
ent....It means changing our philosophy, in the
full sense of the term (Denis Noble).[6]
As a series of operational protocols used for per-
forming research, namely a cycle composed of the-
ory, analytic or computational modelling to propose
specic testable hypotheses about a biological sys-
tem, experimental validation, and then using the
newly acquired quantitative description of cells or
cell processes to rene the computational model or
theory.[7] Since the objective is a model of the in-
teractions in a system, the experimental techniques
that most suit systems biology are those that are
system-wide and attempt to be as complete as pos-
sible. Therefore, transcriptomics, metabolomics,
proteomics and high-throughput techniques are used
to collect quantitative data for the construction and
validation of models.[8]
As the application of dynamical systems theory to
molecular biology. Indeed, the focus on the dy-
namics of the studied systems is the main con-
ceptual dierence between systems biology and
bioinformatics.[9]
As a socioscientic phenomenon dened by the
strategy of pursuing integration of complex data
about the interactions in biological systems from di-
verse experimental sources using interdisciplinary
tools and personnel.[10]
2 3 ASSOCIATED DISCIPLINES

This variety of viewpoints is illustrative of the fact that articles [18][19][20][21][22] on systems medicine, systems ge-
systems biology refers to a cluster of peripherally over- netics and systems biological engineering by B. J. Zeng
lapping concepts rather than a single well-delineated eld. were published in China, and was giving a lecture on
However the term has widespread currency and popular- biosystems theory and systems approach research at the
ity as of 2007, with chairs and institutes of systems biol- First International Conference on Transgenic Animals,
ogy proliferating worldwide. Beijing, 1996. In 1997, the group of Masaru Tomita pub-
lished the rst quantitative model of the metabolism of a
whole (hypothetical) cell.[23]
2 History Around the year 2000, after Institutes of Systems Biology
were established in Seattle and Tokyo, systems biology
Systems biology nds its roots in: emerged as a movement in its own right, spurred on by the
completion of various genome projects, the large increase
the quantitative modeling of enzyme kinetics, a dis- in data from the omics (e.g., genomics and proteomics)
cipline that ourished between 1900 and 1970, and the accompanying advances in high-throughput ex-
periments and bioinformatics.
the mathematical modeling of population dynamics,
In 2002, the National Science Foundation (NSF) put for-
the simulations developed to study neurophysiology, ward a grand challenge for systems biology in the 21st
and century to build a mathematical model of the whole
cell.[24] In 2003, work at the Massachusetts Institute of
control theory and cybernetics. Technology was began to CytoSolve, a method to model
the whole cell by dynamically integrating multiple molec-
One of the theorists who can be seen as one of the precur- ular pathway models.[25][26] Since then, various research
sors of systems biology is Ludwig von Bertalany with institutes dedicated to systems biology have been devel-
his general systems theory.[11] One of the rst numer- oped. For example, the NIGMS of NIH established a
ical simulations in cell biology was published in 1952 project grant that is currently supporting over ten systems
by the British neurophysiologists and Nobel prize win- biology centers in the United States.[27] As of summer
ners Alan Lloyd Hodgkin and Andrew Fielding Huxley, 2006, due to a shortage of people in systems biology[28]
who constructed a mathematical model that explained the several doctoral training programs in systems biology
action potential propagating along the axon of a neuronal have been established in many parts of the world. In
cell.[12] Their model described a cellular function emerg- that same year, the National Science Foundation (NSF)
ing from the interaction between two dierent molecu- put forward a grand challenge for systems biology in the
lar components, a potassium and a sodium channel, and 21st century to build a mathematical model of the whole
can therefore be seen as the beginning of computational cell.[29]
systems biology.[13] Also in 1952, Alan Turing published
The Chemical Basis of Morphogenesis, describing how
non-uniformity could arise in an initially homogeneous 3 Associated disciplines
biological system.[14]
In 1960, Denis Noble developed the rst computer model Chemokines,
Hormones,

of the heart pacemaker.[15]

Survival Factors Transmitters Growth Factors
Extracellular
(e.g., IGF1) (e.g., interleukins, (e.g., TGF, EGF)
Matrix
serotonin, etc.)

The formal study of systems biology, as a distinct RTK

GPCR
RTK cdc42
Integrins
Wnt

discipline, was launched by systems theorist Mihajlo PLC Grb2/SOS

Fyn/Shc
Frizzled

PI3K G-Protein Ras FAK Dishevelled

Mesarovic in 1966 with an international symposium at

Src
Akt Raf GSK-3
PKC Adenylate
cyclase Hedgehog
Akk MEK
Cytokine Receptor

NF-B APC

the Case Institute of Technology in Cleveland, Ohio, en- Cytokines IB

PKA MEKK MAPK MKK -catenin
Patched

JAKs
(e.g., EPC)

titled Systems Theory and Biology.[16][17]

STAT3,5 TCF
Myc: Mad: ERK JNKs
Bcl-xL Max Max -catenin:TCF
Fos Jun
SMO

The 1960s and 1970s saw the development of several ap- Cytochrome C

Caspase 9
CREB CycID
Rb CDK4
p16
p15
Gli

E2F
proaches to study complex molecular systems, such as the Caspase 8 Apoptosis
ARF
Gene Regulation
CyclE
CDK2
p27

metabolic control analysis and the biochemical systems

p21
Cell
FADD mdm2
Bcl-2 Proliferation
p53
Bad
Mt Bax

theory. The successes of molecular biology throughout FasR

Abnormality
Sensor Bim

the 1980s, coupled with a skepticism toward theoretical

Death factors

biology, that then promised more than it achieved, caused (e.g. FasL, Tnf)

the quantitative modelling of biological processes to be-

Overview of signal transduction pathways
come a somewhat minor eld.
However the birth of functional genomics in the 1990s According to the interpretation of Systems Biology as
meant that large quantities of high quality data became the ability to obtain, integrate and analyze complex data
available, while the computing power exploded, making sets from multiple experimental sources using interdisci-
more realistic models possible. In 1992, then 1994, serial plinary tools, some typical technology platforms are:

Phenomics
Organismal variation in phenotype as it
changes during its life span.
Genomics
Organismal deoxyribonucleic acid (DNA) se-
quence, including intra-organisamal cell spe-
cic variation. (i.e., telomere length variation)
Epigenomics / Epigenetics
Organismal and corresponding cell specic
transcriptomic regulating factors not empiri-
cally coded in the genomic sequence. (i.e.,
DNA methylation, Histone acetylation and
deacetylation, etc.).
Transcriptomics
Organismal, tissue or whole cell gene expres-
sion measurements by DNA microarrays or
serial analysis of gene expression
Interferomics
Organismal, tissue, or cell-level transcript cor-
recting factors (i.e., RNA interference)
Translatomics / Proteomics
Organismal, tissue, or cell level measurements
of proteins and peptides via two-dimensional
gel electrophoresis, mass spectrometry or
multi-dimensional protein identication tech-
niques (advanced HPLC systems coupled
with mass spectrometry). Sub disciplines
include phosphoproteomics, glycoproteomics
and other methods to detect chemically mod-
ied proteins.
Metabolomics
Organismal, tissue, or cell-level measurements
of small molecules known as metabolites
Glycomics
Organismal, tissue, or cell-level measurements
of carbohydrates
Lipidomics
Organismal, tissue, or cell level measurements
of lipids.
3
In addition to the identication and quantication of the
above given molecules further techniques analyze the dy-
namics and interactions within a cell. This includes:
Interactomics
Organismal, tissue, or cell level study of in-
teractions between molecules. Currently the
authoritative molecular discipline in this eld
of study is protein-protein interactions (PPI),
although the working denition does not pre-
clude inclusion of other molecular disciplines
such as those dened here.
NeuroElectroDynamics
Organismal, brain computing function as a dy-
namic system, underlying biophysical mecha-
nisms and emerging computation by electrical
interactions.
Fluxomics
Organismal, tissue, or cell level measurements
of molecular dynamic changes over time.
Biomics
Systems analysis of the biome.
Semiomics
Analysis of the system of sign relations of an
organism or other biosystem.
Cancer Systems Biology is an important appli-
cation of systems biology approach, which can
be distinguished by the specic object of study
(tumorigenesis and treatment of cancer). It works
with the specic data (patient samples, high-
throughput data with particular attention to char-
acterizing cancer genome in patient tumour sam-
ples) and tools (immortalized cancer cell lines,
mouse models of tumorigenesis, xenograft mod-
els, Next Generation Sequencing methods, siRNA-
based gene knocking down screenings, computa-
tional modeling of the consequences of somatic
mutations and genome instability).[30] The long-
term objective of the systems biology of cancer is
ability to better diagnose cancer, classify it and bet-
ter predict the outcome of a suggested treatment,
which is a basis for personalized cancer medicine
and virtual cancer patient in more distant prospec-
tive. Signicant eorts in Computational sys-
tems Biology of Cancer have been made in creat-
ing realistic multi-scale in silico models of various
tumours.[31]
4 6
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 technolo-
gies 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 work-
ing to improve the quality of these approaches and to
create, rene, and retest the models to accurately reect
observations.
The systems biology approach often involves the develop-
ment of mechanistic models, such as the reconstruction
of dynamic systems from the quantitative properties of
their elementary building blocks.[32][33][34] For instance,
a cellular network can be modelled mathematically using
methods coming from chemical kinetics and control the-
ory. Due to the large number of parameters, variables
and constraints in cellular networks, numerical and com-
putational techniques are often used (e.g., ux balance
analysis).[34]
4 Bioinformatics and data analysis
Other aspects of computer science, informatics, statistics
are also used in systems biology. These include:
New forms of computational model, such as the
use of process calculi to model biological processes
(notable approaches include stochastic -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 min-
ing.
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.
Development of syntactically and semantically
sound ways of representing biological models.
Network-based approaches for analyzing high di-
mensional genomic data sets. For example,
weighted correlation network analysis is often used
for identifying clusters (referred to as modules),
modeling the relationship between clusters, calcu-
lating fuzzy measures of cluster (module) member-
ship, identifying intramodular hubs, and for study-
ing cluster preservation in other data sets.
REFERENCES
5 See also
Biological computation
Computational biology
Interactome
Exposome
Network Biology
Weighted correlation network analysis
Synthetic biology
List of omics topics in biology
List of systems biology research groups
Systems biologists
Systems biomedicine
Flux balance analysis
Metabolic network modelling
Molecular pathological epidemiology
Systems pharmacology
Cancer systems biology
Network medicine
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6 8 EXTERNAL LINKS

7 Further reading
Asfar S. Azmi, ed. (2012). Systems Biology in
Cancer Research and Drug Discovery. ISBN 978-
94-007-4819-4.

Kitano, Hiroaki (15 October 2001). Foundations

of Systems Biology. MIT Press. ISBN 978-0-262-
11266-6.

Werner, Eric (29 March 2007). All

systems go. Nature 446 (7135): 493
494. Bibcode:2007Natur.446..493W.
doi:10.1038/446493a. provides a comparative
review of three books:
Alon, Uri (7 July 2006). An Introduction to Sys-
tems Biology: Design Principles of Biological Cir-
cuits. Chapman & Hall. ISBN 978-1-58488-642-6.

Kaneko, Kunihiko (15 September 2006). Life: An

Introduction to Complex Systems Biology. Springer-
Verlag. ISBN 978-3-540-32666-3.
Palsson, Bernhard O. (16 January 2006). Sys-
tems Biology: Properties of Reconstructed Networks.
Cambridge University Press. ISBN 978-0-521-
85903-5.
Werner Dubitzky, Olaf Wolkenhauer, Hiroki
Yokota, Kwan-Hyun Cho, ed. (13 August 2013).
Encyclopedia of Systems Biology. Springer-Verlag.
ISBN 978-1-4419-9864-4.

8 External links
Biological Systems in bio-physics-wiki
 7

9 Text and image sources, contributors, and licenses

9.1 Text
Systems biology Source: https://en.wikipedia.org/wiki/Systems_biology?oldid=709317095 Contributors: Edward, Michael Hardy, Lexor,
Kku, Netsnipe, Zoicon5, Steinsky, Fredrik, Stewartadcock, Jondel, Fuelbottle, Alan Liefting, Giftlite, Dmb000006, Waltpohl, Tagish-
simon, Quarl, APH, Thorwald, D6, Jwdietrich2, Discospinster, Rich Farmbrough, Bender235, Ceolas, Fenice, Syp, DanielNuyu, Zlite,
Lenov, Rajah, Srlasky, Mdd, Arthena, Ombudsman, GJeery, Danhash, Bobrayner, Rwcitek, CharonZ, Ggonnell, Halx, Grammarbot,
Kane5187, Rjwilmsi, Edaddison, Mohawkjohn, Jongbhak, NavarroJ, Vonkje, Chobot, Whosasking, Electric sheep~enwiki, YurikBot,
Wavelength, Neilbeach, PaulGarner, Aeusoes1, Cquan, Jpbowen, Kkmurray, HexiToFor~enwiki, Zargulon, Arthur Rubin, SmackBot,
Eskimbot, Ohnoitsjamie, Betacommand, David Ludwig, Jethero, RDBrown, Miguel Andrade, DHN-bot~enwiki, Can't sleep, clown will
eat me, Sholto Maud, Karthik.raman, Kcordina, SeanAhern, Kleuske, O RLY?, Mkotl, Nick Green, Ben Moore, Ckatz, Satish.vammi,
Pkahlem, Lkathmann, Bad Cat, Andreas td, FLeader, Thomas81, Patho~enwiki, CRGreathouse, CmdrObot, N2e, Pgr94, CX, Klipkow,
Skittleys, Blueleezard, Nbaliga, Narayanese, Michael Fourman, Letranova, Thijs!bot, Droyarzun, Crodriguel, Second Quantization, Lau-
ranrg, Vangos, Mbadri, Opertinicy, Natelewis, Asadrahman, NBeale, Gcm, Freshacconci, Magioladitis, VoABot II, MikeHucka, BatteryIn-
cluded, Charlenelieu, JaGa, WLU, Synthetic Biologist, Molelect, Pvosta, Yobol, Garychurchill, Urselius, Nono64, Erkan Yilmaz, Robnpov,
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Stupor Mundi, Benedict Pope, Zuck3434, Snow Rise, Hequba, DGRichard, The Bald Russian, Avimaayan2012, Dexbot, Joeinwiki, Mark
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