EDITORIAL GUIDE
SYSTEMS BIOLOGY amination of the genes represented by the
kernel nodes provide insight into the evolu-
Focus Issue: Series on Computational tion of these core network genes, the genes
represented by the kernel nodes were en-
and Systems Biology riched in disease-associated genes and drug
targets, suggesting that this type of analysis
Nancy R. Gough* may be clinically relevant.
Biologists are beginning to leverage
The application of computational biology and systems biology is yielding quan-
knowledge from engineering to investi-
titative insight into cellular regulatory phenomena. For the month of September,
Science Signaling highlights research featuring computational approaches to gate signaling networks. Sturm et al. ap-
understanding cell signaling and investigation of signaling networks, a series of plied mathematical modeling and experi-
Teaching Resources from a course in systems biology, and various other articles mental validation to demonstrate that the
and resources relevant to the application of computational biology and systems ERK pathway has properties of a negative
biology to the study of signal transduction. feedback amplifier (NFA), an engineering
design principle, and this discovery has im-
Computational biology and systems biology tive Signaling Network Challenge, a crowd- plications for drug development, because
are two approaches to studying biological sourcing approach to predicting signaling inhibitors that target components that are
processes. Computational biology can be networks from a set of experimental data outside the NFA are more effective at inhib-
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defined as the application of mathematical and preexisting knowledge. Also in this is- iting the pathway. Abdi et al. also applied
approaches to biological questions. This is sue is a Research Resource by Vinayagam et an engineering method used to test digital
not a new field. Indeed, the biophysics of al. that describes an algorithmic method for circuits to identify key regulators that, when
membrane excitability dates back to the assigning directionality to protein-protein dysfunctional, would have the largest effect
1950s, and single-channel analysis (1970s) interaction networks to enable modeling on the output of the network.
and electrophysiology are fields in which of signaling dynamics and identification of Systems biology studies frequently have
computational biology is central. What is previously unknown regulators of the mito- implications either for understanding the
new is that more quantitative data and meth- gen-activated protein kinase (MAPK) ERK molecular basis of disease or for the de-
ods for studying cellular signaling events pathway activated by the growth factor epi- velopment of rational therapeutic strate-
and dynamics are becoming available and, dermal growth factor (EGF). The Archives gies. Lau et al. performed a systems-based
thus, computational approaches can now also contain examples of network analysis analysis of the effects of systemic tumor
be applied to answer increasingly complex to identify previously unknown elements of necrosis factor–α in the mouse small intes-
questions related to cellular regulation. signaling networks. In a Research Article in tine and showed that analysis of signaling
Systems biology can be considered the the Archives, Huang and Fraenkel used a dif- at the systems level uncovered apoptotic
analysis of an entire biological system or ferent computational approach based on the and proliferative responses in vivo and led
network rather than of the properties and prize-collecting Steiner tree (PCST) prob- to the identification of potential therapeu-
characteristics of individual components in lem to integrate diverse data sets, identify tic targets from model predictions. Several
the system. With the advent of methods for functionally relevant networks, and discover studies published in the Science Signaling
performing genome-wide and proteome- previously unknown components and con- Archives provide systems analysis related
wide analysis, studies at the systems level nections in the yeast pheromone response to the study of cancer (see Astsaturov et al.,
have become more common, requiring the pathway. For this pathway, the authors relate Schoeberl et al., Bertotti et al., Moritz et
development of new techniques and meth- transcription expression data to data from al., and Rubbi et al.). Berger et al. applied
ods for analyzing these large data sets. genetic screens and from phosphoproteomic a systems approach to identify a network
Systems biology relies on computational analysis through a PCST analysis to reveal associated with a specific heart disease,
biology to reveal statistically significant previously unidentified connections and long QT syndrome, and then combined this
trends in these large data sets and enable hy- components not readily apparent from either network with genetic data to find genetic
pothesis generation. data set. For networks with defined compo- variations that increased susceptibility to
Science Signaling recognizes the im- nents, computational approaches have also this disorder and combined this network
portance of these two complementary ap- revealed information about the topologies with data about adverse effects of drugs to
proaches to the field of signal transduction of signaling networks, as exemplified by find drugs that may induce this condition.
and thus is devoting the month of Septem- the work of Xu et al. in the Archives, who These studies show the potential promise
ber to articles and resources that exemplify used Bayesian inference–based modeling to that systems biology has for advancing per-
these approaches. Highlights from the cur- rank various pathway models and then ex- sonalized medicine and designing rational
rent issue include a Meeting Report by Prill perimentally tested the predictions related customized therapies.
et al. that describes The DREAM4 Predic- to signal transductions paths in the EGF to Relatively few biologists are trained in
ERK pathway. Sometimes it can be useful the computational methods needed to effec-
Editor of Science Signaling, American As-
sociation for the Advancement of Science,
to make complex networks simpler. Kim et tively analyze data quantitatively and per-
1200 New York Avenue, N.W., Washington, DC al. developed an algorithmic approach to form modeling and simulation. Thus, during
20005, USA. reduce network complexity while preserv- the month of September Science Signaling
*Corresponding author. E-mail, ngough@aaas. ing network dynamics to produce simplified will be publishing a series of Teaching Re-
org networks called “kernels.” Not only did ex- sources based on a systems biology course
www.SCIENCESIGNALING.org 6 September 2011 Vol 4 Issue 189 eg8 1
EDITORIAL GUIDE
taught at Mount Sinai School of Medicine dynamic models. Sci. Signal. 2, eg3 P. Hornbeck, L. C. Cantley, S. P. Gygi,
in New York. The course is designed to in- (2009). J. Rush, M. J. Comb, Akt–RSK–S6 ki-
troduce first-year graduate students to com- nase signaling networks activated by
putational techniques applicable to systems Research Articles oncogenic receptor tyrosine kinases. Sci.
biology and uses relevant biological exam- • A. Abdi, M. B. Tahoori, E. S. Emamian, Signal. 3, ra64 (2010).
ples to illustrate how to analyze large data Fault diagnosis engineering of digital
sets, develop and analyze networks, apply circuits can identify vulnerable mol- • L. Rubbi, B. Titz, L. Brown, E. Galvan,
deterministic dynamical models consisting ecules in complex cellular pathways. Sci. E. Komisopoulou, S. S. Chen, T. Low, M.
of ordinary or partial differential equations, Signal. 1, ra10 (2008). Tahmasian, B. Skaggs, M. Müschen, M.
and apply stochastic dynamical models. Pellegrini, T. G. Graeber, Global phos-
The editors hope that the articles and • I. Astsaturov, V. Ratushny, A. Sukha- phoproteomics reveals crosstalk between
resources published as part of this series nova, M. B. Einarson, T. Bagnyukova, Bcr-Abl and negative feedback mecha-
clearly convey the importance of compu- Y. Zhou, K. Devarajan, J. S. Silver- nisms controlling Src signaling. Sci.
tational and systems biology approaches to man, N. Tikhmyanova, N. Skobeleva, A. Signal. 4, ra18 (2011).
understanding cell signaling. Researchers Pecherskaya, R. E. Nasto, C. Sharma,
using these approaches to investigate cel- S. A. Jablonski, I. G. Serebriiskii, L. M. • B. Schoeberl, E. A. Pace, J. B. Fitzgerald,
lular signaling are encouraged to consider Weiner, E. A. Golemis, Synthetic lethal B. D. Harms, L. Xu, L. Nie, B. Linggi,
submitting their work. Competitive manu- screen of an EGFR-centered network to A. Kalra, V. Paragas, R. Bukhalid, V.
improve targeted therapies. Sci. Signal. Grantcharova, N. Kohli, K. A. West,
Downloaded from http://stke.sciencemag.org/ on December 15, 2017
scripts in computational biology (modeling
and simulation) combine computational 3, ra67 (2010). M. Leszczyniecka, M. J. Feldhaus, A.
approaches with model validation and ex- J. Kudla, U. B. Nielsen, Therapeutically
• S. I. Berger, A. Ma’ayan, R. Iyengar, targeting ErbB3: A key node in ligand-
perimentally tested predictions. Systems
Systems pharmacology of arrhythmias. induced activation of the ErbB receptor–
biology studies must include validation of
Sci. Signal. 3, ra30 (2010). PI3K axis. Sci. Signal. 2, ra31 (2009).
the results in order to be considered as Re-
search Resources and must provide insight • A. Bertotti, M. F. Burbridge, S. Gastaldi, • O. E. Sturm, R. Orton, J. Grindlay, M.
into a biological question to be competitive F. Galimi, D. Torti, E. Medico, S. Gior- Birtwistle, V. Vyshemirsky, D. Gilbert,
as Research Articles. See the Information dano, S. Corso, G. Rolland-Valognes, M. Calder, A. Pitt, B. Kholodenko, W.
for Authors for more details (http://stke. B. P. Lockhart, J. A. Hickman, P. M. Co- Kolch, The mammalian MAPK/ERK
sciencemag.org/about/ifora.dtl). moglio, L. Trusolino, Only a subset of pathway exhibits properties of a negative
Met-activated pathways are required to feedback amplifier. Sci. Signal. 3, ra90
Featured in This Focus Issue sustain oncogene addiction. Sci. Signal. (2010).
Research Resource 2, ra80 (2009).
• A. Vinayagam, U. Stelzl, R. Foulle, S. • T.-R. Xu, V. Vyshemirsky, A. Gormand,
• S.-s. C. Huang, E. Fraenkel, Integrating A. von Kriegsheim, M. Girolami, G. S.
Plassmann, M. Zenkner, J. Timm, H. E.
proteomic, transcriptional, and interac- Baillie, D. Ketley, A. J. Dunlop, G. Mil-
Assmus, M. A. Andrade-Navarro, E. E.
tome data reveals hidden components of ligan, M. D. Houslay, W. Kolch, Infer-
Wanker, A directed protein interaction
signaling and regulatory networks. Sci. ring signaling pathway topologies from
network for investigating intracellular
Signal. 2, ra40 (2009). multiple perturbation measurements of
signal transduction. Sci. Signal. 4, rs8
(2011). specific biochemical species. Sci. Signal.
• J.-R. Kim, J. Kim, Y.-K. Kwon, H.-Y. 3, ra20 (2010).).
Lee, P. Heslop-Harrison, K.-H. Cho, Re-
Meeting Report
duction of complex signaling networks Presentation
• R. J. Prill, J. Saez-Rodriguez. L. G.
to a representative kernel. Sci. Signal. 4, • I. J. Farkas, T. Korcsmáros, I. A. Kovács,
Alexopoulos, P. K. Sorger, G. Stolo-
ra35 (2011). Á. Mihalik, R. Palotai, G. I. Simkó, K.
vitzky, Crowdsourcing network infer-
ence: The DREAM Predictive Signaling Z. Szalay, M. Szalay-Beko, T. Vellai, S.
• K. S. Lau, A. M. Juchheim, K. R. Cava- Wang, P. Csermely, Network-based tools
Network Challenge. Sci. Signal. 4, mr7 liere, S. R. Philips, D. A. Lauffenburger,
(2011). for the identification of novel drug tar-
K. M. Haigis, In vivo systems analysis gets. Sci.Signal. 4, pt3 (2011).
identifies spatial and temporal aspects of
the modulation of TNF-α–induced apop-
Related Resources tosis and proliferation by MAPKs. Sci.
Editorial Guides Signal. 4, ra16 (2011). 10.1126/scisignal.2002478
• N. R. Gough, J. F. Foley, Focus Issue:
Unraveling signaling complexity. Sci. • A. Moritz, Y. Li, A. Guo, J. Villén, Y. Citation: N. R. Gough, Focus Issue: Series on
Signal. 2, eg10 (2009). Wang, J. MacNeill, J. Kornhauser, K. computational and systems biology. Sci. Signal. 4,
• R. Iyengar, Why we need quantitative Sprott, J. Zhou, A. Possemato, J. M. Ren, eg8 (2011).
www.SCIENCESIGNALING.org 6 September 2011 Vol 4 Issue 189 eg8 2
Focus Issue: Series on Computational and Systems Biology
Nancy R. Gough
Sci. Signal. 4 (189), eg8.
DOI: 10.1126/scisignal.2002478
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