Allan Kuchinsky1,3, Keiichiro Ono2, Michael Smoot2, Trey Ideker2,Annette Adler1

1 Agilent Technologies, 5301 Stevens Creek Blvd., Santa Clara, CA 95051 USA

2 School of Medicine, University of California, San Diego, CA 92093 USA

3Gladstone Institute of Cardiovascular Disease, San Francisco, CA, 94158-2261, USA

email: allan_kuchinsky@agilent.comJune, 2009

Cytoscape Springs Forward:

Re-architecture for Version 3.0

June 2009

Outline

• Problem area

• Overview of Cytoscape

• Motivating factors for re-architecture

• Architectural/design principles for Cytoscape version 3.0

• Issues

June 2009

June 2009Page 3

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Modern -omics technologies yield “snapshots” of discrete parts of the biological process.

High throughput quantification of:

• nucleic acids

• proteins

• metabolites

The value of looking only at results from individual disciplines is limited.

• chromosomal copy number

• chromatin structure

• nucleotide sequence

• post-translational modification

High throughput characterization of:

June 2009Page 4

Roth et al, n engl j med 356;1 www.nejm.org january 4, 2007) show the molecular mechanisms by which certain drugs may induce Valvular Heart Disease.

The real biological story is in the relationships amongst the biological entities, rather than the entities themselves.

Interpretive value comes from integrating diverse measurements within their biological context.

“Systems biology is about putting together rather than taking apart, integration rather than reduction..”

D. Noble, The Music of life. Biology beyond the genome Oxford University Press 2006. ISBN 0199295735, ISBN 978-0199295739

June 2009

freely available at http://www.cytoscape.org

Cytoscape is a collaboration between

University of California, San Diego

Institute for Systems Biology

Memorial Sloan-Kettering Cancer Center

Institute Pasteur

Agilent Technologies

University of Toronto

Gladstone Institute for Cardiovascular Disease

University of California, San Francisco

Unilever

National Center for Integrative Biomedical Informatics

Cytoscape is an open source software platform for integrating, analyzing, and visualizing measurement data in their biological context.

• 60000+ downloads for 2.x release; 25,000 downloads in 2007 alone; 3000/month• Currently 75 registered plugins, developed by leading research groups, freely available• Community development of plugins strongly encouraged and actively supported by core development

team.• License: The Cytoscape core distribution is available under GNU Lesser Public License (LGPL).

Plugins each have their own licensing policies, most are freely available from the Cytoscape web site.

What is a network tool?

• Networks provide an integrating context for data

• Commonly understood diagrammatic representation for concepts and relationships

• Provides structure that helps reduce underlying complexity of the data

• More efficient than searching databases element-by-element

• Network tools give us functionality for studying complex processes

• Analysis of global characteristics of the data, e.g. degree, clustering coefficient, shortest paths, centrality, density• Identify key elements (hubs) and ‘interesting’ subnets

• Help elucidate mechanisms of interaction

• Visualization of data superimposed upon the network• Help understand how a process is modulated or attenuated by a stimulus

• Cytoscape is fundamentally a general network tool

• Core system implements graph model and views

• Biological semantics/applications provided by plugins

June 2009

Applications of Network Biology• Gene Function Prediction –

shows connections to sets of genes/proteins involved in same biological process

• Detection of protein complexes/other modular structures – discover modularity & higher order organization (motifs, feedback loops)

• Network evolution – biological process(s) conservation across species

• Prediction of new interactions and functional associations – Statistically significant domain-domain correlations in protein interaction network to predict protein-protein or genetic interaction

June 2009

jActiveModules, UCSD

PathBlast, UCSD

mCode, University of Toronto

DomainGraph, Max Planck Institute

Applications of Network Informatics in Disease

• Identification of disease subnetworks – identification of disease network subnetworks that are transcriptionally active in disease.

• Subnetwork-based diagnosis – source of biomarkers for disease classification, identify interconnected genes whose aggregate expression levels are predictive of disease state

• Subnetwork-based gene association – map common pathway mechanisms affected by collection of genotypes (SNP, CNV)

June 2009

Agilent Literature Search

Mondrian, MSKCC

PinnacleZ, UCSD

Selected Cytoscape PluginsI/O Import most

standard formatsImport networks, attributes via web services

WikiPathways BiNoM BioNetBuilder Droid

Analysis Network Analyzer BiNGO mCode ClusterMaker jActiveModules VistaClara

Inference MiMI Agilent Literature Search

CytoProphet Expression Correlation

Domain Graph Monet

Visualization Mondrian GLay ClueGO CyOOG Cerebral BubbleRouter

Structure & Chemistry

SFLD Loader StructureViz Cheminformatics DrugViz OmicsViz MetaNetterMolecular Technologies Lab

Agilent RestrictedApril 2008

June 2009

Cytoscape’s broadening impact• HUPO: Molecular Interaction Workshop (HUPO Proteomics Standards Initiative)

• made Cytoscape the official client for the new standardized web services for the major interaction databases.

• "Cytoscape is a paradigm for NIH-funded open source software“• Peter Good, PhD, program director for genome informatics in NHGRI’s Division of Extramural Research and program director for

the ENCODE (The ENCyclopedia Of DNA Elements) consortium, which is organized by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), which is reporting results of its exhaustive, four-year effort to build a parts list of all biologically functional elements in 1 percent of the human genome). See: http://www.nih.gov/news/pr/jun2007/nhgri-13.htm and http://www.genome.gov/10005107

• "The Cytoscape project has grown into, probably, the most advanced and well known developer's community in systems biology, and we are very glad to participate in it”

• GeneGO Corporation (genego.com/pdf/GeneGo_Cytoscape.pdf), concurrent with their announcement that Cytoscape would be integrated into their MetaCore and MetaDrug bioinformatics platforms. (December 21, 2007)

• “Cytoscape: Hands-Down Winner for Large-Scale Graph Visualization: Where Has the Biology Community Been Hiding This Gem?”

• by Michael K. Bergman at http://www.mkbergman.com/?p=415). Cytoscape is emerging as the visualization tool of choice for the Semantic Web / RDF community (January 28, 2008)

• Google Summer of Code (http://code.google.com)• Collaboration with GenMAPP Group, Gladstone/UCSF.

• This program pays students to write open source software. Grants are highly competitive. We mentored:

• 7 student projects in 2007

• 9 student projects in 2008 (based upon past success, 1 student returning as mentor)

• 10 student projects in 2009 (based upon past success, 2 additional students returning as mentors)

June 2009

Growing Pains

• Cytoscape is a monolithic application

• Large and complex interface for developers.

• API contains >5000 classes

• Parts of the software have evolved organically with contributions from many programmers.

• Difficult to add new features

• Application components have become tightly-coupled and increasingly fragile.

• Small changes in one subsystem can have unintended consequences in another.

• No mechanisms for plugins to communicate with each other

• No mechanisms for supporting different versions of libraries.

June 2009

Cytoscape 3.0 release: re-layering

June 2009

• Make it easier to write plugins• clean up, refactor, restructure• improve event handling• make it easier for plugins to interact with each other• custom graphics: enable plugin developers to define their own shapes and edges .

• Make it easier for components of Cytoscape to be used in different contexts, e.g.• standalone application• ‘headless’ mode: Cytoscape as service/engine• web browser front end• specialized versions for particular workflows

• Clean up the user interface so that it's easier for users. • Utilize standard software frameworks

• OSGI• Spring• Maven

Frameworks  

• OSGi (http://osgi.org)• Provides packaging, versioning, and dynamic loading of Java applications

• Modules register services to be used by other modules

• Enforces modularity

• Spring Dynamic Modules framework (http://www.springsource.org/osgi). • Provides Inversion of Control, Dependency Injection

• Enables advertisement of services by interfaces, independent of implementation

• Provides timing and tracking for dynamically loaded OSGi services

• Re-wire components to build systems for different environments

• Enable plugins written in other languages

• Maven• Project resource management framework

• Provides convention over configuration, can share processes via archetypes.

• Manages dependencies between modules.

June 2009

Spring DM Architecture

OSGi Services Defined as a Complex of Beans

Issues• POJOs and bundles and POMs, oh my!

• New frameworks require training. Are we raising the barriers to plugin development?

• Can templates in Eclipse, Maven archetypes, and tutorials help?

• How simple should the API be?

• If too simple, then do plugin developers resort to ad hoc solutions, working at cross-purposes?

• Where can scripting solve the problem

• Event handling: do we need to batch events?

• E.g. editor should not redrawNetwork() every time a network importer adds a Node to a Network

• But how do you deal with deletion?.

• Top-down vs. Bottom-up

• “I need to see an implementation before I can believe it’s feasible” vs. “I can’t evaluate the implementation unless I can see the API/UI for how it will be used”.

• Who’s in charge here?

• Do we need a bona fide project manager?.

• What is that project manager’s role?

• Does the alternative of ‘distributed ownership of modules’ work?

June 2009

Cytoscape Consortium• Board of Directors: governs and directs strategy, drawn

from Consortium members

• Technical team:• Chief Architect: 1 FTE funded by Consortium member

• Core development team: 12 FTE, responsible for core of Cytoscape functionality, funded by Consortium members

• Core Plugin developers: 10.2 FTE, responsible for extensions that provide common useful functionality, such as layout, editing, web services. Typically funded by Consortium members.

• External Plugin developers: ~50 FTE, provide end user applications. Typically not Consortium members.

• Outreach• User community support through extensive training materials, cased-based

tutorials, roving engineer, annual symposium

June 2009

ISMB Cytoscape Birds-of-a-Feather sessionTuesday 1-2PM, K1

Trey Ideker’s Keynote Address, Tuesday/4:45PMNew Challenges and Opportunities in Network Biology