This document discusses plans for a major re-architecture of the Cytoscape software platform in version 3.0. The goals are to make it easier for developers to write plugins by adopting modern frameworks like OSGi and Spring, and to support different deployment contexts. This will address current issues like a monolithic architecture that is difficult to extend. The re-architecture aims to improve modularity, enable better plugin interoperability, and facilitate use of Cytoscape in new environments like web applications. Challenges include balancing simplicity of the new API with plugin extensibility.

1. Cytoscape Springs Forward: Re-architecture for Version 3.0 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.com June, 2009 June 2009

3. Overview of Cytoscape

4. Motivating factors for re-architecture

5. Architectural/design principles for Cytoscape version 3.0

6. IssuesJune 2009

8. proteins

10. chromatin structure

11. nucleotide sequence

12. post-translational modificationThe value of looking only at results from individual disciplines is limited.

13. June 2009 Page 4 The real biological story is in the relationshipsamongst 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 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.

15. Currently 75 registered plugins, developed by leading research groups, freely available

16. Community development of plugins strongly encouraged and actively supported by core development team.

17. 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.June 2009

19. Commonly understood diagrammatic representation for concepts and relationships

20. Provides structure that helps reduce underlying complexity of the data

21. More efficient than searching databases element-by-element

22. Network tools give us functionality for studying complex processes

23. Analysis of global characteristics of the data, e.g. degree, clustering coefficient, shortest paths, centrality, density

24. Identify key elements (hubs) and ‘interesting’ subnets

25. Help elucidate mechanisms of interaction

26. Visualization of data superimposed upon the network

27. Help understand how a process is modulated or attenuated by a stimulus

28. Cytoscape is fundamentally a general network tool

29. Core system implements graph model and views

30. Biological semantics/applications provided by pluginsJune 2009

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

33. Network evolution – biological process(s) conservation across species

34. Prediction of new interactions and functional associations – Statistically significant domain-domain correlations in protein interaction network to predict protein-protein or genetic interactionJune 2009 jActiveModules, UCSD mCode, University of Toronto PathBlast, UCSD DomainGraph, Max Planck Institute

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

37. Subnetwork-based gene association – map common pathway mechanisms affected by collection of genotypes (SNP, CNV)June 2009 Agilent Literature Search PinnacleZ, UCSD Mondrian, MSKCC

38. Selected CytoscapePlugins Molecular Technologies Lab Agilent Restricted April 2008 June 2009

40. 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

41. "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”

42. 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)

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

44. 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)

45. Google Summer of Code (http://code.google.com)

46. Collaboration with GenMAPP Group, Gladstone/UCSF.

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

48. 7 student projects in 2007

49. 9 student projects in 2008 (based upon past success, 1 student returning as mentor)

50. 10 student projects in 2009 (based upon past success, 2 additional students returning as mentors)June 2009

52. Large and complex interface for developers.

53. API contains >5000 classes

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

55. Difficult to add new features

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

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

58. No mechanisms for plugins to communicate with each other

59. No mechanisms for supporting different versions of libraries. June 2009

61. clean up, refactor, restructure

62. improve event handling

63. make it easier for plugins to interact with each other

64. custom graphics: enable plugin developers to define their own shapes and edges.

65. Make it easier for components of Cytoscape to be used in different contexts, e.g.

66. standalone application

67. ‘headless’ mode: Cytoscape as service/engine

68. web browser front end

69. specialized versions for particular workflows

70. Clean up the user interface so that it's easier for users.

71. Utilize standard software frameworks

72. OSGI

73. Spring

75. Provides packaging, versioning, and dynamic loading of Java applications

76. Modules register services to be used by other modules

77. Enforces modularity

78. Spring Dynamic Modules framework (http://www.springsource.org/osgi).

79. Provides Inversion of Control, Dependency Injection

80. Enables advertisement of services by interfaces, independent of implementation

81. Provides timing and tracking for dynamically loaded OSGi services

82. Re-wire components to build systems for different environments

83. Enable plugins written in other languages

84. Maven

85. Project resource management framework

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

87. Manages dependencies between modules.June 2009

88. OSGi Services Defined as a Complex of Beans Spring DM Architecture

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

91. Can templates in Eclipse, Maven archetypes, and tutorials help?

92. How simple should the API be?

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

94. Where can scripting solve the problem

95. Event handling: do we need to batch events?

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

97. But how do you deal with deletion?.

98. Top-down vs. Bottom-up

99. “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”.

100. Who’s in charge here?

101. Do we need a bona fide project manager?.

102. What is that project manager’s role?

103. Does the alternative of ‘distributed ownership of modules’ work?June 2009

105. Technical team:

106. Chief Architect: 1 FTE funded by Consortium member

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

108. 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.

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

110. Outreach

111. User community support through extensive training materials, cased-based tutorials, roving engineer, annual symposiumJune 2009 ISMB Cytoscape Birds-of-a-Feather sessionTuesday 1-2PM, K1 Trey Ideker’s Keynote Address, Tuesday/4:45PM New Challenges and Opportunities in Network Biology