Systematic mapping of genes

Cost of human genome sequencing versus time

Genetic and proteininteraction networks

Transcriptional networks

Metabolic networks

Systematic mappingof molecular interactionsand molecular profiles

mRNA & proteinexpression

To provide freely available, open-source software technology that broadly enables network assembly, analysis, visualization and network-based biomedical discovery for NIH-funded researchers.

These tools are enabling researchers to assemble large-scale biological data into models of networks and pathways and to use these networks to better understand how biological systems operate under normal conditions and how they fail in disease.

National Resource for Network Biology:

Mission

Components of the Network Resource

• Technology Research & Development (TRD)• Driving Biological Projects (DBP)• Collaboration and Service (CSP)• Training• Dissemination

• Administration• Core infrastructure (Cytoscape, Supercomputing)

Gene / protein expression

Network based applicationsto disease

Assembly of molecular networks via data integration

Genetic interactions

Physical interactions

Network-based rationaldrug design

Network-based disease diagnosis, prognosis, and

stratification

Network wide association studies (NWAS)

Assembling and Using Networks in Biomedicine

The Working Network Map

Network-based prediction of cell fate; regenerative medicine

Genes and gene functions

Advanced Network

Visualization

National Resource for Network Biology Faculty

PI: Trey IdekerUCSD Medicine &

Bioengineering

Gary BaderU Toronto Donnelly Ctr for Mol & Biomol Rsrch

Exec. Director: Alex Pico UCSF / Gladstone

Chris SanderDirector Bioinformatics

@ MSKCC

James FowlerUCSD Medicine / Social Sciences

Benno SchwikowskiSystems BiologyInstitut Pasteur

Chairman of External Advisory Council:Stephen Friend,

Sage Bionetworks

Mike NormanDirector, SDSC

Our flagship tool: www.cytoscape.org

OPEN SOURCE Java platform for integration of systems biology data

•Layout and query of networks (physical, genetic, social, functional)

•Visual and programmatic integration of network state data (attributes)

•The ultimate goal is to provide tools to facilitate all aspects of network assembly, annotation, and use in biomedicine.

RECENT NEWS

• Version 3.0 due July 2011

• Cytoscape ® Registered Trademark

• The Cytoscape Consortium is a 501(c)3 non-for-profit in the State of California

• Centerpiece of the NCRR-funded National Resource for Network Biology

Downloaded approximately 3000 times per month

Shannon et al. Genome Research 2003Cline et al. Nature Protocols 2007

Agenda

08:30 Introductions, overview and organizational structure of NRNB (Friend, Ideker) 08:45 EAC roles, goals, and responsibilities (Pico, Ideker) 09:00 Discussion of technology projects and matched driving biology (Ideker) 10:00 Break 10:15 Progress in Cytoscape 3.0 (Smoot) 10:40 Collaboration, Training, and Service (Bader, Pico) 11:30 EAC recommendations, formulation and review of NRNB policies (Pico)

12:15 Summary (Friend)

12:30 Lunch

EAC roles, goals, and responsibilities

EAC goals and responsibilities

Feedback on technology we’ve been working on over first 8 months Advice on administrative structure Vision and guidance for future years Short written report

Two-way discussion• Not a presentation of annual report• We are prepared to listen!

We will report back next year!

Technology Projects

Questions:

How are we doing? Strengths and weakness?

Where would you want to see these projects in several years?

Are there key network tools that we should be developing yet are not?

Are there network tools we are developing which are not so exciting?

TRD Project A: Network-based biomarkers for diagnosis and personalized therapy

Bandyopadhyay et al. Science (2010)

Visualizing and Analyzing Cancer Genomic Data in the Context of Biological Pathways and Networks

• Algorithm Development• Adding Network Visualization and Analysis to the cBio Portal.

Pathway Commons

?

TRD Project B: How Do Genes Affect Behavior?

GenesDopamineSerotonin

Behaviors

HealthHappinessCooperatio

nPoliticsSocial

Networks

TRD C: Visualization and Representation of Biological Networks

Interactome

Cellularsemantics

Complex data views

Meaningful modules

PIs: Bader, Conklin, Pico

Exons to protein domains

Simplified Network View: Thematic Map

Protein-protein interaction network

Module-module interactions

Simplified Network View: Enrichment Map

Visualizing Complex Data

SPIDs: 23 (Wrensch, CSP), 34 (Fletterick), 38 (Ferrin), DBP (Mercola)

Multiple timepointsviewed simultaneously

Striped nodes Pie chart nodes

Nested metanodes

TRD D: Cytoscape network inference

Mission: Interface Cytoscape with the network inference community

Example inferred regulatory network

• Network induced by pathway search in 418 genes• Transcriptome experiments of selected knockouts underway

DBP: Van Dijl laboratory

Dynamic management of TRDsTRD projects•These projects should present compelling research and development opportunities for NRNB. • TRDs should be coupled to new or existing DBPs. • They should represent significant improvements to critical tools and resources for the research community. • We would provide (or fund) developer time to develop or enhance a novel tool or resource, defining a 2-5 year TRD project. • They should be assessed competitively each cycle with other new proposals and proposals for continuation of ongoing TRD projects.

Infrastructure report:Cytoscape 3.0 and SDSC access   

Mike Smoot

Functional Overview   

• Milestone 2 release just completed.• All core plugins except "Advanced Network Merge" have

been ported.• Cytoscape 3 is functional, but there are lots of bugs and the

code hasn't been tuned for performance.

Why we needed to redesign the API!

3.0 Package Dependency Graph

Architecture Status

• Still using OSGi for modularity.• Still using Spring-DM to configure modules.• Still using Maven to build and pull everything together.

• We now have a "simplified" plugin API.  o You only need to know basic Java.o Just like in 2.X, you extend a single abstract class.

• So far, everything is behaving as planned.o The application starts correctly, services get registered,

APIs are public, implementation is hidden, plugins start, etc..

Documentation Status

• Lots of documentation written on the Wiki:o Overview of the Architectureo Overview of the APIo Plugin Developer's Guideo Plugin Porting Hints

• A Plugin Developer's tutorial has been added to OpenTutorials

Next Steps

• Fix known bugs.• Add missing features.• Analyze and address performance bottlenecks.• Re-evaluate API.• Ensure that proper OSGi metadata is being published.

• Refactor build system to that development code - compile - test cycle is faster.

• Refactor build system so that release generation is easier.

• Help plugin developers port plugins.

SDSC’s “Triton” Resourcehttp://tritonresource.sdsc.edu

Collaboration, Training and Outreach

Collaboration and Training

• Collaboration and training• Win win: collaborators learn network and pathway

analysis, we learn about community needs

• 37 Collaborations and service projects (CSP)• Project management

– Services e.g. training, dissemination– Target # of CSPs?

• Balance of R&D and collaborations

Pinto et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010 Jun 9.

Collaboration Triage Workflow

Collaboration request

Web form input•Request type

• General bioinfo / data processing • Cytoscape training• Development of tools (ex. Plug-ins)• Scientific research collaboration• Data provider

•Contact info•Research proposal•Publications

Check information and process appropriately

Discard if low quality

Simple consultation by E-Mail, giving some options of what they can do (I & some graduate students?)

Cytoscape training

- Recommendation of using Web tutorial, Quick start guide.

- Providing Cytoscape retreat information

Discussion in regular meeting

Development of toolsScientific research collaborationData provider

Discard if proposal is not appropriate for collaboration or no available human resource.

Work member assignment

Researchers, Cytoscape team, Post-docs, graduate students

General bioinfo / data processing

37

If unrelated to network biology

NRNB site

Beginners

Research Collaboration

Services NRNB should provide to select CSPsOrganizational

• Impact: Measure impact of project - e.g. track relevant publications and collaborations

• Interface: identify related resources, project and programs; facilitate new collaborations; hold joint conferences

• Host: link to project download, documentation and tutorial pages from nrnb.org• Advisory: provide recommendations and proposals to project leads regarding

technical development aims and organizational opportunitiesTraining

• Tutorials: prioritize, produce and promote tutorial materials; organize events • Feedback: collect and organize feedback from training events to share with

developersCommunity

• Events: organize, promote and staff lectures, tutorials and workshops• News: highlight news items related to the project and project leads• Communication: coordinate discussion lists, help desk, Facebook, Twitter, etc• GSoC: support project ideas, mentors and students in annual Summer of Code

program sponsored by Google• Retreat: organizing the annual retreat for project in conjunction with Cytoscape and

NRNB

Dynamic management of TRDs and CSPsCSP projects• The NRNB should continually engage in new Collaborative and Service projects which should be highly relevant to network biology and represent the “best in class.” • They should have demonstrated stability and a designated point-person for NRNB collaboration. • There should be obvious and direct synergy with existing NRNB projects. • We should take on such projects as a long-term commitment. • We will commit to providing a set of services to the user and development communities, ranging from organizational to training to communications.

Training and Outreach

1. Launched new NRNB website

2. Redesigned Cytoscape website

3. Launched new tutorial system, Open Tutorials

4. Out training events, presentations and GSoC

4. Handling requests for external training events

What to do with requests for external training support? We send staff, our “Roving Engineer” We provide tutorial materials through OpenTutorials,

(including customizable online content, slideshows, and handouts)

Proposal: Sponsor travel and accommodations for a number of external personnel to attend the annual Cytoscape Retreat. We would use the opportunity to “train the trainers” and thereby multiply our outreach capability with efficient investment of resources.

EAC Discussion

Acknowledgments: NCRR P41 RR031228

PI: Trey IdekerUCSD Medicine / Bioengineering

co- PI: Gary Bader, U TorontoDonnelly Ctr Mol & Biomol Rsrch

Exec. Director: Alex Pico UCSF / Gladstone

Chris SanderDirector Bioinformatics

@ MSKCC

James FowlerUCSD Medicine / Social Sciences

Benno SchwikowskiSystems BiologyInstitut Pasteur

Chairman of External Advisory Council:Stephen Friend,

Sage Bionetworks

Dutkowski et al. submitted

Previous work:

Protein networks as biomarkers of disease

Network guided random forests

Chuang et al. MSB 2007Lee et al. PLoS Comp Bio 2008Ravasi et al. Cell 2010