We view these EAC meetings as an important opportunity to get feedback and guidance *from YOU* for how to run the NRNB resource. * This should NOT be a one-way report of our progress, but rather a two-way discussion * We want feedback on our performance over the first year * We have a number of proposals derived from our first year experience that we need your advice on. We’ll cover these toward the end of the afternoon. * And we want guidance in general for our second year It will be our responsibility to report back on all action items and milestones generated from this meeting, and demonstrate how important this meeting is the success of NRNB.
TRD OVERVIEW: The overall motivation for this TRD is making it easier for biologists to visualize and explore their data in the context of networks. The importance of networks and a systems biology perspective in the study of desease has already been illustrated by the prior TRDs and the growing field NRNB services. The goal of this TRD is to develop tools that make this work more integrative (from interactomes to exons; and across datatypes), more meaningful (biological semantics, both lexical and graphical), and more practical. The field is rapidly growing and more and more researchers are seeking powerful and easy-to-use network biology tools. These 5 images were made using at least 5 different software packages; but this can all be done in Cytoscape with the completion of TRD C.NEXT: The first project relates to this top row of going from networks to biologically meaningful diagrams. And the second project will focus on integrating complex data views and drilling-down to exons and protein domains.
BACKGROUND:This project addresses the problem of viewing exon-level data in the context of networks AND genomic alignments. Here we have a typical pathway with data mapped to P53. We then want to drill down and see the data aligned to gene structure. This tell us about exon-level expression and possible alternative splicing isoforms. The results of this view get passed up to the network view, telling the user that there is information worth digging into. [CLICK] This second example highlights the value of viewing multiple conditions (or timepoints) simultaneously. [CLICK]PROGRESS: So, in terms of progress, we now have Cytoscape features that address stripe and pie chart views on nodes to support the visualization of multiples AND we have extended support for grouping and heirarchical relationships between entities, which is critical to supporting how probesets relate to exons and exons relate to genes and proteins. CSP&DBP: There are many applications of these general visualization solutions. We are applying it to (1) the study of the role of alternative splicing in stem cell differentiation, (2) understanding the role of SNPs associated with Glioma brain tumors, and (3) prioritizing crystallography targets for a Protein Structure Initiative project focused on the pathways involved in stem cell pluripotency.
Our current menu of services is primarily based on the support of Cytoscape. As we look to expand the reach of our support, we propose the following list of services. For each CSP under consideration for NRNB support, we would package a custom set of services from this list on a case-by-case basis: (list)
We are tackling Training and Outreach on a number of fronts. I’m going to briefly review the new features and content rolled out this year as a function of NRNB.[ONLINE – Live demo] * NRNB site: home, tools, training (events, tracker, spreadsheet), outreach (collaborate form), projects (internal tracking, collaboration list). [STATS: ~100visitors/day] Tools>Cytoscape * Cytosacpe: front page redesign (sexy images, targeted sections). Documentation>users>OT * Open Tutorials: portal, new tutorial>Basic-Human (scroll, editable, slideshow, handout). [STATS: 1,000 visits in past month] * Google: “network biology resource” (Note “resources”, then back, mention adwords [STATS: >1,300 clicks per month, potential of $120k/yr], then note: main site, ncrr, gsoc) * GSoC: 10 students, paid for by Google = $55k, start coding on Monday!
We have already received a request to fund an externally-hosted training event for Cytoscape that did not directly involve any NRNB staff or investigators. We rejected this request and came up with the following alternative proposal to be applied in future cases. (Proposal)
NRNB EAC Report 2011
Systematic mapping of genesCost of human genomesequencing versus time
Systematic mappingof molecular interactionsandmolecular profiles Metabolic networksmRNA & proteinexpression Genetic and protein interaction networks Transcriptional networks
National Resource for Network Biology: MissionTo provide freely available, open-source softwaretechnology that broadly enables networkassembly,analysis, visualization and network-based biomedicaldiscovery for NIH-funded researchers.These tools are enabling researchers to assemble large-scale biological data into models of networks andpathways and to use these networks to betterunderstand how biological systems operate undernormal conditions and how they fail in disease.
Components of the Network Resource• Technology Research & Development (TRD)• Driving Biological Projects (DBP)• Collaboration and Service (CSP)• Training• Dissemination• Administration• Core infrastructure (Cytoscape, Supercomputing)
Assembling and Using Networks in Biomedicine Network-based disease Genes and gene functions The Working Network Map diagnosis, prognosis, and stratification Physical interactions Network-based prediction of cell fate; regenerative medicine Genetic interactions Network-based rational drug design Gene / proteinexpression Network wide association studies (NWAS) Advanced Network VisualizationAssembly of molecular networks Network based applications via data integration to disease
National Resource for Network Biology Faculty PI: Trey Ideker Exec. Director: Alex Pico Gary Bader Mike Norman UCSD Medicine & UCSF / Gladstone U Toronto Donnelly Ctr Director, SDSC Bioengineering for Mol&BiomolRsrch Chris Sander James Fowler BennoSchwikowski Chairman of ExternalDirector Bioinformatics UCSD Medicine / Systems Biology Advisory Council: @ MSKCC Social Sciences Institut Pasteur Stephen Friend, Sage Bionetworks
Our flagship tool: Shannon et al. Genome Research 2003www.cytoscape.org Cline et al. Nature Protocols 2007OPEN SOURCE Java platform forintegration of systems biology data•Layout and query of networks(physical, genetic, social, functional)•Visual and programmaticintegration of network state data(attributes)•The ultimate goal is to providetools to facilitate all aspects ofnetwork assembly, annotation, anduse 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 BiologyDownloaded approximately 3000 times per month
Agenda08:30 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 Break10:15 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 goals and responsibilities Feedback on technology we’ve beenworking 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 ProjectsQuestions: 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 fordiagnosis 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.
TRD D: Cytoscape network inferenceMission: Interface Cytoscape with the network inference community
Example inferred regulatory network DBP: Van Dijl laboratory•Network induced by pathway search in 418 genes• Transcriptome experiments of selected knockouts underway
Dynamic management of TRDsTRD projects•These projects should present compelling research anddevelopment opportunities for NRNB.• TRDs should be coupled to new or existing DBPs.• They should represent significant improvements to criticaltools and resources for the research community.• We would provide (or fund) developer time to develop orenhance a novel tool or resource, defining a 2-5 year TRDproject.• They should be assessed competitively each cycle withother new proposals and proposals for continuation ofongoing 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 hasnt been tuned for performance.
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 Architecture o Overview of the API o Plugin Developers Guide o Plugin Porting Hints• A Plugin Developers 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.
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
MHC-I Cell Projection Microtubule Edge type (gene-set overlap) & Cell Motility Cytoskeleton Between gene-sets Centrosome enriched in deletions From disease genes Membrane to enriched gene-sets Between sets enriched in Nucleolus deletions and in disease genes or between disease SMC flexible hinge domain Cell Motility sets only (stricter cluster) Cell ProliferationUrea and amine group metabolism Positive regulation of cell proliferation Cell cycle Intellectual Regulation of Disability Regulation of cell proliferation hormone levels Aminoacid Behavior derivative / amine Organ Morphogenesis metabolism Vasculature develepment CNS Development Palate develepment Glycosylation Autism Kinase Activity/Regulation LIS1 in neuronal Heart develepment Synaptic vescicle maturation migration and development Regulation of GTPase Reelin pathway RHO Ras Tyrosin kinaseZoom of CNS-Development Adhesion Carboxyl Cell projection Neuron Zn finger esterase organization migration domain domain Cell morphogenesis Kinase regulation Cerebral cortex cell migration Ras signaling GTPase regulator Negative cKIT regulation mTor pathway GTPase/Ras Neurite development Cell Motility of cell cycle pathway Signaling Node type (gene-set) (stricter cluster) CNS neuron Enriched Known Enriched only Brain in deletions disease genes in disease genes differentiation development 0% ID ID Axonogenesis CNS Projection neuron development FDR ASD ASD axonogenesis 12.5% BothPinto et al. Functional impact of global rare copy number variation in autismspectrum disorders. Nature. 2010 Jun 9.
Collaboration Triage Workflow NRNB site Check information Discard if low quality and process If unrelated to appropriately network biology Collaboration General bioinfo / data processing requestWeb form input•Request type Development of tools • General bioinfo / data processing • Cytoscape training Scientific research collaboration Beginners • Development of tools (ex. Plug-ins) Data provider Simple consultation by • Scientific research collaboration Cytoscape training E-Mail, giving some • Data provider•Contact info options of what they can•Research proposal do (I & some graduate•Publications students?) Discussion in regular meeting - Recommendation of using Discard if proposal is Web tutorial, Quick start not appropriate for Work member guide. collaboration or no assignment - Providing Cytoscape retreat available human information resource. Research Collaboration Researchers, Cytoscape team, Post-docs, graduate students 37
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 Collaborativeand Service projects which should be highly relevant tonetwork biology and represent the “best in class.”• They should have demonstrated stability and a designatedpoint-person for NRNB collaboration.• There should be obvious and direct synergy with existingNRNB projects.• We should take on such projects as a long-termcommitment.• We will commit to providing a set of services to the userand development communities, ranging from organizationalto training to communications.
Training and Outreach1. Launched new NRNB website2. Redesigned Cytoscape website3. Launched new tutorial system, Open Tutorials4. Out training events, presentations and GSoC
4. Handling requests for external training eventsWhat 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 anumber of external personnel to attend the annualCytoscape Retreat. We would use the opportunity to“train the trainers” and thereby multiply our outreachcapability with efficient investment of resources.
Acknowledgments: NCRR P41 RR031228 PI: Trey Ideker Exec. Director: Alex Pico co- PI: Gary Bader, U Toronto UCSD Medicine / Bioengineering UCSF / Gladstone Donnelly CtrMol&BiomolRsrch Chris Sander James Fowler BennoSchwikowski Chairman of ExternalDirector Bioinformatics UCSD Medicine / Systems Biology Advisory Council: @ MSKCC Social Sciences Institut Pasteur Stephen Friend, Sage Bionetworks
Protein networks as biomarkers of disease Network guided random forestsDutkowski et al. submittedPrevious work:Chuang et al. MSB 2007Lee et al. PLoS Comp Bio 2008Ravasi et al. Cell 2010