Biomarkers as networks, not individual loci October 28, 2010 Trey Ideker UCSD BioEng and Med Genetics

Some Grand Challenges in Biology 1)Develop a global map of cellular machinery which is descriptive and predictive of cellular function 2)Demonstrate key uses of this map in virtually every aspect of healthcare

Computer chip design and manufacture is a multi-billion dollar industry. Given modern microchips can have > 1 billion transistors, this industry relies heavily on computer-aided design & manufacturing tools. Popular design tools and languages are Cadence, Verilog, VHDL, Spice, etc. Why can’t drug development and healthcare do this?

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 simulation. RECENT NEWS Version 2.7 released March 2010 Cytoscape ® Registered Trademark The Cytoscape Consortium is a 501(c)3 non-for-profit in the State of California Centerpiece of the new National Resource for Network Biology, $7 million from NCRR Downloaded approximately 3000 times per month Shannon et al. Genome Research 2003 Cline et al. Nature Protocols 2007

Proliferation of Cytoscape Plugins

Integration of transcriptional interactions with causal or functional links Network model-based study of disease and development Assembly of network maps of the cell through genomics Network evolutionary comparison / cross-species alignment to identify conserved modules Projection of molecular profiles on protein networks to reveal active modules Alignment of physical and genetic networks Rational drug targeting, identification of drug mode of action, ADME/Tox profile Network-based disease diagnosis / prognosis Moving from genome-wide association studies (GWAS) to network-wide “pathway” association (NWAS) Assembling Networks for Use in the Clinic The Working Map Manipulation of cell fates during development

Kelley et al. PNAS 2003 Ideker & Sharan Gen Res 2008 Cross-comparison of networks: (1) Conserved regions in the presence vs. absence of stimulus (2) Conserved regions across different species Sharan et al. RECOMB 2004 Scott et al. RECOMB 2005Sharan & Ideker Nat. Biotech Suthram et al. Nature 2005

Conserved Plasmodium / Saccharomyces protein complexes Plasmodium-specific protein complexes Suthram et al. Nature 2005 La Count et al. Nature 2005 Plasmodium: a network apart?

CLL BIOMARKERS VIA MOLECULAR PROFILES Disease aggression (Time from Sample Collection SC to Treatment TX) Predictive gene markers: ZAP-70 CD38 Beta 2 microglobulin etcetera Disease aggression (Time from Sample Collection SC to Treatment TX) Chuang et al. MSB 2007

MOVING TO NETWORK-BASED BIOMARKERS Disease aggression (Time from Sample Collection SC to Treatment TX) T. Kipps, HY Chuang

The Mammalian Cell Fate Map: Can we predict tissue type using expression, networks, etc? Gilbert Developmental Biology 4 th Edition

An Atlas of Combinatorial Interactions Among Transcription Factors (TFs)  Mammalian Two Hybrid System  Both Human and Mouse TFs  Approximately 1200 TFs assayed  1200x1200 matrix tested for interaction  762 TF-TF interactions in human  877 TF-TF interactions in mouse  qRT-PCR measurements of TF abundance across 34 adult tissues Tim Ravasi, Harukazu Suzuki, RIKENRavasi et al., Cell, 2010

Human vs. Mouse TF-TF Networks in Brain

Interaction coherence within a tissue class B B A A B B A A B B A A Endoderm Mesoderm Ectoderm (incl. CNS) r = 0.9 r = 0.0 r = 0.2 Ravasi et al. Cell 2010

Protein interactions, not levels, dictate tissue specification

“Population” epistatic interactions also run between physical complexes and pathways Hannum, Srivas et al. PLoS Genetics 2009 Physical Interactions Genetic Interactions supported by gene linkage studies

Sponsors NIGMS NIEHS NCRR NIMH NSF Packard Found. Agilent Collaborators (UCSD) Richard Kolodner Tom Kipps Lorraine Pillus Collaborators (external) Nevan Krogan (UCSF) Richard Karp (UC Berkeley) Roded Sharan (Tel Aviv) Bas van Steensel (NKI) Sumit Chanda (Burnham) Michael-Christopher Keogh (Einstein) The Cytoscape Consortium