Biomarkers as networks, not individual loci
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Transcript of Biomarkers as networks, not individual loci
Biomarkers as networks, not individual lociOctober 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 developmentand healthcare do this?
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 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 2003Cline 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 2003Ideker & 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 2004Scott et al. RECOMB
2005Sharan & Ideker Nat. Biotech. 2006
Suthram et al. Nature 2005
Conserved Plasmodium / Saccharomyces protein complexes
Plasmodium-specificprotein complexes
Suthram et al. Nature 2005La Count et al. Nature 2005
Plasmodium: a network apart?
CLL BIOMARKERS VIA MOLECULAR PROFILES
Disease aggression(Time from Sample Collection SCto Treatment TX)
Predictive gene markers:ZAP-70CD38Beta 2 microglobulinetcetera
Disease aggression(Time from Sample Collection SCto Treatment TX)
Chuang et al. MSB 2007
MOVING TO NETWORK-BASED BIOMARKERS
Disease aggression(Time from Sample Collection SCto Treatment TX)
T. Kipps, HY Chuang
The Mammalian Cell Fate Map:Can we predict tissue type using expression, networks, etc?
Gilbert Developmental Biology 4th Edition
An Atlas of Combinatorial Interactions Among Transcription Factors (TFs)
Mammalian Two Hybrid SystemBoth Human and Mouse TFsApproximately 1200 TFs assayed1200x1200 matrix tested for interaction762 TF-TF interactions in human877 TF-TF interactions in mouseqRT-PCR measurements of TF
abundance across 34 adult tissues
Tim Ravasi, Harukazu Suzuki, RIKEN Ravasi et al., Cell, 2010
Human vs. Mouse TF-TF Networks in Brain
Interaction coherence within a tissue class
BA
BA
BA
Endoderm
Mesoderm
Ectoderm (incl. CNS)
F A B
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
SponsorsNIGMSNIEHSNCRRNIMHNSFPackard Found.Agilent
Collaborators(UCSD)Richard KolodnerTom KippsLorraine 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