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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?
www.cytoscape.org
Shannon et al. Genome Research 2003
Cline et al. Nature Protocols 2007
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
Proliferation of Cytoscape Plugins
Assembling Networks for Use in the Clinic
Network evolutionary
comparison / cross-species
alignment to identify conserved
modules
Projection of molecular profiles
on protein networks to reveal
active modules
Integration of transcriptional
interactions with causal or
functional links
Alignment of physical and
genetic networks
Assembly of network maps
of the cell through genomics
The Working Map
Network-based disease
diagnosis / prognosis
Rational drug targeting,
identification of drug mode of
action, ADME/Tox profile
Moving from genome-wide
association studies (GWAS) to
network-wide “pathway”
association (NWAS)
Manipulation of cell fates
during development
Network model-based study of
disease and development
Cross-comparison of networks:
(1) Conserved regions in the presence vs. absence of stimulus
(2) Conserved regions across different species
Kelley et al. PNAS 2003
Ideker & Sharan Gen Res 2008
Suthram et al. Nature 2005
Sharan & Ideker Nat. Biotech. 2006
Sharan et al. RECOMB 2004
Scott et al. RECOMB 2005
Plasmodium: a network apart?
Plasmodium-specific
protein complexes
Conserved Plasmodium / Saccharomyces
protein complexes
Suthram et al. Nature 2005
La Count et al. Nature 2005
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
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 4th 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, RIKEN
Ravasi et al., Cell, 2010
Human vs. Mouse TF-TF Networks in Brain
Interaction coherence within a tissue class
r = 0.9
A
B
Endoderm
r = 0.0
A
B
Mesoderm
r = 0.2
A
B
F  AB
Ectoderm (incl. CNS)
Ravasi et al. Cell 2010
Protein interactions, not levels, dictate tissue specification
“Population” epistatic interactions also run between
physical complexes and pathways
Physical Interactions
Genetic Interactions supported by
gene linkage studies
Hannum, Srivas et al. PLoS Genetics 2009
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