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 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

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