Shankar SubramaniamShankar SubramaniamUniversity of California at San DiegoUniversity of California at San Diego

Data to Biology

UCSD-Bioinformatics & Systems Biology Group

Many Dimensions of Biology• Scales: Molecules, Networks, Cells, Tissues…• Granularity: Structure, Function, Phenotype,

Physiology…• Development: Stem cells, Differentiation, Tissue

Engineering…• Species: Microorganisms, Unicellular

Eukaryotes, Insects, Plants, Animals…• Length/Time: fempto, nano, micro, ….• Cell Processes: Metabolism, Regulation,

Signaling…• Models: Micro, Meso, Macro….• Model Systems: Microbes, Yeast, Worm/Fly,

Plant, Mouse, Rat, Human

UCSD-Bioinformatics & Systems Biology Group

CellState1

State2 State iInput Response

State: genes, proteins, metabolites, ions……

The Parts List Problem!

CELLULAR RESPONSE TO STIMULUS

•proteins•peptides•amino acids •nucleotides•retinoids

Gene Expression

UCSD-Bioinformatics & Systems Biology Group

Automated sequencing machines at the Center for Genome Research in the Whitehead Institute

Deconstructing Biology

• Analysis of components, interactions and phenotypes – in context

• Multiscale and high throughput measurements• Integration of data and knowledge• Coarse grained views of the system• Understanding larger scale function• Quantitative prediction of response to input at the

systems level• Study of dynamical behavior of systems• Perturbation of components to produce changes in

systemic response• Building dynamical models of systems

Challenges in building biochemical models

• Complexity of proteomic states and interactions

• Integration of diverse data to infer biochemical interactions and modules

• Accounting for the temporal state of biochemical models

Papin, Gianchandani and Subramaniam, Current Opinions in Biotechnology 2004

DATA, MEASUREMENTS AND INTEGRATION

Characterizing Biochemical Models - Reconstruction

Pradervand, Maurya and Subramaniam Genome Biology 2006

Basic Challenges for Systems Biology• How will we define and characterize a biological

system? • How can we obtain the information on components

of the system (qualitative and quantitative; static and dynamical)? Technologies and computational methods?

• What mechanisms can we infer from the system behavior?

• What are realistic models of a system?• How can we measure/compute input-phenotype

characteristics of the system?• How will the model of the system be validated

experimentally?

Biological Systems and Models - some Examples…• The Genome as a System

• Guda et al. MITOPRED: a genome-scale method for prediction of nucleus-encoded mitochondrial proteins. Bioinformatics. 2004 Jul 22;20(11):1785-94.

• The Cell as a System• Maurya et al. Systems biology of macrophages. Adv Exp Med Biol. 2007; 598: 62-79.

• A Biological Process as a System• Subramaniam et al. The Macrophage Lipidome. 2008.

• Ogawa et al. Molecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors. Cell. 2005 Sep 9;122(5):707-21.

• A Biochemical Pathway as a System• Maurya MR and Subramaniam S. A kinetic model for calcium dynamics in RAW 264.7 Cells: 1.

Mechanisms, parameters and dose response. Biophysical Journal. 2007 Aug; 93: 709-728. A kinetic model for calcium dynamics in RAW 264.7 Cells: 2. Knockdown response and long-term response. Biophysical Journal. 2007 Aug; 93: 729-740.

• A Functional Module as a System• Bornheimer et al. Computational modeling reveals how interplay between components of a GTPase-cycle

module regulates signal transduction. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15899-904.

• Physiological Function as a System• Avidor-Reiss et al. Decoding cilia function: defining specialized genes required for compartmentalized cilia

biogenesis. Cell. 2004 May 14;117(4):527-39.

• An Organ as a System• Bhargav et al. Pathways associated with cardiomyogenesis from embryonic stem cells.

• A Disease as a System• Sears et al., Insulin Resistance – A systems physiology study Proc. Natl. Acad. Sci. 2009.