9:45 Using Systems Biology to Unravel Design
Principles: Examples from the Institute of Collaborative Biotechnologies at UCSB
Francis J. Doyle, III, Ph.D., Associate Director, UCSB-MIT-Caltech Institute for Collaborative Biotechnologies, and Professor, Chemical Engineering, University of California, Santa Barbara
Systems biology has been a major thrust of the Institute of Collaborative Biotechnologies -- a three-campus Center involving UCSB, Caltech, and MIT. A number of examples will be reviewed from the Center’s research portfolio, with an emphasis on unraveling design principles. A common theme of “robust-yet-fragile” links many of the projects, and tools for robustness analysis will be highlighted. New projects will be described that bring these tools into application with our industrial partners.
10:15 Networking Coffee Break
10:45 Persistence of Memory: How Protein
Interactions Confer Phenotype over Time
Thomas Vondriska, Ph.D., Assistant Professor, Anesthesiology & Medicine, University of California, Los Angeles
Cellular phenotype arises from the interactions among various types of biological information. Signal transduction is known to involve intracellular networks of proteins that maintain the basal phenotype of the cell and allow for this phenotype to change in response to internal and external stimuli. Emergent properties of these networks of proteins impinge upon other scales of information (such as genes, metabolites and organelle behavior) within the cell. What remains unclear are (1) the factors that govern the emergence of control; (2) how signaling networks form; and (3) how changes in network behavior influence phenotype. We are examining these questions with a systems approach combining proteomics (to decipher protein interactions and protein complexes), classical biochemistry and cell/organ physiology and mathematical modeling. Examples will be presented to illustrate how dynamics of protein interactions alter cellular phenotype in a time-dependent manner with an emphasis on the emergent properties governing this behavior that have been revealed with a systems approach.
11:15
Optimal
Cancer Chronotherapeutics Schedules Using a Systems
Biology Approach
Christophe Chassagnole, Ph.D., Chief Operating
Officer, Physiomics plc
11:45 Theory and Applications of a New Integrative Paradigm of Systems Biology
Fredric Young, Ph.D., Chief Scientist, Biophysics, Vicus Therapeutics Inc.
We have developed a complete drug discovery pipeline based on a novel paradigm of systems biology. We model the dynamics of homeostasis, using a general integrated control principle discovered through the reverse engineering of E.coli growth rate control mechanisms. This provides a quantitative model of biological homeostasis where processes are controlled by nested networks of integral controllers. A disease is modeled as a breakdown of homeostasis, within a 3-level hierarchical model of system modules, and molecular networks, using information extracted from the published literature. The novelty of the approach allows development of repurposed combination therapies whose individual components are approved for other uses and have been shown to be safe. Phase II results from a lung cancer cachexia trial are promising, and a Phase I trial of mucositis is in the preparatory stage.
12:15 pm Close of Morning Session
12:30 Luncheon Technology Workshops
(Sponsorships Available) or Lunch on Your Own
2:00 Chairperson’s Remarks
2:05 Peripheral T Cell Repertoire Maintenance
Carmen Molina-Paris, Ph.D., Lecturer, Applied Mathematics, University of Leeds, and member, I2M: Immunology, Imaging and Modelling – Research Network
A healthy immune system requires a T cell population that responds promptly to foreign antigen. This is achieved by using a variety of self-peptides to (i) select a receptor repertoire in the thymus and (ii) keep naive T cells alive and ready for action in the periphery. In this talk I will present a stochastic mathematical model to study T cell repertoire diversity maintenance. The model incorporates the concept of survival stimuli emanating from self antigen presenting cells. I will show that in the mean field approximation clonotype extinction is guaranteed and compute extinction times of T cell clonotypes without thymic input. I will introduce the concept of the mean niche overlap and make use of the quasi-stationary distribution to compute average clonotype numbers for different values of the niche overlap.
2:35 Modeling Proliferation and Differentiation in the Homeostasis of the Adaptive Immune System
Benedict Seddon, Ph.D., Molecular Immunology, National Institute for Medical Research (NIMR), and member of I2M: Immunology, Imaging and Modelling – Research Network
The peripheral T cell compartment is maintained at a remarkable constant size and composition throughout life, in spite of constant cell production and death. The factors and signals that regulate this homeostasis are well characterised at a qualitative level. However, the quantitative importance of these signals for the different T cell subsets and their relative importance in regulating key homeostatic death and cell division events remains unclear. The key issues and points of uncertainty in trying to understand the homeostatic processes will be discussed as will the contribution mathematical modeling may play in aiding our understanding. A simple modeling approach used to understand the most basic homeostatic responses will be presented and discussed.
3:05 Phospho-Signaling Networks, Disease
Mechanism, and Clinical Outcome at the Single Cell Level
Garry Nolan, Ph.D., Director, Stanford National Heart, Lung and Blood Institute Proteomics Centre, Associate Professor, Microbiology & Immunology, Stanford University School of Medicine
The
talk will touch upon the following areas:
-
Single
cell analysis of kinase states in primary cells
from patients. (Immunity/Nature
Immunology/Blood)
-
Cell
subset specific analysis of normal and diseased
signaling networks in cancer and auto-immunity.
(Cell)
-
Applications
in stratification using such data, prognostic
diagnostics, and PD marker development for drug
action against networks as a whole (Nature
Chemical Biology, Opinions).
-
High
throughput drug screening in complex populations
of cells for drug efficacy validation and ‘on
target’/ ‘off target’ determinations.
(Nature Methods & Nature Chemical Biology,
cover article).
-
Automated
derivation of signaling network diagrams from
primary cell materials (Science and work in
progress).
3:35 Technology Spotlight
(Sponsorship Available)
3:50 Networking Refreshment Break
4:15 Interactive Panel Discussion:The Logistics of International Collaborations
Moderator: John Russell, Executive Editor, Bio-IT World
-
Carmen Molina-Paris, Ph.D., Lecturer, Applied Mathematics, University of Leeds, and member, I2M: Immunology, Imaging and Modelling – Research Network
-
Benedict Seddon, Ph.D., Molecular Immunology, National Institute for Medical Research (NIMR), and member of I2M: Immunology, Imaging and Modelling – Research Network
-
Garry Nolan, Ph.D., Director, Stanford National Heart, Lung and Blood Institute Proteomics Centre, Associate Professor, Microbiology & Immunology, Stanford University School of Medicine
5:15 Welcoming Reception in the Exhibit Hall
6:30 Close of Day
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