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ZOO 4903 Fall 2006, MW 10:30-11:45 Sutton Hall, Room 312 Jonathan Wren

Systems Biology

Lecture overview

What weve talked about so far

Pathways & network motifs Simulating evolution in-silico Cellular simulations

Overview

The ultimate goal of biology & bioinformatics is to tie it all together and understand the system In the meantime, forced to live in the real world, we focus on tying a few things together

Though coined 40 years ago, a lot of people still ask, "What's that?" when the term systems biology comes up. "It is used in so many different contexts, nobody is really clear what you mean by it," says John Yates III, a professor at the Scripps Research Institute in La Jolla, Calif. He's not the only one stumped by the term's meaning. David Placek, president of Sausalito, Calif.-based Lexicon Branding, a company that cooks up names for pharmaceutical products such as Velcade and Meridia, says he's not so hot on the moniker. "Systems biology is just so general that it could apply to many things. When you're naming a category, the underlying principle is that if you make a statement like, 'I'm doing systems biology,' do people know what you're talking about?'

Is this just another name for physiology? The study of the mechanisms underlying complex biological processes as integrated systems of many interacting components. Systems biology involves (1) collection of large sets of experimental data (2) proposal of mathematical models that might account for at least some significant aspects of this data set, (3) accurate computer solution of the mathematical equations to obtain numerical predictions, and (4) assessment of the quality of the model by comparing numerical simulations with the experimental data.

http://www.systemsbiology.org/

On the technology side (PUSH): Capabilities for highthroughput data gathering that have made us aware that biological networks have many more components than we previously surmised. On the biology side (PULL): The realization that to the extent that we dont characterize biological systems quantitatively in their full complexity, the scope and accuracy of our understanding of those systems will be compromised. (in classical experimental terms, the uncontrolled variables in the system will undermine our confidence in the conclusions we draw from our experiments and observations)

Experimental techniques in systems biology are high throughput. Intensive computation is involved from the start in systems biology, in order to organize the data into usable computable databases. Exploration in traditional biology proceeds by successive cycles of hypothesis formation and testing; data accumulates during these cycles. Systems biology initially gathers data without prior hypothesis formation; hypothesis formation and testing comes during post-experiment data analysis and modeling.

Genomics

Proteomics

Modelling Tools

9

65-69

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80-84

85-89

90-94

95-99

Period

BIOSSIM (1968) ESSYN (1976) SCAMP (1983) SCOP (1986) METAMOD (1986) SIMFIT (1990) METAMODEL (1991) METASIM (1992) KINSIM (1993) GEPASI (1994) METALGEN (1994 ?) MIST (1995) METABOLIKA (1997 ?) METAFLUX (1997) SIMFLUX (1997) MNA (1998) CELLMOD (1998) FLUXMAP (1999) METATOOL (1999) VCELL (1999)

Genomics (HT-DNA sequencing) Mutation detection (SNP methods) Transcriptomics (Gene/Transcript measurement, SAGE, gene chips, microarrays) Proteomics (MS, 2D-PAGE, protein chips, Yeast-2-hybrid, X-ray, NMR) Metabolomics (NMR, X-ray, capillary electrophoresis)

Pi Calculus

Petri Nets

Differential Eqs

Boolean Networks

Cellular Automata

Atomic Scale 0.1 - 1.0 nm Coordinate data Dynamic data 0.1 - 10 ns Molecular dynamics

Tissue Scale 0.01m - 1.0 m Metabolic input Metabolic output 1 s 1 hr Process flow

Ecosystem scale 1 km 1000 km Environmental impact Nutrient flow 1 yr 1000 yrs Network Dynamics

If one scale (e.g., protein-protein interactions) behaves deterministically and with isolated components, then we can use plug-n-play approaches If it behaves chaotically or stochastically, then we cannot Most biological systems lie between this deterministic order and chaos: Complex systems

Intel Pentium 4 42 million transistors

The Intel Itanium 2 410 million transistors Number of gates > 100 Million By 2007 both Intel and AMD are predicting dies with 1 billion transistors In terms of parts and interconnections, man-made devices will likely have comparable complexity to bacterial cells if not greater by around 2010

System Models

Building computational models of systems seems more and more like a viable project.

Such a project would bring a much clearer understanding of how systems are controlled and ultimately it should bring unprecedented predictive power.

Xo S1 S2 S3 S4 S5 S6 X1

50 %

Xo

S1

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X1

What happens to the steady state? Xo and X1 fixed, all reactions reversible, assume stable steady state.

50 %

Xo

S1

S2

S3

S4

S5

S6

X1

3. The rate v goes down, but thats all. 4. S3 goes up. 5. S4 goes down. 6. Species downstream of v go down. 7. Steady State flow changes but species levels dont. 8. Xo and X1 change

50 %

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S1

S2

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X1

Computer simulation of EGF signal transduction PC12 cells.

Frances Brightman, Simon Thomas and David Fell

http://bms-mudshark.brookes.ac.uk/frances/fabweb5.htm

29 species

Computer simulation of EGF signal transduction PC12 cells.

Frances Brightman, Simon Thomas and David Fell

http://bms-mudshark.brookes.ac.uk/frances/fabweb5.htm

29 species

27 components

We move up the chain from data to knowledge by questioning, observing and then hypothesizing

These X genes are upregulated together, but are they interacting? PPI network data suggests Y are Are these Y part of a complex? If they are always expressed together, that suggests maybe yes

As more data is integrated and systems linked together, this becomes easier

Example of inference

(a) An interaction network of SnzSno proteins of S. cerevisiae. The nodes represent proteins and the lines represent yeast two-hybrid (Y2H) interactions. The red nodes represent proteins that correspond to genes in one transcriptome cluster, whereas the green nodes represent proteins that correspond to genes belonging to a different cluster. The existence of two stable complexes can be hypothesized based on the integrated data. (b) The genes NTH1 and YLR270W have similar expression profiles (upper panel). Red indicates upregulation and green indicates downregulation. mRNA expressions of both genes are upregulated during heat shock and other forms of stress. Deletions of NTH1 and YLR270W each confer similar heat-shock sensitive phenotypes (lower panel).

What kind of inferencing? Is the data validated? Can we take a best guess on how it might work by drawing upon other motifs or systems with similar properties?

Problems?

How is static data interpreted since its a dynamic system?

How do we deal with low-resolution quality?

How do we deal with heterogeneous data types? How can we identify and evaluate competing hypotheses inferred by any system? Yes

E-cell (Keio University, Japan) BioSpice Project (Arkin, Berkeley) Metabolic Engineering Working Group (Palsson & Church, UCSD, Harvard) Silicon Cell Project (Netherlands) Virtual Cell Project (UConn) Gene Network Sciences Inc. (Cornell) Project CyberCell (Edmonton/Calgary)

So where do we start?

Quantitative analysis of components and dynamics of complex biological systems

Static (Tier 1)

Deterministic (Tier 2)

Stochastic (Tier 3)

Nonlinearity

Feedback loops

Open systems (dissipation of energy)

Can have memory (response history dependent)

Response

New protein may remain in cell after initial response, shifting the rate of reaction the next time the cell is exposed to a chemical

Chemical concentration

Nested (modules have complexity)

There are no precise boundaries

So where do we start?

Quantitatively account for these properties

Different levels of modeling

Static (Tier 1)

Three tiers

Static interactions Deterministic Stochastic

Deterministic (Tier 2)

Stochastic (Tier 3)

Principle 1: Modularity

Module

Interacting nodes w/ common function Constrained pleiotropy Feedback loops, oscillators, amplifiers

Network motifs

Common methods to achieve an effect

Principle 3: Robustness

Robustness

Insensitivity to parameter variation

Robustness not present in most designs

Tier 1: Interactome

Which molecules talk to each other in networks?

Tier 2: Deterministic

What is the average case behavior?

Tier 3: Stochastic

What is the variance of the system?

Tier 1

Get parts list

Tier 2 & 3

Enumerate biochemistry Define network/mathematical relationships Compute numerical solutions

Tier 2 & 3

Deterministic: Behavior of system with respect to time is predicted with certainty given initial conditions Stochastic: Dynamics cannot be predicted with certainty given initial conditions

Deterministic

Ordinary differential equations (ODEs)

Concentration as a function of time only

Concentration as a function of space and time

Stochastic

Stochastic update equations

Molecule numbers as random variables functions of time

Y = # molecules at time t

Protein-protein

Signal transduction Cell cycle

Protein-DNA

Gene regulation

Metabolic pathways

Respiration cAMP

Goals

Determine network topology Network statistics Analyze modular structure

Limitations:

Time, space, population average Crude interactions

strength types

typical interactome

Global features

starting point for Tier 2 & 3

first time-varying yeast interactome (Bork 2005)

Analysis methods

Functional Genomics

expression analysis network integration

Graph Theory

scale free small world

Goal

model mesoscale system average case behavior

lumped cell

Three levels

ODE system ODE compartment system PDE data limited

cell compartments

Results

Robust Chemotaxis (Barkai 1997) MinCDE Oscillation (Howard 2003) Feedback in Signal Transduction (Brandman 2005)

Output

time series plots (ODE) condition on parameter values Brandman 2005

Example

Robustness in bacterial chemotaxis

Chemotaxis: bacterial migration towards/away from chemicals Parameters

concentrations binding affinities

Bacterial chemotaxis

model as random walk

Exact adaptation

change in concentration of chemical stimulant rapid change in bacterial tumbling frequency then adapts back precisely to its prestimulus value!!

Random walk

Experimental Design

Is exact adaptation robust to substantial variations in biochemical parameters? Systematically varied concentrations of chemotaxis-network proteins and measured resulting behavior

Tumbling frequency IPTG inducer

pUA4 pUA4 pUA4 pUA4

Adaption time

Adaptation precision = ratio of steady-state tumbling frequency of unstimulated to stimulated cells Summary of results Tumbling frequency 0.3 0.06 (20-fold) Adaption time 3 1 (3-fold) Adaption precision 1.04 0.07

Exact adaptation is maintained despite substantial varations in network-protein concentrations

Exact adaptation is a robust property but adaptation time and steadystate behavior are fine-tuned

Fluctuations in abundance of expressed molecules at the single-cell level

Leads to non-genetic individuality of isogenic population

When stochasticity is negligible, use deterministic modeling

System is large

molar quantities

Fast kinetics

reaction time negligible

infinite boundary conditions

Molecular noise is high:

System is small

finite molecule count matters

Slow kinetics

relative to movement time

relative to molecule size

Transcriptional bursting

Leaky transcription Slow transitions between chromatin states

Translational bursting

Low mRNA copy number

Finite number effect: translocation of molecules from the nucleus to the cytoplasm have a large effect on nuclear concentration Cytoplasm Nucleus

N = average molecular abundance (coefficient of variation) = /N Decrease in abundance results ina 1/N scaling of the noise (=1/N)

Recap

Three tiers

Interactomes Deterministic Stochastic Static (Tier 1)

Modularity Reuse Robustness Deterministic (Tier 2)

Stochastic (Tier 3)

Measurement of chemical kinetics parameters and molecular concentrations in vivo

Differences between in vitro and in vivo data

Compartmental specific reactions

Data is the limit!!!

Functional genomic data (Interactomes) E. Coli chemotaxis (Leibler, deterministic/robustness)

Important

parameter estimation feedback based estimation methods

Sachs 2005

Software

Tier 1: Interactomes

Graphviz, Bioconductor, Cytoscape

Tier 2: Deterministic

Matlab (SBtoolbox), Mathematica (PathwayLab)

Tier 3: Stochastic

R, Stochsim

Software

High-performance algorithms to solve systems of PDEs

Virtual Cell

H-GENESIS STOCK

Summary

Systems Biology can be done by breaking down each system into modules Many problems remain unsolved in exactly how to do this, but independent efforts are being developed in most areas that may one day merge together

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