Systems Biology___ Toward System-level

Understanding of Biological Systems

Hou-HaifengHou-Haifeng

What is Systems Theory?What is Systems Theory?

By By “system”“system”, we mean a bunch of parts that a, we mean a bunch of parts that are connected to one another and work togetherre connected to one another and work together

Mathematical Systems Theory is oncerned with the description and understanding of systems by the means of mathematics

Analysis Modeling Simulation ...

Dynamic SystemsDynamic Systems- Definition- Definition

A system is an object in which variables of different kinds interact and produce observable signals

In a dynamic system the current output value depends not only on the current input value but also on its earlier values

Dynamic SystemsDynamic Systems

What exactly is Systems What exactly is Systems Biology?Biology?

Biology went top-down for the last 50 Biology went top-down for the last 50 yearsyears From cell to protein to gene ..From cell to protein to gene .. Huge amounts of data producedHuge amounts of data produced

Challenge: put the pieces back together Challenge: put the pieces back together againagain

Attempts to create predictive models of Attempts to create predictive models of cells, organs, biochemical processes and cells, organs, biochemical processes and complete organismscomplete organisms

The scope of systems biology is potentially very broad and different sets of techniques may be deployed for each research target. It requires collective efforts from multiple research areas, such as molecular biology, high-precision measurement, computer science, control theory, and other scientific and engineering fields.

What exactly is Systems What exactly is Systems Biology? Biology?

a new field in biology that aims at system-level understanding of biological systems

to understand biological systems grounded in the molecular level as a consistent framework of knowledge

to investigate the behaviour and relationships of all the elements in a particular biological system

What exactly is Systems What exactly is Systems Biology?Biology?

HistoryHistory

Term coined at 1960s, however Term coined at 1960s, however theoretical people and experimental theoretical people and experimental biologists divergedbiologists diverged

Renaissance at 1990sRenaissance at 1990s Biology becoming cross-disciplinary, Biology becoming cross-disciplinary,

information based, high throughput information based, high throughput sciencescience

A systems biology view...A systems biology view...

Components

BuildingBlocks

FunctionalModules

System

Life‘s Complexity Pyramid (Oltvai-Barabasi, Science 10/25/02)

Systems Biology Research Cycle VisionSystems Biology Research Cycle Vision

In vitro, In vivo experiments

In silico experiments

SYSTEMS BIOLOGY: SYSTEMS BIOLOGY: ProjectsProjects

Multi-scale modeling and analysis of Multi-scale modeling and analysis of adaptive cellular and system processesadaptive cellular and system processes

Mammalian systems – neurons, brains, Mammalian systems – neurons, brains, brain functions and diseasesbrain functions and diseases

a model benchmark tool, and a matrix of a model benchmark tool, and a matrix of solutions for Genetic Regulatory Circuits. solutions for Genetic Regulatory Circuits.

Development and Analysis of kinetic signaling Development and Analysis of kinetic signaling modelsmodels

Link of signaling models to Genetic Regulatory Link of signaling models to Genetic Regulatory CircuitsCircuits

Genetic Regulatory Circuits to neuronal Genetic Regulatory Circuits to neuronal electrical behaviorelectrical behavior

IonChannels

Receptors

mRNA

TranscriptionFactors

Ligands

ELECTROPHYSIOLOGY

Extracellularspace

Cytoplasm

NucleusTranslation +

processing

cis sites

IntracellularSignaling

GeneticRegulatory

Network

Expression profiles

Cellularprocesses

Proteins

Nucleus

mRNAsTFsIntracellular

signals

Cytosol

Genomicsequences

cis bindingactivities

Protein interaction network Protein interaction network The colour of a node indicates the phenotypic effect of removing the corresponding protein (red = lethal, green = non-lethal, orange = slow growth, yellow = unknown).

Yeast map of protein–protein interactions based on yeast two-hybrid method

What needs to be What needs to be accomplished?accomplished?

System Structure Identification

BOTTOM-UP APPROACH :

TOP-DOWN APPROACH: make use of high-throughput data and other new measurement technologies to deduce the properties of the systems

PARAMETER IDENTIFICATION :brute force exhaustive search, genetic algorithms, simulated annealing …

Systems

Components

What needs to be What needs to be accomplishedaccomplished

System Behavior Analysis Computer simulation and a set of theoretical

analyses are essential to provide in-depth understanding on the mechanisms behind the circuits

Figure:Software tools for systems biology and their workflow

• a database for storing experimental data• a cell and tissue simulator,• parameter optimization software,• bifurcation and systems analysis software,• hypotheses generator and experiment planning advisor software, and• data visualization software.

What needs to be What needs to be accomplishedaccomplished

System Control

What needs to be What needs to be accomplishedaccomplished

System Design: the strategies to modify and construct biological systems having desired properties can be devised based on definite design principles and simulations, instead of blind trial-and-error

Biological RobustnessBiological Robustness

Robustness is a ubiquitously observed property of biological systems

Robustness is a property that allows a system to maintain its functions despite external and internal perturbations

| Explaining robustness — the aeroplane example.

System control consists of negative and positive feedback to attain a robust dynamic response in the regulatory networks (cell cycle, circadian clock and chemotaxis)

Robustness as an Robustness as an organizationalorganizational principleprinciple

Modularity an effective Mechanism for containing perturbations and damage locally to minimize the effects on the whole system

Decoupling isolates low-level variation from high-level functionalities

Biological RobustnessBiological Robustness

Cancer is an extremely complex and heterogeneous disease that exhibits a high level of robustness against a range of therapeutic efforts

Heterogeneity among tumour cells provides a high level of redundancy, and hence increased chances of survival and growth

Hunt for fragility: weaknesses in tumour growth dynamics could yield new anti-cancer therapies

ConclusionConclusion System biology is a new and emerging System biology is a new and emerging

field in biologyfield in biology A long ways to go before understanding A long ways to go before understanding

biological systemsbiological systems We believe that systems biology will be We believe that systems biology will be

the dominant paradigm in biology, and the dominant paradigm in biology, and many medical applications as well as many medical applications as well as scientific discoveries are expected.scientific discoveries are expected.

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