Systems Biology ___ Toward System-level Understanding of Biological Systems Hou-Haifeng

What is Systems Theory? By “ system ”, we mean a bunch of parts that are connected to one another and work together By “ system ”, we mean a bunch of parts that are 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 Systems - 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 Systems

What exactly is Systems Biology? Biology went top-down for the last 50 years Biology went top-down for the last 50 years From cell to protein to gene.. From cell to protein to gene.. Huge amounts of data produced Huge amounts of data produced Challenge: put the pieces back together again Attempts to create predictive models of cells, organs, biochemical processes and complete organisms Attempts to create predictive models of cells, organs, biochemical processes and complete 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 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 Biology?

History Term coined at 1960s, however theoretical people and experimental biologists diverged Term coined at 1960s, however theoretical people and experimental biologists diverged Renaissance at 1990s Renaissance at 1990s Biology becoming cross-disciplinary, information based, high throughput science Biology becoming cross-disciplinary, information based, high throughput science

A systems biology view... Components Building Blocks Functional Modules System Life‘s Complexity Pyramid (Oltvai-Barabasi, Science 10/25/02)

Systems Biology Research Cycle Vision In vitro, In vivo experiments In silico experiments

SYSTEMS BIOLOGY: Projects Multi-scale modeling and analysis of adaptive cellular and system processes Multi-scale modeling and analysis of adaptive cellular and system processes Mammalian systems – neurons, brains, brain functions and diseases Mammalian systems – neurons, brains, brain functions and diseases a model benchmark tool, and a matrix of solutions for Genetic Regulatory Circuits. a model benchmark tool, and a matrix of solutions for Genetic Regulatory Circuits. Development and Analysis of kinetic signaling models Development and Analysis of kinetic signaling models Link of signaling models to Genetic Regulatory Circuits Link of signaling models to Genetic Regulatory Circuits Genetic Regulatory Circuits to neuronal electrical behavior Genetic Regulatory Circuits to neuronal electrical behavior

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 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 accomplished 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 accomplished System Control

What needs to be accomplished 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 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 organizational principle

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 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

Conclusion System biology is a new and emerging field in biology System biology is a new and emerging field in biology A long ways to go before understanding biological systems A long ways to go before understanding biological systems We believe that systems biology will be the dominant paradigm in biology, and many medical applications as well as scientific discoveries are expected. We believe that systems biology will be the dominant paradigm in biology, and many medical applications as well as scientific discoveries are expected.

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