Systems biologySystems biology-the intro-the intro
張晃猷張晃猷分子醫學研究所分子醫學研究所
[email protected]@life.nthu.edu.tw
What is Systems What is Systems Biology????Biology????
To unravel the mysteries of human biology to identify strategies for predicting and preventing diseases such as cancer, diabetes and AIDS.
http://www.systemsbiology.org/
A cross-disciplinary scienceA cross-disciplinary science
The
The Human Genome ProjectThe Human Genome Project
GoalsGoals
ImpactImpact• Discovery science vs hypothesis-drivenDiscovery science vs hypothesis-driven• Biology is an Informational ScienceBiology is an Informational Science• Tools for high throughput quantitative meTools for high throughput quantitative me
asurement of biological informationasurement of biological information• The use of model organismsThe use of model organisms
Completed prokaryotes eukaryotes
Archae 19 eubacteria 167 ongoing ongoing
Eukaryote 32
Organizational and Organizational and Descriptional LevelsDescriptional Levels
So what is So what is Systems Systems BiologyBiology??
The definitionThe definition The types of biological information (DNA, The types of biological information (DNA, RNA, protein, protein interactions, biomolRNA, protein, protein interactions, biomolecules, cells, tissues, etc.) also have their iecules, cells, tissues, etc.) also have their individual elements (e.g. specific genes or ndividual elements (e.g. specific genes or proteins) and the relationships of these witproteins) and the relationships of these with respect to one another and the elements h respect to one another and the elements of other types of biological information mof other types of biological information must be determined, all of this information iust be determined, all of this information integrated to obtain a view (model) of the sntegrated to obtain a view (model) of the system as a whole. ystem as a whole.
Still vague? Still vague?
Systems Biology is a new field in Systems Biology is a new field in biology that aims at system-level biology that aims at system-level understanding of biological systems.understanding of biological systems.
Hiroaki KitanoHiroaki Kitano(Director, ERATO Kitano Symbiotic Systems Project(Director, ERATO Kitano Symbiotic Systems Project ))
What are biological What are biological systems?systems?
Ranges from Ranges from ecosystemsecosystems (eg. Bi (eg. Biosphere) to the system of reactioosphere) to the system of reactions that form ns that form cellular biochemistcellular biochemistryry
A Systems Approach to the Study A Systems Approach to the Study of Biological Systemsof Biological Systems
Some examplesSome examples
Galactose utilization/galGalactose utilization/galatosemiaatosemia
How a defective How a defective control protein (red control protein (red circle) alters the circle) alters the level of other level of other proteins (circles in proteins (circles in shades of gray) shades of gray) through interactions through interactions among proteins (blue among proteins (blue lines) and lines) and interactions between interactions between proteins and DNA proteins and DNA (yellow arrows). (yellow arrows).
Reverse-engineer the computational principles underlying cellular processes;
Develop tools and techniques for modeling and analysis of experimental data at three levels:
individual genes;network modules; whole networks.
Human immunityHuman immunity
Molecules
Synapses
Neurons
Networks
Systems
CNS
1 cm
100 um
10 cm
m
um
nm
1014 connecting points
Keynote Speakers:
James J. Collins Center for BioDynamics, Boston UniversityJohn Doyle Control and Dynamical Systems, CaltechYoshihide Hayasizaki Genome Exploration Group, RIKEN Genomic Sciences CenterStan LeiblerLaboratory of Living Matter, Rockefeller UniversityMark Ptashne Molecular Biology Program, Sloan-Kettering Institute
System Biology
The quantitative study of biological processes as integrated systems rather than as isolated parts.
The aim is to understand the interactions between the myriad of sub-cellular components.
The traditionally separated scientific disciplines, including physical chemistry, biochemistry, molecular biology, cell physiology and the behaviour of multicellular organisms, are unified by quantitative models.
Advance techniques for global measurements of subcellular dynamics of gene expression, proteins, and metabolites will be applied.
The progress will be crucial for a molecular understanding of many diseases and for development of novel biotechnological applications.
Expression ExperimentsExpression ExperimentsStatic: Snapshot of Static: Snapshot of the activity in the the activity in the cell cell
Time series: Multiple Time series: Multiple arrays at various temporal arrays at various temporal intervals intervals
Time Series Examples: Time Series Examples: DevelopmentDevelopment
Development of fruit flies [Arbeitman, Science 02]
Time Series Examples (cont) Time Series Examples (cont)
Infectious diseases [Huang, Science 01; Nau, PNAS 02]
Function
Transcription factors knockout [Zhu, Nature 00;
Pramilla, Genes Dev. 02]
Interactions
Systems Biology –
from Bioscience to Medicine
Metabolic FluxMetabolic Flux Signal transductionSignal transduction Microbial systemsMicrobial systems Methods and softwaresMethods and softwares Spatial modelsSpatial models Systems biology for medicineSystems biology for medicine
Metabolic fluxMetabolic fluxFrom gene expression to metabolic fluxesFrom gene expression to metabolic fluxes
Vertical genomics: From gene expression to function ... and backVertical genomics: From gene expression to function ... and back
Dynamic metabolomics for systems biologyDynamic metabolomics for systems biology
Metabolic networks in motion: High-throughput analysis of molecular Metabolic networks in motion: High-throughput analysis of molecular fluxesfluxes
Prediction of regulatory pathways using mRNA expression and proteiPrediction of regulatory pathways using mRNA expression and protein-protein interaction data: Application to prediction of galactose ren-protein interaction data: Application to prediction of galactose regulatory pathwaygulatory pathway
Metabolic networks in plants: Statistical analysis and biological interpMetabolic networks in plants: Statistical analysis and biological interpretationretation
Minimal cut sets: Failure modes and target sets in metabolic networkMinimal cut sets: Failure modes and target sets in metabolic networkss
Microbial systems Microbial systems biologybiology
Metabolome analysis and cell simulationMetabolome analysis and cell simulation
Doing it their way: Metabolic differentiation in salmonellaDoing it their way: Metabolic differentiation in salmonella
Receptor cooperativity and signal processing in bacterial cheReceptor cooperativity and signal processing in bacterial chemotaxismotaxis
Bacterial persistence: A phenotypic switch revealed by microflBacterial persistence: A phenotypic switch revealed by microfluidicsuidics
An approach to generate testable hypothesis in microbiologyAn approach to generate testable hypothesis in microbiology
The dynamic response of yeast cells to osmotic shockThe dynamic response of yeast cells to osmotic shock
Methods and Software for Methods and Software for Systems Biology Systems Biology
Software and methods for modeling and simulating biochemical nSoftware and methods for modeling and simulating biochemical networksetworks
A hybrid approach for efficient and robust parameter estimation in A hybrid approach for efficient and robust parameter estimation in biochemical pathwaysbiochemical pathways
A modular approach to building the silicon yeast cellA modular approach to building the silicon yeast cell
Model Orchestration: Addressing the challenges of model managModel Orchestration: Addressing the challenges of model management and model composition in systems biologyement and model composition in systems biology
Dicovering Motifs in Biological Networks using Sub-Graph IsomorDicovering Motifs in Biological Networks using Sub-Graph Isomorphismphism
Principles of Systems Biology, illustrated with modeling of the heaPrinciples of Systems Biology, illustrated with modeling of the heartrt
Spatial ModelSpatial ModelQuantitative temporal and spatial analysis of cell division by 4D iQuantitative temporal and spatial analysis of cell division by 4D i
magingmagingPropagating chemical waves within and among cellsPropagating chemical waves within and among cells
Temporal and spatial control of signaling in the interferon-y/jak/StTemporal and spatial control of signaling in the interferon-y/jak/Stat1 pathwayat1 pathway
Systems analysis of the quorum sensing phenomenon in a peculiSystems analysis of the quorum sensing phenomenon in a peculiar plant pathogen ar plant pathogen Agrobacterium tumefaciensAgrobacterium tumefaciens
Compensation effect of MAPK cascade on formation of phospho-Compensation effect of MAPK cascade on formation of phospho-protein gradientprotein gradient
How to make a neurocrystal: Modelling the development patterninHow to make a neurocrystal: Modelling the development patterning of the fruit fly´s retinag of the fruit fly´s retina
Signal transductionSignal transduction Dynamics and design of signalling networks: The Wnt-paDynamics and design of signalling networks: The Wnt-pa
thwaythway Synaptic signaling: Holding out against noise, diffusion, aSynaptic signaling: Holding out against noise, diffusion, a
nd turnovernd turnover Employing systems biology to quantify receptor tyrosine Employing systems biology to quantify receptor tyrosine
kinase signaling in time and spacekinase signaling in time and space Cellular decision making: Control of kinases and phosphCellular decision making: Control of kinases and phosph
atases on signaling kineticsatases on signaling kinetics Modeling signal transduction systems without ignoring thModeling signal transduction systems without ignoring th
eir combinatorial complexityeir combinatorial complexity New quantitative approaches for modeling and simulatioNew quantitative approaches for modeling and simulatio
n of large signal transduction networks reveal novel insign of large signal transduction networks reveal novel insights into programmed cell deathhts into programmed cell death
Systems Biology and Systems Biology and MedicineMedicine
Mathematical Modelling of metabolic diseasesMathematical Modelling of metabolic diseases
Virus dynamics: Modeling of influenza A virus replicationVirus dynamics: Modeling of influenza A virus replication
Discovering activated regulatory networks in the DNA damage reDiscovering activated regulatory networks in the DNA damage response pathway of yeastsponse pathway of yeast
Metabolic comparison of the in-silico phenotype-genotype relatioMetabolic comparison of the in-silico phenotype-genotype relationship of nship of Pseudomonas putidaPseudomonas putida and and Peudomonas aeruginosaPeudomonas aeruginosa
Systems biology approach to understand the stress response of Systems biology approach to understand the stress response of P. aeruginosaP. aeruginosa to host innate immunity to host innate immunity
Using a mammalian cell cycle simulation in anti-tumor pharmaceUsing a mammalian cell cycle simulation in anti-tumor pharmaceutical development to interpret differential kinase inhibition and biutical development to interpret differential kinase inhibition and biological knock-outsological knock-outs
The position of Systems The position of Systems BiologyBiology
What does it take to carry What does it take to carry out Systems Biology? out Systems Biology?
A cross-disciplinary faculty who speak and understand the A cross-disciplinary faculty who speak and understand the languages of different disciplines languages of different disciplines
Integrate new global technologies with the data acquisition, Integrate new global technologies with the data acquisition, storage, integration, and analysis tools of computational storage, integration, and analysis tools of computational biology and mathematics.biology and mathematics.
High-throughput facilities for genomics, proteomics etc… High-throughput facilities for genomics, proteomics etc…
An integration of effort with academia and industry. An integration of effort with academia and industry.
Integration of discovery science with hypothesis-driven Integration of discovery science with hypothesis-driven science for the integrated global analysis of systems. science for the integrated global analysis of systems.
In another word……In another word……
Why do we care about Why do we care about biological systems?biological systems?
Ability to figure out what the effect will be of Ability to figure out what the effect will be of an intervention in one part of the systeman intervention in one part of the system
What intervention one has to make in order What intervention one has to make in order to obtain some desired resultto obtain some desired result
= Which protein should be either activated or = Which protein should be either activated or deactivated in order to stop a particular deactivated in order to stop a particular disease process while doing the least harm disease process while doing the least harm to the patient?to the patient?
Where do computers Where do computers come in?come in?
Systems modelingSystems modeling simulation, reasoning, discoverysimulation, reasoning, discovery Some properties to investigateSome properties to investigate Structure Structure DynamicsDynamics RobustnessRobustness Methods of control systemsMethods of control systems Methods to design and modify for desired Methods to design and modify for desired propertiesproperties
The SYSTEOME ProjectThe SYSTEOME Project
Systeome is an assembly of system profiles for Systeome is an assembly of system profiles for all genetic variations and environmental stimuli rall genetic variations and environmental stimuli responses.esponses.
Goal: to complete a detailed and comprehensivGoal: to complete a detailed and comprehensive simulation model of the human cell at an estie simulation model of the human cell at an estimated error margin of 20% by year 2020, and to mated error margin of 20% by year 2020, and to finish identifying the system profile for all genetifinish identifying the system profile for all genetic variations, drug responses, and environmental c variations, drug responses, and environmental stimuli by 2030.stimuli by 2030.
Dr. Hiroaki KitanoDr. Hiroaki Kitano
ConclusionConclusion System biology is a new and emerging field in System biology is a new and emerging field in
biologybiology A long ways to go before understanding A long ways to go before understanding
biological systemsbiological systems “… “… systems biology will be the dominant systems biology will be the dominant
paradigm in biology, and many medical paradigm in biology, and many medical applications as well as scientific discoveries are applications as well as scientific discoveries are expected” – Hiroaki Kitanoexpected” – Hiroaki Kitano
Further readingsFurther readings
Biological System Biological System SampleSample
Biological System Biological System SampleSample
Gene Expression and Gene Expression and RegulationRegulation
Intra- and Inter-Cellular Intra- and Inter-Cellular DynamicsDynamics
Heat-Shock RegulationHeat-Shock Regulation
Biology in a Nutshell(for people with little knowledge but infinite intelligence)
Genomes
Gene Products Structure
& Function
Pathways & Physiology
Genome consists of genes
Gene Protein: Object description Object instantiation
Protein Functions
Enzymes: proteins that catalyze biochemical reactions
Pathway: sequence of reactions
Network (directed graph): set of pathways with metabolites as vertices and enzymes as edges
Genome (ROM): assembly code on how to build proteins
Instructions: A, C, T, G
3 variables amino acid