系统生物学简介systemsbiology

SystemsBiology-Introduction系统生物学简介butisthisleadingtoincreasedunder-standingofthenatureoflife?Dowe,infact,understandlifeanybetterthanatthetimeofErwinSchrödinger*in1944?E.Schrödinger(1944)Whatislife?CambridgeUniversityPressWearelivingthroughaperiodinwhichthemainactivityinbiologicalresearchistheaccumulationofmoreandmorefacts,生物化学和分子生物学的局限性•Inaccuracy:noquantitative,i.e.accuratetestingofhypotheses（非量化,无法对假设进行精确的测试）•Inabilitytodealwithemergentproperties（缺乏应对突发性状的能力）•Irreducibility:biochemistryandmolecularbiologytheoriescannotbereducedtophysicalchemicaltheories（生化和分子生物学理论无法简化到理化理论）•Impotency,i.e.inabilitytoaddressLifeitselfandlackofconnectiontoorganismalBiology（不能回答生命本身的问题，并缺乏与组织生物学的联系）局限性•Undefinedness:notallfactorsthatplayimportantrolesareknownandconsequentlyhypothesescannotbetested（不知道所有发挥重要作用的因子，因而无法对假设进行验证）•Inaccessibilitytoexperimentation:thesystemsunderstudycannotbeexperimentedonthroughasufficientnumberofdegreesoffreedom（研究的系统不能够在足够的层次和自由度上进行实验）•Lackofanalyzability（缺乏可分析性）The‘omes’GenomeTranscriptomeProteomeMetabolomeGenomicsisnotenough•Allmoleculescanbemeasured/willbecomemeasurable•Hence:•Biologyisunderstood?Genomics•Allmoleculescanbemeasured/willbecomemeasurable•Hence:•Biologyisunderstood?•No:weknowthehumangenomesequence,butwestilldonotknowallabouthumanbiologyandtoCuredisease-omics:theBiologyofsystemsMakeapictureofalltheleavesIndividually?Transcriptome:hybridizationarrayProteomem/zRelativeAbundanceH2N-NSGDIVNLGSIAGR-COOH200400600800100012001005025075687.4887.0787.7560.2487.4373.2201.71000.41172.386.31114.3GDIVNLGSIAGRNSGDIVNLG[M+2H]2+ATGCGCATCGATGCGCATCGCGCGTAGCTAGCGCGTACGCGTAGCTACGCGTAGCGCGCATCGATCGCGCUACGCGUAGCUACGCGUAGCATPFunctionalgenomics:theanatomyWhatIsSystemsBiology?•过去的50年里生物学是所谓的top-down–从细胞到蛋白到基因..–产生了大量的数据挑战:putthepiecesbacktogetheragain•尝试建立对细胞、器官、生化过程和整个有机体的预测模型（predictivemodels）–用计算机、数学和工程学原理整合数据–Model-simulations-experimentDefinitionofSystemsBiology•Science！•deciphershowpropertiesthatarefunctionalbiologically（解析性状如何发挥生物功能）•ariseintheinteractionsbetweencomponentsoflivingorganisms.（研究有机体各成分间的相互作用）•studiesthegapbetween(‘dead’)moleculesandLife.（连接（“死”）分子与生命（“活”））SystemsBiology•Thefaceofbiologyhasbeenchanging:•Biology:focusonwholebutterflies•MolecularBiology:focusonsinglemolecules•Genomics:focusonallmolecules•SystemsBiology:focusonwhatcomesfromtheirinterrelations一个自稳态系统是一个开放系统，通过由相互依赖的调控机制严格控制的多重动态平衡来维持其结构和功能History•Termcoinedat1960s,howevertheoreticalpeopleandexperimentalbiologistsdiverged•Renaissanceat1990s–Biologybecomingcross-disciplinary,informationbased,highthroughputscienceNET(1931),self-organization(1952),feedbackregulationinmetabolism(1957)系统生物学Molecularbiologygrowsrapidly,hybridization,restrictionenzymes,cloning(1960s&70s)High-throughputsequencing(1980s)Genomesequences,Genome-wideexpressionanalysis;bioinformatics‘90s)Largescalesimulatorsofmetabolicnetworks,dissipativestructures,energycoupling,MCA,BST(1970s)Datapoorinsilicobiology,modelsofviruses,redbloodcell(1980’s&early1990’s)Genome-scalemodelsandanalysis,E-cells,siliconcell(late90’s)Analogsimulation,bioenergetics,Lacoperon(early1960s)DNAstructure(1953)未来:整合系统生物学:基因组水平，由相互作用而产生的功能，对原理/规律的探索，与基础科学的关联团队：多位点的基础建设，理论-实验的整合新课程，培训ThesystemsbiologyagendaGenome-wideprotein-metabolitebindingconstantsRegulatoryinteractionsGenome-wideprotein-proteinbindingconstantsGenome-widehigh-throughputenzymekineticsTranscriptomeProteomeMetabolomeDatabase,schemastandardsModelling;ODEs,Constraint-basedoptimisation,Solvinginverseproblems,NovelstrategiesModelorganism/systemofchoiceExperimentationAnalysisNewtheoryNewmethodologyGenome-wideprotein-inhibitorbindingconstants(Chemicalgenetics)Iterationbetweentheoryandexperiment理论和实验的重复Over-&UnderlyingtheoriesKNOWLEDGE/HYPOTHESISINDUCTIONDEDUCTIONOBSERVATIONS/DATASpiralratherthancycleofknowledge螺旋式上升INDUCTIONINDUCTIONDEDUCTIONDEDUCTIONDEDUCTIONINDUCTIONDEDUCTIONKnowledge/IdeasbyhypothesisKnowledge/IdeasbyhypothesisKnowledge/IdeasbyhypothesisOBSERVATIONS/OBSERVATIONS/DATADATAUnderlyingtheory(Physics,Chemistry)OBSERVATIONS/OBSERVATIONS/DATADATAOBSERVATIONS/OBSERVATIONS/DATADATA系统生物学的目标•理解生命更广泛的原理(‘laws’)•生命系统机制上的理解(‘details’)•预测•生物技术•治疗•从分子角度理解生命：–理解生命的起源–反击‘intelligentdesign’SystemsBiologyis:•NotBiology,because:–Itseekstounderstandandpredict(notwithcircularcausality)–它要去理解和预测（不是环状的因果关系）–Itseekstodiscovergeneralproperties–它尝试去发现更广泛的性质–Itisquantitative,usesmodeswhichitfalsifies/validates–它是定量的PhilosophyofSystemsBiologySystemsBiologyis:•Itsownnewscience•WhichrequiresitsownmethodologyandphilosophyKeyfeaturesofbiologicalsystemsEmergent新发性Robustness鲁棒性Complexity复杂性Modularity组合式EmergentProperties一个系统是具有新发性的相互作用的部分的集合新发性就是整体大于各部分的和EmergentpropertiesRobustnessinSimpleBiochemicalNetworks–BarkaiN,LeiblerS.Nature1997Jun26;387(6636):913-7–“Thecomplexityofbiochemicalnetworksraisesthequestionofthestabilityoftheirfunctioning…Thekeypropertiesofbiochemicalnetworksarerobust:relativelyinsensitivetotheprecisevaluesofbiochemicalparameters.对生化参数的精确数值的相当不敏感性PapersonRobustness–Experimentalsupport:RobustnessinbacterialchemotaxisAlonU,Sure