系统生物学I-概述学习资料

Curriculumarrangement1.Introductiontosystemsbiology2.Advancedmeasurementplatformfor-omics3.Modeling&simulating4.CellularSimulation5.System-levelanalysis6.Systemsbiologysoftware1Lecture1：IntroductiontoSystemsBiology2OutlineIntroduction介绍2.MeasurementTechnology&ExperimentalMethods

测量技术和实验方法3.Next-generationExperimentalSystems

下一代实验系统4.RobustnessofBiosystems稳健性5.Systeome系统体制6.ImpactofSystemsBiology系统生物学的影响7.Conclusion总结31.1.Ultimategoalofbiology？终极目标tounderstandeverydetailandprincipleofbiologicalsystems…；理解生物系统的每个细节和原则AncientfarmingCopyright1996byInterCityOz,Inc./magazine/mag07012001/magf5.htm4Mendel(1822-1884)GregorMendelpublishedhisfindingsonheredityinpeasinVersucheüberPflanzenHybriden.51900:

Mendel’sworkwasdiscovered6Morgan(1866-1945)1915:TheMechanismofMendelianHeredityChromosomesarethevehiclesofheredity.染色体是遗传的载体Genesareonchromosomes.基因存在于染色体上Genescanchange(mutate).基因可变Whataregenesmadeof?A.H.SturtevantC.B.BridgesH.J.Muller7Schrödinger(1887-1961)1944:

Schrödingerasks“whatislife?”“……livingmatter,whilenoteludingthe‘lawsofphysics’asestablisheduptodate,

islikelytoinvolve‘otherlawsofphysics’

hithertounknown…...”

生活的物质，不逃避自古以来建立的物理定律，以及迄今为止没有阐明的物理定律81944:DNAisthehereditarychemical!9Molecularstructureofnucleicacids:astructurefordeoxyribosenucleicacid.Nature171(1953):737–738.WatsonandCrick10MolecularBiologyMauriceWilkins1916-2004RosalindFranklin1920-1958FrancisCrick1916-2004JimWatson1928-1962:

NobelPrize111950-1970:

UnravellingofhowthecelldecodesDNA解开DNA细胞如何解码DNA的机制---中心法则TheCentralDogmaofMolecularBiology121977:

determiningthesequenceofnucleotidesinDNA

确定DNA的核苷酸序列SangerGilbert1980:

FredSanger&WallyGilbertwereawardedtheNobelPrizeinChemistry.CTGGAAGAGGTATGTGCGCCGTTTCTGTTATCACAGTGTGCAATCCCATTACCGCATATCAGTTATAACAATAGTAATGGTAGCGCCATTAAAAATATTGTCGGTTCTGCAACTATCGCCCAATACCCTACTCTTCCGGAGGAAAATGTCAACAATATCAGTGTTAAATATGTTTCTCCTGGCTCAGTAGGGCCTTCACCTGTGCCATTGAAATCAGGAGCAAGTTTCAGTGATCTAGTCAAGCTGTTATCTAACCGTCCACCCTCTCGTAACTCTCCAGTGACAATACCAAGAAGCACACCTTCGCATCGCTCAGTCACGCCTTTTCTAGGGCAACAGCAACAGCTGCAATCATTAGTGCCACTGACCCCGTCTGCTTTGTTTGGTGGCGCCAATTTTAATCAAAGTGGGAATATTGCTGATAGCTCATTGTCCTTCACTTTCACTAACAGTAGCAACGGTCCGAACCTCATAACAACTCAAACAAATTCTCAAGCGCTTTCACAACCAATTGCCTCCTCTAACGTTCATGATAACTTCATGAATAATGAAATCACGGCTAGTAAAATTGATGATGGTAATAATTCAAAACCACTGTCACCTGGTTGGACGGACCAAACTGCGTATAACGCGTTTGGAATCACTACAGGGATGTTTAATACCACTACAATGGATGATGTATATAACTATCTATTCGATGATGAAGATACCCCACCAAACCCAAAAAAAATATGTGCAAAAAAATGCTTGATGATTTGTAATGAGATTGAGGAGGTTTCGAGACAGGCACCAAAGTTTTTACAAATGGAT13Molecularbiologyenablesustounderstandbiologicalsystemsasmolecularmachines,tounderstandtheelementaryprocessesbehindheredity,evolution,development,anddisease,includingreplication,transcription,translation,andsoforth.142001:TheHumanGenome分子生物学使我们了解生物系统作为生物机器的工作机制，了解遗传、进化、发育、疾病背后的基本过程，包括复制、转录、翻译等等。DNA:genome(mycoplasma,E.coli,C.elgans,Drosophila,Homosapiens)

基因组RNA:transcriptome&genesexpressionprofiling

转录组和基因表达谱Protein:proteome(bloodplasma,liver,brain…)蛋白质组Metabolite（代谢物）：metabolome代谢组Ourunderstandingtowardsmolecular-levelmechanismofbiologicalsystemsisaccelerating.Nevertheless,suchknowledgedosenotprovideuswithanunderstandingofbiologicalsystemsassystems.Genesandproteinsarethecomponentsofthesystems.Whatconstitutesthesystemisnecessaryforunderstandingthesystems,butnotsufficient.

我们对生物系统分子水平的了解日益加速，然而这些知识不能为我们提供生物作为一个系统的了解。基因和蛋白质是系统的组件，是我们了解系统构成的必要成分，但远远不够151.2.Goalofsystemsbiology？

aimstodevelopasystem-levelunderstandingofbiologicalsystems.为了在系统水平上了解生物系统

Systemlevelunderstandingrequiresasetofprinciplesandmethodologies方法论thatlinksthebehaviorsofmoleculestosystemcharacteristicsandfunctions.Ultimately,cells,organisms,andhumanbeingswillbedescribedandunderstoodatthesystemlevelgroundedon基于aconsistentframework一致的框架ofknowledgethatisunderpinned支持、基础bythebasicprinciplesofphysics.161.3.OriginofSystemsBiology1933：CannonConceptofHomeostasis内稳态概念

Cannon,W.B.,(1933).Thewisdomofthebody,Norton,NewYork.

1948：WienerBiologicalCybernetics生物控制论

Wiener,N.,(1948).CyberneticsorControlandCommunicationintheAnimalandtheMachine,TheMITPress,Cambridge.1968：vonBertalanffyGeneralSystemsTheory一般系统理论

vonBertalanffy,L.(1968).GeneralSystemTheory,Braziler,NewYork.Withthelimitedavailabilityofknowledgefrommolecularbiology,mostsuchattemptshavefocusedonthedescriptionandanalysisofbiologicalsystemsatthephysiologicallevel.生理水平1718ModernSystemsBiology现代系统生物学Modernsystemsbiologythatdistinguishesitfrompastattemptsisthatthereareopportunitiestoground接触，基础system-levelunderstandingdirectlyonthemolecularlevelsuchasgenesandproteins,whereas然而pastattemptshavenotbeenabletosufficientlyconnectsystemleveldescriptiontomolecular-levelknowledge.

Thus,althoughitisnotthefirsttimethatsystem-levelunderstandinghasbeenpursued继续从事,itisthefirsttimetohaveanopportunitytounderstandbiologicalsystemswithintheconsistentframework一致框架ofknowledgebuiltupfromthemolecularleveltothesystemlevel.19CharacteristicsofModernSystemsBiologyComprehensiveanalysisofallthemoleculesinsidethecell对细胞里全部分子的综合分析Measurementofdynamicchangesofallthemolecules对所有分子进行动态测量Dataintegrationwithmathematicorcomputationalmethod用数学或计算的方法进行数据整合Dynamicanalysisofbiosystemsfrommolecularleveltoorganism对生物系统从分子水平到有机体水平的动态分析Modelingbasedonsystemscience系统科学基础上建模Combinationofdiscoveryscienceandhypothesis-drivenscience对已发现的科学现象和假设的现象结合201.4.Definition定义HiroakiKitano

LeroyHood

Systemsbiologyrepresentsanapproachtoinvestigate调查allthecomponents(genes,mRNAs,proteins,cells,tissuesandorgansetc.)ofabiologicalsystem,andtheirinteractionsinspecificconditions,thusto由此realizetheintegrationofinformationofdifferentlevelsfromgenestocells,tissuesandorganism.

Integration&Quantitation定量21

BiologicalSystems22生命组学，生理组学ComponentInteraction1022313系统复杂性

Forasystem,themostimportantthingisnotthefunctionsoftheindividuals,buttheirinteractions！23Methodtoinvestigatecomplexsystem探究复杂系统的方法1.Reductionism还原论Ontologicalreductionism本体论还原Methodologicalreductionism

方法论还原2.Holism整体论3.Generalsystemstheory一般体系论

Chaostheory混沌理论Cellularautomata细胞自动控制器Catastrophetheory突变理论Hierarchicalsystems分级系统

24ChaostheoryPredictability:DosetheflapofaButterflyWingsinBrazilsetoffaTornadoinTexas?(1972)可预言性EdwardLorenzWhenthepresentdeterminesthefuture,buttheapproximate大概的presentdoesnotapproximatelydeterminethefuture.Unpredictability不可预测性Extremelysensitivetotheinitialcondition对最初的条件十分敏感25SYamanakaNature

460,49-52(2009)StochasticmodelApplication:stochasticmodelingforinducedpluripotentstemcellgeneration应用：诱导多功能干细胞的随机模型26Cellularautomata细胞自动机Acellularautomataconsistsofaregulargrid规则网格ofcells,eachinoneofafinitenumber有限数ofstates,suchasonandoff.Thegridcanbeinanyfinitenumberofdimensions规模.Foreachcell,asetofcellscalleditsneighborhoodisdefinedrelativetothespecifiedcell.Aninitialstate(timet=0)isselectedbyassigningastateforeachcell.Anewgenerationiscreated(advancingtby1),accordingtosomefixedrule(generally,amathematicalfunction)thatdeterminesthenewstateofeachcellintermsofthecurrentstateofthecellandthestatesofthecellsinitsneighborhood.Typically,theruleforupdatingthestateofcellsisthesameforeachcellanddoesnotchangeovertime,andisappliedtothewholegridsimultaneously.JohnvonNeumannCharacteristics:parallelcomputation,local,homogeneousStephenWolframcurrentpatternnewstatusofcentercell27ApplicationProtNet:atoolforstochasticsimulationsofproteininteractionnetworksdynamics一种对蛋白质相互作用动态网络进行模拟的工具BMCBioinformatics.2007;8(Suppl1):S4.28Catastrophetheory突变理论Catastrophetheory,whichoriginatedwiththeworkoftheFrenchmathematicianRenéThominthe1960s,andbecameverypopularduetotheeffortsofChristopherZeemaninthe1970s,considersthespecialcasewherethelong-runstableequilibriumcanbeidentifiedwiththeminimumofasmooth,well-definedLyapunovfunction.Smallchangesincertainparametersofanonlinearsystemcancauseequilibriatoappearordisappear,ortochangefromattractingtorepellingandviceversa,leadingtolargeandsuddenchangesofthebehaviourofthesystem.RenéThom

FieldsMedalin1958ChristopherZeemanWhichtheoryismoreaccurate?Better?29Application:MassivegenomicrearrangementacquiredinaSingleCatastrophicEventduringCancerDevelopment在癌症发展过程中单一灾难性事件中收集到的大量基因组重排FISHProfilingofTK10GenomicFeaturesofChromothripsisSuggestthatMostRearrangementsOccurinaSingleCatastrophicEventPhilipJ.Stephens,etal.Cell144,27–40,201130Hierarchicalsystems分级系统1)Itiseasiertoanalyseand(re)designlarge-scalesystemsiftheyarebrokenintosmallerunits.2)Thesub-systemapproachallowsspecialisation,whereasub-systemisonlyresponsibleforitsowntaskanddoesnotrequireinformationoftheobjectivesoftheoverallsystem.3)Hierarchicalsystemsallowacertaindegreeoffaulttolerance.Thisisduetothefactthatifasub-systembreaksdown,theoverallsystemdoesnotnecessarilystopworking.Furthermore,dueto’modulestructure’thefailureis’localised’andhenceeasytodetectandandrepair.Thecoordinator,however,istheweakpoint,becauseifitstopsworking,theoverallsystemcannotfunctionanymore.4)Evenevolutionseemstofavourtwo-levelhierachicalsystems.Forexampleinahumanbodythebraincanbeconsideredasbeingthecoordinator,whereastherestofthebodyformsthesub-systemlevel.5)Intheevolutionoforganisationstwo-levelhierachicalsystemsplayamajorrole.Evenpre-historictribeshadatribeleader,whomwasresponsibleforcoordinatingtheactionsofindividualtribemembersinordertoimprovetheoverallwell-beingofthetribe.Whytwolevelhierarchicalsystemsaresofrequent?Complexity&Complicatedness复杂度和复杂性31Application:OscillationsinNF-kBSignalingControltheDynamicsofGeneExpressionNF-kBSignaling的震动控制基因表达动力学D.E.Nelsonetal.Science306,704(2004)32SimplestmodelAveragecomplexitymodelMostcomplexmodel33PropertyofBiosystem系统生物的性质Emergence出现Anyfunctionperformedbyasystemthatisnottheresultofasinglepartinthesystem,butratheristheresultofinteractingpartsinthesystem.1)Brandnewproperty:全新的属性Theinteractionofthesepartsgivesrisetonewpropertiesandfunctions.2)Irreducible:

不能削减Systemscannotbereducedto分解为theirindividualpartsorstudiedonepartatatime.3)Unpredictable:不可预测Systems’characteristicscannotbepredictedfromtheirindividualparts.Robustness稳健性Thesystemmaintainsitsfunctionalpropertiesagainstvariousdisturbances.干扰1)Adaptation;适应性

2)Parameterinsensitivity;参数不敏感

3)Gracefuldegradation.功能降低34Scale-free无标度Ascale-freenetwork’s无标度网络degreedistributionfollowsapowerlaw幂次定律,thatis,thefractionP(k)ofnodesinthenetworkhavingkconnectionstoothernodesgoesforlargevaluesofkas:p(k)~k-n

wherenisaparameterwhosevalueistypicallyintherange2<n<3.

InternetProtein-proteinnetwork35PhysicsChemistryBiologyTraditionalMethodology:Reductionism还原论，简化伦36Philosophyshiftsfromreductionistictointegrative37Science2002,763-764Systemsbiology:acombinationofdiscoveryscience&hypothesis-drivenscience381.Systemstructureidentification2.Systembehavioranalysis3.Systemcontrol4.Systemdesign1.5.Mission任务391.5.1.Identificationofsystemstructure系统结构识别1.Genome,transcriptome,proteome,metabolome…;2.Regulatoryrelationshipsamonggenes;3.Interactionsofproteinsthatprovidesignaltransductionandmetabolismpathways;4.Physicalstructuresoforganisms,cells,organelle,chromatin,andothercomponents;5.Physicalstructuresofwholeanimalsprecisely精确地atthecellularlevelformulticellularorganism.401.5.2.Systembehavioranalysis

Onceasystemstructureisidentifiedtoacertaindegree,itsbehaviorneedstobeunderstood.e.g.Sensitivityofcertainbehaviorsagainstexternalperturbations干扰;Howquicklythesystemreturnstoitsnormalstateafterthestimuli刺激.Significance:意义Reveal揭露system-levelcharacteristics;Provideimportantinsights见解formedicaltreatmentsbydiscoveringcellresponsetocertainchemicals.411.5.3.Systemcontrol系统控制

Byapplyingtheinsightsobtained获得bysystemstructureandbehaviorunderstanding,wecanestablishamethodtocontrolthestateofbiologicalsystems.e.g.Transformmalfunctioning出故障的cellsintohealthycells;Controlcancercellstonormalcellsorcauseapoptosis细胞凋亡;Controlthedifferentiation分化status状态ofaspecificcellintoastemcell干细胞,andcontrolittodifferentiateintothedesiredcelltype.SignificanceTechnologiestoaccomplishsuchcontrolwouldenormouslybenefithumanhealth.421.5.4.Systemdesign

Ultimately,wewouldliketoestablishtechnologiesthatallowustodesignbiologicalsystemswiththeaimofprovidingcuresfordiseases.e.g.Designandgroworgansfromthepatient’sowntissue.Suchanorgancloningtechniquewouldbeenormouslyusefulforthetreatmentofdiseasesthatrequireorgantransplants.器官移植Engineeringapplicationsbyusingbiologicalmaterialsforroboticsorcomputation.Byusingmaterialsthathaveself-repairandself-sustainingcapability自我维持能力,industrialsystemswillberevolutionized.43441.6.Keyfieldsinsystemsbiology关键领域1.Biologicalscience:molecularbiology&-omics组学2.Computationscience：

simulation、bioinformatics&software3.Systemscience:systemanalysisbasedoncontroltheory4.Analyticalscience:highthroughput,precisemeasurement4546472.1.ComprehensivemeasurementGenomesequence:capillaryarrayelectrophoresis毛细血管微阵列电泳Geneexpressionprofiling:

biochip,RTPCR基因表达谱Proteinsequence:separation&MS蛋白质序列Interaction:twohybrid,TAP,biochipProteinlocalization:molecularimaging蛋白质定位Metabolite代谢物：separation&MS,NMRModelspecies:Yeast,Celegan,Drosophila

482.2.MeasurementforSystemsBiologyHigh-throughput高通量,comprehensive综合的,andaccuratemeasurement精确测量isthemostessentialpartofSB.Itwillnevergenerateseriousresultswithoutexperimentaldatauponwhichcomputationalstudiescanbegrounded.有充足的理由的Tobesuccessful,measurementhastobe(1)comprehensive,综合性(2)quantitativelyaccurate,定量准确(3)systematic.系统的492.2.1.Comprehensivemeasurement？

1.factorcomprehensivenessComprehensivenessintermsof依据targetfactorsthatarebeingmeasured,suchasnumbersofgenesandproteins.Itisimportantthatmeasurementiscarriedoutintensively强烈地，集中地forthefactorsthatarerelatedtothecentralgenesandproteinsofinterest.Unlessallgenesandproteinsaremeasured,howeffectivelymeasurementcoversthefactorsofinterestismoreimportant,ratherthanthesheer绝对的numberoffactorsmeasured.e.g.toinfer推断geneticregulatorynetworksfromanexpressionprofile概况502.time-series时间序列comprehensivenessInmodelingandanalysisofadynamicalsystem,itisimportanttocaptureitsbehaviorwithfine-grain细粒timeseries.Traditionalbiologicalexperimentstendtoensureonlythechangebeforeandafteracertainevent.Forcomputationalanalysis,datameasuredataconstanttimeintervalareessential基本的inadditiontotraditionalsamplingpoints.样本点e.g.cellularaging细胞衰老513.itemcomprehensivenessTherearecaseswhereseveralfeatures,suchastranscriptionlevel,proteininteraction,phosphorylation,localization,andotherfeatures,havetobemeasuredintensivelyforthespecifictarget.e.g.proteininteractions&expressionprofiles522.2.2.Quantitativelyaccuratemeasurement？Tounderstanddynamics,itisessentialthateachparameterregardingthenetworkisobtained,sothatvariousnumericalsimulationsandanalysescanbeperformed.Suchparametersarebindingconstant,transcriptionrate,translationrate,chemicalreactionrate,degradationrate,diffusionrate扩散率,speedofactivetransport主动转运,etc.Whileaccuracyisimportant,thelevelofaccuracyrequiredmayvarydependingonwhichpartofthesystemistobemeasured.53“accuracy”and“precision精度”542.2.3.Systematicmeasurement？“Systematic”meansthatmeasurementisperformed执行insuchawaythatobtained获得的datacanbeconsistentlyintegrated.Theidealsystematicmeasurementissimultaneousmeasurementofmultiplefeaturesforasinglesample单样本.

Although

thisrequirementsoundsobvious,veryfewdatasetsmeetthesecriteria

标准today.55Highthroughput高通量Automatic自动化Highspeed高速Highaccurate高准确性Lowcost低消耗最大限度提高单位时间内消耗单位资源所获取的生物信息数量与质量。56Next-generationExperimentalSystemse.g.InthedevelopmentalbiologyofC.elegans线虫,identificationofcelllineage细胞系isoneofthemajorissuesthatneedstobeaccomplishedtoassistanalysisofthegeneregulatorynetworkfordifferentiation.Thefirstattempttoidentifycelllineagewascarriedoutentirelymanually手动的.ittookseveralyearstoidentifythelineageofthewildtype.Sulston,J.E.,Schierenberg,E.,White,J.G.,andThomson,J.N.(1983).TheembryoniccelllineageofthenematodeC.elegans.Dev.Biol.100:64–119.Sulston,J.E.andHorvitz,H.R.(1997).Post-embryoniccelllineageofthenematodeC.elegans.Dev.Biol.56:110–156.57C.Elegan线虫s---asmartanimalBrennerHorvitzSulston2002NobelPrizeFireMello2006NobelPrizeSimple,Open,Clever&Correlative---modelanimalforgenetics,neuroscience&developmentalbiology1998Wholegenomesequence58Onami,S.,et.al.(2001).Automaticacquisitionofcelllineagethrough4DmicroscopyandanalysisofearlyC.elegansembryogenesis.FoundationsofSystemsBiology,TheMITPress,Cambridge.Withtheavailabilityofexhaustive彻底的RNAiknockoutforC.elegans,high-throughputcelllineageidentificationisessentialtoexploretheutility效用oftheexhaustiveRNAi核苷酸干扰.Effortsareunderwaytofullyautomatecelllineageidentification.aswellasthreedimensional三维的nuclei核心positiondataacquisition数据采集,fullyUtilizing利用advancedimageprocessingalgorithms处理算法andmassivelyparallelsupercomputers大规模并行超级计算机.593.1.Next-generationexperimentaltechnologyMicroarraychip微阵列芯片Microfluidicchip微流体芯片Nanotechnology纳米技术Femtosecondtechnology飞秒技术……60Human22KOligo-chipscreeningbreastcancerbiomarkergenesI.Microarraychip

Molecularlevel:genechipproteinchip61I.Microarraychip

Cellularlevel:cellchip62I.Microarraychip

Tissuelevel:tissuechip63II.Microfluidicchip19462002200364III.Biomassspectrometer生物质谱仪65IV.Molecularimaging663.2.SystemstructureidentificationMajortasks：

I.MolecularelementII.NetworkstructureIII.ParameterMethodology：

I.bottom-upII.top-down673.2.1.Bottom-up自底而上Toconstructageneregulatorynetworkbasedonthecompilation编辑ofindependentexperimentaldata,mostlythroughliteraturesearches文献检索andsomespecificexperimentstoobtaindataofveryspecificaspectsofthenetworkofinterest.lambdaphagedecisioncircuit判定电路earlyembryogenesis早期胚胎形成ofDrosophilaMcAdams,H.andShapiro,L.(1995).CircuitSimulationofgeneticnetworks.Science269:650–656.Reinitz,J.,Mjolsness,E.,andSharp,D.H.(1995).ModelforcooperativecontrolofpositionalinformationinDrosophilabybicoidandmaternalhunchback.J.Exp.Zoo.271:47–56.68Phagelamdalysis–lysogenydecisioncircuit69Applicabilityofbottom-upapproach适用性Thisapproachissuitablewhenmostofthegenesandtheirregulatoryrelationshiparerelativelywellunderstood.Thisapproachisparticularlysuitablefortheend-gamescenario终极场景wheremostofthepiecesareknownandoneistryingtofindthelastfewpieces.703.2.2.Top-down自上而下Thetop-downapproachtriestomakeuseofhigh-throughputdatausingDNAmicroarrayandothernewmeasurementtechnologies.theyeastcellcycledevelopmentofmousecentralneuralsystems中枢神经系统Brown,P.O.andBotstein,D.(1999).ExploringthenewworldofthegenomewithDNAmicroarrays.NatureGenetics21:33–37.D’haeseleer,et.al(1999).LinearmodelingofmRNAexpressionlevelsduringCNSdevelopmentandinjury.Proc.PacificSymposiumonBiocomputing’99pp.41–52.713.2.3.ParameterIdentificationItisimportanttoidentifyonlythestructureofthenetwork,butasetofparameters,becauseallcomputationalresultshavetobematchedandtestedagainstactual真实的experimentalresults.Inmostcases,theparametersethastobeestimatedbasedonexperimentaldata.Variousparameteroptimization参数优化methods,suchasbruteforceexhaustivesearch穷举搜索,geneticalgorithms基因演算法andsimulatedannealing模拟退火,areusedtofindasetofparametersthatcangeneratesimulationresultsconsistentwithexperimentaldata.723.3.SystembehavioranalysisHowdoesitadapttochangesintheenvironment,suchasnutrition,andvariousstimuli?Howdoesitmaintainrobustnessagainstvariouspotentialdamagetothesystem,suchasDNAdamageandmutation?Howdospecificcircuitsexhibitfunctionsobserved?Toattainsystem-levelunderstanding,itisessentialtounderstandthemechanismsbehind(1)therobustnessandstabilityofthesystem；(2)functionalitiesofthecircuits.733.4.SimulationSimulationofthebehaviorofgeneandmetabolismnetworksplaysanimportantroleinsystemsbiologyresearch;Simulationisanessentialtoolnotonlyforunderstandingthebehavior,butalsoforthedesignprocess.Forsimulationtobeaviablemethodologyforthestudyofbiologicalsystems,highlyfunctional,accurate,anduser-friendlysimulatorsystemsneedtobedeveloped.Thesimulatorneedstobecoupledwithparameteroptimizationtools,ahypothesisgenerator,andagroupofanalysistools.74Softwaresystemsforsystemsbiologyincludes:•databaseforstoringexperimentaldata•cellandtissuesimulator•parameteroptimizationsoftware•bifurcationandsystemsanalysissoftware•hypothesesgeneratorandexperimentplanningadvisorsoftware,and•datavisualizationsoftware.75SystemsBiologyWorkbench，SBWtoprovideacommonmiddlewaresothatplug-inmodulescanbeaddedtoformauniformsoftwareenvironment.SystemsBiologyMark-upLanguage,SBMLaversatileandcommonopenstandardthatenablestheexchangeofdataandmodelinginformationamongawidevarietyofsoftwaresystems.76SBW:旨在提供一个通用中间件用以整合多个插件模块构成一个统一软件环境。SBML:一个多用途且通用的开放标准，允许在大量的软件系统之间交换数据和建模。它是XML的扩展，有希望成为数据和模型交换格式方面的工业与学术标准。3.5.AnalysismethodFBABABorisuk,M.andTyson,J.(1998).Bifurcationanalysisofamodelofmitoticcontrolinfrogeggs.JournalofTheoreticalBiology195:69–85.MCAFell,D.A.(1996).Understandingthecontrolofmetabolism,PortlandPress,London.Edward,J.S.andPalsson,B.O.(1999).SystemspropertiesoftheHaemophilusinfluenzaeRdmetabolicgenotype.JournalofBiologicalChemistry274:17410–17416.77

Robustnessisoneoftheessentialfeaturesofbiologicalsystems.Understandingthemechanismbehindrobustnessisparticularlyimportantbecauseitprovidesin-depthunderstandingonhowthesystemmaintainsitsfunctionalpropertiesagainstvariousdisturbances.透过它可以深入理解系统如何在各种扰动情况下维持自身功能特性：(1)changesinenvironment;(2)internalfailures78RobustnessofBiologicalsystems4.1.LessonsfromComplexEngineeringSystemsinterestinganalogiesbetweenbiologicalsystems&engineeringsystems:1.designedincrementallythroughsomesortofevolutionaryprocesses;2.generallysuboptimalforthegiventask;3.increasedcomplexitytoattainahigherlevelofrobustnessbandstability.e.g.AirplaneMycoplasma794.2.Howtorealizetherobustness?systemcontrolredundancy冗余modulardesign模块化设计structuralstability结构稳定性804.2.1.Control

Theuseofexplicitcontrolschemeisaneffectiveapproachtoimprovingrobustness.Feedforwardandfeedbackaretwomajormethodsofsystemcontrol.81e.g.1：E.colichemotaxisYi,T.-M.,et.al(2000).Robustperfectadaptationinbacterialchemotaxisthroughintegralfeedbackcontrol.PNAS97(9):4649–4653.82e.g.2：HeatshockcircuitHeatshockresponsewithfeedforwardandfeedbackcontrol83e.g.3：Growthcontrolofhumancellsp53relatedfeedbackloop844.2.2.Redundancy冗余在获取系统鲁棒性及处理系统组件意外损坏方面起重要作用。MAP激酶级联反应

MAP激酶级联反应包括并联的通路之间广泛的相互作用。即使因为变异或其他原因导致通路中的一条失效，MAP激酶途径仍能通过其他通路转导信号从而维持其功能。

Redundancyalsoplaysanimportantroleinattainingrobustnessofthesystem,andiscriticalforcopingwithaccidentaldamagetocomponents.RedundancyinMAPkinasecascade854.2.3.ModularDesignModulardesignisacriticalaspectoftherobustness:itensuresthatdamageinonepartofthesystemdoesnotspreadtotheentiresystem.Itmayalsoensureefficientreconfiguration重新配置throughouttheevolutionaryprocesstoacquirenewfeatures.Thecellularstructureofthemulticellularorganismisacleare