Systems Biology of the Cell - Nature

In the words of Marc Kirschner (2005), "Systems biology is the study of the behavior of complex biological organization and processes in terms of the molecular ... Thispagehasbeenarchivedandisnolongerupdated   SystemsBiologyoftheCell By: GeertPotters,Ph.D. (Dept.ofBioscienceEngineering,UniversityofAntwerp) © 2010 NatureEducation  Citation: Potters, G. (2010) SystemsBiologyoftheCell. NatureEducation 3(9):33 HowcanweunderstandalltheinteractionsbetweenDNA,mRNAandproteins,aspartofoneentirenetwork?Recently,scientistshavemademajorstepstowardsansweringthisquestion. 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FromGenetoGenomeOverthelasttwodecades,wehaveseenashiftoffocusinthebiomolecularsciences,fromthedesiretounderstandhowasinglegenefunctions,tounderstandinghowallgenesandgeneproductsofacellworktogether.Thisnewparadigmforunderstandinginterrelationshipsbetweennetworksofbiologicalprocessesistermedsystemsbiology,andwhenappliedtothecellbiology,itisprimarilyaboutthenetworkofgenes,mRNAandproteins.Thisapproachtoscientificanalysisrestsonanewwayoflookingatprocesses:understandingthemwithinamuchbroadercontextthaneverbefore.Consequently,thisapproachrestsonrecenttechnologicalprogressthatallowsdatatobeanalyzedinmuchlargeramounts.Whatistheconceptofsystemsbiologyofthecell—whatareitsroots,whatareitsaims,and(inaminorway)whatarethetechnologicalassetsitdependson?(Figure1).MolecularBiologyIsMaturingFigure1: Systemsbiologyallowsustothinkbroadly.Thisimageshowshowinformationalcomplexityincreasesfromgenometotranscriptometoproteome.Theestimatednumberofentitiesofeachtypeofmoleculeinatypicalcellisindicatedinparentheses.Asanendpointthiskindofanalysis,scientistsmightbesearchingforbiomarkersforcardiovasculardisease,soitcanbedetectedearly.©2008NaturePublishingGroupGerszten,R.E.&Wang,T.J.Thesearchfornewcardiovascularbiomarkers.Nature451,949-952(2008).Allrightsreserved.FigureDetailWiththepublicationofWatsonandCrick'slandmarkpaperonthestructureofDNA(1953),thebirthofmodern,molecularbiologybecameafact.Suddenly,aparadigmwascreatedthatgavethestudyofheritabletraitsaphysical,molecularbasisandmadethetheoriesofMendel,Morganand,yes,evenDarwin,tangible.Overtime,weusedthisknowledgetounderstandthestructureofagene,howitisexpressed,andhowamutationaffectsnotonlyabasepair,butalsotheconcomitantproteinanditsfunctioning.CrucialstepsalongthiswaywereofcoursethedevelopmentofmethodstodeterminethesequenceofshortpiecesofDNA(i.e.,themethodsofMaxamandGilbert1977,andSanger1977),howtoproducemoreDNAinabacterialcell(hence,tocloneagene),andsince1980,howtoamplifydesiredDNAsequencesinvitrobywayofthepolymerasechainreaction(PCR)technique(Mullisetal.1986,MullisandFaloona1987).Thisapproachhasledtoastaggeringamountofdataregardingindividualgenes.Scientistshavebeenabletoask,andanswer,hithertounanswerablequestions.Onwhichchromosomeareparticulargenessituated?Whatistheirfunction?Howandbywhichfactorsaretheyregulated?Atthebeginningofthetwenty-firstcentury,itisabouttimetomakeanewtransition.Insteadoffocusingontheindividualgenesandtheireffects,biologistsandbiochemistshavecreatedanarsenaloftechniquesandmethodologiestoattackaquestionthatissimpleinitself,butwhichrequiresalotofcomplexinformationtobeanswered:howisthecombinationofallgeneswithinacellabletogovernallthereactionsthatgooninacell?Thisquestionstemsfromaninsight,characterizedbyonescientist,that"multi-scaledynamiccomplexsystemsformedbyinteractingmacromoleculesandmetabolites,cells,organs,andorganismsunderliemostbiologicalprocesses"(Vidal2009).Yet,thisisthegoalofbiologyatthemolecularlevel—tounderstandthecollaborativefunctioningoftheelementsasbeingpartofasystemthatformsacell,atissue,evenanorganism.Indeed,nothinginbiologyactsalone:everythingactsinconjunction,opposition,andsynergywithotherelements.Genesregulateeachother'sactivity,geneproductsjoinforcesorinhibiteachother,cellscommunicate,metabolitesmovefromtissuetotissue,andeverythingisinterconnected.Systemsbiologyaimstounderstandthiscomplexity.DefiningSystemsBiologyoftheCellFigure2: Scientistsstudiedmalaria-infectedbloodcellsandobservedtranscriptionpatternsofthepathogen.TranscriptionalprofilesofthemalariapathogenPlasmodiumfalciparumwereisolatedfromhumanbloodsamples.Transcriptionprofilesfromtheseplasmodiawerecomparedtotypicaltranscriptionalprofilesinyeast.Systemsanalysisoftheexpressiondatainthesecellsshowthatexpressionprofilesclusterintothreegroups(colors).ThiscomputationalanalysisandcomparisonwithpreviouslydescribedyeastexpressionprofilesrevealedthreedistinctP.falciparumphysiologicalstatescharacterizedbyglycolyticgrowth(green),astarvationresponse(purple),oranenvironmentalstressresponse(brown).Thisimprovedunderstandingofthephysiologicaldiversityoftheparasitemayhelptoexplaintherangeofoutcomesafterinfectionandleadtonoveltherapeuticapproaches.©2007NaturePublishingGroupDaily,J.P.etal.DistinctphysiologicalstatesofPlasmodiumfalciparuminmalaria-infectedpatients.Nature450,1091-1095(2007).Allrightsreserved.InthewordsofMarcKirschner(2005),"Systemsbiologyisthestudyofthebehaviorofcomplexbiologicalorganizationandprocessesintermsofthemolecularconstituents.Itisbuiltonmolecularbiologyinitsspecialconcernforinformationtransfer,onphysiologyforitsspecialconcernwithadaptivestatesofthecellandorganism,ondevelopmentalbiologyfortheimportanceofdefiningasuccessionofphysiologicalstatesinthatprocess,andonevolutionarybiologyandecologyfortheappreciationthatallaspectsoftheorganismareproductsofselection,aselectionwerarelyunderstandonamolecularlevel."Whatdoesasystemsbiologistdo?Systemsbiologistswanttostudyallgenes,expressedasmessengerRNAs,andactingthroughproteinsandmetabolites,whichplayimportantrolesinaspecificcellortissue,ataspecificmoment.Ingeneral,theireffortsfallintofourcategories(definedbyKirschner2005):quantitativemeasurement,creatingmathematicalmodelsbasedonthesequantitativedata,reconstructionofhowacellreactsunderdifferentconditions,andthedevelopmentoftheoriesthatwillexplainthelargevariationindifferentspeciesinthewaytheyreactandrespondtotheseconditions.Thisgoalhasgivenrisetoseveralnewoffshootsofthescientifictechnicalsubspecialties.First,thereisthedevelopmentofhigh-throughputanalyticaltechnologytobeabletocollectthevastarrayofdatathatsystemsbiologyrequires.Fastandreliablemethodshavebeendevelopedtoassessthedifferentlevelsinacell(theDNAorthegenome,theRNAorthetranscriptome,theproteinpoolortheproteome,andthemetabolitepoolorthemetabolome).Afewofthemostimportantonesarediscussedbelow.Second,thereisthemanagementofthesevastsetsofdata,thefieldofbioinformatics(Rodrigoetal.2008).Indeed,oneofthemostpressingneedsemergingfromthistypeoffocusisanefficientwaytostoretheevergrowingcollectionsofA's,T's,G'sandC's(indatabasessuchastheNCBIGenbank,ortheprotein-centeredSWISS-PROT)whichalsoallowsforfastretrievalofdata.Indeed,theamountofdatathathascomepouringinhasgrownexponentially(Boguski1998).Apartfromthat,anumberofapplicationshadtobedevelopedtofacilitateathoroughanalysisofthesedata.Forexample,thereareanalysistoolsusedtotranslateDNAtoRNAandtoproteinsequences,identifysitesforrestrictionenzymestocut,andidentifypotentialproteinmodifications.(SeethecollectionatEuropeanBioinformaticsInstitute,NationalCenterforBiotechnologInformation,orSwissInstituteofBioinformatics.)Othertoolsenablesearchesforhomologousbutnotcompletelysimilarsequences,suchasthewidelyknownBasicLocalAlignmentSearchToolorBLAST(Altschuletal.1990).Moreover,thereisthemarriagebetweenbiologyandmathematics.Usingsetsofdifferentialequations,scientiststrytosummarizethebiologicaldatatheyamassedintoworking,robustmathematicalmodels(Klein&Hölzel2006,Westerhoffetal.2009).Inthisrespect,systemsbiologystemsfromearlierattemptstodrawupanumberofsimplephysicalandmathematicalmodelsonwhatiscalled"biologicalself-organization."Thisapproachismotivatedbyquestionssuchas,howdobiologicalstructurescomeintoexistence,basedonthepropertiesoftheirconstituentparts,andgiventheiruniquethermodynamicsituation(Prigogyne1967)?Modelslikethosecoveredaspectsofcelldevelopment,suchasmorphogenesis(Turing1952,Cilibertoetal.2003),microtubuleformation(Pollard2003),leafphyllotaxis(Smithetal.2006)orseparatemetabolicpathways(Polle2001).Inthefuture,theyareboundtodescribethebehaviorofthecompletecell.Additionally,thesemodelswillallowforfinely-tunedtargetedmanipulationofacell'smetabolism,andthusformoreefficiencyingeneticengineering(Goryaninetal.1999,Patiletal.2004).OntheHorizonMolecularbiologyiscurrentlyatthecenterofafirestormofnewquestionssupportedbynewtechnologies.Outofthishasemergednewmethodologieslikegenomicsequencingandwholegenomecomparisons,whichenableustochangethewaywestudylivingcells(Figure2).Thesedevelopmentsarenotmerelynewstepsalongthebeatentrack,butheraldanewwayofthinkingaboutandinbiology(Westerhoff&Palsson2004).Afterall,untilnow,biologicalcomplexitycouldonlybeunderstoodthroughthestudyoftheindividualparts.Inmolecularbiologyandbiochemistry,thequestionshavealwaysbeenmoreofaqualitativenature,suchas,haveweclonedtherelevantgeneornot?Isitpresentandactive?Inwhichcells?Systemsbiologyisboundtotakeawaythatburden,tobecomemuchmorequantitative,andtoofferamoreintegratedperspectiveontheinnerworkingsofacell,withouthavingtoresorttovagueness.Thismakessystemsbiologyadifficultyetexacttypeofscience.Formanybiologists(andinparticularmolecularbiologists),equationsweresomethingthatbelongedinphysicslabs,andadvancedmathematicsandindepthstatisticswerealessprevalentandoptionaltool,withtheexceptionoffieldecologists,forwhommultivariatestatisticsaretypicallypresentfromthestart.Theywillhavetolearntocopewithequationsthatwillatleastparallelthoseofadvancedphysicsintheircomplexity.However,therewardsareenormous,andtheirmagnitudeisprobablyonlybeginningtosurface.ReferencesandRecommendedReadingAltschul,S.F.,Gish,W.etal.Basiclocalalignmentsearchtool.JournalofMolecularBiology215,403–410(1990).Boguski,M.S.Bioinformatics-anewera.TrendsinBiochemicalSciences,Supplement,TrendsGuidetoBioinformatics,1–3(1998).Ciliberto,A.,Novak,B.etal.Mathematicalmodelofthemorphogenesischeckpointinbuddingyeast.TheJournalofCellBiology163,61243–61254.doi:10.1083/jcb.200306139.Goryanin,I.,HodgmanT.C.etal.Mathematicalsimulationandanalysisofcellularmetabolismandregulation.Bioinformatics15,749–758(1999).Kirschner,M.W.Themeaningofsystemsbiology.Cell121,503–504(2005).doi:10.1016/j.cell.2005.05.005Klein,C.A.&Hölzel,D.Systemiccancerprogressionandtumordormancy:mathematicalmodelsmeetsinglecellgenomics.CellCycle5,1788–1798(2006).Maxam,A.M.&Gilbert,W.AnewmethodforsequencingDNA.ProceedingsoftheNationalAcademyofSciences,USA74,560–564(1977).Mullis,K.&Faloona,F.SpecificsynthesisofDNAinvitroviaapolymerase-catalyzedchainreaction.MethodsinEnzymology155,335–350(1987).Mullis,K.,Faloona,F.etal.SpecificenzymaticamplificationofDNAinvitro:thepolymerasechainreaction.ColdSpringHarborSymposiaonQuantitativeBiology51,263–273(1986).Pollard,T.D.Thecytoskeleton,cellularmotilityandthereductionistagenda.Nature422,741–745(2003).Polle,A.Dissectingthesuperoxidedismutase-ascorbate-glutathionepathwayinchloroplastsbymetabolicmodelling.Computersimulationsasasteptowardsfluxanalysis.PlantPhysiology126,445–462(2001).Prigogyne,I.IntroductiontoThermodynamicsofIrreversibleProcesses.3rded.NewYork,NY:Interscience,1967.Rodrigo,A.,Bertels,F.etal.Theperilsofplenty:whatarewegoingtodowithallthesegenes?PhilosophicalTransactionsoftheRoyalSocietyofLondon,SeriesB:BiologicalSciences363,3893–3902(2008).doi:10.1098/rstb.2008.0173Sanger,F.,Nicklen,S.etal.DNAsequencingwithchain-terminatinginhibitors.ProceedingsoftheNationalAcademyofSciences,USA74,5463–5467(1977).Smith,R.S.,Guyomarc'h,S.etal.Aplausiblemodelofphyllotaxis.ProceedingsoftheNationalAcademyofSciences,USA103,1301–1306(2006).doi:10.1073/pnas.0510457103Turing,A.M.Thechemicalbasisofmorphogenesis.PhilosophicalTransactionsoftheRoyalSocietyofLondon,SeriesB:BiologicalSciences237,37–72(1952).Vidal,M.Aunifyingviewof21stcenturysystemsbiology.FEBSLetters583,3891–3894(2009).doi:10.1016/j.febslet.2009.11.024Watson,J.D.&Crick,F.H.C.Molecularstructureofnucleicacids.Astructurefordeoxyribosenucleicacid.Nature171,737–738(1953).Westerhoff,H.V.&Palsson,B.O.Theevolutionofmolecularbiologyintosystemsbiology.NatureBiotechnology22,1249–1252(2004).doi:10.1038/nbt1020.Westerhoff,H.V.,Winder,C.etal.SystemsBiology:theelementsandprinciplesofLife.FEBSLetters583,3882–3890(2009).doi:10.1016/j.febslet.2009.11.018 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Close ExploreThisSubject Basic Ribosomes,Transcription,andTranslation Chromosomes GeneExpression ProteinStructure ProteinFunction Advanced AnalyzingRegulatoryNetworksinBacteria MaternalmRNAandthePolyATailinOocytes Intermediate ActivationofERBBReceptors AgingandCellDivision Calreticulin:aMultifacetedProtein EnzymeCatalysis:TheSerineProteases  GermCellsandEpigenetics HowtheHumanGenomeProjectOpeneduptheWorldofMicrobes KinetoplastidsandTheirNetworksofInterlockedDNA MicroRNAsinArabidopsis ProteinMisfoldingandDegenerativeDiseases RegulationofERBBReceptors RegulationofmRNASplicingbySignalTransduction Riboswitches:ACommonRNARegulatoryElement SystemsBiologyoftheCell TheFormationofHeterochromatinandRNAinterference TheProteinDataBank:ExploringBiomolecularStructure TurningSomaticCellsintoPluripotentStemCells TopicroomswithinProteinsandGeneExpression Close Notopicroomsarethere.  |  LeadEditor:  LauraVargas-Parada ProteinsandGeneExpression Loading... 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