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1、Programmablecells:InterfacingnaturalandengineeredgenenetworksHidekiKobayashi,MadsKærn,MichihiroAraki,KristyChung,TimothyS.Gardner,CharlesR.Cantor,andJamesJ.CollinsDepartmentofBiomedicalEngineering,CenterforBioDynamics,andCenterforAdvancedBiotechnology,BostonU
2、niversity,44CummingtonStreet,Boston,MA02215ContributedbyCharlesR.Cantor,April26,2004Novelcellularbehaviorsandcharacteristicscanbeobtainedbycouplingengineeredgenenetworkstothecellsnaturalregulatorycircuitrythroughappropriatelydesignedinputandoutputinter-faces.
3、Here,wedemonstratehowanengineeredgeneticcircuitcanbeusedtoconstructcellsthatrespondtobiologicalsignalsinapredeterminedandprogrammablefashion.WeemployamodulardesignstrategytocreateEscherichiacolistrainswhereagenetictoggleswitchisinterfacedwith:(i)theSOSsignali
4、ngpathwayrespondingtoDNAdamage,and(ii)atransgenicquorumsensingsignalingpathwayfromVibriofischeri.Thegenetictoggleswitchendowsthesestrainswithbinaryresponsedynamicsandanepigeneticinheritancethatsupportsapersistentphenotypicalter-Fig.1.Themodularstructureofasimp
5、leprogrammablecell.ationinresponsetotransientsignals.ThesefeaturesareexploitedtoengineercellsthatformbiofilmsinresponsetoDNA-damagingAsconcretedemonstrationsofthismodulardesignstrategy,agentsandcellsthatactivateproteinsynthesiswhenthecellwehavecreatedthefourEs
6、cherichiacolistrainslistedinTablepopulationreachesacriticaldensity.Ourworkrepresentsastep1.Inthesestrains,agenetictoggleswitch(4)isinterfacedwithtowardthedevelopmentofplug-and-playgeneticcircuitrythattwodifferentsignalingpathways:(i)theSOSsignalingpathwaycanb
7、eusedtocreatecellswithprogrammablebehaviors.(strainsA1andA2),whichdetectssingle-strandedDNAafterDNAdamage(26–28),and(ii)atransgenicquorumsensingheterologousgeneexpressionsyntheticbiologyEscherichiacolisignalingpathwayfromVibriofischeri(29–31)thatdetectsacyl
8、-homoserinelactone(AHL)molecules(strainsB1andB2).TheengineeringofgeneregulatorynetworksisacornerstoneTheV.fischerisignalingpathway,whichhasbeenexploitedtoofsyntheticbiology(1,2)andhasbeen
