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GMmosquitoesinBurkinaFaso

February2018Geneticallymodified(GM)mosquitoeswereexportedfromImperialCollegeinLondontoBurkinaFasoinNovember2016.Theyarecurrentlyin“containeduse”facilitiesinBobo-Dioulasso,andtheyarebeingusedinexperimentsbyaresearchconsortiumcalledTargetMalaria.1TheprojectalreadyreceivedapermitfromtheNationalBiosafetyAgency(undertheMinistryofHigherEducation,ScientificResearchandInnovation,MESRSI)toimporttheGMmosquitoesintoBurkinaFasoforcontaineduseexperiments.TheInstitutdeRechercheenSciencesdelaSanté(IRSS)inBurkinaFasoisamemberofTargetMalariaandwillbemakinganapplicationtoreleasetheGMmosquitoesintotheenvironmentin2018;mostlikelyinthevillageofBana,westofBobo-Dioulasso.2AbouttheTargetMalariaprojectTargetMalariaisaconsortiumofresearchinstitutesthatreceivescorefundingfromtheBill&MelindaGatesFoundationandtheOpenPhilanthropyProjectFund,anadvisedfundofSiliconValleyCommunityFoundation.Individuallaboratoriesalsoreceiveadditionalfundingfromavarietyofsourcestosupporteachlaboratory’swork,includingtheUnitedKingdomgovernment(theUKDepartmentofEnvironment,FoodandRuralAffairsandtheMedicalResearchCouncil),theWellcomeTrust(aUK-basedcharity),theEuropeanCommission,theUgandanMinistryofHealth,andtheUgandaNationalCouncilforScienceandTechnology(UNCST).3TargetMalariaalsoworksinMaliandUganda,but,toourknowledge,hasnotyetsentanyGMmosquitoestothesecountries.TargetMalaria’sultimateaimistomakeopenreleasesof“genedrive”mosquitoes,withtheaimofreducingthepopulationofAnophelesgambiaemosquitoes,whichcantransmittheparasitethatcausesmalaria.Thehopeisthatreducingthemosquitopopulationwillreducetheriskofmalariatransmissionandhencediseaseincidence.“Genedrive”isawayoftryingtospreadgeneticallyengineeredtraitsthroughawholepopulationofplantsoranimals(inthiscase,mosquitoes).Inthisproject,theaimofthegenedriveistospreadagenetictraitthatbiasesthesexratioofthemosquitopopulationtowardsmalemosquitoes,thussuppressingthemosquitopopulation.However,thetechnologytodosodoesnotyetexistandmaynotbesuccessful.Therehavebeenmanywarnings,includingfromscientistsworkingintheareaofgenedrive,thatgenedrivemaybeuncontrollableandcouldhaveunintendedconsequences,andcivilsocietyorganisationshavecalledforamoratoriumonthistechnique.4

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TargetMalariasaysitwilltakeaphasedapproachtoitsultimateaimofreleasinggenedrivemosquitoes,beginningwiththefirstphase,theproposedreleaseof10,000GM“male-sterile”(andnon-genedrive)mosquitoesthisyear,followedbyasecondphaseinwhichasecondtypeof(non-genedrive)GMmosquitowillbereleasedintotheopen.ThissecondphaseisintendedtobiasthemosquitopopulationtobemaleonlysothatmatingsoftheGMmosquitoeswithwildfemaleswillmainlyproducemaleoffspring.Inthethirdandfinalphase,whichinvolveseithermalebiasorfemaleinfertilitycombinedwithgenedrive,thegenedrivemosquitoeswillbereleased.Itisunclearwhetherthisthirdstagewilleverbereached,letalonewhetheritcanbeeffective.Inthemeantime,anyreleaseofGMmosquitoeswillcarryrisks.AllthreeproposedphasesinvolvereleasingGMmosquitoeswithtraitsthatareintendedtoreducethetargetpopulationofAnophelesgambiaemosquitoes(knownas“populationsuppression”).However,TargetMalariadoesnotexpectthephaseonereleasestoactuallyreducetheAnophelesgambiaemosquitopopulation.Whetherphasethreecandoso,willdependonhowwellthegenedriveworks.However,thereisalreadyscientificevidencethatgenedriveisunlikelytowork,becauseresistancetothegenedrivewillevolve,preventingsomemosquitoesfrominheritingthemodifiedgenes.5,6,7,8Thus,thebenefitsoftheprojectoverallareextremelyspeculative. PotentialimpactofpopulationsuppressiononmalariaThefirstproposedreleaseofGMmosquitoesisnotexpectedtomakeanydifferencetothenumberofwildmosquitoesthatcanbiteandtransmitdisease(seefurtherbelow).ButevenifreleasingfutureversionsofGMmosquitoesweretobesuccessfulatreducingthenumbersofwildmosquitoes,howreducingthepopulationofAnophelesgambiaemosquitoeswillimpactontheriskofmalariaisnotfullyunderstood.OnecomplicationisthatseveraldifferentAnophelesmosquitospeciescantransmitmalaria.OtherrelevantspeciesinBurkinaFasoincludeAnophelesarabiensisandAnophelesfunestus.9Reducingonlyonespeciesofmosquitocouldmeanthatmosquitoesfromanothermalaria-transmittingspeciesmaymoveintotakeitsplace,continuingdiseasetransmissionandperhapsbeinghardertoeradicate.However,itisalsopossiblethatreleasedGMAnophelesgambiaemosquitoescanmatewiththeseotherspeciesandperhapstransferthemodifiedgenetictraittothem.Anotherissueishumanimmunityandtimingofinfection,whichcanleadtoa“reboundeffect”.Wherepeoplehaveahighexposuretomalaria,mostareinfectedaschildrenandbuildupsomeimmunitybeforeadulthood.Becauseprimarymalariainfectionsinadultscausemoreseverediseasethaninchildren,inthelongerterm,areductioninmosquitonumberscould–intheory–resultinanincreaseinmalariainadults,iffewerpeopleareinfectedwhiletheyarechildren.10Ifthishappened,thelong-termeffectoffutureGMmosquitoreleasescouldbeharmfultothelocalpopulation.AbouttheGMmosquitoesproposedforreleaseinphaseonein2018TheGMmosquitoesproposedforreleasethisyearareAnophelesgambiaemosquitoes,whichhavebeengeneticallymodifiedtobemale-sterilebyaconstructthatincorporatestheI-PpoIHomingEndonucleaseGene(HEG).TargetMalariareportsthattheseGMmosquitoeshaveshown100%infertility:statingthat,todate,alleggslaidbyfemalesthathavematedwiththeseGMmalemosquitoeshavebeeninfertile.11TwoscientificpapershavebeenpublishedabouttheseGMmosquitoes,includingsometrialsofpopulationsuppressionconductedincagesintheUnitedStates.12,13

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Aspartofthe“containeduse”experimentsthathavetakenplacesofar,thelaboratoryinBurkinaFasohasmatedtheimportedGMmosquitoeswithlocalwildmosquitoes.Theproposaltorelease10,000ofthesemale-sterileGMmosquitoesisatrainingexercisefortheresearchers;TargetMalariasaysthatthemosquitoeswillnotbeusedformalariacontrol.Thisisbecauserepeatedlargereleaseswouldbeneededtoseektosuppressthewildpopulationofmosquitoes,which,evenifsuccessful,wouldbeprohibitivelyexpensive.14Thesamereportalsonotesthat,inBobo-Dioulasso,Anophelesarabiensis(notAnophelesgambiae)hasbecomethemajormalariavector.Therefore,theproposedreleasesin2018arenotintendedorexpectedtoprovideanydirectbenefittothelocalpopulationintermsofmalariacontrol.Conductingexperimentswithnopotentialbenefitmayberegardedasawasteoftimeandmoney,andisunethical.Lackofatransboundarynotification?UnderEuropeanUnion(EU)law,ImperialCollegeshouldprovideapubliclyavailableenvironmentalriskassessmentthatmeetsEuropeanstandardsbeforeexportingGMinsecteggsforopenreleasetoforeigncountries.ThislegalrequirementarisesbecauseGMinsecteggsarelivegeneticallymodifiedorganisms(livingmodifiedorganismsorLMOs)coveredbytheCartagenaProtocolonBiosafety(CPB)totheConventiononBiologicalDiversity,towhichtheUKandBurkinaFasoarebothParties.TherelevantlegalrequirementsforexportareimplementedintheUKthroughtheEuropeanRegulation(EC)1946/2003ontransboundarymovementofgeneticallymodifiedorganisms.15ThisRegulationrequiresthattheenvironmentalriskassessment(ERA)providedbytheexportermeetstheEUstandardsonriskassessmentcontainedinEUDirective2001/18/EC16.ForGMOsthatarenotplants,alistofissuesthatmustbecoveredintheriskassessmentbytheexporterisincludedinAnnexII,D.1oftheDirective.GuidancepublishedbytheEuropeanFoodSafetyAuthority(EFSA)outlinestheissuesandevidencethatImperialCollegewouldneedtoprovideintheERA.17Pages73to107oftheEFSAguidanceprovidedetailsonthefollowingspecificareasofriskofGMinsects:• PersistenceandinvasivenessofGMinsects,includingverticalgenetransfer(VGT);• Horizontalgenetransfer;• Pathogens,infectionsanddiseases;• InteractionsofGMinsectswithtargetorganisms;• InteractionsofGMinsectswithnon-targetorganisms(NTOs);• EnvironmentalimpactsofthespecifictechniquesusedforthemanagementofGMinsects;

and• ImpactsofGMinsectsonhumanandanimalhealth.Regulation(EC)1946/2003isimportantbecauseitrequirestheexporter(inthiscase,ImperialCollege)toprovideacomprehensive,publiclyavailableriskassessmentthatmeetsEUstandards,forGMOsintendedforreleaseintotheenvironment.However,itappearsthatImperialCollegemayarguethatitisnotrequiredtomakeatransboundarynotificationthatincludessuchariskassessmentfortheproposedreleaseofmale-sterileGMmosquitoesinBurkinaFaso,becausetheGMmosquitoeswereexportedforaninitialperiodofcontaineduse(forwhichanotificationisnotrequired)beforerelease.ThisinterpretationwouldmakeanonsenseoftheCartagenaProtocolandthelegalrequirementsthatfollowfromit,becauseGMOsexportedforcontainedusecouldsubsequentlybereleasedintotheenvironmentwithoutmeetingtherequisiteriskassessmentstandards.

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OtherriskassessmentrequirementsandregulationBurkinaFasohasadoptedalawandregulationscoveringgeneticallymodifiedorganisms(GMOs).18ThelawrequiresariskassessmenttobeconductedbeforeanyopenreleaseofGMOs.However,thereisnospecificnationalguidanceonhowtoconductariskassessmentforGMmosquitoes,orwhatpublicconsultationisrequired.EFSA’sriskassessmentguidanceisdirectlyrelevanttoanyexportofGMmosquitoesfromtheUK,sinceRegulation(EC)1946/2003requirestheexporter(i.e.ImperialCollege)tomeetEUstandards.However,otherguidancealsoexists.UndertheCPB,theAdHocTechnicalExpertGroup(AHTEG)onRiskAssessmentandRiskManagementhasproducedguidanceontheriskassessmentofgeneticallymodifiedmosquitoes.19Inaddition,relevantacademicpapersthatdiscusstheriskassessmentofGMinsects,includingGMmosquitoes,includeReevesetal.(2012)20andDavidetal.(2013)21.Todate,TargetMalariahaspublishedonlyariskassessmentrelatedtothe“containeduse”oftheGMmosquitoes,asrequiredbythelawinBurkinaFaso.However,ithasstatedthatitwillalsopublishariskassessmentfortheproposedopenreleases,conductedbytheAustralianCommonwealthScientificandIndustrialResearchOrganisation(CSIRO).Whetherornotthereisapublishedriskassessmentbytheexporter(ImperialCollege)thatmeetsEUstandards,asrequiredbytheimplementationofthetransboundarynotificationrequirementsinEUlaw,remainstobeseen.PublicengagementandfullyinformedconsentTheWorldMedicalAssociation’sDeclarationofHelsinkioutlinestheinternationallyagreedethicalprinciplesformedicalresearchinvolvinghumansubjects.22Itincludesrequirementsthat:

“17.Allmedicalresearchinvolvinghumansubjectsmustbeprecededbycarefulassessmentofpredictablerisksandburdenstotheindividualsandgroupsinvolvedintheresearchincomparisonwithforeseeablebenefitstothemandtootherindividualsorgroupsaffectedbytheconditionunderinvestigation.Measurestominimisetherisksmustbeimplemented.Therisksmustbecontinuouslymonitored,assessedanddocumentedbytheresearcher.”

And:“26.Inmedicalresearchinvolvinghumansubjectscapableofgivinginformedconsent,eachpotentialsubjectmustbeadequatelyinformedoftheaims,methods,sourcesoffunding,anypossibleconflictsofinterest,institutionalaffiliationsoftheresearcher,theanticipatedbenefitsandpotentialrisksofthestudyandthediscomfortitmayentail,post-studyprovisionsandanyotherrelevantaspectsofthestudy…”

AlthoughTargetMalariasaysitisengaginglocalpopulationsandobtainingtheirconsent,consentmustbefullyinformedtomeetethicalrequirements.Thiscannotbethecaseuntilacomprehensiveriskassessmenthasbeenpublishedandopenedforpublicconsultation.Further,thebenefitsofanytrialshouldoutweightherisk.Thisdoesnotappeartobethecasewiththisproposal,sinceTargetMalariaacknowledgesthattherearenobenefitstotheproposedGMmosquitorelease.References1http://targetmalaria.org/2InaremoteWestAfricanvillage,arevolutionarygeneticexperimentisonitsway–ifresidentsagreetoit.STATNews.14March2017.https://www.statnews.com/2017/03/14/malaria-mosquitoes-burkina-faso/3http://targetmalaria.org/who-we-are/

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4170GlobalGroupsCallforMoratoriumonNewGeneticExtinctionTechnologyatUNConvention.5December2016.http://www.etcgroup.org/content/160-global-groups-call-moratorium-new-genetic-extinction-technology-un-convention5Callaway,E.,2017.GeneDrivesThwartedByEmergenceofResistantOrganisms.NatureNews542:15.http://www.nature.com/news/gene-drives-thwarted-by-emergence-of-resistant-organisms-1.213976Hammond,A.,Galizi,R.,Kyrou,K.,Simoni,A.,Siniscalchi,C.,Katsanos,D.,Gribble,M.,Baker,D.,Marois,E.,Russell,S.,Burt,A.,Windbichler,N.,Crisanti,A.,Nolan,T.,2015.ACRISPR-Cas9GeneDriveSystemTargetingFemaleReproductionintheMalariaMosquitoVectorAnophelesgambiae.NatBiotechadvanceonlinepublication.doi:10.1038/nbt.34397Unckless,R.L.,Messer,P.W.,Connallon,T.,Clark,A.G.,2015.ModelingtheManipulationofNaturalPopulationsbytheMutagenicChainReaction.Genetics201:425–4318Unckless,R.L.,Clark,A.G.,Messer,P.W.,2017.EvolutionofResistanceagainstCRISPR/Cas9GeneDrive.Genetics205:827–8419MalariaAtlasProject:BurkinaFasohttp://www.map.ox.ac.uk/browse-resources/?region=&country=53&topic=&subtopic=10Scott,T.W.,Takken,W.,Knols,B.G.J.,Boëte,C.,2002.TheEcologyofGeneticallyModifiedMosquitoes.Science298:117–119.doi:10.1126/science.298.5591.11711TargetMalaria,2015.IndependentRiskAssessmentForContainedLaboratoryStudiesOnASterileMaleStrainofAnophelesgambiae.http://targetmalaria.org/wp-content/uploads/pdf/target-malaria-risk-assessment-sterile-males-plus-executive-summary.pdf12Windbichler,N.,Papathanos,P.A.,Crisanti,A.,2008.TargetingtheXChromosomeduringSpermatogenesisInducesYChromosomeTransmissionRatioDistortionandEarlyDominantEmbryoLethalityinAnophelesgambiae.PLoSGenet4,e1000291http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.100029113Klein,T.A.,Windbichler,N.,Deredec,A.,Burt,A.,Benedict,M.Q.,2012.InfertilityResultingFromTransgenicI-PpoiMaleAnophelesgambiaeinLargeCageTrials.PathogGlobHealth106:20–31.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001508/14TargetMalaria,2015.IndependentRiskAssessmentForContainedLaboratoryStudiesOnASterileMaleStrainofAnophelesgambiae.http://targetmalaria.org/wp-content/uploads/pdf/target-malaria-risk-assessment-sterile-males-plus-executive-summary.pdf15REGULATION(EC)No1946/2003OFTHEEUROPEANPARLIAMENTANDOFTHECOUNCILof15July2003onTransboundaryMovementsofGeneticallyModifiedOrganisms.http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2003:287:0001:0010:EN:PDF16Directive2001/18/ECoftheEuropeanParliamentandoftheCouncilof12March2001ontheDeliberateReleaseintotheEnvironmentofGeneticallyModifiedOrganisms.http://eur-lex.europa.eu/smartapi/cgi/sga_doc?smartapi!celexapi!prod!CELEXnumdoc&lg=EN&numdoc=32001L0018&model=guichett17EFSA,2013.GuidanceontheEnvironmentalRiskAssessmentofGeneticallyModifiedAnimals.EFSAJournal2013;11(5):3200[190pp.].http://www.efsa.europa.eu/en/efsajournal/pub/3200.htm18https://bch.cbd.int/database/results?searchid=68914419BiosafetyClearingHouse.GuidanceonRiskAssessmentofLivingModifiedOrganisms:RiskAssessmentofLivingModifiedMosquitoes.http://bch.cbd.int/onlineconferences/guidancedoc_ra_mosquitoes.shtml(English)oravailableaspdfinEnglish:http://www.cbd.int/doc/meetings/bs/mop-06/official/mop-06-13-add1-en.pdfandSpanish:http://www.cbd.int/doc/meetings/bs/mop-06/official/mop-06-13-add1-es.pdf20Reeves,R.G.etal.,2012.ScientificStandardsandtheRegulationofGeneticallyModifiedInsects.PLoSNeglectedTropicalDiseases,6(1):e1502.http://www.ploscollections.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001502;jsessionid=C3DC4FD0650E395B0FD63D275A9703B5#pntd-0001502-g00121David,A.S.,Kaser,J.M.,Morey,A.C.,Roth,A.M.,Andow,D.A.,2013.ReleaseofGeneticallyEngineeredInsects:AFrameworktoIdentifyPotentialEcologicalEffects.EcologyandEvolution3(11):4000–4015.22WorldMedicalAssociation(WMA)DeclarationofHelsinki–EthicalPrinciplesforMedicalResearchInvolvingHumanSubjectshttps://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/