EthicsofGermline GeneEditing

inNonHumanPrimates
MildredCho
StanfordCenterforBiomedicalEthics

Geneeditinginmonkeys
Feb2014

Cynomolgus CRISPR

Ppar &
Rag1
(Nr0b1)

Niu,Yetal.

Dec2014
Germline
Mar2014 Rhesus&
TALENs
Cynomolgus

MECP2

Chen,Yetal.
Liu,Hetal.

Jun2014

Cynomolgus TALENs

MECP2

Liu,Zetal.

Feb2015

Cynomolgus CRISPR

p53

Wan,Het al.

Apr2015

Rhesus

DMD

Chen,Yetal.

CRISPR

Ethicalconsiderations
Whygermline geneeditingofNHPs?
Geneeditingvs othertransgenicmethods
Ontarget/offtargetmutations
Potentialfornullmutations,multiplexgenetic
manipulation

Germline vs somaticgeneticmodifications
Breedingforhumandiseasemodels

Ethicalconsiderations
Whygermline geneeditingofNHPs?
Nonhumanprimatemodelsofhumandisease
Neuropsychiatricandneurodegenerativediseases
(HD,Rett Syndrome)
Cancer
Immunity
Humanlineagespecificgenes
Language
Cognition
Otherbehavioraltraits

Ethicalconsiderations
Risksandbenefits
Theutilitarianview:weighinglikelihoodof
benefitwithrisk
RiskstoNHPs
Riskstohumans

2011IOM/NRCreport
ChimpanzeesinBiomedicalandBehavioral
Research:AssessingtheNecessity
Biomedicalresearchcriteriaproposed:
Noothersuitablemodelavailable
Researchcannotbeperformedethicallyonhuman
subjects
Forgoingchimpanzeeresearchwillsloworprevent
advancementstopreventortreatlifethreateningor
debilitatingconditions

Ethicalconsiderations
Risksandbenefits
Biomedicalresearchusingstoredsamplesis
exempt
Animalsmustbemaintainedeitherin
ethologicallyappropriatephysicalandsocial
environmentsorinnaturalhabitats

2011IOM/NRCReport
utilitarianjustificationsformpartofthe
rationaleforcontinuedresearchinanimals;
thatis,animalsaresubjectedtoriskforthe
benefitofhumans,andjustificationrelieson
assessmentsthatthebenefitsgainedfrom
researchonanimalsaresufficienttooutweigh
theharmscausedintheprocess.

2011IOM/NRCReport
Purelyutilitarianjustificationsaretempered
inanimalresearchthroughpolicy
requirementsforhumanetreatmentandthe
useofappropriatespeciesandminimal
numberofanimals.
Furthermore,imposingrequirementsfor
justifyingtheuseofhigherspeciesisan
implicitrecognitionthattheuseofhigher
animalscomesathighermoralcosts.

2011IOM/NRCReport
Whilethechimpanzeehasbeenavaluable
animalmodelinpastresearch,mostcurrentuse
ofchimpanzeesforbiomedicalresearchis
unnecessary,basedonthecriteriaestablishedby
thecommittee,exceptpotentiallyfortwocurrent
researchuses:
Alimitednumberofmonoclonalantibodiesalreadyin
thedevelopmentalpipeline
DevelopmentofprophylactichepatitisCvirus(no
consensusoncommittee)
Anew,emerging,orreemergingdiseasemayrequire
futureuseofthechimpanzee

Assessinglikelihoodofbenefit
Relevancetohumandisease,e.g.,
NHPresearchhasnotpredictedhumanresponsetoviral
vaccineswell
Immunesystemsvarygreatlybetweenspecies
(Vallender &Miller2013)
Someneuropsychiatricconditionsofinterest
(schizophrenia,autism)aresuggestedtobehuman
specificandassociatedgenesunderrecentpositive
selection(e.g.,Teffer andSemendeferi 2012)
Limitedcognitivebehavioraltestsformarmosets,small
headsizemakesimagingdifficult(Chan,2009)
Improvingcrossspeciespredictabilityofbehavioral
tests,e.g.distinguishingstatefromtraitanxiety(Markou
etal.2009)

Improvinglikelihoodofbenefit
Speciesspecificgenomicvariation(Vallender &Miller
2013)
GeneticvariationinNHPsismuchmoreextensive
thanvariationinhumans,butlesswellunderstood
Thereareveryfewtransspeciespolymorphismsin
humansandchimpanzees(Hodgkinson &EyreWalker
2010)
ImplicationsofvariationincytochromeP450genes
andeffectsondrugmetabolisminNHPsnotwell
known

Improvinglikelihoodofbenefit
Studydesign(Sena etal.2007)
Animalstudiesofdrugorbiologicaltreatments
areoftensuccessfulwheresubsequenthuman
studiesarenot

Improvinglikelihoodofbenefit
Animalstudiesthatscore
higheronstudyquality
checklistsproduced
substantiallylower
estimatesofeffectsize
thanlowerscoring
studies(Sena etal.2007)

Improvinglikelihoodofbenefit
Nonrandomizedstudies
havehigherestimatesof
efficacythanrandomized
studies
Studieswithoutblinded
outcomeassessment
havehigherestimatesof
efficacythanblinded
studies
(vanderWorp etal.2007)

Conclusions
Germline geneeditingofNHPsraisessimilar
ethicalissuesasthoseraisedbyothertransgenic
methods
However,geneeditinghasthepotentialto
broadenthearrayofNHPmodelsofhuman
diseasetoincludemoredebilitatingphenotypes
Suchinductionofseriousdiseasecanonlybe
justifiedbycarefulandrealisticassessmentof
benefitslikelytoaccruefromNHPmodelsand
useofrigorousstudydesign