Ethics and Gene Editing in Human Embryos: ISSCR Policy

Jonathan KimmelmanSTREAM (Studies of Translation, Ethics and Medicine)McGill University

Guidelines 2.0

labstudies

therapeutictrials

assistedreproduction

?

respecting cultural differences(setting a baseline)

respecting political differences (e.g. mechanism)

Principles

…biomedical research is a collective endeavor. It depends on the contributions of many kinds of individuals, including basic scientists, clinicians, [and] patients... Ethics principles and guidelines help secure the basis for this collective endeavor

Principles

Integrity of the Research EnterpriseRespect for SubjectsSocial JusticeTransparencyPrimacy of Patient Welfare

…research should be overseen by qualified investigators and coordinated in a manner that is sustainable and ensures that the information obtained will be trustworthy, reliable, accessible, and responsive to scientific uncertainties and priority health needs. Doing so entails the need for independent peer review, transparency, and continued monitoring at each stage of research

Parties to the testing and application of stem cell-based interventions should promote timely exchange of accurate scientific information to other interested parties

Physicians and physician-researchers owe their primary duty to the patient and/or research subject. They must never unduly place vulnerable patients at risk. Clinical testing should never allow promise for future patients to override the welfare of current research subjects. Application of stem cell-based interventions outside of formal research settings should be evidence-based, subject to independent expert review, and serve patients’ best interests…

hEmbryo

gene editing

?

1. Process

2. Substance

EMRO

reviewapprovalongoing monitoring

1. Process

2. Substance

research involving the genetic manipulation of human embryos or gametes used to make embryos in vitro

criteria

scientific meritexpertise of investigatorsethical justification

In vitro culture of any post-fertilization human embryo or organized cellular structure that might manifest human organismal potential, regardless of derivation method, beyond 14 days or formation of the primitive streak, whichever occurs first. This prohibition extends to experiments whereby human embryos or organized cellular structures that might manifest human organismal potential are gestated in any non-human animal uterus.

hEmbryo>14d;primitive streak

ISSCR

Xin vitro

nDNAmodification

hEmbryo>14d;primitive streak

ISSCR

Xin vivononhuman

nDNAmodification

Research in which human embryos that have undergone modification of their nuclear genome are implanted into or gestated in a human or non-human uterus . Genome-modified human embryos include human embryos with edits to their nuclear DNA and/or embryos generated from a human gamete that has had its nuclear DNA modified.

hEmbryo implantation

ISSCR

X

nDNAmodification

hEmbryo implantation

ISSCR

X

nDNAmodification

gamete

Emerging Categories of Embryos ResearchThat Merits Close Review

Recommendation 2.1.4

Recommendation 2.1.4: The ISSCR supports laboratory-based research that entails modifying the nuclear genomes of gametes, zygotes and/or pre-implantation human embryos, performed under a rigorous EMRO process….

Recommendation 2.1.4:

…Such research will enhance fundamental knowledge and is essential to inform any thoughtful deliberations about the potential safety and use of nuclear genome editing in strategies aimed at preventing the transmission of genetic disorders…

Recommendation 2.1.4:

…until further clarity emerges on both scientific and ethical fronts, the ISSCR holds that any attempt to modify the nuclear genome of human embryos for the purpose of human reproduction is premature and should be prohibited at this time.

a) safety and long term risks

b) public and international dialogue on the capabilities and limitations of… their application to the human germ line

In contrast, mitochondrial replacement therapy employs distinct methods and does not entail direct modification to the nuclear genome…The Guidelines documented herein and below provide plausible mechanisms of review, approval, and oversight…

Principles

Integrity of the Research EnterpriseRespect for SubjectsSocial JusticeTransparencyPrimacy of Patient Welfare

Parties to the testing and application of stem cell science should promote timely exchange of accurate scientific information… Investigators should communicate with various publics... Research teams should promote open and prompt sharing of ideas, data and materials.

Recommendation 3.2.4.1: Sponsors, researchers, and clinical investigators should publish preclinical studies in full, and in ways that enable an independent observer to interpret the strength of the evidence supporting the conclusions.

3 unresolved points :

1) biosafety

2) non-edited (e.g. lenti)

3) noninheritable (in utero, episomal)

NationalAcademiesofScienceEngineering andMedicine

HumanGenome Initiative

Itwouldbeirresponsible toproceedwithanyclinicaluseofgermline editing unless anduntil

(i) therelevantsafetyandefficacyissues havebeenresolved,basedonappropriateunderstanding andbalancingofrisks,potential benefits, andalternatives, and

(ii)there isbroadsocietal consensus abouttheappropriateness oftheproposedapplication.Moreover,anyclinicaluseshouldproceedonlyunderappropriateregulatoryoversight.

Atpresent, thesecriteriahavenotbeenmetforanyproposedclinical use:thesafetyissueshavenotyetbeenadequately explored;thecasesofmostcompelling benefit arelimited; andmanynationshavelegislative orregulatorybansongermlinemodification.

However,asscientific knowledgeadvancesandsocietal viewsevolve,theclinical useofgermline editingshouldberevisitedonaregularbasis.

Statement ofTask:Thestudywill examine thescientific underpinnings aswellastheclinical, ethical, legal, andsocialimplications of theuse ofhuman genomeediting technologies inbiomedical research andmedicine. ….

What isthecurrentstateofthescience ofhuman geneediting, aswell aspossible future directions…

What arethepotential clinical applications…

What isknown about theefficacy and risks of geneediting inhumans, andwhatresearchmightincrease thespecificity andefficacy of human gene editingwhile reducing risks? …

Canorshould explicit scientific standards beestablished forquantifying off-targetgenome alterations…

Docurrent ethicaland legalstandards forhuman subjects research adequately address human geneediting… What aretheethical, legal, andsocial implications oftheuse of currentandprojected gene-editing technologies inhumans?

What principles orframeworks mightprovide appropriate oversight forsomatic and germline editing inhumans? Arethereexamples ofhow these issues arebeing addressed intheinternational context?

What aretheprospects forharmonizing policies? Whatcanbelearned from theapproaches being applied indifferentjurisdictions?

Thecommittee willaddress these questions andprepare areport thatcontains itsfindings and recommendations. Thereportwill provide aframework basedon fundamental, underlying principles thatmaybeadapted andadopted by anynation thatisconsidering thedevelopment ofguidelines. The reportwill also include afocus on advice fortheUnited States.

Public Meetings

Meeting #1The committee held abrief open session inwhich theydiscussed thechargewith thestudy sponsors.December 3,2015 (4:00 pmeastern) Washington, DC

Meeting #2:Thecommittee willhearinput from selectstakeholder groups.When: February 11, 2016(8:00 ameastern)Where: Washington, DC,Keck Center oftheNational Academies

Meeting #3:Thecommitteewill hearinput fromtheinternational community. Thiswillbethe final public meeting oftheconsensus committee. When: April 29-30, 2016Where: Europe (city TBD)

CommitteeMembers

Formoreinformation:

http://nationalacademies.org/gene-editing/consensus-study/index.htm

Current  and  possible  research  applica2ons  using  human  germline  

genome  edi2ng  

Amander  Clark  PhD  Professor  and  Vice  Chair  

Molecular  Cell  and  Developmental  Biology  University  of  California,  Los  Angeles  

Eli  and  Edythe  Broad  Center  for  Regenera2ve  Medicine  and  Stem  Cell  Research  

Informed  Consent  for  human  embryo  research  

Donated  embryos  will  not  be  used  to  create  a  baby  

Growing  interest  in  human  embryo    dona2on  for  research  purposes  

Donors consented per year

2007

2008

2009

2010

2011

2012

2013

2014

2015

0

50

100

150

Year embryos were received

Num

ber o

f don

ors

Research  preferences  at  2me  of  consent  

Strong  support  from  donors  for  research  into  human  embryo  development  

Human  embryo  development  

Stem  cell  research  

Human  embryo  and  stem  cell  research  

Kalista  et  al.,  Cell  Stem  Cell  2013  

38%   32%  

30%  

Basic  Research  ques2ons  

Improving  IVF  outcomes  

Improving  Stem  cells  and  

Regenera2ve  medicine  

Fidelity  of  CRISPR  in  human  embryos