https://www.chemistryworld.com/news/study-claiming-gene-edited-babies-were-more-likely-to-die-young - PowerPoint Presentation

1. https://www.chemistryworld.com/news/study-claiming-gene-edited-babies-were-more-likely-to-die-young-was-wrong/4010546.articleEthics, governance and policy aspects of human genome editing research Maneesha S InamdarJNCASR, BangaloreGFBR12-13 Nov 2019Singapore

2. Maneesha S InamdarProfessor and ChairMolecular Biology and Genetic UnitJawaharlal Nehru Centre for Advanced Scientific Research, BangaloreVisiting ProfessorTata Institute of Genetics and Society at inStem, BangaloreDeclarationsMember, World Health Organization (WHO) expert advisory committee on Developing global standards for governance and oversight of Human Genome editing. https://www.who.int/ethics/topics/human-genome-editing/committee-members/en/Member, Global Forum on Bioethics in Research (GFBR) planning committee 2019. http://www.gfbr.global/about-the-gfbr/

3. What does human genome editing mean to us?Science, Ethics, governance and policy aspects- must consider the needs and views of those whose genome may be edited. Will treat people with genetic disorders; eradicate disease.Is it safe?It will change the nature of what it means to be human.Science and SocietyDon’t know/ Don’t understand/….. Not my problem.

4. Genome editing technologies should be supported as they promise to fulfil an “unmet need”.Hope and FearTechnologies could be used for enhancement rather than treating serious disease -how should these boundaries be set?Principles, Constitution of WHOWhat is an unmet need?

5. QuestionsCan parents be denied the selection of desirable features? (Gender/Lineage Selection is already done in some cultures/contexts- Disease susceptibility)To what extent should it be regulated? (soft/hard regulation)How will these technologies affect the vulnerable among the present generation?Who is responsible for the rights of the future generation?

6. Advances in science and technology have presented several challenges for ethics, governance and policy- What have we learnt from these?IVF (in vitro fertilization) (1978) (1978, India) Rapid progress; surrogacy; reproductive tourismSaviour Siblings (2000) (2018, India)Three parent babies (2016) ?Biohacking (genome editing 2017) ?Over ten years after first creating an embryo in a dish- A successful pregnancy and normal birthPerspective

7. Emerging genome editing technologies are initiated in resource rich country settings and then introduced in low- and middle- income countries (LMICs)Mechanisms for engagement and governance in LMICs will differ, given the diverse values, beliefs, social and cultural norms and governance systems. Given the rapid advance in genome editing technologies it is important to consider these in the early stages of research and development.Is genome editing a greater cause for worry?Why is this technology a cause for such great concern?

8. Can be tailored to change chromatin structure or gene activity without cutting DNA.Gives the ability to alter almost any DNA sequence at will using the cellular machineryFind target: Guide RNA or primer to recognise specific DNA sequenceCut: A nuclease enzyme- makes a double-stranded (or single-stranded) cut in DNARepair/Replace: simple mutation or substitution/insertion/deletion by providing a DNA template with homologous arms (HDR). Science of Human Genome EditingZFN, TALEN, CRISPR/Cas9, PRIME, MHcut…….

9. Technical issues to be resolvedNon homologous end joining (NHEJ) needs to be avoided Homology Directed Repair (HDR) is desirable(Prime editing overcomes some of these limitations)Efficiency varies from 50-90% depending on method used– resulting mosaicism is a serious problem if working with early embryos.Editing is not precise- there are off-target and other unwanted eventsCRISPR/Cas9- made editing easier to do and more accessible; requires minimal training

10. Types of Genome EditingGermline v/s SomaticHeritable v/s non-heritable

11. safety, efficacy, risk/benefit assessment, impact (short term/long term), heritabilityScience and TechnologySocietal/individual benefits, Equity of access, aggravated inequalities, sanctity of the human genome, autonomy of future generationsEthics and SocietyHuman heritable (germline) genome editingControversial

12. Intervention was unnecessary Did not address a serious medical need.Possibly ineffectiveScientifically flawedAgainst established ethical normshttps://www.theguardian.com/commentisfree/2019/oct/22/gene-editing-crispr-scientistsScientific feasibility; Ethical acceptabilityHe Jiankui said he had followed guidelines on embryo editing set forth by a panel of leading U.S. scientists and ethicists.Committee of the National Academies of Science, Engineering, and Medicine, USA (2017): “If society agrees this is OK, proceed with extreme caution.”Nuffield Council on Bioethics, UK 2018No disorderHeritableGermline editingGermline editing by He Jiankui

13. https://www.businessinsider.com/what-countries-allow-researchers-to-edit-human-embryos-2015-10?IR=T (2015)Promotes medical/reproductive tourism for unsafe, untested therapies in resource poor countries.

14. Multinational Regulatory effortsInternational Commission on the Clinical Use of Human Germline Genome Editing Convened by the U.S. National Academy of Medicine (NAM), the U.S. National Academy of Sciences (NAS), and the Royal Society of the U.K., with the participation of science and medical academies around the worldWHO expert advisory committee on Developing global standards for governance and oversight of Human Genome editing. (WHO- 194 countries)(somatic and germline editing)Several expert groups assembled in various countries to develop regulatory guidelines that could prevent similar actions.(germline editing)

15. 15Statement by the Director-General| Human Genome Editing“Human germline genome editing poses unique and unprecedented ethical and technical challenges,” said WHO Director-General Dr Tedros Adhanom Ghebreyesus. “I have accepted the interim recommendations of WHO’s Expert Advisory Committee that regulatory authorities in all countries should not allow any further work in this area until its implications have been properly considered.”26 July 2019https://www.who.int/news-room/detail/26-07-2019-statement-on-governance-and-oversight-of-human-genome-editingOctober 2019

16. Original plan : to genetically modify the CCR5 gene to provide resistance to HIV. Modified plan : genetic modification of the GJB2 gene to prevent a type of hereditary deafness. the WHO position, “supported by the Russian Federation, should be decisive in the formation of country policies in this area.” – Russian Ministry of Health’s press releaseJuly 2019October 2019Human heritable (germline) genome editingDenis Rebrikov

17. Types of Genome EditingHeritable v/s non-heritable Germline v/s Somaticrelatively uncontroversial

18. Scientific feasibilityEthical acceptabilityBenefit to SocietyHuman somatic genome editingSufficient scientific knowledge; Robust oversight mechanisms in place for therapeutic use. What about in LMICs?

19. HIV-AIDS - infuse CCR5 mutant blood stem cellsAcute lymphoblastic anemia (ALL) - TALEN genome-edited immune cell (CAR-T cell) therapy to treat an 'incurable' cancer. (Layla Richards)Small cell lung cancer- CRISPR/Cas9 for CAR-T cells Trial in China just started.Hemoglobinopathies: Clinical trials by CRISPR Therapeutics and Vertex Pharmaceuticals Germany: February 2019 b-thalassemia USA: Aug 2019-October 2019 Sickle cell diseaseex vivoGene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy (DMD) Amoasii et al. (2018). Science Exon skippingHuman non-heritable (somatic) genome editing

20. Human non-heritable (somatic) genome editingCould be used for enhancement purposesCould promote medical tourism for unsafe or untested cures in regions where regulation is weak/absent (Exploitation by fraudulent use of technology- ethics dumping in countries with limited resources and regulatory oversight)Could further promote inequitiesImportant to have wide dissemination of information, transparency and responsible stewardship of scienceex vivoConcerns

21. Even though the technology may be safe from the perspective of science and medicine, opinions of society must be considered. Outreach, education and engagement activities should aim to empower people so that they can make an informed choice. Unlike resource-rich countries, most LMICs lack the resources and capacity to do this. Capacity building required- “…skew subsequent deliberations within LMICs by the force of precedent, despite the potentially very different local circumstances and worldviews”. Public Engagement and EmpowermentGFBR 2019 booklet

22. gametes are generated in vitro after editing in somatic (stem) cells and used to create zygotes.editing is done in utero or in the oviduct- which could technically be termed somatic.in vivo delivery of editing components to somatic cells is used, which could be misdirected to the germline. Delivery using: micro/nanoparticles; viral vectors; sperm (ICSI)Human heritable (somatic) genome editingComing soon….it could lead to inheritable changes when-in vivo

23. “The Committee also recognised that relatively few countries have established an appropriate translational pathway for somatic treatments involving human genome editing, with robust regulation and oversight to ensure patient safety and public confidence.”Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome EditingREPORT OF THE SECOND MEETING

24. WHO expert advisory committee on developing global standards for governance and oversight of Human Genome editingHuman GenomeEditingOctober 2019

25. October 2019| Human Genome Editing25http://www.ibe.unesco.org/en/geqaf/technical-notes/concept-governanceCompositionEighteen members coming from all parts of the world, representing a broad range of disciplines, expertise, and experience.Members from:AfricaAsiaEuropethe Middle EastOceaniaNorth AmericaSouth AmericaWide range of backgrounds, including:Genetics and genomicsReproductive medicineNeuroscienceDevelopmental biology and stem cell researchMedicines and drug therapiesGeopoliticsTechnology developmentPhilosophyBioethics and Biomedical ethicsLawAll 6 WHO regions are represented:Countries (15)

26. To examine the scientific, ethical, social & legal challenges associated with human genome editingFocus on both somatic and germline editingTo advise the WHO DG & make recommendations on appropriate institutional, national, regional and global governance mechanisms for human genome editingTo this end the committee will:Review relevant literatureConsider existing & proposed governance measuresSolicit societal attitudes to the use of technologiesExplore methodologies for ensuring transparent & trustworthy practicesCharge to the committee26Advisory committee| Human Genome EditingOctober 2019

27. Work in a consultative mannerBuild on existing initiativesLiaise with relevant UN & other international agenciesCommunicate with other relevant bodies, including:Academies of Science and MedicineNational or professional bodiesPatient groups Civil society organizationsMethod of work27Advisory committee| Human Genome EditingOctober 2019

28. 28Governance Framework| Human Genome EditingOctober 2019The committee determined that a governance framework must:Identify relevant issues, a range of specific mechanisms to address them, and be developed in collaboration with the widest possible range of stakeholders. Be scalable, sustainable and appropriate for use at the international, regional, national and local levels. Work in parts of the world where there are weaker systems of regulation of scientific and clinical research and practice, and where genome editing may not yet be pursued with great intensity. Provide all those responsible for the oversight of genome editing with the tools and guidance they need.

29. PrinciplesHuman Genome Editing29Governance frameworkTransparency – sharing information on what is happening, how & why it is necessary;Inclusiveness – drawing on the full contributions of all parts of society, thereby providing diverse points of view, skill sets & additional methods of program management & measurement;Responsible stewardship of science - following good practice in scientific conduct, attempting to maximize potential benefits & minimize risk of harm;Fairness - equal access to opportunities; Social justice - celebrating & promoting diversity.October 2019

30. ElementsHuman Genome Editing30Governance frameworkIssues, such as:Scope of coverage, differences in capacity or approach, maximizing benefit & minimizing risk, technical developments, incentivizing responsible R&D, and public perceptions, awareness & preferences;Mechanisms, such as: Codes, conference, engagement strategies, funding requirements, incentives, insurance requirements, laws and regulations, licensing, moratoria, policies, publication requirements, registration, self-regulation, standards, and technical advances;Actors, such as: Advisory boards, civil society, funders, industry, R&D institutions, IGOs, lawyers, governments, patient groups, professional bodies, publishers, science fiction, and scientists and clinicians.October 2019

31. RegistryScopeFormatResponsible stewardship of scienceRisk havensWhistleblowingOversight issuesReviewing national governance measures obtained by WHOScenario developmentTerminologyEducation, engagement, and empowermentOpportunities to build capacityRelevant partners to work withHuman Genome Editing31Working groupsOctober 2019

32. 32Timeline| Human Genome Editing201920202018FirstMeeting(18-18 March)SecondMeeting(26-28 August)ThirdMeeting(Early 2020)FourthMeeting(Summer 2020)Committeeannounced(14 December)Firstonline consultation(Late 2019)Secondonline consultation(Spring 2020)Views from under-representedFinalizeframeworkExplore wider viewsFill gaps inevidenceTestframeworkOctober 2019

33. Governance and Policy considerations–Based on Current scientific knowledge – (yet nimble)In harmony with global action - (yet alert to local needs)Must engage with highly complicated ethical issues- requires public engagement and empowerment.Must be applicable in multiple contextsBe seen in the broader context of how we develop and use emerging technologies and their impact for public healthHow can the immense health benefits and health risks be balanced?Ethics, governance and policy aspects of human genome editing research.

34. Thank you!!