Workgroup on the Implications of Genome Editing. Douglas Mortlock Kelly Ormond On behalf of the workgroup

Transcription

1 Workgroup on the Implications of Genome Editing Douglas Mortlock Kelly Ormond On behalf of the workgroup

2 Workgroup membership (to date) Douglas Mortlock Larry Brody TJ Cradick Beverly Davidson Kiran Musunuru ESHG members pending Other societies pending Thus far, NSGC, CAGC and AGNC (UK) are formally collaborating Kelly Ormond Yvonne Bombard Andy Faucett (NSGC) Nanibaa Garrison Laura Hercher (NSGC) Rosario Isasi Anna Middleton (AGNC) Alice Virani (CAGC)

3 This discussion is not new, but new methods have brought the reality closer. If a technical breakthrough occurs that makes germ-line gene therapy feasible, the anticipatory discussion of the topic may turn out to have been essential for the calm formulation of rational oversight processes. LeRoy Walters and Julie Gage Palmer, The Ethics of Human Gene Therapy. (1997)

4 Genome editing starts with targeted DNA nucleases ZFNs, TALENs, and CRISPR CRISPR is simpler, cheaper, and can be highly efficient They work in human cells, as they do in many other species Jinek et al. Science, 2012 v.337 (6096) pp

5 If DNA cleavage occurs in mammalian cells, what happens? Homology-Directed Repair Pathway Non-Homologous End Joining Pathway Non-Homologous End Non-Homologous Joining Pathway End Joining Pathway Directed changes SNPs, codons, insertions Usually, small indel mutations From Menke, DB. Engineering subtle targeted mutations into the mouse genome. Genesis, 2013 v.51 (9) pp

6 Important technical issues remain with genome editing Not 100% efficient Cells: How many need to be altered? Embryos: Mosaicism Instead of the desired edit, the target site might gain an unwanted new mutation Off-target mutations (induced mutations not at the target site) are sometimes observed

7 April 2015: Genome editing can be done in human embryos

8 Key ethical issues/concerns identified thus far Similar issues as have been considered around germline gene therapy techniques since early 1990s Evolving assessment of true risks (e.g., safety), true benefits and unintended impacts General issues around the social acceptance and responsibility of science and scientists Distributive justice: disparities in access

9 Unintended health consequences Off-target alterations: rates, impacts? Can we minimize off-target effects without sacrificing efficiency? Are edited cells still otherwise normal? Consequences of mosaicism on health? Gene-environment interactions, pathway interactions and systems biology impacts Unknowns

10 Unintended societal consequences Population genetics impact Impact on genetic diversity Potential loss of protective variants Social impact Impact on societal tolerance for disability, diversity Deepening of societal inequities Use by bad actors : (use to create persons for specific roles such as soldiers, use to enforce stereotypes or prejudice) Unknowns

11 Unintended adverse effects Inadvertent impact on germline through somatic applications Is germline editing an ethical alternative, given available prenatal testing/pgd options? Risk for misuse of gametes and embryos Unintended consequences in a liveborn child Unintended consequences in the population propagation of undesirable alleles, creation of new illnesses or susceptibilities Unknowns

12 Things to think about in setting policy Strive for a proactive policy Unnecessarily broad restrictions can limit progress Could ethical debates about embryo editing shut down work in somatic cells? (Lanphier and Urnov, 2015) Governance re: appropriate use: Who decides on use? parental autonomy vs. best interests of the child vs. future generations vs. societal interests Who/what groups decide which diseases are appropriate for intervention? How will this be decided? What are the distinctions between therapeutic use and enhancement?

13 4 approaches to regulation 1. Existing, relevant laws 2. Independent agency 3. Moratorium 4. Professional guidelines and statements

14 What is the nature and intent of use? Should there be restrictions to experimenting on embryos as humans? Is there research value beyond proof of principle for reproductive use? If so, what is the most advanced stage embryo permissible for research? Can this limit be enforced? Can we adopt a wait-and-see attitude toward human germ line engineering? Use in embryos with reproductive intent to alter existing DNA using existing human templates what value does this add beyond existing techniques? Use in embryos with reproductive intent to insert nonhuman DNA Use in embryos with reproductive intent to alter population using gene drive

15 Next steps Recommendations and white paper: TBD, likely spring 2016 Areas to explore further Any current trials/examples in humans Comparisons to IVF/ART Comparisons to somatic gene therapy and other technologies that could lead to germline modification

16 We want your comments and input! @Doug_mortlock