Human Germline Gene Editing:
Points to Consider from a Canadian Perspective

December 2016

At the Canadian Institutes of Health Research (CIHR), we know that research has the power to change lives. As Canada's health research investment agency, we collaborate with partners and researchers to support the discoveries and innovations that improve our health and strengthen our health care system.

CIHR is committed to promoting health research that meets the highest standards of excellence and ethics. CIHR encourages interdisciplinary, innovative and integrative ethics research in all aspects of health, health care and health research; it also wishes to foster the discussion of ethical issues to strengthen the culture of research ethics and integrity in Canada.

Please note that this document was originally created to inform the CIHR Standing Committee on Ethics at their June 2016 meeting.

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Executive Summary

This document outlines Points to Consider about human germline gene editing and the applications of gene editing technologies in human embryos in the Canadian context. Gene editing in human germline cells is prohibited under the Assisted Human Reproduction Act. These Points to Consider are designed to inform future discussions in this area for research, teaching, and outreach.

Acknowledgments

The Canadian Institutes of Health Research (CIHR) would like to thank the Standing Committee on Ethics (SCE) for its leadership of and support for this document. Special thanks and appreciation are extended to Vardit Ravitsky (SCE Member) and Lynne Scholten (Advisor, Ethics), for their time, effort and expertise in the creation of this publication.

Introduction

Human gene editing is often divided into general categories:

  • that which does not result in heritable genetic changes (i.e., changes to genes in human somatic cells);
  • that which does result in heritable genetic changes (i.e., changes to human germ cells);
  • that which will not be tested directly in humans (i.e., basic and preclinical research); and
  • that which will be tested directly in humans (i.e., clinical research).

The ethical challenges raised by human gene editing in somatic cells in basic, preclinical and clinical research are addressed by existing frameworks. Such research has the potential for many therapeutic uses. In 2015, a one-year-old child in the UK with an aggressive form of acute lymphoblastic leukemia was treated with modified T-cells from donors.Footnote 1

Gene editing in the human germline causes heritable changes because it modifies the egg, sperm or embryo, passing DNA to subsequent generations. This document outlines points to consider in discussions about human germline gene editing in the Canadian context. While refraining from taking a positional stance, the CIHR Standing Committee on Ethics requested these Points to Consider to highlight relevant distinctions and considerations on this issue for CIHR and other relevant stakeholders.

Policy Context

The distinction between basic and preclinical research versus clinical research refers to modifications to germ cells that are not intended to be used to establish a pregnancy, versus modifications that are intended to establish a pregnancy. Gene editing in human germline cells is prohibited under the Assisted Human Reproduction (AHR) Act.Footnote 2 This is similar to those jurisdictions signatory to the Council of Europe's "Oviedo Convention".Footnote 3

Other jurisdictions, such as the United Kingdom,Footnote 4 expressly regulate human germline gene editing in preclinical research, though the clinical use of germline gene editing is prohibited.

Canada is an outlier with respect to its strict criminal prohibition on all forms of human germline gene editing, though few jurisdictions expressly permit preclinical applications of the technologies or allow the creation of human embryos for purposes other than reproduction.Footnote 5

Some international groups, such as the International Society for Stem Cell Research,Footnote 6 the HinxtonFootnote 7 Group, and the Organizing Committee of the International Summit on Human Gene EditingFootnote 8 are recommending that basic and preclinical research be permitted with careful oversight, while the International Bioethics Committee of UNESCOFootnote 9 calls for a moratorium on all human germline gene editing.

It is not known whether the AHR Act continues to reflect the values of Canadians in this respect, or if public sentiment has evolved. Recently published research on the perspective of the American public suggests that "the majority do not support gene editing in human embryos or germline cells, but the level of opposition varies depending on its goals",Footnote 10 which may be a reasonable gauge of the Canadian perspective, though – to our knowledge – no data has been collected to support this inference.

On one hand, as noted by the Hinxton GroupFootnote 7 "there is serious concern that genome editing technologies might be used in reproductive contexts long before there are data sufficient to support such use, and before the international community has had the opportunity to weigh the benefits and harms of moving forward."

On the other hand, if current prohibitions remain, Canadian researchers may fall behind on the international scene. Going forward, restrictive research policies may lead to medical tourism, as has been the case in stem cell research.Footnote 17

If human germline gene editing were to be decriminalized, without being replaced by federal or provincial regulations, other options for regulation and guidance include:

  • Professional self-regulation: Clinical practice standards could be applied to human germline gene editing, which could fall to those responsible for medical licensing standards, as well as the Canadian Medical Association (CMA), the Society of Obstetrics and Gynecology of Canada (SOGC), the Canadian Fertility and Andrology Society (CFAS), and relevant provincial and territorial partners.
  • Funding policy: Funding organizations could outline the conditions under which they would be willing to support research that involves human germline gene editing (for example, through provisions in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans).

Basic and preclinical research using gene editing in human germline cells

Basic and preclinical research using gene editing in human germline cells, specifically embryos, has the potential to:

  • inform the understanding of human development;
  • improve assisted reproduction technologies;
  • prevent pregnancy loss;
  • inform the understanding of pluripotency and placenta, and the use of that knowledge to translational stem cell research.Footnote 11

Most studies could make use of early embryos that are no longer needed for reproduction and would not require the creation of human embryos for research purposes.Footnote 12 The creation of human embryos for research purposes is also prohibited by the AHR Act, though it may be permissible for the purpose of "improving (…) assisted reproduction procedures".Footnote 2

It should be noted that fertility clinics are increasingly freezing embryos for future reproductive use at the blastocyst stage (day 5), rather than at an earlier stage (day 2),Footnote 13 which subsequently limits the stage of development that can be studied. Thus, once earlier-stage embryos that have been frozen and are no longer needed for reproduction are no longer available, it may become necessary to create embryos in order to undertake such research.

Further, using single cell embryos (approximately 1 day-old, which would have to be created for research purposes) will be required for other studies (e.g., preclinical research on germline gene editing)Footnote 12 to control against mosaicism (i.e., where not all cells are modified).

Creating human embryos for research purposes in Canada would require changes to the AHR Act.

Clinical research using gene editing in human germline cells and potential subsequent clinical use of such cells

The primary benefit of using germline gene editing in humans is the prospect of disease prevention, particularly in monogenic dominant diseases, such as Huntington's, or in recessive diseases where the parents are aware that they are carriers of a monogenic disease.

Germline gene editing could also have the potential to improve the efficiency of the procreation of "saviour siblings": embryos chosen for transfer based on a match to the sibling could be corrected to be disease-free should they also inherit genetic disease, potentially requiring fewer in vitro fertilization cycles to achieve pregnancy.Footnote 14

There are important limitations of this approach to disease prevention:

  • Avoiding devastating genetic diseases can be addressed by genetic testing and counselling of ALL couples to identify and assess risk. Most couples are unaware that they carry a genetic disease until an affected child is born.Footnote 15
  • Most Mendelian diseases can be prevented by undergoing in vitro fertilization and pre-implantation genetic diagnosis to select unaffected embryos.Footnote 15 The others, while compelling, are extremely rare, presenting challenges in terms of development (e.g., determining acceptable clinical trial design),Footnote 16 affecting the cost of treatment, and possibly raising questions of resource allocation.
  • Due to the cost of gene editing techniques and the lack of public funding for them, clinical uses will likely be limited to those with the means to use them.

Further, the statement issued by the Organizing Committee of the International Human Gene Editing SummitFootnote 8 enumerates the following concerns about the clinical application of human germline gene editing:

  • the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism);
  • the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment;
  • the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations;
  • the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country;
  • the possibility that permanent genetic 'enhancements' to subsets of the population could exacerbate social inequities or be used coercively; and
  • the moral and ethical considerations in purposefully altering human evolution using this technology.

Hype is also emerging as a concern that can lead to medical tourism and costly unproven treatments.Footnote 17

There is general consensus that the technology is not "sufficiently developed to consider human genome editing for clinical reproductive purposes at this time".Footnote 7 However, while some argue that clinical uses of human germline gene editing should never proceed, the Hinxton Group and the Organizing Committee of the International Human Gene Editing Summit argue that it could eventually proceed "only under appropriate regulatory oversight".Footnote 8 Their respective statements raise several points to consider should clinical uses of human germline gene editing be decriminalized in Canada:

  • Much more preclinical research is needed;
  • Extensive consultations with various stakeholder groups are needed to determine if this would be a suitable approach and at what point it might become appropriate;
  • "As with most emerging biomedical technologies, human genome editing raises substantial concerns about justice and equity, such as questions about for whom treatments are developed and who will have access. (…) Attention should be paid to how applications are prioritized and based on what criteria, such as magnitude and frequency of need, nature of the genetic change being made, anticipated feasibility, and the presence of accepted alternative approaches—all of which bear directly on the risk/benefit analysis and the justification for any given use."Footnote 7

Conclusion

These Points to Consider can inform future discussions with respect to subsequent activities (e.g., issues scan, consultation with researchers, public engagement) in this area as well as future approaches towards the use of gene editing in humans.

More information about Ethics at CIHR and the Standing Committee on Ethics or contact ethics-ethique@cihr-irsc.gc.ca.

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