WHO: Are You Ready for Human Genome Editing?

The World Health Organization Releases a Series of Recommendations Toward a Global Governance of Human Genome Editing

The last of the major reports due on human genome editing (HGE)—released in July by the World Health Organization (WHO) Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing—adequately puts its focus on the establishment of a world registry of HGE clinical trials; appropriately develops global standards for governance and oversight of HGE; and commendably underlines inclusivity and engagement of all society groups. Unfortunately, the report fails to discuss in depth the current and emerging scientific and clinical trends particularly with regard to CRISPR gene inactivation and base (and prime) editing.

The WHO commission's long-awaited report ¹ is the culmination of more than 2 years of work by 18 members, coordinated by the WHO's Katheline Littler (co-lead, Health Ethics and Governance Unit), with guidance from John Reeder (Director, Research for Health) and Soumya Swaminathan (Chief Scientist).

The report, following multiple in-depth reports on HGE from other distinguished bodies,^2–6 is divided into three documents: a position paper, a framework for governance, and a summary of recommendations. These studies were prompted by the expectations—and precedent—for editing the human genome triggered by the use of CRISPR. Medical applications for treating or preventing diseases have raised many ethical issues, including adequate balance between benefit and harm, safety and speed, and innovation and universal access.

Established by the WHO in December 2018, the commission was made up of scientists, ethicists, and legal experts, including Robin Lovell-Badge, Alta Charo, Hervé Chneiweiss, and Francoise Baylis. It was tasked with make recommendations on appropriate institutional, national, regional, and international governance mechanisms for HGE. (Matters of safety and efficacy were addressed in several previous reports.) The committee received input from more than 400 individuals and institutions around the world.

The exercise resulted in nine key recommendations (see Table 1). The first declares the WHO and its leaders as a moral authority to voice the ethical issues associated with HGE and the consequences of failing to address them. It recommends a significant international collaboration across countries and institutions, seeking to establish standards and looking for harmonized approaches under the WHO umbrella.

Perhaps the most precise and practical recommendation (#3) underlines the need to establish an international and unified registry on HGE clinical trials: only those cases reviewed and approved by national ethics committees will be listed—where national registries clearly identify HGE clinical trials, where those posing concerns can be readily flagged and reviewed by an expert committee, as well as developing two additional registries on basic and preclinical research efforts. This WHO online registry (https://www.who.int/groups/expert-advisory-committee-on-developing-global-standards-for-governance-and-oversight-of-human-genome-editing/registry), launched in 2019 as a pilot project, currently holds 126 HGE clinical trials, but its functionality still needs improvement. Another recommendation tackles the need to identify jurisdictions wit domestic policies and oversight mechanisms under which somatic and heritable HGE research should be permitted.

Recommendation #5 emerged from He Jiankui's infamous “CRISPR babies” experiment in 2018. It seeks to prevent similar cases by providing accessible mechanisms where confidential whistleblower reports could be submitted to flag suspected illegal, unregistered, unethical, or unsafe HGE research and other activities. This would be managed by the WHO in collaboration with other entities, but the process has yet to be defined in detail. The sixth recommendation focuses on the need to make HGE research, applications, and potential benefits universally available through the adoption of ethical licensing requirements.

The need to educate, engage, and empower under-represented groups (#7) again self-establishes the WHO to propel inclusive and extensive dialogue on HGE, including scientific, ethical, and societal aspects. These basic important goals are shared with the aims we have at ARRIGE ⁷ (Association for Responsible Research and Innovation in Genome Editing) that I am honored to chair. This inclusive process proposed in the WHO report is a distinct element not developed by the National Academies' International Commission ⁴ or other reports. It is one where ARRIGE will be eager to jump in and participate in the future.

The final two recommendations task the WHO with creating a set of ethical values to be used internally and self-impose a term of 3 years for reviewing the implementation of these proposals.

Seven Scenarios

The largest of the three WHO documents focuses on establishing a framework for governance on HGE, divided into six parts. The WHO committee evaluated the legal situation in 2020 across many countries concerning somatic and germline HGE. ⁸ The report defines good governance, an ongoing process, as well as the values associated with governance in seven plausible HGE scenarios (see below), including openness, transparency, honesty, and accountability, along with inclusiveness, caution, fairness, social justice, non-discrimination, equal moral worth, respect, solidarity, and global health justice.

In an interesting exercise, the report fashions seven hypothetical clinical trial scenarios: (1) somatic HGE for sickle cell disease, (2) Huntington disease, (3) unscrupulous entrepreneurs and clinics, and (4) somatic and epigenetic editing to enhance athletic performance. The other case studies are (5) heritable HGE for reproduction, (6) unscrupulous entrepreneurs and clinics expanding assisted reproduction, and (7) in utero HGE for cystic fibrosis. These seven scenarios have practical relevance because they illustrate situations where HGE might be applied, planned, or marketed.

Whereas dozens of CRISPR clinical trials (47, according to the latest data from ClinicalTrials.gov) are in progress, mostly for ex vivo somatic gene therapy, germline human genome editing is currently considered too premature, unsafe, and irresponsible. This is clearly stated in the WHO report, which cites numerous technical and medical conditions that would need to be met before reconsidering such attempts—as previously indicated in the National Academies reports in 2017³ and 2020⁵ by the National Academies' International Commission. ⁹

The need to extend access to innovative HGE research and medical applications to all populations around the world is another important aspect. Africa is highlighted as an example of the limited amount of genome information available from underdeveloped nations, compromising access to these technologies.

Answers and Questions

The WHO report raises several important points that had to be made. They are novel and complementary to previous reports, including the establishing of registries, the call for inclusivity, and the recommendations for good governance, and they are illustrated with clear examples. The report proposes a multiscale, multifaceted approach anticipating a future where no single regulatory process will prevail. This is already evident in current scientific and technological developments in this rapidly advancing field.

Even though we are continuously talking about “editing,” the reality is that most HGE applications currently being assessed using CRISPR-Cas9 are designed to inactivate, ¹⁰ interfere, ¹¹ or block ¹² the expression of genes, not to edit them (in the sense of “correcting” them). Replacement of mutant by wild-type sequences is still a challenging step, adequately addressed in preclinical experiments where we can progress with 1–5% efficiencies and amplify them subsequently by breeding steps in animal models, but unrealistic for current clinical translation.

By contrast, the precision editing afforded by base editors is rapidly advancing, with outstanding recent preclinical examples in mice for progeria ¹³ or nonhuman primates for heart disease, ¹⁴ paving the way for clinical implementation. The use of advanced versions of base (and prime) editors, combined with the use of standard CRISPR approaches for gene inactivation, might become the predominant tools in somatic HGE, associated with negligible (or undetectable) off-target and on-target effects. In this novel scenario, all the safety and efficacy considerations—not specifically discussed in the WHO documents but addressed in other reports—will have to be revisited.