Regulation

Talk less, do more: Germline gene editing needs real plans, not just moratoria

Editor's Commentary: Why the international community should fund, coordinate labs for safe use of germline gene editing

We’ve moved on from sound and fury. We’re now just signifying nothing. The latest public proclamation on germline gene editing, couched in a call for a moratorium, is as much preaching to the choir as the litany of public statements that came before it.

Despite at least two summit meetings and numerous position papers on what should and shouldn’t be allowed, the international community has failed to map any credible path or put any significant dollars behind nailing the criteria under which germline gene editing could ever be safe.

Last week, a group of 18 scientists and ethicists published a comment in Nature calling for a moratorium on germline gene editing until an “international framework” is created in which nations “voluntarily commit to not approve any use of clinical germline gene editing unless certain conditions are met.” The comment itself noted that 30 countries already have prohibitive rules or laws in place.

The call for a moratorium, not a ban, puts the authors firmly in the camp that germline gene editing can have a place in the armamentarium, albeit a very restricted one. BioCentury’s editorial team has been in this camp, arguing that a technology that can address severe genetic diseases with no alternative solutions should be explored (see “From ‘No’ to ‘How’”).

The other camp is opposed to use of germline gene editing under any circumstances, either because it’s morally wrong, or because they don’t accept the risk is worth the benefit.

The international community has failed to map any credible path or put any significant dollars behind nailing the criteria under which germline gene editing could ever be safe.

But the reality is that banning germline gene editing will not prevent illegitimate use of the method by unprincipled scientists, however many pronouncements and policies are issued.

The safer and wiser path is to bring germline gene editing under a transparent, highly regulated umbrella, and avoid creating an underworld of bootleg operations.

Discussing what circumstances constitute permissible use is important, but not enough.

There needs to be similar urgency around establishing the technical parameters of safety.

Academic organizations, government bodies and industry need to create a well-funded program, containing wet labs, run by top scientists, to do the necessary experiments to define what “safe” would look like when it comes to germline gene editing.

The first meeting of the WHO advisory committee to develop standards for human genome editing takes place over the next two days. This is an opportunity to lay solid plans not only for how to govern the field, but how to advance it towards the goal of defining safety.

More of the same

The Nature comment, published March 13, was headlined by Feng Zhang and Emmanuelle Charpentier, two of the inventors of CRISPR-based gene editing. The technique has become so widely accessible that controlling who uses it and how is virtually impossible. That genie cannot go back in the bottle.

The comment was part of the loud, global outcry to the November announcement by Chinese scientist He Jiankui that he had used CRISPR on human embryos, leading to the birth of the first two gene edited babies.

Other prominent authors include Eric Lander, president and founder of the Broad Institute of MIT and Harvard, where Zhang is a member, Canadian bioethicist Françoise Baylis, a professor at Dalhousie University, and Paul Berg, emeritus professor at Stanford University who was a driver of the Asilomar conference that laid the groundwork for responsible use of recombinant DNA technology in 1975. Charpentier is director and scientific member at the Max Planck Institute for Infection Biology.

Absent from the comment was University of California Berkeley’s Jennifer Doudna, the third in the trifecta of CRISPR pioneers, who told BioCentury she thinks a moratorium is “of indefinite length and provides no pathway towards possible responsible use.”

Doudna has been a prime driver of moves to bring international consensus, and to map a path to safe methods. Her absence reflects that, in a field with broad agreement that germline gene editing is too premature for clinical use, there is still much to disagree about.

The past four years has seen calls for moratoria, calls for not-quite-moratoria, calls for outright bans, calls for responsible use for compelling purposes, calls for a rigorous, responsible translational pathway, calls for expedited reports, and more.

In the U.S., NIH has a policy against funding “any use” of gene-editing in human embryos unless it is for research purposes. FDA is prohibited from considering clinical trial applications involving the intentional creation or modification of human embryos with heritable genetic modifications.

And the Chinese government has expressed zero tolerance for editing human embryos. China’s vice minister of science and technology, Nanping Xu, said He Jiankui’s study “blatantly violated China’s relevant laws and regulations.”

He Jiankui was fired from the Southern University of Science and Technology in Shenzhen, and has been ostracized from the scientific community.

That sends a loud message, but it won’t deter the next fringe scientist. Alone, those messages will not solve the problem.

Reaching safety

In its editorial comment, published in 2015, BioCentury called on the U.S. National Academies of Science and Medicine and their international counterparts to define safety and demarcate the range of experiments that would be acceptable once safety is established.

In nearly four years, the field has barely scratched the surface of either of those.

The Nature authors put a five-year frame for their moratorium, which Lander told BioCentury reflects how long they think it will take “to resolve the technical issues about safety, to consider the various issues, and to establish a governance framework.”

But this timeline is not backed by any actual plan for establishing safety, any commitment of money, any agreement of who will do the experiments, where they will do them, who will evaluate them, or by what criteria they will do so.

What is key is that these experiments be brought under a well-controlled, transparent organization that monitors protocols and results.

However, there are models for what responsible studies could look like.

In 2017, a group at Oregon Health & Science University reported a gene editing study in human embryos that tested off-target activity and examined editing efficiency by looking at mosaicism. The embryos were destroyed after three days (see “The Other Side of the Rubicon”).

At the time Doudna called it “to date the clearest direct step” towards successful germline editing, and New York University bioethicist Arthur Caplan told BioCentury, “I would say this is absolutely rocket fuel for more studies.”

The study’s results gave rise to challenges, but that is the nature of science. The study, which did not use NIH funding, was largely deemed a responsible and well-conducted piece of work (see “Confirming CRISPR”).

Caplan was right; that study should spur more. The field will only define safety by investing in responsibly conducted studies that assess the types of edits that can be made accurately and throughout all the necessary tissues in the embryo.

These can springboard from experiments using somatic gene editing, which is laying the groundwork for analytical methods and paving a regulatory path (see “Proofreading the Editors”).

In addition, the National Institute of Standards and Technology (NIST) has created a precompetitive consortium made up of six biopharmas, 13 tools, services and diagnostics providers, two academic hospitals and an agbio company, to define measurement standards for somatic gene editing.

Germline editing is not in scope for NIST -- the U.S. prohibits federal funds from being used in research that manipulates human embryos -- but the consortium and its protocols provide a template that could be mimicked by international organizations (see “Germline Gene Editing Gets Technical”).

As with somatic gene editing, the place in the genome where an off-target edit occurs will make a difference to its impact. For germline editing, there may be a different cutoff for how many edits can be tolerated per given length of DNA. Nature has provided some ground rules through mutation rates that occur during reproduction. Other treatments, including chemotherapy, introduce changes to germline DNA that can serve as reference points.

The field needs sequencing and other technological protocols for addressing these issues in edited embryos, and a framework for including such studies in a regulatory package.

What is key is that these experiments be brought under a well-controlled, transparent organization that monitors protocols and results.

They should be funded by the academies and national agencies, such as NAS, NAM, NIH and their international counterparts.

WHO is stepping into the fray with an Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing.

Its brief is to create a governance system to cover scientific, ethical, social and legal concerns of genome editing, but its impact could be bigger.

This is an opportunity for a neutral, international organization to do more than lay out boundaries for what can and can’t be done, by mapping a detailed, controlled path forward.

This should be a global operation -- biology’s version of the international space station. There’s no precedent within the life science field, but now would be a good time to create one.

Signed commentaries do not necessarily reflect the views of BioCentury.

Companies and Institutions Mentioned

Broad Institute of MIT and Harvard, Cambridge, Mass.

China Ministry of Science and Technology (MOST), Beijing, China

Dalhousie University, Halifax, Nova Scotia

Max Planck Institute for Infection Biology, Berlin, Germany

National Institute of Standards and Technology (NIST), Gaithersburg, Md.

National Institutes of Health (NIH), Bethesda, Md.

National Academy of Medicine (NAM), Washington, D.C.

National Academy of Sciences (NAS), Washington, D.C.

New York University, New York, N.Y.

Oregon Health & Science University (OHSU), Portland, Ore.

Southern University of Science and Technology, Shenzhen, China

Stanford University, Stanford, Calif.

University of California Berkeley, Berkeley, Calif.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.

World Health Organization (WHO), Geneva, Switzerland