EXPERT REACTION: Call for moratorium on human genome editing

Gene editing was reported to have been performed on human embryos by Chinese scientist He Jiankui at the Second International Summit on Human Genome Editing in Hong Kong on Wednesday, Nov. 28, 2018. It is perhaps an important point of note that this work has not been published, nor subjected to peer-review and amidst most of the presentations at this meeting being made available online, the slides for this work have not.

The work He presented reportedly introduced a mutation/polymorphism into a gene (CCR5) encoding a receptor used by the HIV virus to infect human cells of the immune system. By doing this, the immune system cells of the resulting fetus should then be rendered “immune” to HIV infection.

Implantation of allogeneic stem cells whose genome contained this CCR5 mutation into people with HIV was recently reported to have been the second case of curing HIV (“London Patient”, reported on March 5, at the Conference on Retroviruses and Opportunistic Infections, Boston by Ravindra Gupta-University College London; https://www.cam.ac.uk/research/news/hiv-remission-achieved-in-second-patient).

This shows that the approach proposed by He has the possibility to provide immunity from HIV infection in the embryos that he had introduced the mutation into. The procedure used by He is presented in the attached image of a slide presented by He (AP Photo/Kin Cheung) (http://www.apimages.com/metadata/Index/Hong-Kong-Gene-Edited-Babies/a5b3fcf827cf490a80e4a139ad92e402/11/0)...

HOWEVER... there are several issues raised by the work presented by He. Some of the most important ones are as follows:-

1. The mutation was introduced into an ovum from a woman without HIV at the time of in vitro fertilisation with sperm from a man carrying the HIV virus; Possibility of carry-over of HIV virus from the sperm;
2. CRISPR/Cas9 gene editing system has KNOWN issues of targeting the wrong genes; Genes other than the targeted CCR5 gene could be affected and cause life-long disease in the treated offspring when they grow;
3. From point 2, there is the possibility of introducing new mutations that have not been filtered by natural selection processes (over time) and rapidly establishing/fixing these into the human genome;
4. The mutation was found only in SOME (not ALL) cells of the children; The procedure may not result in mutating cells that will become the child’s immune system;

In short, the gene editing procedure applied to the twin subjects of this study is hugely premature and at best, can only be described as highly irresponsible with little regard to the possibility that the two PEOPLE resulting from this experiment may acquire mutations in other genes that will cause different diseases, possibly without any benefit (as they most likely would not have had HIV if they were not exposed to it during their lives) and which they will have for their entire lifetimes.  The presence of an alternative emerging therapy for HIV (ie the CCR5 stem cell approach) lays further discredit on the application of unstable/unpredictable gene editing technologies to human embryos at this point in time.  These issues are amongst many that relate specifically to the case reported by He Jiankui and underpin the reaction from the field that culminated in the call for this moratorium on gene editing in germ-line cells.

There have been successful applications since 2014 of germ-line gene editing in animals that have eradicated the disease from the mouse model of human Duchenne’s Muscular Dystrophy (DMD), (see Science. 2014 Sep 5;345(6201):1184-1188. doi: 10.1126/science.1254445), a disease for which there is no cure and which affects 1 in every 3500 boys born (the mutation is on the X chromosome and is transmitted from the mother’s genome to the male offspring). However it is a different proposition to apply this to laboratory animals than it is to applying this to humans. The (safer) application of gene editing technologies to the (mdx) mouse model of DMD in non-germline tissues has been established (by Australian seminal research) for far longer (Hum.Gene Ther. (2001), 12(6):629-42;  Neuromuscul.Disord. (2005), 15(9-10):630-41) and today presents a better option much closer to clinical relevance.

The proposed moratorium addresses and promotes the need to evaluate and control gene editing in germ line cells and in embryos to prevent the fixation of deleterious mutations into the human genome as a first instance, which is a high probability with current gene editing technologies. In addition, it is possible that such gene editing of the germ line may eventually be used for enhancement of human functions to produce “superhumans”, thereby widening sociological gaps between the “haves” and “have nots” in the global community or otherwise that people can be  genetically modified to be subservient to others.

As such, the moratorium proposes that germ-line gene editing should be allowed in animal research, but not in human clinical application. Whilst it is always tempting for researchers (as the optimists that they are trained to be... 😊) to see their work “sunny-side up”, it is equally important to search for, see and acknowledge the potential for harm that may exist as the darker side of the coin of their research. It is only through a measured and careful search, address, redress in a step-wise approach that  the enormous potential of scientific discovery can be safely delivered to the global community. It is often the premature application of such promising technologies that impede their delivery to the community as viable clinical options.

It is also important, in fact CRITICAL, that the proposed moratorium is constructed by an inclusive process that embraces as much (exhaustive) informed input as possible from those who have been active in the forging of these exciting technologies as well as those affected by the diseases that the technologies target, and that it  focuses on the “how to” as much as on the “why not to” so that these technologies of such huge potential to impact positively on the amelioration of human suffering are delivered from the laboratory to the human clinical community in as timely a manner as possible.

This is a promising proposal. It puts forward a nuanced rationale for a moratorium on clinical use of heritable genome editing. The agreement would be driven by voluntary and transparent commitments from individual countries, with light-touch oversight from an international body.

The proposal covers not only the technology itself, but also procedures for reporting inappropriate activity. It will also set the tone for how debate on heritable genome editing should proceed: in the public domain, with time for in-depth discussion to identify core values, in consultation with many different groups.

That said, getting this right won’t be simple. Drafting will need to be precise and barriers to quality public engagement will need to be addressed.

Proportionality is also important: we need to have this debate without over-hyping the potential of genome editing or framing its use as inevitable. Genome editing is an exciting and technically dazzling technology, but it remains one very small contributor to the urgent problem of global health equity and opportunity.

Clinical use of heritable gene editing would be premature, so a moratorium would be welcome. Ensuring voluntary commitments, and then that they are enforced, is not easy, but not putting anything in place would be a worse outcome. The call reiterates clear criteria that must be met for heritable editing to become a viable option in specific circumstances, but it also proposes a framework to shape the global discussion on human gene editing. Ultimately society as a whole will decide which applications of gene editing are acceptable, in health as well as in other domains. More than ever, engagement and education around advanced biotechnologies is crucial.

A moratorium on heritable genome editing strikes me as the bare minimum necessary to restore public confidence in the scientific establishment after the revelation that a Chinese scientist had already tried to produce genetically enhanced humans.

It's far from clear, though, that the voluntary pause the authors are calling for would be effective in preventing similar experiments by scientists who are in thrall to the fantasy of super babies promoted by transhumanists and by science fiction.

As the signatories to this document recognise, moratoria are very blunt instruments.

What will be even more important than the proposed initial voluntary bans on clinical germline editing will be the processes of public consultation and engagement in which nations subsequently engage.

Involving diverse stakeholders and generating consensus around ongoing policy in this domain will be extremely difficult but morally essential.

A small, international group of leading scientists and ethicists have come together to call for a global moratorium on germline editing and the development of an international governance framework. In the light of the recent CRISPR baby scandal driven by the actions of the Chinese scientist Dr. He, this is a wise move. Arguably, this should have been in place a few years ago when it became clear that editing viable embryos was possible. There is no law to prevent germline editing in China although guidelines prohibit it. Therefore, even though many prominent international scientists were aware of Dr. He’s work, they were unclear if they should blow the whistle on the rogue scientist, and if so, to whom.

A governance framework around this issue would provide much needed clarity. Would it have prevented Dr. He from carrying out his ill-informed experiments? Perhaps not in light of the fact that Dr. He allegedly recruited patients using coercion, forged documents and swapped blood samples to achieve his goals – each of these suggest extreme unscrupulous behaviour. 

Will it hamper research and use in the clinic? No – the moratorium will not apply to germline editing for research purposes or to the editing of somatic cells. The call to limit the clinical use of germline editing is proposed for a fixed and limited time of perhaps five years. This is warranted as many technical issues still need to be resolved to allow this method to be safely used in the clinic. In addition, it is still debatable whether there is a sufficient unmet need to warrant its use in the clinic. It is clear that many issues, both technical and ethical, remain to be resolved.

One good thing that has emerged from this fiasco is the knowledge that the international scientific community will not tolerate unethical research and that they are actively looking for solutions to prevent it in the future.

The call for an international moratorium on clinical uses of germ-line editing in humans is important and timely. CRISPR-cas9 technologies are relatively easy to use, and have been shown to be effective in humans. This raises the possibility that germ-line editing could be commonly used to permanently edit the human genome to manage disease, or to improve human characteristics. This raises challenging ethical and societal issues that must be generally addressed. A moratorium while those discussions proceed is critical. I fully support this call.

Problematically, however, most scientists believe that such a moratorium already exists. That gene edited children have been born in China shows that moratoria are not effective to stop illegitimate behaviour. The case in China is a salutary one. The scientist involved appears to have broken laws and regulations and behaved at the least unethically, at most illegally. That China has tightened its regulations, and sanctioned the scientist is good news; clearly they also the recognise the need to think carefully about gene editing in humans.

I hope this moratorium is achieved and effective. Perhaps, however, we should be asking how it is a highly trained, internationally educated, scientist could feel that they have the right to ignore international opinion, ethical standards and law? Solving that problem may be one way to assure that this proposed moratorium is effective.