“Whether” or never: Reproductive genome editing in humans

Originally published as Vererbbares Genome Editing am Menschen in Gen-ethischer Informationsdienst 265; translated by the author.

In March 2023, an international summit took place for the third time to discuss the future of applications of new genetic technologies such as CRISPR-Cas in the biomedical field and to present the current state of research – this time in the impressive Francis Crick Institute in London. On the first day of the three-day conference, the approximately 400 scientists, bioethicists, patients and journalists who made their way into the glass-enclosed building were greeted by a small group of protesters. The members of the Stop Designer Babies UK (SDB UK) initiative held signs reading “Never again to Eugenics” and distributed flyers against the plans of some scientists to promote the creation of so-called designer babies.

The existence of children who have been genetically modified in the embryonic stage so that they can pass on these interventions to potentially all future generations is no longer science fiction. On the one hand, the first child was born in 2016 after a so-called mitochondrial transfer – a somewhat misleading term, because the technology is more similar to cloning: people whose eggs have genetic, disease-causing aberrations in their mitochondria (certain cell components that have a separate genome) have the nucleus of their eggs removed and transferred into “healthy” eggs from third parties. The embryos and subsequent children created from these eggs, also called “three-parent children,” are genetically modified in a way that would not be possible without the intervention.

On the other hand, shortly before the previous international genome editing summit, in November 2018, the Chinese scientist He Jiankui confronted the world with the news that the first children treated with CRISPR-Cas had been born.

Breaking taboos or pioneering work?

The scientific community – as well as the public – reacted with shock when He presented his research results at the congress. In response to the news, attempts were made to portray him as a "rogue scientist," an isolated lone perpetrator, but later the information emerged that he had talked to leading scientists about his plans but no one had raised the alarm.

He’s move shouldn't come as a surprise, as important ethics and scientific bodies, such as the British Nuffield Council on Bioethics and the US National Science Academies (NAS), had previously spoken out in principle in favor of heritable genome editing to prevent “serious diseases or disabilities.” The Nuffield Council even mentioned the creation of super senses and super abilities as possible goals that should be left to the “reproductive freedom” of individuals.

The German Ethics Council has now also ruled that inheritable genome editing is fundamentally morally permissible. All of these organizations formulate vague cost-benefit estimates as a basis for starting clinical trials, which assume a reduction in the technology's error rate but do not specifically state how much risk is acceptable. He obviously made this assessment differently than the scientific mainstream and assessed the technology as already precise enough for use in the clinic. He seemed surprised by the negative reactions, including from the science community.

The 2018 summit ended with a statement from the organizing committee condemning He's experiments, but at the same time proclaiming, based on the current state of research, that it was “time to define a rigorous, responsible translational pathway” towards clinical trials. As the US organization Alliance for Humane Biotechnology (AHB) summarizes in a discussion paper, these plans have been taking a very concrete form since 2018: A commission set up by the NAS and the UK Royal Society was intended to develop the framework conditions for clinical studies. In their report, potential areas of application are not limited to genetic diseases; “enhancements” are discussed as well.

The commission, made up of scientists and doctors, produced plans to establish an international governing body that will pave the way from laboratory research to human experimentation, and standardize the long-term observation of genetically modified children. As AHB and other civil society organizations point out, this practically preempts society's decision for or against germline interventions. Although the commission envisages public participation, the authors of the discussion paper elucidate that by separating the scientific feasibility debate from social issues, the opportunities to oppose germline changes and research in principle are limited.

As SDB UK’s David King told NPR, it would be an “extreme case of scientific irresponsibility” if researchers presumed to decide the future of genome editing alone. King described the organizers of the scientific summit in London this year as demonstrating “unwillingness to accept that society has any right to set ethical limits upon science.”

In fact, heritable genome editing is currently banned in over 70 countries. In Germany, for example – apart from the German Embryo Protection Act – the EU's Oviedo Convention applies. It prohibits interventions aimed at “altering the genome of offspring.” However, driven by the promise of science, these legal restrictions may soon crumble: in the UK, there is currently talk of legalizing germline modifications this year. Due to these developments, further steps towards the implementation of designer babies in reproductive medicine were expected for the third summit in London in March, which had been postponed by a year due to the COVID19 pandemic.

It wasn't just SDB UK that protested against this prospect. In the run-up to the summit, several civil society organizations including the Center for Genetics and Society and the Gen-ethical Network came together around the British initiative to form an International Coalition to Stop Designer Babies. On the day before the start of the summit, this alliance published an International Declaration Against Legalisation of Human Genetic Modification. The authors see heritable genome editing as a violation of human dignity, among other things because it reduces people to the “status of designed and optimised consumer objects.”

Focus on somatic gene therapies

The summit’s organizing committee seemingly tried to minimize the possibility of controversy following He Jiankui's scandalous performance in 2018. Unlike the two previous summits, heritable applications of CRISPR-Cas and similar tools were only discussed on the third day of the conference.

On the first two days, the moderators repeatedly called for the discussions after expert talks to be limited exclusively to somatic applications in humans. Somatic refers to treatments that only affect the body of the respective person and genetic modifications which are not heritable. In principle, there is little ethical controversy about such gene therapies, the discussion mainly focuses on how safety risks for patients can be limited – and about their enormous price. The dose of a novel CRISPR-Cas-based gene therapy for the genetic disease sickle cell anemia is expected to cost around $2.8 million. This does not include the chemotherapy, hospital stays, etc. necessary for the treatment. The price is not calculated from the actual production costs of the gene therapy, but rather based on what the lifelong standard treatment of a person with sickle cell would cost in the current healthcare system in the US.

At the summit in London, the question of equity and distributive justice was raised many times, but could not be answered. The blatant injustice in access to health care becomes particularly clear when it comes to sickle cell anemia. In the US, African Americans are particularly affected, as they often have no or inadequate health insurance due to structural racism. Globally, 90% of sickle cell anemia cases occur on the African continent and India. In one panel discussion, Indian patient representative Gautam Dongre provocatively asked how gene therapies are supposed to reach the average population when they still have no access to the standard drug hydroxyurea, 40 years after its introduction.

No medical benefit

The question about the benefits of germline interventions, which was finally allowed to be asked on the last day of the summit, seems remote given that most people do not have access to modern gene therapies. As the bioethicist Tina Rulli explained in her contribution to the panel “Are there compelling reasons for heritable changes to the human genome?,” reproductive genome editing is not about treating sick people, but rather creating embryos for the sole purpose of gene editing to alter the traits of the person born from that embryo.

In the more supportive contribution by human geneticist Ephrat Levy-Lahad and the subsequent discussion, it became clear that germline interventions are not about prevention or medical benefits – there are always alternative options for couples who want to have children and are afraid of passing on serious genetic diseases, such as sperm donation, adoption, or (also critically discussed) preimplantation diagnosis. Germline interventions only make “sense” if the parents are concerned about 100% biological relationship – without taking into account the immense risk for the future child who is unable to consent.

CRISPR-Cas and its more precise derivatives are not flawless, as the presentations in a panel on the state of research impressively showed. The “genetic scissors” sometimes cut so radically that entire chromosomes are missing. However, comprehensive control for unwanted genetic changes in all cells of an embryo before its implantation is currently not possible.

Civil society needs to act

The organizers and participants at the meeting in London repeatedly pointed out the high diversity of perspectives among the speakers compared to previous meetings. Conspicuously missing, however, were representatives from the disability rights movement, who would certainly have contributed a completely different perspective to the vision of wanting to cure all possible disabilities. The  Center for Genetics and Society therefore organized a counter-summit at the end of February in which diverse voices from civil society were given space.

Nevertheless, social and ethical problems of germline interventions were also discussed here and there in London. Social scientist Sarojini Nadimpally, for example, drew on her work on surrogacy in India, where the practice of reproductive technologies is embedded in postcolonial and sexist social structures that prioritize light-skinned children and the birth of sons. If existing power structures are not reflected, genome editing could also promote discrimination against already marginalized population groups, says Nadimpally.

The criticism before and at the congress seems to have left its mark on the organizing committee. The concluding statement of this year's summit reads significantly less ambitious than the 2018 statement. The authors write: "Public discussions and policy debates continue and are important for resolving whether this technology should be used." This little word “whether” should be understood as an urgent invitation for civil society to participate vigorously in the debate about the future of germline interventions.

Dr. Isabelle Bartram is Program Director at Gen-ethisches Netzwerk (Gen-ethical Network), a Berlin-based nonprofit organization advocating for the responsible use and governance of human genetics. She is a molecular biologist at the University of Freiburg’s Institute of Sociology.