EXECUTIVE SUMMARY

A Chinese scientist’s recent announcement of a genome-editing procedure performed to protect children from HIV has significant implications for the bioethics and genomics fields.

• Multiple ethical principles were violated, such as the need for informed consent and transparency.

• More stringent requirements are expected.

• Researchers are concerned that legitimate work in this area may be hindered.


Clinical trials using heritable genome editing might be ethically permissible in the future — but only within a “robust and effective regulatory framework” including maximum transparency and a reliable oversight mechanism, concluded a 2017 report from the National Academy of Sciences (NAS) and the National Academy of Medicine (NAM).1

Editing the DNA of a human embryo could be morally permissible, according to a 2018 independent inquiry by the Nuffield Council on Bioethics — but only after a number of measures were put into place to ensure it proceeds in ethically acceptable ways.2 Canada, Germany, France, Switzerland, Sweden, and Italy have all passed laws prohibiting germline intervention on human embryos for implantation.

Despite this international consensus, a Chinese scientist recently took responsibility for the world’s first gene-edited babies. He Jiankui, an associate professor at the Southern University of Science and Technology in Shenzhen, stated that the procedure was done specifically to protect the children from HIV. This revelation only compounded the issues troubling many ethicists.

“Having listened to Dr. He, I can only conclude that this was misguided, premature, unnecessary, and largely useless,” says R. Alta Charo, PhD, co-chair of the NAS/NAM committee. Charo is Sheldon B. Lubar distinguished chair and Warren P. Knowles professor of law and bioethics at the University of Wisconsin-Madison.

The shocking announcement served as a reminder that there probably is very little any nation, professional society, or institution can do to prevent “rogue” actors from breaking the rules, says Carolyn P. Neuhaus, PhD, a research scholar at the Garrison, NY-based Hastings Center. This is the case whether those rules are codified in law or institutional policy or scientific societies. “But we always knew that. The question is, ‘What does it look like to do our very best to prevent it?’” asks Neuhaus.

A “renewed sense of urgency about transparency” is needed, says Neuhaus. This means fostering a culture, especially among young scientists, that rewards raising questions, whistleblowing, and sharing works in progress. “Included in this should be lab technicians, postdocs, students, and also IVF providers or nurses who might be involved in future studies that would seek to implant edited embryos,” says Neuhaus.

Ethical Principles Violated

Instead of a peer-reviewed journal, the research was publicized via YouTube. “There was an immediate public, scientific, and ethics outcry,” says Charis Eng, MD, PhD, FACP, chair of the Genomic Medicine Institute and director of the Center for Personalized Genetic Healthcare at the Cleveland (OH) Clinic.

A previous attempt at gene editing, though controversial, was performed in the setting of a clinical trial. It was vetted by a multi-institutional IRB and addressed a life-threatening medical problem that would result in death shortly after birth.1 In contrast, says Eng, “From what I understand of this current situation, this researcher did not vet his protocol through any IRB.”

Kiran Musunuru, MD, PhD, MPH, associate professor of cardiovascular medicine and genetics at University of Pennsylvania, says the experimental procedure that resulted in gene-edited twins violated “bedrock principles of ethical medical research,” including the following:

• Beneficence. Although the procedure was reportedly intended to confer resistance to HIV infection, only one of the embryos received sufficient editing to possibly gain HIV resistance. “The other did not but was permitted to proceed through pregnancy anyway,” says Musunuru.

Additionally, the chance of either twin becoming infected with HIV and progressing to full-blown AIDS in their lifetimes was negligible. “There was little good to be gained,” says Musunuru.

• Nonmaleficence. “The gene editing was imperfect and incomplete across the cells in the embryos,” explains Musunuru. There is evidence of undesired, potentially harmful mutations. These could raise the risk of cancer or other diseases — not just for the twins but also their descendants. Even if the gene editing had been perfect, says Musunuru, “the edits to confer HIV infection also increase the likelihood of having serious illnesses or dying from infections with other viruses, such as flu.”

• Autonomy. As the twins had no opportunity to consent for procedures performed on them as embryos, this responsibility fell to the parents. Yet, says Musunuru, “it was clear that the ‘informed consent’ procedure was not truly informed.” One reason is that the potential benefits and harms were misrepresented.

“Indeed, the full extent of potential harms with gene editing is still a big unknown to scientists,” says Musunuru.

The consent claimed the infants were likely to benefit from the procedure. This conflated research with therapy, says Charo: “In fact, there is not only very little chance these babies would be in need of a benefit, given their low risk, but there is no way to evaluate if this indeed conferred any benefit.” Additionally, if the twins do remain HIV-negative, there is no way to show it has anything to do with the editing.

The consent form focused largely on risks of participating in in vitro fertilization (IVF), with minimal information on gene editing. Kelly E. Ormond, MS, CGC, LGC, acknowledges it is possible it was conveyed verbally. However, consent forms are meant to document what was in the conversation. “It did not make it clear that there are a lot of unknowns and that this is experimental,” says Ormond, co-director of Stanford (CA) University’s master’s program in human genetics and genetic counseling and faculty at the Stanford Center for Biomedical Ethics.

Dr. He revealed that there is a second, early pregnancy, and 16 more embryos from other couples — all frozen while his work is paused. “What will happen to those embryos, or even who decides what happens, is unknown,” says Charo.

Opportunity to Educate

The worrisome event has important implications for healthcare ethics. “When something so serious has occurred, one opportunity is to educate the public on ethical issues,” says Eng.

Musunuru predicts that the episode will end up being required reading for future generations of scientists, as “a textbook case of all the different ways one can violate the ethical principles of medical research.”

As for future rogue scientists, the international outcry from the scientific community is likely to discourage at least some of them. “The backlash is turning out to be so immense that scientists will be deterred from similar ethical violations in the future, although there will always be bad actors,” says Musunuru.

Recent surveys suggest most Americans would like to see gene editing move forward. “It will be interesting to see if this affects the degree of public’s acceptance of this as being OK,” says Ormond. One of the challenges in this regard, says Ormond, is “You have no idea what the people responding actually know about it.”

Respondents may be completely uninformed, or misinformed. While survey respondents tend to differentiate between therapeutic use and enhancement, they do not see the distinction between somatic cell gene therapies that affect only the treated individual and germline editing that affects future offspring. “Certainly, bioethicists, scientists, and clinicians see a stark difference between somatic and germline therapies,” says Ormond.

More discussion around somatic gene editing is sorely needed, says Ormond. Potential treatments are a realistic possibility in the near future. In contrast, she says, “Germline editing is more ethically sticky, and that’s why people gravitate to it. But it’s not going to be the majority of what gets done.”

Various policy boards are seeking to engage the public in discussion on ethics of genomics. The highly publicized gene-edited babies could open the door to vigorous debate. “It’s gotten people talking about it, which could lead to deliberative democracy conversations,” says Ormond.

Neuhaus says there is an opportunity here “to reflect on the role of gene editing in our lives.” She says reflection is needed on these questions in particular:

• Does the need to edit out certain diseases and disabilities express that existing people with those diseases or disabilities are less than able-bodied persons?

• How, if at all, does gene editing differ from other ways in which we intervene in or exert power over future humans’ lives?

• How much control should parents have over their child’s traits? Does a “good” parent use gene editing?

• What level of risk should parents be allowed to assume on behalf of their future children?

There’s a tendency to think that if the benefits of new medical technologies outweigh the risks, then the ethical conversation is over, says Neuhaus.

Recent discussions on gene editing have been held at various museums and high schools. “I hope that more public-facing discussions, whether in print or online or in classrooms, take up these complex and nuanced and messy discussions,” says Neuhaus.

Researchers Fear Shutdown

Many ethicists now see stricter regulations as inevitable, since the episode is a stark reminder of the limitations of self-regulation in the scientific community.

External legislation and regulation will be needed, says Musunuru, “to ensure that egregious ethical violations of this kind do not happen again going forward.”

Some fear that too much regulation will stifle scientific innovation. “It’s always going to be a tradeoff,” says Ormond. “That’s what the conversation needs to be about.”

Regardless of how much restraint is urged by the scientific community or the general public, the reality is that no global body can actually enforce any of it. “Without laws that have actual consequences in any particular country, it’s going to be very hard to prevent this,” says Ormond.

As for the ethical challenges of moving from in vitro research to clinical translation, Ormond says there is no need to reinvent the wheel. The field of assisted reproduction has already been through it, with the first IVF, first preimplantation genetic diagnosis, and first mitochondrial transfer cases. “Those were very controversial when first done, as well,” says Ormond.

Likewise, the clinical genetics field can share insights as to whether a given condition meets criteria for gene editing. “I hope that this one case doesn’t make all of this research shut down,” says Ormond. “We would really lose out on some great potential treatments if that happens.”

REFERENCES

1. National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press.

2. Nuffield Council on Bioethics (2018). Genome Editing and Human Reproduction: Social and Ethical Issues. London: Nuffield Council on Bioethics.

3. Ma H, Marti-Gutierrez N, Park SW, et al. Correction of a pathogenic gene mutation in human embryos. Nature 2017; 548(7668):413-419.

SOURCES

• R. Alta Charo, JD, Warren P. Knowles Professor of Law & Bioethics, University of Wisconsin Law School, Madison. Phone: (608) 262-5015. Email: racharo@wisc.edu.

• Charis Eng, MD, PhD, FACP, Chair, Genomic Medicine Institute/Director, Center for Personalized Genetic Healthcare, Cleveland (OH) Clinic. Phone: (216) 444-3440. Email: engc@ccf.org.

• Carolyn P. Neuhaus, PhD, Research Scholar, The Hastings Center, Garrison, NY. Phone: (845) 424-4040, ext. 255. Email: neuhausc@thehastingscenter.org.

• Kiran Musunuru, MD, PhD, MPH, Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania. Phone: (215) 573-4717. Email: kiranmusunuru@gmail.com.

• Kelly E. Ormond, MS, CGC, LGC, Department of Genetics, Stanford (CA) University. Phone: (650) 736-9847. Email: kormond@stanford.edu.