Abstract

Twin girls were born in China in November 2018 to an HIV-positive father and an HIV-negative mother, through in vitro fertilisation in combination with CRISPR-Cas9 genome editing which altered their CCR5 genes. An investigation found that regulations were broken, and documents were forged. The government needs to address various regulatory defects, improve oversight of research, and implement institutional policies on conflict of interest.

Initial investigation results

On January 21, 2019, the provincial investigation committee of Guangdong, where the experiment was carried out, reported that Prof He’s research team of foreign and domestic researchers had started the project conducting gene editing with IVF as far back as 2016, looking for HIV discordant couples, in which the male was HIV positive. Eight couples were recruited between March 2017 and November 2018. One couple withdrew from the programme. Of the remaining seven couples, two women became pregnant. One gave birth to Lulu and Nana. (10).

The investigation concluded that Prof He’s experiments violated scientific integrity and research ethics and broke regulations. It also found that Prof He had forged the ethics review approval. He had also replaced the men’s HIV positive blood samples in the records (10), as the regulation on ARTs bars the use of this technology for people with a sexually transmitted disease.

Personnel and institutions involved with Prof He are now the subject of a criminal investigation. The provincial government announced it would monitor Lulu and Nana, and the other pregnant woman.

The US universities where Prof He studied abroad, Stanford (11) and Rice (12) announced inquiries on their faculty’s involvement in the CRISPR baby project. Stanford cleared its researchers; the results of the other investigation are awaited.

Existing guidelines and regulations

The CRISPR babies research would have been governed by existing regulation on the use of ARTs but there were no national guidelines on the use of gene editing. The US National Academy of Sciences, Engineering and Medicine’s document, Human Genome Editing: Science, Ethics, and Governance (13), gives clear guidance on the use of such techniques. Recommendation 5 states:

• the absence of reasonable alternatives;
• restriction to preventing a serious disease or condition;
• restriction to editing genes that have been convincingly demonstrated to cause or to strongly predispose to that disease or condition;
• restriction to converting such genes to versions that are prevalent in the population and are known to be associated with ordinary health with little or no evidence of adverse effects;
• the availability of credible preclinical and/or clinical data on risks and potential health benefits of the procedures; ……(13)

In response to the scandal, the National Health Commission (NHC) drafted a “Regulation on clinical uses of new biomedical technologies” and called for suggestions from the public on February 26, 2019 (14). Research on high risk biomedical technology, which includes gene-editing, will be reviewed at the provincial level and then submitted to the national health agency for review. Clinical applications of technologies proven safe and effective may be used by local institutions after approval by the provincial government. Violations of the regulations will be punished.

However, the NHC regulation covers only healthcare institutions and will not regulate biology departments in non-medical universities or biotechnology companies. It was not mere serendipity that the gene-editing case happened at the biology department of Southern University of Science and Technology which is responsible to the Ministry of Education, not the NHC. Research oversight is done in a highly fragmented governance system lacking effective departmental functioning and coordination. For example, universities are usually under the Ministry of Education, and hospitals are usually under the NHC.

Conflict of interest

Another related issue being discussed in the scientific community is that of conflict of interest.

Prof He was encouraged by the University’s policy on translating knowledge into industrial use or for production and patenting. This policy is supported by the Central Government to promote the commercialisation of research and is exemplified in policies such as Promoting the Transformation of Scientific and Technological Achievements. The policy encourages colleges and universities to undertake measures for the transfer of scientific and technological achievements: “If the transformation is successful, [in]obtaining patent, or getting licensing, then not less than 50 percent of the net income from the technology transfer or licensing can be rewarded to individuals who complete this translation…” (15).

These policies are meant to foster innovation as scientists receive financial incentives when innovations are brought to the market. Benefiting from such an effort to encourage faculty to launch startups, Prof He was CEO of Han Hai Gene, a company developing gene sequencing for clinical diagnosis as well as of Direct Genomics Biotechnology, among others (16). There has been no investigation into the possible conflicts of interest, and how this might have influenced his decisions.

Institutions must develop mechanisms of oversight in the translation of research from bench to bedside. Prof He was both an academic researcher with government funding and the CEO of a for-profit gene-sequencing company. This does not necessarily mean that he was guilty of misconduct. It is not known whether the institution where he was employed had developed a COI policy. If it had done so, the institution should have made sure researchers followed it.

Final reflections

Prof He defended his actions at the press conference where he announced the birth of the CRISPR babies: “I know my research has caused big debate… I am proud of providing hope to the kids to [be] immune from the HIV virus. I will continue to work hard to take responsibility for them for life…if it were my child, I will also take this measure” (17).

Currently, there is consensus that it is not yet time to use germline gene-editing for medical treatment. If it is impossible to predict either the benefits or harms of such techniques, this is sufficient reason for banning their use.

It is reported that the parents in this experiment strongly requested the research team to conduct this procedure on them (17). It is true that many doctors follow unreasonable requests from families, instead of the patient’s best interests.

There is another issue which is not discussed widely: whether or not Lulu and Nana’s parents had the right to make the decision to remove CCR5 to avoid HIV infection. Parents should, and need to, make decisions for their children. But did the parents act in the best interests of their children? If not, should the government interfere?

Finally, if follow up data of the twin girls provides evidence that Prof He’s research was beneficial, how would we view today’s condemnation? Which is more acceptable: a good outcome, but breaking the rules? Or following the rules, with a bad result for the babies? Is it tenable to make result-based judgements, or is the rule itself sufficient?

What should the fundamental values be behind such decisions?

Acknowledgements

Dr Yeyang Su for her help in collection of material and discussion.