The He Jiankui affair is a scientific and bioethical controversy concerning the use of genome editing following its first use on humans by Chinese scientist He Jiankui, who edited the genomes of human embryos in 2018. He became widely known on 26 November 2018 after he announced that he had created the first human genetically edited babies. He was listed in Time magazine's 100 most influential people of 2019. The affair led to ethical and legal controversies, resulting in the indictment of He and two of his collaborators, Zhang Renli and Qin Jinzhou. He eventually received widespread international condemnation.
He Jiankui, working at the Southern University of Science and Technology (SUSTech) in Shenzhen, China, started a project to help people with HIV-related fertility problems, specifically involving HIV-positive fathers and HIV-negative mothers. The subjects were offered standard in vitro fertilisation services and in addition, use of CRISPR gene editing (CRISPR/Cas9), a technology for modifying DNA. The embryos' genomes were edited to inactivate the CCR5 gene in an attempt to confer genetic resistance to HIV. The clinical project was conducted secretly until 25 November 2018, when MIT Technology Review broke the story of the human experiment based on information from the Chinese clinical trials registry. Compelled by the situation, he immediately announced the birth of genome-edited babies in a series of five YouTube videos the same day. The first babies, known by their pseudonyms Lulu (露露) and Nana (娜娜), are twin girls born in October 2018, and the second birth and third baby born was in 2019, named Amy. He reported that the babies were born healthy.
His actions received widespread criticism, and included concern for the girls' well-being. After his presentation on the research at the Second International Summit on Human Genome Editing at the University of Hong Kong on 28 November 2018, Chinese authorities suspended his research activities the following day. On 30 December 2019, a Chinese district court found He Jiankui guilty of illegal practice of medicine, sentencing him to three years in prison with a fine of 3 million yuan. Zhang and Qin received an 18-month prison sentence and a 500,000-yuan fine, and were banned from working in assisted reproductive technology for life.
He Jiankui has been panned as a mad scientist. The impact of human gene editing on resistance to HIV infection and other body functions in experimental infants remains controversial. The World Health Organization has issued three reports on the guidelines of human genome editing since 2019, and the Chinese government has prepared regulations since May 2019. In 2020, the National People's Congress of China passed Civil Code and an amendment to Criminal Law that prohibit human gene editing and cloning with no exceptions; according to the Criminal Law, violators will be held criminally liable, with a maximum sentence of seven years in prison in serious cases.
Origin
Since 2016, He Jiankui, then associate professor at the Southern University of Science and Technology (SUSTech) in Shenzhen, with Zhang Renli and Qin Jinzhou, have used human embryo in gene-editing technology for assisted reproductive medicine. On 10 June 2017, a Chinese couple, an HIV-positive father and HIV-negative mother, pseudonymously called Mark and Grace, attended a conference held by He at SUSTech. They were offered in vitro fertilisation (IVF) along with gene-editing of their embryos so as to develop innate resistance to HIV infection in their offspring. They agreed to volunteer through informed consent and the experiment was carried out in secrecy. Six other couples having similar fertility problems were subsequently recruited. The couples were recruited through a Beijing-based AIDS advocacy group called Baihualin China League. When later examined, the consent forms were noted as incomplete and inadequate. The couple were reported to have agreed to this experiment because, by Chinese rules, normally HIV positive fathers were not allowed to have children using IVF.
When the place of the clinical experiment was investigated, SUSTech declared that the university was not involved and that He had been on unpaid leave since February 2018, and his department attested that they were unaware of the research project.
Experiment and birth
He Jiankui took sperm and eggs from the couples, performed in vitro fertilisation with the eggs and sperm, and then edited the genomes of the embryos using CRISPR/Cas9. The editing targeted a gene, CCR5, that codes for a protein that HIV uses to enter cells. He was trying to reproduce the phenotype of a specific mutation in the gene, CCR5-Δ32, that few people naturally have and that possibly confers innate resistance to HIV, as seen in the case of the Berlin Patient. However, rather than introducing the known CCR5-Δ32 mutation, he introduced a frameshift mutation intended to make the CCR5 protein entirely nonfunctional. According to He, Lulu and Nana carried both functional and mutant copies of CCR5 given mosaicism inherent in the present state of the art in germ-line editing. There are forms of HIV that use a different receptor instead of CCR5; therefore, the work of He did not theoretically protect Lulu and Nana from those forms of HIV. He used a preimplantation genetic diagnosis process on the embryos that were edited, where three to five single cells were removed, and fully sequenced them to identify chimerism and off-target errors. He says that during the pregnancy, cell-free fetal DNA was fully sequenced to check for off-target errors, and an amniocentesis was offered to check for problems with the pregnancy, but the mother declined. Lulu and Nana were born in secrecy in October 2018. They were reported by He to be normal and healthy.
Revelation
He Jiankui was planning to reveal his experiments and the birth of Lulu and Nana at the Second International Summit on Human Genome Editing, which was to be organized at the University of Hong Kong during 27–29 November 2018. However, on 25 November 2018, Antonio Regalado, senior editor for biomedicine of MIT Technology Review, posted on the journal's website about the experiment based on He Jiankui's applications for conducting clinical trial that had been posted earlier on the Chinese clinical trials registry. At the time, He refused to comment on the conditions of the pregnancy. Prompted by the publicity, He immediately posted about his experiment and the successful birth of the twins on YouTube in five videos the same day. The next day, the Associated Press made the first formal news, which was most likely a pre-written account before the publicity. His experiment had received no independent confirmation, and had not been peer reviewed or published in a scientific journal. Soon after He's revelation, the Southern University of Science and Technology stated that He's research was conducted outside of their campus. China's National Health Commission also ordered provincial health officials to investigate his case soon after the experiment was revealed.
Amidst the furor, He was allowed to present his research at the Hong Kong meeting on 28 November under the title "CCR5 gene editing in mouse, monkey, and human embryos using CRISPR–Cas9". During the discussion session, He asserted, "Do you see your friends or relatives who may have a disease? They need help," and continued, "For millions of families with inherited disease or infectious disease, if we have this technology we can help them." In his speech, He also mentioned a second pregnancy under the same experiment. No reports were disclosed, but the birth was around August 2019, and it was affirmed on 30 December when the Chinese court returned a verdict mentioning that there were "three genetically-edited babies". The baby was later revealed in 2022 as Amy.
Reactions and aftermath
On the news of Lulu and Nana having been born, the People's Daily announced the experimental result as "a historical breakthrough in the application of gene editing technology for disease prevention." But scientists at the Second International Summit on Human Genome Editing immediately developed serious concerns. Robin Lovell-Badge, head of the Laboratory of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute, who moderated the session on 28 November, recalled that He Jiankui did not mention human embryos in the draft summary of the presentation. He received an urgent message on 25 November through Jennifer Doudna of the University of California, Berkeley, a pioneer of the CRISPR/Cas9 technology, to whom he had confided the news earlier that morning. As the news already broke out before the day of the presentation, he had to be brought in from his hotel by the University of Hong Kong security. Nobel laureate David Baltimore, the chair of the organizing committee of the summit, was the first to react after He's speech, and declared his horror and dismay at his work.
He Jiankui did not disclose the parents' names (other than their pseudonyms Mark and Grace) and they did not make themselves available to be interviewed, so their reaction to this experiment and the ensuing controversy is unknown. There was widespread criticism in the media and scientific community over the conduct of the clinical project and its secrecy, and concerns raised for the long term well-being of Lulu and Nana. Bioethicist Henry T. Greely of Stanford Law School declared, "I unequivocally condemn the experiment," and later, "He Jiankui's experiment was, amazingly, even worse than I first thought." Kiran Musunuru, one of the experts called on to review He's manuscript and who later wrote a book on the scandal, called it a "historic ethical fiasco, a deeply flawed experiment".
On the night of 26 November, 122 Chinese scientists issued a statement criticizing his research. They declared that the experiment was unethical, "crazy" and "a huge blow to the global reputation and development of Chinese science". The Chinese Academy of Medical Sciences made a condemnation statement on 5 January 2019 saying that:
We are opposed to any clinical operation of human embryo genome editing for reproductive purposes in violation of laws, regulations, and ethical norms in the absence of full scientific evaluation. In the rapidly developing area of genome editing technology, our scientific community should uphold the highest standards of bioethics in undertaking responsible biomedical research and applications and uphold our scientific reputation, the basic dignity of human life, and the collective integrity of our scientific community.
The Chinese Government prohibits the genetic manipulation of human gametes, zygotes, and embryos for reproductive purposes ... Jiankui He's operations violated these regulations.
A series of investigations was opened by He's university, local authorities, and the Chinese government. On 26 November 2018, SUSTech released a public notification on its website condemning He's conduct, mentioning the key points as:
- The research work was conducted off-campus by Associate Professor He Jiankui without reporting to the university and the Department of Biology, and the university and the Department of Biology were unaware of it.
- The Academic Committee of the Department of Biology considers that Associate Professor He Jiankui's use of gene editing technology for human embryo research is a serious violation of academic ethics and academic standards.
- SUSTech strictly requires scientific research to comply with national laws and regulations and to respect and abide by international academic ethics and academic norms. The university will immediately hire authoritative experts to set up an independent committee to conduct an in-depth investigation, and will publish relevant information after the investigation.
On 28 November 2018, the organising committee of the Second International Summit on Human Genome Editing, led by Baltimore, issued a statement, declaring:
At this summit we heard an unexpected and deeply disturbing claim that human embryos had been edited and implanted, resulting in a pregnancy and the birth of twins. We recommend an independent assessment to verify this claim and to ascertain whether the claimed DNA modifications have occurred. Even if the modifications are verified, the procedure was irresponsible and failed to conform with international norms. Its flaws include an inadequate medical indication, a poorly designed study protocol, a failure to meet ethical standards for protecting the welfare of research subjects, and a lack of transparency in the development, review, and conduct of the clinical procedures.
On 29 January 2019, it was learned that a U.S. Nobel laureate Craig Mello interviewed He about his experiment with gene-edited babies. In February 2019, He's claims were reported to have been confirmed by Chinese investigators, according to NPR News. Around that time, news reported that the Chinese government may have helped fund the CRISPR babies experiment, at least in part, based on newly uncovered documents.
Consequences
On 29 November 2018, Chinese authorities suspended all of He's research activities, saying his work was "extremely abominable in nature" and a violation of Chinese law. He was sequestered in a university apartment under some sort of surveillance. On 21 January 2019, He was fired from his job at SUSTech and his teaching and research work at the university was terminated. The same day, the Guangdong Province administration investigated the "gene editing baby incident", which is explicitly prohibited by the state.
On 30 December 2019, the Shenzhen City Nanshan District People's Court found He Jiankui guilty of illegal practice of medicine (equivalent to the crime of "practicing medicine without a license" in many other jurisdictions), sentencing him to three years in prison with a fine of CN¥3 million (about US$434,000). According to the district court's judgment, He Jiankui's gene editing was deemed medical practice by the court. He had never obtained a medical degree or held a medical license in any jurisdiction. The court also found that he deliberately concealed crucial information and failed to disclose any details or risks associated with the program to the parents of the gene-edited babies. He recruited other people to impersonate the parents to undergo physical examinations. He also evaded government and university regulations through forgery and other means, and committed several other illegal acts. In its judgment, the court stated that He Jiankui, in pursuit of fame and profit, crossed the bottom line of scientific research and medical ethics by rashly applying gene-editing technology to human assisted reproductive medicine, violating national regulations concerning practicing medicine and research, disrupting medical management order, and the circumstances were serious.