He Jiankui affair
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The He Jiankui affair is a scientific and bioethical circumstance concerning the use of gene-editing in human cases following the first use by Chinese scientist He Jiankui, who made the first genome-edited human babies in 2018. The affair led to legal and ethical controversies with an indictment of He and his two collaborators, Zhang Renli and Qin Jinzhou.
He Jiankui, working at the Southern University of Science and Technology (SUSTech) in Shenzhen, China, started a project to help people with 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. Specifically, the embryos were edited of their 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 exposed the story about 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 videos on YouTube the same day. The first babies, known by their pseudonyms Lulu (Chinese: 露露) and Nana (Chinese: 娜娜), are twin girls born in October 2018, and the second birth or the third baby born was in 2019. He reported that the babies were born healthy.
The reaction to He's actions was widespread criticism and included concern for the well-being of the girls. He presented his research at the Second International Summit on Human Genome Editing at the University of Hong Kong on 28 November 2018. The next day, Chinese authorities suspended all his research activities. He was immediately detained in SUSTech campus and kept under surveillance. On 30 December 2019, Chinese authorities announced that he was found guilty of forging documents and unethical conduct; he was sentenced to three years in prison with a fine of 3 million yuan (US$430,000).
As a consequence to He's work, the World Health Organization launched a global registry in 2019 to track research on human genome editing, after a call to halt all work on genome editing. In May 2019, lawyers in China reported, in light of He's experiment, the drafting of regulations that anyone manipulating the human genome by gene-editing techniques, like CRISPR, would be held responsible for any related adverse consequences.
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 Jiankui at the Southern University of Science and Technology (SUSTech) in Shenzhen. They were offered in vitro fertilisation 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.
When the place of the clinical experiment was investigated, the Southern University of Science and Technology 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, the researcher, 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 — 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 gene 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.
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 university at which He was previously employed, 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 furore, 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 about a second pregnancy under the same experiment. No reports disclosed, the baby might have been born around August 2019, and the birth was affirmed on 30 December when the Chinese court returned a verdict mentioning that there were "three genetically-edited babies".
Reactions and aftermath
On the news of Lulu and Nana being 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 by the University of Hong Kong security from his hotel. 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 He's work.
He 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 not known. 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."
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 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 Jiankui was sequestered in a university apartment under some sort of surveillance, and may face serious consequences. In February 2019, news was reported that suggested the Chinese government may have helped fund the CRISPR babies experiment, at least in part, based on newly uncovered documents.
Michael W. Deem, an American bioengineering professor at Rice University and He's doctoral advisor, was involved in the research, and was present when people involved in He's study gave consent. He was the only non-Chinese out of 10 authors listed in the manuscript submitted to Nature. Deem came under investigation by Rice University after news of the work was made public. As of 31 December 2019, the university had not released a decision.
Stanford University also investigated its faculty of He's confidants including William Hurlbut, Matthew Porteus, and Stephen Quake, He's main mentor in gene editing. The university's review committee concluded that the accused "were not participants in [He Jiankui’s] research regarding genome editing of human embryos for intended implantation and birth and that they had no research, financial or organizational ties to this research."
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. Later in February 2019, news was reported that suggested the Chinese government may have helped fund the CRISPR babies experiment, at least in part, based on newly uncovered documents.
On 30 December 2019, the Shenzhen Nanshan District People's Court sentenced He Jiankui to three years in prison and with a fine of 3 million RMB (US$430,000). Among the collaborators, only two were indicted – Zhang Renli of the Guangdong Academy of Medical Sciences and Guangdong General Hospital, received a two-year prison sentence and a 1-million RMB fine, and Qin Jinzhou of the Southern University of Science and Technology received an 18-month prison sentence and a 500,000 RMB fine. The three were found guilty of having "forged ethical review documents and misled doctors into unknowingly implanting gene-edited embryos into two women."
On 7 March 2017, He Jiankui applied for ethics approval from Shenzhen HarMoniCare Women and Children's Hospital. In the application, He claimed that the genetically edited babies would be immune to HIV infection, in addition to smallpox and cholera, commenting: "This is going to be a great science and medicine achievement ever since the IVF technology which was awarded the Nobel Prize in 2010, and will also bring hope to numerous genetic disease patients." It was approved and signed by Lin Zhitong, the hospital administrator and one time Director of Direct Genomics, a company established by He. Upon an inquiry, the hospital denied such approval. The hospital's spokesperson declared that there were no records of such ethical approval, saying, "[The] gene editing process did not take place at our hospital. The babies were not born here either." It was later confirmed that the approval certificate was forged.
Sheldon Krimsky of Tufts University reported that "[He Jiankui] is not a medical doctor, but rather received his doctorate in biophysics and did postdoctoral studies in gene sequencing; he lacks training in bioethics." However, He was aware of the ethical issues. On 5 November 2018, He and his collaborators submitted a manuscript on ethical guidelines for reproductive genome editing titled "Draft Ethical Principles for Therapeutic Assisted Reproductive Technologies" to The CRISPR Journal. It was published on 26 November, soon after news of the human experiment broke out. The journal made inquiry concerning conflicts of interests, which was not disclosed by He. With no justification from He, the journal retracted the paper with a comment that it "was most likely in violation of accepted bioethical international norms and local regulations."
He Jiankui also attended an important meeting on "the ethics and societal aspects of gene editing" in January 2017 organized by Jennifer Doudna and William Hurlbut of Stanford University. Upon invitation from Doudna, He presented a topic on "Safety of Human Gene Embryo Editing" and later recalled that "There were very many thorny questions, triggering heated debates, and the smell of gunpowder was in the air."
The consent form of the experiment titled "Informed Consent" also indicates dubious statements. The aim of the study was presented as "an AIDS vaccine development project", even though the study was not about vaccines. Present was technical jargon which would be incomprehensible to a layperson. One of the more peculiar statement is that if the participants decide to abort the experiment "in the first cycle of IVF until 28 days post-birth of the baby", they would have to "pay back all the costs that the project team has paid for you. If the payment is not received within 10 calendar days from the issuance of the notification of violation by the project team, another 100,000 RMB [over £11,000] of fine will be charged." This violates the voluntary nature of the participation.
Scientific works are normally published in peer-reviewed journals, but He failed to do so regarding the birth of gene-edited babies. This was one of the grounds on which He was criticized. It was later reported that He did submit two manuscripts to Nature and the Journal of American Medical Association, which were both rejected, mainly on ethical issues. He's first manuscript titled "Birth of Twins After Genome Editing for HIV Resistance" was submitted to Nature on 19 November. He shared copies of the manuscript to the Associated Press, which he further allowed to document his works. In an interview, Hurlbut opined that the condemnation of He's work would have been less harsh if the study had been published, and said, "If it had been published, the publishing process itself would have brought a level of credibility because of the normal scrutiny involved; the data analysis would have been vetted."
It is an established fact that C-C chemokine receptor type 5 (CCR5) is protein essential for HIV infection of the white blood cells by acting as co-receptor to HIV. Mutation in the gene CCR5 (called CCR5Δ32 because the mutation is specifically a deletion of 32 base pairs in human chromosome 3) renders resistance to HIV. Resistance is higher when mutations are in two copies (homozygous alleles) and in only one copy (heterozygous alleles) the protection is very weak and slow. And not all homozygote individuals are completely resistant. In natural population, CCR5Δ32 homozygotes are rarer than heterozygotes. In 2007, Timothy Ray Brown (dubbed the Berlin patient) became the first person to be completely cured of HIV infection following a stem cell transplant from a CCR5Δ32 homozygous donor.
He Jiankui overlooked these facts. Two days after Lulu and Nana were born, their DNA were collected from blood samples of their umbilical cord and placenta. Whole genome sequencing confirmed the mutations. However, available sources indicate that Lulu and Nana are carrying incomplete CCR5 mutations. Lulu carries a heterozygous mutant CCR5 that has a 15 bp in-frame deletion; while Nana carries a homozygous mutant gene with a 4 bp deletion and a single base insertion. Because the babies' mutations are different from the typical CCR5Δ32 mutation it is not clear whether or not they are prone to infection. There are also concerns about adverse effect called off-target mutation in CRISPR/Cas9 editing and mosaicism, a condition in which many different cells develop in the same embryo. Off-target mutation may cause health hazards, while mosaicism may create HIV susceptible cells. Fyodor Urnov, Director at the Altius Institute for Biomedical Sciences at Washington, asserted that "This [off-target mutation] is a key problem for the entirety of the embryo-editing field, one that the authors sweep under the rug here," and continued, "They [He's team] should have worked and worked and worked until they reduced mosaicism to as close to zero as possible. This failed completely. They forged ahead anyway." But George Church of Harvard University, in an interview with Science, explained that off-target mutations may not be dangerous, and that there is no need to reduce mosaicism excessively, saying, "There's no evidence of off-target causing problems in animals or cells. We have pigs that have dozens of CRISPR mutations and a mouse strain that has 40 CRISPR sites going off constantly and there are off-target effects in these animals, but we have no evidence of negative consequences." As to mosaicism, he said, "It may never be zero. We don’t wait for radiation to be zero before we do positron emission tomography scans or x-rays."
In February 2019, scientists reported that Lulu and Nana may have inadvertently (or perhaps, intentionally) had their brains altered, since CCR5 is linked to improved memory function in mice, as well as enhanced recovery from strokes in humans. Although He Jiankui stated during the Second International Summit on Human Genome Editing, that he was against using genome editing for enhancement, he also acknowledged, that he was aware of the studies linking CCR5 to enhanced memory function.
In June 2019, researchers suggest that the purportedly genetically edited humans may have been mutated in a way that shortens life expectancy. Rasmus Nielsen and Wei Xinzhu, both at the University of California, Berkeley, reported in Nature Medicine of their analysis of the longevity of 409,693 individuals from British death registry (UK BioBank) with the conclusion that two copies of CCR5Δ32 mutations (homozygotes) were about 20% more likely than the rest of the population to die before they were 76 years of age. The research finding was widely publicized in the popular and scientific media. However, the article overlooked sampling bias in UK Biobank's data, resulting in an erroneous interpretation, and was retracted four months later.
The first successful gene-editing experiment of CCR5 in humans was in 2014. Researchers at the University of Pennsylvania, Philadelphia, Albert Einstein College of Medicine, New York, and Sangamo BioSciences, California, reported that they modified CCR5 on the blood cells (CD4 T cells) using zinc-finger nuclease which they introduced (infused) into HIV patients. After complete treatment, the patients showed decreased viral load, and in one, HIV disappeared.
In January 2019, scientists in China reported the creation of five identical cloned gene-edited monkeys, using the same cloning technique that was used with Zhong Zhong and Hua Hua – the first ever cloned monkeys – and Dolly the sheep, and the same gene-editing Crispr-Cas9 technique allegedly used by He Jiankui in creating the first ever gene-modified human babies Lulu and Nana. The monkey clones were made in order to study several medical diseases.
The first clinical trial of CRISPR-Cas9 for the treatment of genetic blood disorders was started in August 2018. The study was jointly conducted by CRISPR Therapeutics, a Swiss-based company, and Vertex Pharmaceuticals, headquartered in Boston. Preliminary report announced on 19 November 2019 states that the first two patients, one with β-thalassemia and the other with sickle cell disease, were treated successfully.
In June 2019, Denis Rebrikov at the Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology in Moscow announced through Nature that he was planning to repeat He's experiment once he got official approval from the Russian Ministry of Health and other authorities. Rebrikov asserted that he would use safer and better method than that of He, saying, "I think I'm crazy enough to do it." In a subsequent report on 17 October, Rebrikov said that he was approached by a deaf couple for help. He already started in vitro experiment to repair a gene that causes deafness, GJB2, using CRISPR.
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