MORE than a billion people live in China, but researchers in the country have proposed the creation of a healthcare institute to look after just three: Amy and twins Lulu and Nana. These three children are the first genetically engineered humans in history.
Known publicly only by these pseudonyms, as embryos their genomes were edited using CRISPR technology by scientist He Jiankui in an effort to prevent them contracting HIV from their fathers. After announcing the experiment to the world in 2018, He was denounced as highly unethical. He was imprisoned in China in 2019 and was released in April this year.
The children are now toddlers, and as they grow up the scientific community faces a complex dilemma: how to care for their well-being and any fallout from He’s experiment, while also respecting their private lives.
“In my opinion, the best way to provide them with special protection is to establish a centre to perform surveillance, regular or irregular examination, and treat and care for them when they fall ill, which may be caused by genetic abnormalities,” says Qiu Renzong, a bioethicist at the Institute of Philosophy at the Chinese Academy of Social Sciences. Along with his colleagues, Qiu has presented a proposal for this facility to other scientists and several Chinese government ministries.
CRISPR is a molecular technology that can find a specific region in the genome and cut through it. He used it to delete a portion of the gene CCR5 in the three children’s genomes, an alteration known to be protective against HIV. But this technology isn’t infallible.
“CRISPR is often referred to as molecular scissors, but this implies more precision than it has”
Anomalies in the children’s genomes are very likely, says Kiran Musunuru, a cardiologist and geneticist at the University of Pennsylvania and author of The CRISPR Generation: The story of the world’s first gene-edited babies. “CRISPR is often referred to as molecular scissors, but this implies a level of precision that it does not have,” he says. “Rather than cutting a precise point in a page like scissors would do, it is more like tearing through the page.”
After a cell’s DNA has been cut by CRISPR, its molecular infrastructure puts the two ends back together. But this is often imperfect, either adding or removing some DNA letters.
“Another, more serious, issue is that the edit in the target gene could also affect the genes around it. In some cases, whole pieces of chromosomes could be deleted, which could lead to all sorts of developmental issues,” says Musunuru, such as problems with the heart.
These “off-target” edits are a known issue with CRISPR. Such uncontrolled cuts could have happened anywhere in the children’s genomes. According to Musunuru, who is one of the few researchers in the world to have had access to He’s unpublished scientific paper after being given a copy by the Associated Press, there is very strong evidence suggesting this occurred.
“From the data in He’s manuscript, it was clear that there were off-target edits. He described some of these edits found in placenta tissue and umbilical cord tissue, but he dismissed them because the ones they saw were not in genes. But this showed that these edits were happening,” says Musunuru. “And their location cannot be predicted, so this may happen in a gene related to cancer, increasing the risk of developing cancer early in life. This is the biggest clinical risk.”
Another alarming finding is that these edits were different from one cell to another, known as mosaicism, making their consequences even more unpredictable.
“CRISPR was injected when the embryo was only a single cell, but it stays in the cell for hours and even days while the embryo starts to divide within hours. So CRISPR could potentially go into all of these cells and do different edits in all of them, creating a patchwork of genetic edits,” says Musunuru. “When I saw the data from the embryos, it was immediately clear that there was mosaicism in the embryos that gave rise to Lulu and Nana: they had different edits in different cells. This mosaicism, where cells in the same tissue could behave differently because of genetic differences, can cause health problems like heart disease.”
All of this suggests there is a strong argument for closer medical monitoring for the three children than for other children. But Qiu sees another reason for life-long monitoring: the potential for deepening our understanding of the heritability of human genome editing.
Although heritable genome editing is banned in many countries, Qiu argues we need to study it anyway, in order to be prepared for any further illegal experiments. His proposed research centre would not only treat all such children, but also improve gene-editing technology to make it safer for future, legal use.
“Properly treating genome-edited persons is an ethical imperative and a prerequisite for smoothly developing heritable genome editing,” he says. He points to conditions such as thalassaemia, an inherited blood condition that causes anaemia and affects 47 million people in China. Thalassemia can be treated with regular blood transfusions, but there is currently no cure – something gene editing could change.
Bioethicist Françoise Baylis at Dalhousie University in Canada, author of Altered Inheritance: CRISPR and the ethics of human genome editing, says the twin goals of Qiu’s institute would be at odds. “There is a critical ethical difference in monitoring to promote the patient’s best interests and monitoring for knowledge production,” she says.
Baylis says any efforts focused on the best interests of the children would need to protect their privacy and confidentiality, not prioritise science. “Long-term follow-up is essential, but this should be done by a team of clinician-scientists in a healthcare facility,” she says. “It is important to ensure that the children have as normal a life experience as possible. Already they will be subject to many more medical visits than other children; they ought not to bear the additional stigma of having to report to a research centre.”
“As a physician, I would like to keep a much closer eye on them than with any other child and have them come for check-ups, imaging tests and blood tests much more frequently, to see if there is anything strange going on in their bodies,” says Musunuru. “But this care could be given in the community. A full research centre for them feels like really treating them as experimental subjects, because such a centre would imply invasive testing and taking a lot of tissue samples for examination and DNA analysis. That level of scrutiny feels a little dehumanising.”
“It is important to ensure that the children have as normal a life experience as possible”
Qiu argues that normal healthcare facilities aren’t equipped to deal with the special health risks of these children. “They could live a normal life and go to a normal hospital when they get a cold or other minor disease. However, if there is any clinical symptoms or signs related to genetic abnormalities, the general hospital will not be able to treat them nor provide appropriate genetic surveillance and examination. The onset of clinical symptoms of a gene abnormality may take time, that is why the surveillance and examination of their genome are very important.”
Musunuru takes a different view. “If the genetic issues are there, it is hard to stop them from happening; we could only act once a tumour is starting to form to give the appropriate treatment,” he says. “Scientifically, it would be of interest, but it would not help the health of these kids directly.”
Ultimately, the final decision belongs to the Chinese government. “The situation is completely unprecedented and we cannot predict what the government will do,” says Musunuru. “It is my hope that they choose a reasonable middle course where the girls are taken care of but not in a way that is too burdensome to them.”
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The next generation
The type of healthcare chosen for the first three gene-edited children could have consequences throughout their lives, including for their most intimate decisions, such as having a child. While gene editing may have generated harmful mutations in their genomes, these would probably only be present in some cells or tissues.
Such mutations may not cause any medical issues for the girls, but they could represent a risk for future generations. If one of these harmful mutations is in an egg cell, and this ends up becoming a child, the child would have this mutation in every cell of their body, which would cause medical issues.
These second-generation CRISPR children would then have a higher probability of passing harmful mutations on to their own children.
One solution would be for the children to only have children through in vitro fertilisation (IVF), to allow exhaustive screening of their eggs and embryos to be sure that a worrisome mutation can’t be inherited.
A more drastic approach would be sterilisation, preventing the three children from passing on their genes. This suggestion is likely to be considered highly unethical by most people, but the Chinese government has allegedly forced women from the Uighur ethnic minority group to be sterilised – an accusation the government denies.
Article amended on 30 June 2022
We have corrected details of bans on heritable genome editing.
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