Controversial gene-edited Chinese twins at risk of early death

Controversial gene-edited twin sisters are at a greater risk of death in later life after ‘monstrous’ experiment by disgraced Chinese scientist He Jiankui, study warns

  • Dr He tried to give ‘Lulu’ and ‘Nana’ two copies of the CCR5-Δ32 gene mutation 
  • Dr He’s justification for the experiment was to confer the embryos HIV immunity 
  • The CCR5-Δ32 mutation is common among Northern European populations 
  • Experts studied more than 400,000 DNA and other records from the UK Biobank
  • People with two mutations had a 21% higher death rate between ages 41 and 78 

The genetic mutation introduced into two babies by a Chinese scientist in 2018 may be associated with a 21 per cent higher chance of early death in later life.

Controversial scientist He Jiankui’s justification for his experiment was to confer HIV immunity to the embryos to avoid infection from the father, who is HIV positive.

Dr He reported using CRISPR-Cas9 technology to edit the human CCR5 gene in an attempt to artificially replicate a natural mutation, called ‘CCR5-Δ32’. 

However, this mutation had previously been linked to an increased susceptibility to certain diseases such as influenza.

As the CCR5 gene codes for a protein involved in many body functions, researchers say that there could be many different possible reasons for the risk of early death.

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The genetic mutation introduced into two babies by Chinese scientist He Jiankui (pictured) in 2018 may be associated with a 21 per cent higher chance of early death in later life, researchers say (file photo)

Biologists Xinzhu ‘April’ Wei and Rasmus Nielsen of the University of California, Berkeley, analysed more than 400,000 human genomes and their associated health records from the UK Biobank, a British medical database.

They found that individuals that had two copies of the CCR5-Δ32 mutation had a 21 per cent higher death rate between the ages of 41 and 78 than those with only one of no copies of the mutation.

In addition, fewer people with two of the mutations had enrolled in the UK Biobank database than was expected, suggesting that they had died at a higher rate than the general population.

‘Beyond the many ethical issues involved with the CRISPR babies, the fact is that, right now, […] it is still very dangerous to try to introduce mutations without knowing the full effect of what those mutations do,” said Professor Nielsen.

‘In this case, it is probably not a mutation that most people would want to have.’

‘You are actually, on average, worse off having it.’

‘Both the proportions before enrolment and the survivorship after enrolment tell the same story,’ Professor Nielsen added. 

‘You have lower survivability — or higher mortality — if you have two copies of the mutation,” he said.

‘There is simply a deficiency of individuals with two copies.’

Previous studies had linked possession of two copies of the CCR5-Δ32 mutation with a four-fold increase in the rate of death following influenza infection.

It is possible, therefore, that the higher mortality rate identified by the researchers is associate with ‘flu-related deaths.

However, the researchers say that there could be other possible causes, as the protein coded for by the CCR5 gene — which is non-functional in individuals with two of the mutations — is involved in many different functions within the body.

‘Here is a functional protein that we know has an effect in the organism, and it is well-conserved among many different species, so it is likely that a mutation that destroys the protein is, on average, not good for you,’ Professor Nielsen said. 

‘Otherwise, evolutionary mechanisms would have destroyed that protein a long time ago.’

This graphic reveals how, theoretically, an embryo could be ‘edited’ using the powerful tool Crispr-Cas9 to defend humans against HIV infection

The CCR5-Δ32 mutation is relatively common among Northern European populations, Nielsen noted, indicated that it must have been beneficial and therefore favoured by natural selection at some point.

It is unlikely that this benefit was protection against HIV, however, as the virus has only been circulating among humans since the 1980s. 

According to Dr Wei, there is some evidence to suggest instead that the mutant genes might increase the chance of survival after stroke and protect against smallpox and flaviviruses such as the dengue, Zika and West Nile viruses.

Pictured, an embryologist who was part of the team working with scientist He Jiankui adjusts a microplate containing embryos at a lab in Shenzhen in southern China’s Guandong province

However, the researchers caution that the potential unintended effects from artificially creating genetic mutations — such as the early death identified here — is cause for caution.

‘One gene could affect multiple traits,’ noted Dr Wei, who added that the effects of a given mutation can also differ depending on the environment.

‘I think there are a lot of things that are unknown at the current stage about genes’ functions,’ Dr Wei said. 

‘The CRISPR technology is far too dangerous to use right now for germline editing.’ 

The full findings of the study were published in the journal Nature Medicine.

Dr He used gene-editing technology CRISPR-Cas9 to alter the embryonic genes of the twin girls, nicknamed ‘Lulu’ and ‘Nana’.

The disgraced researcher’s justification for the experiment was to confer HIV immunity to the embryos to avoid infection from the father, who is HIV positive.

Dr He said he chose to try embryo gene editing for HIV because these infections are a big problem in China. 

The fathers had their infections deeply suppressed by standard HIV medicines and there are simple ways to keep them from infecting offspring that do not involve altering genes.

Instead, the appeal was to offer couples affected by HIV a chance to have a child that might be protected from a similar fate.

Dr He has since been fired from his university post and is under investigation by Chinese authorities.

Dr He was trained as a physicist, not a biologist, and was therefore unqualified and likely unable to carry out the research himself.

It is believed he used his own £40 million fortune to fund the project and privately recruited highly-trained scientific professionals to carry out the research. 

Little is known about the research which staggered scientists for its brazen flaunting of every rule and guideline on ethics and legality in genetics. 

The whereabouts of the Chinese researcher have been a mystery since November. Reports claimed He was placed under effective house arrest in Shenzhen after making an appearance at the Second International Summit on Human Genome Editing in Hong Kong in late November.

He and his family are living in university housing on the grounds of Southern University of Science and Technology in Shenzhen, with guards stationed outside his apartment, according to a recent Bloomberg report citing Dr William Hurlbut, an adjunct professor at Stanford Medical School who has been in touch with the Chinese scientist.

‘He told me that in both his living situation and in the process of the investigation, he’s being treated respectfully,’ Dr Hurlbut, a neurobiologist whom Dr He had consulted over the past two years on his genetics research, told reporters. 

The two children, LuLu and Nana, were born in October, it is believed, and the  potentially dangerous changes made to their genome may then be passed down to future generations, a field of research still in its infancy and widely unknown.

He’s controversial work, which earned him the nickname of ‘Chinese Frankenstein’, was condemned by the medical community and Chinese health officials, who said they know nothing of the experiment.

Gene editing is banned in Britain, the US many other parts of the world, and researchers said that, if Dr He’s claims are true, the ‘monstrous’ experiment was ‘not morally or ethically defensible’.

There is no independent confirmation of Dr He’s claim, and it has not been published in a journal, where it would be vetted by other experts.

It’s ‘unconscionable … an experiment on human beings that is not morally or ethically defensible,’ said Dr Kiran Musunuru, a University of Pennsylvania gene editing expert and editor of a genetics journal.

‘This is far too premature,’ said Dr Eric Topol, who heads the Scripps Research Translational Institute in California. ‘We’re dealing with the operating instructions of a human being. It’s a big deal.’

‘If true, this experiment is monstrous,’ said Professor Julian Savulescu, Director of the University of Oxford’s Uehiro Centre for Practical Ethics.

‘These healthy babies are being used as genetic guinea pigs. This is genetic Russian Roulette.’

WHAT IS CRISPR-CAS9?

CRISPR-Cas9 is a tool for making precise edits in DNA, discovered in bacteria.

The acronym stands for ‘Clustered Regularly Inter-Spaced Palindromic Repeats’.

The technique involves a DNA cutting enzyme and a small tag which tells the enzyme where to cut.

The CRISPR/Cas9 technique uses tags which identify the location of the mutation, and an enzyme, which acts as tiny scissors, to cut DNA in a precise place, allowing small portions of a gene to be removed

By editing this tag, scientists are able to target the enzyme to specific regions of DNA and make precise cuts, wherever they like.

It has been used to ‘silence’ genes – effectively switching them off.

When cellular machinery repairs the DNA break, it removes a small snip of DNA.

In this way, researchers can precisely turn off specific genes in the genome.

The approach has been used previously to edit the HBB gene responsible for a condition called β-thalassaemia. 

 

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