Gene mutation in genome-edited babies linked to shorter life

The gene mutation that Dr He Jiankui aimed to emulate in the world's first genome-edited babies has been linked to increased risk of death in later life.

The birth of twin girls, genome-edited to be 'HIV-resistant' was announced by Dr He to a global outcry in November 2018. Dr He, then at the Southern University of Science and Technology in Shenzhen, and colleagues used CRISPR/Cas9 to delete a gene called CCR5 in the original embryos (see BioNews 977).

Dr He said his rationale for doing this was that a natural mutation in this gene has been shown to confer resistance to the HIV virus.

In response to the controversial experiment, Professor Rasmus Nielsen and Dr Xinzhu (April) Wei at the University of California, Berkeley, examined the genomes and related health records of over 400,000 people from the UK BioBank.

They found that people with two copies of the mutated CCR5 gene (known as CCR5-Delta32) had higher death rates between the ages of 41 to 78 compared with those with one copy or no copies of the mutant gene. They showed a 21 percent increase in mortality in later life.

'Beyond the many ethical issues involved with the CRISPR babies, the fact is that, right now, with current knowledge, it is still very dangerous to try to introduce mutations without knowing the full effect of what those mutations do,' said senior study author 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.'

Study first author Dr Wei added: 'I think there are a lot of things that are unknown at the current stage about genes' functions. The CRISPR technology is far too dangerous to use right now for germline editing.'

One of the twin babies born from the genome-edited embryos has both copies of CCR5 deleted, while the other reportedly has one copy only deleted.

Professor Robin Lovell-Badge at the Francis Crick Institute in London, said it was 'impossible to predict if the mutations carried by the twin girls will have any effect'.

He added: 'All this shows once more that He Jiankui was foolish to choose CCR5 to mutate in his attempts at germline genome editing. We simply do not yet know enough about the gene.'

About 11 percent of northern Europeans carry the CCR5 gene mutation which confers resistance against HIV. The mutation has been linked to better recovery from stroke (see BioNews 988).

Professor Lovell-Badge suggested that 'it is likely that mutations in the gene also have bad effects'. But because the new study only looks at overall mortality – rather than causes – it does not yield any clues as to why people with two mutated CCR5 genes appear to have shorter lives.

'Human beings have CCR5 genes for a reason, even if we do not yet know the fully details about its functionality,' said Professor David Curtis, honorary professor at University College London's Genetics Institute.

'This sends us a warning that we should be extremely cautious around the introduction of therapies involving modifying the genetic code, since we can expect that there will be unexpected consequences.'

The study was published in Nature Medicine.