Gene edited babies may not reach a venerable old age

Published 18 June 2019

The twin girls whose controversial birth in China followed a gene modification experiment to remove susceptibility to HIV infection may have had their life expectancy reduced. Sofia Makieva reports for Focus on Reproduction.

The world's first CRISPR babies, whose birth reported late last year brought a furore of outrage, may not live to a venerable old age. New evidence suggests that the 9-month old Chinese twins edited to acquire a mutation on the CCR5 gene giving resistance to HIV may not make it past their 76th birthday. Rasmus Nielsen and Xinzhu Wei of University of California Berkeley analysed data from the UK Biobank and found that individuals with a mutation on the CCR5 gene had a 20% higher chance of death from any cause before the age of 76. The work, published in Nature Medicine, is an attempt to put into perspective the action of the Chinese scientist Jiankui He, who created in complete secrecy the first genetically modified humans and faced widespread condemnation.(1,2)

He announced last November that two girls had been born as a result of an experiment, which, notably, remains unpublished. Using CRISPR-cas9, a tool recommended in position statements as only for research-related applications in humans, He mutated the CCR5 gene to strip the embryos of a presumed susceptibility to HIV infection, an assumption based on the HIV positive status of their father.

Genetic resistance to HIV
In the mid-1990s it emerged that Caucasians with a specific mutation on the CCR5 gene (called Δ32) were resistant to infection from HIV. However, other studies since then have shown that the presence of Δ32 makes individuals susceptible to influenza, while its reported facilitation of post-stroke recovery only applies to males. Studies are currently under way to establish the impact of the Δ32 and other mutations on the CCR5 gene in various systems to predict the twins’ future.

One such is this latest study of Wei and Nielsen exploring the impact of the Δ32 mutation on lifespan.

Because of the high prevalence of that mutation among Britons, the authors selected the UK Biobank for their analysis. This Biobank contains genetic data from more than 400,000 UK volunteers with death age information on 13,831 individuals aged between 41 and 78. The all-cause mortality rate was initially evaluated by age and was found to be 3-46% higher in people with two Δ32 copies (homozygous) as opposed to one copy (heterozygous) or no mutated copy (wild type). Following data correction, the homozygous people were 20% more likely to die before the age of 76 than the heterozygous or wild types. It is critical to note that an effect was specific to homozygosity; heterozygous people had similar longevity to wild type.

Mixed reaction
The authors acknowledged that their study was limited by the absence of volunteers under 40 years old, as this likely influenced the incidence of mortality and, consequently, the observed effect. The paper received mixed reactions from scientists, many of whom over-debated on social media the statistical strategies used. Headlines in the press featuring ‘early death’ and ‘shortened lifespan’ served to feed the fire. Nielsen himself rushed to respond on ‘the many news stories arguing that the CRISPR babies will likely die young’, describing them as ‘not valid or responsible’. Importantly, Nielsen also pointed out that the Chinese twins were edited to acquire a different mutation on the CCR5 gene, which only theoretically mimics the effect of Δ32.

Commenting on the findings Robin Lovell-Badge from the Francis Crick Institute in London described He as 'foolish' to choose CCR5 for his attempts at germline genome editing. 'We simply do not yet know enough about the gene.' said Lovell-Badge in a press statement. 'Nevertheless, it is impossible to predict if the mutations carried by the twin girls will have any effect. The reduction in lifespan noticed by Wei and Nielsen did not affect all homozygotes – genetic background and environmental influences are likely to play a part. And their study was in the UK, not China where both such influences will be very different.'

Against this controversial background, another scientist has recently revealed a plan to implant Russian CRISPR-edited embryos with a mutated CCR5 gene before the end of the year. Such efforts wilfully ignore the much repeated cautious recommendations of the scientific community.

1. Wei X, Nielsen R. CCR5-∆32 is deleterious in the homozygous state in humans. Nat Med 2019; 25: 909-910.

2. See www.nature.com/articles/d41586-018-07545-0