Meet Lulu and Nana, the world’s first CRISPR genome-edited babies…

It has been nearly 2 years since He Jiankui, a Chinese researcher and ex-professor at the Southern University of Science and Technology in Shenzhen, China, created the first germline edited babies. He sparked an international outcry and was sentenced to prison for 3 years for violating government bans on the clinical procedures of gene-editing on human embryos for reproductive purposes [1]. He claimed to give the twins, known by their pseudonyms Lulu and Nana, resistance to HIV by disabling a gene, CCR5, involved in helping HIV enter healthy cells [2, 3]. However, the hard facts remain somewhat unclear as he was never transparent about his work, and his manuscript remains unpublished.

 

It has also come to light that a third child was born. A court in Shenzhen found He and two collaborators had forged ethical review documents and misled doctors into unknowingly implanting gene-edited embryos into two women. One gave birth to twins in November 2018, and it is not clear when the third child was born, in fact, there is almost no information readily available about this third child at all [4]. In addition to his prison sentence, He was fined 3 million yuan (£350,000), and the Chinese government tightened restrictions on their human genome editing policies. Experts from around the world agreed that there are safer and more effective ways to prevent HIV infections. The experiment was deemed irresponsible, premature, and unjustified as it exposed the babies to risks associated with genome editing for no benefit [4].

 

Kiran Musunuru had the opportunity to read through He’s manuscript last year and says he identified many problems with the work [5]. The most prevalent was widespread mosaicism in both twins. This means the edits to the gene were not displayed uniformly in cells, the changes made showed up differently in different cells, and so some parts of their bodies may contain the edits He made, some may contain other edits, and others no edits at all. He also only managed to edit half of Lulu’s CCR5 genes, and the rest are apparently completely normal, meaning she is either heterozygous (every cell in her body has one normal copy of CCR5 and one edited copy) or mosaic (half her cells have two edited copies and the other half have two normal copies) for the edited CCR5 gene now [3]. It is apparent that both twins could be fully vulnerable to HIV [5].

 

Even worse, there is no way to tell whether this is the case or not, meaning there is no ‘up side’ to He’s work. “Although the twins’ father had HIV, they were at virtually no risk of contracting HIV. If they remain HIV-negative, there is no way to show it had anything to do with the editing that was done” said Alta Charo, a bioethicist from the University of Wisconsin [3, 4]. He deactivated a perfectly normal gene attempting to reduce the risk of a disease neither child had, and one that could be controlled with anti-viral drugs and safe sex nonetheless [3]. Even if the attempt had been successful, the deactivation of CCR5 does not bestow complete immunity to HIV, as some strains can enter healthy cells through a different protein altogether [3]. When assessing the embryos for edits, a few cells were taken, and their DNA was analysed. The remaining 200-300 cells, which went on to multiply and make up Lulu and Nana, were not assessed and so it is possible off-target edits may be present in them. If so, there are risks these edits could cause problems such as cancer and heart disease, and they may even be passed onto the twins’ future children [5].

 

Another large fault in He’s work was the edited cells were not edited in the intended way. A small section of CCR5 was supposed to be deleted to mimic a naturally occurring mutation called delta 32. According to Sean Ryder, a Biochemist from the University of Massachusetts Medical School, He’s slides show no sign of delta 32 in either girl. In fact, Lulu has an entirely different CCR5 mutation, and Nana has two! Although He’s edits were roughly in the same area as where the delta 32 mutation would have been, it is an outrageous assumption that just changing the same region would lead to the same outcome. Entirely new mutations were made, in the same way that scientists test new mutations on mice and rats for the first time, and there is no way to tell what the consequences will be at this point [3].

 

This happened two years ago, why are we highlighting it now? He’s work revealed some serious unresolved safety concerns and needs to be published so the full details can be discussed, and measures can be taken to help prevent this kind of work from taking place again in secret. International committees brought together by the World Health Organisation have been trying to put together better regulatory frameworks regarding germline editing [5]. How can they do that without the disclosure of the full details of this experiment? This is the only real-world example of human germline editing gone wrong, we need to make an example of it and ensure everyone understands what really happened.

 

Worryingly, there are those who want to ‘push the boundaries’ and carry out similar work to He Jiankui, so there is a real risk of this happening again. Denis Rebrikov has claimed he can edit the human germline safety in Russia. How can the Russian authorities fully evaluate the risks and use this example for guidance if He’s work isn’t publicised and full details disclosed? A group of scientists resurrected a virus called horsepox a couple of years ago. They were criticised by others on the basis that the work would make it easier for others to recreate the related and significantly more dangerous virus, smallpox [3]. This further elucidates that small groups of researchers can make independent decisions about experiments that could have global consequences, and everyone else only realises afterwards. The details of He Jiankui’s experiment need to be fully disclosed, it’s been two years and it’s time his work was made an example of to the scientific community.

 

Mia Georgiou

 

References:

 

[1] BBC News. 2020. China Jails ‘Gene-Edited Babies’ Scientist. [online] Available at: <https://www.bbc.co.uk/news/world-asia-china-50944461> [Accessed 22 September 2020].

 

[2] Time. 2020. How China’s Gene-Edited Twins’ Lives Could Be Forever Changed By Controversial CRISPR Work. [online] Available at: <https://time.com/5466967/crispr-twins-lives/> [Accessed 22 September 2020].

 

[3] Yong, E., 2020. The CRISPR Baby Scandal Gets Worse By The Day. [online] The Atlantic. Available at: <https://www.theatlantic.com/science/archive/2018/12/15-worrying-things-about-crispr-babies-scandal/577234/> [Accessed 22 September 2020].

 

[4] Science | AAAS. 2020. Chinese Scientist Who Produced Genetically Altered Babies Sentenced To 3 Years In Jail. [online] Available at: <https://www.sciencemag.org/news/2019/12/chinese-scientist-who-produced-genetically-altered-babies-sentenced-3-years-jail> [Accessed 22 September 2020].

 

[5] MIT Technology Review. 2020. Opinion: We Need To Know What Happened To CRISPR Twins Lulu And Nana. [online] Available at: <https://www.technologyreview.com/2019/12/03/65024/crispr-baby-twins-lulu-and-nana-what-happened/> [Accessed 22 September 2020].

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