Report on the first genetically modified newborns
During in vitro fertilization procedure in February/March 2018, He Jiankui team – as they describe – conducted gene surgery on embryo cells. It was the first genetic modification aimed to influence a new human being. In November 2018, healthy twins Lulu and Nana were born. Another pregnancy may be underway, but the clinical trial was suspended because of public critique.
Popular genetic modification toolbox named CRISPR/Cas9 was used to disrupt CCR5 gene. By the experiment intentions, the change should mimic natural mutation occurring in 10-15% of North-European individuals, which are immune to the most of HIV strains.
This surgery removed the doorway through which HIV enters to infect people.
He Jiankui in YouTube statement
The clinical trial was approved in March 2017 and recruited couples with HIV-positive males. Sperm washing eliminated the risk of HIV transmission to offspring. Rather than protecting from parent-to-children infection, the goal was to allow upbringing of children in communities with a high incidence of HIV carriers.
They need this protection. HIV vaccine is not available. I personally (have) experience with some people in AIDS where 30% of a village people are infected. They even have to give their children to relatives and uncles to raise just to prevent potential transmission.
He Jiankui at Human Genome Editing Summit
Details of genetic modification
CCR5 gene resides on chromosome 3 and encodes a protein receptor presented on the surface of immune system cells. HIV uses that molecule to enter and infect human body. Simple deletion of 32 nucleotides in the gene (called delta 32) leads to improper functioning of the protein. Despite some disadvantages in diseases like influenza, the deletion gives virtual immunity to AIDS.
Genetic modifications of CCR5 in HIV context were previously conducted in the clinical setting (i.e., 2014, 2015, 2017, 2018) without clear results. Lack of the desired effect was attributed to remaining heterozygosity and low accuracy of sequence change.
He Jiankui team tested modification procedures on multi-generation mice models, monkey embryos and human cell lines. They established a double injection method to reach high efficiency and eliminate heterozygosity.
Exact results and raw sequence data were not posted yet, but Sean Ryder compiled a figure based on the conference presentation:
It is possible that both children have heterozygotic modifications – as humans have two copies of nearly every gene, introduced genetic changes may be different in each copy. Immunization to HIV might be reached only if all of those changes disrupt the protein.
Lulu has probably one unedited copy and one copy with a deletion of 15 nucleotides but staying within original reading frame. It means that probably she has CCR5 with normal function, and the goal of the immunity might be not reached.
Nana has a deletion of 4 nucleotides with a frameshift in the first copy and an insertion of 1 nucleotide with a frameshift in the second copy. Both changes should lead to CCR5 disruption and therefore HIV immunity.
Off-target effects of CRISPR/Cas9 were assessed to be minimal, with one detected neutral mutation. Eventual mosaicism (presence of changes in only part of the body’s cells) is not known and will be measured in the future.
We will continue with our assessments, including blood tests for HIV infection potential. We also further investigate off-target effects in mosaicisms across multiple tissues. There is a plan to monitor the children for the next 18 years, with the hope that they will consent as adults for continued monitoring and support.
He Jiankui at Human Genome Editing Summit
Disappearance from the internet
At the moment, there is available only one original source about the research: a presentation by He Jiankui (plus a transcript).
All other original sources were deleted:
– entry in a clinical trial registry (archived here),
– content of patient consent describing details of the trial (archived here),
– website of He Jiankui laboratory (archived here).
These measures reflect negative reaction of scientific community.
Future of similar experiments
The trial was put on hold. Public outcry invokes mainly low accuracy of CRISPR/Cas9 modifications in embryos. Major research organizations stated rebuttals of the experiment.
Apart from 2015 international committee suggestion that “it would be irresponsible to edit heritable genome” (more), some scientists recently have proposed a global moratorium for any similar experiments until safety and accuracy problems will be solved. The final statement from the same committee in 2018 repeated the warning about irresponsibility but did not imposed any formal withhold (more).