Biopsy of a preimplantation human embryo. Picture: Microsoft Office 360 photos.
In the field of gene editing, a rumour had been circulating for at least six months about two manuscripts prepared by two leading laboratories that had applied, with surprising success, base editors (the second-generation CRISPR gene-editing tools) to edit the genome of human embryos effectively, with double-digit efficiencies and virtually no unwanted side effects. This would bring back to the forefront the increasingly technologically imminent possibility of genetically editing human embryos.
However, six months after that rumour surfaced, we still knew nothing about the two manuscripts. Until last week, on June 5th, when, unexpectedly, the journal Nature decided to comment on one of these two scientific articles (comment corrected on June 8th), which had finally been deposited on the bioRxiv preprint server, from the laboratory of Dieter Egli (Columbia University, New York, USA). This comment in Nature comes after an article published on the same topic by science writer Carl Zimmer in The New York Times on June 4th. We still know nothing about the other article, although the rumour anticipates results similar to those obtained by Egli.
The first thing to remember is that the bioRxiv preprint server hosts manuscripts that haven’t yet been peer-reviewed. However, they can be openly commented on by the scientific community, as Nature does. This is especially true considering that Nature is one of the journals where this work might ultimately be published. This plot twist is certainly unprecedented.
The laboratory of researcher Dieter Egli was one of the first to raise concerns about the use of first-generation CRISPR-Cas9 tools in human embryos, due to the large number of unintended modifications occurring in other parts of the genome and the significant number of chromosomal abnormalities detected. That work, published in the journal Cell in 2020, came two years after the ill-fated experiment by He Jiankui, who was responsible for the genetic editing of three Chinese girls, the first humans born with their genomes edited, not only in the selected gene (albeit in a way different from the planned changes) but also in other parts of the genome, with unforeseen consequences. That study (and others like it published around the same time) reminded us that first-generation CRISPR tools were not yet ready to be applied safely and effectively to human embryos. That it was not prudent to use them on human embryos.
However, six years later, the landscape appears to have changed. Egli’s new manuscript applies base editors (specifically those called ABEs, capable of changing an A to a G at specific positions within a gene) to redundant human embryos, derived from in vitro fertilization procedures in assisted reproduction clinics, targeting two genes with biomedical significance: PCSK9 and HBG1/HBG2. The former allows for a reduction in circulating cholesterol levels by inactivating it. The latter two are the genes for gamma-globins, components of foetal hemoglobin, and whose regulatory regions are edited so that a repressor cannot inactivate them after birth and they continue to be expressed in adults, as a treatment for two very serious blood diseases such as sickle-cell anaemia and beta-thalassemia.
The results obtained are very good, with efficient editing but without the presence of chromosomal abnormalities or large deletions detected with first-generation CRISPR tools. Researchers continue to detect some insertions or deletions, albeit very limited, and modifications in other parts of the genome still depend on the guide RNA used. The efficiencies they achieve are remarkable when analysing a biopsy of blastocysts (a few cells, called blastomeres) from embryos microinjected with these base editors. 76% of the blastomeres analyzed had the planned homozygous modification (in both copies of the gene) in the PCSK9 gene, while the planned mutations appeared in 52% with the HBG1 gene and in 68% with the HBG2 gene—double-digit success rates never before seen in mammalian embryos, let alone in humans!
This is a study with surprising results that, nevertheless, harbours a latent danger. The problem with this certainly interesting research is the possibility that someone might decide to apply this technique to human embryos obtained through in vitro fertilization to correct certain mutations inherited from their parents, then implant the edited embryo and await the birth of a child without the pathology. However, we are still far from that hypothetical scenario. This is partly because, in the best-case scenario, these children would be mosaics, with an unpredictable percentage of their cells seemingly well-corrected, with few unwanted changes, but they would still carry the mutation in a variable fraction of their cells. And we mustn’t forget that this final stage (implantation, gestation, and birth) remains prohibited in most countries, particularly in those that, like Spain, signed the 1997 Oviedo Convention, which prohibits the genetic modification of our offspring.
Naturally, criticism has been swift. The most forceful has come from researcher and pioneer in gene editing Fyodor Urnov (University of California, Berkeley), who ironically stated that Egli’s manuscript illustrates “a solution in search of a problem.” He pointed out that, indeed, before attempting to genetically edit an embryo, there are much simpler and more advisable techniques, such as embryo selection after preimplantation genetic diagnosis. This involves a biopsy (one or a few cells from a blastocyst) of each embryo to identify the one that does not carry the mutation for implantation. This is a far more effective solution than attempting to genetically edit this embryo, which, despite achieving double-digit success rates, will still produce mosaic embryos (and, if implanted, children).
Urnov hits the nail on the head by warning on social media that this manuscript will surely spark interest among individuals and private assisted reproduction clinics interested not only in curing embryos but also in enhancing them, endowing them with supposedly desirable, beneficial characteristics that provide physical or psychological improvements to the children derived from them. A euphemism for eugenics. And this is truly worrying, if these groups assume that sufficiently robust success rates have already been achieved in human embryos to attempt their “genetic enhancement.”
And we’re probably not far from what could happen, given that Dieter Egli himself collaborates with Nucleus, a company partnering with assisted reproduction clinics and offering genetic selection of human embryos to choose those supposedly lacking the risk of developing diseases or “longer-lived,” based on a set of genetic polymorphisms (SNPs) that the company believes can predict whether the person born from that embryo will live a long life or develop diseases. The genomic data from the base edited human embryos reported in the preprint were analysed by another company: Genomic Prediction.
In some ways, this scientific advance reminds us of the film GATTACA, directed by Andrew Niccol in 1997, which ceases to be science fiction and veers dangerously close to reality. In this regard, it might also be prudent to remind the International Call for a 10-Year Moratorium on Heritable Human Genome Editing, issued jointly by the ISCT, ARM and ASGCT. This initiative calls for a global 10-year moratorium on heritable germline editing, extendable until at least 2035, to give the international community sufficient time to reflect on the necessary scientific, ethical and regulatory safeguards.
Lluis Montoliu, ARRIGE Vicepresident
endorsed by the ARRIGE Board
