"Four cell embryo" by Nina Sesina / CC BY-SA 4.0

First CRISPR babies: 6 questions that remain

Nov 30, 2018

By David Cyranoski

The meeting where He Jiankui explained his extraordinary claim to have helped produce the first babies — twin girls — born with edited genomes came to a close with a statement that came down hard on the scientist.

“We heard an unexpected and deeply disturbing claim that human embryos had been edited and implanted, resulting in a pregnancy and the birth of twins,” reads the statement released by the organizing committee of the Second International Summit on Human Genome Editing in Hong Kong on 29 November. “Even if the modifications are verified, the procedure was irresponsible and failed to conform with international norms.”

Similar criticism rained down since the revelation earlier this week that He had used the CRISPR–Cas9 to modify the CCR5 gene in two embryos, which he then implanted in a woman. The gene encodes a protein that many strains of HIV use to infect immune cells, in two embryos, which he then implanted in a woman.

As researchers take stock of the week’s events, Nature summarizes six big questions that are still unanswered.

Continue reading by clicking the name of the source below.

One comment on “First CRISPR babies: 6 questions that remain”

  • Ok, so this is actually some very cool stuff but of course the ethics side of it is an abomination. Setting that aside, here’s what they were going for as explained in the Nature article linked above:

     

    Similar criticism has rained down since the revelation earlier this weekthat He had used the CRISPR–Cas9 genome-editing technique to modify theCCR5gene in two embryos, which he then implanted in a woman. The gene encodes a protein that some common strains of HIV use to infect immune cells.

    The HIV virus MUST attach to a receptor located on the outside of cells named CCR5. The virus and the receptor fit together like a chemical lock and key. Sometimes it’s referred to as “docking”. After that, the virus breaks into the cell and replicates.  Production of CCR5 and other receptors is genetically driven and there are variations in our population as to production of these receptors. Again, from the Nature article:

    He Jiankui told the gene-editing conference that he targeted the CCR5gene because some people naturally carry a mutation in CCR5 — a 32-DNA-letter deletion known as delta-32 — that inactivates the gene. But Ryder says that that the CCR5 deletions that He claimed to introduce into the babies’ cells by CRISPR gene editing are not identical to the delta-32 mutation. “The point is that none of the three match the well-studied delta 32 mutation, and as far as I can tell, none have been studied in animal models. Unconscionable,” Ryder wrote in the post.

    From an article on NIH website:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185609/

    Reduced or abolished expression of the CCR5 receptor has been found in Caucasians and in other ethnic groups worldwide; the delta-32 mutation – the first to be described – causes a deletion in the receptor sequence that prevents exposure of the truncated receptor on the cell surface [4]. Consequently, homozygous delta-32 individuals are substantially ─ but not completely ─ resistant to HIV infection, but do not show any pathologic phenotype [32,33,34].

     

    Heterozygous CCR5-delta-32 alleles have been found to be more prevalent in long-term non-progressing population than in progressing cohorts, therefore confirming that CCR5 load and functions may play a more complex role than that of coreceptor in the pathogenesis of HIV infection [39,40]. Some hypotheses have been drawn to explain the evolution and the selective advantage conferred by CCR5 delta-32 allele in humans, such as an increased resistance to plague or smallpox, but none is presently conclusive [41].

    HIV entry engages the viral env glycoprotein complex, the CD4 antigen, and a chemokine receptor, nearly always CCR5 ─ sometimes CXCR4, especially in later stages of disease ─ both located on the surface of the host cell.

     

    Clinical observations confirm that mucosal transmission of HIV is nearly exclusively due to CCR5-dependent HIV strains [67]. Dual-tropic, R5X4 viruses, or the rarer CXCR4-dependent viruses, are observed in late phases of the infection, and are usually associated with a faster progression to AIDS and to a marked decline of immune response [66].

    In the second paragraph beneath the NIH link, notice the last sentence – …resistance to plague or smallpox…

    Years ago there was speculation that the reason why Northern Europeans had a subset of people who were homozygous delta-32, meaning that an individual had a nonexistent or disabled CCR5 receptor situation, was because of the very high selective pressure on the population that was exposed to the plague in Europe in the Middle Ages. Y. pestis (plague) also uses CCR5 as an attachment mechanism and it was thought that those individuals with a homozygous delta-32 deletion were at least somewhat resistant to the plague because of it and lived to pass on the deletion to offspring. Apparently the jury is still out on this idea. It’s interesting though, if an individual is delta-32 then they may be resistant to both the bacteria that causes plague and also HIV.

    Here’s an explanation from another NIH abstract:

     
    Evolutionary genetics: Ambiguous role of CCR5 in Y. pestis infection.
    Elvin SJ1, Williamson EDScott JCSmith JNPérez De Lema GChilla SClapham PPfeffer KSchlöndorff DLuckow B.

    Author information

    Abstract

    Mecsas and colleagues suggest that a deficiency in the chemokine receptor CCR5 in humans is unlikely to confer protection against plague, based on their study of Yersinia pestis infection in Ccr5-deficient mice. They were testing the hypothesis that a mutation in the CCR5 gene, frequently found in Caucasians, may have been selected for in the past because it provided protection against (bubonic) plague; the mutation, called CCR5Delta32, is characterized by a 32-base-pair deletion. We have also tested this hypothesis by using Y. pestis infection in mice and, in addition, we have done phagocytosis experiments with macrophages from wild-type and Ccr5-deficient mice. Although, like Mecsas et al., we did not see any difference in the survival of the two groups of mice, we did find that there was a significantly reduced uptake of Y. pestis by Ccr5-deficient macrophages in vitro. Our results indicate that the role of Ccr5 in Y. pestis infection may therefore be more complex than previously thought

     

    And finally, for those who are unfamiliar with the famous Berlin patient case – here’s a description by the patient himself. The patient received a transfusion from a donor who was delta-32 CCR5 deficient and the patient’s HIV was effectively knocked out!

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287108/

    As I said above, the CRISPR experiment described in the article above is unethical but the idea of CCR5 deletion is irresistible.



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