Before the new Sunday, Chinese researcher He Jiankui had used CRISPR genome modification technology to create genetically modified twins. He was little known in scientific circles. But the controversial experiment aimed at making humans potentially HIV-resistant has also placed another actor in the limelight: the CCR5, a molecule of the immune system that he has attempted to invalidate. Here is the scientific logic underlying this choice and its concerns.
What is CCR5?
CCR5 covers the surface of white blood cells, where it acts as a chemokine receptor. These chemical messengers direct different populations of immune cells. HIV, which selectively targets white blood cells, uses CCR5 to stick to and pierce their membranes. The researchers discovered more than 20 years ago that a mutant version of the CCR5 The gene, which lacks 32 base pairs of DNA, prevents HIV from infecting these cells and thus confers a resistance infection. It's this mutant, known as CCR5-δ32– this interests him.
What did he do with CRISPR?
The team used in vitro fertilization to make embryos, then applied CRISPR to these embryos in an attempt to transform the normal CCR5 gene in a mutant that looks like the δ32 version. As explained in an informed consent form for volunteers who participated in this trial, he considered that it was a genetic form of vaccination. "The main goal of this project is to produce infants who can be immunized against the HIV-1 virus," says the form.
Who naturally has the mutation?
Nearly 10% of Europeans and Americans have inherited CCR5-δ32 genes from at least one parent. However, most of these people also have a normal variant and remain just as vulnerable to the AIDS virus as everyone else. But the 1% who inherit mutations from both parents – called homozygotes – are very resistant: studies show that if they are exposed to HIV, they are 100 times less likely to get the infection. (There are rare cases where they have been infected with HIV variants that favor a different chemokine receptor.) Timothy Ray Brown, an HIV-infected man who received a bone marrow transplant in 2007 from Homozygous donor during CCR5-δ32, became the only person cured of HIV infection. The case has added further evidence that crippled receptors provide a solid defense against the virus.
What are the risks of using CRISPR for the CCR5 mutation in human embryos?
CRISPR can make unintended and "off target" changes to the genome, which could theoretically lead to cancers and other health problems.
How well did the CRISPR work in its experience?
There is no published article to review, but he claims that one of the implanted embryos was homozygous for the disturbed CCR5. The other one had only one of the two genes altered. Only the homozygous baby would become potentially resistant to HIV. He presented evidence today that neither one nor the other baby had untargeted mutations, but researchers remain skeptical about the relevance of his analysis.
Is it possible that CRISPR has led to mutations that do not paralyze CCR5?
Yes. Mutated genes sometimes still produce functional proteins. He has not yet shown any evidence that the mutated CCR5 in babies was paralyzed, but he said he was considering taking blood samples from infants to try to Infect their cells with HIV.
People who are homozygous for CCR5-δ32 do you suffer from related health problems?
Potentially. For a decade, it seemed like the mutation was not hurting. But researchers have shown in 2005 that West Nile virus is highly lethal in mice that are designed to be homozygous for mutation. Epidemiological studies on West Nile Disease subsequently revealed that humans homozygous for the CCR5 mutation were suffering from a more serious disease and had higher mortality rates from this virus. It is now clear that the unmutated gene regulates trafficking of white blood cells to brains infected with West Nile virus. It therefore probably plays a role in the fight against other infections by similar mechanisms.
How is crippling CCR5 with CRISPR help slow down the HIV / AIDS epidemic?
He claims that his experience meets an "unmet medical need," an ethical principle essential to conducting CRISPR experiments on human embryos that may lead to hereditary changes. It bases its findings on the fact that new rates of HIV infection remain high in many countries; babies exposed to the virus but uninfected (by their mother in utero, during delivery or through breastfeeding) may still have health problems; and many infected people are discriminated against. But this logic has left many researchers on HIV / AIDS to swarm their heads. Even if CRISPR can paralyze safely CCR5 in embryos, it would take a massive campaign of IVF followed by the birth of an unfathomable number of genetically modified babies to have an impact on the epidemic.
Are there any other potential benefits to invalidating CCR5?
The Medical Ethics Approval Application form posted on He's website states that CCR5-δ32 mutations can make people "significantly resistant" to smallpox and cholera. But the scientific support for that is lean.