Last November, Chinese researcher He Jiankui stunned the world when he announced the birth of twin girls whose genomes were altered before birth using CRISPR gene-editing techniques. The feat wasn’t necessarily a technical breakthrough—other researchers had the tools to do a similar project, but ethics and scientific regulations held them back from tinkering with the DNA of viable embryos that would be taken to term. He glossed over these concerns, making his experiment the subject of international outcry. Now, a new study in Nature Medicine suggests the alteration to the twins’ genomes could have an unexpected consequence—an abbreviated life expectancy.
As Antonio Regalado first reported for MIT Technology Review, He’s team used CRISPR—“molecular scissors” that can cut DNA at a programmable location—to genetically edit human embryos. Their target was a gene called CCR5, which produces a protein that allows H.I.V. to enter cells. By disabling CCR5, He hoped to make the embryos immune to H.I.V., replicating the effect of a CCR5 variant called delta 32 that arises naturally in about 10 percent of northern Europeans but is much rarer in China. The embryos were created from the eggs of a healthy mother and the sperm of an H.I.V.-positive father, but, as Marilynn Marchione wrote for the AP when the news broke, the experiment also used other, less-drastic methods to prevent paternal H.I.V. transmission, so the genetic editing wasn’t medically necessary.
Once edited, the embryos were implanted into the mother’s uterus. The babies, Lulu and Nana, were born prematurely in October 2018. Nana was born with two edited copies of CCR5, which theoretically means she cannot contract the most common strain of H.I.V., while her sister Lulu has one functional and one edited copy of the gene.
However, Ian Sample at the Guardian reports that newly published research suggests losing the gene isn’t necessarily a biological advantage for the twins or any future offspring they pass their altered DNA on to. Researchers from the University of California, Berkeley, analyzed the health records of more than 400,000 people who registered their genomes with the UK Biobank. They found that people aged 41 to 78 who carried the delta 32 mutation in both sets of the gene were on average 21 percent more likely to die by age 76 than people with one copy or no copies of the mutation. (The group with one delta 32 variant had the same mortality rate as the group with no mutation at all.)
It’s not clear why the mutation is linked with earlier mortality. While delta 32 grants H.I.V. immunity and may protect against smallpox, previous research suggests the genetic variant makes people more vulnerable to other illnesses, including the flu and West Nile virus. “In this case, the cost of resistance to H.I.V. may be increased susceptibility to other, and perhaps more common, diseases,” the researchers write in the new study.
While the edits He made approximate the delta 32 mutation by deactivating the gene, they don’t duplicate it exactly. As the AP’s Malcolm Ritter points out, this discrepancy means we can’t be certain how the Berkeley study translates to the CRISPR twins’ future. Epidemiologist David Melzer, who works separately with the UK Biobank data to research longevity, also tells Nature’s Sara Reardon that many other genes have a more dramatic impact on lifespan than CCR5. Prominent stem cell scientist Robin Lovell-Badge, who was also not involved in the recent research, says that He had been “foolish” because the Chinese researcher “may have compromised lifespan in the two girls,” reports Karen Weintraub of Scientific American.
This is hardly the first controversy over the CRISPR babies. He’s work, which has been presented at a gene-editing summit but not published in a peer-reviewed journal, has been widely criticized as rash, lacking in transparency, medically unnecessary and even ineffective. He was fired from his job at the Southern University of Science and Technology in January, and publicly, the Chinese government condemned his research. He’s experiment even prompted some influential scientists from around the world to call for a moratorium on germ-line editing.
The Nature Medicine study highlights another of the many reasons why He’s use of CRISPR on viable human embryos was so ill-advised. “There are many reasons not to make CRISPR babies at this stage,” Rasmus Nielsen, the computational biologist who co-authored the study, tells NPR. “And one of them is [the] fact that we can't really predict the effect of the mutations that we induce.”