Substandard, Superficial, And Absurd: Experts Slam The Science Behind The CRISPR Baby Experiment

He Jiankui at the Human Genome Editing Conference in Hong Kong on November 28, 2018. (Image: AP/Kin Cheung)

A pair of genetic experts are claiming that the controversial human gene-editing experiment conducted by Chinese scientist He Jiankui was not only unethical, it was also deeply flawed from a scientific perspective. The experiment, they said, likely won’t work as intended, and the two girls produced by the project now face uncertain health risks.

The authors of the new PLOS Biology commentary article, geneticists Wang Haoyi and Yang Hui from the Chinese Academy of Sciences (CAS), did not mince words as they offered a severe rebuke of the gene-editing experiment conducted by Chinese geneticist He Jiankui.

“[We] believe there is no sound scientific reason to perform this type of gene editing on the human germline, and that the behaviour of He and his team represents a gross violation of both the Chinese regulations and the consensus reached by the international science community,” wrote the authors. “We strongly condemn their actions as extremely irresponsible, both scientifically and ethically.”

At the Second International Summit of Gene Editing held in Hong Kong this past November, He, an associate professor from Southern University of Science and Technology, shocked the world by announcing the birth of twin girls, whose DNA he had modified by using the CRISPR/Cas9 gene-editing tool. Working with embryos, He disabled the CCR5 gene, which encodes for a receptor that, along with another receptor, serves as a gateway for the HIV virus to penetrate and infect white blood cells. The point of the project was to confer a built-in genetic immunity to the virus. He said the procedure was medically necessary given that the girls’ father is HIV-positive.

Wang and Yang took issue with the rationale behind the project and how the experiment was conducted. Though the full details of the work have yet to be disclosed, the authors said the experimental design and the data presented at the Hong Kong summit “revealed serious misconduct on both the scientific and ethical levels.” The authors felt the need to write the commentary article “because we believe that responsible scrutiny and discussion of this event requires a good understanding of the scientific facts.”

The procedure was not medically necessary, they said, because an HIV infection at the conception stage can be avoided by sticking to established assistive reproduction protocols. As for the risk of infection after birth, “simply avoiding potential risk of HIV exposure suffices for most people,” the authors wrote, adding that “editing early embryos does not provide benefits for the babies, while posing potentially serious risks on multiple fronts.”

Those “multiple fronts” included a poor understanding of how the absence of the CCR5 gene might affect Asian individuals, particularly the way in which the introduced allele, or mutated gene, might cause unforeseen health risks. This seemingly fortuitous mutation can happen naturally, and scientists have studied the resulting effects on Europeans, who seem healthy for the most part. That said, the CCR5 mutation does not protect individuals from all HIV strains.

What’s more, the effects of this mutation have not been studied thoroughly in Chinese populations, therefore “it is very difficult to predict the risk of introducing the [CCR5 allele] into a Chinese genetic background,” the authors wrote.

“While He claimed that there was a long-term health follow-up plan, there are no details on who will fund this or assume responsibility in the event that any medical issues arise,” they wrote.

Wang and Yang described the quality of the science employed by He as “substandard.” During He’s presentation in Hong Kong, for example, the scientist said he used data about CCR5 knockout in mice in order to determine if the deleted gene would “cause undesirable genetic, physiological, or behavioural consequences,” as worded in He’s slide.

“This is absurd,” wrote Wang and Yang, saying it’s “not possible to answer that question simply by comparing histology staining of four different tissues without any quantification and by doing two simple behaviour tests in mice,” adding that the science was “very poor and superficial.”

Other issues exposed by Wang and Yang included certain experiments that could not be replicated, and a lack of attention paid to the potential problems produced by off-target mutations (in which CRISPR/Cas9 might have inadvertently altered other genes) and the potential for mosaicism (in which an individual has acquired multiple, distinct genomes). Wang and Yang wrote that the approach used by He was not sophisticated enough to detect any possible off-target mutations, and that “He probably underestimated the rate of mosaicism and the risk of introducing harmful genetic alterations.”

The authors concluded their commentary article by strongly urging the international community of scientists and regulators to “initiate a comprehensive discussion as soon as possible to develop the criteria and standards for genome editing in the human germline for reproductive purposes.” Once consensus is reached on this matter, jurisdictions can then pass laws and build the institutions needed for oversight and enforcement, the authors wrote.

“I agree 100% with the authors,” Brendan Parent, a bioethicist at NYU School of Medicine, wrote in an email to Gizmodo. “He Jiankui contravened every tenet of responsible research for the purpose of being the first to attempt. He did not go through sufficient approval channels, his informed consent process for the parents was misleading, and his justification was wrong.”

Parent, who is not affiliated with the new commentary paper, said parents with HIV can have a child unaffected by the virus through the use of in vitro fertilization (IVF) and preimplantation genetic testing (PGT), which involves the screening of embryos for disease prior to implantation.

“We have no clear picture what kinds of health risks these children will experience, not knowing how genetic manipulation affects development, and being mosaic for the CCR5 gene that was intended to be edited out—meaning they each have partial expression for the gene,” Parent told Gizmodo. “Furthermore, we are unaware what the mere process of germline editing does to a human embryo brought to term, even if it was a technical success for the intended gene edit.”

The good news about all of this is the overwhelming consensus that He did a bad thing and that measures need to be put into place to prevent something like this from ever happening again. Let’s hope this consensus actually leads to action.

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