Reviewers of Chinese CRISPR Research: "Ludicrous" and "Dubious At Best" – BioSpace

Posted: December 6, 2019 at 1:44 pm

In November 2018, He Jiankui, a researcher in Shenzhen, China, claimed he utilized CRISPR-Cas9 gene editing to alter the DNA of embryos for seven couples. A set of twins, whose names are Lula and Nana, were born. The research was met by global condemnation and calls for a moratorium on this type of gene editing.

However, aside from the public presentations and the resulting controversy and government crackdown on He Jiankui in China, the actual technical results have not been published. This week, the MIT Technology Review announced they had received a copy of Hes unpublished manuscript titled Birth of Twins After Genome Editing for HIV Resistance. They also received a second manuscript that discussed laboratory research on human and animal embryos. The research was apparently reviewed earlier by Nature and JAMA but is as yet unpublished. The MIT group had the papers reviewed by four experts, a legal expert, an IVF physician, an embryologist, and a gene-editing specialist.

MIT Technology Review writes, Their views were damning. Among them: key claims that He and his team made are not supported by the data; the babies parents may have been under pressure to agree to join the experiment; the supposed medical benefits are dubious at best; and the researchers moved forward with creating living human beings before they fully understood the effects of the edits they had made.

The analysis found 13 key problems, but one of the most relevant is that the stated purpose of the researchwhich is also under attackdid not occur. That is to say, He Jiankui and the authors of the research claim that the goal was to modify the CCR5 gene to make the children resistant to HIV. Not only did that not appear to have happened, but its questionable if it was the real reasonthe real, less scientific reason being to be the first scientists to modify human embryos using CRISPR gene that are then born.

One of the reviewers, Fyodor Urnov, a genome-editing specialist at the University of California Berkeley, said, The claim they have reproduced the prevalent CCR5 variant is a blatant misrepresentation of the actual data and can only be described by one term: a deliberate falsehood. The study shows that the research team instead failed to reproduce the prevalent CCR5 variant.

Another of the reviewers, Rita Vassena, scientific direct or the Eugin Group in Spain, noted, Approaching this document, I was hoping to see a reflective and mindful approach to gene editing in human embryos. Unfortunately, it reads more like an experiment in search of a purpose, an attempt to find a defensible reason to use CRISPR/Cas9 technology in human embryos at all costs, rather than a conscientious, carefully thought through, stepwise approach to editing the human genome for generations to come.

Vassena goes on to say, The idea that editing-derived embryos may one day be able to control the HIV epidemic, as the authors claim, is preposterous.

Hank Greely, professor of law at Stanford University, agreed with that assessment, calling it ludicrous. He also noted, We have no, or almost no, independent evidence for anything reported in this paper. Although I believe that the babies probably were DNA-edited and were born, theres very little evidence for that. Given the circumstances of this case, I am not willing to grant He Jiankui the usual presumption of honesty.

There is also significant doubt as to whether the parents involved in the study understood the procedures and the lack of necessity for having it performed. The father was HIV seropositive and it was under control using anti-retroviral therapy. There was little or no risk of HIV being transferred to the children under a normal in vitro fertilization treatment.

Jeanne OBrien, reproductive endocrinologist with Shady Grove Fertility in Atlanta, said, Being HIV-positive in China carries a significant social stigma. In spite of intense familial and societal obligations to have a child, HIV-positive patients have no access to treatment for infertility. The social context in which the clinical study was carried out is problematic and it targeted a vulnerable patient group. Did the study provide a genetic treatment for a social problem? Was this couple free from undue coercion?

Another problem, one of many, is that the gene edits performed were not the same as the mutations that are known to confer natural HIV resistance. The researchers indicated in the papers that they expect the edits to confer HIV resistance, because they are similar but not identical to CCR5 delta 32, the natural mutation that confers resistance. One of the babies only had edits to one of the CCR5 genes, which at best would only provide partial HIV resistance.

Greely said, Successfully is iffy here. None of the embryos got the 32-base-pair deletion to CCR5 that is known in millions of humans. Instead, the embryos/eventual babies got novel variations, whose effects are not clear. As well, what does partial resistance to HIV mean? How partial? And was that enough to justify transferring the embryo, with a CCR5 gene never before seen in humans, to a uterus for possible birth?

There is also significant concern, as there often is with CRISPR, of possible off-target edits. Urnov called it an egregious misrepresentation of the actual data that can, again, only be described as a blatant falsehood. It is technically impossible to determine whether an edited embryo did not show any off-target mutations without destroying that embryo by inspecting every one of its cells. This is a key problem for the entirety of the embryo-editing field, one that the authors sweep under the rug here.

In short, review of He Jiankuis research finds it deeply flawed in terms of rationale, procedures and results, with what can only be described as serious ethical problems and what appears to be a deliberate misrepresentation of the facts.

Originally posted here:
Reviewers of Chinese CRISPR Research: "Ludicrous" and "Dubious At Best" - BioSpace

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