Scientists have heavily criticized the gene-editing performed on Chinese twins last year by He Jiankui, following the first public release of the original research.
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Experts said yesterday that the gene-editing that Jiankui claimed was intended to provide long-life protection against HIV infection might have failed in its purpose and introduced unwanted, "off-target" mutations.
Excerpts from the original manuscript, published by MIT Technology Review, reveal how Jiankui ignored the usual ethical and scientific boundaries while creating the twin girls. The announcement of the girls' birth last November sent shockwaves through the scientific community, with researchers and ethicists worldwide calling the experiment unlawful, unethical, and unacceptable.
Jiankui made the bold and expansive claim that his research could one day be used to "control the HIV epidemic." However, at the time, it was not clear whether the experiment had even been successful at immunizing the girls against HIV because the researchers had not reproduced the precise gene mutation that is known to confer protection.
This work offers little justification for the editing and subsequent transfer of human embryos to generate a pregnancy. The idea that editing-derived embryos may one day be able to 'control the HIV epidemic', as the authors claim, is preposterous. Public health initiatives, education, and widespread access to antiviral drugs have been shown to control the HIV epidemic."
Rita Vassena, scientific director at the Eugin Group
About the mutation
A small proportion of people are born with a mutation in a gene called CCR5 that can make them immune to HIV infection. It is this mutation, called CCR5 delta 32, that Jiankui claimed he had "successfully reproduced" using the powerful gene-editing tool CRISPR/Cas9. However, the team did not actually reproduce this exact mutation. Instead, they introduced new edits that may or may not be protective, and according to the original article, Jiankui and colleagues never checked to see.
Genome-editing scientist at the University of California, Fyodor Urnov, says: "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. The statement that embryo editing will help millions is equal parts delusional and outrageous."
In their paper, the authors describe the changes that they did make to the twins' DNA. When they removed a few cells from the embryos to check their DNA, they found that the edits they hoped would disable CCR5 had indeed taken hold. However, while they intended the edits to confer HIV resistance, it could not be certain, since the edits are only similar and not identical to the naturally occurring delta 32 mutation.
Hank Greely, professor of law at Stanford University, says using the word "successfully" here is tentative: "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."
The researchers could have introduced unwanted CRISPR edits
Furthermore, despite CRISPR having revolutionized the genomics field since its introduction in 2012, it remains an imperfect tool since it can introduce what is known as "off-target" edits.
In their paper, the researchers claim they did search for unintended edits in the early-stage embryos and that they only found one. However, the search was not comprehensive, and the paper ignores an important point: that any cells taken from early-stage embryos would not actually contribute to the twins' bodies. The remaining cells that would differentiate and proliferate to become the twins could have also harbored off-target edits, and it would not be possible to know that before the pregnancy began.
Urnov says the glossing over of this important point is 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.' This is a key problem for the entirety of the embryo-editing field, one that the authors sweep under the rug here."
Further ethical concerns
Further ethical concerns that experts have raised include that the twins' parents may have participated in the experiment for the wrong reasons.
The father had HIV, which carries a significant social stigma in China that makes it virtually impossible for couples to access fertility treatment.
According to reproductive endocrinologist Jeanne O'Brien at Shady Grove Fertility, the parents' inability to access to fertility treatment may have motivated them to take part in the experiment despite the huge risks to their children: "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?"
The researchers also seem to have made it difficult to find the family by omitting the names of the fertility doctors and by stating a false date of birth. Jiankui claimed the twins were born in November 2018, while many other reports indicate that they were born in October.
Jiankui has attempted to have his manuscript published by prestigious journals, including Nature and JAMA, but it remains unpublished.