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Geneticists withdraw study and suggest that first CRISPR babies could die early



  A hand in a plastic glove holds a transparent plastic bottle over a screen displaying DNA profiles.

Errors in Tracking Techniques Downshifting genetic mutations resulted in erroneous results in a now-defunct study. Credit: Getty

A study raising questions about the future health of the world's first genetically modified baby was withdrawn due to key failures that affected its impact.

The study published in Nature Medicine 1

in June 2019 found that people with two copies of a natural genetic mutation conferring HIV resistance have an increased risk of dying earlier than others People. It was conducted following controversial experiments by Chinese scientist He Jiankui, who attempted to understand the implications of this mutation in the gene CCR5 with the CRISPR gene-editing tool in human embryos. The twin girls who were born last year as a result of the work did not exactly carry this mutation, but the research attracted attention because of their potential relevance to such experiments.

But a flood of studies 2 3 4 that looked new natural medicine – some of which When analyzing new data from genome databases, the sequences of hundreds of thousands of people, the results were rejected and no evidence was found that people with the mutation die early. The inaccurate conclusion to CCR5 was caused by technical errors in the identification of the mutation in a population health database.

"I feel I have the responsibility to improve the records for the public," says Rasmus Nielsen, a population geneticist at the University of California at Berkeley, who led a study that the authors withdrew on October 8 to have. Nielsen was also co-author of one of the works that refuted their findings.

Some researchers point out that the original research and its withdrawal would not necessarily provide insights into their health, as the twins did not get exactly the same mutation that naturally occurs. However, the episode raises questions about how best to assess the safety of future attempts to process genes in human embryos.

CRISPR Concern

He Jiankui shocked the scientific world when he announced in November 2018 that his team had used CRISPR to disable the CCR5 gene in two babies born this month. He, who at the time was a biophysicist at the Southern University of China in Shenzhen, said he had opted for CCR5 (19459016) because people with a 32-DNA-letter deletion known as delta-32 in the gene is resistant to CCR5 (19459017) are HIV, but seems to have no significant health problems.

He has not published any data that substantiates his work, but his announcement – which was submitted at a scientific meeting – showed that for one of the twins both copies of CCR5 were changed while the other twin only had changes in one of its two copies. None of the changes matched exactly with the Delta 32 variant.

Research has shown that the delta-32 mutation, which is relatively common in people of European descent, may have drawbacks – a small study 5 found that carriers die of influenza more frequently than other people , To answer the question in larger datasets, Nielsen and his Berkeley colleague Xinzhu Wei examined British Biobank, a database of genome and health data of 500,000 Britons.

Their Nature Medicine paper 1 reported that humans with two copies of delta-32 – which in their estimation make up about 1% of biobank participants – something More were likely to die at the age of 76, than those with or without a copy. They also found that the database housed fewer people with two copies of delta-32 than evolutionary theory predicted-a sign that on average, people with two copies die earlier than the total population, argued Wei and Nielsen.

] Results not replicated

Questions on the conclusion emerged as soon as the paper was published. Sean Harrison, epidemiologist at the University of Bristol, UK, attempted to replicate the results that night. He did not have British biobank data on the gene variant that Wei and Nielsen used to identify delta-32 carriers, and therefore analyzed genetic variants near the genome that would have yielded the same result (neighboring parts of the genome) inherited) so that scientists can infer the presence or absence of a DNA sequence by analyzing adjacent variants). When this was not the case, he described his results in a series of tweets and later in a blog post.

The discrepancy noted by Harrison aroused the interest of David Reich, a population geneticist at Harvard Medical School in Boston, Massachusetts, whose laboratory is currently under investigation CCR5 . In collaboration with Nielsen, his team discovered 2 that Neilsens and Wei's method had led them to undercut the number of people in the British biobank with two copies of the delta-32 mutation because: the probe had measured the variant The tracking did not always identify the target sequence. This, and not the supposed deleterious effects of the mutation, explained the obvious lack of carriers from the UK biobank database, says Nielsen.

He emphasizes that the problem of enumeration occurs only in the gene variant examined by his team and not in a General problem with data from the UK Biobank. "There were controls that we could have performed and should have performed what we did not do, we missed the fact that a genotyping error occurred," says Nielsen.

Another follow-up study 3 published last week on a preprint server and based on genome databases that together make up nearly 300,000 people. Iceland and Finland also found no evidence that humans with two copies of Delta-32 die earlier than others.

Not a green one Light

Researchers emphasize that the deciphering of the results of Wei and Nielsen does not imply that this is a sound idea aimed at CCR5 on gene editing. "It is very reasonable to expect that there is a has valuable function that we simply can not measure. It seems very unwise to cut it out, "says Reich.

Gaetan Burgio, a geneticist at the Australian National University in Canberra, said the original paper Nature Medicine offered no insights into the health of the genedited twins. "For this reason, the withdrawal and these additional studies on the European population are, in my opinion, still not relevant for CRISPR babies," he says. Population-based studies barely shed any light on these two babies who do not carry the CCR5 delta-32 mutation, he says. Nielsen hopes his team's mistake will not deter others It's enough to use databases like the UK Biobank to understand the implications of working on the human germ line, the DNA that can be passed down to future generations.

Kári Stefánson, director of deCODE genetics in Reykjavík and co-author of One of the publications that found no evidence that delta-32 is harmful, Nielsen's original study was not a valuable contribution to debates on the processing of germline genes , However, he agrees that resources such as the UK Biobank and its company's data on the Icelandic population can influence future efforts. "I think databases like these provide a pretty good way to evaluate the likely effect of changing the bases, no question," he says.


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