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First CRISPR babies: No Evidence To Show That They Will Die Early

A research study that raised questions over the future health of the world’s first gene-edited CRISPR babies has been retracted because of the key errors that undermined its conclusion.

The study, published in June 2019 in Nature Medicine, had suggested that people with 2 copies of a natural genetic mutation that confer HIV resistance are at an increased risk of dying earlier than the other people. The study was actually conducted in the wake of controversial experiments by a Chinese scientist He Jiankui, who attempted to recreate the effects of gene mutation in the gene CCR5 by using the CRISPR gene-editing tool in human embryos. Twin girls born who were last year as a result of the work didn’t end up carrying this exact mutation, but this research study attracted attention because of its potential relevance to such experiments.

But a flurry of studies that looked anew at the Nature Medicine research — some of which analyzed new data from genome databases comprising sequences from hundreds of thousands of people — have rejected the results & find no evidence that people with the mutation will die early. The erroneous conclusion about the CCR5

gene was caused by technical errors in how these mutations were identified in a population-health database.

Rasmus Nielsen who is a population geneticist at the University of California, Berkeley, who led the study, which the authors retracted on 8th October, said that he feels that he has a responsibility to put the record straight to the public  Nielsen also co-authored one of the papers rebutting its findings.

Some of the scientists stress that because First CRISPR babies didn’t receive exactly the same mutation that occurs naturally, the original research study & its retraction wouldn’t necessarily offer insights into their health anyway. But the episode actually raises questions about how best to assess the safety of similar future attempts to edit genes in the human embryos.

The CRISPR concerns

He Jiankui shocked the scientific world by announcing, in November 2018, that his research team had used the CRISPR technique to disable the CCR5 gene in two babies born that same month. Jiankui, who was at the time a biophysicist at the Southern University of China in Shenzhen, said he chose to target the CCR5 gene because people with a 32-DNA letter deletion known as the delta-32 in the gene are resistant to HIV infection but seem not to experience significant related health problems.

Jiankui has not published his research data supporting his work, but his announcement which was presented at a scientific meeting indicated that, for one of the twins, both copies of CCR5 genes were altered, whereas the other twin carried the edits in just one of her 2 copies. And none of the changes exactly matched the delta-32 variation.

The study has hinted that the delta-32 mutation, which is relatively common in people of European ancestry, might carry downsides, one small research study found that the carriers were more likely than other people to die from influenza infection. In order to tackle the question in larger data sets, Nielsen & his Berkeley colleague Xinzhu Wei looked at the UK Biobank, a database that contains genome and also the health data from 500,000 British people.

Their Nature Medicine paper reported that the people with 2 copies of delta-32, whom they estimated to make up about one percent of biobank participants, were slightly more likely to die by the age of 76 years than were those with one or no copies. The team also found that the database harbored fewer people with 2 copies of delta-32 than evolutionary theory predicted it should- a sign that individuals with two copies were dying earlier, on average, than the population at large, Wei & Nielsen argued.

Results are not replicated

There were plenty of questions over the conclusion that emerged as soon as the research paper was published. An epidemiologist at the University of Bristol, United Kingdom, Sean Harrison, attempted to replicate the study findings that night. But he did not have UK Biobank data on the gene variant that Wei & Nielsen used to identify carriers of delta-32, so he analyzed genetic variants near it on the genome that should have given the same result i.e, the adjacent parts of the genome tend to be inherited together, allowing researchers to infer the presence or absence of a DNA sequence by analyzing neighboring variants). When they did not, he described his study findings in a series of tweets & later a blog post.

First CRISPR babies: No Evidence To Show That They Will Die Early

The discrepancy Harrison actually identified piqued the interest of David Reich, a population geneticist at the Harvard Medical School in Boston whose lab is studying the CCR5 gene. Working with Nielsen, his research team discovered that Neilsen & Wei’s method had caused them to undercount the number of people in the United Kingdom Biobank with 2 copies of the delta-32 mutation because of the probe that measured the variant they were tracking didn’t always identify its target sequence. This (and not the supposed harmful effects of the mutation) explained the apparent absence of carriers from the UK Biobank database, said, Nielsen.

He also stresses that the undercounting problem is unique to the gene variant his research team looked at & not a general issue with UK Biobank data. Nielsen sais that there were checks they could have done & should have done that they didn’t do. His team missed the fact that there was a genotyping error, he added.

Another follow-up study, posted on a preprint server last week & based on genome databases that together include nearly 300,000 people from Iceland & Finland, also found no evidence that people with 2 copies of delta-32 die earlier than others.

No green light

Scientists stress that the unraveling of Wei & Nielsen’s results does not mean that it is a sound idea to target the CCR5 gene for gene editing. Reich said that it is very reasonable to expect that it might have valuable functions that we just don’t know how to measure. And it seems very unwise to edit it out.

Gaétan Burgio who is a geneticist at the Australian National University in Canberra, says that the original Nature Medicine paper offered no insights into the health of the gene-edited twins. Therefore, the retraction to this & these additional studies on European populations will still have no relevance to the CRISPR babies. And population-based studies are very unlikely to give real insights on these 2 babies, who do not carry the CCR5-delta-32 mutation, he added.

Nielsen hopes that his research team’s error doesn’t dissuade others from using databases such as the United Kingdom Biobank to understand the effects of human germline editing, the DNA that can be passed on to the future generations.

Kári Stefánson who is the head of the company deCODE genetics in Reykjavik & a co-author of one of the research papers that found no evidence that delta-32 mutation is harmful, says that Nielsen’s original CRISPR study was not a valuable contribution to debates over the germline gene editing. But Kári Stefánson agrees that the resources such as the UK Biobank & his company’s data on Iceland’s population can inform future efforts. He added that the databases like this provide a fairly good way of assessing the probable effects of altering bases, no question about it.


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First CRISPR babies: No Evidence To Show That They Will Die Early

Editor’s Note: First CRISPR babies, Gene editing, No Evidence To Show That CRISPR babies Will Die Early, Geneticists retract study suggesting first CRISPR babies might die early, Researchers rapidly corrected finding through discussions on social media and preprints.

Ria Roy completed her Post Grad degree at the Visvesvaraya Technological University. She has a great grounding in the skills, including technical, analytical and research skills. She is a motivated life science professional with experience of working in famous research institutes