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Researchers provide more evidence for their landmark claim that gene editing rid embryos of a disease mutation \u2014 but scientists are still arguing over the results.<\/h6>\n
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<\/p>\n Eight-cell embryos injected with the gene editor CRISPR\u2013Cas9.<\/span>Credit: H. Ma et al.\/Nature<\/p>\n<\/figcaption><\/figure>\n <\/p>\n <\/p>\n <\/p>\n Biologists who last year made a blockbuster \u2014 but controversial \u2014 claim that they had\u00a0fixed a disease-causing mutation in human embryos using CRISPR gene editing<\/a>\u00a0have released fresh evidence in support of their work.\u00a0Critics argued that the researchers\u2019 evidence wasn\u2019t persuasive<\/a>and that the feat did not seem biologically plausible, intensifying the existing\u00a0controversy surrounding the use of gene editing in human embryos<\/a>\u00a0to prevent diseases.<\/p>\n Now, a year after the study was published in\u00a0Nature<\/i>1<\/a><\/sup>, its authors, led by reproductive biologist Shoukhrat Mitalipov at the Oregon Health & Science University in Portland, have backed up their claims with new data2<\/a><\/sup>, published on 8 August alongside a pair of letters critiquing the original results.3<\/a><\/sup>,<\/sup>4<\/a><\/sup><\/p>\n Whatever happens next, it is likely that questions about whether it is possible to repair mutations in human embryos will persist until other researchers can repeat the feat \u2014 no easy task in\u00a0a field that is strictly regulated<\/a>, and\u00a0even illegal in some countries<\/a>.<\/p>\n <\/p>\n <\/p>\n Mitalipov\u2019s team was not the first to attempt to correct disease-causing mutations in human embryos \u2014\u00a0work in China crossed that Rubicon in 2015<\/a>. But its efforts seemed to be the most promising.<\/p>\n The researchers created human embryos by fertilizing healthy donated eggs with sperm from a man who carried a mutated copy of a gene that causes a heart condition called hypertrophic cardiomyopathy. Because humans carry 2 copies of each gene, left to chance, around half of the 58 embryos the researchers created would have carried the mutated copy. But the team used the gene-editing technique CRISPR\u2013Cas9 to seek out and repair any mutated copies of the gene.<\/p>\n Genetic testing showed that 42 of the 58 treated embryos had two normal copies of the target gene, called\u00a0MYBPC3<\/i>\u00a0\u2014 many more than would be expected if editing hadn\u2019t occurred. Just one of the corrected embryos contained a mix of edited and unedited cells \u2014 a phenomenon known as mosaicism that had dogged past human-embryo-editing studies.<\/p>\n In their experiments, Mitalipov\u2019s team provided a normal synthetic copy of\u00a0MYBPC3<\/i>\u00a0to act as a template for CRISPR to fix the mutation. Surprisingly, the researchers reported that the mutations, which stemmed from the sperm, were instead corrected using the healthy version of\u00a0MYBPC3<\/i>\u00a0found in the egg genomes. This process of templating from the egg genome is not well understood and was thought to happen only rarely in gene-editing experiments.<\/p>\n <\/p>\n <\/p>\n Numerous critics have since\u00a0questioned the plausibility of that claim<\/a>, and have offered alternative explanations for the team\u2019s results.<\/p>\n Tony Perry, an embryologist at the University of Bath, UK, says the architecture of an early embryo makes it unlikely that an egg\u2019s genome could serve as template for the repair a mutation stemming from sperm. In the first stages of development after fertilization, the genetic material of the egg and sperm reside in far away, distinct compartments in the embryo, he says: \u201cThe genomes are separated by what are, in cellular terms, intergalactic distances.\u201d Perry\u2019s work in mice suggests that CRISPR acts extremely quickly in their embryos, making it unlikely that a maternal genome could guide correction at these early stages5<\/a><\/sup>.<\/p>\n Perry\u2019s concerns are echoed in one of the critiques published today3<\/a><\/sup>, led by developmental biologist Maria Jasin at the Memorial Sloan Kettering Cancer Center in New York City, and stem-cell biologist Dieter Egli at nearby Columbia University (the response was\u00a0first posted last year to the bioRxiv preprint server<\/a>).<\/p>\n Another possibility, suggest Jasin, Egli and some other critics, is that CRISPR deleted\u00a0MYBPC3<\/i>\u00a0in the sperm genome and some genetic information around it, instead of actually repairing the gene. If the missing chunk of DNA were large enough, the genetic tests that Mitalipov\u2019s team applied to the embryos would detect only the mother\u2019s version of\u00a0MYBPC3<\/i>, giving the impression that the paternal copy had been corrected when it was actually missing.<\/p>\n Such deletions occasionally happen when mouse embryos are edited with CRISPR, reports a second team of critics4<\/a><\/sup>, led by developmental geneticist Paul Thomas at the University of Adelaide in Australia. These findings echo similar ones reported last month in CRISPR-edited human embryonic stem cells6<\/a><\/sup>. \u201cIt\u2019s absolutely critical that we fully understand what\u2019s happening in these embryos,\u201d says Thomas.<\/p>\n Mitalipov says that his team looked for deletions around\u00a0MYBPC3<\/i>\u00a0and couldn\u2019t find any within a certain range. In their new data, they provide more proof that the edited embryos carried two copies of the mother\u2019s versions of the gene, and preliminary evidence that CRISPR might also act at later stages in the early embryo, which could explain how the egg genome could provide a template for the corrections. Mitalipov adds that in further, unpublished experiments, his team has corrected mutations in a different gene responsible for hypertrophic cardiomyopathy, and that gene repair again occurred using the healthy maternal copy of the gene in those experiments.<\/p>\n Thomas says that Mitalipov\u2019s team still hasn\u2019t fully addressed theconcerns about large deletions. He thinks that the issue will be settled only when others attempt gene correction in human embryos. \u201cThat will probably take some time. By their nature, these experiments are strictly regulated or not permitted in some jurisdictions,\u201d he says.<\/p>\n Mitalipov is eager for his results to be independently replicated. \u201cPeople are going to see this kind of repair over and over again with human embryos,\u201d he predicts. He also points to a bioRxiv preprint published earlier this year that used CRISPR in mouse embryos to correct genes in much the same manner as proposed by Mitalipov\u2019s team in humans7<\/a><\/sup>.<\/p>\n \u201cI would love for this all to be correct,\u201d says Perry. \u201cWe need to sort it out.\u201d<\/p>\n <\/p>\n <\/p>\n <\/p>\n <\/p>\n","protected":false},"excerpt":{"rendered":"![\"Greyscale](\"https:\/\/media.nature.com\/w800\/magazine-assets\/d41586-018-05915-2\/d41586-018-05915-2_16019956.jpg\")
<\/div>\n<\/div>Gene rundown<\/h6>\n
Tough crowd<\/h6>\n