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Was the big paper about the successful editing of human embryo genes wrong?

A 3-D artist's rendering of the powerful genome editing tool, CRISPR/Cas9, the technology that was used in a recent Nature paper to modify human embryos. (Stephen Dixon)

A month ago, an international team of researchers announced that they had used a gene-editing technique to safely erase a heritable heart condition from a human embryo. This blockbuster news was greeted with both excitement and fear. Now the scientific community is buzzing about a new critique that questions the main conclusions of their paper.

Columbia University's Dieter Egli, Harvard University’s George Church and other respected names in the field are raising doubts about whether the experiment — using the groundbreaking laboratory tool known as CRISPR (or Clustered Regularly Interspaced Short Palindromic Repeats) — was successful at all or at least in the way the researchers originally described it. This group of scientists argues that the results could have been interpreted in other ways. Writing in a so-called preprint paper in Biorxiv that has not been peer-reviewed, they say that each embryo needs to be carefully evaluated “to confirm (or not) gene correction and mosaicism.”

The second part of that sentence is very important. Mosaics in the gene-editing process result when the changes are incomplete, leaving an embryo with a mix of edited and unedited cells. This can happen when cells don't make repairs until after they have replicated their DNA, allowing some cells to pick up unrepaired DNA. This could mean a child could still have a strong chance of inheriting a disease the treatment was supposed to erase.

“Absent such data, the biomedical community and, critically, patients with disease-causing mutations interested in such research must be made aware that numerous challenges in gene correction remain,” Egli and his co-authors caution.

Paul Knoepfler, a stem-cell scientist at the University of California at Davis who was not involved in either paper, called Egli's arguments “rather compelling.” He wrote in a blog post, “To me, these possible alternative explanations just simply make a lot of sense and are things that should have been ruled out as alternative explanations.”

One of the original paper’s lead authors, Shoukhrat Mitalipov of the Oregon Health & Science University, responded in a statement that his team recognizes that “these results must be confirmed by additional studies, and that independent verification of important new findings is a cornerstone of science.” He encouraged other scientists to try to reproduce the findings through their own experiments, although he called the critique “pure speculation.”

His team will respond point by point in a formal, peer-reviewed reply in the coming weeks, he said.

“The critique leveled by Egli et al offers no new results but instead relies on alternative explanations of our results,” Mitalipov said. “We stand by our study’s key finding that human embryos are capable of effectively repairing disease-causing mutations by using a normal copy of the gene from a second parent as a template. We based our finding and conclusions on careful experimental design involving hundreds of human embryos.”

Read more:

First human embryo editing experiment in U.S. ‘corrects’ gene for heart condition

A new CRISPR breakthrough could lead to simpler, cheaper disease diagnosis

Ethicists urge caution in applying CRISPR to humans