Nature Methods on March 30 retracted a controversial 2017 study on potential gene-editing errors associated with CRISPR–Cas9.
CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is a gene-editing technology that enables scientists to modify an organism's DNA. Many scientists consider the CRISPR-Cas9 system — which creates modified RNA segments to exploit select enzymes — to be one of the most precise and least expensive gene-editing techniques in use.
Here are seven things to know about the 2017 study and its retraction.
1. In June 2017, Nature Methods published a peer-reviewed study documenting the use of CRISPR-Cas9 to restore sight in blind mice. The technology successfully corrected the genetic mutation that caused blindness, however, the multi-institutional research team also identified "off-target mutations," or unintentional edits in the DNA of two CRISPR-edited mice. The researchers concluded these secondary mutations presented continued areas for concern.
2. The study garnered criticism from various groups, including pushback from gene-editing companies like Editas Medicine, which argued the observed mutations were likely present in the mice prior to the use of CRISPR-Cas9. The editors of Nature Methods issued an editorial expression of concern acknowledging any observed differences between the control group and the CRISPR-edited mice may be due to normal genetic variation, since the researchers did not record the initial genetic variation in the two groups.
3. In a March 26 study released on BioRxiv, an archive of unpublished research papers, the original research team acknowledged it had not been able to reproduce results indicating CRISPR-Cas9 resulted in unintended mutations. After an additional study using CRISPR-Cas9 to correct a genetic mutation in blind mice, the researchers concluded whole genome sequencing "suggest[ed] no excess mutations."
4. The editors of Nature Methods issued a retraction of the original study March 30, arguing that without additional controls or analysis of the mice's genetic background, the observed genetic differences cannot be attributed to CRISPR-Cas9 gene editing. The editors emphasized "the question of whether CRISPR has effects on the in vivo genome will require further study."
5. The Nature Methods editors outlined their decision to retract the study in a March 30 editorial. The editors engaged four independent referees to evaluate the initial study, along with some of the responses to the study from its critics. The editors noted this step was missing from their initial decision to publish the study in 2017. "The original paper was peer reviewed, but we should have sought at least one additional referee with expertise in the genetics of inbred mouse strains," the editors wrote.
6. The retraction is a welcome decision for many researchers interested in pursuing CRISPR trials in humans, the MIT Technology Review notes. A team of researchers from the University of Pennsylvania in Philadelphia are hoping to receive FDA clearance to conduct the first CRISPR trial treating human patients in the U.S. as early as 2018. The study would attempt edit DNA from cancer patients to improve their ability to fight the disease.
7. While the initial study in Nature Methods lacked the foundation to establish a causal role between CRISPR-Cas9 and unintended mutations, the journal's editors said the study highlighted limitations in existing research into off-targetmutations.
"There is relatively little published data on genome-wide effects of in vivo CRISPR treatment," the Nature Methods editors wrote in the March 30 editorial. "On the question of whether CRISPR can be safely used in vivo, the stakes are high for many. But for none are they higher than for the people in whom this technology may be used in the future. They are owed a careful and rigorous answer."