Nature Methods retracts publication that claimed to have found numerous unexpected mutations after CRISPR-Cas9 experiment in vivo

Nature Methods Editorial retraction of the publication: Unexpected mutations after CRISPR-Cas9 editing in vivo. Schaefer KA, Wu WH, Colgan DF, Tsang SH, Bassuk AG, Mahajan VB. Nat Methods. 2017 May 30;14(6):547-548.

Today, the scientific journal Nature Methods, retracted a publication by Schaefer et al. that appeared on 30 May 2017 claiming to have found numerous unexpected mutations after a CRISPR-Cas9 experiment in vivo, in mice. The unexpectedly high number of off-target mutations reported in the study caught the field by surprise, where noone else appeared to have found similar data. However, this was a most relevant issue, should have been true, directly affecting the expectatives of the CRISPR-derived uses and applications. That publication negatively impacted in the nascent field of genome editing applications, particularly those related to biomedicine, to develop innovative gene therapy approaches. However, almost immediately, many groups around the world expressed doubts and critized the experimental design of the study and the interpretation of the observed results. Soon thereafter, several manuscripts and publications were released with more plausible alternative explanations (low number of cases analyzed, mice genetically unrelated, persisting Cas9 expression…). Anyone interested to review a timeline of events associated with this publication can visit the corresponding section of the CRISPR web at the CNB-CSIC, maintained by Lluis Montoliu.

Eventually, today, Nature Methods adopted an Editorial decision and retracted this publication, with the agreement of two of its authors and the disagreement of the rest, including the first and last author of the study. This was the most logical and expected decision. Simultaneously, Nature Methods has released five different responses from five independent laboratories, experts in the field of genome editing, with alternative explanations for the original study, now retracted.

The first phrase of the Editorial Retraction note explains this decision: “This paper is being retracted because the genomic variants observed by the authors in two CRISPR-treated mice cannot be conclusively attributed to CRISPR–Cas9.“. In other words, the most plausible explanation for the original findings were the underlying genetic differences between control and experimental mice, in principle derived from the same genetic background, but in reality selected from unrelated, and hence, genetically different, mouse colonies.

Author: Lluis

Lluis Montoliu (Barcelona, Spain, 1963) graduated in Biological Sciences (1986) and obtained his PhD in Molecular Genetics (1990) at the University of Barcelona. Research Scientist of the Spanish National Research Council (CSIC) at the National Centre for Biotechnology (CNB), in Madrid (Spain) since 1997, after two postdoctoral periods in Heidelberg (German Cancer Research Center, 1991-1995) and Barcelona (Autonomous University of Barcelona, 1995-96). Since 2007 appointed researcher at the Spanish Research Initiative on Rare Diseases (CIBERER-ISCIII) where he is now serving at its Steering Committee. Since 1998 he is Honorary Professor at the Autonomous University of Madrid and, since 2007, Director of the Spanish node of the European Mouse Mutant Archive (EMMA/INFRAFRONTIER) Spanish node. Including his PhD, from 1986, where he worked in plant molecular genetics, in maize, he has been always working on the genetic modification of organisms (GMOs). Since 1991 he has been working in several scientific projects within the field of animal transgenesis. At the CNB he leads a research team interested in basic science, to understand the mechanisms controlling gene expression and organization in mammalian genomes, and in applied science, generating animal models for the study of human rare diseases, such as albinism. He has pioneered the use of in vivo genome-editing CRISPR approaches in Spain for the functional analysis of the non-coding genome. He is the current President of the European Society for Pigment Cell Research (ESPCR) and serves at the boards of additional societies (IFPCS, IMGS, ACB). In 2006, he founded the International Society for Transgenic Technologies (ISTT) for which he has served as President since inception to 2014. He is a member of the CSIC Ethics Committee and the Ethics Panel of ERC in Brussels. In addition to research he is also interested in bioethics, education and popular science.

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