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CRISPR/Cas9 off target effects: Hyperactive cutting or media hype?

There has been a lot of media coverage in recent months surrounding CRISPR/Cas9 and the potentially life changing impact the gene-editing technology could have. More recently though, this coverage has focused on the potential for serious consequences in the form of off-target effects. The fear with off-target effects is that CRISPR/Cas9 editing is not as specific as initially thought, and that the gene-editing technology may cause unintended genetic modifications. But is this fear of hyperactive cutting legit, or is it all just media hype?

Although there have been many publications discussing off-target effects, many of them contain little data and poorly-designed studies. These publications instantly create a buzz due to their controversial and somewhat scary subject. A study published in 2017 suggesting high rates of off target mutagenic activity due to Cas9 was one such study, and created a large online stir. Despite the initial buzz though, the publication has since been retracted, and authors have published a follow up admitting poor study design contributed to these findings8,9.

So, are off target effects really something we should be worrying about? I am not totally convinced. Studies in C. elegans, Arabidopsis thaliana, mice and zebrafish have all found minimal evidence of off-target activity in CRISPR/Cas9 mutagenesis experiments 2,7,5,4.

Unfortunately, despite vast evidence to the contrary, many pop-sci articles about CRISPR/Cas9 technology mention or even exaggerate these off-target effects, seeding public distrust and potentially hindering research efforts using these technologies3. These articles create a huge stir, and result in many follow up articles all trying to “get in on the buzz” as well.  Even before the Nature Methods paper citing off-target effects was published, there were numerous pop-sci articles based on the initial media release, hyping the fear of off-target effects. These pop-sci articles are latching onto the fear angle in order to gain popularity, and even though the Nature publication has since been retracted, the follow up articles remain live and are constantly circulating.

So how do we, as researchers and scientists, reach the general public through all of the hype and misinformation? How do we stem the tide of misleading pop-sci news in the first place? How do we ensure we’re incorporating proper methodology into our experimental design to avoid another Nature Methods incident? These are the questions I continue to ask myself and my colleagues, because gene-editing technologies such as CRISPR/Cas9 have the potential to greatly improve the lives of so many people, but not if the general public has a fear of the technology based on misleading information. It’s important to note that rigorous CRISPR off-target analysis techniques have been developed and refined, offering reliable ways to assess and mitigate these concerns in research applications.


  1. Burgio, G. (2017, June 03). Should we be worried about CRISPR/Cas9 off target effects? Retrieved from https://medium.com/@GaetanBurgio/should-we-be-worried-about-crispr-cas9-off-target-effects-57dafaf0bd53
  2. Dickinson, D. J., & Goldstein, B. (2016). CRISPR-based methods for Caenorhabditis elegans genome engineering. Genetics, 202(3), 885-901.
  3. Gurev, S. CRISPR in Popular Media: Sensationalism of Germline Editing in Human Embryos. (2017)
  4. Hruscha, A., Krawitz, P., Rechenberg, A., Heinrich, V., Hecht, J., Haass, C., & Schmid, B. (2013). Efficient CRISPR/Cas9 genome editing with low off-target effects in zebrafish. Development, dev-099085.
  5. Iyer, V., Boroviak, K., Thomas, M., Doe, B., Ryder, E., & Adams, D. (2018). No unexpected CRISPR-Cas9 off-target activity revealed by trio sequencing of gene-edited mice. bioRxiv, 263129.
  6. Paper on Off-Target CRISPR Effects Pulled. (2018, April 02). Retrieved from https://www.genomeweb.com/scan/paper-target-crispr-effects-pulled#.W464UehKhPY
  7. Peterson, B. A., Haak, D. C., Nishimura, M. T., Teixeira, P. J., James, S. R., Dangl, J. L., & Nimchuk, Z. L. (2016). Genome-wide assessment of efficiency and specificity in CRISPR/Cas9 mediated multiple site targeting in Arabidopsis. PloS one, 11(9), e0162169.
  8. Schaefer, K. A., Wu, W. H., Colgan, D. F., Tsang, S. H., Bassuk, A. G., & Mahajan, V. B. (2017). Unexpected mutations after CRISPR-Cas9 editing in vivo. Nature methods, 14(6), 547-548.
  9. Schaefer, K. A., Darbro, B. W., Colgan, D. F., Tsang, S. H., Bassuk, A. G., & Mahajan, V. B. (2017). Corrigendum and follow-up: Whole genome sequencing of multiple CRISPR-edited mouse lines suggests no excess mutations

About The Author

Ben Jussila

Ben is an R&D scientist at InVivo Biosystems, specializing in genome editing with CRISPR/Cas9 technology in zebrafish. He received his Bachelor of Science from the University of Minnesota in Genetics, Cell Biology & Development in 2014, and worked as a research technician in the laboratory of Dr. Kristen Kwan at the University of Utah prior to joining the InVivo Biosystems team in 2018. Ben is passionate about nature and conservation, and in his spare time enjoys science outreach, field herpetology, his cats, and raising and breeding reptiles and amphibians.

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