Tripping the alarm: how CRISPR genome editing can accidentally trigger immune responses

You may be familiar with the term CRISPR/Cas9 after the biohacker, Josiah Zayner, injected his arm with DNA that he thought would enhance his muscles (don’t do it! It didn’t work out for Mr. Zayner). But what exactly is CRISPR/Cas9? While we have only recently realized the genetic editing potential of CRISPR (or Clustered Regularly Interspaced Short Palindromic Repeats), this system has existed in nature for billions of years. It is actually a mechanism used by bacteria to defend themselves against viral infections. Simply put, CRISPR/Cas9 acts like a pair of molecular scissors to cut out very specific pieces of DNA, and we have co-opted this system to edit human cell genomes. This system has revolutionized genome editing, which was quite inefficient using prior methods. It is hoped that CRISPR genome editing will enable prevention or cure of a variety human diseases.


The CRISPR/Cas9 system uses a remarkable molecule known as a guide RNA (gRNA) to precisely target a location on the genome for editing. It has been difficult to deliver gRNAs to cells, but new methods have recently been developed that allow gRNA delivery into all kinds of cells, including immune cells and stem cells that play important roles in many diseases.

There is new research that indicates that gRNA delivery into cells can have some unintended consequences. The human body has an array of natural defences against foreign invaders. Upon recognizing certain molecules on the surfaces of foreign invaders, the immune system attempts to eliminate the invader. Some studies have even shown that the body may have pre-existing defenses against Cas9, however, the immune response to the gRNA component has not been extensively studied.

In this review article, Wienert, et. al. investigate immune responses that occur following the insertion of gRNA into mammalian cells. They showed that even a very small amount of gRNA increased the production of immune response proteins by 30-to-50-fold. Higher doses of gRNA induced innate immune responses similar to a Hepatitis C virus infection!

These findings are important because they show that we must be particularly cautious when using CRISPR/Cas9 genome editing in therapeutic treatments that involve primary cells. Further research will be required to fully understand the effects of these inadvertent immune responses.

Summary written by: Elmira Farrashzadeh

To read the full article, please click the following link:

In vitro–transcribed guide RNAs trigger an innate immune response via the RIG-I pathway

Beeke Wienert, Jiyung Shin, Elena Zelin, Kathleen Pestal, Jacob E. Corn


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