Codifying the verbiage in the world’s most potent new genetic technology
I was reviewing a manuscript for a junior faculty member, as I normally do. He repeatedly made the claim that he “CRISPR’d” something. In another review I read about how “CRISPR” was used to introduce new traits. Today I read many headlines where “CRISPR” used to solve a problem.
CRISPR does not do any of that. CRISPR is not a verb.
The sunrise of any new technology introduces an avalanche of new terminology to the pedestrian lexicon. Sadly, a lack of cohesion in the use of new terminology often leads to confusion and even misinformation. The new genetic engineering technologies around gene editing permit scientists to install precise changes in DNA are already revolutionizing medicine and agriculture, and we need to get the verbiage straight in the interest of clear communication.
CRISPR is an acronym that stands for Clustered Regularly Interspaced Palindromic Repeats. This refers to how some genetic information is stored in bacterial cells as part of acquired immunity against viral pathogens. Yes, bacteria get viral infections. The clustered repeats of DNA sequence provide the bacteria with the information of where to cleave the genetic materials of viral invaders. The CRISPR part provides the information of where to cut — it is not the direct mechanism of DNA alteration. In other words, the CRISPR road map where the something else actually does the driving.
The enzyme that facilitates the DNA change is called Cas9, or any one of a number of enzymes called nucleases. Nucleases are enzymes that digest nucleic acids, the “NA” in DNA or RNA. Remember that DNA is the solid genetic blueprint of an organism, RNA is the flimsy temporary information noodle that shuttles genetic information from where it is stored to where it is made into the cell’s structure and function. Nuclease enzymes can be amazingly specific, cutting at precise sequences, or general — just nibbling off the ends of DNA that has already been damaged or cut.
Cas9 is a very special nuclease. Cas9 and its near relatives digest DNA at a spot dictated by a little piece of RNA that tells it where to cut. In other words, the little RNA piece literally guides the cutting hardware to the location where it performs its cleavage. That cut has to be precise. In genome of a pea or human there are 3.2 billion base pairs (or DNA letters) that make up the genetic code. The Cas9 cut can happen at a precise spot in that 3.2 billion letters, analogous to one second in 100 years.
In the bacterium the Cas9 cut happens where the CRISPR region tells it to cut. In the modern biology laboratory scientists provide the guiding RNA that tells the enzyme where to do its work. It is actually called a guide RNA. For five bucks a scientist can order a test tube full of custom guide RNA that targets the gene of interest for editing. That RNA, plus the Cas9 enzyme, are then put to use to perform that precise genetic change.
Technically speaking, nothing is CRISPR’d. That’s a physical thing, a noun. We could argue that it was Cas9’d, but even that is not terribly accurate. That’s because Cas9 is only one of several gene-editing nucleases.
When we edit genes with precision, can we all agree to call it gene editing? Even that’s not perfect because not all DNA represents a gene. DNA editing anyone?
How about guided nuclease mutation? Site-directed nuclease?
We probably should sort this out sooner than later, as this technology clearly has a critical place in the next generation of medicine and agriculture.