Recently featured in Science, Valentino Gantz and Ethan Bier have developed a novel genome editing method that subverts traditional heritability. Termed the mutagenic chain reaction, this process  can insert new mutations in the genome that automatically spread themselves to neighboring chromosomes. Thus, homozygous mutants are generated after just one generation, instead of the two generations normally required under Mendelian rules of heritability.

To successfully impart mutations, the system uses CRISPR/Cas9 technology. CRISPR/Cas9 consists of two parts: a bacterial protein (Cas9) that cuts DNA and a guide RNA (gRNA), which determines where cutting will occur. When expressed together in cells, Cas9 cuts DNA at a site in the genome specified by the gRNA. The CRISPR system can be used to silence genes or to insert new genetic material into the genome. In this report, the researchers use genes encoding CRISPR components as their insert. This powerful and potentially dangerous improvement led to creation of homozygous mutants in fruit flies after only one generation.

First, genetic material encoding CRISPR components is injected into a fruit fly embryo. After being expressed in the injected flies, the CRISPR components find and cut the DNA at the gRNA-specified site. After the DNA is cut, the chromosome must be repaired through a process called homology-dependent repair. This is a process by which DNA sequences are exchanged between identical or similar DNA molecules to repair the damaged DNA. If there are extra genes included in one of those sequences, they will be inserted as well. As you might guess, the genetic material that was originally injected carries the aforementioned identical DNA sequences, leading to permanent incorporation of the CRISPR components into the genome.

Next, the process begins again. The second target sequence, residing on the second copy of the chromosome, is cleaved, and the identical DNA sequences from the first chromosome are incorporated. The end result is a genome, previously unedited, that possesses two copies of brand new DNA. Traditional models of heritability dictate that homozygous mutants should take at least two generations to be present in the genome. The mutagenic chain reaction can achieve this effect in only one generation.

The implications of this research are a double-edged sword. The mutagenic chain reaction has tremendous potential in expediting the creation of model organisms. Additionally, scientists could modify mosquitoes and other human disease carriers, reducing their potential to spread disease. However, once an edit is in the wild, its effects, good or ill, are irreversible. Discoveries such as this are exciting, but must be carefully controlled. The authors acknowledge this fact, and went to great lengths to ensure that their engineered flies never made it out of the laboratory. The flies were kept inside three layers of containment, and were only ever handled by one researcher in secure biosafety areas. The authors even suggest having another major molecular biology conference, similar to the 1975 Asilomar conference on recombinant DNA, to set guidelines for future use of genome editing technology.

Technology like CRISPR and the mutagenic chain reaction hold potential to fundamentally change how humans interact with nature, for better and for worse. Already, much knowledge has been gained from CRISPR. For one, we now know better than ever that rules—even 150 year-old ones—are made to be broken.

edited by Rachel Cohen and Erinn Brigham

Gantz and Bier Article: Valentino Gantz and Ethan Bier, “The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations”. DOI: 10.1126/science.aaa5945

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This article was co-published on the TIBBS Bioscience Blog.