What if CRISPR could be used not just to edit genes, but also to alter the epigenome—the vast network of chemicals and proteins that orchestrates the actions of genes? A study from biomedical engineers at Duke University describes a new CRISPR technology that could allow scientists to do just that.
The most commonly used gene editing technology, CRISPR-Cas9, uses just one Cas protein to cut DNA. In the CRISPR field, this is known as a “class 2” system. Class 1 systems, by contrast, are more complicated because they rely on multiple proteins to bind to DNA and then recruit a Cas3 protein to cut it. That network of proteins is called Cascade (CRISPR-associated complex for antiviral defense).
The Duke team used a class 1 CRISPR system to edit the epigenome in cells. In a study published in Nature Biotechnology, they reported that they were able to attach gene activators to the Cascade complex and regulate levels of gene expression in cells. They also connected a repressor to Cascade to turn genes off altogether.
"We have found Cascade's structure to be remarkably modular, allowing for a variety of sites to attach activators or repressors, which are great tools for altering gene expression in human cells," said Adrian Oliver, Ph.D., a postdoctoral fellow and lead author of the study, in a statement.
The potential of CRISPR-Cas3 is already generating some excitement in the biopharma world. In January, Locus Biosciences inked a deal with Johnson & Johnson to develop its platform for using CRISPR-Cas3 to solve the problem of antibiotics resistance. The deal could be worth up to $818 million for Locus, a 2019 Fierce 15 company.
Meanwhile, several academic groups are investigating various ideas for improving CRISPR, including another Duke team that’s focused on improving the Cas9 enzyme. In April, it described a technique for adding a short tail to the guide RNA that’s used in CRISPR systems to improve the accuracy of gene cuts.
Researchers at Columbia University are hoping to sidestep DNA cutting altogether. They’re using a transposon, or “jumping gene,” in a system designed to insert DNA in exact locations in the genome without cutting.
The Duke researchers working on class 1 CRISPR technology are planning further studies to determine whether it might help solve some of the shortcomings of CRISPR-Cas9 in addressing human disease, including the risk of dangerous immune responses. They are also investigating whether the tool could be used to perform many different genome engineering tasks simultaneously.
"We know CRISPR could have a big impact on human health," said Charles Gersbach, Ph.D., Duke professor of biomedical engineering. "But we're still at the very beginning of understanding how CRISPR is going to be used, what it can do, and what systems are available to us.”