CRISPR systems are powerful tools for genetic engineering, but they have their limitations. Now, scientists have discovered almost 200 new CRISPR systems in their native habitat of bacteria, and found that some can edit human cells even more precisely than existing ones.
The CRISPR-Cas9 gene-editing tool is one of the most important scientific developments of the past decade, earning its discoverers a Nobel Prize in Chemistry. Scientists can use it to make efficient cut-and-paste edits to human cells, potentially treating a huge range of diseases, as well as improving crops, controlling pests, and manipulating bacteria.
The system contains a guide RNA that targets a segment of DNA, such as one that causes disease, then uses an enzyme, usually Cas9, to snip out that sequence and replace it with something more beneficial. More recently, alternatives to Cas9 have been developed with other properties, including higher precision or larger edits.
Now, that family has potentially grown much bigger. Researchers at the Broad Institute, MIT and the National Institutes of Health (NIH) used an algorithm to search for new CRISPR systems. In nature, CRISPR is a self-defense tool used by bacteria, so the team performed a deep dive into three databases of bacteria, found in environments as diverse as Antarctic lakes, breweries and dog saliva. The algorithm is built around a technique called locality-sensitive hashing, which groups similar objects together, and in this case, the team set it to look for genes linked to CRISPR.
Within a few weeks, the system identified thousands of CRISPR systems, including 188 that were previously unknown to science. In lab tests they demonstrated a range of functions, and fell into both known and brand new categories.
Several belonged to a class called Type I CRISPR systems, which have longer guide RNA sequences than Cas9. That means they can be directed to their targets more precisely, reducing the risk of off-target edits – one of the main problems with CRISPR gene editing. In tests, two of these Type I systems were found to be capable of editing human cells, and their size should allow them to be delivered in the same packages currently used for CRISPR-Cas9.
Another Type I system showed what’s known as “collateral activity,” breaking down nucleic acids after binding to the target. This mechanism has previously been used in diagnostics tools like SHERLOCK to identify disease from samples as little as a single molecule of DNA or RNA.
A Type VII system was found to target RNA, which could unlock a range of new tools through RNA editing. Others could be adapted to record when certain genes are expressed, or as sensors for activity in cells.
Not only does this study greatly expand the field of possible gene editing tools, but it shows that exploring microbial ecosystems in obscure environments could pay off with potential human benefits.
“Some of these microbial systems were exclusively found in water from coal mines,” said Soumya Kannan, co-first author of the study. “If someone hadn’t been interested in that, we may never have seen those systems. Broadening our sampling diversity is really important to continue expanding the diversity of what we can discover.”
The research was published in the journal Science.
Source: Broad Institute
