Ancient RNA-Guided System Could Simplify Gene Editing Therapies: A Breakthrough Discovery

In a groundbreaking discovery, scientists at MIT’s McGovern Institute for Brain Research and the Broad Institute of MIT and Harvard have unveiled ancient RNA-guided systems, dubbed TIGR (Tandem Interspaced Guide RNA) systems, that promise to revolutionize gene editing therapies. These systems offer a compact and versatile alternative to CRISPR, potentially simplifying the delivery of gene editing tools.

Published in the journal Science on February 27, the findings highlight the potential of TIGR systems to target specific DNA sites using RNA guides. Unlike CRISPR, TIGR systems boast a modular design, allowing researchers to swap in new features and functionalities into natural Tas proteins. The compact size of Tas proteins, averaging a quarter of the size of Cas9, addresses a major obstacle in therapeutic gene editing by making delivery more efficient.

Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, who led the research, emphasizes the versatility of these systems. The TIGR-associated (Tas) proteins identified by Zhang’s team interact with an RNA guide that directs the protein to a specific location in the genome. Some of these proteins can cut DNA at the targeted site using an adjacent DNA-cutting segment, underscoring their modular nature.

Zhang, also an investigator at the McGovern Institute, Howard Hughes Medical Institute, a core member of the Broad Institute, and a professor at MIT, notes the incredible diversity of nature and the potential for harnessing natural biological mechanisms for manipulating biological processes. His team previously adapted bacterial CRISPR systems into revolutionary gene editing tools.

The search for novel programmable systems began with a focus on a structural feature of the CRISPR-Cas9 protein responsible for binding to the enzyme’s RNA guide. By iteratively searching millions of biological proteins, the team identified distantly related proteins, eventually turning to artificial intelligence to cluster them based on evolutionary relationships. This led to the discovery of TIGR-Tas systems, encoded by genes with regularly spaced repetitive sequences.

The team discovered over 20,000 different Tas proteins, predominantly in bacteria-infecting viruses. Sequences within the TIGR arrays encode RNA guides that interact with the RNA-binding part of the protein. Experiments showed that some Tas proteins can be programmed to make targeted cuts to DNA in human cells.

One notable advantage of TIGR Tas proteins is their lack of requirement for short DNA motifs known as PAMs, which are essential for CRISPR systems. Rhiannon Macrae, a scientific advisor on the team, points out that this means theoretically, any site in the genome should be targetable. The team’s experiments further indicate that TIGR systems utilize a “dual-guide system,” interacting with both DNA strands to ensure precise targeting.

Currently, Zhang’s team is exploring the natural role of TIGR systems in viruses and investigating how they can be adapted for research and therapeutic applications. They have determined the molecular structure of one Tas protein that functions in human cells, which will guide efforts to enhance its efficiency. The team also plans to investigate connections between TIGR-Tas systems and RNA-processing proteins in human cells.