Scientists from CIC bioGUNE (Derio, Spain), in collaboration with the Helmholtz Institute Würzburg (HIRI), have created ReChb, a CRISPR tool that allows for more flexible and precise nucleic acid editing, due to ancestral sequence reconstruction (ASR). This breakthrough, recently published in Nature Biotechnology, has the potential to revolutionize nucleic acid editing, enhancing applications in biomedicine, gene therapy, and molecular diagnostics.
An international team of scientists, led by the Cooperative Research Center in Biosciences (CIC bioGUNE, Derio, Spain), in collaboration with the Biofisika Institute of the University of the Basque Country (Leioa, Spain) and the Helmholtz Institute Würzburg (HIRI), has achieved a significant milestone in genetic editing and biotechnology.
Under the direction of Raúl Pérez-Jiménez, Ikerbasque Research Professor and group leader of the Synthetic Biology laboratory at CIC bioGUNE, a new CRISPR tool called ReChb has been developed. This tool expands the capabilities of existing Cas12a nucleases, offering greater versatility and precision in nucleic acid editing and detection. This advancement is attributed to the technique of ancestral sequence reconstruction (ASR), which brings back long-extinct proteins from millions of years ago.
Unlike natural or engineered variants of Cas12a, ReChb does not require any specific PAM DNA sequences, enabling it to edit regions of the genome that were previously inaccessible. Additionally, it has the unique ability to recognize and recognize both DNA and RNA, thereby broadening its range of applications. This tool is designed to perform precise genetic edits in human cells, and its capacity to degrade double-stranded DNA, single-stranded DNA, and RNA without the need for specific sequences makes it one of the most versatile tools of its kind to date.
Wide range of applications
ReChb not only overcomes the limitations of traditional CRISPR tools but also enables applications across various fields, from biomedical research and gene therapy to precise molecular diagnostics. Its ability to be activated with different types of nucleic acids positions it as an essential tool for addressing genetic and viral diseases, eliminating previous restrictions of similar technologies.
“The new ReChb nuclease has molecular properties that have not been achieved with any other enzyme design technique, making it a perfect tool for multiple applications in medicine and biotechnology”, affirmed Raul Pérez-Jiménez.
In ALS (Amyotrophic Lateral Sclerosis) research, ReChb is already being used to facilitate advances in the diagnosis and treatment of this neurodegenerative disease. Its flexibility and precision in recognizing and editing nucleic acids open new possibilities for investigating ALS and other complex pathologies, as it can potentially correct any genetic modification, even those inaccessible to conventional CRISPR techniques, contributing to the development of new therapies against these currently incurable diseases.
“The unique versatility of ReChb expands the application space of CRISPR-Cas nucleases, enabling the editing of ALS mutations that are inaccessible to current genome editing systems”, explains Ylenia Jabalera, a postdoctoral researcher at CIC bioGune. In 2023 and 2024, Jabalera spent time as a visiting scientist in the laboratory of HIRI department head Chase Beisel, who also contributed to the study.
This advancement has been made possible thanks to the support of national and international institutions, including the European Research Council, the Spanish Ministry of Science and Innovation, the Basque Government, and foundations such as FUNDELA. The cryo-electron microscopy capabilities of CIC bioGUNE and the Biofisika Institute also played a crucial role in the study of ReChb.
ReChb not only represents a breakthrough in gene editing but also highlights the potential of ancestral sequence reconstruction (ASR) for developing biotechnological tools with unique properties. Thanks to this technique, a protein has been obtained with functionalities superior to any modern Cas12a, significantly expanding opportunities in biotechnology and precision medicine.
Original Publication
Jabalera Y, Tascón I, Samperio S, López-Alonso JP, Gonzalez-Lopez M, Aransay AM, Abascal-Palacios G, Beisel CL, Ubarretxena-Belandia I, Perez-Jimenez Raul
A resurrected ancestor of Cas12a expands target access and substrate recognition for nucleic-acid editing and detection
Nature Biotechnology (2024), DOI: 10.1038/s41587-024-02461-3
Text: CIC bioGUNE (adapted by HIRI)
Photo: Adobe Stock / Jacqueline Weber
