Reacción a "AI-designed proteins could expand the CRISPR genome-editing toolkit beyond those produced by evolution"

When Jennifer Doudna and Emmanuelle Charpentier first met at a scientific conference in San Juan, Puerto Rico, in March 2011, they did not have the same level of experience in the field of CRISPR. Charpentier was a newcomer, with a paper in the pipeline that would be published in *Nature* and would describe one of the main components of CRISPR systems: tracrRNA. Doudna, however, had already been working for years and publishing excellent papers on RNA projects and CRISPR systems, primarily analysing the structures of various Cas proteins. Once again, serendipity had meant that a colleague at her institution, the University of California, Berkeley, Jill Banfield, had alerted her to Francis Mojica’s 2005 paper, in which he described CRISPR systems for the first time as a new immune defence system used by bacteria to defend themselves against viruses. Charpentier was introducing herself to the world with her first CRISPR paper, but Doudna had already published numerous articles on the subject. They agreed in Puerto Rico to collaborate and, a year and several months later, in June 2012, they jointly published an article in Science in which they proposed transforming Mojica’s CRISPR systems into new tools for gene editing. In October 2020, they both deservedly received the Nobel Prize in Chemistry for that proposal, and the rest is scientific history.

Charpentier has undoubtedly been the more successful of the two in her entrepreneurial venture, having founded the company CRISPR Therapeutics which, together with Vertex Therapeutics, has developed the first CRISPR therapy approved by the EMA and the FDA, Casgevy, to treat two serious blood disorders: sickle cell anaemia and beta-thalassaemia. Doudna has also founded several companies, and one of them, Intellia, is likely to be the one to secure approval for the second CRISPR therapy, this time to treat a rare disease: transthyretin-associated congenital amyloidosis. But if there is one area in which Doudna has stood out from her colleague Charpentier, it is in her scientific excellence, having regularly published remarkable advances not only on the basic mechanisms of how CRISPR-Cas systems work, but also on the identification and characterisation of new CRISPR-Cas systems, and on the origin and evolution of these marvellous tools that have transformed the lives of researchers in biology, biomedicine and biotechnology.

This is the case with the latest paper from Doudna’s laboratory, published in Science, yet another example of her scientific excellence. In this new study, Doudna has set out to explore the design of new Cas proteins with unique properties—not derived from nature, but developed in the laboratory—based on a minimal version of Cas proteins known as TnpB.

By harnessing the benefits of artificial intelligence, they have succeeded in developing new Cas proteins with characteristics that surpass those of known Cas proteins, for use in gene-editing applications in bacteria, plants and animals alike. Drawing on their extensive knowledge of protein structure, they have analysed (with the aid of cryo-electron microscopy) how the various domains of these new Cas proteins arrange themselves, whilst maintaining their RNA-guided nuclease activity.

This new strategy, which combines the identification of structural domains with the characterisation of essential amino acids in these proteins, offers an unexpected source for generating new Cas proteins—distinct from those found in nature but retaining their Cas activity—for use in various applications where CRISPR-Cas systems still require optimisation in terms of both efficacy and safety.

This publication is sure to generate a great deal of discussion and will provide the scientific community with countless new Cas proteins to experiment with in our laboratories. Many thanks, Jennifer Doudna.