Of CRISPRs, chemistry, and women
Authors: None The Lancet Microbe
Journal: The Lancet Microbe (2020)

When clustered regularly interspaced short palindromic repeats (CRISPRs) were first observed in the genomes of a handful of microbial species, nobody would have predicted that these enigmatic segments of DNA would become the foundation of the genome-editing tool CRISPR-Cas9 that has revolutionised life-science research. In recognition of the extraordinary versatility of this tool and of their role in its development, Emmanuelle Charpentier (Max Planck Unit for the Science of Pathogens, Berlin, Germany) and Jennifer Doudna (University of California, Berkeley, CA, USA) have been awarded the Nobel Prize in Chemistry 2020. In a year dominated by the COVID-19 pandemic, the acknowledgment of these two scientists—only the sixth and seventh women to win the Nobel Prize in Chemistry and the first pair of women to jointly share any Nobel Prize— came as a breath of fresh air. Awarded just 8 years after the CRISPR-Cas9 system was developed, the Prize is a testament to the scientific rigour of Charpentier and Doudna's research and to their far-sighted intuition of the potential of CRISPR-Cas9. This year's Prize is a reminder that fundamental microbial research can have implications reaching far beyond the purely exploratory. The journey that led to the development of CRISPR-Cas9 as a genome-editing tool started in the early days of DNA sequencing and genomic investigation. It was advanced by a small community of scientists including environmental microbiologists, who observed CRISPRs were widespread in prokaryotes; evolutionary microbiologists, who identified snippets of viral DNA between CRISPR repeats; functional genomics researchers, who probed the role of CRISPRs and identified CRISPR-associated (Cas) proteins; and food microbiologists, who sought to protect food processes reliant on bacteria from the deleterious effects of viral infections and recognised CRISPRs as a mechanism of bacterial defence. The collective efforts of these scientists revealed CRISPRs to be genetic records of previous viral infection, used by microbes to identify and, in conjunction with Cas proteins, silence invading viruses, in what essentially is a microbial adaptive immune system. In their seminal article published in Science in 2012, Charpentier and Doudna elucidated the molecular mechanism of Streptococcus pyogenes immunity: two RNA molecules guide the Cas9 protein to a target DNA sequence, which is then cut. They further demonstrated how the CRISPR-Cas9 system could be tailored to recognise any DNA sequence and cleave a desired site, enabling the modification of the sequence at that site. The life-science research community did not miss the almost limitless potential of this tool and immediately engaged in increasing its specificity and range of possible mutations. The simplicity of the CRISPR-Cas9 system democratised genome editing and extended the reach of genetic investigation beyond traditional model organisms, to include species that had previously been impossible to modify and whose traits could only be interrogated via observation. In the biomedical field, the possibility of correcting genetic mutations that cause disease in humans has been the major drive of CRISPR-Cas-based research. The most promising targets at present are diseases that affect tissues or organs that can be manipulated or accessed easily—with phase 1–2 clinical trials to treat sickle cell disease, β-thalassaemia, and Leber congenital amaurosis already underway—and cancer immunotherapy. However, it might become possible to target diseases such as cystic fibrosis, muscular dystrophy, and neurodegenerative diseases. In infectious diseases, CRISPR-Cas systems have been used: to probe host–pathogen interactions to identify potential therapeutic or vaccine targets; to disrupt fertility of pathogen vectors such as mosquitoes or make them immune to infection (eg, with dengue virus), thus interrupting the pathogen transmission cycle and preventing human infection; and to develop diagnostic tools. Several technical hurdles, most notably the risk of off-target edits, will need to be overcome before any of these potential uses can be translated to real-world applications. Furthermore, the scientific community and regulatory bodies worldwide need to ensure safe, responsible, and ethical use of genome editing. Risks and concerns are inevitable with any new technology, but by no means do they diminish the phenomenal impact of the discovery of CRISPR-Cas9. The breadth of applications that this humble three-component bacterial immune system has unleashed leaves us wondering what other game-changing tricks might be hidden away in the genomes of prokaryotes. For more on CRISPR-Cas-based SARS-CoV-2 diagnostics see Nature Biotechnology 2020; 38: 870–74 For more on CRISPR-Cas-based SARS-CoV-2 diagnostics see Nature Biotechnology 2020; 38: 870–74