CRISPR's origin: salt-pond microbes, repeated rejections, and sickle cell treatment

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In December 2023, the FDA approved the first CRISPR-based therapy — a treatment for sickle cell disease — tracing back to a Spanish microbiologist, Francisco Mojica, who spent the 1990s puzzling over strange repetitive DNA sequences in a salt-loving microorganism from coastal salt flats near Alicante, Spain. In 2003 Mojica matched those spacer sequences against public genome databases and realized they were snippets of past viral DNA — a memory system that bacteria use to recognize and destroy viruses they've encountered before. He had discovered an adaptive immune system in single-celled organisms. His paper was rejected by Nature, the Proceedings of the National Academy of Sciences, and two other journals before appearing in a smaller journal in 2005. Danisco, a yogurt company, provided key experimental confirmation in 2007 because phage infections are a serious industrial problem in dairy fermentation.

Jennifer Doudna and Emmanuelle Charpentier — who won the 2020 Nobel Prize in Chemistry — showed in 2012 that the CRISPR system could be programmed with a custom guide RNA to cut DNA at any specific location and incorporate new DNA into the cut site, effectively editing any gene in any organism. The approved sickle cell therapy, Casgevy, uses this mechanism. Peter Attia notes it is complex, expensive, and requires bone marrow conditioning, but for patients who can access it, the vaso-occlusive crises that defined their lives essentially stopped. An early-phase trial in familial hypercholesterolemia — an inherited condition causing dangerously high LDL cholesterol — has also posted promising results.