Variation in the DNA sequences that constitute the blueprint of life is essential to the fitness of any species, yet thousands of DNA alterations are thought to cause disease. After decades of research in genetics and molecular biology, tremendous progress has been made in developing genome-editing tools for correcting such alterations. But a seemingly fundamental limit to the efficiency and precision of gene editing was reached, owing to the tools’ reliance on complex and competing cellular processes. Writing in Nature, Anzalone et al. describe ‘search-and-replace’ genome editing, in which the marriage of two molecular machines enables the genome to be altered precisely. The technique has immediate and profound implications for the biomedical sciences.
Human efforts to engineer genomes pre-date knowledge of genes or even of the source of heredity. The first genome engineering relied on natural variation and artificial selection through selective breeding. Modern maize (corn), for example, was ‘engineered’ from its wild ancestor, teosinte, through artificial selection more than 9,000 years ago. Later progress was fuelled by the realization that DNA sequences shape life, and that evolution can be augmented and artificially accelerated through the use of mutagenic agents, such as radiation or chemicals.
Next came the discovery that cellular processes for repairing mistakes in DNA sequences could be hijacked, allowing sequences from a foreign ‘template’ DNA to be inserted into the genome at DNA breaks. This process is greatly enhanced if the DNA is intentionally damaged — a finding that sparked a search of more than 20 years for an enzyme that could specifically cut DNA at locations of interest. The search culminated in the adoption of the bacterial CRISPR–Cas9 system, in which the enzyme Cas9 uses a customizable RNA guide to search for DNA sequences to cut in human cells…
