CRISPR Base Editing Gives Live Cell Computation an Upgrade

Think of living cells as minicomputers that can, given sufficiently precise read-write hardware, record and process single-nucleotide mutations and DNA segments instead of bits and bytes. Such hardware has just been introduced by MIT scientists. At its heart is a CRISPR base editing system that can introduce cytosine (C) to thymine (T) mutations to stretches of DNA targeted by guide RNA. CRISPR base editing systems can reliably overwrite DNA at the “bit level” because these systems, unlike ordinary CRISPR gene editing systems, don’t subject DNA to double-strand breaks. Ordinary CRISPR gene editing systems rely on the cell’s own DNA repair machinery, which can lead to uncertain mutational outcomes, limiting the amount of information that can be stored. With their application of CRISPR base editing, the MIT scientists may bring about Cellular Computation 2.0. They have created a system—called DOMINO (DNA-based Ordered Memory and Iteration Network Operator)—that could be used to record the intensity, duration, sequence, and timing of many events in the life of a cell, such as exposures to certain chemicals. Cellular “memories” could then be processed so that one event, or series of events, would trigger another event, such as the production of a fluorescent protein. “We need better strategies to unravel how complex biology works, especially in diseases like cancer where multiple biological events can occur to transform normal cell into diseased ones,” said Timothy Lu, MD, PhD, an electrical engineer and computer scientist at MIT and the Broad Institute. Lu and colleagues, including Fahim Farzadfard, PhD, a Schmidt Science Fellow, developed DOMINO to surpass the recording and scaling capabilities of existing strategies.