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In the mid-1990s, University of Cambridge biochemists David Klenerman and Shankar Balasubramanian were trying to solve a fundamental problem: how to watch a single DNA polymerase molecule at work. Their approach used modified nucleotides, called reversible terminators, tagged with four different colors of fluorescent molecules. If one of these “terminators” was grabbed by the DNA polymerase and incorporated onto the replicating DNA strand, it would block the addition of any other bases until removed using a separate chemical reaction.