Zinc finger

Proteins need to recognize specific DNA sequences to regulate genes. But DNA is just four bases—adenine, thymine, guanine, cytosine—arranged in long sequences. How can a protein find a particular 9 or 12 base-pair sequence among billions? The answer, discovered in 1985, was the zinc finger: a small protein domain that uses a zinc atom to hold a precise shape capable of reading DNA like fingers reading Braille.

Aaron Klug at the Medical Research Council's Laboratory of Molecular Biology in Cambridge was studying TFIIIA, a transcription factor from the African clawed frog Xenopus. His colleague Jonathan Miller noticed that the protein contained multiple repeating sequences, each about 30 amino acids long. When they analyzed the structure, they found something unexpected: each repeat folded into a compact domain stabilized by a single zinc ion coordinated by cysteine and histidine amino acids. The finger-like domains extended outward, each recognizing a specific three-base-pair sequence of DNA.

The discovery opened a new understanding of gene regulation. Zinc fingers weren't rare anomalies—they were everywhere. The human genome encodes roughly 700 zinc finger proteins, making them one of the most common protein domains in biology. Each zinc finger recognizes a specific DNA triplet; stringing multiple fingers together allows recognition of longer, more specific sequences. Evolution had discovered modular DNA recognition, building complex specificity from simple repeated units.

The adjacent possible had assembled over the previous two decades. X-ray crystallography had advanced enough to reveal atomic-level protein structures. DNA sequencing, pioneered by Fred Sanger (also in Cambridge), allowed researchers to correlate protein sequences with function. The MRC Laboratory of Molecular Biology had become the world's center for structural biology, with Klug having already won the 1982 Nobel Prize for developing crystallographic electron microscopy. The intellectual infrastructure for this discovery was concentrated in one building.

The Cambridge location mattered beyond mere coincidence. The LMB had pioneered protein structure determination since the 1950s—Francis Crick had worked there, Max Perutz had solved hemoglobin's structure there. The laboratory's culture prioritized fundamental discovery over immediate application. Klug's group could pursue basic science on transcription factors without pressure to demonstrate practical utility. When the zinc finger's significance became clear, the same environment would foster decades of follow-on research.

The cascade from discovery to application took time. In the 1990s, researchers realized zinc fingers could be engineered: by changing the amino acids at key positions, you could alter which DNA triplet each finger recognized. Carl Pabo at MIT and colleagues systematically determined the recognition rules. By the early 2000s, scientists could design zinc fingers to target almost any DNA sequence. Attaching a nuclease domain created zinc finger nucleases (ZFNs)—the first programmable tools for cutting DNA at specific locations, enabling precise genome editing before CRISPR made it easier.

By 2025, zinc finger proteins had enabled the first wave of therapeutic genome editing. Sangamo Therapeutics developed ZFN-based treatments for HIV, hemophilia, and rare genetic diseases. Though CRISPR eventually eclipsed ZFNs for research applications due to its simpler design, zinc finger therapeutics retained advantages in certain contexts—smaller size, reduced immunogenicity, proven clinical track records. A discovery about frog transcription factors had become a foundation for rewriting human DNA.