Phage display

Phage display emerged in 1985 when George Smith at the University of Missouri demonstrated that peptides could be displayed on the surface of bacteriophages—viruses that infect bacteria—by inserting DNA encoding the peptide into the phage's coat protein gene. This seemingly simple technique became a platform for drug discovery, enabling the selection of binding molecules from libraries containing millions of variants. Smith shared the 2018 Nobel Prize in Chemistry for work that spawned an industry.

The adjacent possible opened through understanding of bacteriophage biology and recombinant DNA techniques. Filamentous phages—particularly M13—were well characterized: their genetics understood, their life cycle mapped. Recombinant DNA technology allowed precise insertion of foreign DNA into phage genomes. Smith's insight was that a peptide fused to a phage coat protein would be displayed on the viral surface, where it could be selected based on its binding properties.

Smith spent the 1983-1984 academic year at Duke University with Robert Webster, where he began the work that would lead to the Nobel Prize. His 1985 Science paper demonstrated the basic technique: inserting foreign DNA into gene III of filamentous phage caused the encoded peptide to appear on the phage surface. The phage became a molecular billboard advertising the peptide it carried.

The breakthrough's power became clear with phage-displayed peptide libraries. In 1988, Smith and PhD student Stephen Parmley published a landmark paper describing how to create libraries of a million or more phage clones, each displaying a different random peptide. 'Biopanning'—selecting phages that bound to a target—could identify peptides with desired binding properties from this enormous diversity. Evolution in a petri dish.

Gregory Winter at Cambridge extended phage display to antibodies, enabling the isolation of human antibodies without immunizing animals. This application proved commercially transformative. Humira (adalimumab), discovered using phage display and approved in 2002, became the world's best-selling drug. By 2024, at least six major antibody medicines and the majority of therapeutic antibodies in development pipelines traced their origins to phage display.

The cascade spawned biotechnology companies and transformed drug discovery. Companies including Cambridge Antibody Technology, Dyax, and others built businesses around phage display libraries. The technique enabled directed evolution—systematically improving proteins through rounds of selection. Smith's 1985 insight that phages could display foreign peptides had become foundational technology for the biopharmaceutical industry.