Polymerase chain reaction

The polymerase chain reaction emerged from a Friday night drive through California redwoods. In April 1983, Kary Mullis was cruising Highway 128 from San Francisco to Mendocino when he realized that by using two opposing primers and repeated cycles of heating and cooling, he could exponentially amplify any segment of DNA. The idea was so simple it seemed impossible that no one had thought of it—but the conditions had only just aligned.

The adjacent possible required several advances. DNA polymerase, which copies DNA, had been understood since the 1950s. Synthetic oligonucleotides (short DNA primers) had become commercially available. And crucially, Mullis worked at Cetus Corporation synthesizing these primers; he understood their potential better than anyone. What he conceived on that drive was not a new molecule but a new process: denature DNA with heat, anneal primers to each strand, extend with polymerase, repeat. Each cycle doubles the DNA. Twenty cycles yields a million copies.

Multis demonstrated PCR on December 16, 1983, but colleagues remained skeptical amid ambiguous results. The early protocol was laborious: the E. coli DNA polymerase was destroyed by each heating cycle and had to be replenished. Cetus workers built a thermal cycler nicknamed "Mr Cycle" to automate enzyme addition. The real breakthrough came in 1985 when Mullis proposed using Taq polymerase from Thermus aquaticus, a bacterium living in hot springs at 72°C. Taq survived the 94°C denaturation step, making the process practical and automatable.

The cascade from PCR transformed molecular biology, forensics, medicine, and diagnostics. Suddenly, researchers could work with infinitesimal DNA samples. Crime scene technicians could amplify DNA from a single hair. Paleontologists could sequence extinct species from fossils. Prenatal testing became possible from a few fetal cells. HIV diagnosis improved dramatically. And when COVID-19 emerged in 2020, PCR testing became the global standard for detection.

Mullis received the 1993 Nobel Prize in Chemistry, but Cetus owned the patents. He received a $10,000 bonus for his invention; Cetus sold the PCR rights to Hoffmann-La Roche for $300 million in 1992. The disparity between inventor compensation and commercial value became a cautionary tale in biotechnology.

Path dependence favored PCR's particular implementation. Alternative amplification methods exist—LAMP, NASBA, SDA—but PCR's installed base of thermal cyclers, reagent kits, and trained technicians made it the default. The last major PCR patents expired in 2017, enabling widespread generic production.

By 2026, PCR remains foundational. Quantitative PCR measures gene expression. Digital PCR enables absolute quantification. The technique Mullis conceived on a dark highway became as essential to molecular biology as the microscope—a way of seeing what would otherwise remain invisible.