DNA sequencing

DNA sequencing emerged because molecular biologists could finally read what evolution had written. By the mid-1970s, scientists understood that DNA's four-letter alphabet encoded all biological information—but reading that alphabet remained impossibly tedious. Restriction enzymes could cut DNA at specific sequences; gel electrophoresis could separate fragments by size. What was missing was a systematic method to determine the order of nucleotides in those fragments.

Convergent evolution proves the conditions had aligned. In 1977, two completely independent methods emerged on opposite sides of the Atlantic within months of each other. Frederick Sanger at the MRC Laboratory of Molecular Biology in Cambridge developed the "dideoxy" chain-termination method. Walter Gilbert and Allan Maxam at Harvard developed chemical cleavage sequencing. Neither team knew the other was close. Both methods worked; both earned Nobel Prizes.

Sanger's method exploited a elegant trick. Normal DNA polymerase builds new DNA strands by adding nucleotides one at a time. Sanger modified some nucleotides—dideoxynucleotides—to act as chain terminators. When DNA polymerase incorporated one, the chain stopped growing. By running four reactions, each with a different terminating nucleotide, and separating the resulting fragments by size, the sequence could be read directly from the gel.

Gilbert and Maxam took a different approach. Their chemical method used specific reagents to cleave DNA at particular bases, generating fragments that revealed the sequence when separated. The technique was powerful but required hazardous chemicals and was more labor-intensive. Path dependence would favor Sanger's method, which proved easier to automate.

The cascade from DNA sequencing transformed biology into an information science. Sanger's team sequenced the first complete DNA genome—bacteriophage φX174 with 5,386 nucleotides—in 1977. They discovered that some genes overlapped, sharing the same DNA for different proteins. By 1981, Sanger had sequenced human mitochondrial DNA (16,569 base pairs) and bacteriophage λ (48,502 base pairs). The Human Genome Project, completed in 2003, sequenced all 3 billion base pairs of human DNA.

Automation accelerated the cascade. When Leroy Hood and Applied Biosystems replaced radioactive labels with fluorescent dyes and automated detection in 1986, sequencing throughput exploded. What once required weeks of manual labor could be accomplished in hours. Successive generations of sequencers—capillary electrophoresis in the 1990s, next-generation sequencing in the 2000s—reduced costs from dollars per base to fractions of a cent.

By 2026, sequencing has become routine. Clinical whole-genome sequencing diagnoses rare diseases and guides cancer treatment. Consumer ancestry tests have sequenced tens of millions. The technology Sanger pioneered—reading biology's source code—now shapes medicine, agriculture, forensics, and our understanding of evolution itself.