Genetics & Molecular · 1978
Recombinant Human Insulin (synthesis of the gene)
By the mid-1970s, the global supply of therapeutic insulin depended entirely on the pancreases of slaughtered pigs and cattle. The insulin itself was biologically active in humans, but it differed from human insulin at one or three amino acid positions, and a small but clinically significant fraction of patients developed antibody responses that blunted its effect or caused local reactions. More urgently, the supply chain was inherently finite. Projections suggested that porcine and bovine pancreas might not scale fast enough to meet the growing demand as the prevalence of type 1 and insulin-requiring type 2 diabetes increased.
The solution came from the newly formed company Genentech and its collaborators at City of Hope National Medical Center in Duarte, California. In 1977 and 1978, David Goeddel and a small team at Genentech, working with Arthur Riggs and Keiichi Itakura at City of Hope, synthesized the DNA sequences encoding insulin's A chain and B chain separately, inserting each into E. coli expression vectors. The bacteria produced each chain as a fusion protein that could be cleaved and purified. The two chains were then combined chemically under oxidizing conditions to form active insulin through correct disulfide-bond pairing.
Herbert Boyer, Genentech's co-founder and the scientist whose recombinant DNA cloning techniques made bacterial expression possible, had helped establish the methodological basis for the entire project through his earlier work with Stanley Cohen on plasmid-based gene cloning. The completed results were reported in Science in 1979. The insulin produced was chemically identical to human insulin, not merely similar to it, which eliminated the immunogenicity concerns associated with animal-derived preparations.
Eli Lilly licensed the technology from Genentech and invested in scaling the fermentation and purification processes to pharmaceutical-grade manufacturing. The FDA granted approval for Humulin, recombinant human insulin, in October 1982, making it the first recombinant DNA-derived drug to reach patients. The approval came less than four years after the initial gene synthesis, an unusually fast progression that reflected both the urgency of the supply concern and the relative familiarity of insulin as a therapeutic target.
The insulin project demonstrated that bacteria could be engineered to produce a complex human protein at scale with clinical-grade purity. That proof shaped the entire field of biologics. Recombinant growth hormone, erythropoietin, clotting factors, and eventually monoclonal antibodies all followed the same fundamental logic: identify the gene, express it in a tractable host, purify the product, and validate its equivalence to the endogenous protein. The regulatory pathway Humulin established required documentation of manufacturing consistency, purity, and bioequivalence that became the standard submission framework for subsequent biologics.
Key People
- David Goeddel — Genentech scientist who led the gene synthesis and bacterial expression work
- Herbert Boyer — Genentech co-founder whose recombinant DNA methods made the project possible
- Arthur Riggs — City of Hope chemist who collaborated on the synthetic gene construction
- Keiichi Itakura — City of Hope scientist who synthesized the oligonucleotide gene sequences
Proc Natl Acad Sci U S A. 1979
Related landmarks
- 1977 · Sanger DNA Sequencing (dideoxy chain-termination method) (Genetics & Molecular)
- 1975 · Southern blot: DNA detection by gel transfer and hybridization (Genetics & Molecular)
- 1985 · Polymerase Chain Reaction (PCR) (Genetics & Molecular)
- 1990 · First Approved Human Gene Therapy (ADA-SCID, Ashanthi DeSilva) (Genetics & Molecular)