From muck to molecule: insulin discovery over 50 years

A pancreatic extract which was successful in lowering glucose in diabetes was developed and commercialized with leadership from the University of Toronto in 1921-1922. The active principle remained unknown, though it was assumed to be the `insulin' (or `isletin' or `insuline') identified microscopically in the islets of Langerhans from work in the previous 50 years. Within four years the active principle was crystallized by Abel and co-workers, and convincing proof given that it was a peptide. Determining the amino acid sequence of this relatively small protein proved a 30-year task for science, due to the confounding effects of two short chains united by di-sulphide bridges. Even then it was a mystery how the sequence related to insulin activity. That remained the case when the early X-ray diffraction work in the 1930s by Crowfoot (Hodgkin) matured in 1969 with the determination of the 3-dimensional structure of the insulin hexamer. Meanwhile 25 years of work, much in industry, invented useful extended-acting insulin preparations and, over an even longer time course, insulin preparations of high enough purity to be non-immunogenic in clinical practice. In the 1960s and 1970s work on radioimmunoassay and on glucose clamps provided tools that would prove critical to the further development of insulin as a medication over its second 50 years.