Insulin's first century: what the earliest peptide drug taught regulators

The story people know about insulin is the discovery story, and it is a good one: a surgeon, a medical student, a physiologist, a biochemist, one Toronto laboratory, and a dog. The story that matters more for how medicines are regulated today is the one that comes after — the two decades in which a promising extract had to be turned into a product that behaved the same way in Toronto in March and in Indianapolis in September. Almost every durable lesson in the insulin record is a manufacturing lesson.

The Toronto winter

Frederick Banting arrived at the University of Toronto in 1921 with an idea about ligating the pancreatic duct and a request for laboratory space. J. J. R. Macleod gave him the space, a student assistant in Charles Best, and left for the summer. By the end of that year the group had an extract that lowered blood glucose in depancreatised dogs, and James Collip — the biochemist brought in that December — had worked out a purification good enough for human use.

The first attempt on a patient, in January 1922, went badly: the preparation caused a sterile abscess and had little effect. The second attempt, after Collip's reworked purification, worked. That gap of a few weeks is the whole subject of this article in miniature. The molecule had not changed. What changed was the process, and the process was the medicine.

The 1922 Canadian Medical Association Journal report is worth reading for its tone as much as its content. It is cautious to the point of flatness. The authors describe what they observed in a small series of patients and decline to generalise. Within eighteen months the same institution would be fielding letters from every continent.

The patent decision

Banting, Best and Collip were granted the patent and assigned it to the University of Toronto for a nominal sum — one dollar each, in the version that gets repeated. The gesture is usually told as pure altruism, and altruism was part of it. But the Insulin Committee's own correspondence shows a second, more practical motive: control.

Holding the patent let the university licence manufacturers on conditions. Licensees had to meet the committee's standards, submit to its testing, and could lose the licence if their product failed. Without the patent, anyone could have sold anything under the name "insulin," and in 1923 there was no federal apparatus in either the United States or Canada that could reliably have stopped them. The patent was not being used to extract rent. It was being used as a quality-control instrument, because no better instrument existed yet.

From pancreas to bioreactor

For six decades, insulin came from animal pancreases — mostly bovine and porcine, collected at slaughterhouses and processed in bulk. This worked, and it had two structural problems. Supply was tied to meat production rather than to patient need, and it was not obvious that it could scale indefinitely. And the product was not human insulin; it was a closely related animal protein, differing by a small number of amino acid residues, with the immunological consequences that implies for some patients.

The 1978–1982 stretch changed the manufacturing base. Work reported in Proceedings of the National Academy of Sciences in 1979 described expressing chemically synthesised genes for the human insulin A and B chains in Escherichia coli. Regulatory approval of a recombinant human insulin product followed in 1982 — the first recombinant DNA-derived medicine cleared anywhere.

What mattered was less the novelty than the consistency. A fermentation process can be characterised, held within defined parameters, and audited. A supply chain that begins at an abattoir cannot be, not to the same degree. The shift decoupled supply from livestock and moved insulin manufacturing into a framework where process control could be inspected directly.

What standardization actually solved

Here is the part that quietly built the modern system. Early extract batches varied in strength enough that describing a quantity by weight or volume told a physician very little. The response was to define potency biologically — by measured effect against a reference preparation, expressed in units — and to hold a physical reference standard that laboratories everywhere could compare their material against. International standardization conferences took this up in the 1920s, and the arrangement was eventually inherited by the WHO Expert Committee on Biological Standardization.

The chemistry came later. Frederick Sanger's sequencing work through the early 1950s established the amino acid sequence, and that made a chemical definition of identity possible for the first time. But the biological unit came first, out of necessity, and it established a principle that still governs biologics: when a product cannot yet be defined by its structure, define it by a measured, reproducible activity against a shared reference — and make everyone measure against the same one.

The through-line across the century is a gap: the distance between a molecule that does something interesting in a laboratory and a medicine that does the same thing reliably, in a stranger's body, in a batch made two years later in a different country. In 1922 that gap was closed by a purification protocol, a licensing committee, and a reference standard kept in a jar. Today it is closed by process validation, pharmacopeial monographs, inspection, and post-market surveillance. The apparatus has grown enormously. The gap it exists to close has not gone anywhere, and no amount of promise on the discovery end substitutes for the unglamorous work at the other.