How Is a Hormone Discovered The Arduous Path to Purified Insulin

Millions of people with type I (insulin-dependent) diabetes mellitus inject themselves daily with pure insulin to compensate for the lack of production of this critical hormone by their own pancreatic 3 cells. Insulin injection is not a cure for diabetes, but it allows people who otherwise would have died young to lead long and productive lives. The discovery of insulin, which began with an accidental observation, illustrates the combination of serendipity and careful experimentation that led to the discovery of many of the hormones.

In 1889, Oskar Minkowski, a young assistant at the Medical College of Strasbourg, and Josef von Mering, at the Hoppe-Seyler Institute in Strasbourg, had a friendly disagreement about whether the pancreas, known to contain lipases, was important in fat digestion in dogs. To resolve the issue, they began an experiment on fat digestion. They surgically removed the pancreas from a dog, but before their experiment got any farther, Minkowski noticed that the dog was now producing far more urine than normal (a common symptom of untreated diabetes). Also, the dog's urine had glucose levels far above normal (another symptom of diabetes). These findings suggested that lack of some pancreatic product caused diabetes.

Minkowski tried unsuccessfully to prepare an extract of dog pancreas that would reverse the effect of removing the pancreas—that is, would lower the urinary or blood glucose levels. We now know that insulin is a protein, and that the pancreas is very rich in proteases (trypsin and chymotrypsin), normally released directly into the small intestine to aid in digestion. These proteases doubtless degraded the insulin in the pancreatic extracts in Minkowski's experiments.

Despite considerable effort, no significant progress was made in the isolation or characterization of the "antidiabetic factor" until the summer of 1921, when Frederick G. Banting, a young scientist working in the laboratory of J. J. R. MacLeod at the University of Toronto, and a student assistant, Charles Best, took up the problem. By that time, several lines of evidence pointed to a group of specialized cells in the pancreas (the islets of Langerhans; see Fig. 23-24) as the source of the antidiabetic factor, which came to be called insulin (from Latin insula, "island").

Taking precautions to prevent proteolysis, Banting and Best (later aided by biochemist J. B. Collip) succeeded in December 1921 in preparing a purified pancreatic extract that cured the symptoms of experimental diabetes in dogs. On January 25, 1922 (just one month later!), their insulin preparation was injected into Leonard Thompson, a 14-year-old boy severely ill with diabetes mellitus. Within days, the levels of ketone bodies and glucose in Thompson's urine dropped dramatically; the extract saved his life. In 1923, Banting and MacLeod won the Nobel Prize for their isolation of insulin. Banting immediately announced that he would share his prize with Best; MacLeod shared his with Collip.

By 1923, pharmaceutical companies were supplying thousands of patients throughout the world with insulin extracted from porcine pancreas. With the development of genetic engineering techniques in the 1980s (Chapter 9), it became possible to produce unlimited quantities of human insulin by inserting the cloned human gene for insulin in a microorganism, which was then cultured on an industrial scale. Some patients with diabetes are now fitted with implanted insulin pumps, which release adjustable amounts of insulin on demand to meet changing needs at meal times and during exercise. There is a reasonable prospect that, in the future, transplantation of pancreatic tissue will provide diabetic patients with a source of insulin that responds as well as normal pancreas, releasing insulin into the bloodstream only when blood glucose rises.

Frederick G. Banting, 1891-1941

Charles Best, 1899-1978

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