Around the time that Emil von Behring was advancing
the treatment of diphtheria, other scientists
were gaining understanding of diabetes, another terrible disease. At the time, diabetes inevitably led to a patient's death. Doctors knew that sugar made diabetic symptoms worse. So patients were often prescribed strict diets of only 800 to 1,000 calories with minimal sugar. These diets, however, were not a cure, and patients would only survive a few extra years at best. At worst, the patient would die of starvation. In 1889, Oscar Minkowski and Joseph von Mering at the University of Strasbourg removed the pancreas from dogs. They noticed that each of the dogs then developed diabetes. Based on this observation, it was concluded that an unknown substance in the pancreas, which we now know is insulin, was responsible for regulating sugar levels in the body. Isolation of insulin proved to be challenging, however. Several scientists in the early 20th century made pancreatic extracts that reduced hyperglycemia. Yet in all cases, toxic reactions to the extracts halted further experiments. In 1920, Frederick Grant Banting was teaching anatomy and physiology at what is today the University of Western Ontario in Canada. While preparing for his lectures, he thought of a new method to prepare pancreatic extracts. Banting convinced John James Rickard MacLeod, the head of the physiology department at the University of Toronto and an authority on carbohydrate metabolism, to give him lab space and a student-- Charles Herbert Best-- to pursue his idea. Banting and Best extracted what they hoped was insulin from the pancreas of dogs. When these extracts were administered to diabetic dogs, the dogs reliably showed a decrease in their blood sugar levels. They realized that they would be able to isolate and test more insulin if they used a larger animal. So they began using cow pancreases instead. [MOOING SOUND] In January of 1922 Banting and Best prepared an extract that would be used in the first clinical trial. It was given to 14-year-old Leonard Thompson, who was severely diabetic. The trial was a failure. There appeared to be no clinical benefit and young Leonard developed an immunologic response at the site of the injection. A second trial would happen later that January. This time the insulin extract would be subjected to an additional purification step. In December of 1921, James Bertram Collip, a biochemist from the University of Alberta in Edmonton, had joined the project to work on the purification of insulin. Banting and Best would prepare another extract and give it to Collip for further purification. This purified extract was injected again in Leonard Thompson. This time his blood sugar and glucose excretion, both indicators of diabetes, dropped significantly. This was the first successful clinical test of insulin on a human diabetic subject. And six more patients were treated successfully shortly thereafter. For their work in the discovery and isolation of insulin, Banting and MacLeod awarded the 1923 Nobel Prize in medicine. Best and Collip were not included on the award, and Banting and MacLeod each shared half of the award with them. Given their clinical success, the researchers began collaborating with Connaught Laboratories in Toronto in an attempt to manufacture insulin on a large scale. Collip, who developed the insulin purification, was set to direct the commercial-scale production. The procedure he had developed, however, no longer worked. Scaling up from small-scale to large-scale production was a significant challenge. Even today, this is one of the main challenges in modern biomanufacturing. They turned to Eli Lilly and Company to help them produce larger quantities of insulin. They too had difficulty with the purification until Lilly's chief chemist, George Walden, noticed that at the right pH the insulin would crystallize and that those crystals had the highest purity to date. Eli Lilly began producing large quantities of insulin, which allowed more than 25,000 diabetic subjects to begin treatment by the fall of 1923. This previously untreatable disease was no longer the death sentence that it once was. Yet a few key challenges still remained. First, porcine- and bovine-derived insulins were not identical to human insulin. Similar to the anti-toxins produced in horses, the non-human insulin caused an immunogenic reaction. In the worst cases, the therapeutic benefit was completely eliminated. Second, production of insulin depended on the availability of animal pancreases. This supply is largely driven by consumer demand for pork and beef, not on a diabetic subject's need for insulin. In the early 1970s, there became a growing concern that the world's supply of porcine and bovine pancreases may not meet the global demand for insulin. Just as with anti-toxins, these drawbacks would be important drivers in the search for new ways to manufacture insulin. Despite this, the production of insulin from porcine and bovine sources represented a huge step forward in the manufacture of protein therapeutics. It would take another war, however, to bring about the next advance. [GUNFIRE SOUNDS]