Curing The Pissing Evil

How A Toxic Work Environment Led To A Monumental Treatment

Diabetes as a distinct clinical entity was probably first described in the 5th century BC by Sushruta, using the term madhumeha (honey-like urine) and he pointed out not only the sweet taste of the urine but also its sticky feeling to the touch and its ability to attract ants. Diabetes was named and very well characterized in the 2nd century AD by Aretaeus of Cappadocia who proposed the consumption of cereals, milk and wine as treatment, the topical application of cataplasms and the administration of Theriac, the famous cure all remedy of antiquity.

Thomas Willis, one of the greatest physicians of the 17th century, added the term mellitus to describe how "honey-like" the urine of diabetics tasted, but it was up to Matthew Dobson, another English physician to actually discover a century later that sugar was indeed the reason why diabetic urine was sweet.

Oskar Minkowski and Joseph Von Mering performed a pancreatectomy in a dog in 1889 at the University of Strasbourg and discovered that the dog developed polyuria soon after and that the urine contained 12% sugar. Minkowski then successfully implanted a small portion of the pancreas subcutaneously in the dog and the hyperglycemia resolved.

In 1901, Paul Opie at Johns Hopkins made the association between the degeneration of "islets of Langerhans" (named in 1893 after the medical student Paul Langerhans' brilliant drawings of them in 1868) and the development of diabetes.

The eminent English physiologist Ernest Starling (who coined the term hormone in 1905) wrote "we don’t know yet how the pancreas affects sugar production or utilization in the same animal. It is generally assumed that it secretes into the bloodstream a hormone which may pass to the tissues."

The stage was now set for the discovery of the protein that would revolutionize the treatment of what, up until that point, had been a fatal disease.

Frederick Banting, a surgeon born in Alliston, Ontario in 1891, returned to Toronto in 1919 after serving honorably in World War I. He opened a small orthopedic surgery practice in London, Ontario but soon floundered as the earnings from this practice were meager. As such, he was forced to take a second job as a demonstrator at University of Toronto Medical School. As he prepared for a lecture on the pancreas and its possible function, he read a paper by Dr. Moses Barron, a pathologist from Minnesota on the Islets of Langerhans on October 31, 1920. This captivated him and he jotted down some notes about a possible experiment to perhaps isolate the long-sought after anti-diabetic hormone from the pancreas.

He approached the Chair of the Physiology Department, Dr. James Macleod, a renowned expert on the pancreas on November 7, 1920. Macleod listened for awhile then appeared to lose interest in the conversation. He did not think that Banting possessed the surgical skill or actual knowledge of the pancreas to actually carry it out. However, he was impressed with Banting's enthusiasm enough to grant him some lab space, some dogs, and a medical student assistant, Charles Best. The 29 year old orthopedic surgeon and his 22 year old assistant, who had just graduated with a degree in physiology and biochemistry, started their research in May 1921.

Throughout the summer of 1921, they worked in earnest on multiple dogs. The base experiment was straightforward but inspired. They would initially ligate the pancreatic ducts of dogs, achieving atrophy of the exocrine region and almost ten weeks later they removed the dog’s degenerated pancreas. They crushed the atrophied pancreatic glands in a cool mortar and froze it in salt water. Then the mass was ground down and added to 100 mL of physiological salt. Afterwards, they administrated 5 mL of this extract intravenously to a de-pancreatized dog, number 410, on July 30, 1921.

Amazingly this extract actually worked and resulted in a dramatic lowering of the blood sugar levels of diabetic dogs. Dog 408 received this extract on August 4, 1921 and the extract was called "isletin" for the first time.

Dog 92, completely de-pancreatized, was given a series of these injections and lived for 20 days. This was the eureka moment!

Macleod, who had been away that entire summer in Scotland, continued to criticize the work, felt it was inconsistent and lacked appropriate controls. Upon his return to Toronto in November, 1921, he asked James Collip, a biochemist from University of Toronto to help Banting and Best purify their extract. His method, utilizing alcohol instead of saline, proved extremely effective.

On December 20, 1921, a friend of Banting, Dr. Joseph Gilchrist, took the extract orally, becoming the first human test subject. No obvious hypoglycemic effect was noticed however.

On December 30, 1921, the team went to present their findings at the annual meeting of the American Physiological Society at Yale University. Banting stood up to deliver the paper but the prestige of the audience took its toll on him and the presentation was a disaster! Macleod, who was moderating the session, took over the talk and delivered the findings to the audience. Banting left the meeting angered, firmly believing that this was a coup to steal his thunder over the monumental discovery.

Upon his return to Toronto, he found an opportunity to reassert his authority over the process. Leonard Thompson, a 14 year old boy with diabetes, had been admitted to Toronto General Hospital emaciated, lethargic, ketotic, and appearing on the verge of death. Between January 11 and January 23, 1922 a series of injections of Banting's extract proved lifesaving for this patient and was heralded in newspapers around the globe.

At the same time, though, personal tension was mounting among the four scientists, as Banting became increasingly bitter toward Macleod and pitted himself and Best against Collip in the race to purify the extract further. At the end of January, Collip came to Banting and Best’s lab and informed the two that although he had discovered a method to produce pure extract, he would share it only with Macleod. They all almost came to blows. As he sank further into a festering stew of fear and suspicion, Banting began calming his nerves with alcohol stolen from the lab. “I do not think that there was one night during the month of March 1922 that I went to bed sober,” he said.

Macleod made the formal announcement to the world of the discovery of insulin in May 1922 in Washinton, D.C. Banting was not at his side, claiming that he could not afford the train fare.

At the end of this meeting, Eli Lilly Pharmaceutical Company entered into an agreement with University of Toronto to begin commercial production of insulin derived from pig and bovine sourced pancreas. On January 23, 1923, United States Patent number 1,469,994 for the manufacture of insulin is awarded to J. B. Collip, C. H. Best and F. G. Banting

On October 25, 1923, the Nobel Prize in Medicine was awarded to Banting and Macleod for the discovery of insulin.

Banting was absolutely incensed that he would have to share his prize with Macleod and publicly offered to share his half of the prize with Best. He wrote this: "Macleod on the other hand was never to be trusted. He was the most selfish man I have ever known. He sought at every possible opportunity to advance himself. If you told Macleod anything in the morning it was in print or in a lecture in his name by evening … He was unscrupulous and would steal an idea or credit for work from any possible source." In response, Macleod decided to share his half of the prize with Collip. If Banting, however, thought that this offer would soothe Best's resentment at not actually having won the prize, he would be sadly mistaken and the two former friends and colleagues became lifelong enemies. Best went on to try and turn the public narrative, making many appearances and writing many publications claiming that without his efforts and successes in the purification process, insulin would have never been useful clinically.

By the end of October 1923, insulin was widely available commercially throughout North America, saving thousands of lives.

In February 1941, Banting died in a tragic plane crash and is buried at Mount Pleasant Cemetery in Toronto. In 1994 he was inducted into the Canadian Medical Hall of Fame and in 2004 he was voted as one of the top 10 Canadians in history.

Charles Best ultimately went on to a long and storied career (especially in the development of heparin) and died of natural causes in Toronto in March 1978. He is buried not far from his old friend Banting at Mount Pleasant Cemetery.

Although Banting, Best, Collip and Macleod are universally credited with the discovery of insulin, there may be other truths to this story.

In 1908, German doctor Georg Zuelzer isolated extracts from the calf pancreas that he called Acomatol. He worked in partnership with Hoffman La Roche and purified the substance substantially, where it worked very well in curing diabetic animals. This research was brought to a crashing stop however with the start of World War I in 1914 when his lab was turned over to the German military.

In 1916, Romanian Professor of Physiology Nicolae Paulescu discovered pancreine, an extract of bovine pancreas that was also antidiabetic and antiketogenic. World War I interrupted his research until 1921 when he published four papers on this substance. He felt it was too toxic for human use but did experiment with it in humans in 1922. He petitioned the Nobel Committee that his work too should be considered for the 1923 award but this was denied. Ultimately his efforts were lost to history as he later became strongly antisemitic and likely helped incite the Holocaust in Romania.

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