Insulin100: The Discovery and Development
The discovery and the development of insulin in the early 1920s by a team of scientists in Canada saved the lives of people suffering from diabetes all over the world and continues to have impact on the lives of diabetics today. It is a UNESCO recognized historic milestone and remembered every year on 14 November, World Diabetes Day (also Frederick Banting’s birthday!). This timeline will tell the story of the discovery, the people involved, and insulin’s impact in Canada and globally.
To read more in-depth historical articles about the events during the early history of insulin, follow the links throughout the timeline or start here.
In 1920, on the eve of the discovery of insulin, Canada was hesitantly emerging from four tumultuous years of war. The final months of World War I, which ended on November 11, 1918, coincided at home with the enormous suffering caused by the global influenza pandemic of 1918-19. Emerging from the pandemic, the federal government set up a national department of health in 1919. At the same time, significant labour unrest erupted, most dramatically in the Winnipeg General Strike.
At this time, a diagnosis of diabetes was essentially a death sentence, especially for a child with rapid onset of what later was defined as Type 1. Life expectancy was generally less than a year from diagnosis. Slower onset diabetes, mostly among adults and later defined as Type 2, was more manageable, yet still deadly in many cases. At the time there was no exact definition of diabetes as diagnostic methods were uncertain and changing, as were statistical methods. Thus, it was impossible to know just how many diabetics there were in Canada, or anywhere else. The best estimate was that between 0.5 and 2.0% of the residents of industrialized countries had diabetes in 1920. In more prosperous and well-nourished societies, the disease seemed more prevalent. In fact, by 1920, diabetes was most visible in the richest countries, notably the United States and Germany, as well as Canada. Learn more about diabetes before the discovery of insulin.
October 25, 1917 – The new Connaught Laboratories farm site and buildings is officially opened. The Connaught Antitoxin Laboratories and University Farm was established in collaboration with the University of Toronto after Dr. John G. FitzGerald had hoped U of T would establish a Pasteur Institute. In early 1914, FitzGerald made a presentation to the university’s Board of Governors who were impressed by his efforts and joined his project on May 1, 1914. To learn more about Dr. FitzGerald and the history of Connaught, click here.
31 October 1920 – Banting’s original idea
In the early hours of October 31, 1920, in London, Ontario, 28-year-old Dr. Frederick G. Banting woke up suddenly. He had had a flash of insight for a novel experiment to isolate the elusive internal secretion of the pancreas as a means of treating diabetes.
Banting, had been reading about carbohydrate metabolism and diabetes. After a few hours of disturbed sleep, he awoke with a compelling idea that he quickly jotted down in a notebook.
While in Toronto for a friend’s wedding, Banting is able to secure a meeting with the head of physiology at the University of Toronto, Dr. John J. R. Macleod, to speak about his pancreatic extract idea.
Banting and Macleod never provided full details of this initial discussion, though Banting did note that Macleod sat back in his chair and closed his eyes while he thought for a few minutes. He then said, “This might be the means of getting rid of external secretion.” As far as he knew, Macleod continued, this method had not been tried before. “It was worth trying…[N]egative results would be of great physiological value.”
It was agreed that Banting would come to U of T in Spring 1921 to begin the research, with Macleod’s support.
There are many different interpretations of the initial meeting between Dr. Banting and Dr. Macleod. You can compare some of them in these video clips.
“The Quest” – a National Film Board of Canada short film produced in 1958. [Meeting at the 2:33 mark]
“Comet Among the Stars” – a 1973 BBC TV-movie about Dr. Macleod. This clip from the movie focuses on the meeting.
Michael Bliss’ The Discovery of Insulin and his Banting: A Biography were the basis of the 1988 CBC min-series, “Glory Enough For All.” A digitized home recording of the full min-series is available on YouTube (except for the last few minutes). The 7 November 1920 Banting-Macleod meeting scene begins at the 33:28 mark of the video.
11 March 1921 – “…the problem of Pancreatic Diabetes…”
Dear Dr. Banting,
I will be glad to have you come up here on May 15th, as you suggest, to see what you can do with the problem of Pancreatic Diabetes, which we spoke about. I doubt, however, whether it would be advisable to attempt any preliminary operations during the Easter holidays, since between that time and May 18th, there will be no one here personally interested in the supervision of the animals, and this supervision, as you know, is of extreme importance in all researches of this character. Between these dates, everyone on the staff in the laboratory, will be under the unfortunate necessity of devoting a great part of his time to examinations, detail and to other things pertaining to the winding up of the session. I think that after May 15th, when you could get close personal attention to the work, it could proceed satisfactorily within the tie which you suggest you could give to it.
With regards, I am Sincerely yours
May 1921 – Banting meets Best
Banting is finally able to leave London for Toronto in order to begin his research. Macleod assigns him a 4th-year student from his Honours Physiology and Biochemistry course, Charles Best. Best would assist Banting with the testing of blood sugar levels, as well as nitrogen and sugar levels in urine.
The first task that Banting and Best undertook when they arrived at the University of Toronto’s Medical Building was cleaning the physiology department’s animal operating room.
17 May 1921 – The first pancreatectomy took about 80 minutes and the dog recovered. Banting and Best operated on two more dogs the next day, but both died. By 21 May 1921, the original dog and one more had also died after initially recovering from surgery.
28 May 1921 – An operation on Dog #387 proves successful and Best removes the remaining segment of the dog’s pancreas. The dog develops diabetic symptoms, and although it dies on 1 June 1921, Banting and Best felt that their first completed experimental work went more or less according to plan.
By mid-June, after four weeks of work, things seem to be going well. Two of the dogs that had their pancreases removed were healing, and seven of the dogs that had had the duct ligation procedures were doing well. Now Banting and Best had to wait a few weeks before they would be ready to proceed with the third and most critical part of their experimental work, preparing their first pancreatic extract to test of the diabetic dogs.
July 1921 – Early in the month, Banting and Best discovered that many of the duct ligations had not worked, and only two of seven dogs had degenerated pancreases. They re-ligated the other five dogs, but unfortunately four of the dogs died within a few days. Both men felt the week was a disaster, and took the long weekend off to rest and re-group.
30 July 1921 – Banting removed the clearly degenerated pancreases from Dog #391; he and Best proceeded to prepare their first pancreatic extract, using detailed instructions left by Macleod.
On the same day, Dog #410 was the first to receive an injection of the pancreatic extract. Despite mixed results, it was clear the extract had a marked effect. Dog #410 died after falling into a diabetic coma the next day.
1 August 1921 – Dog #406 was in a coma and on the brink of death when Banting administered some of the extract. Its blood sugar fell, and it was soon up and walking around. This was impressive, but unfortunately the dog did fall back into a coma and died.
4 August 1921 – Dog #408 receives an injection of the extract, successfully dropping its blood sugar. The dog remained in good condition. Banting and Best referred to their pancreatic extract as “Isletin” for the first time. Dog #408 would eventually die of an infection, after successfully receiving injections for a number of hours. Banting and Best had learned much about “Isletin” and its anti-diabetic properties and were eager to send a report to Macleod.
9 August 1921 – Writing to Macleod, Banting was very excited to report that the extract “invariably” caused a reduction in blood sugar. But he also had plenty of questions and was very anxious to continue the work in a better equipped lab. In particular, he and Best needed more help looking after the animals, and they needed better operating facilities.
Dear Prof McLeod [sic]:-
I have so much to tell you and ask you about that I scarcely know where to begin. I think you will be pleased when you see how the problem is unrolling from one end & rolling up at the other.
At present I can honestly state my opinion that 1/ the extract universally causes a decrease in the percentage of blood sugar & in the excretion of sugar in diabetic dogs. 2/ That it is active at least for four days if kept cold. 3/ That it is destroyed by boiling. 4/ That extracts of spleen & liver at least, prepared under similar conditions, have no such action. 5/ The clinical aspect of the animal is improved by the extract. Thus far is unrolled.
The number of problems that are presenting themselves is becoming greater & greater. Some of them I would wish to present for your approval.
- The securing of the most active and concentrated forms of the substances (which Best & I call “Isletin”) by testing the effect obtained from various positions of the degenerated gland & at the various periods after ligation of the ducts.
- After securing the most active product an investigation of its chemical properties. (The extract used was neutral to litmus, we are going to try acid & alkali extracts next dog)
- Is it destroyed by Typrin? (I would like to repeat Kleiner’s experiment.
- Can a dog be kept alive by the use of an extract with the pancreas removed?
- The whole problem of tissue grafting.
- Is the substance universal in the animal kingdom in regard to carbohydrate metabolism & all it act in other species.
- Its relation to fat metabolism (our animals lost weight progressively & rapidly & no fat was found at autopsy)
- Relation of diabetus [sic] & infection
- Relation to glycosurea [sic] & other forms of diabetus [sic]
- Relation of the extract to sugar infections
- Relation of the extract to its internal secretions
- Relation to thirst & huger (water metabolism) (vol of urine decreased after infections and while under the influence & after the very large doses in 408, excretion ceased)
- Its clinical application
- Where & in what manner does the substance act
I am very anxious that I be allowed to work in your laboratory and yet especially during the hot weather we have been so greatly hampered by infection despite our utmost care, and since we have lost so many dogs, I strongly desire more help to keep the place clean & gloves & gowns & a thorough fitting up of our operating room. I told Dr. Starr of my difficulties and he has secured the use of the surgical research operating room (for operations only) and I will take the dogs down & bring them back when the operation is over. We have only two dogs left with ducts tied. I would like to do about ten so as to have a supply of the extract for you when you return. I have told Dr. Starr all about my results and he advised me to go ahead so I will proceed slowly and if I do not hear from you I will take it that I have your permission. Please let me knoww as soon as possible your wishes. I will not proceed immediately however as I am going to London Ont. to close up my affairs and have them off my mind. And that will give this letter time to get to you.
Mr. Best has expressed the desire to work with me and I should be more than pleased to have him. His work as been excellent and he is absolutely honest, careful, and impartial, and has taken a great interest in the work. He has assisted me in all the operations and taught me the chemistry so that we work together all the time & check up each others readings.
I hope that you will be able to make out our report. Hoping to hear from you soon and eagerly awaiting your return.
Yours very sincerely,
F. G Banting.
11 August 1921 – While waiting for a reply from Macleod, Banting and Best began another round of experiments, working around the clock for several days. The goal was to remove the pancreases of two more dogs, give “Isletin” to one of them (Dog #92) and compare its effects with Dog #409, which would not receive the extract so as to act as an experimental control.
As expected, Dog #409’s condition steadily declined and it soon died. Meanwhile, Dog #92’s diabetes remained well controlled and it became something of a pet in the laboratory.
17 August 1921 – With Dog #92 frisky and doing well, Banting and Best decided to proceed with some different experiments. One involved removing the whole pancreas from a dog and preparing an extract from it, rather than starting with a degenerated pancreas. When they gave Dog #92 injections of this type of extract, it seemed to have a similar effect, the dog’s chart showing blood sugar reduced to the levels achieved with the extract prepared from a degenerated pancreas.
Banting and Best next tried an alternative to the duct ligation technique. They stimulated the pancreas with a hormone known as secretin, which is produced in the duodenum, i.e., the top section of the small intestine.
20 August 1921 – Despite the complicated process to obtain secretin and inject it slowly into the pancreas over a period of four hours until the production of pancreatic juice stopped, Banting wanted to try the surgical procedure and soon he and Best had an extract to test on Dog #92. When it received the first injection, it was quite sick. By the next morning, when Banting and Best arrived back to the lab, Dog #92 excitedly jumped out of its cage and ran around the lab. This was a profound moment for Banting and indeed he later described it as one of the greatest days of his life.
22 August 1921 – Until the end of the month, Banting and Best conducted some further experiments involving Dog #92, including preparing an extract from the pancreas of a cat using the secretin stimulation procedure. That extract, however, sent the dog into shock, bringing a quick end to further experiments.
31 August 1921 – Dog #92 finally died after lingering for nine days. “I have seen patients die and I have never shed a tear,” Banting later wrote. “[B]ut when that dog died, I wanted to be alone for the tears would fall despite anything I could do.”
23 September 1921 – Macleod’s letter finally arrived. Their research had progressed so much since Banting wrote to Macleod on August 8th. Macleod was certainly pleased with their progress, but also advised caution in being overconfident with their results. There had to be “no possibility of mistake,” he emphasized. “You know that if you can prove to the satisfaction of everyone that such extracts really have the power to reduce blood sugar in pancreatic diabetes, you will have achieved a very great deal.” But, as he added, “It’s very easy often in science to satisfy one’s own self about some point but it’s very hard to build up a stronghold of proof that others cannot pull down.”
1 October 1921 – Banting secures a special lecturer position in the Pharmacology Department at a salary of $250 per month, a reasonable amount. Macleod had found a room large enough for two dog cages and a laboratory desk, and also arranged for retroactive pay for Banting ($150) and Best ($170). All parties looked forward to continuing experimentation.
October 1921, began with considerable excitement and confidence for Banting, Best and Macleod. The success of the pancreatic extract work so far led to lots of new questions, prompting Banting and Best to explore many different ideas. Macleod, however, tried to rein them in, advising they stay focused on solving the outstanding problems associated with confirming the effectiveness of the pancreatic extract in controlling diabetes. Read more.
4 October 1921 – Banting had made a connection with Dr. John G. Fitzgerald, director of U of T’s Connaught Antitoxin Laboratories. In order to test a theory that the pancreatic duct of a calf could be ligated to isolate the internal secretion, Banting and Best visited the farm to try a pancreatic duct ligation procedure on a calf. However, the operation was unsuccessful as the calf died from the anaesthetic. The experience, although frustrating, fuelled further ideas.
Banting and Best spent considerable time in October doing research in the medical library, reading journal articles about diabetes and the pancreas, and jotting down ideas on index cards. Unlike Best, Banting was not the typical academic medical researcher. He had a practical streak and was driven by a desire to test the extract on human diabetics.
14 November 1921 – Banting’s 30th birthday. Banting and Best gave a talk to the Journal Club of the Department of Physiology and a small audience of students, faculty and staff. The presentation seemed to go well, with an important suggestion made during the discussion by Dr. N.B. Taylor, who thought a longevity experiment with the extract given regularly to a diabetic dog over an extended period of time would be useful.
16 November 1921 – Banting woke from a fitful sleep with an idea, sparked by a memory about the cattle he had helped to slaughter on his father’s farm in Alliston, Ontario. This led he and Best to procure pancreases from foetal calves from a local slaughterhouse and immediately prepared extract. They administered the extract to Dog #27 and its blood sugar fell; 24 hours later, after additional injections, the dog’s urine was sugar-free. This success meant that extract could be prepared more steadily and the scientists could focus on a longevity experiment.
17 November 1921 – Banting and Best removed the pancreas of Dog #33, “Marjorie”.
23 November 1921 – After working to improve the purity of the extract, Banting and Best took a daring step and injected each other with small 1.5 c.c. doses (about 1/3 teaspoon) of extract. Banting and Best’s brief note only said, “No reaction,” which meant no harmful effects.
7 December 1921 – “Marjorie” (Dog #33) and Dog #23 received extract prepared with a new alcohol method. They believed that alcohol would remove the contaminating impurities in the extract solutions.
8 December 1921 – To further test this, Banting and Best removed the pancreas from Dog #35 and proceeded to prepare an extract from it using the alcohol extraction method.
11 December 1921 – Dog #35 was given an injection of extract prepared from its own whole pancreas. The animal’s blood sugar level dropped from .38 to .18 in four hours. It was clear that alcohol worked to extract the internal secretion from the whole pancreas.
12 December 1921 – The successes led Macleod to formally invite Dr. James Bertram Collip to join the pancreatic extract research team so he could use his specialized biochemistry skills to further the development and purification of the extract. Collip began working to reliably purify the extract from the whole beef extract in a lab at the Toronto General Hospital.
At the same time, Banting and Best were also attempting to purify the whole beef extract. Banting and Best prepared a large batch of extract, but when they tested it, they found it lacked potency, based on tests on diabetic dogs. However, they still had some extract they knew to be potent and on December 21st, decided to try it on a fellow physician, Dr. Joseph Gilchrist, who was suffering from diabetes. They administered the extract through a stomach tube rather than by injection. To Banting and Best, it was worth a try in light of Gilchrist’s declining health. However, the extract had no effect on Gilchrist, either positive or negative.
Christmas 1921 – Banting and Best break for Christmas. Collip was making significant progress. He was able to use a vacuum still to evaporate the alcohol from the extract solution, although only partially, followed by filtration. This extract worked very well at reducing the a diabetic dog’s blood sugar level. Collip also tested the dog’s urine and discovered the extract left it completely sugar and keytone free. This finding marked another significant step.
On Christmas Day, 1921, Dr. George H.A. Clowes travelled to New Haven, Conn., where he planned to see a presentation entitled, “The Beneficial Influences of Certain Pancreatic Extracts on Pancreatic Diabetes.” It was to be given on December 30th by Banting, Best and Macleod at the American Physiological Society’s annual meeting. Dr. Clowes was the research director of Eli Lilly and Company and he had recently heard about some interesting research being done in Toronto in the University of Toronto’s physiology department and headed by Macleod. If this work was being overseen by someone with Macleod’s credentials, Clowes felt, he was confident in its significance and determined to get to New Haven, even if it kept him from his young family over Christmas.
28-30 December 1921 – Thirty-Fourth Annual Meeting of the American Physiological Society, held in New Haven. Banting delivered a paper detailing their accomplishments so far, but became overwhelmed by the questions and response from experts in the audience. Macleod stepped in to rescue him.
The internal secretion of the pancreas. F. G. Banting, C. H. Best, and J. J. R. Macleod.
The hypothesis underlying our experiments was that the usual extracts of pancreas do not satisfactorily demonstrate the presence of an internal secretion acting on carbohydrate metabolism, because this is destroyed by the digestive enzymes also present in such extracts. To circumvent this difficulty we have taken advantage of the fact that the acinus, but not the insular cells become degenerated in seven to ten weeks after ligation of the ducts.
A neutral or faintly acid extract of the degenerated gland, kept at a low temperature, was therefore prepared and its effect on pancreatic diabetes investigated. Ten weeks after ligation of the pancreatic ducts the degenerated gland was removed was removed and extracted with ice-cold Ringer’s solution. This extract injected intravenously or subcutaneously invariably caused marked reduction of the percentage of sugar in the bloo and the amount of sugar excreted in the urine. Extracts of liver, spleen or boiled extract of degenerated pancreas have no effect.
Further investigations have shown the following: a, incubation of the extract, in alkaline reaction, for 2 hours with pancreatic juice removes its effect; b, glucose given intravenously or per os is administered; c, the clinical conditions of he animal is improved by the extract; d, hemoglobin estimations before and after administration of the extract are identical; e, neutral extract kept in cold storage retains its potency for at least seven days; f, subcutaneous injections have a less rapid but more prolonged effect. Rectal injections are not effective
The experiments have been repeated on ten animals several of which were under observation for over 2 weeks.
Despite the skepticism from the specialists in the audience, the director of research at Eli Lilly & Co of Indianapolis, Dr. George Clowes, was impressed by what he heard. Afterwards, Clowes approached Macleod, offering the collaboration of Eli Lilly to help develop the extract. He discussed the idea with Banting and Macleod, but they politely declined the offer as the work was not sufficiently advanced to be considering commercial preparation. However, Clowes suggestion would be kept in mind.
10 January 1922 – Best prepared some whole beef pancreas extract using the method developed in December, which integrated the use of the vacuum still as developed by Collip. They tested its potency on a dog and then Banting and Best gave each other small injections of the extract to make sure it was safe.
11 January 1922 – They took a vial to the Toronto General Hospital and it was administered to Leonard Thompson. The results of “Macleod’s serum”, as was noted on Thompson’s chart, were positive, but disappointing to Banting, Best and Macleod. There had been a 25% drop in blood sugar, a reduction in sugar in the urine, but the extract’s modest impact did not outweigh the reaction to it, an abscess at one of the injection sites.
14 January 1922 – The press coverage begins.
Work on diabetes shows progress against disease
Toronto medical men hoping that cure is close at hand
A boy is treated
Effect of first treatment was so good that injections are continued
16 January 1922 – Collip discovered that at a precise limit in the alcohol concentration (a little over 90%), he could actually trap the internal secretion in the purest form yet seen.
23 January 1922 – Treatment of Leonard Thompson resumed with Collip’s extract; he had only received the one insulin treatment of Banting and Best’s extract, but then returned to a diet-based treatment. This time, after Thompson received Collip’s extract, the effect was quite dramatic; sharp drops in blood sugar levels and glygosuria (sugar in the urine) almost disappearing. Leonard quickly became brighter, more active, looked better and was stronger. Moreover, there were no abscesses or other side effects. This time, the pancreatic extract clearly worked.
25 January 1922 – FitzGerald formalized a seminal research and development agreement between Connaught and Banting, Best, Collip and Macleod. Signed by the four men, as well as the chairman of U of T’s Connaught Committee, Albert E. Gooderham, the agreement was based on two key conditions: One, that the collaborators agree not to take out a patent with a commercial pharmaceutical firm during an initial working period with Connaught; and two, that no step that would involve any modification in policy concerning the research work would be allowed unless first discussed among FitzGerald and the four collaborators.
By February 1922, six more diabetic patients at TGH has been successfully treated with the extract, along with Dr. Gilchrist. Throughout the Spring, more patients would be treated with insulin. Read about some of them here.
March 22, 1922 – Roy Greenaway wrote a comprehensive front-page article for the Toronto Star, titled “Toronto Doctors on Track of Diabetes Cure,” the publication of which was timed to coincide with the release of the Toronto team’s seminal paper in the March issue of the Canadian Medical Association Journal. Greenaway’s article featured photos of Banting, Best, Macleod and Collip, and quoted extensively from the CMAJ article. Greenaway’s article described the discovery story from Banting’s perspective and highlighted a special moment for Banting and Best before they proceeded with the first human trial. Despite the upbeat coverage, The Star article prompted only a minor flurry of attention locally, and very little attention outside of Toronto.
March 30, 1922 – Dr. Clowes, research director at Eli Lilly, wrote a letter to Macleod, re-affirming Eli Lilly’s interest in assisting in developing methods to produce the extract on a large scale. As he emphasized, “Public interest in this work will naturally be very great and the demand for the product will be such as to lead to attempts on the part of unprincipled individuals to victimize the public unless some steps are taken to arrange for the manufacture of the product by the procedures recommended by Dr. Collip and the control of the products by means of such tests as you and your associates would consider necessary.”
Spring, 1922 – Chemist, David A. Scott “Scotty,” received a letter from Connaught’s director, Dr. J.G. FitzGerald, inviting him to join the Connaught Labs team that was focused on restoring pancreatic extract production. To learn more about Dr. Scott, click here.
April 12, 1922 – Banting, Best, Collip, Macleod and J.G. FitzGerald, director of Connaught, write a letter to University of Toronto president Robert Falconer, the Toronto group had been advised that it was “unsafe for us not to hold a patent for the method of preparation of [insulin] extracts.”
There were very few news reports about the pancreatic extract during April, May and into June. The next stories to appear were in papers outside of Toronto. The first was a short report on June 12th in a Battle Creek, Mich., newspaper promoting an upcoming visit by Banting, Best and Clarke Noble to give a presentation at a local physician’s clinic. The second was a prominent front-page article in the June 21st edition of the Winnipeg Tribune. “Canadian Doctor Discovers Cure for Diabetes,” was the banner headline, with the story highlighting Banting’s address to the convention of the Canadian Medical Association.
May 3, 1922 – Macleod called the extract “Insulin” for the first time during an especially successful presentation in Washington, D.C., at a meeting of the Association of American Physicians.
May 10, 1922 – Best was placed in charge of all aspects of the development, purification and production of insulin at Connaught. Best had the full support of FitzGerald and Connaught’s assistant director, Dr. Robert D. Defries. At about this time the group began referring to the extract as “insulin,” which had been suggested by Macleod based on the Latin root word for “island.”
May 25, 1922 – Following the meetings with the Eli Lilly delegation, Macleod, FitzGerald, Banting and Best wrote a follow-up letter to Falconer, formally recommending that the Board of Governors accept, in the name of the University of Toronto, patent rights for the U.S. as had already been done for Canada. The process for applying for a U.S. patent had begun in the names of Best and Collip, following unanimous advice warning “that unless it is done, patents are certain to be secured by commercial firms interested in the production of the extract for sale.”
May 26, 1922 – Jim Havens, the 22-year-old son of the vice-president of Eastman Kodak, is given the first dose of insulin administered in the United States. An appeal from his physician to Banting prompted Connaught to ship a package of insulin on May 21st. Banting followed up on May 26th, personally delivering more insulin and consulting with Haven’s doctor. To find out more about Jim, click here or here.
May 30, 1922 – The collaboration between the U of T Board of Governors and Eli Lilly was signed and formally established with an “Indenture”. There was to be a complete pooling of knowledge between the Toronto and Indianapolis groups (Eli Lilly) and a several-stage development of insulin that would involve large-scale clinical tests in Toronto and the U.S., with Eli Lilly supplying insulin free of charge in the initial stages, and then selling it at cost. The Lilly group agreed not to divulge production process details to anyone else, although the contract did not place such restrictions on the Toronto team. They intended to publish Connaught’s method in order to ensure others would know how to make insulin when Lilly’s exclusive rights expired, and to protect themselves from potential charges of unethical secrecy. To learn more about the history of Eli Lilly and how they came to play a crucial role in the development and distribution of insulin, click here.
June 28, 1922 – Although Eli Lilly began its insulin production development work on May 30th, the University of Toronto’s agreement with the firm only formally came into effect on June 28, 1922. That agreement launched a unique and intensive one-year exclusive partnership focused on developing large-scale insulin production methods. The agreement also allowed Eli Lilly to take out U.S. patents on any improvements it made in the manufacturing process, but it would assign patent rights for the rest of the world to the University of Toronto.
July 9, 1922 – 57-year-old Charlotte Clarke, suffering from severe diabetes complicated by a badly infected, gangrenous leg, had been referred to Banting and was admitted to Toronto General Hospital, but there was no insulin available for her. However, Banting felt there was a chance to save Clarke, and possibly other diabetics needing critical surgery, if she was given insulin. As the alternative was certain death, Banting felt there was little risk in trying. To learn more about the story of Mrs. Clarke, click here.
Eli Lilly’s insulin plant operated continuously during the summer of 1922, with more than 100 employees working in three shifts focused solely on the challenges of large-scale production. Although yields increased, not unlike at Connaught, Lilly encountered problems securing sufficient pancreas tissue to meet production demands. By early August, Connaught and Eli Lilly were both producing fairly reliable supplies of insulin and able to provide it to more diabetic specialists.
August 15, 1922 – Elizabeth Hughes, an 11 year old diabetic and the daughter of a U.S. secretary of state, arrived in Toronto with her mother and nurse. They met with Banting the next day, who was surprised Elizabeth was still alive. She was extremely emaciated and could barely walk due to her weakness. Banting began the insulin treatment immediately and very quickly the sugar was cleared from her urine. Banting also began increasing her diet. Within two weeks, her condition was stabilized and she was consuming what a normal girl her age would eat. To learn more about Elizabeth, click here or here.
October, 1922 – Elsie Needham, an 11-year-old from Galt, Ontario becomes the first reported almost literal “resurrection” of a diabetic after administering insulin — a resurrection from what otherwise would have been a fatal diabetic coma. Elsie had been diagnosed with diabetes for six months when she lapsed into a coma. While her family doctor had little hope for recovery, Elsie’s parents took her to the Hospital for Sick Children, where she was seen by Dr. Gladys Boyd, who was in charge of the hospital’s endocrine service. Dr. Boyd consulted with Banting and together they gave Elsie insulin. Banting stayed with Elsie around the clock to closely monitor her symptoms as the coma persisted. As Banting later wrote, “I lived at the hospital day and night for three days and there every few hours for a week.” After further treatment, during which she experienced fever, delirium and many fluctuations in her condition, Elsie finally regained consciousness. To learn more about Dr. Boyd, click here and to find out more about Elsie, click here or here.
October 1, 1922 – Eli Lilly’s new large-scale insulin production plant was in operation and employing the isoelectric point precipitation and purification process. The new facility quickly produced a surplus supply, which then prompted discussions between Clowes and the U. of T. Insulin Committee about how best to distribute it. To learn more about the second instalment of making insulin, click here.
Fall 1922 – Professor August Krogh, one of the world’s best-known biomedical scientists and Nobel Prize winner in Physiology and Medicine for his work with capillaries and their role in regulating blood flow during exercise, his wife, Marie Krogh, a scientist in her own right and also a recently diagnosed diabetic, learn about the discovery, development and purification of insulin in Toronto. The Kroghs, living in Denmark, were so intrigued by the dramatic clinical effectiveness of insulin that they began correspondence within their network which eventually led to a collaboration between Novo Nordisk and the University of Toronto’s Insulin Committee. To find out more about the history of Novo Nordisk, and how they came to produce and distribute insulin, click here.
The increased U.S. and European press attention prompted a Toronto Star article on October 14th, likely by Greenaway, that focused on the heightened media coverage, much of which had emphasized how insulin was a “certain cure.” But, as the article also observed, “While the University of Toronto remains officially silent, distorted reports in some of the papers of the United States give wrong impressions regarding where the credit is due.”
October 20, 1922 – U of T’s Insulin Committee assumed a more direct role in controlling the insulin story in the press, beginning with an official statement detailing the university’s formal application for patents.
December 7, 1922 – Press attention shifted away from the patent issue towards dramatic accounts of how insulin had revived patients in diabetic comas. Two almost simultaneous cases are published by the Toronto Star in which insulin injections resurrected diabetics on “death’s door” in Edmonton and New York City. In Edmonton, Collip’s insulin revived an eight-year-old girl, while a 16-year-old New York City boy emerged from a coma following treatment. To learn more about these early child patients who were ‘resurrected’ click here or here.
December 18, 1922 – Banting finally relented and allowed his name to be included in a generally written insulin patent application that now placed more emphasis on what the Toronto pancreatic extract did, physiologically and clinically, as a diabetes treatment, than on detailing a definitive method of its production. To learn more about why Banting did not initially want his name included on the patent, click here.
January, 1923 – Banting, W.R. Campbell and A.A. Fletcher reported in an article for the British Medical Journal that by the end of December 1922, 50 diabetic cases had been successfully treated with insulin at TGH, with ten patients revived from complete comas.
July, 1924 – Professor August Krogh and Hans Christian Hagedorn establish Nordisk Insulin Laboratory as an independent institution by royal charter, with Hagedorn as director. Insulin production flourished in Denmark, with “Nordisk Insulin” produced at a lower cost than anywhere else in the world except the insulin produced by Connaught Labs in Toronto. The profits from Nordisk’s sales were directed to the Nordisk Insulin Foundation, set up in December 1926, to support scientific and clinical studies in physiology, endocrinology and metabolism (August Krogh was its first chair). Nordisk’s head start with insulin production and distribution enabled it to become well established across Scandinavia before Novo began operations. To learn more about the history of Novo Nordisk and their role in the development of insulin, click here.