Taming of the Sugar: The Story of the Mellitus Men

“The only reason for time is so that everything doesn’t happen at once.” Albert Einstein

October 25, 1923: The Nobel Prize in Physiology and Medicine is awarded to Frederick Grant Banting and John JR Macleod

This was a historic moment for science, on the whole, and medicine, specifically. This was the shortest duration between a discovery and the Nobel, just a year. “The Professorial Staff of the Karolinska Institute has considered the work of Banting and Macleod to be of such importance theoretically and practically, that it has resolved to award them the great distinction of the Nobel Prize,” the Nobel citation read.[1] Banting was the first Canadian to win the Nobel Prize and remains the youngest person to have won it at the age of 32 [Fig. 1].

Figure 1.

Canadian stamp, year 2000, denomination 46: The Millennium Collection, Medical Innovators series: Celebrating the Nobel achievement of Sir Frederick Banting. Depicted also are Dr. Charles Best, Banting's handwritten note, and Marjorie[2]

November 14, 1891, Ontario, Canada: Frederick Banting is born

Frederick Grant Banting was born in Alliston, Ontario to an Irish father and a Scottish mother. He entered the University of Toronto as a student of Theology but transferred to the medical school in 1912, finding his calling in surgery. As World War I loomed, Banting enlisted in the army. He served with an ambulance corps in France and was awarded the Military Cross of Valor for his courage in the line of fire, suffering a shrapnel wound in his right arm in the Battle of Cambrai and almost losing his arm.[1] He returned in 1919 and completed his medical training in The Hospital for Sick Children in Toronto, with particular interest in orthopedics. He started practice with an office in London, Ontario. Work and income being slow, he joined as a part-time lecturer at the University of Western Ontario.[3]

December 10, 1923, Stockholm, Sweden: The Nobel prize is distributed

Neither of the two joint winners was present for the ceremony. The British Ambassador accepted the award on their behalf. Macleod gave his Nobel lecture on May 28, 1925 during a promotion and installation ceremony by the Karolinska Institute while Banting gave his lecture on September 15, 1925 in the Swedish Medical Assembly.[4]

1550 BC to 1916 AD: The perils and pearls of diabetes are studied, experiments conducted, and treatments attempted

The first reference of diabetes can be found in papyrus scrolls in the writings of Hesy-Ra, one of the first physicians, who wrote about the polyuria noted in diabetics. Charaka, in 330 BC, noted the glycosuria and called the debilitating disease “madhumeh.”[4] The prognosis of patients with diabetes was poor, with children not surviving beyond a year from the diagnosis, and only 20% of the adults lived for more than 20 years.[3] Bloodletting, blistering, opium, increased sugar consumption and fasting had all been tried to ease the suffering and attempt a cure.[5] Over the years, the structure and functions of the pancreas in the digestion of food were identified. In 1869, Paul Langerhans, a German medical student, discovered different types of cells floating like islands in the sea of acinar cells of the pancreas.[5] It was only in 1893 that Gustave-E’douard Laguesse suggested their role in the regulation of blood sugar and called them the islets of Langerhans.[4] Experiments conducted by Dr. Joseph Freiherr von Mering and Dr. Oscar Minkowski on pancreatectomized dogs provided more evidence for different types of secretions by the pancreas that regulated blood sugar.[5] Dr. Moses Barron, during an autopsy, found obstruction of the pancreatic duct by stones. While the acinar cells were destroyed, the islet cells were preserved. John MacLeod, one of the recipients of the 1923 Nobel Prize, summarized all the knowledge about diabetes in his textbook “Physiology and Biochemistry in Modern Medicine.” Nicolai Paulescu (1916) in Romania was the first to develop an aqueous pancreatic extract that normalized blood glucose in dogs with diabetes but the World War I disrupted his experiments.[4]

July 1924 and February 1925, Denmark: Nordisk and Novo are founded

Frederick Banting, Henry Best, and James Collip patented their discovery and transferred the rights to the University of Toronto for one Canadian dollar, with the condition that the income would be used to fund research. With the demand outgrowing the production, the Eli Lilly company stepped in (August 1922) to produce large quantities of the refined product for sale. In Denmark, H C Hagedorn, August Krogh, and August Kongsted established the Nordisk Laboratory in July 1924. A year later, brothers Harald and Thorvald Pedersen founded the Novo Therapeutic Lab Oratory. The two companies later merged, and Novo-Nordisk became the largest producer.[4]

October 31, 1920, Ontario, Canada: Banting is inspired and struck by an idea

As a part of his work at the University of Western Ontario, Banting would take lectures for medical students. One night as he sat preparing for a lecture on the pancreas, he came across an article in the journal “Surgery, Gynecology and Obstetrics” by Dr. Moses Barron on “Relation of the Islets of Langerhans to Diabetes with Special Reference to Cases of Pancreatic Lithiasis.”[4] “It was one of those nights when I was disturbed and could not sleep. I thought about the lecture and about the article… Finally about two in the morning after the lecture and article had been chasing each other through my mind for some time, the idea occurred to me. I got up and wrote down the idea and spent most of the night thinking about it.” On a loose sheet of his notebook, scratching out the date of inception of the idea that took shape over the next day and night, he wrote: “Diabetus. Ligate pancreatic duct of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate internal secretion of these to relieve glycosuria.”

November 1922–October 1923: The nomination and differences of Banting and MacLeod

Banting presented the results of their study at the annual conference of the American Physiological Society in New Haven on December 30, 1921, which he attended along with MacLeod, Best, and Collip.[4] While the world was hailing the four as heroes and witnessing the miracles of their discovery as described by diabetologist Elliott Joslin, “so many near resurrections that I realized I was seeing enacted before my very eyes Ezekiel's vision of the valley of dry bones,” the Noble Prize was itself marred in controversy.[1]

August Krogh, a Nobel Laureate and one of the founders of Nordisk Laboratory, visited MacLeod's laboratory in 1922. His wife suffered from diabetes and he was keen on understanding the breakthrough taking place in the Canadian Institute. In 1923, August Krogh was among the laureates who nominated MacLeod and Banting for the Nobel for the first time.[4] According to the will of Alfred Nobel (1833–1896), “the prize is to be awarded for a most important discovery and it cannot be shared by more than three persons, who all have to be alive when awarded.” The task to select laureates for the prize in physiology or medicine was assigned to Karolinska Institute, Stockholm, Sweden. Usually, candidates have to be nominated multiple times from different sources and at a gap of at least a year and upon thorough investigation by independent specialists before they are considered for the award. For the 1923 Nobel, Collip was not nominated because his contribution was in the purification of the product rather than the discovery itself. Henry Best was excluded because he was perceived as a medical student who helped with the experiment rather than the theoretical input. When the award was announced, Banting was furious that MacLeod was a recipient and Best was not mentioned. He initially refused the honor. After much persuasion, he accepted and publicly acknowledged the contribution of Best, sharing half of his prize money with him. MacLeod, on the other hand, shared his prize money with Collip.[3]

May 17, 1921, Toronto, Canada: Banting and Best begin their experiments

Banting was consumed by his idea to develop a purified extract from the islet cells of the pancreas and presented the same to Professor John MacLeod, an expert in carbohydrate metabolism at the University of Toronto in November 1920. Though skeptical of the young man's theory, MacLeod allowed him to use his laboratory. He assigned Dr. Charles Best, an undergraduate medical student, to help him with the experiments over the summer. Banting and Best worked day and night, ate and slept in the lab from May to September, learning from their mistake and refining their methods [Fig. 2]. They ligated the pancreatic duct in one group of dogs and after several weeks, once the acinar cells were atrophied, they extracted the secretion from the islet cells and injected it into the veins of another group of dogs who had been pancreatectomized. On August 3, 1921, Marjorie, a pancreatectomized dog was noted to show a dramatic improvement in symptoms following the injection. The sugar levels were controlled but only for a short period. Aware that fetal and newborn animals have more islet cells to produce larger quantities of pancreatic extract, he used discarded cow embryos for the production, which worked successfully. When MacLeod was informed of the results, he demanded more data and experiments. While MacLeod came across as suspicious, Banting was offended and the relationship between the two soured. MacLeod, still realizing the importance of the discovery, provided his entire laboratory facility and included Dr. James Collip, a biochemist, in the team. Collip used 90% alcohol to produce a soluble form of the extract, free from impurities which could be used in humans[1,3] [Fig. 3].

Figure 2.

Canadian stamp, year 1991, denomination 40, Canadian Doctors series: Honoring the doctor, scientist, Nobel Laureate and Knight, Sir Frederick G. Banting with the University of Toronto medical building where the historic experiments were conducted but which no longer exists[2]

Figure 3.

Canadian stamp, year 1971, denomination 6: Commemorating 50 years of the discovery of Drs. Banting and Best. The stamp shows the drawing of the original laboratory in which they worked[2]

February 20, 1941, Canada: Frederick Banting is killed in a plane crash at the age of 49 years

Banting continued research in the Banting and Best Department of Medical Research. He was bestowed Knighthood in 1934. As World War II began, Banting returned to Canadian military service and was the coordinating chairman of medical research.[6] On February 20, 1941, he took the fateful flight to England for a council on research with scientists in Britain. Shortly after take-off, the engines of the plane failed. Despite the heroic efforts of the pilot to land on a frozen lake, the wing struck a tree and crashed. Banting sustained fatal injuries and the world lost one of the brightest minds far too young, far too early.[3]

January 23, 1922, Toronto, Canada: Leonard Thomson becomes the first diabetic to be treated successfully

When 14-year-old Leonard, a child with type 1 diabetes, was brought in by his father to Toronto General Hospital, he was in a terrible, emaciated state. The intramuscular injections of the extract purified by Collip improved his condition and saved his life.[5]

2021: Insulin is Hundred and Counting

History can be found in stories, diaries, memoirs, obituaries, paintings, sculptures, newspapers, videos, coins, stamps, fossils, weapons, and medals. Some are glorified, some subject to criticism, but part of history, nonetheless. The pieces are scattered, like the timeline presented here. They alone do not make sense, but when put together and in order, the jigsaw is completed to reveal the real picture. It is not one individual or a single contribution but the collaborative effort of each member that ultimately led to the discovery and development of insulin [Fig. 4]. As it completes a century, we try to trace the events and important people associated with the birth of insulin and leave it to you to put the puzzle together.

Figure 4.

Canadian Stamp, year 2021, denomination, Permanent: Marking the hundred years of the miracle drug insulin that has saved countless lives since its discovery. It features an early insulin vial and Dr. Banting's notes.[2]

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Conflicts of interest

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