Beyond Banting and Best: 100 years after insulin discovery, advances, challenges continue
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The discovery of insulin in 1922 is heralded as a monumental achievement in diabetes research, but decades of work before and since show no single group is responsible for one of the great modern advances in medicine, according to a speaker.
No one disputes that Frederick Banting, Charles Best, James Collip and John Macleod, all of the University of Toronto, were the first to develop an insulin preparation as an effective therapy for humans with diabetes, and no other group can lay claim to that accomplishment, Gary F. Lewis, MD, FRCPC, director of the Banting and Best Diabetes Centre, the Sun Life Financial Chair in Diabetes and the Drucker Family Chair in Diabetes Research at the University of Toronto, Canada, said during a keynote presentation at the American Association of Clinical Endocrinology annual meeting. Leading up to that discovery, however, were decades of incremental advancements and a large body of knowledge that had already localized an “internal secretion” to the pancreas, Lewis said.
“Most research advances do not come out of the blue and build on decades of careful, experimental work by many players,” Lewis told Healio. “This was indeed the case with the ‘discovery’ of insulin by the Toronto Group in 1921. This momentous advance in the treatment of a formerly incurable and lethal condition, diabetes, was in fact the purification of insulin in a form that could safely be administered to humans. The discovery of insulin’s chemical structure, sequencing of the insulin gene and its bioassay would follow during the course of the 20th century, after 1921-1922.”
A common pitfall
A common pitfall in research is believing in one’s hypothesis to the point that it impairs judgement, Lewis said. Initially, Banting’s central theory was that the ligation of the pancreatic duct would result in degeneration of the exocrine pancreas, enabling isolation of the “internal secretion” — insulin.
In late 1920, there were delays in generating duct-ligated dogs for the researchers’ work; Banting and Best began to “take some shortcuts,” using only partially degenerated pancreas from dogs, with good results, Lewis said during his presentation.
At first, they failed to recognize their own findings.
“When they wrote up the findings, they claimed the degenerated pancreas was more effective, when their own experimental findings really did not show that,” Lewis said. “They were blinded to what they were finding.”
Then Banting read a paper showing that newborn or fetal pancreas had more plentiful islets, and he obtained bovine fetal pancreas from a local abattoir, with good success, Lewis said. Finally, the researchers resorted to using pancreas from a non-ligated adult dog and observed a successful decline in blood glucose.
“They pivoted completely from this idea that you had to ligate the pancreatic duct and have degeneration of the exocrine pancreas,” Lewis said. “I find this very interesting because I myself have fallen into this trap more than once, where I believe in my hypothesis so much that it is difficult to be led by the data and see that, perhaps, your hypothesis was not correct.”
‘The race is on’
After the first humans with diabetes were successfully dosed with purified insulin, international media attention led to “tremendous pressure” on the researchers to scale production as quickly as possible, Lewis said.
“The race was on to supply insulin to the world,” Lewis said. “People were dying. Children were dying, and they had to move to large-scale insulin production. Production started to fail in spring 1922, and they were in trouble. Everybody wanted insulin.”
After frustrating failures, Connaught laboratories and the University of Toronto entered into a collaboration agreement with Eli Lilly & Co of Indianapolis to improve production, Lewis said.
The discoverers sold their rights to the University of Toronto for $1 apiece, and the university filed an application for a patent, considered controversial at the time. The goal was to prevent their discovery from being commercially exploited by a single company, Lewis said.
“Banting famously declared that ‘Insulin does not belong to me, it belongs to the world,’” Lewis said. “They had very high ethical concern that ensured that even the most financially destitute of patients would not be deprived of insulin by commercial forces. Unlike today, in which commercialization of medical discoveries is a point of pride for researchers and universities, in 1921-1922, researchers and universities felt uneasy about profiting from medical discoveries which were, first and foremost, to benefit humanity.”
100 years later
Insulin has advanced dramatically since 1922. Animal insulins were eventually replaced by human insulin, and advancements in glucose self-monitoring, the discovery of HbA1c and later continuous glucose monitoring and other diabetes devices allowed for improved diabetes care. Today, ultrarapid and ultra-long-acting insulin provide even better glucose response.
But a century after the discovery of insulin purification, the therapy is still widely unavailable to people in need, Lewis said. The WHO Global Report on Diabetes, issued in 2016, states, “People with diabetes who depend on lifesaving insulin pay the ultimate price when access to affordable insulin is lacking.”
Globally, one in two people needing insulin lack access, Lewis said.
“Improving insulin availability and affordability is very complicated and needs to be addressed through national and global actions, including prioritizing the supply of more affordable human insulin, increasing competition through use of lower-priced, quality-assured biosimilars, negotiating lower prices from manufacturers and improving distribution systems,” Lewis said.
For type 1 diabetes, the “holy grail” remains physiologic insulin replacement, Lewis said. Advancements in closed-loop insulin delivery and cell-based therapies have brought researchers closer to that goal, but it is important to remember insulin’s long history when moving forward.
“It is extremely interesting to gain insight into why the purification of insulin occurred in Toronto, what the contributions of the four primary members of the group were, what motivated them both to pursue this line of work and then to make insulin as widely available as possible, some of the ethical concerns they had and the relationship between academia and the pharmaceutical industry,” Lewis told Healio. “Understanding these issues is relevant for the present day, particularly in light of the lifesaving development of vaccines for COVID-19.”
Perspective
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It is important to keep in mind the perspective that many researchers contributed to the discovery — as well as viability — of insulin use therapeutically in treating diabetes mellitus.
Dr. Lewis also made an important point about being open to changing accepted paradigms of experimental protocol. A significant step forward in the insulin story was Dr. Lewis's mention of the beneficial progress in abandoning the accepted approach of required pancreatic duct ligature in the experiments.
Continuous glucose sensor systems have had a significant impact on diabetes self-management, not just with regard to medication adjustments, but in lifestyle choices. This is principally due to the immediate feedback received regarding lifestyle choices made by the person with diabetes. Pre-mixes of insulin can be advantageous in specific populations, but not for all.
Unfortunately, 100 years later, the accessibility of insulin for those needing it remains a very significant global challenge that needs to be addressed internationally.
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Lewis G. The discovery of insulin revisited: Lessons for the modern era. Presented at: American Association of Clinical Endocrinology Annual Scientific and Clinical Conference; May 26-29, 2021 (virtual meeting).
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