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The discovery of insulin: a story of monstrous egos and toxic ...

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The discovery of insulin: a story of monstrous egos and toxic rivalries

It’s one that dates back 100 years, but in a time of Covid-19 and climate change has important lessons

Kersten Hall
Frederick Banting, right, and Charles Best on the roof of the medical building at the University of Toronto in August 1921.
BETTER DAYS Frederick Banting, right, and Charles Best on the roof of the medical building at the University of Toronto in August 1921.
Image: Thomas Fisher Rare Book Library, University of Toronto

When Frederick Banting’s phone rang one morning in October 1923, it was the call every scientist must dream of receiving. On the other end of the line an excited friend asked Banting if he had seen the morning newspapers. When Banting said no, his friend broke the news. Banting had been awarded the Nobel prize for discovering insulin.

Banting told his friend to “go to hell” and slammed down the phone. Then he went out and bought the morning paper. Sure enough, there in the headlines he saw in black and white that his worst fears had come true: he had indeed been awarded the Nobel, but so had his boss, John Macleod, professor of physiology at the University of Toronto in Canada.

This is a tale of monstrous egos, toxic career rivalries and injustices. But, of course, there is another character in this drama: diabetes.

According to a recent World Health Organisation (WHO) report, about 9-million people with type 1 diabetes are alive today thanks to insulin. I’m one of them, and it was my own shock diagnosis with this condition just over 10 years ago that led me to investigate the discovery of insulin, the drug I would be injecting several times a day for the rest of my life.

‘The pissing evil’

Diabetes derives its name from the ancient Greek word for “to flow”, a reference to one of its most common symptoms and for which 17th-century English doctor Thomas Willis (1625-75) gave it the far more memorable name, “the pissing evil”. But frequent trips to the toilet were the least of a patient’s worries.

Before the discovery of insulin, a diagnosis of type 1 diabetes meant certain death. Unable to metabolise sugar from carbohydrates in their diet, patients became weak and emaciated until, due to the production of toxic compounds known as ketones, they slipped into a coma and died. Even at the start of the 20th century there was little that could be done for patients with this condition, other than put them on a starvation diet that might at best delay the inevitable.

Little wonder then that doctors were stunned at the discovery of a hormone that could return the elevated sugars in diabetic patients to healthy levels and even bring them out of a coma. And since it was made by small patches of islet-like tissues in the pancreas, this substance was given the name “insulin”, derived from the Latin for “island”. When the eminent American diabetes doctor Elliott Joslin first used insulin to treat his patients in early 1922, he was so stunned by its power that he likened it to the “Vision of Ezekiel”, the Old Testament prophet who is said to have seen a valley of dry bones rise up, be clothed in flesh and restored to life.

Joslin’s colleague, Walter Campbell, was equally impressed, but much less poetic. He described the crude pancreatic extracts as “thick brown muck” and though the thick brown muck was saving lives, it very quickly became apparent that it could also take them. If injected in the wrong dose it would cause a patient’s blood sugar levels to crash, sending them into hypoglycaemic shock and the possibility of a fatal coma.

For the newspapers, however, insulin was hailed as a miracle. And accolades quickly began to flood in for its discoverer.

Why so angry?

But why was Banting so furious? As far as he was concerned, having to share the award with Macleod was not just a travesty, but an insult. He thought Macleod had no right to any claim on the discovery of insulin.

By the end of 1921 things had worsened. Macleod felt it was now time for Banting and Best to present their work at a formal scientific conference. But when Banting rose to address the American Physiological Society at the University of Yale that December, the prestige of the audience took its toll on his nerves. His presentation was a disaster.

Yet had it not been for Macleod, Banting might never have been awarded the prize and would probably have remained a struggling GP in Ontario.

After his return to Canada from the western front as a wounded war hero, Banting found his career going rapidly downhill. Hopes of an alternative career as a landscape painter were quickly shot down in flames when his creative efforts were met with scorn by a local dealer. In every direction he looked, Banting saw a hostile world.

This was also the case in his first meeting with Macleod. Banting approached him with what he believed to be a novel approach for isolating the much sought-after anti-diabetic hormone made by the pancreas that might at last tame diabetes. But instead of being greeted with unfettered enthusiasm, Banting recalled that Macleod listened for a while and then began reading some letters on his desk.

It wasn’t that Macleod lacked enthusiasm. Rather, he was concerned that though Banting had the inspiration for the work, he lacked the specialist surgical skills to carry it out. But he gave Banting the benefit of the doubt and arranged for him to begin work with Charles Best, a final-year honours student.

Banting and Best sweated away in the laboratory throughout the summer of 1921, making pancreatic extracts and testing their effects on the blood sugar levels of diabetic dogs.

.With Macleod away in Europe for the summer, Banting wrote in great excitement to tell him about their latest results. But his response came as a disappointment.

Macleod gently pointed out that some of the experimental results were inconsistent and lacked appropriate controls. And later, when Macleod informed Banting that the University of Toronto could not agree to a list of his demands for more lab space and resources, Banting stormed out of the room raging: “I’ll show that little son of a bitch that he is not the University of Toronto,” threatening to take his work elsewhere.

By the end of 1921 things had worsened. Macleod felt it was time for Banting and Best to present their work at a scientific conference. But when Banting rose to address the American Physiological Society at the University of Yale that December, the prestige of the audience took its toll on his nerves. His presentation was a disaster. He later wrote: “When I was called upon to present our work I became almost paralysed. I could not remember nor could I think. I had never spoken to an audience of this kind before — I was overawed. I did not present it well.”

Desperate to snatch victory from the jaws of defeat, Macleod took over and finished the presentation. For Banting, this was a brazen coup by Macleod to rob him of the credit for having discovered insulin. It confirmed Banting’s growing suspicions that insulin was slipping from his grasp and he desperately needed to reassert his authority over the discovery.

An opportunity to do so came in January 1922. By the time 14-year-old Leonard Thompson’s father brought him into Toronto General Hospital, the boy was at death’s door from type 1 diabetes.

On the afternoon of January 11 1922 Thompson was injected with 15cc of pancreatic extract that had been prepared by Best. Hopes were high, but the effect was disappointing. Despite causing a 25% drop in Leonard’s blood sugar levels, he continued to produce ketones, a sure sign the extract had only limited anti-diabetic effect. But much more seriously, the extract triggered a toxic reaction, resulting in the eruption of abscesses at the injection site.

Two weeks later Thompson was injected once again and the result was starkly different. His blood sugar levels were markedly reduced. But perhaps the most important result of all was that there were no toxic side-effects.

This is a danger every type 1 patient is taught to recognise

So what had changed in those two weeks? The answer was that this second batch of extract had not been prepared by Banting and Best, but by their colleague, James Collip. He was a biochemist and with his expertise had been able to remove enough of the impurities from the raw pancreatic extract so that, when injected, it did not cause a toxic reaction.

The secret of Collip’s success was alcohol. Banting and Best had used alcohol to clean up their preparations of impurities, but it was Collip who really cracked the method of doing this to make an extract that could be used to successfully treat a patient with no adverse reactions. He had also discovered that though insulin might save lives, it could take them too. For when Collip injected some of his purified preparation into healthy animals, they became convulsive, comatose and eventually died. This was because Collip’s preparations were now so pure they were plunging the animals into hypoglycaemic shock. This is a danger which every type 1 patient is today taught to recognise and — again thanks to Collip’s work — remedy with some quick-acting sugar.

For Banting, however, Collip’s discoveries were not a cause for celebration, but a new threat. When Collip was reluctant to divulge the secrets of his success, Banting’s temper boiled over.

As he sank further into a festering stew of fear and suspicion, Banting began calming his nerves with alcohol stolen from the lab.

Two months later, when Macleod made the first formal announcement of the discovery of insulin to the scientific world at a meeting of the Association of American Physicians in Washington, Banting was not present. He said he could not afford the train fare.

But Banting was not the only person left seething at the decision of the Nobel committee. There was yet another expert who could claim he discovered insulin — more than 20 years before the Canadians.

The tragedy of Georg Zuelzer

In 1908 German doctor Georg Zuelzer had shown that pancreatic extracts could not only reduce the sugars and ketones in the urine of six diabetic patients, but also bring at least one of those patients out of a diabetic coma. Calling his preparation Acomatol, Zuelzer was so confident about its effectiveness in treating diabetes that he filed a patent on it.

Only now did Zuelzer realise that the side-effects of convulsion and coma were not due to impurities, but  the symptoms of hypoglycaemic shock arising from a preparation of insulin that was so pure it was causing a catastrophic crash in blood sugar levels.

Like Banting and Best, he also faced problems with side-effects. Impurities in the preparation caused fever, shivering and vomiting in patients and Zuelzer knew this would have to be overcome if Acomatol were ever to be used clinically. But he also knew how to do this because in his patent he explained how alcohol could be used to remove these impurities.

By 1914 things were looking hopeful. Zuelzer now had the support of Swiss pharmaceutical Hoffman La Roche and, best of all, his preparations were causing no signs of fever, shivering or vomiting. But he observed some new — and serious — side-effects. Test animals became convulsive and sometimes slipped into a coma. And before Zuelzer had the chance to work out what was going on, disaster struck.

With the outbreak of World War 1 that year Zuelzer’s research on insulin was brought to an abrupt halt from which it never recovered. Then, nearly a decade later, came the news that the Nobel prize had gone to Banting and Macleod. This was a severe blow that was quickly followed by another.

Only now did Zuelzer realise that the side-effects of convulsion and coma were not due to impurities, but the symptoms of hypoglycaemic shock arising from a preparation of insulin that was so pure it was causing a catastrophic crash in blood sugar levels. He had a potent preparation of insulin in his hands, only to have it snatched from his grasp by circumstances well beyond his control.

‘That son-of-a-bitch Best’

So why don’t we remember Zuelzer? According to the late historian Michael Bliss, the answer has much to do with Charles Best who, like Zuelzer, felt hurt by the award going to Banting and Macleod. When Banting heard he had been awarded the Nobel, he sent a telegram to Best saying: “Nobel trustees have conferred prize on Macleod and me. You are with me in my share always.”

True to his word, he publicly announced he would share half of his prize money with Best. But if Banting was hoping this might offer Best some consolation for not having shared in the prize, he was mistaken. Best’s resentment at having been overlooked began to irritate Banting. In 1941, shortly before boarding a flight on a secret wartime mission to the UK, Banting made clear that his former generosity towards Best was long since gone: “This mission is risky. If I don’t come back and they give my [Professorial] Chair to that son-of-a-bitch Best, I’ll never rest in my grave.”

His words proved to be tragically prophetic. Shortly after take-off, Banting’s plane crashed and he was killed. As Macleod had died in 1935, Best and Collip were now the only remaining members of the original research team from Toronto that discovered insulin. And Best was determined his name would be remembered.

But to stake his claim on the discovery, Best needed to make clear exactly when this had taken place. Had it been during the summer of 1921 when, working alone, he and Banting had isolated pancreatic extracts that could reduce the blood sugar levels in a diabetic dog? Or had it been in January 1922 when Thompson had first been successfully treated? If it was the latter, then Best had somehow to deal with the inconvenient fact that it had been Collip’s preparation — not his — that had been used to successfully treat the boy.

As Best’s star began to rise in the North American medical establishment, he gave many addresses in which, if he mentioned Collip’s contribution at all, it was either diminished or used only to highlight the crucial role that Best played in recovering the production of insulin after Collip temporarily lost the secret of its purification.

Best insisted the pivotal moment in the story of insulin was when Thompson was injected for the first time with an extract made by himself and Banting. That the real moment of therapeutic success had been two weeks later, when the boy was treated with Collip’s preparation, was conveniently played down. At the same time, Best also claimed the crucial innovation of using alcohol to remove toxic impurities was largely been his own.

He would subsequently go even further by insisting insulin was discovered during the summer of 1921 when he and Banting were working alone, testing their extracts on diabetic dogs, well before Collip arrived in Toronto. Collip’s response was largely one of stoic silence.

Convincing the world

Best appeared to have finally secured his place in medical history. At least so it seemed, until the late 1960s, when he received a letter that gave the wasps’ nest yet another poke. It revealed that in 1921, just as Banting and Best were embarking on their research, a Romanian scientist called Nicolai Paulescu had already published similar experiments in a European scientific journal. But Paulescu’s scientific work has since been overshadowed by the ugly revelation of his anti-Semitic politics and the role he played in inciting the Holocaust in Romania.

When Best was asked whether researchers such as Paulescu, Zuelzer and a handful of others, such as Rockefeller scientist Israel Kleiner, deserved any credit for the discovery of insulin, his reply spoke volumes: “None of them convinced the world of what they had ... This is the most important thing in any discovery. You’ve got the convince the scientific world. And we did.”

Bliss, who has written extensively on the work of Banting and Best, has written about how Best appears to have been “deeply insecure about and obsessed with his role in history”. He added: “The fumbling attempts to manipulate the historical record would have been pathetic and hardly worthy of comment had they not been so grossly unjust to Best’s former associates and, for a time, so influential.”

Wall Street gold

Whatever judgments we may pass on Best, there is no denying he grasped a crucial insight about an important way in which science was changing. Doing experiments in the lab was only half the story: scientists had also to persuade the wider world of the value of those experiments. And by the time of his death in 1978, this was a lesson scientists were taking to heart.

That September a team of scientists from the City of Hope Hospital in Southern California and the fledgling biotechnology company Genentech in San Francisco gave a press conference to announce they had done something amazing. Ever since the days of Banting and Best type 1 patients had been having to treat themselves by injecting insulin recovered from the tissues of cows or pigs as a by-product of the meat industry. Now, thanks to the Genentech/City of Hope collaboration, they could, for the first time, inject themselves with human insulin.

This achievement was a decisive victory in helping to win the hearts and minds of the media and public who were fearful of the new technology. Wall Street loved it too.

When the bell was rung to open trading on the morning of October 14 1980, dealers dived into a feeding frenzy for shares in the newly floated Genentech. It made its founders, venture capitalist Bob Swanson and scientist Herb Boyer, multimillionaires.

But diabetes remained an incurable chronic condition. Even as he was comparing its power with the Vision of Ezekiel, Elliott Joslin was also offering a stark warning: “Insulin is a remedy which is primarily for the wise and not for the foolish.” Joslin’s point was that insulin could only be effective if its use went hand in hand with discipline, thought and responsible behaviour on the part of the patient.

This lesson applies elsewhere too, but may well be one we don’t always want to hear. Speaking at the recent COP summit in Glasgow, the UK government’s chief scientific adviser, Sir Patrick Vallance, pointed out that we can’t expect technology alone to solve all the problems we face. The truth is, as much as we may wish for technological solutions to do all the heavy lifting, they can only be effective when they are accompanied by changes in our behaviour.

This is as true for managing diabetes with insulin as it is for dealing with challenges of a pandemic through vaccines, masks and social distancing, or climate change through carbon capture, electric cars and turning off the lights when we leave the room. And so, as we face challenges of the future, the story of insulin has important lessons for us all.

Kersten Hall is author and honorary fellow in the School of Philosophy, Religion and History of Science at the University of Leeds in the UK.

This article was first published by The Conversation, as part of its Insights series.

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