If you search for “who discovered insulin”, you’ll find these two, Frederick Banting, and Charles Best from the University of Toronto. But their version of insulin was a gunk extracted from mushed up animal pancreases, which other scientists had already made before. And Banting and Best’s extract didn’t work well in humans; it was one of their collaborators who came up with a purification process that turned insulin into something usable. Basically, their discovery of insulin wasn’t a discovery and it wasn’t pure insulin. So for this video, I had two research questions. Number one, what kept earlier scientists from making a successful insulin product? And number two, what exactly did Banting and Best do to get eternal Wikipedia glory? We’ll start off at the beginning — humans have known about diabetes for a long time. Like there are references to a disease that’s probably diabetes in Ancient Egypt back around 1550 BCE. Same with ancient Indian medical texts from over two thousand years ago. But the name diabetes comes from second century Greece meaning “to siphon” or “to flow”. A few hundred years later, a Scottish physician added mellitus from the Latin root for honey, to describe how a diabetic’s urine tasted sweet. For those wondering, yes, that was a thing. Tasting urine was the high tech urinalysis back in ye olden chemistry days. So in addition to symptoms like excessive urination and thirst, physicians could diagnose diabetes using the telltale sign of sugar in their patient’s urine. And as a result, the goal of early diabetes treatment was to lower glucose in the urine. And in the days before good drugs, the best way to do that was through diet. That same Scottish doctor I just mentioned hypothesized that all that sugar came from eating vegetables, so he thought you should be able to counteract it with a special low-carb diet diet. Pretty much just meats, fat and pork. Now, by the 19th century, doctors could recognize the disease, but didn’t understand the physiology yet. So we need to take a detour and talk about some basic physiology research. But bear with me, because it’ll help us understand the insulin story. By the mid 1800s, a French physiologist named Claude Bernard found this starchy substance in the liver that could create glucose. He called it glycogen, which means glucose generating. And that helped explain how someone could have glucose in their urine even if they hadn’t eaten a bunch of carbs. So that was step one. Step two involved looking at the pancreas. In 1869, a medical student named Paul Langerhans noticed that the pancreas had two main types of tissues. Most of the pancreas was made of acinar cells, which were involved in digestion, but he also noticed little islands of secondary tissue throughout the pancreas. These days, we call them the Islets of Langerhans. And their discovery opened up a whole new thread of research — what do the Islets do? Well, towards the end of the 19th century, researchers at the University of Strasbourg, Oskar Minkowski, and Joseph von Mering, were doing some seemingly unrelated research which ended up having implications for diabetes. They wanted to know how the pancreas influenced fat metabolism — so they removed the pancreas from an otherwise healthy dog and noticed that it peed all the time. And that was weird because excessive urination was historically a sign of diabetes. So the researchers were like “Should we check that dog’s urine for sugar?” and when they did, it was way higher than normal. Which meant they had accidentally discovered that removing a dog’s pancreas could induce diabetes. Now, at this point, we knew that the acinar cells of the pancreas released a bunch of enzymes and pre-enzymes into the gut that helped digest food, so maybe they also secreted something that affected glucose. And in order to test this, scientists would tie off the duct that connects the pancreas to the gut, assuming the pancreas pumped some kind of diabetes-preventing juice into the small intestine. But that didn’t induce diabetes, so something different was happening. The breakthrough involved switching focus from the organ to one of the chemicals it produced, which was a pretty new concept. See, a few years earlier, a French physiologist named Charles Edward Brown Sequard found that the adrenal gland, that little guy above your kidneys, could secrete chemicals directly into the bloodstream. Since it came from the adrenal glands, that chemical was called adrenaline. Brown Sequard proposed that the body was sending this chemical through the blood as a way of communicating with other parts of the body. And this was a big deal because most scientists thought that communication between body parts was strictly a job for the nervous system. These communicator chemicals were called hormones, and physiologists saw the potential right away. Like if they could identify the gland that secreted a particular hormone, then they could treat a deficiency of that hormone by transplanting a healthy gland into that person. Now, when he was older, Brown Sequard took this to an extreme level and started injecting himself with testicle extracts. Like he was so convinced that testosterone was the key to longevity, that he shot himself up with testicles. But coming back to the University of Strasbourg, Minkowski decided to take a page out of Brown-Sequard’s book…obviously without the testicles. He tried to reverse the diabetes he’d induced by transplanting a whole pancreas and all its anti-diabetes hormones back into depancreatized dogs. But it didn’t work. So next, he and his contemporaries injected custom-made extracts of pancreatic tissue into diabetic dogs hoping to lower blood or urine sugar. But nobody was able to get consistent results. And even worse, sometimes these extracts would cause shock or kidney failure in the test animal. But then a Russian scientist found something peculiar about the islets of langerhans in the pancreas — they were surrounded by capillaries, or tiny blood vessels. And that meant that the islets might create the hormone they were looking for. He also noticed that diabetic patients tended to have fewer Islets than non-diabetics. So he wondered if the Islets alone were the tissues that made the anti-diabetes hormone. This became part of the growing body of evidence that there were two major secretions from the pancreas — the external secretions from the acinar cells which included all those digestive enzymes going to the small intestine, and the internal secretions which included whatever anti-diabetes hormone the Islets of Langerhans pumped out. In 1909, even though nobody had actually found the internal secretion yet, a Belgian scientist named the substance insulin after the islets of Langerhans that it came from. These days we know that the Islets have multiple cell types, including the beta cells that produce insulin, and the alpha cells that produce a hormone called glucagon . Glucagon is gonna show up again in a few videos when we cover GLP-1 agonists like Ozempic. So make sure to subscribe so you see that one. By the first decade of the twentieth century, a few doctors tried to perfect the idea of the pancreatic extract for diabetes. And there was a German doctor named Georg Ludwig Zuelzer who tried to bring an extract to market. See, Zuelzer thought that diabetes was actually caused by too much adrenaline, and that the pancreas secreted a hormone that neutralized adrenaline. He tested his extract in humans, and showed that it could reduce glucose in the urine. Unfortunately his preparation also came with some severe side effects like vomiting and convulsions. Zuelzer spent years working on it, and even managed to secure some funding and to develop an extract that he patented. He called this product Acomatol, but when it entered production, it was the same story as before — the product had gnarly side effects. This is probably why his name isn’t enshrined in headlines like Banting and Best. In 1915, an American scientist named Israel Kleiner prepared his own pancreatic extract, tested it on dogs, and got it to lower blood sugar. But the best of these extracts before Banting and Best came from Romania’s Nicolae Paulescu. Kind of like Zuelzer, he created a pancreatic extract, then gave that substance to a dog whose pancreas had been removed. He called his extract pancreine, and used it to successfully lower blood and urine glucose in dogs. His big research paper was published in 1921 in a French journal. Now, all of these preparations, whether from Zuelzer, Kleiner, or Paulescu, had side effects that made them clinically unusable. And even as late as the 19-teens, diabetes experts around the world were starting to lose faith that they’d ever find a usable pancreatic extract. According to a 1913 publication by diabetes expert Fredrick Allen “injections of pancreatic preparations have proved both useless and harmful. The failure began with Minkowski and has continued to the present without an interruption”. It must’ve been heartbreaking. By the start of the twentieth century, doctors could confidently diagnose diabetes but, at best, their treatments only slowed the disease’s progression. The best they had were severely restricted diets, which is putting it kindly. Doctors like Frederick Allen and another famous one named Elliott Joslin would essentially prescribe starvation to to their diabetic patients. According to popular theories, diabetic bodies were overwhelmed by sugar and carbohydrates, so restricting food would slow their inevitable breakdown. On the practical level, that meant that when a diabetic patient came into the hospital, they would be told to fast until the doctors couldn’t measure glucose in their urine anymore. Then the medical team would increase the patient’s calories until they detected sugar in the urine again. Your new caloric prescription was just a little bit lower than that number. Now I know that I’ve been talking a lot about urinalysis in this video already, but if you excuse the pun, these diets were a piss poor way to live. They created a terrible quality of life for the patient and at best extended their lifespans just a little. And that’s what made research out of Toronto such a big hit. This is Fredrick Banting, and he had a hectic early career. He originally wanted to study art, but had to dropout after failing French. So he did what anyone would do in that situation and decided to study medicine instead. He spent some time volunteering for the Canadian Army Medical Corps before getting sent to England during World War I. But in September of 1918, he suffered a shrapnel wound to the forearm which earned him the Military Cross and the right to go home. He came back to Toronto in 1919 where he interned at a few hospitals in Toronto and further honed his surgical skills. And when the internship was over he moved to London, Ontario where he started a private practice. But the practice wasn’t a big money maker right away, so he fell into severe debt and resorted to teaching part time at Western University to make ends meet. According to his memoir, one night in 1920, he was getting ready for a lecture and read an article titled “The Relation of the Islets of Langerhans to Diabetes with Special Reference to Cases of Pancreatic Lithiasis”. And for whatever reason, it captured his attention and he stayed up thinking about it. See, Banting subscribed to a hypothesis that claimed the digestive enzymes made by the acinar cells broke down insulin before it could be extracted from the pancreas. So if you wanted to extract insulin, you’d have to find a way to keep the digestive enzymes away from the Islets so that they could make the hormone safely. That’s why this paper was so interesting to Banting. The author had shown that when the duct connecting the pancreas to the small intestine was ligated, or tied off, the acinar cells atrophied while the Islets were unaffected. And Banting thought this might be the way he could protect insulin from the digestive enzymes. If he tied off the pancreatic duct, then the acinar cells should shrink, and the resulting pancreatic extract should have plenty of undamaged insulin. That was the hypothesis anyway. So Banting tells his idea to one of his colleagues, who recommends that he talks to this guy named JJR Macleod, an expert on carbohydrate metabolism at the University of Toronto,. And about a week later, Banting was in Macleod’s office, pitching his research idea, where Macleod was encouraging but realistic. He was well aware of the history of scientists who’d tried to isolate the internal pancreatic secretion before. But Banting’s idea interested him because, as far as Macleod knew, nobody had tried to create a medicine from pancreatic tissue with atrophied acinar cells. Plus, Banting had experience as a surgeon, so he was a good candidate for an experiment that involved a surgical procedure. And even if he got negative results, it would be academically interesting. So Banting went home, and after a couple of months, Macleod offered Banting, not a job, but the opportunity to do his pancreas project at a lab in Toronto. He would start in the spring of 1921. Macleod assigned Banting two students to help in the experiment — Clark Noble and Charles Best. But Banting wanted to work in July when the academic term was over, so the students flipped a coin to see who would work when, and in the end, Best got the July slot. Now the research could begin. Step one was learning whether pancreatic enzymes actually destroyed insulin. So the plan was to take a dog and tie off the duct between the pancreas and gut, then over the course of a few weeks, the acinar cells would shrink, and leave behind the still-functional Islets cells and the insulin inside. Then they’d take another dog and surgically remove its pancreas to incite Type 1 diabetes. They’d prepare the atrophied pancreas from dog 1, and inject it into diabetic dog number 2, and hopefully see a drop in blood sugar. Unfortunately, they just kept getting unlucky. Their dogs were more likely to die from infection or surgical complications than diabetes, and the university didn’t have an unlimited supply of dogs. Plus, Banting’s procedure for tying off the the pancreatic duct wasn’t always effective, so sometimes they’d wait for weeks and the pancreas was still full size. So by the middle of June, Banting and Best were frustrated but still optimistic. It seemed like the original premise of atrophying a pancreas was at least a possibility. And in early August, one of their diabetic dogs seemed to respond to the treatment. They gave it pancreatic extract and its blood sugar dropped. Unfortunately, that dog died a few days later from infection. A few days after that though, Banting and Best finally started to see the expected drop in blood sugar after giving dogs the extract, what they’d named Isletin at that point. But as Macleod pointed out in a letter to Banting, they hadn’t used control experiments and they hadn’t seen a consistent relationship between a standard dose of insulin and a corresponding response in blood sugar. So they they shouldn’t get too excited. Banting and Best were running out of materials fast, especially the pancreatic extract since their procedure wasn’t creating the atrophied pancreases as well as they expected. So to save some time and resources, they started using preparations of whole pancreas instead of atrophied pancreas. And unexpectedly, this stuff still lowered blood sugar. They thought that the whole pancreas would still have those enzymes that destroyed insulin, but the fact that it lowered blood sugar as well as it did contradicted Banting’s original hypothesis. Sidenote, a few years later, a British researcher critiqued Banting for not predicting this would happen. Some of those digestive enzymes they were trying to prevent, like trypsin, don’t form until they come in contact with other enzymes in the small intestine. From his perspective, the duct-ligation experiments were pointless from the beginning. But back in the fall of 1921, they’re still desperately in need of materials, plus Banting hadn’t been paid all this time. So Banting asked Macleod for a salary, plus funding, and a bigger lab. But Macleod says no. Banting throws this big tantrum, he threatens to quit, and he storms out of Macelod’s office. It’s this big drama. Fortunately, a pharmacology professor at U of T had a job opening, and offered it to Banting which persuaded him to stay at the university. The research picked back up in October, and it was clear that the degenerated pancreatic extracts weren’t worth the effort. But the whole pancreas extract still wasn’t good enough either. So Banting and Best would need to change something. They documented their last dog in this round of experiments on November 10 of 1921, and submitted their paper for publication soon afterwards. A few days later, Macleod says “hey, you guys should talk about your research at an upcoming journal club for the university”. And they do it, but afterwards, they’ve got a clean slate to work from and they direct their attention to the supply problem — if they wanted to make a medicine, they would need a better way of extracting the internal secretion. So Banting spends the night of November 15, the night after journal club, reading as much as he could about pancreas physiology. And one of the things he learned was that newborn animals and fetuses have a higher concentration of Islet cells compared to acinar cells than adult animals. Also, since fetuses don’t eat, they probably wouldn’t have those digestive enzymes that would break down insulin. So the thought was, fetuses would be a natural opportunity to find a more potent source of insulin. So Banting and Best went to a local slaughterhouse, and got 9 pancreases from fetal calfs and created extract from those. This was game changer number one for insulin research — they were able to consistently drop blood sugar in the first dog they gave fetal pancreatic extract to, and eventually got the blood sugar down to zero. Game changer number two was how they made the extract. Up until December of 1921, they’d been crushing the pancreas into a solution of saline. And if they had a little too much saline, they’d boil it to get rid of the excess water. But that decreased the potency of the insulin in the solution. So they switched to dissolving their pancreatic extracts in alcohol, which evaporates at a lower temperature. And that resulted in increased potency. They eventually put the two together, and noticed that the alcohol preparation was more important than the source of pancreas. And this was the third game changer. Fetal pancreases were hard to get, and this alcohol preparation allowed them to use whole pancreases, which would save them time going forward. So finally, after months of experimentation, they’d created an extract that got diabetic dogs to survive for months. Now, this success was the catalyst that allowed the team to grow, so before we go further let’s zoom in on what Banting and Best actually did. Now remember that Banting’s eureka idea of tying off the pancreatic duct didn’t lead to anything. And other scientists had created pancreatic extracts before. But Banting and Best had created potent extracts out of three things: duct-ligated pancreas, fetal pancreas, and pancreas dissolved in alcohol. According to Macleod, their contribution was providing solid evidence that there was an anti-diabetes hormone in the pancreas. To quote Michael Bliss’s book, The Discovery of Insulin, “Banting and Best alone did not discover insulin. Their work was part of the discovery of insulin. It was not the whole discovery. Banting and Best began the process that led directly and without significant interruption to success at Toronto.” The final game changer towards creating a usable insulin product was James Collip, a biochemist from the University of Alberta in Edmonton. He had heard about this project from Banting and Macleod back in May of that year and left his contact info in case they needed his help. And by the late fall, they were at the point where they could use a skilled biochemist, so Collip started intently working on insulin sometime in December of 1921. Collip figured out a technique for purifying the pancreatic extract even better. By using higher concentrations of alcohol, the insulin would precipitate out. Meaning it created these little chunks. From there, he could put the chunks into a new solution and inject it into a test animal. But while Collip was refining his process, Banting and Best were struggling. Their most recent batch of extract wasn’t working for some reason. And while it’s not clear why they did it at this moment exactly, they decided to try out some of the old, potent batch of extract on a human. His name was Joe Gilchrist, a diabetic man that Banting knew from medical school. And on December 20, 1921, Banting gave him some of extract …and it didn’t have any effect. They gave it to him by mouth, and while they didn’t know it at the time, insulin is broken down by enzymes in the stomach. So it’s no surprise that insulin never got to his blood. Now, between the time they submitted their first paper in November and the time it was published in the spring, Macleod said “hey, we should present your experiment at the conference of the American Physiological Association in New Haven on December 30th”. Banting and Best agreed, and Collip came too. One of the people watching the talk was the research director for the pharmaceutical company Eli Lilly. And after the talk, he called Macleod and said “if you ever need help scaling up production, let us know”. Macleod basically said “Thanks, we'll keep that in mind, but we’re not ready. We haven’t even done human trials. Let’s keep in touch though”. I won’t say anything else, because that’s the topic of the next video. After the meeting ends, the Toronto crew takes the train home and starts looking at next steps. At this point, Collip is using rabbits as test animals instead of dogs. And he notices a weird phenomenon where, when he gives the rabbits pancreatic extract, sometimes they start breathing really fast, or they’ll convulse on the floor, then enter a coma. They later called this insulin shock, but we’d probably call it hypoglycemia, or low blood sugar. Meanwhile, Banting is chomping at the bit to do human trials. So the researchers got in touch with U of T’s teaching hospital, Toronto General, and convinced their head of medicine to let the extract be tested there. I’m using the passive voice because Banting didn’t have privileges at that hospital, so someone else would have to do the injections. That lined up with the admission of Leonard Thompson to Toronto General. He was diagnosed with diabetes in 1919 when he was 10 or 11 and put on a starvation diet. By the time he was admitted to Toronto General on December 2nd of 1921, he had no energy, he felt miserable, and he only weighed 65 pounds. Thompson continued to get worse in the hospital, and a doctor told his dad “Look, your son is going to die. But some local reseachers have something that might make him feel a little better”. So the father agreed to try it. On January 11th 1922, a house physician injected Thompson him with 15cc of Banting and Best’s pancreatic extract and it didn’t do much. The extract reduced blood sugar by about 25 percent, but Thompson was still in ketosis, meaning he wasn’t cured of diabetes, and he developed some sizable boils at the injection site. According to the paper the Toronto team wrote afterwards, they saw this as no clinical benefit. Regardless, a few weeks after the first failed injection, Collip had a new extract ready for testing. So on January 23rd 1922, Thompson got a small dose of Collip’s extract, which was followed by multiple injections over the next few days. And this time, not only were there no boils, but his blood sugar levels consistently responded to the drug. He would continue pancreatic extract therapy and live many more years. This photo is of him at age 22, obviously much healthier than the 65 pound teenager he used to be. After Thompson, the Toronto crew gave Collip’s extract to a few more patients in the hospital. And if I can stray from the timeline a bit, by fall of that year, there was enough insulin for a few doctors in North America to start using it clinically. One of the most famous cases was Elizabeth Hughes — a 14 year old American girl who, like Thompson, was on the brink of death before insulin. At her most emaciated, she only weighed about 50 pounds. But within just a few days of insulin treatment, she was able to tolerate bread, potatoes, and a healthy amount of calories again. She survived to be seventy three years old. And other reports were even more impressive. Even diabetics that were close to coma status could sometimes wake up and live healthy lives on insulin. Like it’s hard to properly contextualize how dramatic these first treatments were without sounding hyperbolic. Like it must have seemed like an actual miracle by 1920s standards. And this is all happening at a super fast pace. Banting and Best’s first paper, the one that described experiments before they started using fetal calf pancreas, the one they finished in November of 1921, was finally published in February of 1922. And that’s mind blowing to me. In just three months, the U of T scientists went from nobody knowing about their preliminary results to saving someone’s life with the extract. They published their results from human trials, this miracle of modern medicine, in the March 1922 edition of the Canadian Medical Association Journal. And on the second page of their paper, they’re pretty clear with their conclusions. “These results taken together have been such as to leave no doubt that in these extracts we have a therapeutic measure of unquestionable value in the treatment of certain phases of the disease in man”. In May of that year, Macleod presented a summary of their work at a meeting of the Association of American Physicians where they debut the name of the substance: insulin. And immediately, the audience knew this was it. This was the thing that would cure their starving and frail patients on the brink of death. They gave Macleod a big standing ovation and there’s all this celebration. But there was one big question — how do we get some? In the next video, you’ll learn how pharmaceutical companies brought insulin to the world, and how this drug created two of the biggest companies in modern medicine.