Glucose is used by cells as a prime source of energy. Insulin acts as a kind of key that unlocks a special door on the cell membrane, allowing glucose to enter hungry cells. In the absence of insulin, glucose builds up to high levels in the blood, but the sugar molecules cannot enter cells to feed them. After a while, the high level of glucose overwhelms the kidneys’ ability to reabsorb it and the excess sugar starts to spill out into the urine, producing the characteristic “honey urine.”
Based on Von Mering and Minkowski’s pioneering work, scientists speculated that it should be possible to treat type 1 diabetes patients by giving them insulin. Initially, drug hunters presumed that all they needed to do was remove a healthy pancreas, grind it up, extract the insulin, and inject it into a diabetic person. But harvesting useful insulin turned out to be a near-impossible task. The reason it was more difficult than anybody expected was because of an odd physiological complication unique to the pancreas. One of the two main functions of the pancreas is producing hormones, including insulin. But the other function is to produce enzymes that the small intestine uses to digest proteins. Unfortunately, insulin is a protein. Whenever researchers ground up a pancreas in the hope of extracting insulin, they inevitably mixed together the insulin protein with the protein-digesting enzymes, destroying the insulin.
Despite this daunting obstacle, the medical consensus about insulin remained firm. If you could somehow figure out a reliable way of getting insulin, you would have a cure for diabetes. Scientists all around the world began to investigate different ways of extracting insulin from animals, all without success. One man who came late to the quest for insulin was Frederick Banting.
Born on a farm in Ontario, Canada, Banting had a slow start to his medical career. In 1910, he enrolled in the General Arts program at the University of Toronto but failed his first year. Nevertheless, he managed to get admitted into the University of Toronto medical program in 1912. When Canada was drawn into World War I in 1914, he tried to join the army as a medic. He was rejected. He applied again and was rejected again due to poor eyesight. He applied a third time and was finally accepted, perhaps because of the great need for army medics. He started serving the day after he graduated, but after the war ended, he encountered more professional difficulties. Though he landed a residency at the Hospital for Sick Children, he was unable to secure a permanent spot once his residency ended. He had no choice but to set up his own private medical practice, but he was not successful at that, either.
After a career full of disappointments and failures, Banting had become highly sensitive to perceived professional slights, a quality which would haunt him as he switched to a new career track. After reading a 1920 scientific paper describing an experiment in which the pancreatic duct was tied off, Banting became interested in the quest for insulin. The pancreatic duct is a tube that delivers the digestive enzymes to the small intestine, and the article reported that when the duct was clamped shut the enzyme-producing cells in the pancreas died—but there was a kicker. The insulin-producing cells remained alive and functional.
After reading the article, Banting guessed that if the enzyme-producing cells in a duct-clamped pancreas were no longer producing enzymes, it would finally be possible to safely harvest insulin. It was a pretty good idea—so good, in fact, that it had already been tried by other research teams. Those previous attempts, however, had always resulted in failure. Banting was completely unaware of these prior failures. Inspired by the possibility of curing diabetes using what he wrongly believed was his own original approach, he abruptly made the decision to switch from being a full-time physician to a full-time drug hunter.
In order to pursue his dream of extracting insulin, he recognized that he would need a fully-equipped laboratory where he could work. So he visited the lab of a world famous physiologist at the University of Toronto, J. J. R. Macleod. Macleod listened to Banting’s proposal with tremendous skepticism—unlike Banting, he was well aware of all the failed attempts at extracting insulin—but he was ultimately swayed by Banting’s passion and drive. Since Macleod was about to leave Toronto for the Scottish Highlands for his summer holidays, he figured it would not hurt to let Banting try out his ideas while he was away. Macleod generously provided Banting with laboratory space and even appointed a medical student to assist him.
During the scorching hot Toronto summer of 1921, Banting and his young assistant, Charles Best, initiated their experiments in clamping off the pancreatic ducts of dogs. This turned out to be excruciatingly difficult surgery, one of the reasons that previous research teams had failed in their efforts to isolate insulin. The first dog Banting and Best operated on was killed by an overdose of the anesthetic. The second dog died from loss of blood. The third perished from an infection. Seven dogs eventually survived the procedure, but the ligation process remained very tricky. If they tied the suture too tightly, it caused infection. If they tied it too loosely, the enzyme-producing cells would not shrink and die. Five of the seven dogs that survived the operation still produced insulin, but the enzyme-producing cells never atrophied. When they re-operated on these five dogs in a second attempt at clamping off their pancreatic ducts, two more died from complications.
Banting and Best were now halfway through their planned research program and had nothing to show for their efforts. Plus, they were running short on dogs. They combed the Toronto streets for stray dogs, which they snatched up and brought back to their lab, where the unlucky canines were rewarded with invasive surgery. Three weeks later, Banting and Best were finally able to harvest the first atrophied pancreas from a successfully ligated dog. They ground up the pancreas and injected the extract into a test dog, which they had made diabetic through the removal of its own pancreas. At last, success! Within an hour, the dog’s blood glucose level had declined by almost half.
They painstakingly repeated this experiment on other diabetic dogs. Though not every dog responded to their insulin treatment, enough did respond to convincingly demonstrate that Banting and Best had produced a feasible treatment for diabetes. Yet even though this triumph was both thrilling and gratifying, their process of extracting insulin remained highly unreliable, often failing to produce any insulin at all. Moreover, each surgically sacrificed dog only produced enough insulin for a few doses. The method certainly could not create enough insulin to help a single human diabetic, who would need to take several doses of the drug every day for the rest of their lives—and the idea of treating the country’s entire population of diabetics using the makeshift method of extracting insulin from dogs was downright farcical.
In fact, there was no precedent at all for Banting’s novel extraction process. Until now, all commercial drugs were either extracted from plants or created through synthetic chemistry. Banting and Best had invented an unprecedented way to extract a useful drug directly from the bodies of animals. Yet if they wanted to harness this process to deliver enough medicine to treat even a handful of diabetes patients, they had to somehow ramp production up to an industrial scale, while their process barely worked on a micro scale. (You might also consider the disconcerting fact that the only way to get enough insulin to save a diabetic child’s life was by slaughtering many, many mammals.)
When Macleod returned from Scotland in the fall, he was astonished to discover that the amateur scientist and young medical student had somehow become the world’s first researchers to successfully isolate insulin. Macleod grasped the problem of large-scale production and immediately recognized they needed someone who could optimize the insulin-extraction process. He recruited James Collip, a highly regarded biochemist at the University of Toronto, to join the project. Collip applied state-of-the-art biochemistry techniques to refine the insulin extracted from dogs into a more purified form.
You might think that Banting would have been delighted by this turn of events. They were on the verge of possessing a legitimate treatment for one of humanity’s oldest and most deleterious diseases. Instead, after a lifetime of professio
nal failures, Banting viewed Collip as a rival who was butting in to steal credit. In fact, he viewed Collip with such cynical disregard that he frequently stoked fights with him. Sometimes these fights turned physical. On one occasion, Banting became so enraged at Collip’s involvement that the contretemps devolved into a fistfight. Collip ended up with a black eye.
By late 1921, the uneasy team of Banting, Best, Collip, and Macleod had discovered a reliable—though still nonscalable—method of extracting insulin from the pancreas of dogs and had shown that this insulin could be used to successfully treat diabetes in dogs. But if they hoped to demonstrate its effectiveness in humans, they would need a way to scale up the extraction process still further—a prospect that looked increasingly dim in the face of Banting’s belligerence toward anyone he perceived as trying to swipe his glory. And this is where Eli Lilly comes into the story.
When Alec Clowes was put in charge of looking for new drug development opportunities at Eli Lilly, he knew that insulin stood a good chance of becoming a blockbuster—if someone could figure out how to make it on an industrial scale. In 1921, Clowes attended an academic conference at Yale where he heard Banting’s first major public presentation on his work. As Banting shared their promising results, Clowes was filled with a rising sense of excitement. When the presentation ended, Clowes immediately sent a three-word telegram back to Lilly in Indianapolis: “This is it.”
Banting had a very different reaction. He did not like the way Macleod had introduced him to the audience before his talk, speaking in a restrained manner that seemed to reserve all the credit for Macleod himself. He did not like the way all the scientists rushed to Macleod after Banting finished speaking, posing their questions to Macleod instead of Banting. He left the meeting feeling disappointed, angry, and aggrieved, convinced that once again other people were swiping credit for his hard work.
Before leaving New Haven, Clowes left a note at Macleod’s hotel saying that Lilly wanted to collaborate with his team to develop commercial insulin production. But Macleod, a Canadian, was reluctant to get involved with an American pharmaceutical company. He had been hoping to work with Connaught Laboratories, a vaccine-producing company affiliated with the University of Toronto. He declined Clowes’s offer.
George Clowes was not going to take no for an answer. During the next four months, he made four trips to Toronto to press his case with Macleod. At each meeting, Macleod insisted that he wanted to keep the development of insulin within Canada, while Clowes talked up the advantages that Lilly could bring to the project. Macleod might have been able to maintain his resolve if not for the fact that his research team was falling apart.
During the first few months of 1921, the relationships among the team members were deteriorating fast, and their interactions with the Connaught scientists were only adding to the friction. Much of the strife was driven by Banting’s jealous fear of losing credit for and control of a project he still considered his own. By early April, things had gotten so bad that Macleod finally succumbed to Clowes’s relentless advances. He wrote to Clowes informing him that they were on the verge of perfecting an insulin isolation method that could be used for commercial production at a new site—preferably a site far away from Toronto and the squabbling team.
Macleod began negotiations for licensing insulin production to Lilly. Clowes quickly arranged for Lilly’s Indiana site to obtain large quantities of pig and cow pancreases for the anticipated collaboration. Meanwhile, the Toronto team began looking around Toronto General Hospital for a diabetic patient who could serve as their first human guinea pig. They found Leonard Thompson, fourteen years old and a mere sixty-five pounds. The emaciated boy had been suffering from diabetes for three years and was starting to slip into a coma. Death always followed a diabetic coma. Since Thompson would soon die anyway, the team felt that it would be justifiable to test the insulin on him. But the pilot test got stalled by an unexpectedly contentious question: whose hand would actually get to inject Leonard Thompson with the insulin?
The maneuverings were fierce. Banting, of course, thought he should be the one to perform the injection since he viewed himself as the sole inventor of the insulin-extraction method. However, the director of the teaching wards at Toronto General Hospital where Thompson was a patient refused to allow it. The director insisted that a physician with expertise in the treatment of diabetes perform the injection, not Banting. He selected an intern working under his supervision to conduct the historic injection. Banting exploded. He was being blocked from participating in the first test of his great discovery, and instead some random young intern who had nothing at all to do with the discovery was granted the honor.
Banting demanded that he be the one to wield the syringe. As a rather peculiar compromise, the director of the teaching wards agreed to allow the intern to inject an insulin preparation made by Banting and Best, rather than the more highly purified material from Collip’s process. This way, even if Banting’s fingers were not actually on the syringe, the material in the syringe could rightfully be said to have been the direct result of Banting’s personal efforts. Though this managed to satiate Banting’s furor, it turned out to be a big mistake.
Banting and Best’s concoction produced only a marginal improvement in Thompson’s health. Worse, it provoked an allergic reaction, probably due to the presence of contaminants mixed in with the unpurified insulin. Banting’s insistence on using his unrefined version of insulin had made the life of a suffering young boy even worse. The team immediately decided to try Collip’s highly purified version instead, while there was still time. This time, it worked. Thompson’s blood sugar levels declined dramatically and he began to regain his strength and energy. His hunger and thirst diminished, and he began putting on weight again.
It was the first time any human diabetic patient had been treated successfully.
Thompson continued receiving (purified) insulin injections and, even though insulin was not a cure for the disease, managed to live another thirteen years. Previously, a child was lucky to survive a whole year after getting diagnosed with diabetes. Today, with daily doses of insulin, diabetics can expect to live a full life that is only ten years shorter than a non-diabetic’s life, on average. Clowes realized that Eli Lilly had just acquired a true blockbuster. It was the dream scenario for any pharma company: there were more than ten thousand diabetics in the USA—and new ones every year, since type 1 diabetes strikes one in four thousand children—and they would each need to take the drug over and over again for their entire lives. All Lilly needed to do was manufacture insulin on a large scale. But how do you ramp up production when the only known way to manufacture a drug is by growing it inside a living pancreas?
Clowes estimated that it would take at least a year to fully develop a commercial insulin process. Lilly budgeted $200,000 to cover the development costs (about $2.5 million today). Collip and Best immediately departed for Indianapolis, where they explained to the Lilly chemists everything they knew about purifying insulin. Within weeks, the Lilly chemists had replicated their small-scale method. The first industrial-scale run was completed just two weeks after that, producing one hundred times more insulin than the Toronto team’s method. Soon, the Lilly insulin plant was running three shifts around the clock, involving over more than hundred scientists. Within two months, the insulin yield increased dramatically … but its potency declined. Each forward step seemed to be accompanied by a backward step. It took almost two years, but in late 1922, Lilly finally established a reliable process that produced potent insulin on an industrial scale.
In 1923, insulin was offered for sale to diabetic patients throughout North America for the first time. Though the Canadian drug company Connaught owned the rights to sell insulin in Canada, Lilly was granted exclusive rights in the United States. It was not only a pharmaceutical revolution but a revolution in medical practice—a revolution of the syringe. Even though the hypodermic needle had been invented in 1853, it had always been the exclusive
domain of trained physicians. But now, insulin treatment required that patients inject themselves, since type 1 diabetics typically require three or four injections per day, too many for a visit to the doctor. Ordinary kids—and ordinary parents of kids—were taught how to administer the protein drug on their own.
Though Eli Lilly’s drug worked, the insulin produced by cows and pigs is not identical to human insulin. As a result, bovine and porcine insulin can sometimes trigger allergic reactions in patients. Some individuals develop a rash, though the most common response to animal insulin was lipoatrophy, a loss of subcutaneous fat. The solution, of course, would be to use authentic human insulin. But how do you get it? The only known way to get insulin was to take a pancreas and grind it up—and there were not too many human volunteers willing to offer up their organs. For more than five decades after insulin went on sale, diabetic patients were stuck using animal insulin and frequently having uncomfortable allergic reactions.
But in the 1970s—a half-century after Banting extracted insulin from a dog pancreas—a new opportunity emerged. In 1972, Paul Berg, a Stanford University professor who studied viruses, performed one of the most important experiments of the twentieth century. He removed a piece of DNA from a cell of bacteria and inserted it into the DNA of a monkey cell. He accomplished this by attaching the bacteria DNA to a harmless virus that Berg used as a kind of Trojan Horse to penetrate the monkey cell’s defenses and deliver the bacteria’s genes directly into the monkey’s genome. This process is known as “recombinant DNA” since it combines the DNA of two different organisms—the bacteria and the virus.
The Drug Hunters Page 13