FOURTEEN

The University of Toronto, Summer 1921

ON SATURDAY, MAY 14, 1921, BANTING LOCKED THE HOUSE IN LONDON, Ontario, and left for Toronto. He had made plans to stay with his cousin Fred Hipwell and his wife, Lillian, until he found a place of his own.

Macleod asked two student research assistants, Charles Best and Clark Noble, to come to his office. He explained to them the opportunity to assist a surgeon in a research project for part of the summer. Both young men were biochemistry majors and so, he reasoned, some exposure to surgery would be good experience. Further, if they decided to pursue a career in medical research, they would almost certainly find themselves working in an animal lab; it would be good for them to know whether this environment appealed to them. Macleod suggested that they each take a turn under Banting and that they work out the details about how to do it between them. Noble and Best decided to split the summer into two four-week periods so that each would have part of the summer to spend with family and friends. They flipped a coin to see who would go first.

Shortly after his arrival in Toronto, Banting met Macleod in his office, and was introduced to a handsome, blond, twenty-two-year-old student named Charley Best. Macleod ushered them to the second floor of the Physiology building to the animal laboratory where Banting could pursue his idea over the summer months. It was hardly the gleaming vision that Banting had imagined. In fact, it looked more like the laboratory in Mary Shelley’s Frankenstein. The counters, racks, and apparatus were shrouded with veils of dust and cobwebs. But the equipment looked new. A dedicated animal operating room was an idea ahead of its time; the scientific researchers on campus had not quite caught on to availing themselves of the facility. The three men stood in the doorway, speechless. Macleod broke the silence.

“I guess you’ll want to begin with a thorough cleaning. I’ll see to it that the janitor sends over some supplies,” Macleod chirped, dropping two keys into Banting’s hand.

“Here’s a key for each of you. Any questions?”

Banting ventured into the center of the room, swiping his hand over the slate bench, furry with dust, then turned back to face Macleod. He opened his mouth to speak but didn’t.

“Very well, then. I’ll let you two get to it.”

And then he was gone down the hallway. Banting turned to Best.

“Well, Charley. This is what you get for winning the coin toss with Noble.”

“What makes you think I won?”

There was a long tense moment, after which Best broke into a broad grin. Banting laughed loud and long.

Just then they heard the janitor turn the corner of the corridor, bringing cleaning equipment.

“This looks more like archeology than physiology,” Banting said. “Somewhere underneath all this I’m told there’s an operating table. Shall we attempt to find it?”

“Now?”

Neither man was dressed for manual labor. Banting had observed Charley’s pale soft hands, small and clean; they looked like they’d never held anything more demanding than a croquet mallet. Charley had grown up in West Pembroke, Maine, where his father was a respected doctor. He enjoyed a youth of culture and privilege, varsity sports, a sterling academic record, and a paid assistantship to the head of the physiology department. By contrast, Banting’s mother had been the first white child born in a newly settled area of Ontario. Most of the boys in Alliston grew up in bare feet and overalls and left school before completing the eighth grade, just before they would have to take the entrance examinations for high school. All three of Fred’s brothers pursued the farming life, but Fred remained in school, sometimes riding to high school on their horse, Old Betsy. Tramps and hobos wandered the countryside, sometimes stopping by the house to beg a meal or permission to spend the night in the barn. Arrowheads and spearheads frequently turned up in the field of the farm to the north of the Banting property, where there was a spring. Banting thought he would find out what his young assistant was made of. Banting threaded his arms through his suspenders and let them hang, then he unbuttoned his shirt and hung it on the doorknob.

“There’s no time like the present,” Banting said.

Somewhat reluctantly, Best did the same. And so one of the greatest advances in medical science began with bleach, a bucket, sponges, and mops.

As they scrubbed, Banting learned that Best was engaged to be married to a beautiful young woman, Margaret Mahon. Their courtship sounded like an endless string of parties and dances. Banting could not help but think of his tortured experience with Edith. Their courtship had taken place largely through the mail and in church, listening to Edith’s father preach. But all that was behind him now: Edith, his practice, his friend Bill, and the big white brick house. Before him were eight weeks, ten dogs, and an idea.

Banting learned that Best’s favorite aunt had died of diabetes. Banting’s good friend Joe Gilchrist, a fellow member of the University of Toronto’s class of 1917, had diabetes. For most CAMC veterans the war was over, but having fought for his country poor Joe now had to fight for his life.

In a few hours the animal operating theater was ready to receive its first patient and Banting and Best looked like coal miners. Macleod had estimated that over the course of the summer, Banting might use ten to twelve dogs. Each experiment would require two dogs—a donor dog and a recipient dog. The donor dog would be ligated and sacrificed to supply the pancreatic extract for the second, depancreatized dog.

Although Banting had never operated on a dog, it had not occurred to him that this might prove an obstacle to his success. It had, however, occurred to Macleod. On May 17 Macleod performed the first pancre- atectomy with Banting and Best observing. Macleod demonstrated the correct procedure for depancreatizing and thus preparing the recipient dog for experimental treatment. In the Hedon procedure, which was the accepted practice of the time, the pancreas was removed in two phases. First, after cutting into the abdomen, Macleod cut away most of the pancreas, but left a small piece intact. He pulled this piece up and sewed it into place just under the skin. Then he closed the abdominal wound layer by layer with catgut. The small functioning piece of the pancreas would prevent the dog from becoming diabetic while it recovered from the surgery. Several days after the surgery, this piece would be snipped away and the process of depancreatization would be complete. The dog would become diabetic and die in about a week unless it could be kept alive by the administration of the pancreatic extract. Banting was surprised at the delicacy of the procedure, at how small and close the cavity was compared with a human being’s.

Still, he reasoned, there was no way to learn but to do. Banting had performed his first operation in 1916, during his final year in school while working at the soldiers’ convalescent hospital. A soldier with a large abscess on his throat needed it opened and drained so he could go overseas with his battalion. Seeing no other medical personnel, the orderly officer asked Banting to do it, assuming he was experienced. Banting thought he was as qualified as anyone, and so he did not object. The operation was a success and the soldier rejoined his battalion within forty-eight hours.

Banting and Best began with a literature review. They discussed Moses Barron’s article of course, as well as work by Murlin, Kleiner, Hedon, Opie, Knowlton and Starling, and Mering and Minkowski. They read Macleod and Pearce’s textbook, Physiology and Biochemistry in Modern Medicine. One of the most useful books they read was Dr. Frederick M. Allen’s Glycosuria and Diabetes. (This was the book for which Allen had borrowed five thousand dollars from his father.) Best said he and Banting used it almost as a bible in the development of the work on insulin.

When Charley wasn’t in the lab, he was often playing tennis or golf or enjoying the company of his perfect mate, Margaret. Banting’s extracurricular activity ranged from the grim to the glum and often involved extended analyses of what went wrong with him and Edith. Occasionally, Charley encouraged Fred to go out with him and Margaret, and sometimes Fred would, gamely escorting one of the secretaries from the medical building, but the experience rarely rated higher than “pleasant, if awkward” for all involved.

At last Banting and Best began the work in earnest. Best would perform all the blood and urine testing and Banting would perform the surgeries. The first dog was accidentally killed by too much anesthesia. The second died from loss of blood. The third died from infection. By the time Macleod left for Scotland on June 14, 1921, Banting and Best had lost three dogs to surgical problems and ligated six dogs successfully, or so they thought. From Macleod’s perspective, this was a bit of a bumpy start, but duct ligation was a difficult procedure, and the losses were not wholly surprising. If the ducts were tied too tight there could be infection, if they were tied too loose the acinar tissue would not atrophy. The experiment could also fail if the ducts were tied incompletely or incorrectly. Each dog’s anatomy was different; what worked on one dog might not work on the next, and it was easy to overlook a duct altogether.

The conditions in which they worked were not optimal. The floor of the operating room could not be properly scrubbed because the wash water would seep down through the floor to the ceiling below. The operating table was wood and so could not be effectively sterilized, and the operating linen was stained and tattered. And then there was the heat—1921 was one of the hottest summers on record. The heat and the stench in the laboratory and the kennels were nearly intolerable.

Roaming the sweltering, abandoned campus fueled Banting’s misery. He was practically penniless. Having already borrowed money from his parents to buy the house in London, he could not ask them to borrow more. In May and June he had made a little money performing tonsil- lectomies, and he had sold some surgical instruments for twenty-five dollars. At night, he often cooked his modest meals on a Bunsen burner at the lab, and he sometimes fished for an invitation to join the Hip- wells. On Sundays, he frequented the free suppers at the Philathea Bible Class of St. James Square Presbyterian Church, which he had attended as a student.

In mid-June, Best left for ten days of militia training in Niagara. This left Banting alone in the lab to feed the dogs and clean their cages. He was living in a boardinghouse on Grenville Street, the same one he had lived in as a student, paying two dollars a week for a seven-by-nine-foot room. He blamed Macleod for this sad state of affairs and could not help but resent his comment that even negative results would be useful.

When Best returned in late June, he went to visit Margaret first, reuniting with her and reporting his experience with the militia. Later he decided to swing by the lab for a quick look around. He arrived about 11:00 p.m. and much to his surprise found Banting there. More to his surprise Banting was boiling with rage. He launched into a tirade about the state of the lab, furiously pointing out example after example of smeared glassware, detritus encrusted on metal instruments, and dubious stains on countertops. Charley was astonished. As the assistant, he had only been following Banting’s lead, allowing his superior to set the standard. Until this moment, he had thought Banting was pleased. If there had been disappointments, they had been surgical. Banting went on and on about the potential importance of this work, about what he had sacrificed, and about his soldierly expectations of loyalty, dedication, and honest effort. When Banting was finished, Best was shaking. For an instant Best looked like he might throw a punch, and Banting prepared for a fight. After a long hot moment, Best turned and in stony silence began to scour the lab. Banting left without a word. Best worked well into the early morning hours, cleaning every square inch of equipment. When Banting arrived the next morning, the lab was spotless. Not a word was said then or later about the night before. From that day on, Banting and Best were a team.

When the time came for Clark Noble to take over for Charley Best, everyone agreed that it was best for Charley to remain now that he and Banting had worked out the kinks in their relationship. The effort continued. Banting and Best depancreatized two recipient dogs in preparation for the harvesting of the atrophied tissue from the previously ligated donor dogs. On July 5, Banting opened up one of the donor dogs. He was shocked to find that the pancreas, which should have degenerated, was normal. The duct ligation had failed utterly. Now Banting opened all of the donor dogs, one after another. The mercury rose to 97 degrees Fahrenheit. Banting cut the sleeves off of his lab coat and tied a towel to his head. During the operation Best wiped runnels of perspiration from Banting’s face and arms but still, sweat dripped into the open cavities. Banting discovered that in five of the seven dogs the duct ligation had failed. It was a crushing blow, but he swallowed hard and set himself to the task of re-ligating the five dogs. This time he used silk ligatures. Two of the dogs died within a day of the surgery. Then the two depan- creatized recipient dogs died for lack of extract.

They were now seven weeks into their research and had nothing to show for it but carcasses.

After Banting and Best ran through the original allotment of dogs, they found their own supply on the streets of Toronto, either paying between one and three dollars each for them, no questions asked, or resorting to prowling around and capturing stray dogs themselves. Banting was quite fond of dogs and handled them as gently as possible, but the truth was that it was not always possible. He would later say that it was as if the dogs knew of the importance of the work and willingly participated. He said that one dog in particular got used to the routine of having its blood drawn and jumped onto the table when it was time.

On July 11 Banting and Best depancreatized Dog 410, a white terrier. They took the rest of the week off while they waited for it to heal. Charley told Margaret that he was tired of the work and the miserable conditions. On July 18, they removed the pedicle, or pancreatic remnant, from Dog 410. The dog became only moderately diabetic. Banting speculated that part of the pancreatic tissue remained in the dog or possibly the diabetic condition was slow to develop in it. They determined to wait and watch. In the meantime, they depancreatized Dog 406, a collie. Around this time they abandoned the two-step Hedon procedure, and began removing the pancreas all at once so that the dogs became diabetic immediately.

On Saturday, July 30 they chloroformed donor Dog 391 and removed its pancreas. The tissues had degenerated as expected. Adhering to Macleod’s instructions for preparing the extract, Best sliced up the pancreas and put the pieces in a chilled mortar with Ringer’s solution. The mortar was partially submerged in freezing brine until the pancreatic mixture partially froze. Then he macerated the contents with a chilled pestle and strained the mixture. The result was a pinkish-brown liquid, which was warmed to body temperature just prior to injection.

At 10:15 in the morning they injected four cubic centimeters (4cc) of the extract into recipient Dog 410. A normal dog’s blood sugar should meaiure between .08 and .13. Before the injection Dog 410’s blood sugar measured .20. One hour after the injection Dog 410’s blood sugar had fallen to .12—a forty percent decrease. An hour later they administered a second injection and the blood sugar fell again, but just slightly, to .11. They were encouraged. At 2:15 Dog 410’s blood sugar had risen to .14, despite another injection. That afternoon they tried feeding sugar water to the dog, in the hopes of testing whether the extract would allow the dog to metabolize it. They accidentally inserted the feeding tube into a lung and the dog nearly drowned. After fifteen minutes it seemed recovered and they tried again. This time they succeeded, but Dog 410’s blood sugar began to rise into the .18 to .21 range, despite hourly injections of the extract.

After so many weeks they were finally in a position to record results in a viable patient. Despite this they left the lab at 6:15 p.m. and did not return until the following morning. When they arrived they found Dog 410 in a coma. They were able to take one blood sugar reading before it died. It measured .15. Inexplicably, they did not perform an autopsy. In a paper published in the Journal of Laboratory and Clinical Medicine in February 1922, they speculated that Dog 410 was likely dying from infection at the time they ran the final blood test.

On Monday, August 1, the collie, Dog 406, lay unconscious and close to death, either from infection or from diabetes. Banting and Best injected 8 cc of extract into a vein. The collie’s blood sugar started to fall. At once the dog awoke, rose to its feet, and walked around the lab. Banting and Best cheered. Then, just as suddenly, the collie lapsed into a coma and died, despite repeated injections.

On Wednesday, August 3, they began an experiment on Dog 408, another collie. Injections of pancreatic extract on Dog 408 were definitively positive. They injected extracts of the liver and the spleen and showed that these injections did not produce the same effect. They tried boiling the pancreatic extract and injecting that and showed that that didn’t work either. Over the next four days they injected the dog with the extract and each time the extract reduced the dog’s blood sugar. On the fourth day, they conducted an all-night experiment, after which the dog died. An autopsy indicated infection. At last they had results good enough to report to Macleod. For the first time, Banting and Best gave their extract a name: isletin.

On August 9, Banting wrote to Macleod, “I have so much to tell you that I scarcely know where to begin.” In addition to reporting the experimental results to Macleod, Banting also made five requests: (1) he asked to stay on and continue the work, (2) he asked for a salary, (3) he wanted a better room to work in, (4) he asked for a boy to take care of the dogs and clean the operating room, and (5) he asked that the floor of the operating room be repaired. On the issue of employing a boy to feed the dogs and clean their cages Banting was particularly insistent.

In the same letter, Banting listed sixteen questions related to their central question of whether they could cause a reduction in blood sugar by introduction of a pancreatic extract. These were questions concerning the chemical composition of the extract, the method of preparing the most potent form of it, the method of delivery, whether trypsin really did destroy the active principle of the pancreatic extract, and, of course, the clinical application. He wrote, “I am very anxious that I be allowed to [continue to] work in your laboratory.”

Banting and Best realized that it would likely take three weeks to receive Macleod’s reply, and he was due back in four weeks, so rather than wait for Macleod’s return post, Banting and Best decided to assume that his answer to the first request would be yes and they would negotiate the other points once Macleod returned to Toronto. Ideally, this would provide them with more persuasive results to report to Macleod on his arrival.

Next they depancreatized two dogs, number 92 and number 409. Their plan was to give isletin to Dog 92. Dog 409 would serve as a control, meaning that they would allow it to recover from the surgery but not provide any isletin. As they worked, sweat dripped onto the operating table, the clamps and scalpels, and the linens that they used to wipe them. That infection continued to be a problem was hardly a surprise.

The results of the comparative experiment with Dog 92 and Dog 409 were unmistakable. On August 13, Dog 409 was barely able to walk while Dog 92, a yellow collie, was prancing around the lab, following Banting like a house pet. On August 14, they gave Dog 92 an overdose of extract to see if it would reduce its blood sugar to below normal. It did. They continued to experiment with different concentrations of the extract as Dog 409’s condition worsened. On August 15, Dog 409 died. The extract seemed to be keeping Dog 92 in perfect health. She was an especially cooperative patient and Banting grew very fond of her.

On August 17 Banting and Best made extract using a dog’s fresh whole pancreas and injected this into Dog 92 to see if the preparation would have the same sugar-lowering effect on the blood as degenerated pancreas. It did. In fact, using the fresh whole gland seemed to be even more effective than using the ligated gland. Yet they did not recognize this very important finding. Best continued to believe that it was necessary to eliminate the acinar secretion prior to preparing isletin. Their beloved Dog 92 began to weaken. There were no duct-tied donor dogs on hand to supply the wondrous extract.

On August 19, desperate to keep his favorite patient alive, Banting conceived of a way to procure the internal secretion. It was well known that the hormone secretin, which was produced by the duodenum, stimulated the pancreas to produce the digestive enzyme trypsin. Banting’s idea was to open up a dog and use secretin to milk all of the digestive secretion from the acinar tissue. Then he could chloroform the dog and remove the pancreas, which would contain only isletin. From this, Best could prepare the extract. Time was running out for Dog 92; she could no longer rise to her feet. They hurriedly prepared for this procedure. The surgery was extremely complicated, requiring a resection of the bowel to procure the secretin. It took nearly four hours for the pancreas to be exhausted of trypsin.

On the evening of August 20, Dog 92 received the extract that was procured in this way. She responded marvelously. By the following morning their yellow collie was wagging her tail and following Banting around the lab again, resting her head in his lap when he sat down to make notes. That very afternoon he recorded that Dog 92 jumped down from her cage to the lab floor, a distance of some two and a half feet, and landed without falling. Banting would later describe the event as one of the greatest experiences of his life. But despite his elation, Banting realized that this could be only a temporary reprieve. Dog 92 would soon need more isletin to stay alive.

Over the next few days, Banting and Best carried out several experiments, mixing sugar and extract in a test tube, and injecting Dog 92 with a mixture of extract and trypsin to see if it would lower the blood sugar. It didn’t. By August 22 they were again out of extract. They decided to use the opportunity to answer the question of whether the extract would work across species. After all, clinical application and not medical research had always been his goal. That day they repeated the procedure of stimulating the pancreas with secretin, operating on a cat this time. The cat died on the table but they decided to remove the pancreas and prepare the extract anyway. They injected the extract into Dog 92. She lapsed into shock. Dog 92 then began a long slow decline, her blood sugar gradually rising. For nine days she hung on, while becoming increasingly listless and weak. On August 31, the collie died. She had lived for a remarkable twenty days without a pancreas. Banting turned his face away from Best and wept. “I shall never forget that dog as long as I shall live,” Banting wrote in 1940. “I have seen patients die and I have never shed a tear. But when that dog died I wanted to be alone for the tears would fall despite anything I could do.”

Banting complained long and loud to anyone who would listen about the deplorable state of the lab and continued to blame Macleod for their difficulties and lack of progress. One of the people he persuaded to help him was Dr. C. L. Starr, who was making arrangements for Banting and Best to use the surgical research operating room from then on. Another sympathetic ear was Professor Velyien Henderson of Pharmacology, whose mannerisms had earned him the nickname of Vermin Henderson among the students of the class of 1917. Banting didn’t think too much of him when he was a student, but he enjoyed getting to know him as an equal in the summer of 1921. Henderson agreed to let Banting know if a job became available in the pharmacology department. A salary would be a nice change; he was running out of things to sell. Henderson advised Banting to start thinking about writing a paper, so Banting and Best decided to make an effort to start taking better notes. As far as aca- demia was concerned, making the discovery wasn’t as important as publishing the discovery. Publication was a way to claim credit for the idea. And he wasn’t about to let some beady-eyed Scot like Macleod keep him from it.

In late August Macleod said goodbye to his sisters and visited the graves of his brothers. He was now the only surviving son. His brother’s children were fatherless. He and his wife were childless. Futility and grief weighed heavily on him. A recent letter from Banting, full of grandiose claims and indignant demands, had put him in a foul mood. Where was the sense in the world when a boor like Banting could make demands and a good, brave, talented doctor like Clement had been reduced to dry bones beneath the moss?

He and Mary steeled themselves for the two-week ocean journey, leaving their beloved Scotland behind, for how long they did not know. It was now apparent that it would be only a matter of time before violence once again shattered the hard-won peace in Europe.

According to the armistice that Woodrow Wilson negotiated in 1918, Allied hostilities would resume within forty-eight hours if the Germans deviated from the terms agreed upon. An Allied Reparations Commission toured Belgium, France, and parts of England to assess the damage. In April 1921 the amount was announced: 132 billion gold German marks (Reichsmarks), or £4,990,000,000, to be paid at the rate of 2.5 billion marks per year until 1961. France viewed the terms as too lenient. Germany viewed them as too punitive. Germany made its first payment in 1921, but as the year drew to a close the German economy was near collapse and would not be able to manage the 1922 payment. Britain agreed to a three-year hiatus, but Belgium and France began seizing German factories, commodities, and intellectual property, including the patent for aspirin—ironically, an anti-inflammatory compound.

Over the next four years one man would rise above all others as a dominant figure in world diplomacy, doing more to negotiate the seemingly intractable international relationships than anyone. This man was Charles Evans Hughes.