TWENTY-ONE

Success and Failure, The University of Toronto, January 1922

AFTER BANTING AND BEST RETURNED FROM THE AMERICAN PHYSIOLOGICAL Society meeting, their race with Collip intensified. As the reality of a human trial became more plausible, Duncan Graham discussed the practicalities with Macleod. Graham was the recently appointed Eaton Professor of Medicine at the University of Toronto with jurisdiction over the teaching wards of Toronto General Hospital. It was decided that Collip, as the best biochemist, would supply the purified extract. Since neither Macleod nor Collip was a practicing clinician, Dr. Walter Campbell was chosen to oversee the clinical administration of the trial, under the direction of Graham. The test would take place in Ward H, the diabetic clinic of Toronto General Hospital. Graham occasionally dropped by Collip’s lab on the top floor of the pathology building to check on his progress and then joined Macleod and Collip for lunch.

When Banting caught wind of this plan he was predictably furious. He had assumed he would be the one to administer the first clinical test. After all, it was his idea, and the clinical application had been his focus from the start. But Duncan Graham would not allow it. Banting had never treated a human diabetic. Further, he had no affiliation with Toronto General Hospital and only a temporary affiliation with the university.

Banting stormed into Macleod’s office and demanded that Graham use his and Best’s extract rather than Collip’s for the first human trial and that Banting himself administer it. Macleod argued that where human life was at stake, precedence was irrelevant. He tried to persuade Banting that everyone on the team would benefit from a successful trial. But Banting bellowed that for these very reasons his extract should be used—the extract that had kept the dog Marjorie alive for two months, the only extract that had been proven safe and effective over time. Macleod was grateful for the enormous desk between him and Banting. He wondered what his secretary, sitting just outside the door, must be thinking. He told Banting he would consider it.

Although it galled him to do so, Macleod tried to persuade his good friend Duncan Graham to acquiesce to Banting’s wishes, just to keep the peace. Graham insisted that Dr. Campbell administer the human trial. Furthermore, neither Banting nor Best would be granted hospital privileges as long as he was in charge. However, as a personal favor to Macleod, Graham reluctantly agreed to use Banting and Best’s extract, despite its being less pure than what Collip could prepare. Macleod was so mortified by this turn of events and his role in them that he couldn’t bring himself to talk to Collip before the trial began.

Amid this high drama and posturing, a listless, slack-jawed fourteen- year- old, sixty- five-pound diabetic boy was admitted as a charity case to Toronto General Hospital on December 2, 1921. Leonard Thompson had been the patient of Dr. Campbell, who, recognizing that the boy was now entering the final, fatal stage of juvenile diabetes, asked Graham for help. Leonard was so weak and wasted that his father carried him into Graham’s office. He had lost most of his hair, and his stomach was grotesquely distended. His breath smelled of acetone. His blood sugar ranged from 3.5 to 5.6 milligrams per cubic centimeter versus the normal range of 1 mg per cc. He was immediately placed on a severely restricted diet of 450 calories, but he continued to fail, spiral- ing into the pitiless and irrevocable pattern that Dr. Campbell had witnessed many times before. Dr. Campbell was compelled to tell Mr. Thompson that, barring a miracle, there was no hope.

On January 11, Dr. Ed Jeffrey, an intern under Dr. Campbell’s supervision carefully sharpened a 26-gauge steel needle on a whetstone. Then he assembled the syringe by screwing the needle into the glass barrel. Finally, he drew the opaque, brown extract into the barrel and entered the room where Leonard Thompson lay. Dr. Jeffrey injected the boy with 15 cc of extract—7.5 cc into each buttock. This was roughly half the dose that a dog of equal weight would get. On Thompson’s hospital chart, the medication administered was recorded as “Macleod’s serum.” The result was inconclusive: There was a modest lowering of blood sugar and the formation of large abscesses at the injection sites.

When Collip learned of the reversal of the established plan, he considered it a personal betrayal by Macleod. Meanwhile, Banting told everyone that the trial had failed because the quantity was insufficient. Banting voiced his tale of injustice and tribulation loudly and without discrimination to whomever he could trap long enough to listen. With each telling he became more convinced of his own maltreatment at the hands of Macleod. Unwisely, he confided his views to Duncan Graham, who was alarmed to discover just how unhinged Banting really was. He immediately reported the conversation to Macleod, encouraging him to terminate Banting’s appointment right away and put as much distance as possible between Banting and the university. But how?

Unfortunately for Macleod, it was impossible to dismiss Banting. His constant caterwauling about his relegation to the status of a bystander had begun to win some sympathizers. Velyien Henderson was Banting’s primary confidant, and Henderson’s own personal dislike of Macleod influenced his perspective on Banting’s situation. There was Banting’s cousin Fred Hipwell who was predisposed to favor Banting’s point of view. There was his old University of Toronto classmate Joe Gilchrist and his former instructor Dr. George W. Ross, better known as Billy Ross.

Dr. Billy Ross was the son of the Honorable Sir George William Ross, who had been until recently the Liberal premier of Ontario. As such, Dr. Ross was extremely well connected and not in the least bit shy about plying that influence to achieve a personal or political agenda. He was also a passionate nationalist. Ever since the decisive battle at Vimy Ridge, in 1917, which the Canadians had won for the Allied forces, there had been a renewed push for a unified and independent Canadian identity, separate and distinct from the British Crown. Vimy intensified the Canadian desire for pol itical self-government that began with the Constitution Act in 1867 and culminated first in the Statute of Westminster in 1931, which granted Canada (and other commonwealth realms) legislative autonomy, and later affirmed in the Canada Act of 1982 which definitively dissolved legislative dependence on the United Kingdom. In Frederick Banting, Billy Ross saw an opportunity for Canadian glory and distinction. To Ross’s mind, Banting’s subjection at the hands of Macleod was emblematic of Canada’s subjection to the British Crown, and he was eager to take up the cause of his defense.

One of Ross’s patients was a young reporter for the Toronto Daily Star named Roy Greenaway. Seeing an opportunity, Ross mentioned to Greenaway Banting’s tale of woe and its latest manifestation of the disappointing clinical trial, making sure to emphasize Banting’s perspective. Now Greenaway had a scoop and an underdog hero.

In short order Greenaway made his way to the Physiology Building where he found Charley Best working alone. Best was amused to see Greenaway recoil at the odor of decaying offal and dog feces that permeated the laboratory.

“Not your brand of cologne?” he joked.

Charley, ever politically cautious, walked Greenaway over to Macleod’s office. Greenaway, seeing the story as his big break, was eager to talk with anyone and everyone connected with the story. Macleod was appalled at the idea of the popular press prematurely releasing information about their experiments. As if his professional life wasn’t complicated enough, he could hardly imagine the deluge of trouble that such a news release might bring down upon the university. He warned Greenaway that the only successful experiments had been performed on animals and that it would be irresponsible, even unconscionable, for Greenaway to suggest otherwise. He was reluctant even to say this much for fear of bringing a picket of antivivisectionists to the campus.

“Medical progress is a slow process,” he advised sternly. “All I can say is that since the summer we have been working with a pancreatic extract that appears to show some promise in alleviating the symptoms of diabetes in animals. To raise people’s hopes that a cure is at hand would be a cruel and self-serving exercise.”

The article appeared in the Toronto Daily Star on January 14 under the headline:

WORK ON DIABETES SHOWS PROGRESS

AGAINST DISEASE

Toronto Medical Men Hoping That

Cure Is Close at Hand

A Boy Is Treated

Effect of First Treatment Is So Good That

Injections Are Continued

For the most part Greenaway had honored Macleod’s advice, and the language was considerably more subdued than what he had originally planned. Macleod and Banting were the only two directly quoted.

Banting read the article and focused on just two words—”we” and “our”—both of which were used by Macleod to describe the eight months of experiments. Banting’s ire rose as he remembered the summer months when Macleod was vacationing in Scotland. It did not occur to him that Macleod might be protecting him, protecting the interests of the university, and even protecting the work itself.

In Indianapolis, Eli Lilly and Alec Clowes read the article and together marched into J.K. Sr.’s office to read it to him. J.K. instructed Clowes to do whatever he had to do to secure a role for the company in the development of insulin.

Between January and April Clowes made four trips to Toronto. He usually met with Macleod and rarely spoke with Banting. President Falconer urged Macleod to “keep it Canadian” and so Macleod painted a bright picture of the team and the process for Clowes, constantly reassuring him that they were getting along just fine without help from Indianapolis.

The reality was quite different. It was increasingly difficult for Macleod to take himself to the office in the morning. Mary watched helplessly as her husband became brittle and withdrawn, and the dark days in Cleveland seemed to be beginning all over again in Toronto. His health began to deteriorate. His joints were stiffening with arthritic pain, and he rarely felt well enough to golf. One morning as Macleod lingered at the breakfast table with Mary for an especially long time, he muttered that he felt he should take a chair and a whip to work like a lion tamer. That morning he and Mary quietly decided to look toward moving back to their beloved Scotland.

On the night ofJanuary 16 Collip was working in his lonely aerie, conjuring batch after batch of extract at a pulse-accelerating pace. He no longer paused to make notes about his process. It was as if he had entered into the process, become a part of it. His mind and body were directed by an unseen force, perhaps the will of the extract itself to be discovered.

He was performing a series of methodical tasks called fractionation. He mixed whole, macerated pancreas with increasing amounts of alcohol and centrifuged each incrementally concentrated mixture to precipitate out all the impurities that were not soluble in that percentage of alcohol. For example, Collip would mix pancreas with alcohol to a 30 percent concentration, place it in a test tube and spin the tube in a centrifuge. Thirty or so minutes later, the centrifuge would stop spinning. Inside the tube he would find a pellet of insoluble proteins or impurities and the supernatant liquid. He would discard the pellet and dilute the liquid with alcohol until it reached a 40 percent concentration. Then he would place a test tube containing this mixture into the centrifuge and repeat the process. When the spinning stopped he would have a pellet of proteins insoluble in alcohol of 40 percent concentration. Again he would dilute the supernatant liquid with alcohol incrementally increasing the concentration to 50, 60, 70, and 80 percent.

When he reached 90 percent, Collip discovered that the active principle of the extract was insoluble in a 90 percent alcohol solution. In other words, when the centrifuge stopped spinning on the test tube of 90 percent alcohol solution, Collip had trapped the active principle—the insulin—in the pellet. Moreover, the insulin was in a relatively pure state, as most of the impurities had been precipitated out through the frac- tionation process. This he would later confirm through rabbit assay tests. Years later Collip would say, “I experienced then and there all alone on the top floor of the old pathology building perhaps the greatest thrill it has ever been given me to realize.”

Sometime within the following days, Collip went to the second floor of the Physiology Building to tell Charley Best the news. There he found both Banting and Best in the lab. He told them that he had purified the extract but wouldn’t tell them how he’d done it. His refusal to reveal his secret—whatever his reasons—s ent Banting into a rage. According to Time magazine in 1941, “Banting leaped on Collip in the university halls, threw him down, banged his head on the floor and bellowed: So, you will call this Collip’s serum will you?” Charley grabbed Fred by the neck and struggled to pull him off. As soon as Collip could scramble free of Banting’s grip, he stood up and stormed out of the building without a word.

The next day Collip went directly to Macleod to report the incident. Macleod went to speak to Falconer, for now he would certainly have Falconer’s support for ejecting Banting. But instead of finding an ally, he ran headlong into a barrage of blame. Falconer held Macleod responsible for the dysfunction of the department and the disgrace to the university.

“Collip will return to Alberta in a few months,” he said. “What do you think he will say of his time here?”

Macleod was too stunned to respond.

Falconer suggested that Macleod call a meeting and try to work things out, and he recommended that Macleod ask someone else to run the meeting, someone who had the authority to control the situation. Falconer proposed Dr. FitzGerald of the Connaught Antitoxin Laboratories. Macleod swallowed his pride and asked FitzGerald to help mediate the personal tensions that had arisen among the discovery team. FitzGerald agreed and also offered to help with the larger-scale production methods and costs of preparing the new extract for clinical trial. The meeting was set for January 25, a Wednesday.

During all this tumult, the science somehow managed to continue, on two tracks—research and clinical. On January 21, Banting and Best discontinued the dog Marjorie’s injections in order to reserve their extract for another chance at a human trial. Predictably, their affectionate laboratory mascot began to weaken and fail.

On Monday, January 23, at eleven o’clock in the morning, Dr. Walter Campbell gave Leonard Thompson his second insulin injection—5 cc of Collip’s extract. Six hours later, the boy received another injection of 20 cc of Collip’s extract. The following day there were two injections of 10 cc each. Thompson’s glycosuria nearly disappeared. His blood sugar plummeted from 5.2 milligrams to 1.2 milligrams per cc. It was nothing short of miraculous.

By this time, Marjorie could hardly stand. Unable to watch her deteriorate further, Banting injected Marjorie with some of the precious remaining extract. She immediately rebounded and was her old affectionate self again, following him around the lab and willingly subjecting herself to blood draws.

On January 25, Banting, Best, Collip, Macleod, FitzGerald, and Falconer assembled for the meeting. Collip’s face bore the plum-colored vestige of a black eye. Banting arrived unshaven and dressed in a crumpled wool jacket, his ungloved hands raw from the cold. His trousers were riddled with burn holes from cigarette ashes. Until this meeting, the true extent of Banting’s mental disintegration had not been apparent to anyone but Charley Best.

Banting accused Macleod of trying to steal credit for his discovery, using the example that the extract was listed on Thompson’s chart, the document of historical record, as “Macleod’s serum.” With a cold, sickening dread, Macleod wondered how Banting could have known that detail except through Graham.

“Perhaps it has nothing to do with credit. Perhaps it has to do with blame,” FitzGerald offered quietly. “If Thompson had died, someone would have to take responsibility; someone with official standing at the University. I doubt Graham would have allowed your name to go on the chart. It’s not that you aren’t deserving; it’s that you can’t answer for the university in case of failure. If anything, Macleod put his name on the record to protect you. Am I right, Professor Macleod?”

Macleod nodded stiffly.

Neither Macleod nor Falconer would say more than a few words during the meeting; Falconer because he wouldn’t, and Macleod because he couldn’t. Anything Macleod might have said would be misconstrued as a slight against the myopic Banting. He had been effectively silenced.

There were several results of the meeting. The most concrete was a document, signed by Banting, Best, Collip, and Macleod. It bore the rather unwieldy title of “Memorandum in Reference to the Co-operation of the Connaught Antitoxin Laboratories in the Researches of Dr. Banting, Mr. Best, and Dr. Collip—Under the General Direction of Professor J. J. R. Macleod to Obtain an Extract of Pancreas Having a Specific Effect on the Blood Sugar Concentration.” There were two key points. The first was that during the period in which the discovery team would be cooperating with Connaught, neither Banting, Best, nor Collip would endeavor to obtain a patent or seek a partnership with a commercial firm to produce or exploit the extract product or the process by which it was made. The second point was that any modification in this policy could not be made without prior consultation among Banting, Best, Collip, Macleod, and FitzGerald. Around this time it was also agreed that going forward, the names on all research papers would appear in alphabetic order: Banting, Best, Collip, Macleod.

While Collip returned to the lab to make more extract on January 25 and 26, Leonard Thompson did not receive any extract, but injections resumed on the 27, as did his steady recovery. He was more alert and animated. His blood sugar continued to show suppressed values. Best of all, as Collip’s batches became more pure and potent, Leonard Thompson’s daily dose was reduced to two injections of 4 cc per day.

All appeared to be back on track with Collip’s serum producing good results at Toronto General Hospital and Best working closely with FitzGerald at Connaught to make the extract in high volume. But Banting continued to feel sidelined. He was more desperate than ever to secure some way to indelibly document his rights and primacy as the idea’s originator.

He came to see Marjorie as his answer. She had survived for seventy days without a pancreas—longer than any living creature. The fact that daily doses of the extract had sustained her was clear evidence that Banting and Best had produced effective, nontoxic pancreatic extract.

On January 27, Banting went to the lab early in the morning, alone. He opened Marjorie’s cage and cut her a slice of the raw pancreas that he had stored on ice. Then he pretended to busy himself in the lab. She stayed close at his heels, nearby but never underfoot. Whenever he glanced down in her direction she wagged her tail. He tried not to let her see the tears in his eyes. He picked her up and placed her gently on the table. He was careful to avoid her abscesses; she never complained. He stroked her speckled fur and she looked back at him with an uncanny understanding of what was about to happen. He wiped his nose on the sleeve of his lab coat.

He asked her to sit and then lie down. She obeyed as she always had, and for the last time. As Banting administered a fatal dose of chloroform he spoke softly to her, thanking her for her loyalty and kindness, her bravery and generosity. He apologized for all the pain that she had endured and for the unhappy fact of her final sacrifice. He promised her that her death would not be in vain, that he would redeem it with the lives of children, and that each child he saved would know her name. When he was sure that she was gone he wrapped her in a blanket and carried her across the campus to Toronto General Hospital. He hugged her body to his chest, even as he felt the warmth leaving her. He bowed his head into her soft fur to blot his tears. It seemed to him that the dogs were the only civilized creatures on the insulin discovery team and the humans treated them more humanely than they treated each other. Now he had killed the best of the best. How much more sacrifice could possibly be required to bring this inkling of an idea into practical use?

He would soon have an answer. Macleod had always questioned whether Marjorie’s pancreas had been completely removed. In order to dispel these doubts Banting had arranged for a disinterested pathologist at Toronto General Hospital to perform an autopsy. Banting delivered Marjorie’s body to Dr. W. L. Robinson.

Later that day Banting was to learn, much to his disbelief and distress, that Robinson had found that Marjorie did indeed still have a small nodule of pancreatic tissue, about three millimeters in diameter, under the lining of her duodenum. Although he found no islet cells in it, the presence of the nodule was enough to cause skepticism about the conclusiveness of Banting and Best’s most successful longevity experiment.

Banting was now utterly crushed.