TWENTY

The American Physiological Society Meeting, New Haven, Connecticut, December 28—30, 1921

THE FRANTIC EFFORT IN TORONTO CONTINUED RIGHT UP TO THE hour of departure for the American Physiological Society meeting. Less than a week before an exhausted Banting boarded the train for New England, Macleod gave in to Banting’s insistent pleas and Collip officially joined the insulin team. Apparently Macleod was finally convinced that Banting and Best’s discovery was worthy of additional resources, because he enlisted not only Collip but also Almon A. Fletcher, John Hepburn, J. K. Latchford, and Clark Noble. They, too, participated in the race to achieve two objectives: first, to produce an extract pure enough for human trial, and second, to develop a procedure that would consistently produce effective extract in large quantities.

Reining in the new team’s exuberance, Macleod attempted to organize the effort. He assigned specific duties to each team member. Clark Noble would focus on the extract’s stability and potency by assisting Collip with assays using rabbits. Collip was to focus on making an extract pure enough for human trial. Dr. John Hepburn, who had initially come to Toronto to study with Macleod under the auspices of the American Physiological Society’s first fellowship, was assigned to work with Charley Best on respiratory quotient tests. (At that time it was thought that you could learn whether carbohydrates were being burned in the body by measuring the ratio of carbon dioxide exhaled to oxygen inhaled.) Last but not least, Banting was charged with performing any surgery that might be required by the group.

Most of the pressure fell directly on the shoulders of Bert Collip. He was a particularly talented and intuitive biochemical savant, well suited to the task. That he happened to be available to join the insulin team was a great stroke of luck. By December 1921 he should have moved on from Toronto to begin the next part of his Rockefeller Traveling Fellowship in London or New York. Instead, he quarantined himself in his lab in the pathology building on the grounds of the Toronto General Hospital and worked around the clock, pushing himself to his limits. Acutely aware of the enormous significance of his assignment, he had decided to forego the rest of the fellowship and remain in Toronto for the duration.

At this time, Collip was working very closely with Macleod, which was another reason for his decision to remain in Toronto. The two professors met for lunch nearly every day. The work made fast and significant progress. A diabetic Airedale injected with Collip’s extract passed sugar-free urine.

Collip used rabbits to assay the potency of the extract. He determined that one unit would be the amount sufficient to send a rabbit into convulsions, hypoglycemic coma, and death. This proved to be an expensive method. With rabbits billed to the Department of Physiology at $1.25 each, Collip was going through rabbits at an alarming rate. It was Macleod, observing Clark Noble drawing blood from the rabbits for blood sugar analysis, who first suggested that they might restore comatose rabbits with glucose, thereby preserving the subject for further testing.

In addition to their officially assigned roles, Banting and Best continued to experiment with whole-pancreas extract and fetal calf pancreas extract as well as various methods of preparation. They adopted methods that Collip had worked out, such as the use of a vacuum still. They tried different ways of administering the extract, including through a stomach tube. They even injected dogs with extracts of liver, spleen, thyroid, and thymus; none but the pancreatic extract lowered blood sugar. For the first time, they began to experiment on normal dogs, perhaps because they were running out of diabetic subjects and time to prepare them. Banting and Best turned what was supposed to be a collaboration into a competition. They were determined to purify the extract before Collip did, which only served to infuriate Collip.

On December 20, 1921, Banting’s old friend and colleague Dr. Joe Gilchrist became the first human diabetic to receive insulin. Banting had hoped that this historic moment would allow him to make a dramatic announcement at the conference, an announcement that he would not tell Macleod about beforehand. Because the extract was not pure enough for injection into a human being, Joe was given an oral dose. There was no benefit.

Now that most of the work was in the hands of the chemists, Banting began to feel tangential and insecure. All around him people were merrily preparing for the holidays with wives and sweethearts. Charley would go home to Maine and Margaret. Collip would celebrate with his wife, Ray, and their young family. Jake and Mary Macleod would celebrate in their cozy, comfortable English country-style home in the Rosedale section of Toronto.

Banting isolated himself in his bivouac in the boardinghouse and glared through the soot streaks on the window at the happy shoppers on the street below. He dreaded returning to his family in Alliston, from whom he felt increasingly estranged. There, he knew, he would face the inevitable questions, questions for which he had no answers. They would be the questions of farmers, steeped in the practicalities of financial and physical survival from harvest to harvest.

Banting’s life made no sense to them. How could it? He was thirty years old, unattached, and only marginally employed. He had given up everything to pursue an idea the merit of which few seemed to recognize— until now. Now that others finally saw the potential, he felt like they were elbowing him out of the way in order to take credit for the idea. He made his apologies to his family and remained in Toronto, ostensibly to prepare for what would be his first public presentation of a scientific paper. In reality, he did little more than take long cold walks on the abandoned campus. In the afternoon he often found himself at the Christie Street Hospital, visiting with the veterans, or at the lab with his devoted companion, Marjorie, who on Christmas Day had lived for thirty-seven days without a pancreas.

Just when he thought his circumstances could not possibly get worse, they did.

* * *

Once he reached New Haven, Banting’s sense of isolation grew more acute. The American Physiological Society in 1921 was an exclusive group of three hundred eminent men, nearly all of whom knew one another. From a distance Banting observed with disgust the groups of distinguished scientific luminaries tripping over themselves to shake Macleod’s hand. A few times he overheard them telling him how much they were looking forward to “his” presentation—and he noted that Macleod did not hasten to correct them. Among those whom Macleod sought out at the conference was Alec Clowes. He was particularly interested in his fellow Briton’s work at the Lilly marine biological laboratory Woods Hole. Banting had yet to recognize a single familiar face among the attendees; Charley was to arrive later, coming directly from Maine.

The conference began on Wednesday, December 28. Banting attended the lectures and presentations, hoping to gain some insights into how to make the best show of his own presentation. He loathed public speaking, and as the dreaded hour drew closer, Banting’s anxiety grew until he began to have second thoughts about the whole idea. He sat in on a talk by N. B. Taylor from Toronto, who had been present at Banting’s talk to the Canadian Journal Club. He also listened to two papers by Ernest L. Scott. Not only had Scott ligated the pancreatic ducts of dogs as part of his master’s degree at Columbia University, he had also used alcohol to extract insulin from the whole pancreas, a procedure that had recently been adopted at the University of Toronto. Although Scott himself believed he had discovered insulin, his results were not easily replicated. His 1912 article described his work in such cautious terms that the significance of his findings was not recognized. Scott ultimately abandoned the work, and his presentation that December addressed an entirely different subject.

What everyone really came to New Haven to hear that December was the paper on pancreatic extract by Jake Macleod and his associates, which the conference planners made sure to schedule for the afternoon of the final day of the conference so that no one would leave early. When the fateful Friday came, the room was packed with a discerning audience of scientific experts, including Frederick Allen, Elliott Joslin, Alec Clowes, Israel Kleiner, Anton Carlson, and Ernest L. Scott. The slightest flaw in the experimental work would be noted by these men.

As neither Banting nor Best was a member of the American Physiological Society, Macleod began by introducing them and describing the work they had done over the summer. Macleod, having observed Banting’s mounting trepidation, provided a rather thorough description of the experiments in case Banting proved unable to do so. Banting noticed that Macleod repeatedly used the word “we” in describing the work. Banting’s neck turned red with rage as he reflected on the long weeks in July and August when he had labored alone, hungry, and desperate, in the stench of the lab. Lost in these bitter ruminations he did not hear Macleod invite him to the podium.

“Dr. Banting?” Macleod repeated his invitation, gestured to the podium and stepped aside.

Banting rose and crossed to where Macleod had stood. As he turned to the distinguished crowd, he gripped the podium with such intensity that his knuckles turned white.

He commenced haltingly, managing to say that on that very day, December 30, 1920, there was a dog in Toronto who had lived without a pancreas for an unprecedented forty-two days by being given daily injections of pancreatic extract. The goal now was to prepare a refined extract suitable for human use. As Banting continued, his face grew redder and his voice grew quieter, until he was muttering. Those in the back of the room could not hear him at all. He concluded by saying that his colleague, Charles Best, had prepared some charts and graphs that illustrated their work. Then he crossed to the empty chair beside Charley and sat down.

It was not clear to the audience whether Banting intended to retrieve the charts and graphs and continue or was finished speaking, so no one clapped. Banting looked at his feet. Charley looked at Macleod. Macleod cleared his throat and went to the podium. The presentation had ended early. There was still quite a bit of time before the next presentation began.

“Thank you, Dr. Banting,” Macleod said authoritatively, rescuing the room from awkward silence. There was brief applause before everyone stood up and moved en masse toward Macleod, some to question his data and others to offer cautious congratulations. Scott was among the first to reach him. He wanted to be sure that Macleod knew he had performed essentially the identical experiment as they had in Toronto with mixed results. Allen, who had come to the meeting in part to recruit contributors to his scientific periodical Journal of Metabolic Research, buttonholed Macleod and invited him to be a contributing editor in the upcoming issue. Each issue compiled the research writing of a large and impressive list of scientific investigators. The names of Banting, Carlson, Clowes, Macleod, Murlin, Paullin, and Woodyatt would appear at various times on the masthead. As he waited for his turn to talk with Macleod, Allen thought of Elizabeth Hughes. How right he was to dissuade Antoinette from sending her to Bermuda. Now, vindicated at last, he could go to her with concrete evidence that a breakthrough had come and that he had personally shaken the discoverer’s hand.

While the crowd continued to shuffle around Macleod, Clowes approached Banting and Best, who remained seated to the side of the podium, alone and bewildered. He extended his hand, smiling down at Fred Banting.

“Well done, Dr. Banting. Well done.” he said in a clipped, upper class British accent. “Thank you for sparing us a long academic review of previously published experiments when we all know that the only thing that matters is what progress we can make from here forward.”

Banting blinked and looked questioningly into the piercing blue eyes of Alec Clowes.

“Alec Clowes. Eli Lilly and Company.” He spoke in a booming voice.

Clowes held out a business card to Banting. Banting took it and said, “I’m very impressed with your card, Dr. Clowes. I regret that I don’t have one to offer you in return. Anyway, it’s not just my work. It’s Charley’s work, too.”

Best jumped to his feet and shook Clowes’s hand. Clowes handed him a business card.

“As I see it, the challenge ahead is to scale up production. Agreed?”

Banting nodded.

“Then I intend to recommend that Mr. Lilly provide full support for that effort: funding, purification, dosage, manufacturing, marketing, the works. You’re going to need it. This will take corporate horsepower. If you leave a discovery this important in an academic setting, you’ll spend too much time in committees and conferences and not enough time saving diabetics. You’ll hear from me again soon.” And then he was gone.

Later, Clowes left a note for Macleod at his hotel to the effect that Eli Lilly and Company would like to assist in the effort to produce a pharmaceutical-grade product. As much as Macleod respected Clowes, he was suspicious of commercial interests, particularly that of an American corporation. Besides, the university had the resources to manufacture insulin without help from south of the border. Macleod promptly scribbled a reply on the back of the note: “Many thanks for your interest and generosity but the University of Toronto is equipped with a commercial manufacturing facility—Connaught Laboratories.”

Macleod was referring to the unique medical research and public service enterprise affiliated with the University of Toronto. It had begun years before in the basement and subbasement of the same building in which Banting and Best made their discovery. It had been established to prepare a Canadian supply of diphtheria antitoxin for free distribution through provincial health departments. It was the brainchild of Department of Hygiene professor John G. FitzGerald. A global tetanus antitoxin shortage in 1915 during the height of the war prompted the expansion and relocation of Connaught to a fifty- eight- acre farm site twelve miles northwest of the campus. Macleod had thought all along that, when the time was right, Connaught could be tapped to launch the large-volume production of insulin. He had already discussed this with President Falconer, who heartily endorsed the idea of claiming credit and control of the development and manufacture for the University of Toronto.

Macleod remained in New Haven for a few days on American Physiological Society business. He spent the evening after the presentation dining at a fine steak house with his fellow APS officers, oblivious to any ill feelings toward him from Banting. As far as he knew, all was proceeding splendidly, and the meeting had been a tremendous success.

Banting and Best left that night. They couldn’t afford to stay another night in New Haven, financially or emotionally. They had reserved a sleeping car on the overnight train back to Toronto, but Banting never even folded down his berth. He stayed up all night in the smoking car, reflecting on what seemed to him yet another humiliation at the hands of his nemesis.

“They’re all vultures and vipers,” Banting muttered as he and Best settled into their seats. “I tell you one thing Charley. If I’m going down, you can be sure I’m taking Macleod with me.”

“Going down? You just discovered insulin!” Charley erupted in a rare display of emotion. “Aren’t you always telling me this is the biggest medical breakthrough since Pasteur discovered the rabies virus?”

“Bigger than that, Charley. A lot more people get diabetes than get rabies.”

“Well?”

“Sure, sure, but now that I’ve served my purpose and the semester is over, Macleod is hoping I’ll just shuffle quietly back to Alliston to milk cows.”

“But you have Henderson’s position in pharmacology. Your name is on every publication. By the time we get back, Collip may have a pure enough extract for human trial. And let’s see what this fellow from Eli Lilly can do.”

“Forget him. He’s a friend of Macleod’s. I saw them talking in the lobby of the hotel.”

“It’s too bad you feel that way, Fred, because he seems to believe in you.”

“No one believes in me but me. Not my family, not Edith, not Macleod. From now on, it’s war, Charley. And that’s one subject I daresay I know more about than Macleod.”

Charley retreated to the sleeper, worrying about how he could possibly avoid being sliced to ribbons in the crossfire between the two main influences in his academic career.

Back when Clowes had worked in Buffalo, he studied the natural repel- lency between oil and water. It would be the best preparation Clowes could have undertaken for his future dealings with Jake Macleod and Fred Banting.

Not the slightest bit discouraged by Macleod’s initial rejection of Eli Lilly’s assistance, Clowes walked briskly to the nearest Western Union office and wired Lilly a three-word report on the APS meeting: “This is it.”