Oskar Minkowski: who discovered the relationship of diabetes and the pancreas.
N.C. Paulesco: the Romanian who almost discovered insulin.
Georg L. the German who almost discovered insulin.
E.L. Scott (left), and Israel Kleiner (right): the Americans who came closest to discovering insulin.
Frederick M. Allen: father of the “starvation” therapy for diabetes.
Elliott P. Joslin: the master clinician of diabetes.
Banting’s idea, as written in his notebook (October 31, 1920). Later he always misquoted himself.
Frederick Grant Banting (1891–1941).
John James Rickard Macleod (1876–1935).
James Bertram Collip (1892–1965).
Charles Herbert Best (1899–1978).
Edith Roach: Banting’s sometimes fiancée. They never married.
Margaret Mahon: Best’s fiancée in 1921. They married in 1924.
The Medical Building at the University of Toronto in which Banting and Best worked.
May 17, 1921. Banting’s notes of the first pancreatectomy, on dog 385.
The experiments continue, with heavy loss of dogs.
Banting’s notes on his plan of work and discussions with Macleod.
July 30, 1921. The first administration of extract: Banting and Best’s joint notebook.
Best, Banting and a dog on the roof of the Medical Building. Thought to be in the summer of 1921, but dated April 1922 by Banting in his scrapbook.
Velyien Henderson, the professor of Pharmacology who befriended Banting.
G.H.A. Clowes, research director of Eli Lilly and Company, whose interest in the Toronto work paid off handsomely.
Dr. Joseph Gilchrist, Banting’s diabetic classmate; human rabbit in the early testing.
Oral administration meant that this first test on Gilchrist was bound to fail.
Collip in his lab, about 1922. His purification made clinical testing possible.
Elsie Needham. Revived from coma at the Hospital for Sick Children. The caption is in Banting’s handwriting.
Leonard Thompson. A later picture of the first patient treated successfully with insulin.
Elizabeth Evans Hughes (1907–1981). Banting’s prize patient, who found insulin “unspeakably wonderful.” The photograph is from Banting’s scrapbook.
James Havens: the first diabetic to receive insulin in the United Stales. A snapshot taken dining the first months of treatment.
Before insulin.” J.L.” Age 3 years, weight 15 lbs., December 15, 1922. Eli Lilly and Company Ltd.
After insulin. “J.L.” February 15, 1923, weight 29 lbs. These spectacular pictures first appeared in the issue of the Journal of the American Medical Association that introduced insulin to the profession. Eli Lilly and Company Ltd.
Before and after pictures of a 1922 patient of Dr. H. Rawle Geyelin. Thought to be too indelicate for lay viewing in the 1920s.
Clippings from Banting’s scrapbook, preserved in his papers at the Fisher Library, University of Toronto.
Collip, Best, (Mrs. F.N.G. Starr), Banting, about 1936. The only photo of more than two of the discoverers of insulin together.
Grinding pancreas to make insulin at Eli Lilly’s Indianapolis plant, 1923. Eli Lilly and Company Ltd.
CHAPTER SIX
“Unspeakably Wonderful”
A totally unexpected, almost incredible disaster in insulin production took place sometime between late February and the end of March. Certain of the fact of their discovery and of its therapeutic benefit for human diabetics, the Toronto group had gone ahead with plans to manufacture insulin in large quantities. The Connaught Anti-Toxin Laboratories was to finance and administer production. Collip was to direct insulin manufacture.1 Special equipment was installed in the basement of the medical building. Everything seemed set for smooth progress. All the problems with purification, the fights about credit, and the rest of the strains, were surely in the past.
Then, to his and everyone’s surprise, Collip found that he could not make insulin. First he could not make it in large batches using the apparatus set up in the special manufacturing area. Then he started to have trouble making it by any method, even in his own lab, apparently being unable to duplicate his own successful procedures of January and February. The result of Collip’s failure was an insulin famine in Toronto during the spring of 1922, a frantic struggle by everyone on the team to find some way of regaining the knack of making insulin, and fundamental changes in policy regarding the handling and development of the frighteningly elusive discovery.2
I
It was one of the most trying periods in Collip’s life: brilliant success in the winter; failure after failure, with more and more serious consequences, all through the spring; endless hours in the lab trying to make insulin. Everything was complicated by a serious attack of flu in the Collip household, while at the lab the breakdown in relations with Banting was total, apparently not having been restored since the fight in January. Banting and Collip probably did not speak.5 Collip may not have been physically safe in Banting’s presence: so many of the stories about the Banting-Collip fight have it taking place in public, or centre it on the loss of insulin production, that there is a reasonable possibility of a second violent incident of some kind having taken place. He was unquestionably vulnerable to Banting’s angry scorn. How could Collip have possibly lost the secret? How the hell could he have done it? Obviously, according to Banting, by being so secretive. If not secretive, or as well as being secretive, by being inexcusably sloppy.4 Collip had known the pure joy of discovery in January. Now he knew dark nights of despair.
People who understand biochemistry tend to be more charitable than Banting was in understanding Collip’s situation. Failures like these were not uncommon in primitive extractions working with unknown substances. Before and during Toronto’s agony with insulin, for example, years of effort and hundreds of thousands of dollars were going into the still unsatisfactory effort to purify thyroxin, insulin’s predecessor as a hormone with great therapeutic possibilities.5 Pioneering chemists were working with delicate procedures, crude and unreliable equipment, and such frustrating unknowns as the chemical composition of the substance they were trying to produce. In Collip’s case, as well, Banting’s belief that his records left much to be desired was probably right. Collip’s only surviving comment on the problem is a laconic statement that “great difficulties were encountered chiefly because the conditions of time and temperature which were adhered to in the original method could not be obtained in a large scale process with the facilities then at hand.”6
A few humans had been given insulin, all at Toronto General Hospital. There are few records of how they were dealt with when the supply failed. Some of them, having regained enough weight and strength to carry on starving for a few more months, were put back on their diets. Leonard Thompson, for example, was sent home in May without insulin. The most needy cases received whatever small amounts of insulin Collip could produce. The neediest of these was a young girl, a friend of Best’s from a Toronto suburb, who was admitted in February suffering from emaciation, dehydration, and severe acidosis. She was given insulin as supplies permitted. The injections eliminated the acidosis. There was no more insulin to inject. The acidosis returned. The girl gradually slipped into a coma. The doctors gave her massive doses of weak, only partially prepared extract, and were able to bring her back to consciousness. This was the first “recovery” from coma at Toronto. It was only temporary. “Collip gave us the last bit of partially completed extract at two o’clock one morning,” Campbell recalled, “and then no more could be completed for days. It was not enough.” The little girl’s death in April 1922 was the one time in Toronto that a patient who had been treated with the extract died for lack of it.7 Some years later in England, the first patient to receive penicillin suffered a similar fate.
II
It was a season for real-life melodrama. Banting, it will be remembered, spent most ev
enings in March drinking himself comatose to get his mind off his troubles. Charley Best came to his room on the night of March 31, Banting wrote later. The young man found the boarding-house room blue with smoke and Dr. Banting half drunk. Best proceeded to give Banting a bawling-out. In passing, he mentioned the situation at the lab and the opportunity they had to go back to work together trying to make an effective extract.
Banting said he wasn’t interested. They could have the whole damn thing. He was going to finish the teaching term with Henderson and then get out of Toronto and find a place where there were decent people to live with.
“Then Best said probably the only thing that would have changed my attitude, ‘What will happen to me?’“
‘“Your friend Macleod will look after you’, I said.”
“Best replied, ‘If you get out I get out’.”
“There was silence for some moments. I thought of all the joy of the early experiments which we had known together. Here was loyalty. I emptied my glass. ‘That is the last drink which I will ever take until insulin circulates in diabetic veins. Shake on it, Charley. We start in tomorrow morning at nine o’clock where we left off.’“
“Best was pleased. We sat down and as we had done hundreds of times, planned experiments.”8
III
While these larger-than-life events were taking place among his associates, J.J.R. Macleod was worrying about the future of their work. Toronto had announced to the world its discovery that certain extracts of pancreas were effective in the treatment of diabetes. Toronto knew how to make these extracts… in theory. In reality Toronto could not make effective extracts in large quantities, sometimes not in any quantities. The researchers were sure it could be done, but they had no idea when they themselves would be able to do it again.
Suppose someone else set to work and learned how to make effective pancreatic extracts. The ugly question of patenting had already been raised within the Toronto group. Surely it was a much more pressing question when outsiders were considered. Suppose some enterprising drug company, or even an enterprising chemist, took up the pancreatic extract problem now, either found out the basic details of the Toronto people’s methods, or, knowing success was possible, worked out some successful variation, and then took out a patent on the discovery?
Drug companies were certainly interested. Late in March, Clowes of Eli Lilly and Company wrote Macleod about his firm’s continuing interest in developing the new extract. He urged a reconsideration of the decision not to work with a major manufacturing firm:
Public interest in this work will naturally be very great and the demand for the product will be such as to lead to attempts on the part of unprincipled individuals to victimize the public unless some steps are taken to arrange for the manufacture of the product by the procedures recommended by Dr. Collip and the control of the product by means of such tests as you and your associates would consider necessary.
If Clowes knew about the researchers’ collaboration with the very small Connaught Laboratories, he dismissed it as inconsequential. The Lilly company would be delighted to work with Toronto, Clowes wrote, and hinted, perhaps intentionally, perhaps not, that Toronto could be bypassed: “I have thus far refrained from starting work in our laboratories on this question as I was anxious to avoid in any way intruding on the field of yourself and your associates until you had published your results. I feel, however, that the matter is now one of such immediate importance that we should take up the experimental end of the question without delay, preferably cooperating with you and your associates…. “9
Macleod replied that Clowes’ firm would have first consideration if Toronto decided it needed help, but that for the next month or two the group would continue on its own. Toronto hoped to publish its method for everyone to use, and would try to protect the public by publishing specifications for the determination of insulin’s toxicity.10 Actually, Macleod was not so sure of his course and in early April began seeking other advice. He approached the deputy minister of health for Canada, who consulted with the commissioner of patents and confirmed the unhappy possibility that a competitor’s patent could interfere with Toronto’s work, even bring it to a complete halt. At best, the litigation necessary to frustrate such competition, on the ground of Toronto’s announced priority, would be lengthy and expensive.11
Macleod also wrote to at least one other discoverer, E.C. Kendall, who had isolated thyroxin at the Mayo Clinic in 1914. Kendall had patented his process of isolating thyroxin, and enthusiastically recommended that the Toronto group do the same with their pancreatic extract. He explained to Macleod the arrangement between himself, the brothers Mayo, and the University of Minnesota, by which the patent had been given to the university. It had then established a special committee to license manufacturers of the product.12
Macleod was more cautious than Kendall about patenting. Chemists and drug companies had few qualms about taking out patents on their processes or products (Kendall wrote of the Toronto situation, for example, “I can see no more reason why the man that separates the active constituent of the pancreas should not share financially as much as the man that makes a new wireless telephone”). But medical men, such as Macleod and Banting, were bound by their profession’s code to make all advances in health care freely available to humanity. If nothing else, it would violate a physician’s Hippocratic oath to engage in the profiting from a discovery that patenting normally implied. During preliminary discussions of this problem in Toronto, Banting was apparently particularly reluctant to be in any way associated with patenting.13
The possibility of losing the discovery seemed so real, however, that the group decided Toronto had to have the insurance patenting offered. On April 12, Banting, Best, Collip, Macleod, and Fitzgerald wrote jointly to the president of the University of Toronto, Sir Robert Falconer, explaining the situation. They proposed that a patent on the process be taken out in the names of the two “lay members” of the group, Best and Collip, and then immediately assigned to the Board of Governors of the University of Toronto. It was to be a purely defensive manoeuvre, one which would never stop anyone else from making the extract. In fact the point was to stop anyone from ever being in a position to stop anyone else:
The patent would not be used for any other purpose than to prevent the taking out of a patent by other persons. When the details of the method of preparation are published anyone would be free to prepare the extract, but no one could secure a profitable monopoly.14
The Board of Governors of the university agreed to the arrangement. An application was filed for a Canadian patent in the names of Collip and Best.
IV
All four of the principal researchers worked long hours in April and May trying to regain the secret of making insulin. Although their later accounts tend to disagree on credit for important suggestions, it seems that the research was more than ever effectively a team effort, with at least three of the four making vital contributions.15
They gradually became convinced that the crux of the problem was in the heating that the extract experienced as part of the process of evaporating off the alcohol. Best discovered significant variations in the pressure of the water being supplied to the crude vacuum pumps they were using. These caused significant variations in temperature and distilling time. (A similar problem twenty years later frustrated early attempts to purify penicillin.)16 Macleod, who had been investigating different grades of alcohol, as well as the influence of different degrees of acidity, then turned his attention to what was happening in the evaporation. He found that the high temperature was causing some of the proteins in the solution to break down, an observation which seemed to reinforce previous experience that heat somehow neutralized the active principle. Macleod suggested abandoning the use of vacuum stills, and going back to the warm-air current method of evaporation that Banting and Best had used earlier at his urging. Collip, too, had decided the temperature had to be kept down, and to do this had experimented with acetone rat
her than alcohol as the principal extractive.17
By mid-May the group had recovered the ability to make insulin. The method involved using acetone with slight acidification. (The degree of acidity was the other variable that was constantly tinkered with; the solubility of elements in the mixtures varied according to the degree of acidity as measured by pH determinations. As was realized later, adjustments in the pH range of the solutions were in fact far more important than the temperature of distillation.) The pancreas-acetone mixture was filtered and then set out in enamel-lined trays placed in a make-shift wooden tunnel. A big old exhaust fan, formerly used in the medical building’s heating system, supplied the wind. Coils in the roof of the tunnel heated the air as it passed over the trays. After an hour in the tunnel, five hundred cc. of solution in a tray would be reduced to fifty cc, the temperature never exceeding 35C. The rest of the process, involving Collip’s method of “trapping” the active principle in various percentages of alcohol, was fairly straightforward, though it took several days before the final product emerged.
The method produced a few cubic centimetres of insulin solution. It was expensive, mainly because of the cost of alcohol, and hazardous. “You can’t imagine a more dangerous set-up,” Peter Moloney told me. He was the first chemist added to the production facility to work on insulin in that spring of 1922. In 1980, when we talked in his room in St. Michael’s College, the distinguished, white-haired, chuckling old man, still an active chemist as he approached his ninetieth birthday, brought back vividly the reek of acetone that spring and summer, the rattling of the motor driving the big fan, and his horror when a bottle of picturic acid was shaken off its shelf, fell to the floor, and shattered. Only the placing of its cork stopper, Moloney thought, saved an explosion that would have ignited the acetone, causing a dreadful fire. Toronto would have sacrificed its medical building and several chemists in its haste to make insulin.18
The Discovery of Insulin Page 18