THIRTY-ONE

The Nobel Prize and Beyond

THROUGHOUT 1923, NOBEL PRIZE NOMINATIONS ARRIVED IN STOCKHOLM. Banting was nominated by Dr. George Washington Crile of Cleveland and by Francis G. Benedict, a leading researcher who had worked with Elliott Joslin. Macleod was nominated by a former colleague from Western Reserve University, Professor G. N. Stewart. August Krogh, the Danish Nobel laureate, nominated both Banting and Macleod. To address the conflicting views about who should receive credit for the discovery of insulin, the Nobel Committee solicited two independent appraisals of the discovery. On October 25, 1923, nineteen professors of the world-renowned Karolinska Institute voted by secret ballot. The result was that Banting and Macleod were to be corecipients of the 1923 Nobel Prize in Physiology.

It was Canada’s first Nobel Prize. As the news spread, spontaneous celebrations erupted throughout Toronto. Banting was an instant celebrity—a local Ontario boy, a veteran, and a Nobel laureate. Toronto’s leading medical and political men congratulated each other. It was a great day for all of Canada.

Banting reacted to the news not with gratitude but with fury that Macleod had been included and Best overlooked. When Gooderham went to Banting’s office to congratulate him, Banting threatened to refuse the prize. Gooderham told him to book a passage to Stockholm immediately, and that the University would pay for it. While Banting ultimately accepted the prize he made public his disagreement and announced that he would share his half of the financial award with Best. This left Macleod with no choice but to announce that he would share his half of the prize with Collip. The prize totaled $24,000, which was split between Banting and Macleod, and further split to $6,000 for each of the four members of the discovery team. Privately, Macleod grumbled that Banting’s sudden prosperity made sharing the prize money an easy matter for him.

The 1923 Nobel Prize for Literature was awarded to William Butler Yeats, who had written the poem “The Second Coming,” which was published the month that Banting first met Macleod.

Neither Banting nor Macleod attended the ceremony in Stockholm, largely because Banting refused to share the stage with Macleod and Macleod didn’t dare accept the prize on Banting’s behalf for fear of being accused of grandstanding. In 1923, Macleod, who had wanted to be elected to the Royal Society, got his wish. Banting finally delivered his Nobel lecture in 1925.

In November 1923, the University of Toronto held a celebratory banquet for four hundred guests in the Great Hall of the elegant Hart House. It was a lavish affair with some guests traveling many miles to attend. There was a jazz orchestra and after-dinner speeches. An official photographer documented the great event for posterity, but Banting refused to pose for a photograph sitting next to Macleod. To this day there exists not a single photograph of the four members of the discovery team in a single frame.

A Nobel Prize in Physiology (Medicine) would not be awarded to another Canadian for nearly fifty years.

After the Nobel Prize announcement, a number of bona fide researchers came forward with claims of having discovered insulin prior to Banting. Georg Zuelzer and Nicolas Paulesco appealed directly to the Nobel Committee. E. L. Scott published a claim to priority in the isolation of the active principle in the pancreas. Paulesco had applied for a Hungarian patent in 1922. Murlin applied for a patent for an antidiabetic pancreatic extract in 1923. Even Collip published a paper stating that he had succeeded in keeping a depancreatized dog alive for sixty-six days with injections of an extract he named “glucokinin,” derived from plants such as lettuce and onion greens. But the insulin patent that had been secured (with help from Hughes) for Toronto and assigned to Toronto’s board of governors held fast.

Now discussions began about the disposition of royalties. It was agreed that half of the insulin royalties would go to the University of Toronto and half would be split among the patent signatories, Banting, Best, and Collip. This income supplied these three scientists with many years of steady funding for their research. From 1923 to 1967 the University of Toronto’s royalties from insulin totaled $8 million. By separate arrangement with Lilly, Clowes received a generous percentage of the insulin profits for his lifetime. Macleod never received any remuneration from the patents.

The year 1923 would prove to be both the most profitable year, to that point, in the history of Eli Lilly and Company and the year of its greatest growth. This was in large part due to the tremendous success of Lilly’s insulin product, trademarked “Iletin® (Insulin, Lilly).” In January 1923 Eli Lilly and Company began to sell limited quantities of insulin to physicians through retail druggists. In October 1923, Iletin was released for distribution directly through physician prescription. At that time it was estimated that 7,500 physicians were treating 25,000 diabetic patients with Iletin. The first-year sales of Lilly’s insulin came to $1,110,000—three times as much as any specialty drug had brought in for Lilly before in a single year. By the end of 1923, Lilly had sold almost sixty million units. Frozen glands now arrived at the Lilly plant by the refrigerated train car load.

In an address to an annual meeting of life insurance professionals in December 1923, Dr. Clowes said:

To give you some conception of the speed with which this valuable remedy has been applied to the treatment of diabetics, I can state that a year and a half ago there were less than ten cases under treatment; a year ago not more than five hundred, while today there are probably not less than sixty thousand cases under treatment of which more than forty thousand are in the United States.

This rapid delivery of an effective extract would not have been possible were it not for the isoelectric and organoprecipitation methods—both of them George Walden’s inventions on behalf of Eli Lilly and Company—which resulted in a purer and more stable product. According to the original indenture, the patents for the isoelectric and organoprecipitation methods were turned over to the University of Toronto.

Insulin was now not only readily available, but also affordable. George Walden’s improved methodology also allowed Eli Lilly and Company to reduce the price per unit several times after its introduction. Although Eli Lilly held the exclusive franchise of insulin production in the United States, the company was committed to keeping the price as low as possible so that it would be available to all diabetics. A local newspaper reported:

Many persons have the idea that insulin is as rare as radium and as hard to obtain. Those who have that opinion are in error. The enemy of diabetes is now being produced in quantities sufficient to meet the world’s needs. Its cost is so nominal that, as Mr. Lilly said, it is available to the consumer at a price below what the average man spends daily for his cigars or a supply of gasoline for his pleasure automobile. Iletin costs less than three cents a unit, thus proving that the humblest man or woman may enjoy its benefits.

By the end of 1923 the cost of treatment per patient was frequently less than one dollar per week and seldom more than two dollars. (Consider that this was just two years after the initial announcement in New Haven and one year after Elizabeth left Toronto to begin a new and normal life.)

J. K. Lilly Sr. could not have been more proud of his sons. In one letter to Eli he wrote, “A glow of pride pervades my being as I contemplate the splendid manner in which you have steered the good ship Iletin to the harbor of success.”

Each of the four members of the discovery team went on to make significant individual medical research contributions, with the possible exception of Banting. By March 1924 he was no longer engaged in the clinical investigation of insulin and had stopped advising patients. He devoted himself to the Banting Research Foundation, which was created to foster imaginative scientific research. He concentrated on trying to apply to other problems, primarily cancer, the model of sudden inspiration and insight that had led to the discovery of insulin. As he explained to an audience in Chicago in March 1925:

We do not know whence ideas come, but the importance of the idea in medical research cannot be overestimated. From the nature of things ideas do not come from prosperity, affluence and contentment, but rather from the blackness of despair, not in the bright light of day, nor the footlights’ glare, but rather in the quiet, undisturbed hours of midnight, or early morning, when one can be alone to think. These are the grandest hours of all, when the progress of research, when the hewn stones of scientific fact are turned over and over, and fitted in so that the mosaic figure of truth, designed by Mother Nature long ago, be formed from the chaos.

Many of the projects that the Banting Research Foundation pursued were related to military research. He was especially interested in biological and chemical warfare; at one point he suffered serious chemical burns after conducting an experiment in which he applied mustard gas to his own leg. The Banting Research Foundation played a major role in supporting the development of the first anti-gravity or G-suit, designed to prevent pilots from blacking out when subjected to extreme acceleration. These suits were used during World War II, and all G-suits worn by pilots, astronauts, and cosmonauts are based on this original design.

Banting married Marion Robertson on June 4, 1924. They had one son. Notwithstanding his dislike for public speaking, Banting joined the National Research Council of Canada in 1927 and became the country’s leading spokesperson for medical research. Despite this distinction and although he would be knighted in 1934, he remained a man who looked and felt uncomfortable in a tuxedo. He once threatened that the next person who called him sir would “get his ass kicked.”

Banting divorced Marion amid a well-publicized scandal in April 1932. Whatever favors the press had done him by launching his career and lionizing him in 1922, they withdrew ten years later by savaging his reputation as Canada’s first-ever Nobel laureate. After the divorce, Banting struggled with depression. He married Henrietta Ball in 1937, but at Christmastime 1938, he was again beset with a dark mood. He wrote in his diary:

God how I hate the whole fuss this so called festive season of the year. To me it is festering rather than festive. Cards. Presents. Gratuities. Sentiment. Good Lord how I hate the display of sentiment. Another word for sentiment is weakness. Christmas this year of 1938 symbolized futility . . . oh cruel time of year and assaying when one analyzes one soul to see if it is of any value.

And yet he would always have warm feelings for his early insulin patients. The same week he wrote to Teddy Ryder:

I shall always follow your career with interest and you will forgive me if I add, a little pride, because I shall always remember the difficult times we had in the early days of insulin. The outstanding thing I remember was your strength and fortitude in observing your diet and the manly way in which you stood up to the punishment of hypodermic injections. I am sure that you will be a success in life if you maintain the same spirit in meeting the rebuffs of the world.

As Nazi Germany rose to power in Europe, Banting advocated the use of biological weapons in the event of a German invasion of England. When World War II began he applied to be sent to the front lines, but the Canadian government refused, holding that he would be of greater service in Canada. But Banting continued to worry about Canada’s military vulnerabilities and in 1941 he embarked on a secret mission to England to test a G-suit developed at the Banting and Best Medical Research Institute.

On February 21, 1941, Banting boarded a Lockheed Hudson patrol bomber to go to England on a secret mission that was reportedly related to the use of chemical weapons or combat aviation problems. The plane crashed shortly after takeoff from Gander Airport in Newfoundland. Both the radio operator and the navigator were killed on impact. Banting and the pilot were badly injured. Banting was able to dress the pilot’s wounds before he succumbed to his own injuries. The pilot survived to recount that in his final hours Banting, who was delirious, believed he was dictating a new scientific breakthrough to a stenographer. Banting was forty-nine years old at the time of his death and was survived by his second wife, Lady Henrietta Ball and his son by Marion, Bill. He spent his last night on earth in Montreal with Bert Collip, with whom he had become good friends.

John James Rickard Macleod continued to suffer the many indignities of Banting’s hatred, and as the Ontario native’s popularity increased so did acceptance of his view of Macleod. By 1928, Macleod’s situation had become unbearable. He left Toronto to return to Scotland as the Regius Professor of Physiology at the University of Aberdeen. The University of Toronto hosted a lavish farewell dinner for him. Not only did Banting refuse to attend the dinner, he requested that an empty place be set at the table for him. Upon Macleod’s return to Aberdeen, he was duly appreciated as a great physiologist, a brilliant scholar, and the author of eleven books and monographs. In 1930 he became a member of the Royal College of Physicians, London; and in 1932 he joined the Royal Society of Edinburgh. He never discussed his years in Toronto.

James Bertram Collip continued to work in endocrinological research. Always hoping to discover the next magic hormone, he undertook several collaborations with drug companies, including Eli Lilly. He significantly contributed to isolating the parathyroid hormone secreted by the parathyroid gland and adrenocorticotropic hormone (ACTH) secreted by the pituitary gland. In 1927 he declined an offer to join the Mayo Clinic. In 1928 he accepted a position as chair of biochemistry at Mc- Gill University in Montreal. Upon Banting’s death, Collip succeeded him as senior administrator of medical research at the National Research Council Canada. After the war Collip moved to the University of Western Ontario, where Banting was working when he had had his inspiration.

While Collip and Banting had become friends, Best and Banting’s relationship had cooled considerably. Charles Best never forgot the disappointment of not being officially recognized for his contribution to the discovery of insulin. In a letter dated 1945 to Dr. Elliott Joslin, Best wrote, “Dr. Ross was very friendly with me during the early stages of insulin but some years later he apparently decided that as I had not been born in Ontario little credit should be given me. I am told that he was largely responsible for the fact that the Dominion Government did not include me when they gave Banting his annuity. With Sir William Mu- lock, Dr. Ross apparently played a part in my complete exclusion from the tenth anniversary celebration of the discovery of insulin here in Toronto. It was on that occasion that Sir William announced that ‘only the name of our Ontario bred boy will be mentioned.’ “ The 1972 official history of the Nobel Prize states that it was impossible to include Best in the 1923 prize because no one had nominated him.

From 1926 to 1928 Best did postgraduate research in the laboratory of Sir Henry Dale in London. This research led him to the discovery of histaminase, an antiallergic enzyme. He continued his research during his long and successful career at the University of Toronto. He had replaced Macleod there as professor of physiology. He was twenty-nine years old at the time of his appointment. In the 1930s, Best found that lecithin prevented depancreatized dogs from developing fatty livers. He and his colleagues isolated choline as the active nutritional component of lecithin, and studied the role of choline in metabolism. Also in the 1930s, Best became interested in the anticoagulant drug heparin, which had just been discovered, and worked to purify it for human use. In 1941, the year of Banting’s death, Best was appointed director of the medical research unit of the Canadian navy.

Dr. John G. FitzGerald, Banting’s good friend and director of the Connaught Laboratories, died shortly after Banting was killed. During the 1930s he had begun to suffer from mental illness and attempted suicide. He was sent to Connecticut for insulin shock treatments. After returning to Toronto and making another suicide attempt, he was admitted to Toronto General Hospital, where he managed to hide a knife after a meal. He opened an artery in his hip and bled to death.

Billy Ross, the Canadian patriot and Banting booster, suffered the loss of both of his sons, casualties of World War II.

Dr.Joseph Gilchrist, the self-described “human rabbit,” died at Sunnybrook Hospital, suffering from poorly controlled diabetes and manic depressive psychosis.

J. K. Lilly Sr. had the privilege of making history when he signed the indenture with the University of Toronto in 1922. He took a personal interest in the lives of the early insulin patients and corresponded with many of them. A boy named Rodger MacQuigg wrote that he was sticking close to his diet and “feeling as frisky as ever.” He promised Mr. Lilly, “After I get a little fatter, I will send you my picture and you can publish it in your paper [the company’s internal newsletter, Tile and Till] and say, ‘This is the result of taking Iletin!’” J. K. Lilly replied, “I hardly believe you can realize what a joy it is to me to have you and others benefit by the use of this new discovery. It is an everlasting joy day by day to get letters such as yours and to feel that good is being accomplished.” Through regular correspondence, Elizabeth Mudge and J. K. Lilly developed a friendship. At her death the company had supplied her with insulin free of charge for twenty-five years. The elder Lilly turned the company over to his son Eli in 1932. In 1975 the company began providing sterling silver medals to men and women who had been kept alive by insulin injections for at least fifty years, and Eli Lilly (then in his ninetieth year) personally signed every one of the eighty-three letters that accompanied the medals during that year.

In 1947, Clowes was awarded the Banting Medal by the American Diabetes Association. It was the first time ever that an industrial corporation had been recognized for its contribution to medical research. Alec Clowes spent forty summers working at the laboratory at Woods Hole. At his home there in 1958 he died of a cerebral hemorrhage, two days before his eighty-first birthday. Three months later Eli Lilly and Company decided to discontinue operations at Woods Hole. A new generation of scientific research had begun. Collaboration between research universities and pharmaceutical companies was no longer uncommon, and extraordinary efforts to facilitate these alliances were no longer necessary.

George Walden remained an employee of Lilly for his entire career. He became vice president of biochemical manufacturing and a member of the board of directors. Reflecting later on his years at Lilly, Walden would say that the biggest thrill was being in on the romance of the development of insulin.

Eli Lilly Jr. shared his father’s deep commitment to pharmaceutical research and development. He was president of Eli Lilly and Company from 1932 to 1948, subsequently becoming chairman of the board. Although he was never interested in politics, he became one of Indianapolis’s most influential citizens through his major philanthropic efforts. His deep interest in local history led him to write two books and play a leading role in the Indiana Historical Society, the creation of the Glenn A. Black Laboratory of Archaeology at Indiana University in Bloomington, and the development of the Conner Prairie historic preservation and the prehistoric Angel Site. His significant personal financial contributions almost always came with the stipulation that they be anonymous.

J. K. Lilly Jr., who was known as “Joe,” became president upon his brother’s retirement in 1948. He was a man of many interests, from rare books and manuscripts to miniature soldiers to eighteenth-century paintings. His collection of rare books consists of 20,000 volumes and 17,000 manuscripts, including one of the 26 copies of the Dunlap broadside of the Declaration of Independence. It was considered among the finest general collections of books and manuscripts in the United States in the twentieth century. Lilly gave it to Indiana University in 1954, and it is housed today at the Lilly Library there. In the early 1950s, Mr. Lilly became a numismatist. His collection of gold coins quickly became one of the world’s largest, eventually comprising 6,000 items. It now belongs to the Smithsonian Institution. The family’s primary residence, Oldfields, now belongs to the Art Association of Indianapolis.

Together, J. K. Lilly Sr. and his sons established the Lilly Endowment in 1937. This private family foundation supports the causes of religion, education, and community development, with 60 to 70 percent of the grants paid each year going to charities in Indianapolis and Indiana. In 1968, the company established the Eli Lilly Foundation, a $7 billion organization that operates separately from the Endowment. The Foundation contributes almost $400 million annually to worthwhile charitable pursuits—50 percent of which has gone to universities, hospitals, and other nonprofit institutions in the state of Indiana. The Lilly family remains one of the largest benefactors to their home state.Dr. Elliott Joslin devoted his life to diabetes treatment, education, and research and founded the Joslin Diabetes Center. Affiliated with Harvard Medical School, Joslin Diabetes Center is the world’s largest diabetes research center, diabetes clinic, and provider of diabetes education. Joslin pioneered the idea of educating diabetics about their illness so that they could care for themselves. This approach, which is now widely accepted, is called DSME, for Diabetes Self-Management Education. Joslin maintained a diabetic registry for his entire career. In it he re- corded each diabetic patient he treated, beginning with Mary Higgins in 1893, listing for each name, the address and age, as well as the dates of onset, diagnosis, and death. When he died at age ninety-two there were eighty volumes, representing some 58,784 names.

Dr. Joslin often described his experience witnessing the postinsulin resurrection of starved children in terms of what he called the “Banting Chapter” of the Bible (Ezekiel 37), which reads:

The hand of the Lord was upon me and set me in the middle of a valley; it was full of bones and He said to me, “Prophesy to these bones and say to them, ‘Dry bones, hear the word of the Lord! I will make flesh come upon you and put breath in you, and you will come to life.’ “ So I prophesied as I was commanded and the bones came together but there was no breath in them. Then He said to me, “Prophesy to the breath; prophesy, son of man, and say to it, ‘Come from the four winds, O breath, that they may live.’ “ So I prophesied as he commanded me, and breath entered them; they came to life and stood up on their feet.

As Banting’s star ascended, Allen’s fell. The stock market crash of 1929 marked four crushing years of bankruptcy for Allen and the Physiatric Institute. Allen owed over $25,000 to Otto Kahn, who turned the matter over to an attorney. Allen tried to work out an arrangement with his creditors and committed his entire savings to ameliorating the situation, but it was not enough. Desperate for a second chance for his beloved institute, Allen returned to his initial investors, including Hughes, and begged for money. One by one the investors turned him down. Allen was incredulous. One of the founding ideals of the institute was that diabetics could find help there, regardless of their financial means. No worthy patient was ever refused help. Now Allen himself was being refused help. An eviction notice was nailed to a wooden stake and driven into the front lawn of the institute. Allen was given two weeks to vacate the premises. Later, the contents were auctioned off. Worst of all, he had buried his parents in a quiet corner of the grounds and hoped to be buried there himself. The bodies were now hurriedly exhumed and moved to a lot in a nearby town.

After the collapse of the Physiatric Institute, Dr. Allen and Belle Wishart Allen divorced. Allen persevered with his animal experiments in rented basements and outbuildings, drifting from one mediocre, ill- equipped facility to the next. Despite these impediments Allen continued to work on an idea that he had first experimented with while serving at the Army General Hospital in Lakewood in 1918—the relationship of dietary salt to high blood pressure. Now he introduced a low-salt diet for patients with hypertensive cardiovascular disease. Although this treatment was not as widely accepted as was his starvation diet for diabetics, the relationship of salt to high blood pressure was later proved.

Upon hearing of the collapse of the institute, a group of Allen’s grateful patients scraped together a research fund of three hundred dollars a month for several years so that he could continue his work. It was an unprecedented amount of money for Allen, but, tragically, he had no laboratory facilities in which to continue his work at that time.

Allen was to remain an outsider for the rest of his career. In a letter to The New York Times dated May 14, 1937, Dr. Allen wrote:

Practically all medical discoveries have been made by individuals or small voluntary groups. The idea of an organized mass attack therefore lacks basis in past experience. . . . The great majority of medical investigators work on small salaries or none, and all their discoveries are given to humanity free. Secretiveness, selfish ambitions, and particularly the evil known as “politics” belong to institutional organizations rather than to the individual investigators, and they tend to increase, along with regimentation and barrenness, according to the size of the institution and its endowment.

Otto Kahn’s mansion was razed in 1939, and the ground was left vacant to reduce taxes. Although he lived another twenty-five years, Allen never returned to the property.

In 1949 Allen was awarded a Banting Medal by the American Diabetes Association. Accepting the award, Allen expressed “deep appreciation of your medal as a unique recognition of my mostly unsuccessful efforts” and said that his “ambition once was so high that I regarded both the diet and the extract as temporary steps toward a position where I could attack the real problem of cure.” Frederick Allen is buried in Greenfield Cemetery on Long Island, New York. Not a single blood relative is buried with him. His is one of six plots purchased by his second wife, Anne. Allen’s granite footstone bears the word “DOCTOR” in large capital letters, beneath which appear his name and the year of his death, 1964.

“The thing that has hurt me more than anything,” Belle Wishart Allen wrote, decades later “was to see that very brilliant idealist, believing in the good in people, gradually becoming that bitter disillusioned old man.”

Although Joslin always referred to the years of 1914 to 1922 as the “Allen era in diabetes,” the contributions of Dr. Frederick M. Allen are now largely forgotten. His likeness is absent from the portraits of famous scientists displayed in the lobby of the Joslin center in Boston. The words of the eleventh century Persian poet, mathematician and astronomer Omar Khayyam, whose writing Allen especially favored, describe the brief, bright trajectory of the Physiatric Institute:

The Worldly Hope men set their Hearts upon

Turns Ashes—or it prospers; and anon,

Like Snow upon the Desert’s dusty Face

Lighting a little Hour or two—is gone.