A Line in the Sand – Mayo Clinic’s role in insulin research
Millions of patients with diabetes lead normal lives because they take insulin on a daily basis to control their condition. Prior to 1922, their lives would have been much more tenuous. Mayo Clinic was at the forefront of the first clinical trials on insulin back then, ensuring that the new drug was safe and determining the proper doses for patients.
Bessie Bakke had been perfectly healthy for 28 years until she suddenly became fatigued, lost weight and developed fainting spells. Misdiagnosed as having anemia, her condition deteriorated until she was nearly comatose. In October 1920, her parents brought her to Rochester, Minnesota, where she was diagnosed by Mayo Clinic endocrinologist and researcher Russell M. Wilder, M.D., as having juvenile diabetes, as type 1 diabetes was then known.
It was before the discovery of insulin, when patients with diabetes often were subjected to extreme treatments and had little hope for the future.
"Bessie B.," as she became known in the scientific literature, stayed at St. Marys Hospital where she was placed on a ketogenic diet, similar to the one pioneered by Frederick Allen, M.D., of the Rockefeller Institute.
The diet consisted of a precise proportion of carbohydrates, proteins and fats determined by her weight and her blood glucose levels, and it included a series of adjustments to customize it for her specific metabolism.
Dr. Wilder and his colleague, physiologist Walter M. Boothby, M.D., tried Bessie B. on 12 different diets during her 74-day stay in the hospital.
It was one of the first attempts at individualized medicine.
Every element of her diet was prepared in a special kitchen under the direction of trained dietitians. Dr. Wilder and his staff accounted for and analyzed everything that went into and was eliminated from her body.
Laboratory tests determined how quickly she was metabolizing food so that doctors could properly balance and time her feedings. The amount of food she received was small, just 850 to 900 calories a day. In order to survive, patients with diabetes during that time had to nearly starve.
Insulin, normally produced by the pancreas, helps control glucose, or sugar, levels in the blood. When pancreatic islets or cells slow or stop producing insulin, diabetes mellitus results. The blood is flooded with glucose, potentially causing a coma and death.
Hired by William J. Mayo, M.D., in 1919 to run Mayo Clinic's diabetes unit, Dr. Wilder had few options at his disposal to treat Bessie B. Putting her on an extreme diet was crucial.
Dr. Wilder was not alone in attempting to control diabetes through diet. A handful of doctors in New York, Chicago and Boston also were having mixed success with these specialized diets. Some patients were living for three, four or five years after the onset of diabetes, provided they adhered strictly to the feeding regimen.
One of those patients was Elizabeth Hughes, daughter of Charles Evans Hughes, the former U.S. chief justice and, in 1920, secretary of state.
The "Hughes Child," as Dr. Wilder would later refer to her, was kept alive by Dr. Allen's special ketogenic diet. After several years on the treatment, she weighed 45 pounds and was barely able to walk.
Another patient was a 12-year-old boy from Chicago named Randall Sprague, who was kept alive by Rollin Woodyatt, M.D., Dr. Wilder's mentor at the University of Chicago.
What happened next was to change medicine forever.
A new era
Frederick Banting, M.D., and Charles Best with one of their test dogs on the roof of the Medical Building at the University of Toronto, August 1921. Photo courtesy of the Thomas Fisher Rare Book Library, University of Toronto.
As they made their hospital rounds in the fall of 1921, Dr. Wilder and his colleagues at Mayo Clinic heard the news.
University of Toronto researcher Dr. Frederick Banting and medical student Charles Best had been experimenting with dogs in the university laboratory of physiology professor Dr. J.J.R. Macleod. They had isolated, refined and proved the effectiveness of insulin in an arduous series of animal studies. The formal presentation of their discovery was made at a research conference that December in New Haven, Connecticut.
"What a Christmas gift that was — an extract of the pancreas developed at Toronto, which effectively controls the symptoms of diabetes!" writes Dr. Wilder in his memoirs. "We learned still more about it at the meeting of the Association of American Physicians in the spring of 1922. Excitement prevailed."
In early January 1922, using a modified formula for the dog-derived insulin developed by biochemist James Collip, Dr. Banting injected a 14-year-old boy named Leonard Thompson. Daily doses of insulin allowed him to live another 13 years.
Drs. Banting and Macleod received the Nobel Prize for Physiology or Medicine in 1923 for the discovery of insulin.
Correct insulin dosage critical
Photo of the same patient on Dec. 15, 1922, and again on Feb. 15, 1923, after receiving insulin treatment. Photo courtesy of Eli Lilly and Company Archives.
A stark contrast: The same patient on Dec. 15, 1922, and again on Feb. 15, 1923, after receiving insulin treatment. Photo courtesy of Eli Lilly and Company Archives.
The Canadian doctors and researchers were instrumental in the first use of insulin, but still no one knew the best strategy to administer insulin to the wide variety of patients who were hanging on to life, some with multiple complications.
Getting the dosage right was critical to keeping the patients alive. Too much insulin would cause a person to go hypoglycemic, with abnormally low blood glucose levels. With too little insulin, the body could no longer move glucose from the blood into the cells, causing high blood glucose levels. Both conditions could lead to diabetic comas and even death in severe cases.
The Toronto group turned to a handful of top clinical researchers for help in determining optimal insulin dosing through experimental studies on patients. One of those was Dr. Russell Wilder at Mayo Clinic.
"Samples of insulin were first received at Mayo Clinic in the early spring of 1922," reports Dr. Wilder. "They were for experimental trials ... but an adequate amount of insulin to insure everyone getting it who needed it was not available until the autumn of 1922, and October 1 of that year is the date which divides for us the insulin era from the pre-insulin era."
It was as if someone had drawn an arbitrary line in the sands of time.
Once clinical studies and mass production would make insulin available, the line would be crossed. That was when the vast majority of patients with childhood diabetes had their first chance at a relatively normal life.
Most people today have no idea how dire a diagnosis of diabetes was in that time.
"We had 32 children with diabetes in the Mayo Clinic between October 1, 1919, and October 1, 1922, a three-year period," Dr. Wilder writes. "One was moribund on arrival, 28 received satisfactory training and a dietary regimen. Nine survived long enough to benefit from insulin. The others died before it came."
Meeting of the minds
In November 1922, Dr. Wilder traveled to Ontario to attend a meeting of North America's foremost clinical experts in diabetes at the time.
In addition to the Toronto hosts, also present were experts from New York City, Chicago, Boston, Rochester, New York, and Indianapolis — and from Eli Lilly and Company. The international pharmaceutical manufacturer would play a major role in the first mass production of insulin.
Dr. Wilder's enthusiasm about the meeting leaps from the page of his notes: "Never again was I to experience a thrill equal to that of being invited to attend the meeting in Toronto of a small committee of experts, called together by Professor J.J.R. Macleod to undertake an extensive clinical evaluation of the product, insulin."
Over a cold weekend, the experts compared experiences on how to treat patients with the newly discovered insulin, what worked best to revive them from diabetic comas, and what symptoms might indicate potentially fatal complications.
Dr. Wilder's notes show that the doctors were trying to establish dosage standards for insulin:
"Allen has given one dose every six hours. Campbell gives his dosage 3/4 hour before meals."
"Woodyatt — reported a death contributed to by overdosage — no post mortem. Four other patients receiving same dosages had symptoms but no ill effects."
"Gilchrist — has been testing potency of preparations on himself. Reaction — fatigue — preparation increased pulse rate, tremor sensation."
"Banting — four children tell that they feel shaky."
The physicians also discussed hyperglycemia and how to treat it and any unusual cases. If one had observed something, the others had to know. It was their only guide at this point. And they discussed the handful of patient deaths — from heart failure, sepsis and tuberculosis. Autopsies were important, so they would know if insulin fatally interacted with other conditions.
At the time, Eli Lilly and his managers had been urging Drs. Banting and Macleod to patent their insulin formula so that it could be standardized and safely manufactured.
Patenting discoveries was not routine in academic circles at the time. In fact, it was frowned on, and Dr. Macleod was reluctant. Yet colleagues told him it was the only way dosages could be mass-produced for further study. Without a patented formula, others might develop weak or ineffective versions.
In the middle of Dr. Wilder's notes is a stand-alone statement, apparently written as part of this effort and shared at the meeting:
In my opinion, the course being pursued by the University of Toronto in offering a patent to control the manufacture of insulin is wise and commendable. Without such control it will be impossible to protect humanity from dangerous preparations. Dr. W. J. Mayo concurs in the above.
— Russell M. Wilder
The last three pages of notes are devoted to a clinical description of the Hughes Child. Any doubt of her identity is erased by Wilder's margin note: "This is the daughter of the Chief Justice of the Supreme Ct."
The notes continue: "In August, at age 15, weight 45 lbs., height 60 inches. In November, the weight is 74 lbs., height 61 inches."
The notes reveal that she was now on a different and more substantial diet, tolerating the insulin well, and thriving. After the discussion, the doctors were invited into her rooms, where they formed a semicircle around her as she was about to eat lunch. It was one of the most remarkable medical rounds in history.
Beyond the line
Randall Sprague, M.D., one patient who survived long enough to benefit from the discovery of insulin and become a physician at Mayo Clinic.
Dr. Wilder returned to Minnesota after that November meeting but kept in close
correspondence with his colleagues, continuing his clinical studies in an attempt to refine insulin dosing.
After 40 patients, they published a seminal paper in 1923 in the Journal of Metabolism Research, indicating that a range of 10 to 30 insulin units was needed to transition a patient to a normal diet. They dosed before breakfast and kept patients to a strict eating schedule, with meals at 8 a.m., noon and 5:30 p.m.
They presented detailed charts on patients of varying ages, offered first aid (epinephrine and orange juice) for patients slipping into lethargy, and concluded that physicians needed to treat patients qualitatively, watching them closely to establish the right dose for the individual.
Soon, 200 case studies confirmed their early findings, along with two more major papers. After the arrival of insulin, 167 children were admitted to the hospital at Mayo Clinic in those first six years of the new era. Only 17 were known to have died later of complications, and most of those Dr. Wilder attributed to care issues outside his influence.
For Bessie Bakke, however, insulin came too late.
After spending two and a half months at Mayo Clinic, she was doing well and had gone home, only to die a month later in October of 1921.
Dr. Wilder, Dr. Walter Boothby and chemist Carol Beeler had fully documented Bessie B.'s complete metabolic activity for the 74 consecutive days, the first detailed clinical study of its kind. They presented their findings that December and published them in January 1922 in the Journal of Biological Chemistry.
In contrast, Elizabeth Hughes, who was treated with insulin, lived long enough to become one of Dr. Banting's first patients. When she died, she had received 42,000 insulin injections in 58 years.
Young Randall Sprague made it across the line into the insulin era, as well.
In fact, he thrived, attended medical school and eventually became a Mayo Clinic physician and a world-class endocrinologist. One of Dr. Wilder's closest colleagues in later years, Dr. Sprague wrote his friend's obituary in 1959.
The Mayo Clinic team treated diabetic patients, saving most of them thanks to insulin, while developing one of the best-tested metabolic diets for patients with diabetes in the nation and an excellent diabetes education program. They added papers on insulin use for pregnant women and patients with comorbidities.
Today, Mayo Clinic still trains patients about the proper care for their diabetes using many of the methods established by Dr. Wilder.
The diabetic handbook that bore Dr. Wilder's name — The Primer for Diabetic Patients — went through nine editions. He also launched The Mayo Clinic Diet Manual, which had six editions, the last authors being Drs. Michael Jensen and Cliff Gastineau and nutritionist Jennifer Nelson.
The American Diabetes Association (ADA) now awards the Banting Medal for Scientific Achievement Award as its highest scientific honor. Three Mayo Clinic physicians have received the award: Drs. Wilder, Leonard Rowntree and Robert Rizza. And four have headed the ADA, including Dr. Wilder.
Dr. Wilder, who treated and saved thousands of patients and aided thousands more through his pioneering clinical research, remained the modest gentleman.
In one of his last presentations before his death he said, "I can lay no claim to any great discovery, but I was a member of the crew and several of the ships engaged in exploration … and I must admit to a degree of pleasure in recalling these adventures."