Anabelle S. Slingerland
Leiden, the Netherlands
Where science and human nature meet
Figure 1. Niels Stenseens Hospital including apple orchard
In November 2017 the Niels Steensens Hospital or Steno Memorial Hospital of Copenhagen, celebrated its 85th anniversary (Figure 1). It was named after the distinguished Danish scientist Nicolaus Steno(nis) (1638-1688), a modern-day Renaissance man, autodidact and polyglot, who explored anatomy, geology, and religion. He was so intense in his work that it was said he often forgot to eat! He was from humble beginnings, but working in his father’s goldsmith shop developed a keen eye for detail, surviving many hardships as father after stepfather after stepfather (all goldsmiths) died, half of his schoolmates passing during the epidemics of his time, and he himself suffering from ill-health. With the help of a small inheritance, he was able to travel and work in Amsterdam and Leyden, then at the Thevenot’s Academy of Sciences in Paris where he discovered several anatomical structures such as the parotid duct (ductus Stenonis, Stensen’s duct). Moving to Florence he was supported by the Medici banking family and made discoveries in fossils, paleontology, and geology. He later converted to Catholicism and became a bishop, a move not appreciated in his own country. Recognition came only later after his death, and now he remains a role model for a small nation that became a leader in diabetes patient care and research.
Early days of insulin
Before the discovery of insulin Dr. Christian Hagedorn was a Danish country general practitioner whose passion for research had resulted in his 1918 discovery of a micro-method to measure blood glucose. In 1921 one of his patients, Birte Marie Jørgensen-Krogh, (herself a physician and a diabetic) accompanied her Nobel Prize laureate husband August Krogh to a talk at Yale New Haven, where learning about the discovery of insulin she was so excited that she wrote to Hagedoorn and asked her husband to write a letter to Mc Leod, one of the discoverers of insulin. Hagedorn wrote back saying he would be willing to test the new drug and help purify and optimize the substance if granted permission. The Toronto group soon granted this, and back in Denmark the Kroghs experimented with insulin in Hagedorn’s house and within a week produced a strong pancreatic abstract. They continued their experiments in Krogh’s Institute (the laboratory of Zoophysiology), and the pharmacist-manufacturer August Kongsted (1870-1939) of Leo Pharmaceuticals financed further work. This resulted in the founding of the Nordisk Insulin Laboratory (NIL), which first purified the insulin and named it after the financier, hence ‘Leo’ or lion. The first patients were treated by the spring of 1923; and Christian Hagedorn, just like Joslin, replaced ‘measuring glucose’ with ‘add insulin’ to his regimen of diet and exercise.
Two institutes, one hospital
Figure 2. Hvidøre Sanatorium
Hagedorn was very organized and result-driven as a businessman, but seems to have been difficult to get along with, so that two of his employees, the Pedersen brothers, Harald (1887-1961) and Thorvald (1887-1966), left the company and in 1925 started their own institute, the new or ‘Novo’ Therapeutisk Laboratorium. The two companies became unfriendly competitors and whenever possible copied each other. When in 1926, Nordisk started their Nordisk Insulin Foundation (NIF) to support scientific and humanitarian causes, Novo started their own Novo Foundation (NF).
In 1932 the Nordisk Insulin Laboratory realized the value of having their own patients who would also serve as research subjects. They founded a hospital, the first diabetes hospital in Scandinavia, and named it after Niels Stensen. This was a pioneer in the field and soon became the largest and most well-known hospital in Scandinavia, with Dr. Christian Hagedorn (1888-1971) as its first director. He focused on prevention, diet, and exercise as an integral part of treatment and had the hospital designed so as to inspire the patients to live well. He had the hospital luxuriously equipped, had an apple orchard planted in its garden, and made obese patients take the long steep stairway and forbade them to take the elevator. He was notorious for his authoritarian and paternalistic approach to patients.
New and improved insulins
In 1936 Hagedorn benefited from a suggestion by Norman Jensen that an alkaline protein protamine derived from the river trout could be used to dissolve insulin so it would persist longer in the body’s neutral pH and require fewer insulin injections a day. The beginning of the later Steno Studies was also in 1936. In 1937, Dr. E.P. Joslin, the American diabetologist, ranked the discovery of protamine as one of the great breakthroughs in the history of diabetes.
But the old competition between the two laboratories showed no signs of abating. In 1936 D.A. Scott and A.M. Fischer added zinc to make Zinc-Protamine-Insulin (ZPI), so patients had only to merely shake the vial instead of first add neutralizing liquid before injecting it. When in 1938 Novo marketed the new product, Hagedorn claimed it was Nordisk’s, leading to a lawsuit. The Pederson brothers denied the allegations, but Hagedorn won his case in the Supreme Court, resulting in Novo to having to share the profits of their sales of ZPI with Nordisk.
Then in 1946 C.Krayenbuhl and T.Rosenburg at Nordisk developed crystalline protamine insulin, a mix of protamine with rapid-acting insulin. In 1950, it would be launched as Neutral Protamine Hagedorn and the demand for long-acting insulin increased.
A second diabetes hospital – then a merger
|Figure 3. Monument of Niel’s Stensen. Copenhagen, Denmark|
In 1957 a research lab was attached to the Niels Steensen Hospital, baptized in 1978 as the Hagedorn Research Lab for basic research. Then the Pederson brothers at Novo started their own diabetes institution, the Hvidøre Diabetes Sanatorium in Klampenborg (Figure 2), converted in 1949 to Hvidøre Hospital. It was there that in 1940, despite the difficulties of the German occupation, two hospitalized diabetic patients were so impressed by the large number of children admitted for diabetes that they assembled a group of leaders of the profession and founded the National (Danish) Association of Diabetics. Within a few months they had their own bulletin, administration and out-reach, created their own support to finance treatment at either one of the diabetes hospitals.
Much later, in 1989, Nordisk and Novo labs and companies merged to become Novo Nordisk, and in 1991 the two hospitals also merged, becoming the new Steno Diabetes Center Copenhagen (SDCC). The buildings were extended, new research laboratory and clinics were added, and outpatient facilities expanded because diabetics no longer required hospitalization and even complications could mainly be dealt with in outpatient clinics. By then Hagedorn’s paternalism had turned into a more cooperative effort of teaching patients how to take care of themselves. A department of ‘Steno Education’ organizes courses and seminars for diverse (inter) national audiences and reaches out to schools, workplaces, and local communities to disseminate knowledge about diabetes.
At SDCC science and patient care still go hand in hand. The translational research is integrated within the clinic, in the Biomedical Research and within cross-disciplinary and administrative Research and Innovation departments. As fewer patients now need hospitalization, the patient section has been transformed into the ‘Steno Daghospital’ Outpatient Clinic, where physician-patient relationships are emphazised and support comes from government and the Novo Nordisk Foundation. From SDCC originated several Steno Studies, now transcending the initial focus on insulin, covering genetics, auto-immunity, and public health, and in recent years achieving much fame for the efforts of its investigators to detect and treat type 2 diabetes, now one of the most deadly killers in many parts of the world.
Allan Flyberg, Dorte Tecza, Liz Dorflinger of the Steno Diabetes Center, and Professor Bjarne Bruun Jensen, Professor Flemming Konradsen, Professor Dirk Christensen.
- Diabetes and Denmark edited by Christian Binder, Torsten Deckert and Jørn Nerup GAD Publishers, 2007.
- History of the Steno Diabetes Center :
- History of Novo Nordisk:
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ANNABELLE S. SLINGERLAND, MD, DSc MPH, MScHSR, earned her medical degree from the University of Health Services Research and Genetics from Erasmus University in Rotterdam. She has worked and collaborated internationally, and (co-) authored research articles in high impact medical journals.