Schack August Steenberg Krogh. The Nobel Prize.

Just a day before Dr. Frederick Banting was struck with the late-night idea that would lead to his Nobel Prize for discovering insulin, Professor August Krogh, in Copenhagen, Denmark, was celebrating news of his own Nobel. During the first decade of the 20th century, Krogh was one of the world’s best-known biomedical scientists thanks to his fundamental research into how the body absorbs oxygen and eliminates carbon dioxide. Krogh’s Nobel Prize for Physiology and Medicine was awarded for his work with capillaries and their role in regulating blood flow during exercise. It was the first such Nobel awarded since 1914. This honour led to an extensive lecture tour in the United States during the fall of 1922 that Krogh enjoyed with his wife, Marie Krogh, a scientist in her own right, and also a recently diagnosed diabetic. The Kroghs’ travels brought them to Boston in early October, where they met Dr. Eliot P. Joslin, one of the world’s leading diabetic specialists. At a private dinner, Joslin told Marie about the discovery, development and purification of insulin in Toronto.

Marie Krogh’s diabetes had been diagnosed by Hans Christian Hagedorn, a young Danish physician specializing in the condition. In 1918, he had worked with a local pharmacist to develop a method for determining blood sugar levels using very small samples of blood drawn from the earlobe. Hagedorn and August Krogh met at a conference, where they forged a close friendship. During 1919 and 1920, Hagedorn closely followed developments in diabetes research, publishing a paper on the Allen-Joslin treatment and, in 1921, completing his Ph.D. thesis on blood sugar regulation. It was sometime in 1921 or early 1922 that Hagedorn diagnosed Marie Krogh’s diabetes, but her condition was kept secret beyond her immediate family.

Marie Krogh.

Marie Krogh was thus especially intrigued to hear from Joslin about the dramatic clinical effectiveness of insulin and recent advancements in purification. She had been aware of the initial insulin development. Upon hearing directly from Joslin about the recent clinical work, she wanted to take advantage of her trip to North America in order to visit Toronto and learn more in hopes of somehow making insulin available in Denmark. Marie was aware that an arrangement had been made with the Medical Research Council to facilitate insulin production in the United Kingdom. Joslin told her that other doctors in Boston had received doses. “There is a possibility that you, too, might get some,” he said. 

Marie then wrote to Hagedorn and sent details of what she’d learned about insulin, although she remained somewhat skeptical. As August’s lecture tour continued through October, news about insulin could not be avoided and Marie became increasingly excited about its possibilities. She visited diabetic clinics and heard more about the use of insulin and also how the chief of a sanatorium in Battle Creek, Michigan, had visited Toronto to learn the method for preparing insulin so the facility’s staff could make it themselves. 

As Marie told Hagedorn, “Since I think that you, from a theoretical as well as a practical point of view, will be interested in this preparation, I have persuaded my husband to write to Dr. Macleod in Toronto and ask him if it is possible to get the production method so that it could be possible for you to make experiments with the preparation in Denmark.” Interestingly, in all of Marie’s correspondence about insulin, she made no reference to her own diabetes, nor did she mention the names of Banting and Best. 

Hans Christian Hagedorn. Novo Nordisk.

On October 23rd, August Krogh wrote to Macleod, telling him of his U.S. lecture tour. “I have been hearing everywhere about the experimental treatment of diabetes with insulin and I have been wondering if perhaps it might be consistent with the plan of yourself and your collaborators to have experiments carried out in Denmark also.” He noted that Dr. Hagedorn was a frequent guest in his lab and “a very competent investigator and specialist in diabetes. He has done some very good work which has unfortunately so far only been published in Danish. He has worked out and thoroughly tested a new micro-method for blood sugar determination, which I think is the best in existence.” 

Later in his letter, Krogh told Macleod that Hagedorn “would be able to do very good work with the insulin and I would, of course, be willing to undertake any supervision which you might desire.” To ensure sufficient quantity and reliable quality, Krogh noted his lab had “at least one organic chemist with considerable experience in preparative work who would be able and willing to undertake the preparation of insulin for our own use, if you would give us the necessary directions.” Furthermore, Krogh was confident “The pancreas material and the money would, I have reason to believe, be easily obtainable in Denmark.” Krogh asked if it would be possible to visit Toronto at the end of November after a lecture in Cleveland. “I do hope that it will be found possible to extend to Denmark the privilege of taking part in the work of delivering this wonderful new discovery.”

Macleod was delighted to have the Danish scientists visit Toronto, which was arranged for November 23-25, and, as he replied to August Krogh, “to have your department take up some work on Insulin, particularly since it will be put in charge of Dr. Hagedorn, with whose work, of course, I am familiar.” He added, “I should like very much to go over our Insulin work with you and get the benefit of your advice and cooperation.” While in Toronto, the Kroghs stayed at Macleod’s home and spent considerable time in meetings with Macleod and Banting. August also delivered a guest lecture on capillaries and left for home with formal authorization from the University of Toronto Insulin Committee to introduce insulin to Scandinavia. 

In a 1924 article, “Insulin: A discovery and its significance,” Krogh wrote of his time in Toronto: “I was received with the greatest kindness from all sides. I got an opportunity to see not only the insulin production and standardization, but in addition they reviewed for me the methods then used in treatment with insulin. I was invited to be present at meetings between clinicians, leaders of the insulin production and the insulin committee. At the time the difficulties in producing insulin from mammalian pancreas was very much on their minds since not only quantitatively but also qualitatively the insulin production left much to be desired.”

While Krogh agreed with the principles established by the Insulin Committee, and initially thought that he could take out a patent and be delegated control of insulin production in Denmark, he soon realized that had to decline any patents. “This was not possible,” he informed Macleod, since medicines could not be patented in Scandinavia. However, to ensure quality control of insulin, Krogh maintained that he must hold the exclusive rights in Denmark, Sweden and Norway, as he did not want to get into any kind of race with other companies in the region to prepare and market insulin. Krogh told the Insulin Committee that he was confident that by announcing to the Scandinavian medical community that he had the authority to prepare insulin for the region, he would deter the emergence of possible competitors. 

August and Marie Krogh. Novo Nordisk.

August and Marie Krogh returned to Denmark on December 13, 1922. The next day, August met with Hagedorn and others to discuss how best to move forward with producing insulin. They first had to familiarize themselves with the production process and standardization from the materials provided by Macleod and Connaught Laboratories. They also needed money. Instead of asking the Danish government for funds, which would have taken too long, they approached a private pharmaceutical company, Løven’s Chemical Company (also known as Leo Pharmaceutical Products), to establish a partnership. Marie had worked with Løven’s before. The firm’s owner, August Kongsted, was willing to pay the costs incurred for the experimental work, and then for starting insulin production, provided the first insulin product be called “Insulin Leo.” By December 21st, after further production details were provided by Macleod, and August Krogh and Hagedorn had hired pharmacist, Norman Jensen, the Danish group prepared their first experimental insulin using shark and beef pancreas. This initial work took place at Hagedorn’s house as well as at Krogh’s Institute, the Laboratory of Zoophysiology.

On January 2, 1923, August Krogh gave his first public talk about insulin, noting that he would be setting aside his own research work “to promote this matter with the greatest strength possible.” He highlighted the role of Løven’s in manufacturing insulin as soon as possible. “The price will here as in America be set as low as it possibly can.” “Naturally,” he continued, “I must warn you that it may take several months, possibly a whole year, before insulin becomes available to the clinicians.” There were “great difficulties” associated with insulin production, “and before it can be factory produced the necessary machinery and other materials must be procured.” Therefore, as he emphasized, “I ask you however, to rest assured that we will spare no effort in as fast as possible producing a non-toxic and effective preparation in such amounts that the therapeutic use can begin.” Intensive work continued through January, during which production focused on using pig pancreas instead of shark, which was in short supply. Denmark had a large pork processing industry, which provided plenty of pancreas tissue. However, as pig pancreas was richer in fat than beef or shark pancreas and contained a potent trypsin, an additional boiling of the pancreas in alcohol process was required.

By March, as insulin production increased, the first diabetic patients were treated, although not always successfully. However, Hagedorn wrote about one nine-year-old diabetic girl who received insulin: “… this child, who was previously very quiet, has become lively and alert, almost uncontrollable.” As in Toronto during the initial production and use of insulin, there were hectic and terrible days with diabetics dying for want of insulin. Hagedorn and Krogh were approached by many people pleading for insulin, but they had to be strict and ensure that once a patient began insulin treatments there would be enough to continue, even if production lapsed. 

By the spring of 1923, insulin production was increasing sharply, especially as a new and larger production facility was utilized. In May, August Krogh and Hagedorn, along with August Kongsted, founded the “Nordisk Insulinlaboratorium” as part of the Løven Chemical Company. To facilitate the export of insulin, Krogh, Hagedorn and Kongsted then established an independent company for the distribution of “Insulin Leo,” which could also be supplied to hospitals in tablet form so it could be dissolved in sterile saline for injection.

Despite the progress, there were still impurities in the Nordisk insulin. In October 1923, assistance with further improvement came when Thorvald Pedersen was hired. Thorvald was the brother of the head machinist at Krogh’s Zoophysiological Lab, Harald Pedersen, who had built a machine that could shave slices of frozen pancreases. The shavings fell into ice-cold acid alcohol to expedite insulin extraction. In addition, Harald’s daughter was hired to help with insulin standardizations. The addition of the Pedersens to the Nordisk staff gave a significant boost to the purity and output of Insulin Leo, bringing the Danish insulin to a level of mass production approaching that of Eli Lilly and insulin produced in Britain.

However, the Scandinavian insulin situation changed rather abruptly in the spring of 1924 after Thorvald Pedersen and Hagedorn had a falling-out. It was no secret that Hagedorn and Krogh could be difficult to work with and a clash with Pedersen was not surprising. The particular reason or reasons for the conflict are not recorded, but the tensions led to Hagedorn firing Thorvald. This situation became more significant when Harald Thorvald and his daughter abruptly left Krogh’s lab, and with Thorvald, started producing insulin in their own basement. 

When Hagedorn and Krogh hired Thorvald, he had signed a declaration promising he would not use what he had learned about insulin production for competitive purposes. However, his brother and his daughter were not asked to sign any documents and felt free to use what they’d learned from Thorvald and their own experience to produce insulin. Thus, the two Pedersen brothers, together with other members of their family, started producing their first stable vials of “Insulin Novo” in 1924. Harald Pedersen also designed a special syringe, known as the “Novo Syringe,” which ensured that patients could easily self-inject correctly dosed insulin. However, the Pedersen brothers had limited marketing experience. After an offer of cooperation with Krogh and Hagedorn was rebuffed, they decided to proceed on their own. As was described in a February 16, 1925, letter to Danish pharmacists, the Pedersen’s new firm would be called “Novo Terapeutisk Laboratorium” and it would now be offering Insulin Novo and the Novo Syringe for sale.

There seemed little Krogh and Hagedorn could do about the emergence of rival insulin producers in Scandinavia. The situation put Krogh in an awkward position with respect to the medical profession, the public, and with the discoverers of insulin in Toronto, to whom he had expressed confidence in controlling insulin production in Scandinavia. However, when Krogh told Macleod about Pedersen’s efforts, as well as those of another former assistant, Gad Andersen, to establish their own insulin production operations, Macleod told him not to worry. He was confident that the others would never be able to produce insulin as pure as Krogh and Hagedorn’s. Still, Krogh remained concerned that competition in Scandinavia would ultimately lead to the end of local production in the face of much greater competition from the insulin producers in England and America, with their large and secure domestic markets.

In the meantime, Krogh and Hagedorn established Nordisk Insulin Laboratory in July 1924, as an independent institution by royal charter, with Hagedorn as director. Insulin production flourished in Denmark, with “Nordisk Insulin” produced at a lower cost than anywhere else in the world except the insulin produced by Connaught Labs in Toronto. The profits from Nordisk’s sales were directed to the Nordisk Insulin Foundation, set up in December 1926, to support scientific and clinical studies in physiology, endocrinology and metabolism (August Krogh was its first chair). Nordisk’s head start with insulin production and distribution enabled it to become well established across Scandinavia before Novo began operations. Novo’s growth strategy thus became focused primarily on serving export markets in Europe and beyond. Both companies grew rapidly and remained rivals over subsequent decades. In 1989, they merged to form Novo Nordisk Pharmaceuticals Inc., becoming the largest producer of insulin and diabetes care products in the world.

Novo Terapeutisk Laboratorium, c.1920s. Novo Nordisk.
Nordisk established its first factory buildings in Gentofte, 1927. Novo Nordisk History, Novo Nordisk.