On Christmas Day, 1921, Dr. George H.A. Clowes boarded a train in Indianapolis, Ind., bound for New York City, and then transferred to another to New Haven, Conn., where he planned to see a presentation entitled, “The Beneficial Influences of Certain Pancreatic Extracts on Pancreatic Diabetes.” It was to be given on December 30th by Banting, Best and Macleod at the American Physiological Society’s annual meeting. Dr. Clowes was the research director of Eli Lilly and Company, a pharmaceutical firm located in Indianapolis. He had recently heard about some interesting research being done in Toronto in the University of Toronto’s physiology department and headed by Macleod. Clowes and Macleod were acquainted, but it was through a U of T graduate who had moved to the U.S., Dr. Lewellys Barker, that Clowes first learned about the Toronto diabetes research. If this work was being overseen by someone with Macleod’s credentials, Clowes felt, he was confident in its significance and determined to get to New Haven, even if it kept him from his young family over Christmas.
Clowes had joined Eli Lilly in 1919 as a special research chemist and was appointed director of research in 1920, which, at the time, was an unusual position within a commercial pharmaceutical company in the U.S. However, after the First World War, Eli Lilly’s leadership decided to strengthen the firm’s connections to the scientific community, although relationships between the worlds of commercial industry and academic research labs were traditionally avoided. Despite that, productive bridges between these worlds had been built in Europe and accelerated during the war. So it made sense, amidst the progressive spirit of the period, for Eli Lilly to lead in a similar bridge-building initiative in the U.S.
Eli Lilly was founded in 1876 by Colonel Eli Lilly in Indianapolis as an integrated manufacturer and wholesaler. It grew rapidly after 1898 under the leadership of Eli’s son, Josiah Kirby Lilly, Sr., who presided over some 50 years of considerable growth, innovation and modernization. J.K. Lilly had graduated from the Philadelphia College of Pharmacy and returned to the family business excited and prepared to place the pharmaceutical industry on an equal footing with medicine. By the early 1900s, Eli Lilly was a family-owned “ethical” drug company, operating under a policy of advertising and selling only to doctors and pharmacists. It made neither “patent medicines,” nor extravagant claims about its products. Among Lilly’s most popular products were Charcoal Lozenges for indigestion, Cape Aloes for constipation, Passolaria for insomnia and anxiety, Liquid Blaud for anemia and Elixir #63 (which contained catnip and fennel) for colds, headaches, colic and fever.
By the 1910s, Eli Lilly was one of the first pharmaceutical firms to comply with the U.S. Food and Drug Act, led in applying scientific management principles, and actively hired botanists, chemists, pharmacologists, biologists and clinicians to support a growing commitment to research. One of the company’s key priorities was the development of a variety of glandular extracts. Hiring Clowes gave greater legitimacy, focus and direction to Eli Lilly’s commitment to research at a critical time.
George Clowes was born in England in 1877 and earned a Ph.D. in chemistry in Germany. He did his postdoctoral studies in England and France before seeking greater scientific research opportunities in the U.S. He had a restless curiosity about all kinds of knowledge, but was particularly interested in studying cancer, and spent several years at a state research institute in Buffalo, N.Y. Clowes’ background and research work, some of which he conducted at the Marine Biological Laboratory at Woods Hole, Mass., as well as his British and European connections and his gregarious temperament, attracted the attention of J.K. Lilly, who was looking for someone to lead the company’s post-war research plans. After his promotion to director of biochemical research, Clowes had ample access to lab facilities and staff, and the freedom to pursue avenues of interest in all sciences.
He split his time between Indianapolis and Woods Hole. In fact, Clowes’ position at Woods Hole provided Eli Lilly with a research lab located near several university labs operated by Stanford, Harvard, Yale and a variety of other schools. Through his appointment at Woods Hole, Clowes had plenty of opportunities to expand his network of medical contacts, which would include Macleod and Barker, as well as J.B. Collip, who spent some of the summer of 1921 doing research at Woods Hole.
Banting struggled through the December 30th presentation in New Haven, and Macleod felt compelled to step in to answer questions. Still, Clowes was quite impressed with Banting and the significance of what he and Best had accomplished. As Clowes later wrote, “It is true that Banting presented his material somewhat haltingly and certainly very modestly. However, anyone who was at all cognizant with the subject must have realized that a great discovery had been made and that provided the work could be brought to fruition there was every prospect that an important means of treating diabetes would be developed.”
After the session, Macleod introduced Clowes to Banting and Best, and they had several discussions that day and the next. As he later recalled, Clowes pointed out “that before long their problem might well be one of large-scale production, in which case they would need the help of chemical engineers, who were not to be found at that time in any university group.” Before leaving New Haven, Clowes left a note with Macleod offering the assistance of Eli Lilly. But Macleod politely declined, noting that the work was not yet sufficiently advanced for commercial preparation. Moreover, the University of Toronto did have the Connaught Antitoxin Laboratories, as well as some chemical engineers.
Back in Indianapolis, Clowes kept an eye on news from Toronto and likely saw the March 22, 1922, Toronto Star feature, “Toronto Doctors on Track of Diabetes Cure.” On March 30th, Clowes wrote a letter to Macleod, re-affirming Eli Lilly’s interest in assisting in developing methods to produce the extract on a large scale. As he emphasized, “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 products by means of such tests as you and your associates would consider necessary.”
Clowes was anxious to see the development work move forward, but, as he emphasized to Macleod, he did not want to intrude on the research taking place in Toronto until results were published. “I have thus far refrained from starting work in our laboratories.” “I feel,” Clowes continued, “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.”
Clowes initially seemed unaware of the significant role Connaught Antitoxin Laboratories had been playing in developing production methods since January. In replying to Clowes on April 3rd, Macleod emphasized that the Toronto group had decided “we would rather carry the thing as far as we can ourselves here and then publish all we know.” Clowes understood Macleod’s position, but hoped Eli Lilly would be able to contribute soon. By early May, when Connaught’s insulin production was back on track after interruptions earlier in the year, pressure on Macleod intensified to expedite and expand production, especially after his May 3rd presentation at the Association of American Physicians annual meeting in Washington, D.C., which Clowes attended.
The meeting was a triumph for the Toronto group, although Banting and Best did not attend due to the expense of the trip. The focused attention on Macleod during and after the meeting that Banting heard about added to his simmering distrust of his collaborator. Clowes sensed the tensions between the two men and after the May 3rd meeting made a concerted effort to build cordial relationships with both. With Banting, it was more personal and friendly, and with Macleod, professional and scientific. To Banting, Clowes sent kind and congratulatory notes and telegrams, as well as friendly invitations to visit Indianapolis and Lilly’s labs in Woods Hole. He also offered unrestricted amounts of insulin for the treatment of his patients. To Macleod, Clowes engaged in professional dialogue with detailed letters of support, inquiry and encouragement of U of T’s leadership in managing the development of insulin.
On May 11th, Clowes wrote to Macleod, concerned about patents for insulin and the necessity of starting on the problem of large-scale production as soon as possible. A few days later, Macleod invited Clowes, along with several others from Eli Lilly, to Toronto to give a presentation on how the company could be of assistance. The Eli Lilly delegation of Clowes, chemist, Harley W. Rhodehamel, patent attorney George B. Schley, and vice-president Eli Lilly, arrived in Toronto on May 22nd for a series of meetings over three days at the King Edward Hotel. The meetings led to a unique agreement, a key part of which was that a temporary exclusive license be given to Eli Lilly. The company was prepared to invest $250,000 in the development of large-scale production methods, which represented 6% of the firm’s capital. (In today’s currency, that sum would be equivalent to $3.2 million.) Clowes had initially asked for exclusive rights for two years, but ultimately the Lilly team agreed to an exclusive one-year “experimental period” licence limited to the U.S. and Central and South America.
As well, there was to be a complete pooling of knowledge between the Toronto and Indianapolis groups and a several-stage development of insulin that would involve large-scale clinical tests in Toronto and the U.S., with Eli Lilly supplying insulin free of charge in the initial stages, and then selling it at cost. The Lilly group agreed not to divulge production process details to anyone else, although the contract did not place such restrictions on the Toronto team. They intended to publish Connaught’s method in order to ensure others would know how to make insulin when Lilly’s exclusive rights expired, and to protect themselves from potential charges of unethical secrecy. This collaboration was formally established with an “Indenture” between the U of T Board of Governors and Eli Lilly signed on May 30, 1922.
The team at Eli Lilly began its work immediately, led by George Walden, Harley Rhodehamel and Jasper P. Scott, as well as Eda Bachman, a chemist who would later marry Walden. George Walden was an analytical chemist in organic research who had joined Eli Lilly in 1917; as Clowes noted, he was “not just a chemist but a chemical engineer,” which was “a great rarity” in university labs at the time. Walden had also studied electrical engineering and after a year of war service, focused on Lilly’s research program on vitamins, hydrogen peroxide and the analysis of the company’s existing lines, which included more than 20 glandular products. Walden’s research with Bachman also included a basic science program focused on determining the isoelectric points of materials in several of Lilly’s products.
(The isoelectric point was a well-known chemical principle, defined by the pH of a medium at which a protein carries no net charge and thus will not migrate in an electric field. Proteins precipitate — fall out of solution — most readily at their isoelectric points, a property that can be utilized to separate mixtures of proteins or amino acids.)
Rhodehamel had joined Lilly as a biochemist in 1907 and worked on the first standardized vitamins and various synthetic organic compounds and was among the first Eli Lilly delegation invited to the Toronto meetings in late May. Jasper Scott, like Walden, had a background in chemistry and after Navy service during the war, joined Eli Lilly as a research chemist in 1920.
The Lilly team’s first task was to repeat the small-scale insulin production experiments led by Collip and Best, and also focus on scaling up, with both lines of work going on in tandem. This process depended on direct input from Collip and Best, who spent June 2nd and 3rd in Indianapolis. Best would be a frequent visitor to Indianapolis, making nine train trips during June to consult with Clowes and the Eli Lilly insulin team. After he arrived in Indianapolis on June 1st, Best wrote to his fiancée, Margaret Mahon, and remarked about the luxury of his accommodations at the Claypool Hotel, which had “a private bath and all conveniences.” More significantly, he told her that Lilly had “a very large and well-equipped plant here.”
During that initial trip to Eli Lilly, Collip and Best oversaw Lilly’s first laboratory-scale run of insulin. There were daily runs that followed, but the greater challenge was large scale production. Collip and Best shared all they had learned at Connaught with Walden and the other Lilly chemists. Lilly’s first large-scale lot of insulin was completed on June 17thand on June 19th, the company sent its first insulin shipment to Banting, totaling 50 units. Best also brought back to Toronto valuable practical advice to solve a variety of Connaught’s insulin production challenges.
Eli Lilly, the company vice-president, was very pleased with the progress that had been made, as he told Macleod in a June 17th letter. “Our chemists have been working very intently on the production of insulin, and have gotten a good deal of experience, and at last have turned out about 20 doses of something that approximates very closely the material made in Toronto.” But he asked Macleod to send ten doses of Connaught’s product so that the team at Lilly could compare the preparations. Lilly was also anxious to receive the official signed indenture agreement between his firm and U of T. On June 28th, Macleod replied to say the agreement would be signed and sent the next day; there had been some difficulty getting the members of the Board of Governors together at that time of year. Macleod was happy to hear about the progress in Indianapolis and hoped that this collaborative enterprise would be so successful as to drown all possible criticism.
Indeed, by July 3rd, Best was sufficiently confident in the stability of Connaught’s insulin production to take a much-needed break and visit his family in Maine. Just before he left, Eli Lilly’s first official shipment of “Iletin” arrived, ten 5 c.c. vials, for testing at U of T’s physiology department. After the rabbit potency tests were passed, Best immediately took four vials to Banting’s clinic, followed by another two vials, which were delivered by George Eadie, who was conducting the tests because the clinic was so short of insulin. Dr. R.D. Defries, Connaught’s assistant director, asked that all future shipments from Lilly be sent directly to Banting’s clinic, as long as a sample was sent to the physiology department for testing. On July 5th, Lilly completed its second factory-scale production run of insulin, yielding about 30 units from 34 kg of pork pancreas. During June and July, almost all of Lilly’s insulin output was sent to Banting.
With Best on holiday, David A. Scott led Connaught’s insulin operations and faced some unexpected challenges trying to increase the scale of production. Arthur Wall, a senior technician at Connaught, kept Best up to date with regular reports, noting completed lots, but also news of reactions to some injections, mostly abscesses, that seemed to resolve after an additional washing and centrifugation process (although this took extra time). Of particular concern was procuring a steady supply of pancreas, especially from a local abattoir, known as Harris.’ The manager wanted to get a better price for what had formerly been worthless pancreas glands. Connaught’s demand for pancreas had created a new market that this one firm felt the need to exploit. Indeed, Harris planned to send all of its animal glands to England, packed in ice. Fortunately, by July 12th and 13th, Scott and Wall were able to turn to another source, the city-owned Civic Abattoir, to secure pancreas tissue. As Wall reported to Best, “They showed great willingness to give us the glands, but conditions there are not the best for collecting (entrails fall on the floor).” Connaught also faced a shortage of acetone, which was also critical to insulin production.
The insulin production crisis in Toronto that summer kept growing. As Banting wrote to Best on July 10th, “You are lucky to be out of the heat that prevails here at present, and even worse than the heat as a disturbance is that diabetics swarm around from all over and think we can conjure the extract from the ground.” A few days later, Clowes informed Macleod that Eli Lilly’s small-scale method was giving good results and hoped to maintain limited but steady production with this method as the company built a larger production plant.
Clowes also noted that Banting was getting good results with Lilly’s insulin on the diabetic cases he was treating. He said Eli Lilly would continue to supply insulin to Toronto and hoped to soon start clinical work with several diabetic specialists in the U.S., particularly Dr. Joslin in Boston, Dr. MacDonald in Indianapolis, Dr. Williams in Rochester, and Dr. Woodyat in Chicago. To further discuss the clinical plans, Clowes planned to visit Toronto on July 16th to meet with Banting and visit Connaught.
When he arrived in Toronto, Clowes was surprised to hear about Connaught’s production problems and visited the Labs just as the pancreas supply challenges had become critical. As Wall informed Best in a July 17th letter, “Work here had been going along well until Thursday afternoon when we had two weak lots in succession. This put us out a little, but Sunday’s extract was OK so have quit worrying.” However, he added, “Harris’s shut down on us this morning. They have a couple of girls collecting the glands and packing them in ice.” There was then a scramble to get more pancreas from three other local abattoirs. “We are getting so little pancreas that it is a mighty difficult job to keep the regular patients going. But trust me to get it somewhere. What do you think about paying for the glands?” Wall suspected that if they had paid the price Harris wanted, they would not have lost this reliable source of supply. Wall also told Best of Clowes’ visit, “but he refused to tell anything of [Lilly’s] process, beyond that they placed acetone a second time on the minced glands. Also, they were pig’s glands. Were they not supposed to co-operate with this Lab in making the Xtract?”
To help meet Banting’s immediate needs, Clowes wired Eli Lilly to expedite sending more insulin. He also made some suggestions to Connaught’s chemists. They could improve their yields by evaporating the alcohol at lower temperatures, discontinue use of a makeshift wind tunnel evaporation method, and instead use a vacuum distillation system with which Lilly had been successful. In the midst of the breakdown of Connaught’s insulin production, due as much to pancreas and acetone supply shortages as production technology, the idea of scrapping one production method for another was very daunting for the Toronto team, particularly in the absence of Best until August 1st. Macleod was also away, doing research at the Marine Biological Station in New Brunswick. Connaught’s director, Dr. J.G. FitzGerald was in the U.K. and Dr. Defries, assistant director, had also been away, leaving Dr. Donald Fraser in charge of the Labs.
After Clowes’ Toronto visit, he wrote to Best on July 26th, noting the suggestions he had made to Banting and Fraser about how to reduce the impurities causing reactions. “I understand that you intend to return to Toronto August 1st and am glad to hear that you will be in charge of production of Insulin for the Connaught Laboratory.” Clowes suggested they meet in Boston when Best was on his way back to Toronto “so that we may have a chance to talk over the latest developments in Indianapolis and make some plans for the future.”
However, Best had already heard about Clowes’ Toronto visit through a July 21st letter from Banting: “Dr Defries was down yesterday and we had a meeting and decided that Scott and I should go to Indianapolis. We had a letter from Dr. Clowes in which he said that we should almost ‘scrap’ our plant and install a vacuum system. I am having a copy forwarded to you. We thought it better to go to Indianapolis because I have a hunch that Clowes, since he would not tell us how that batch was made, is holding back a little, and furthermore since the extract we are making here is pretty rough I think they might supply us with more of theirs, for the patients are needing extract very badly.”
Banting also mentioned that Defries was taking up the pancreas supply problem and getting a legal opinion on how to best deal with abattoirs. He also noted that Dr. Peter Moloney was now working on the chemistry and refining, while David Scott was doing his best with the production.
Banting and Scott’s urgent trip to Indianapolis on July 23, 1922, signalled a new phase in the unique collaborative effort between Connaught and Eli Lilly to figure out how make insulin on a large scale.
Note: The author would like to acknowledge the work of historian, Kathi Badertscher, Ph.D. of the Lilly Family School of Philanthropy, Indiana University, Indianapolis, IN. We have worked together on a research project focused on the insulin development partnership between Eli Lilly & Co. and the University of Toronto. Kathi’s documentation of the history of Eli Lilly has been helpful to the preparation of this article.