Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation

Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation

Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation

ORDER CUSTOMIZED, PLAGIARISM-FREE PAPERS NOW

read and write 5 annotations

each annotation should be about 100 words

 

The Discovery and Manufacture of Insulin By Gene E. McCormick, Historian Eli Lilly and Company, 1971 At the annual meeting of the American Physiological Society held during the Christmas holidays of 1921 at New Haven, Connecticut, a young Canadian physician reported that he and an associate had isolated from the pancreas an internal secretion that lowered the blood-sugar level of depancreatized dogs to normal and that by periodic injection of the substance and special dietary measures, they had maintained the animals diabetic free for several weeks.(1) The discovery of insulin by Dr. Frederick Grant Banting and his student assistant, Charles Herbert Best, was profound at that point in time in the field of medical science. Their work conclusively demonstrated that the pancreas, by internal secretion, serves a direct function in carbohydrate metabolism, and, thus, a thirty-year search of international scope to find the elusive, hypothetical hormone was culminated. The discovery of insulin also established the unitary nature of diabetes and, consequently, brought together the observations and explorations of many who had struggled over the millenniums to understand the disease and assuage its ravages.(2) Diabetes was not a widespread disease at the time Banting conceived his surgical method of isolating insulin— Best and Banting Patient JL before and after insulin a method he was unaware others had tried. For by 1920, life expectancy was too short to manifest the major incidence of its maturity onset. But the disease was vicious and implacable. Little could be done to check the victim’s unquenchable thirst, excessive urination, gnawing hunger and gradual wasting away. Although the starvation diets devised a few years before Banting’s discovery did prolong the diabetic’s life somewhat—a little more than two years on the average— the suffering they imposed was almost as cruel as the disease itself. This was as far as the nutritional concept of diabetes therapy had evolved after 200 years of trial and error to restore balance in the bodily conversion of food into energy. In fact, until the advent of insulin, diabetes generally was a fatal disease. The body, unable to metabolize carbohydrates, turns to its fats as an energy source and, in the process of burning them in conversion, produces by-products that eventually smother internal processes. At this stage, the body is forced to derange its precious chemical balance to counteract the disruptive congestion of its environmental pathways. This radical effort to survive brings its final destruction. The heavy 1 gulping of air by the unconscious victim to expel the smothering ketones of burning fat cannot stave off the fatal coma. Thus, 50 years ago, the conquest of diabetes was defined as the prevention of coma, and the unusual severity of the disease in children gave particular urgency to that conquest. The death throes of diabetes most frequently occurred in the young. Scientists and physicians the world over fully appreciated the need of specific therapy for diabetes. As late as 1920, while many noted authorities were skeptical about the existence of an internal pancreatic secretion— and in face of the numerous failures to isolate it since the turn of the century—there were others who were intrigued by indications increasingly coming to light since the work of Oskar Minkowski and Joseph von Mering in 1889.(3) Dr. G.H.A. Clowes was among the latter, and aware of the investigation of Banting and Best almost four months before their first report to the outside world at New Haven, he was in the audience to hear what Banting had to say. Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation
Impressed by the experimental conclusiveness reported on the action of insulin and with authorization from Eli Lilly, the vice president of Eli Lilly and Company, he promptly offered to Banting and Professor James J.R. Macleod, head of the department of physiology at the University of Toronto, under whose auspices Macleod and Clowes Leonard Thompson Banting had pursued his work, the services of the pharmaceutical company for the large-scale production of the vital hormone. It was not until the middle of the following May, however, that Macleod accepted the offer of collaboration on behalf of the university.(4) Aware of the importance of the discovery of insulin to patients with diabetes, and likewise, the obligation to prevent fraudulence and exploitation, the University of Toronto had much to do before making commitments of any kind. Testing of the extract in human cases had not started at the time of Clowes’ overture; development of manufacturing procedures from laboratory methods had barely begun; and the means to administer control of product efficacy, clinical trials and licensing had to be resolved. During this period, the university took measures to establish an advisory group of its representatives and officials of the Connaught Antitoxin Laboratories affiliated with the university to oversee the development and distribution of an effective, standardized agent. It also obtained, in gratuity patent rights, that which had been applied for on insulin and its process of manufacture. Vested as an official body responsible to the university for the insulin program, the advisory group was formally established as the Insulin Committee toward the end of 1922. 2 children follow strict dietary discipline were now While these rewarded with “a hope for life, which they hardly dared affairs were in process, the first to anticipate.”(6) clinical trial of Attempts at Toronto to devise a standard extracinsulin was yieldtion procedure for large-scale manufacture were not ing encouraging successful however. From March to May, there was no results. On Januproduction of acceptable material. Dr. James B. Collip, ary 11, 1922, professor of biochemistry on leave from Edmonton Banting and his University who had been engaged by Macleod to associates at the develop process standards, declared he was unable to Medical Service of solve the problem of potency loss and instability that the Toronto accompanied increased yields and withdrew from the General Hospital, project.(7) The fact that seven diabetics were now Drs. Walter R. supported by insulin was, of course, a crucial matter. Campbell and But in the wider view, it was also important to the Almon A. university to establish reliable extraction standards for Fletcher, had the purposes of licensing—since it recognized that it had administered neither the funds nor the facilities to support the manuinsulin to Leonard facture of insulin on a scale equal to general demand. Thompson, a 14Accordingly, the university concluded that developyear-old boy ment work must now turn to outside assistance, and on Dr. Elliot P. Joslin suffering from May 15, Macleod invited Clowes to come to Toronto to juvenile (severe) diabetes. Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation
The initial injections did not discuss the collaboration proposed at New Haven.(8) produce notable response, but with the use of more Two weeks later an agreement was committed to paper potent extracts administered two weeks later, there was as an “indenture” pertaining to experimental producmarked improvement, and the boy soon was restored tion and clinical supply and was signed by the univerto normal life. He died 11 years later from bronchopsity and the company. The agreement stipulated, neumonia resulting from a motorcycle accident. among several things, that: Six additional patients were put on clinical trial as laboratory supply of the precious extract increased. In l Lilly had one year in which to develop an a preliminary report published in March, the investiga- agent complying with university standards, during which time the company had tors said, “It is difficult to put exclusive right to make, use, and into words what is meant by sell the extract in the United States, clinical improvement.”(5) Tentative though it was, the Mexico, Cuba, and Central and Latin America only advance was unique. For the first time in man’s existence, l batches of the product there was promise of liberation from this dreaded disease. acceptable to both parties on the basis of approved testing could be “With bright news from distributed on a cost basis or gratis Toronto,” said Dr. Elliott P. to physicians and institutions Joslin, eminent American selected by agreement between diabetologist, parents who had Laboratory where Banting and Best scrupulously made their both parties discoverd insulin 3 l Lilly was to provide the university 28 percent of each approved lot of insulin when distributed gratis and 12 percent when supplied at cost l all clinical reports received by Lilly were to be submitted to the university and company use of them would be governed by the discretion of the university for both professional and promotional purposes l there was to be full collaboration between the two parties on the divulgence of production methods and testing and on improvements either might make, in which case if Lilly developed patentable methods, it was to assign U.S. patents in gratuity to the university “upon being requested to do so” l after successful conclusion of the experimental period, Lilly was to be granted a license and pay a five percent royalty on net sales to the university l the university agreed not to divulge to others any information provided by Lilly within the time limit of the indenture and assured the company that the licensing of other firms would be on the same terms as it would receive.(9) In the development of safe and effective medicine, the stipulations of the agreement were without precedent and, as far as is known, signified the first voluntary, cooperative Jasper P. Scott in his laboratory endeavor among an academic institution, the medical profession, and a commercial house to apply a major therapeutic advance on an international scale. Clowes lost no time. He assigned George B. Walden, the supervisor of insulin production, and placed under him Harley W. Rhodehamel and Jasper P. Scott, thus forming a team of three to carry out the concurrent projects of experimental and factory-scale processing. Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation
(10) Based on protocols by Collip and Best— and some modifications of its own—Lilly began experimental runs almost daily during early June and on the nineteenth of that month sent Banting its first insulin, a shipment of 50 units, which he found satisfactory.(11) The first factory-scale lot was made on June 26 and the second on July 5—the latter amounting to a yield of 30 units from 75 pounds of fresh hog pancreas and a potency of one unit per cc. By the end of July, production averaged 1,200 units a week as a result of various modifications of alcoholic concentrations, temperatures, extraction steps, and lot combinations, and potencies as high as two units per cc. were being achieved. By the first of September, the company had produced a cumulative total of 5,390 units, of which 2,985 had been shipped to Toronto, or a little more than twice the percentage specified in the indenture.(12) Connaught production, on the other hand, was The Toronto agreement 4 beset with difficulties and when large-scale production would Banting visited J.K. Lilly, Sr., amply fill the needs of the 16 president of the company, in Canadian and American cliniIndianapolis in the latter part of cians now supplied by Lilly and July, he said there was not a drop the commitment to Banting of of insulin in Toronto. Now that he 500 additional units per week. had charge of a large clinic, The exhausting, frantic effort on wrote Mr. Lilly to his son, Eli, everyone’s part, however, was “He certainly was in trouble. We not rewarded. The final product had 150 units ready for him and from the new process deteriorated when I told him that he could badly—50 percent and more— take it back with him Monday which meant that, in spite of Early insulin night, he fell on my shoulder and greater yields, production would wept, and when I told him that on Tuesday evening we have to be doubled to make up the loss. In addition, would send him another 150 units, he was transported clinicians began to report extremely variable patient into the realm of bliss. Banting is really a fine chap and response to different lots and incidence of abscesses, in we must back him to the limit.”(13) duration and sensitivity at the injection site—all of which The night and day work Walden and his team had denoted a highly impure product. In an effort to overcome production problems in given to the insulin program since the first of June brought highly encouraging results by September. The general, Walden worked himself to the verge of colamount of active material being extracted reached new lapse, and Clowes insisted he take two weeks off. Scott, who took over in Walden’s absence, did suffer a breaklevels of 90 to 120 units per pound of gland and total down and remained off the job for three weeks.(14) output of September was as much as had been produced in July and August combined. In August, equipBecause of all the setbacks, J.K. Lilly, Sr., instructed ment for large-scale Clowes to release Walden from experiproduction had begun to arrive and mental work and Rhodehamel—who assign him excluhad been bending sively to pressing full-time effort production needs. toward layout of Clowes also decided facilities in Building to return to the initial 20—was busy with extraction protocol installation that, since house samples hopefully, would be from that process in regular operation had retained full by the first of Octopotency since June. ber. It was expected It was believed that, based on the that the problem of experience of prevideterioration in the ous increasing yields large-scale method and potencies, the was the cumulative output from the result of errors not shakedown phase of unlikely to occur in Harley W. Rhodehamel George B. Walden 5 initial development attempts. Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation
In sible. A way had been found to brief, Lilly was encountering the achieve high purity with large same difficulties that had hayield.(15) rassed Collip and which were What Walden unearthed in still frustrating production at the exasperating month of Connaught. It was apparent to September 1922 was followed by both parties that potency loss in many weeks of trial and error in the final product had to be application before the highly surmounted before production pure material could be produced and clinical work could be in large volume. But in early advanced. 1923, production problems had Out of this necessity came a been largely overcome. By April startling revelation. In noting that of that year, the weekly rate was stability was dependent upon the running at a little more than hydrogen ion concentration of 180,000 units—a sharp contrast to the solution from which the final the 2,500 rate seven months product was obtained, Walden earlier. Potency also had risen to discovered that most of the 20 units or more per cc. deterioration did not result from Such progress did not come Grinding glands c. 1924 destruction of the insulin horwithout financial burdens. A mone in processing but rather from the slow formation large investment had been made without assurance of of the precipitate in the final product solution. These returns for some time or of protection against obsolesdeterminations were fundamental and, moreover, cence. The matter of arranging for and maintaining radical, for they revealed that insulin activity was not in proper icing of glands at a time when artificial refrigthe solution—the premise upon which both Connaught eration was still in its infancy imposed heavy costs in and Lilly extraction methods were based—but in the shipping and storage. To assay insulin required many very precipitate heretofore considered a contaminant hundred rabbits, and yet the few animal suppliers there and discarded during the extraction process. Carrying were could not consistently provide animals of uniform this finding further, Walden found that the rate and size and weight or assure normal health—factors that extent of the formation of the hormone-bearing precipi- vitally affected test data. And feeding and caring for the tate was governed by the hydrogen-ion concentration of animals under proper conditions required special provisions on a scale the company had never faced the solution, and this suggested that, by pH adjustment before. During the latter half of of the solution, an optimum point 1922, more than 100,000 rabbit could be established at which the assays were conducted. insulin hormone would split off Determination of the value from the bearing precipitate. In of the unit of insulin, highly other words, it was discovered complicated by wide variability that iso-electric precipitation of animal response, was a subject could be employed for the of great debate between Lilly and purification of insulin. Discovery of Insulin Therapy for Diabetes Fraudulence & Exploitation
Its nitrothe Insulin Committee over a gen content could be significantly period of several months. While reduced, and equally important, as high as a 90 percent recovery it was not technically possible at of insulin activity became posthe time to derive precise value— First insulin products 6 which was the crux of the debate—it, nevertheless, was a over which it was to exercise authority. The desire of the committee to have this priority was fully apprecibasic factor interlocking the economics of yields, capacity projections, and future facility demands. In the ated by the Americans and carefully observed throughout the clinical program. first six months of production at Lilly, unit standards On November 22, 1922, a roundtable meeting were modified four times. Believing it had absorbed all was held at Toronto, attended by the Canadian clinithe expense it could, the company requested and cians, members of the Insulin Committee, representaobtained Toronto’s approval to sell insulin to clinicians tives of Connaught and Lilly, and six American physiat cost, and distribution on this basis began in late January 1923.(16) Shipment was direct to physicians, but cians—all noted authorities on diabetes management—to plan distribution control billing was handled through procedures, special studies, the drug trade in keeping and unit standardization. The with the company’s estabAmerican doctors overseeing lished policy. At the time, clinical work in the United Lilly was supplying sixty States in liaison with the clinics in Canada and the (17) Insulin Committee were: United States. The extension of the l Dr. Elliott P. Joslin, clinical program to this Boston level within a year after the first administration of l Dr. Frederick M. insulin by Banting seems Allen, Morristown, New remarkable considering the Jersey (after whom the Allen small output of insulin Era of dietary management, during the period. All Insulin filling line c. 1924 1914-1921, was named) clinical work had been dependent upon insulin from Lilly until the end of 1922, l Dr. H. Rawle Geyelin, New York (an authorwhen Connaught Laboratories finally overcame equipment problems and swung into initial mass production. ity on juvenile diabetes) Considering, too, that unit potency was low, relatively l Dr. John R. Williams, Rochester, New York large daily dosages were necessary to maintain a (the first American physician to use Banting’s extract) patient. Since the action of the hormone was not a precisely known entity, much precaution had to be l Dr. Rollin T. Woodyatt (a brilliant clinician taken in selecting physicians for clinical work. Assignfrom Chicago) ment of specific investigators to hospital-affiliated laboratories in major urban areas had to be planned in l Dr. Russell M. Wilder, of the Mayo Clinic, order to gather data most efficiently from a limited Rochester, Minnesota. supply of insulin. The value of the unit, based on the original rabbit assay unit, also had to be raised to better It was at this meeting that clinical trial developi…
Get a 10 % discount on an order above $ 100
Use the following coupon code :
SAVE10