The Discovery and Manufacture of Insulin
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The Discovery and Manufacture of Insulin
By Gene E. McCormick, Historian
Eli Lilly and Company, 1971
At the annual meeting of the American Physiologi-
cal Society held during the Christmas holidays of 1921
at New Haven, Connecticut, a young Canadian physi-
cian 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, hypo- Patient JL before and after insulin
thetical hormone a method he was unaware others had tried. For by
was culminated. 1920, life expectancy was too short to manifest the
The discovery major incidence of its maturity onset. But the disease
of insulin also was vicious and implacable. Little could be done to
established the check the victim’s unquenchable thirst, excessive
unitary nature of urination, gnawing hunger and gradual wasting away.
diabetes and, Although the starvation diets devised a few years before
consequently, Banting’s discovery did prolong the diabetic’s life
brought together somewhat—a little more than two years on the average—
the observations the suffering they imposed was almost as cruel as the
and explorations of disease itself. This was as far as the nutritional concept
many who had of diabetes therapy had evolved after 200 years of trial
struggled over the and error to restore balance in the bodily conversion of
millenniums to food into energy.
understand the In fact, until the advent of insulin, diabetes gener-
disease and as- ally was a fatal disease. The body, unable to metabolize
suage its ravages.(2) carbohydrates, turns to its fats as an energy source and,
Diabetes was in the process of burning them in conversion, produces
not a widespread by-products that eventually smother internal processes.
disease at the time At this stage, the body is forced to derange its precious
Banting conceived chemical balance to counteract the disruptive conges-
his surgical method tion of its environmental pathways. This radical effort
Best and Banting of isolating insulin— to survive brings its final destruction. The heavy
1
gulping of air by the unconscious Banting had pursued his work,
victim to expel the smothering the services of the pharmaceuti-
ketones of burning fat cannot cal company for the large-scale
stave off the fatal coma. Thus, 50 production of the vital hormone.
years ago, the conquest of diabe- It was not until the middle
tes was defined as the prevention of the following May, however,
of coma, and the unusual severity that Macleod accepted the offer
of the disease in children gave of collaboration on behalf of the
particular urgency to that con- university.(4) Aware of the impor-
quest. The death throes of diabe- tance of the discovery of insulin
tes most frequently occurred in to patients with diabetes, and
the young. likewise, the obligation to pre-
Scientists and physicians the vent fraudulence and exploita-
world over fully appreciated the tion, the University of Toronto
need of specific therapy for had much to do before making
diabetes. As late as 1920, while commitments of any kind.
many noted authorities were Testing of the extract in human
skeptical about the existence of cases had not started at the time
an internal pancreatic secretion— of Clowes’ overture; develop-
and in face of the numerous ment of manufacturing proce-
failures to isolate it since the turn Macleod and Clowes dures from laboratory methods
of the century—there were others had barely begun; and the means
who were intrigued by indica- to administer control of product
tions increasingly coming to light efficacy, clinical trials and licens-
since the work of Oskar ing had to be resolved.
Minkowski and Joseph von During this period, the
Mering in 1889.(3) Dr. G.H.A. university took measures to
Clowes was among the latter, establish an advisory group of its
and aware of the investigation of representatives and officials of
Banting and Best almost four the Connaught Antitoxin Labora-
months before their first report to tories affiliated with the univer-
the outside world at New Haven, sity to oversee the development
he was in the audience to hear and distribution of an effective,
what Banting had to say. Im- standardized agent. It also
pressed by the experimental obtained, in gratuity patent
conclusiveness reported on the rights, that which had been
action of insulin and with authori- applied for on insulin and its
zation from Eli Lilly, the vice process of manufacture. Vested
president of Eli Lilly and Com- as an official body responsible to
pany, he promptly offered to the university for the insulin
Banting and Professor James J.R. program, the advisory group
Macleod, head of the department was formally established as the
of physiology at the University of Insulin Committee toward the
Toronto, under whose auspices end of 1922.
Leonard Thompson
2While these children follow strict dietary discipline were now
affairs were in rewarded with “a hope for life, which they hardly dared
process, the first to anticipate.”(6)
clinical trial of Attempts at Toronto to devise a standard extrac-
insulin was yield- tion procedure for large-scale manufacture were not
ing encouraging successful however. From March to May, there was no
results. On Janu- production 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 manu-
insulin to Leonard facture of insulin on a scale equal to general demand.
Thompson, a 14- Accordingly, the university concluded that develop-
Dr. Elliot P. Joslin year-old boy ment work must now turn to outside assistance, and on
suffering from May 15, Macleod invited Clowes to come to Toronto to
juvenile (severe) diabetes. 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 produc-
marked improvement, and the boy soon was restored tion and clinical supply and was signed by the univer-
to normal life. He died 11 years later from bronchop- sity 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
tors said, “It is difficult to put which time the company had
into words what is meant by exclusive right to make, use, and
clinical improvement.”(5) sell the extract in the United States,
Tentative though it was, the Mexico, Cuba, and Central and
advance was unique. For the Latin America only
first time in man’s existence,
there was promise of liberation l batches of the product
from this dreaded disease. acceptable to both parties on the
“With bright news from basis of approved testing could be
Toronto,” said Dr. Elliott P. distributed on a cost basis or gratis
Joslin, eminent American to physicians and institutions
diabetologist, parents who had selected by agreement between
scrupulously made their Laboratory where Banting and Best both parties
discoverd insulin
3l 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”
Jasper P. Scott in his laboratory
l after successful conclusion of the experimental
period, Lilly was to be granted a license and pay a five endeavor among an academic institution, the medical
percent royalty on net sales to the university profession, and a commercial house to apply a major
therapeutic advance on an international scale.
l the university agreed not to divulge to others Clowes lost no time. He assigned George B.
any information Walden, the supervisor of insulin production, and
provided by Lilly placed under him Harley W. Rhodehamel and Jasper P.
within the time Scott, thus forming a team of three to carry out the
limit of the inden- concurrent projects of experimental and factory-scale
ture and assured processing.(10) Based on protocols by Collip and Best—
the company that and some modifications of its own—Lilly began experi-
the licensing of mental runs almost daily during early June and on the
other firms would nineteenth of that month sent Banting its first insulin, a
be on the same shipment of 50 units, which he found satisfactory.(11)
terms as it would The first factory-scale lot was made on June 26 and the
receive.(9) second on July 5—the latter amounting to a yield of 30
units from 75 pounds of fresh hog pancreas and a
In the devel- potency of one unit per cc.
opment of safe By the end of July, production averaged 1,200
and effective units a week as a result of various modifications of
medicine, the alcoholic concentrations, temperatures, extraction
stipulations of the steps, and lot combinations, and potencies as high as
agreement were two units per cc. were being achieved. By the first of
without precedent September, the company had produced a cumulative
and, as far as is total of 5,390 units, of which 2,985 had been shipped to
known, signified Toronto, or a little more than twice the percentage
the first voluntary, specified in the indenture.(12)
cooperative Connaught production, on the other hand, was
The Toronto agreement
4beset 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 clini-
Indianapolis 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 Early insulin which meant that, in spite of
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.
given to the insulin program since the first of June In an effort to overcome production problems in
brought highly encouraging results by September. The general, Walden worked himself to the verge of col-
amount of active material being extracted reached new lapse, and Clowes insisted he take two weeks off. Scott,
levels of 90 to 120 units per pound of gland and total who took over in Walden’s absence, did suffer a break-
output of September was as much as had been pro- down and remained off the job for three weeks.(14)
duced in July and August combined. In August, equip- Because of all the setbacks, J.K. Lilly, Sr., instructed
ment for large-scale Clowes to release
production had Walden from experi-
begun to arrive and mental work and
Rhodehamel—who assign him exclu-
had 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 Octo- potency since June.
ber. It was expected It was believed
that, based on the that the problem of
experience of previ- deterioration 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
5initial development attempts. In sible. A way had been found to
brief, Lilly was encountering the achieve high purity with large
same difficulties that had ha- yield.(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 Grinding glands c. 1924 Such progress did not come
destruction of the insulin hor- without 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 obsoles-
determinations 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 refrig-
the 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
the solution, and this suggested that, by pH adjustment provisions on a scale the company had never faced
of the solution, an optimum point before. During the latter half of
could be established at which the 1922, more than 100,000 rabbit
insulin hormone would split off assays were conducted.
from the bearing precipitate. In Determination of the value
other words, it was discovered of the unit of insulin, highly
that iso-electric precipitation complicated by wide variability
could be employed for the of animal response, was a subject
purification of insulin. Its nitro- of great debate between Lilly and
gen content could be significantly the Insulin Committee over a
reduced, and equally important, period of several months. While
as high as a 90 percent recovery it was not technically possible at
of insulin activity became pos- the time to derive precise value—
First insulin products
6which was the crux of the debate—it, nevertheless, was a over which it was to exercise authority. The desire of
basic factor interlocking the economics of yields, the committee to have this priority was fully appreci-
capacity projections, and future facility demands. In the ated by the Americans and carefully observed through-
first six months of production at Lilly, unit standards out the clinical program.
were modified four times. Believing it had absorbed all On November 22, 1922, a roundtable meeting
the expense it could, the company requested and was held at Toronto, attended by the Canadian clini-
obtained Toronto’s approval to sell insulin to clinicians cians, members of the Insulin Committee, representa-
at cost, and distribution on this basis began in late tives of Connaught and Lilly, and six American physi-
January 1923.(16) Shipment was direct to physicians, but cians—all noted authorities on diabetes management—to
billing was handled through plan distribution control
the drug trade in keeping procedures, special studies,
with the company’s estab- and unit standardization. The
lished policy. At the time, American doctors overseeing
Lilly was supplying sixty clinical work in the United
clinics in Canada and the States in liaison with the
(17)
United States. Insulin Committee were:
The extension of the
clinical program to this l Dr. Elliott P. Joslin,
level within a year after the Boston
first administration of
insulin by Banting seems l Dr. Frederick M.
remarkable considering the Allen, Morristown, New
small output of insulin Jersey (after whom the Allen
during the period. All Era of dietary management,
Insulin filling line c. 1924
clinical work had been 1914-1921, was named)
dependent upon insulin from Lilly until the end of 1922,
when Connaught Laboratories finally overcame equip- l Dr. H. Rawle Geyelin, New York (an author-
ment problems and swung into initial mass production. ity on juvenile diabetes)
Considering, too, that unit potency was low, relatively
large daily dosages were necessary to maintain a l Dr. John R. Williams, Rochester, New York
patient. Since the action of the hormone was not a (the first American physician to use Banting’s extract)
precisely known entity, much precaution had to be
taken in selecting physicians for clinical work. Assign- l Dr. Rollin T. Woodyatt (a brilliant clinician
ment of specific investigators to hospital-affiliated from Chicago)
laboratories in major urban areas had to be planned in
order to gather data most efficiently from a limited l Dr. Russell M. Wilder, of the Mayo Clinic,
supply of insulin. The value of the unit, based on the Rochester, Minnesota.
original rabbit assay unit, also had to be raised to better
indicate clinical response. All of these considerations It was at this meeting that clinical trial develop-
were worked out along deliberate lines. ment was set up to provide the greatest number of
At the behest of Clowes, the Insulin Committee cases for test information within the limits of available
agreed to the creation of a team of American investiga- supply. The plan of individual patient therapy followed
tors to put clinical work on a systematic basis in the Joslin’s philosophy. “It has been our policy to treat
United States according to committee requirements and many rather than few diabetics. We have felt it more
7humanitarian to prolong available for attacking the
the lives of many old and disease.
faithful patients rather than As one of Joslin’s
attempt to secure marvel- early insulin patients
ous results with a few.” wrote, a professor of
Drs. Banting, Greek at the University of
Campbell, and Fletcher Vermont, “If the true
published in the January 6, Christian be the close
1923, issue of The British imitator of Christ, then the
Medical Journal their discoverer, and the one
findings on insulin therapy who applies the discovery,
with 50 cases, a paper that should feel that they are
was the first comprehen- literally following the one
sive report of the Canadian who said: ‘I am come that
trials, and by agreement they might have life, and
with the Insulin Commit- that they might have it
tee, the American investi- more abundantly.”(19) Also
gators subsequently pub- among Joslin’s cases was
lished their findings. These an indefatigable researcher
appeared in late May in a at Boston who was within
series of papers in The a few years to discover
Journal of Metabolic treatment for pernicious
Research, which, including anemia, George Richards
the above Canadian report, Minot.
discussed experiences with By the time the
approximately 600 cases findings of the American
since the inception of investigators had been
clinical work in January published, the company
1922. (18) had distributed more than seven million units of insulin
Brought to light by scientific data was reliable and, in conjunction with Connaught, was supporting
evidence that insulin did have widespread value thera- about 10,000 patients with diabetes. The Insulin Com-
peutically when the specific requirements of the indi- mittee in early spring of 1923 arranged that Lilly ship
vidual patient were recognized in the administration of quantities of insulin to the British Isles to support the
the agent. Though the number of reported cases was program there under patents granted to the public
small in relation to the estimated million people with domain by the University of Toronto, and the Commit-
diabetes in the United States at the time, this collective tee also permitted broadened clinical work in the
experience was an enormous advance. By virtue of the United States.
stringent controls exercised in treating variable mani- Lilly was allowed to submit names of physicians
festations of the disease, the basis was laid upon which who had interest in insulin and were qualified to use it,
the practicing physician could hope to bring patients so that the Committee could rule on additional eligibili-
with diabetes under control, and through carefully ties. Such, in brief, were the events behind the official
calculated diet, regulated insulin dosage, and proper June announcement by the Insulin Committee that a
exercise, guide them toward a normal way of life. For safe and standardized product was available in large
the first time, there was extensive practical knowledge volume and that firms could be licensed for the manu-
8facture of insulin.(20) Thus, in a 12- and it amounted to a 66 percent
month period, a clinical entity of decrease. It was estimated that
wholly new origin and value had 7,500 physicians were treating
been developed into a useful and, 25,000 diabetes patients with
for many, a lifesaving product. Iletin. At the close of 1923, Lilly
Of the role of Eli Lilly and had sold almost 60 million units
Company in this achievement, during the year.(23)
the Committee announcement With the introduction of
said, “Without this collaboration, Iletin, the company prepared an
it is unlikely that a non-irritating extensive literature program to
product of such satisfactory provide the practicing physician
potency and durability could useful guidelines on dosage
have been produced in adequate determination, suitable potencies,
amounts to meet the demand of dietary measures, and urine and
the medical profession in this blood analyses and also devel-
comparatively short time.” oped a variety of accessories for
On the last day of June, the the patients with diabetes self-care
University of Toronto prepared a needs.(24) It also introduced,
license contract for Lilly for the within the following year, new
manufacture and sale of insulin in potencies of the amorphous
the countries specified in the material so that it had on the
original indenture agreement, market in 5- and 10-cc vials
and the license was approved and strengths of U-10, U-20, U-40,
accepted by the company’s board and U-80. Part of the motive
of directors on July 11. However, behind this attempt at wide
approval for the company to market development was, to be
begin commercial distribution did not come until the sure, the likelihood of competition, which began to
following October, after the unit value disagreement materialize in 1925. But more pressing was the critical
had been resolved (the Committee insisted that its matter of overproduction. Diabetic treatment was still
standards had to prevail); additional clinical evidence largely confined to hospital or clinical supervision by
had been gathered; and approval the very nature of the disease and
had been given of the company’s so consumption did not rise
literature and label copy, an commensurately with the esti-
approval based on rigorous mated incidence of diabetes. As
control.(21) experience with diabetes manage-
On October 15, Iletin®, the ment extended through the
company’s brand name for its medical profession, however, and
insulin, was released for distribu- the company was allowed to sell
tion through regular drug trade insulin in certain other foreign
channels available on physician countries, demand for it rose. By
prescription.(22) Simultaneously, 1925, units distributed amounted
a price reduction was made—the to 217,681,150, thirteen million of
third since it was first sold on a which went into export.(25) Price
cost basis ten months earlier— reductions effected in 1924 and
91926 considerably reduced the return on the line but a Joslin spoke of the many happy homes there were at
profit continued to be made as unit sales increased. The Christmastime because of the contribution of Eli Lilly
eighth reduction was made in 1932, when unit sales and Company, and to this, Mr. Lilly replied:
reached 792,451,300, and resulted in a cumulative The great and refreshing discovery through this
decrease of 90 percent from the original price in experience was that the really great men in any line of
January 1923. endeavor are the most approachable, simple, and direct
With the collaborative development of insulin, the in their reasoning and contacts. Both in letter and in
battle against diabetic coma ended and there began the spirit, we have endeavored to indicate to you how
long campaign against the complications of the disease precious our relations have been with you and your
arising with the prolonged life span of diabetic victims. associates, and sometimes we are haunted with a fear
The role of Eli Lilly and Company and others in this that probably we have not been able to do our part in as
campaign—which has been waged in ever-widening full measure as it was humanly possible to do so. Yet
circles to this day—remains to be accounted for in later your generous words have tended to make us more
chapters; only the beginning has been given in these satisfied with that phase.(26)
few pages. Writing to J.K. Lilly, Sr., in December 1930,
10Bibliography
(1)
Dr. Frederick Grant Banting and Charles University of Toronto at the time he and another
Herbert Best first reported their findings to the Physi- student were assigned by Macleod to assist Banting. By
ological Journal Club of the medical faculty at the a toss of a coin, Best won the chance to first work with
University of Toronto, November 14, 1921, and the him. In 1925, he obtained his medical degree from the
paper was first published in The Journal of Laboratory university, and, two years later, his doctor of science
and Clinical Medicine, Vol. 111, No. 5, February 1922. degree from the University of London. Upon his return
The paper delivered at New Haven was considered a to Toronto in 1927, he was appointed professor of
summary by Banting and Best and, consequently, its physiology at the medical school (later to head the
publication in the American Journal of Physiology, Vol. department) and became director of Connaught Labo-
59, No. 1, February 1922, was not regarded by them as ratories, director of the Banting and Best Department of
their first report. Nonetheless, the Nobel Prize for the Medical Research, and head of the Banting and Best
discovery was based on this article, and since Professor Institute. He retired from those duties in 1967. In
James J.R. Macleod was listed as co-author (because he addition to devoting his career to diabetes, he made
was the head of the department of physiology at the significant contributions to studies of choline and liver
university under whom Banting had carried out his damage, heparin, and thrombosis. He also was the
work), he was recognized as the co-discoverer and not discoverer of the enzyme histaminase. Best died in
Best. Banting was much distressed by this and said so 1978.
many times.
(3)
As a part of their studies on fat digestion with
(2)
A Canadian farm boy in origin and a graduate depancreatized dogs, these German investigators
of the University of Toronto, Banting was an orthopedic discovered that the urine of the animals possessed an
surgeon and part-time instructor in physiology at excessively high sugar content. Thus, they had demon-
Western Ontario University, London, where he was in strated the relation of pancreatic function to diabetes,
the practice of medicine. It was in preparation of a and Oskar Minkowski went so far as to conduct pre-
lecture that he had read the now famous article on liminary experiments as further confirmation, but, for
pancreatic lithiasis by the obstetrician, Moses Barron, reasons unknown, he abandoned these very promising
that prompted his search for insulin. This was in the fall leads. The history of diabetes is replete with such
of 1920, and by May of the following year he had ironies.
convinced Macleod to provide him with laboratory
(4)
facilities. Within a few years after his discovery of Professor J.J.R. Macleod to Dr. G.H.A. Clowes,
insulin, Banting forsook studies of diabetes and concen- May 15, 1922. Copy in the files of the Insulin Commit-
trated on other fields, such as the adrenal cortex, tee, University of Toronto.
cancer, and silicosis. He also did important work on the
(5)
Franks antigravity suit for the Canadian Air Force at the F.G. Banting, C.H. Best, J.B. Collip, W.R.
outbreak of World War II. On February 21, 1941, Campbell and A.A. Fletcher, “Pancreatic Extracts in
Banting was killed in an airplane crash in Newfound- the Treatment of Diabetes Mellitus,” The Canadian
land while in the service of his country. He had recently Medical Association Journal, Vol. 12, No. 3, March
turned 49. 1922.
(6)
Born in West Pembroke, Maine, in 1899, Best was “Today’s Problems in Light of Nine Hundred
working on his master’s degree in physiology at the and Thirty Fatal Cases,” The Journal of the American
11Medical Association, Vol. 78, No. 20, May 20, 1922. In procedure, and assay results. The volumes are in the
another article of the time, Dr. Elliott P. Joslin referred Lilly Archives.
to the co-discoverers as “the young Lochinvars of
(12)
Toronto.” Clowes, undated reports on distribution of R-
4320-D to clinical investigators for the periods June 19
(7)
Dr. Charles H. Best, interview with author, to September 1 and July to September 25, 1922. The
September 24, 1968. first report states that 3,085 units had been sent to
Banting by September 1, but the second report gives
(8)
J.J.R. Macleod, “Insulin and the Steps Taken to the amount as 2,985. Reports in the files of the Insulin
Secure an Effective Preparation,” The Canadian Medi- Committee. R-4320-D was the first successful lot of
cal Association Journal, Vol. 12, No. 12, December insulin Lilly made, and four house samples of this lot
1922. Years later, Best recalled, “It was his (Clowes) have been preserved in the Lilly Archives.
scientific training, his great interest, and his ability
(13)
which were in part responsible for the selection of Eli July 26, 1922. Letter in the Lilly Archives.
Lilly and Company as the first company in the United
(14)
States to collaborate with the University of Toronto in Clowes to Macleod, October 20, 1922. Letter
the production of Iletin. . . . Of course, he was inter- in the files of the Insulin Committee. This seven-page
ested in large-scale production, it was so much easier summary of events was written to explain the reasons
for the Lilly company than for us here because we’d for production setbacks and product deterioration.
had no experience in the use of large stills or other
(15)
apparatus for concentrating large volumes of material.” U.S. Patent No. 1,520,673, George B. Walden,
Transcript of interview with author, September 24, “Purified Anti-diabetic Product and Process of Making
1968. Copy in the Lilly Archives. It,” assigned to the Governors of the University of
Toronto and granted December 23, 1924. See also
(9)
The agreement, dated May 30, 1922, was transcript of Walden interview with author, November
signed June 28 by representatives of the Board of 5, 1968. Copy in the Lilly Archives.
Governors of the university and on July 7 by J.K. Lilly,
(16)
Sr., and General Manager and Secretary Charles J. General Letter No. 13, February 20, 1923.
Lynn on behalf of the company. Copy in the Lilly Copy in the Lilly Archives.
Archives.
(17)
General Letter No. 13, February 20, 1923.
(10)
Jasper P. Scott, a graduate of Franklin College, Copy in the Lilly Archives. The company had estab-
Franklin, Indiana, joined the company in 1920 as a lished a clinic to carry out its own investigation of
research chemist upon the recommendation of George insulin. The unit was organized in July 1922 at Method-
B. Walden. He held various positions in research until ist Hospital, Indianapolis, and headed by Dr. John A.
1946, when he was appointed a director in Industrial MacDonald, professor of medicine at Indiana Univer-
Engineering and Facilities Planning. Scott died in 1953. sity and personal physician to the Lilly family. His staff
consisted of Dr. Cecil L. Rudesill; Dr. John H. Warvel,
(11)
Information about early insulin production at head of the hospital’s pathology laboratory; and Miss
Lilly was obtained from a six-volume series of labora- Ruth Michaels, a nurse whom Warvel later married.
tory data entitled “Insulin Research” for the years 1922 Michaels received training under Dr. Rollin T.
to 1925. The entries, mostly recorded by Mrs. George Woodyatt for the care and training of the clinic’s pa-
B. Walden, who was an employee at the time, noted the tients. The first therapeutic dose given at the clinic was
date of each lot, the number assigned it, the extraction on August 12 to Mrs. Nellie Underwood, the hospital’s
12housekeeper. Joslin was the first American physician to H. Lacey, “The Unit of Insulin,” Diabetes, Vol. 16, No.
use Lilly’s insulin when, on August 7, it was adminis- 3, March 1967, and “International Insulin Standards,”
tered to one of his regular, long-time patients, Miss Diabetes, Vol. 17, No. 11, November 1968. Lacey was
Elizabeth Mudge. Mudge and J.K. Lilly, Sr., struck up a Chief Chemist of the Insulin Committee from 1931
friendship and corresponded many years until her until his retirement in 1969.
death in 1947.
(23)
Records of the Insulin Committee.
(18)
Vol. 2, Nos. 5 and 6, November-December
(24)
1922. From the outset of commercial distribution,
Lilly offered specifically calibrated syringes, a urinary
(19)
Samuel E. Bassett to Joslin, November 30, test kit, plain agar, saccharin tablets and the “Ever
1922. Letter in the Lilly Archives. Joslin sent the letter Aseptic lletin Syringe Outfit,” designed and patented by
to J.K. Lilly, Sr., with the notation that it was a nice Mr. Eli Lilly. In time, supply houses began to carry
Christmas present for the company and Banting. diabetic accessories and the company eventually
discontinued them.
(20)
Report of the Insulin Committee, “Insulin: Its
(25)
Action: Its Therapeutic Value in Diabetes and Its Records of the Insulin Committee, op. cit.
Manufacture,” The Canadian Medical Association
(26)
Journal, Vol. 13, No. 7, July 1923. The same report was J.K. Lilly, Sr., to Joslin, February 6, 1931. Copy
also published in The Journal of the American Medical in the Lilly Archives. The company anonymously
Association, Vol. 80, No. 25, June 23, 1923. contributed $50,000 to the Banting Research Founda-
tion in 1925, which was created to advance further
(21)
In the summer of 1923, F. Lorne Hutchison work by private means. Lilly also provided unrestricted
was appointed Executive Secretary of the Insulin grants to Best, which were paid periodically for several
Committee, a position that was created when Macleod years. After the expiration of the patent on amorphous
asked to be relieved of his Insulin Committee duties in insulin and royalty payments in 1941, it made annual
order to give full attention to his responsibilities as head grants to the Banting and Best Department of Medical
of the department of physiology. Some years later, he Research. All royalty payments on sales of later insulin
was appointed Regius Professor of Physiology at his preparations ended in 1969, when the Food and Drug
alma mater, the University of Aberdeen, a post he held Administration assumed full authority for safety and
until his death in 1935. Hutchison served as Executive potency determination.
Secretary until his death in 1952.
(22)
General Letter No. 88, October 9, 1923. Copy
in the Lilly Archives. With the adoption of unit potency
specified by Toronto, unit designation was changed
from “H” used in the clinical trials (presumably stand-
ing for human) to that of “U”, which began with com-
mercial introduction. The “U” was 40 percent greater
in potency than the “H” and thus resulted in fractional
calculation in converting dosage from the latter to the
former. For example, one unit of “H” = 0.7 of “U,” 10
= 7, 20 = 14.5, 30 = 21.5. For derivation of unitage and
establishment of an international standard, see Albert
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