March 11, 2020 • 39 mins
Last time we talked about how diabetes has been described through history, including treatment before the development of insulin. Today, we’re telling the insulin part of the story, which was at times fraught and contentious.
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Episode Transcript
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Speaker 1 (00:01):
Welcome to Stuff You Missed in History Class, a production
of I Heart Radio. Hello, and welcome to the podcast.
I'm Tracy B. Wilson and I'm Holly Frying if you
are just tuning in today. This is a two parter.
It is on the development of insulin. And last time
(00:23):
we talked about how diabetes has been described through history,
including how people were being treated with starvation diets in
the years just before the development of insulin, and today
we are going to tell the insulin part of the story,
which does build on research that we talked about last
time around. This will the easiest to understand if you
have heard part one. As was the case last time,
(00:45):
we're going to be talking about how experiments on animals
led to this discovery, as well as how the byproducts
of animals that were slaughtered for food we're used to
make insulin. It is not clear who coined the term insulin.
It comes from the word insula or island, as a
nod to the islets of langer Hans. As we talked
about in Part one. The islets of langer Hans are
(01:07):
cells in the pancreas that produce insulin and other hormones.
Jean de Meyer of Belgium used the word insuline with
an E on the end in nineteen o nine, and
apparently independently of that, Ernest Henry Starling, who coined the
word hormone, also used the word insulin with an E.
Four years later. In the early nineteenteen, Sir Edward Albert
(01:29):
Sharpie Schaffer also described a hypothetical substance secreted by the
islets of langer Hans, which controlled the body's glucose levels,
and he called that insulin. This time there was no
E on the end. None of these people are the
ones credited with the discovery of insulin, though that story
starts with Frederick Grant Banting. Banting was born on a
(01:51):
farm in Ontario, Canada, and initially he had planned to
go to divinity school, but after enrolling at the University
of Toronto, he's changed his major to medicine. When World
War One started, he joined the Canadian Army Medical Corps
and was placed on an accelerated medical study program. During
the war, he was wounded in action and awarded the
Military Cross in After the war was over, Banting completed
(02:15):
a surgical residency and tried to set up a private
surgical practice, it did not grow quickly enough for him
to make ends meet, so he also took a part
time teaching position at the University of Western Ontario that's
now known as Western University. The classes that he was
teaching included physiology, something that he had studied as part
of his own medical education, but also something that he
(02:38):
really needed to brush up on in order to teach.
On October thirty one, nineteen twenty, Banting was brushing up
on the pancreas he read a paper called the Relation
of the Islets of Longer Hauns to Diabetes with Special
Reference to Cases of Pancreatic Lithiasis by Moses Barron. This
paper discussed the autopsy of someone you turned out to
(03:00):
have a pancreatic stone that had totally blocked their main
pancreatic duct. The person's pancreas still had islets cells, but
the asiner cells had atrophied. This paper also noted earlier
experiments in which the main pancreatic ducts of various animals
had been partially or totally legated, which had caused similar results,
(03:21):
and that is research that we talked about some of
back in our previous episode. Banting was inspired by this idea.
He wrote a note in his journal which read, quote
diabetes legate pancreatic ducts of dog keep dogs alive till
assony degenerate, leaving islets. Try to isolate the internal secretion
(03:41):
of these to relieve glycosuria. So a few things to
note at this point. One of the Banting's note is
about glycosyria, or sugar in the urine, rather than blood sugar.
Banting also was not really aware of all those experiments
that we talked about in part one. He didn't really
realize that rees As had spent more than two decades
(04:02):
trying to do basically what he was describing without yielding
something that was safe enough to use in human patients.
It's also not clear how exactly that he thought he
might quote try to isolate the internal secretion of the
islets of langer huns, or whether he was thinking about
preparing a pancreatic extract or thinking he might try to
(04:23):
find the secretion itself. Later on, when he told people
from memory what he'd written down in his journal that night,
he said it was quote legate pancreatic ducts of dogs
weight six to eight weeks for degeneration, remove the residue,
and extract, and that is a lot more specific. Also,
part of Banting's basic idea here was a little bit off.
(04:44):
His rationale for causing the acid our cells to atrophy
was that they produced digestive enzymes, and he thought those
enzymes might destroy whatever vital substance was being produced in
the islets of langer Huns. But really these enzymes are
not active until they come into contact with other enzymes
in the small intestine. The relationships between those two different
(05:06):
sets of enzymes had been discovered back in nineteen o four. Also,
it's possible that there's some other explanation, but his misspellings
of both diabetes and glycosuria suggests that Banting wasn't all
that familiar with what he was writing about. So at
this point Banting went to his boss at the University
of Western Ontario about this idea. His boss referred him
(05:28):
to John James Rickard MacLeod at the University of Toronto.
McLeod was born in Scotland and had studied medicine at
the University of Aberdeen. He had also taught at several
universities and institutes in Europe and North America before becoming
professor of physiology at the University of Toronto and also
director of its physiological Laboratory. McLeod was a leading expert
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in carbohydrate metabolism at the time, and in nineteen he
had published Diabetes, Its Pathology and Physiology. He had been
trying to identify which part of the nervous system controlled
the liver's glycogen storage functions. Unlike Banting, McLeod knew all
about those earlier attempts to make a pancreatic extract that
could treat diabetes, and he thought there was some kind
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of pancreatic secretion that could be the key to an
effective treatment, but he had his doubts about it's ever
being isolated and used. And it wasn't just that McLeod
had doubts about whether it was possible at all to
make a usable pancreatic extract. Those earlier researchers also all
had training and skills and experience that Banting just didn't have.
(06:36):
Mcloud's impression of Banting was that he had a very basic,
textbook level understanding of the pancreas and its role in diabetes,
and really this was pretty accurate. So McLeod was reluctant
to offer Banting the lab space, assistance, materials and animals
that he was going to need to research his idea.
The two men had multiple meetings to talk through the situation,
(06:58):
and then when McLeod finally agreed to let Banting do
some experiments over the summer, Banting actually got a little
nervous about it. Banding still thought that his idea might
lead to a breakthrough, but he also understood that if
he left his practice and his job to pursue an
idea that didn't work out, he would basically have to
start his career over while also trying to pay off
(07:19):
debts from a failed project. On March eighth, one, Banting
and McLeod finally agreed on the terms of the project.
The work would take place over the summer of nine
starting in mid May. Two students, Charles Best and Edward
Clark Noble, would assist Banting. They would divide the summer
between the two of them. These two young men flipped
(07:41):
a coin to see who would take the first shift
with Banting, with Best planning to take the first half
of the project and Noble planning to take the second half.
Best at that point had finished his bachelor's degree in
physiology and biochemistry and was preparing to start medical school.
For about a month, Banting, Best in McLeod all were
together in the lab, with McLeod fine tuning their plan
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and process and surgical techniques and instructing them on how
to best prepare an extract. Then in mid June he
left for a vacation in Scotland that he had previously arranged.
We will talk about how Bantings and bests work proceeded
over the summer, which will have more about their animal
experiments after a quick sponsor break. When Frederick Banting and
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Charles Best started their experiments on dogs to try to
find a treatment for diabetes, things did not go well.
Their plan was to legate the pancreatic ducts of some
of the dogs, which would cause the assent our cells
to atrophy, but theoretically at least leave the islets of
longer hunts mostly unaffected. By that point, Banting would have
learned that the digestive enzymes were inactive while they were
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actually in the pancreas. But this atrophy of the assenter
cells would at least in theory, deuced the amount of
material that needed to be removed from the extract before
it could be safely used. Once enough time had passed
after this legation procedure to allow the asdenter cells to atrophy,
they would euthanize the dog and remove its pancreas, using
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it to prepare an extract. Then they'd inject that extract
into another dog whose pancreas had been removed entirely. However,
these surgical procedures could be difficult. It was also summer,
so the facilities where they were working were hot and uncomfortable.
Several of the dogs that they were working with died
of infections or other complications, and they started buying stray
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dogs as replacements. It was mid July before they had
a deep pancreatized dog and one with an atrophied pancreas
ready to work at the same time. The process of
preparing a pancreatic extract was also long and complex. It
included chopping the pancreas, chilling it, grinding it up, filtering it,
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and warming it back up to body temperature. On July,
they tried injecting their extract for the first time. Although
the sugar levels in the dog's urine did drop, they
rose again pretty quickly. The dog died the next day,
most likely from an infection. Banting and Best kept trying, though.
When Edward Noble came back to the lab to take
(10:19):
over his shift as assistant, he found that the two
of them had worked out this whole rhythm and flow
to their work. At that point, Noble thought that if
he tried to take Best's place, as was previously planned,
he would just become a hindrance to the project. He
would have to learn everything that Best was doing pretty
routinely at that point, so he left Best to it,
although he did come back to the project later on,
(10:41):
which we will get to. In August, Banting and Best
ran out of legated dogs, so they switched to using
the whole pancreas something that, as it turned out, worked
just as well. They kept refining their work and taking notes,
and when McLeod returned to the lab on September one,
they had results. This seemed promising. They were still seeing
(11:03):
some complications, but their extract did seem to be lowering
the glucose levels of deep pancreatized dogs. McLeod, as we
said earlier, was very skeptical about this whole project from
the very beginning, and he was surprised enough at these
results that he questioned whether they were accurate. Banting was
highly insulted by the suggestion, and the two men butted
(11:25):
heads over it. Ultimately, McLeod told them to repeat their experiment.
Apart from taking offense at being questioned about the accuracy
of his work, Banting was also worried about his finances.
He had planned to take the summer to do this research,
but he had not planned for it to continue into
the next academic year. He also thought the facilities where
(11:47):
he'd spent the summer working left a lot to be desired.
For example, he said that they couldn't scrub the floors
thoroughly because if they did, water leaked through the ceiling
of the room below. He thought that was to blame
for some of the infections and the deaths of their
research animals. So Banting asked for a salary and one
for best as well as repairs to the floor of
(12:09):
the lab and an assistant to take care of the animals.
Banting also asked for a biochemist to be added to
the team to help them better refine their pancreatic extract.
McLeod didn't think they were ready for that last step yet,
but he did give Banting and Best retroactive salaries. He
also hired somebody to take care of the dogs and
arranged to have the laboratory floor waterproofed with tar, which
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was like the least expensive way to deal with this
water seepage problem. Eventually, Banting and Best tried another source
for their pancreas tissue. After learning that fetal and newborn
calves had proportionally more islet cells than older animals do.
They started buying fetal pancreas from slaughterhouses. They still had
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trouble getting enough pancreas for their work, though, so they
ultimately started using the whole pancreas of adult animals, also
purchased from slaughterhouses. In November of one, Banting and Best
published a paper, the Internal Secretion of the Pancreas. Banting
also presented the paper publicly that December in New Haven, Connecticut.
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This presentation once again caused tension between Banting and McLeod.
Banting was just not a very good public speaker, and
some of the people who were in the audience on
that day were literally at the top of their field.
He just didn't have the breadth of knowledge to answer
some of the very probing questions that they asked him.
When Banting had trouble fielding questions, McLeod stepped in. He
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did have that breadth of knowledge, and he was also
polished and well spoken in his presentation. He also used
the word we a lot, something that wasn't necessarily unusual
considering that the work was happening in his lab ultimately
under his supervision. But Banting felt like McLeod was taking
credit for work that he had not actually done. And
(13:59):
the audience that day was the research director for Eli
Lily Pharmaceuticals, who asked if the company could be involved
in this project, and in McLeod's opinion, once again, they
were not there yet. By the end of though, McLeod
thought the project was promising enough that he finally did
bring on a biochemist, James Bertram Collop, who took a
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sabbatical from the University of Alberta at Edmonton to work
on it. McLeod also dedicated the whole lab to the project,
thinking that they were on the verge of a life
saving breakthrough. The extraction method that Collip developed was a
lot more effective but also still very involved. I initially
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had like all of the steps written into this outline,
and it went on for paragraphs. He realized that different
pancreatic materials could be extracted at different strengths of alcohol,
and so he developed this method that included multiple extraction steps,
with the results of those extractions being concentrated in centrifu,
huged and precipitated. It went on. He also discovered that
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the extracts lowered the blood sugar of rabbits, so they
no longer needed to work with deep pancreatized dogs. Edward
Clark Noble rejoined the project at this point to help
with the studies on rabbits. Running parallel to this work
at the University of Toronto were developments in blood sugar testing,
which made it easier to test their extracts effects on
(15:25):
blood sugar directly, rather than relying on how it affected
glucose levels in the urine. More efficient and effective blood
sugar testing was a huge part of the ongoing development
of insulin. In late December of Banting tried one of
their extracts on a human subject. Dr Joseph Gilchrist had
been one of Banting's classmates and had developed diabetes not
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long after they graduated from medical school. This extract did
not work at all, though, and it wasn't because the
extract itself was bad. Even if they had made completely
pure insulin, if taken orally, that would have been digested
in the stomach way before it could have been absorbed
into the bloodstream. In January of the team was ready
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for their first attempt at injecting their extract into a
human patient. The patient was Leonard Thompson, who was fourteen
years old and critically ill. He weighed only sixty five
pounds that's about thirty ms when he was admitted to
Toronto General Hospital. He had been on a starvation diet
like we talked about in Part one, which had taken
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him down to about four hundred fifty calories per day.
His daily yearine output was about four leaders that's more
than a gallon. A typical amount is more like eight
hundred to two thousand million leaders. And he was also
showing signs of diabetic keto acidosis, which is when the
body starts burning fat instead of sugar for fuel and
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as a result, acids start to build up in the
blood stream. So this whole time Banting had felt like
McLeod had been stealing credit for his work, second guessing him,
and undermining him every step of the way. Added to
all of that, Banting could not really control this first
human trial at all. He did not have the background
or the experience that was needed to run a trial
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on human subjects. He also did not have the authority
to work with patients at Toronto General Hospital, So when
it came to their first human trial, Banting really insisted
that they use an extract that he and Best had prepared.
They did this on January eleventh. Of This preparation did
lower Leonards blood sugar somewhat, but it did not alleviate
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any of his outward symptoms of diabetes. The boy also
developed an abscess at one of the injection sites. Colip,
who was still refining his methods for extraction, really went
into overdrive at this point, finally producing an extract he
thought was pure enough to use. Several days later. They
tried again with this extract on January twenty three of
nineteen twenty two, and this time the results were immediately
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and dramatically affected. Leonard's blood sugar dropped significantly, as did
the glucose in his urine, and he also was just
visibly improved. It was obvious to other people that he
was doing better. In the words of Charles Best's notes quote,
daily injections of the extract were made from January to
February fourth, accepting January and February fourth. This resulted in
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an immediate improvement. The excretion of sugar became much less,
the acetone bodies disappeared from the urine. The boy became brighter,
more active, looked better, and said he felt stronger. Leonard,
whose condition had been critical when he was admitted, lived
another ten years. After the success, though, the ongoing backbiting
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and hostility in the lab became even more dramatic, and
we will get to that. After another sponsor break at
Leonard Tom Sin was getting his first injections of a
working pancreatic extract. The already contentious relationships among the team
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from the University of Toronto got even worse. James Callip,
who had not shared the details of his extraction method
with anyone else, threatened to quit the project and patent
it himself. The details here are a little bit sketchy,
but Banting was outraged and he and Collip had a
physical altercation in the lab, with Banting grabbing Collip by
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the color of his coat and slamming him into a chair,
and Best writing that he had to restrain Banting with
all of his force. After this, on January two, Banting, Best,
and call Up all signed a memo that none of
them would be seeking a patent for insulin. This was
part of a manufacturing agreement with Connu Laboratories, which is
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a public pharmaceutical company that had been established in Canada
during World War One to make diphtheria anti toxin. After
that first successful treatment of Leonard Thompson, six more patients
were treated in February of nineteen two. From there, they
moved quickly into a clinical trial, and at that point
the project largely moved out of Bantings and Best's hands.
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As we said earlier, Banting just did not have the
training or experience to run a clinical trial on human subjects,
and he was deeply frustrated by his exclusion, and he
tried to cope, unfortunately by drinking to excess. On March
two of nineteen twenty two, a paper was published in
the Canadian Medical Association journal called Pancreatic Extracts in the
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Treatment of Diabetes melitists. It's authors were F. G. Banting, C. H. Best, J. B. Collip, W. R. Campbell, A. A. Fletcher, J.
J R. McLeod, and E. C. Noble. The two names
from that long list of authors that we haven't mentioned
specifically before this point our Campbell and Fletcher, and those
were the doctors who administered the actual injections to the
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diabetes patients. On May third, nine two, McLeod presented a
paper called the Effects Produced on Diabetes by Extracts of Pancreas.
It described that extract as insulin, once again from the
Latin route for islands and apparently not related to the
earlier uses of the same term from the same source.
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Both Banting and Best refused to go to this presentation.
Between roughly these two papers, between March and May, the
clinical trials of insulin had run into a huge stumbling
block When Connaught laboratories tried to replicate Collips extraction methods.
It just didn't work. Multiple sources described this as Collip
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losing the knack for making insulin, or as problems with
translating Collips small scale batches from the laboratory into a
large scale production. They finally did resolve the issues and
started production in mid May of ninety two. For Banting's part,
he believed that Collip had wanted to keep his method
secret for his own benefit, and that consequently he had
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not kept good enough records, and that that's why they
were having so much trouble. One patient died during this shortage,
and Banting and call Up had another massive altercation. As
words started to spread about insulin, families started trying to
get their children included in the clinical trials. The most
famous of these patients was Elizabeth Hughes, who was daughter
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of former New York Governor Charles Hughes. Her father, Charles
later became Secretary of State in nineteen twenty one and
Chief Justice of the U. S. Supreme Court. Elizabeth had
been born in nineteen oh seven and had developed diabetes
in nineteen nineteen. Elizabeth had been one of doctor Frederick
Allen's patients and had been on a starvation diet before
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starting insulin therapy. Alan saw her at a conference later
in nine two, and she was so improved that he
literally did not recognize her. She later wrote. Quote Dr
Allen said, with his mouth wide open. Oh, and that's
all he did, and after starting insulin therapy, Elizabeth lived
until the age of seventy three. Soon there was so
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much demand for insulin that cannot labs could not produce
enough on their own, and that is when Eli Lilly
and Company was brought on to increase the output. This
led to yet another challenge, which was trying to standardize
this treatment across two different drug makers who were operating
in two different countries. It wasn't yet possible to measure
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the strength of insulin itself. You had to administer a
sample of it to rabbits and then measure the rabbits
blood glucose levels to figure it out. One issue in
this whole process turned out to be because the two
drug makers were using different sized rabbits, with one of
them using rabbits that had been fasted and the other
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using rabbits that had been fed normally. He seemed like
such small but important details, very very important details. Uh.
This standardization process ultimately led to the first deaf nition
of a unit of insulin, which was the amount that
it took to lower the blood sugar of a rabbit
weighing two kilograms from zero point one to zero point
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zero four five, with that drop happening over five hours
and the rabbit having been fasted for twenty four hours.
Insulin is still measured in units today, but we can
also measure insulin itself now, so today one unit is
equivalent to thirty four point seven micrograms of crystalline insulin.
Throughout the nineteen twenties, Connaught Laboratories, ELI Lily, and numerous doctors, clinicians, researchers,
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and others were working on standardizing insulin, with one of
the major contributors being Sir Henry Dale. Sometimes he's described
as being the person who did it, but like there
were a lot of people and entities involved. Another big project,
including most of these same basic entities, was refining the
extraction process and improving the yield of that process over
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a few year or as drug manufacturers went from being
able to extract fifteen units of insulin from a kilogram
of pancreas to extracting almost four hundred units per kilogram.
In late nineteen twenty two, George Wilden at ELI Lily
developed a method for isoelectric precipitation of insulin, but the
relationships among banting best McLeod and call up, we're not
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nearly as productive. In September of nine two, hoping to
create a definitive account of the discovery of insulin and
put all of the arguing to rest, Colonel Albert Gooderham
asked Banting, Best in mcleoud to each right up their
account of what happened. By that point, coleb had returned
to the University of Alberta at Edmonton, but McLeod wrote
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him and asked for his thoughts. This whole process did
not really resolve anything, though. Banting characterized McLeod as constantly
undermining and criticizing him and taking credit for his work,
and he ended his write up with an appendix of
six additional is that he said showed quote a lack
of trust and cooperation on mcloud's part. McLeod characterized his
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caution as very reasonable, giving bantings and experience, and he
pointed out that he had frequently taken a lot of
care to give credit to Banting and Best whenever that
credit was due. Best's account was relatively brief and fairly
neutral between the two of them, although Banting, Best, and
McLeod had all agreed not to personally apply for patents
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on insulin as part of their agreement with Connent Laboratories.
Patents were needed to ensure quality and safety. This was
a brand new drug that could be life threatening if
made incorrectly, not just because of all the side effects
that we talked about earlier from poorly made extract, but
because of formulation that was too weak or too strong
could be life threatening for patients. At the same time,
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the goal was to make insulin widely available as quickly
as possible and for it to be affordable. An in
Culin Committee had been established in early nineteen twenty two
to help coordinate patenting and licensing issues. Numerous patents were
issued on insulin and the process for making it in
the early nineteen twenties. By nineteen twenty six, insulin was
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patented in twenty six different countries, and it had become
the standard of care in managing type one diabetes, especially
around the world. The relationship among those men who had
created it was never smooth, though in many ways. Banting
became the face of the discovery. On August nineteen twenty three,
he was on the cover of Time magazine. He received
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numerous awards and honors, and he met King George the fifth.
The Banting and Best Chair of Medical Research was established
at the University of Toronto, and Banting was the first
person appointed to it. However, none of that seemed to
outweigh Banting's feelings about another award, which was the nineteen
three Nobel Prize and Physiology or Medicine, which was awarded
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to both him and McLeod. Banting was so outraged at
McLeod's inclusion and getting the Nobel Prize that he threatened
to decline the award until somebody pointed out to him
how unfortunate it would be for the very first Canadian
Nobel laureate to refuse the honor. Banting ultimately decided to
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give best half of his prize money, and McLeod gave
half of his prize money to call it. The team
also faced criticism from a number of directions in the
early nineteen twenties. Anti vivisectionists objected to the research in general,
and to Banting's admission that they had been buying stray
dogs off the streets when they ran out of research animals,
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some of which may have actually been people's pets. Within
the medical community, there were people who criticized the whole
project because even though it had a good outcome, it
had started with Bantings fundamentally incorrect ideas. And then there
was Nicolay Paul Askew, who he talked about briefly in
Part one. He claimed aimed that Banting and McLeod had
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stolen his work and that they had only become known
as the people to discover insulin because they had just
made the first commercially viable extract. Poliscue had sent Banting
his papers in ninety one and had asked him to
keep up a correspondence with him, but Banting had never
answered him. Banting and Best had also mischaracterized some of
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Poliscue's earlier work in their own writing, something that really
seems to have been because of a mistranslation of a
document that was in French, rather than a deliberate misstatement
on their parts, like trying to cover something up. And
we should also know that there are still people who
make the argument that Polisque should be credited as the
discoverer of insulin, while others point out that he also
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published multiple anti Semitic documents and that he helped found
anti Semitic parties that later formed the fascist organization known
as the Iron Guard in Romania. In a strange turn
of events, the one collaborator that Banting was actually on
good turn arms with at the end of his life
was James Collop, who he had shoved into a chair
earlier in this story. By the time Banting died in
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nineteen forty, he had fallen out with Best, who he
had previously been close to. That year, being nineteen forty,
Best was scheduled to travel to Europe to act as
a medical liaison during World War Two. He canceled that
trip and Banting took his place, reportedly telling a friend
just before leaving, quote, if they ever give that chair
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of mine to that expletive deleted Best, I'll roll over
in my grave. Having made that statement, Banting's flight on
this trip crashed after taking off from Gander Bay, Newfoundland,
on February nineteen forty. Banting survived the actual crash, but
died of his injuries before he could be rescued. In
terms of the other three of those first four contributors,
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Charles Best did succeed Banting as the chair of the
Banting and Best Department of Medical Research. He continued to
do groundbreaking work on insta land and he was part
of the development of the drug heperin. He died on
March thirty first, nineteen seventy eight. John McLeod left the
University of Toronto for the University of Aberdeen in ninety eight,
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and he died in nineteen thirty five at the age
of fifty nine. James Collup ultimately became the Dean of
Medicine at the University of Western Ontario. He died on
June nineteenth, nineteen sixty five. There have been a lot
of developments in the worlds of endo chronology, diabetes and
insulin since the nineteen twenties. That first preparation made in
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nineteen twenty two only lasted for about six hours and
people could have really dramatic spikes and blood sugar as
it wore off. He had to be really careful with it,
so researchers started trying to develop versions of insulin that
would be absorbed more gradually and predictably and would last longer.
Researchers also worked on isolating insulin itself and figuring out
(31:55):
its exact chemical structure. John j Abel crystallized insulin and
nineteen twenty six ten years later, insulin was combined with
the hormone protomine to make a version that was absorbed
more slowly and consistently. In nineteen thirty nine, a version
that combined protomine and zinc was introduced that could last
for up to forty eight hours. Slow acting, buffered lente
(32:18):
insulin's were developed in the early nineteen fifties. Beyond McLeod
and Best, multiple other researchers have been awarded Nobel Prizes
for work that was related to insulin. In nineteen fifty five,
Frederick Sanger was awarded the Nobel Prize in Chemistry for
his work in identifying the amino acids that make up
a molecule of insulin. In nineteen sixty four, Dorothy Mary
(32:41):
Crowfitt Hodgkin was awarded the Nobel Prize and Chemistry quote
for her determinations by X ray techniques of the structures
of important biochemical substances. One of those important biochemical substances
was insulin. Then, in nineteen seventy seven, rosalind Yellow was
one of the recipients of the Nobel Prize in Physiology
Your Medicine Quote for the development of radio immuno assays
(33:04):
of peptid hormones. This was tied to a discovery that
people who got injections of hormones, including insulin, could develop
antibodies to that hormone. Those two decades saw a lot
of other advances in addition to those Nobel prizes. You're
in glucose self test strips were introduced in the nineteen sixties.
In nineteen sixty three and nineteen sixty five, two different
(33:27):
teams each synthesized insulin for the first time. The first
insulin pump was also developed in nineteen sixty three, although
at the time it required a pump the size of
a backpack. Amy's Diagnostics introduced the first blood glucometer in
nineteen sixty nine. The first fully synthetic insulin was introduced
in nineteen seventy five, was made using recombinant DNA rather
(33:51):
than by extracting insulin from animal pancreas. Before this point,
it took an estimated twenty steers or eighty hogs to
get enough insulin for a patient for one year, and
although most people are using synthetic insulince now, animal sourced
insulin is still made today and there are still people
who are using it to manage their diabetes. The ability
(34:12):
to synthesize insulin made it possible for researchers to create
insulin analogs in the nineteen eighties and nineties. These have
slightly different amino acid chains from human insulin, so they
lower blood sugar the way that insulin does, but they
also behave a little bit differently in the body. In
most cases, they're made to be absorbed more quickly or
(34:33):
more slowly than human insulin. Is this research into ways
to improve insulin is ongoing, including attempts to make insulin
that can be administered orally. In the United States, there
have been a lot of headlines about how expensive insulin
has become, and a big reason for that is that
all these refinements and synthetic analogs and other developments, they're
(34:54):
all patented and so drugmakers can set their own price,
and especially with these newer versions, there's just not a
generic alternative available. In general, the lower cost alternatives that
are available we're developed decades ago, so they haven't had
all those tweaks and things like absorption rates that we
just talked about. Using insulin to manage diabetes is a lifelong,
(35:18):
daily process and researchers are still trying to find a
way to treat diabetes directly, rather than using insulin to
manage its effects. This can include pancreatic graphs or transplants,
or finding a way to prevent the body's immune system
from damaging the pancreas in the first place. The introduction
of insulin also made it possible for people with diabetes
(35:39):
to live much longer, so research is ongoing into ways
to treat and prevent the complications that can arise later
in life, including retinopathy, neuropathy, and foot problems. So that
in two parts is insulin? Yeah? Uh, you did some
listener mail on part one? Do you have some more
for part do I do? It is from Ian. Ian
(36:04):
sends a note about Woolworth's lunch counters, and Ian says, Hi, ladies,
thank you for your episode on the lunch counter sit ins.
Although it does feel funny to say thank you for
an episode which essentially involved people being nasty to each
other for something they did not choose, like the color
of their skin. If you want to have lunch at
a Woolworths lunch counter, you can still do so. If
(36:24):
you visit Sydney, Australia. The Woolworths at town Hall Station
still has a lunch counter on the top floor of
its store. It's not quite the same Woolworths though. Many
years ago I got a new workmate who had just
moved from South Africa to Australia. He told me his
wife had worked as a store manager for Woolworths in
South Africa, but that it wasn't the same store as
(36:45):
the one we had in Australia, so I looked it
up out of curiosity. The original woolworth was founded in
eighteen seventy nine and Utica, New York by Frank Winfield Woolworth.
The store name was either Woolworth without an S on
the end, or with and an apostrophe and an S
on the end. It was originally a discount five and
dime store, specializing in selling items five to ten cents,
(37:07):
and grew to become at one time the largest department
store chain in the world. The podcast Useless Information did
a Christmas special last year that talked about how it
popularized Christmas tree decorations in the US. Sadly, changing times
in competition from new stores like Walmart led to its
decline in the original Woolworths department stores were closed and
(37:27):
the parent company focused on its foot locker brand instead.
Woolworths did, however, set up several overseas subsidiaries in Mexico, Germany, Austria, Cyprus, Britain, etcetera.
The German and Mexican subsidiaries still survived, but the British
chain went out of business in two thousand nine. This
was kind of sad, as Woolworths was a British institution.
My mom even worked in one when she was in
(37:49):
high school in England in the nineteen sixties. Meanwhile, back
in some Australian businessmen want to set up their own
woolworth style store. They had one or two ideas for
the name, but they found the name Woolworths had not
been registered in Australia, so they copied the name. Note
this spelling has an S on the end and no apostrophe.
(38:10):
Wolworths Australia started as a department store, but after World
War Two started selling groceries and developed its own supermarket chain. Eventually,
the department stores were rebranded as Big w for Big
Woolworths and continue today, competing with the discount department stores
like Target and Kymart. Woolworth's and its arch rival Coals
are two big supermarket chains in Australia and control something
(38:31):
like eighty percent of the market. It continues on from there,
but the part about the Australian Woolworths was the part
that I really wanted to read because I found that
all very interesting. Thank you so much to Ian for
writing in about that. Something that we didn't really mention
in the episode or in any of the listener mail
at this point is that a lot of the former
Woolworth's buildings have been converted into something like the building
(38:54):
is still standing with the original historic Woolworths facade on
there um. And one that I have been to is
now the Woolworth Walk in Asheville, North Carolina, which is
like an art and studio space that also has a
fifties style lunch counter in there. So if you'd like
to write to us about this or anither podcast or
(39:14):
a history podcast at iHeart radio dot com and then
we're all over social media at missed in History. That's
where you'll find our Facebook, Twitter, Pinterest, and Instagram, and
you can subscribe to our show on Apple podcast The
iHeart Radio app, and anywhere else to get your podcasts.
Stuff you Missed in History Class is a production of
(39:36):
I heart Radio. For more podcasts from i heart Radio,
visit the iHeart radio app, Apple Podcasts, or wherever you
listen to your favorite shows.
Welcome to Stuff You Missed in History Class, a production
of I Heart Radio. Hello, and welcome to the podcast.
I'm Tracy B. Wilson and I'm Holly Frying if you
are just tuning in today. This is a two parter.
It is on the development of insulin. And last time
(00:23):
we talked about how diabetes has been described through history,
including how people were being treated with starvation diets in
the years just before the development of insulin, and today
we are going to tell the insulin part of the story,
which does build on research that we talked about last
time around. This will the easiest to understand if you
have heard part one. As was the case last time,
(00:45):
we're going to be talking about how experiments on animals
led to this discovery, as well as how the byproducts
of animals that were slaughtered for food we're used to
make insulin. It is not clear who coined the term insulin.
It comes from the word insula or island, as a
nod to the islets of langer Hans. As we talked
about in Part one. The islets of langer Hans are
(01:07):
cells in the pancreas that produce insulin and other hormones.
Jean de Meyer of Belgium used the word insuline with
an E on the end in nineteen o nine, and
apparently independently of that, Ernest Henry Starling, who coined the
word hormone, also used the word insulin with an E.
Four years later. In the early nineteenteen, Sir Edward Albert
(01:29):
Sharpie Schaffer also described a hypothetical substance secreted by the
islets of langer Hans, which controlled the body's glucose levels,
and he called that insulin. This time there was no
E on the end. None of these people are the
ones credited with the discovery of insulin, though that story
starts with Frederick Grant Banting. Banting was born on a
(01:51):
farm in Ontario, Canada, and initially he had planned to
go to divinity school, but after enrolling at the University
of Toronto, he's changed his major to medicine. When World
War One started, he joined the Canadian Army Medical Corps
and was placed on an accelerated medical study program. During
the war, he was wounded in action and awarded the
Military Cross in After the war was over, Banting completed
(02:15):
a surgical residency and tried to set up a private
surgical practice, it did not grow quickly enough for him
to make ends meet, so he also took a part
time teaching position at the University of Western Ontario that's
now known as Western University. The classes that he was
teaching included physiology, something that he had studied as part
of his own medical education, but also something that he
(02:38):
really needed to brush up on in order to teach.
On October thirty one, nineteen twenty, Banting was brushing up
on the pancreas he read a paper called the Relation
of the Islets of Longer Hauns to Diabetes with Special
Reference to Cases of Pancreatic Lithiasis by Moses Barron. This
paper discussed the autopsy of someone you turned out to
(03:00):
have a pancreatic stone that had totally blocked their main
pancreatic duct. The person's pancreas still had islets cells, but
the asiner cells had atrophied. This paper also noted earlier
experiments in which the main pancreatic ducts of various animals
had been partially or totally legated, which had caused similar results,
(03:21):
and that is research that we talked about some of
back in our previous episode. Banting was inspired by this idea.
He wrote a note in his journal which read, quote
diabetes legate pancreatic ducts of dog keep dogs alive till
assony degenerate, leaving islets. Try to isolate the internal secretion
(03:41):
of these to relieve glycosuria. So a few things to
note at this point. One of the Banting's note is
about glycosyria, or sugar in the urine, rather than blood sugar.
Banting also was not really aware of all those experiments
that we talked about in part one. He didn't really
realize that rees As had spent more than two decades
(04:02):
trying to do basically what he was describing without yielding
something that was safe enough to use in human patients.
It's also not clear how exactly that he thought he
might quote try to isolate the internal secretion of the
islets of langer huns, or whether he was thinking about
preparing a pancreatic extract or thinking he might try to
(04:23):
find the secretion itself. Later on, when he told people
from memory what he'd written down in his journal that night,
he said it was quote legate pancreatic ducts of dogs
weight six to eight weeks for degeneration, remove the residue,
and extract, and that is a lot more specific. Also,
part of Banting's basic idea here was a little bit off.
(04:44):
His rationale for causing the acid our cells to atrophy
was that they produced digestive enzymes, and he thought those
enzymes might destroy whatever vital substance was being produced in
the islets of langer Huns. But really these enzymes are
not active until they come into contact with other enzymes
in the small intestine. The relationships between those two different
(05:06):
sets of enzymes had been discovered back in nineteen o four. Also,
it's possible that there's some other explanation, but his misspellings
of both diabetes and glycosuria suggests that Banting wasn't all
that familiar with what he was writing about. So at
this point Banting went to his boss at the University
of Western Ontario about this idea. His boss referred him
(05:28):
to John James Rickard MacLeod at the University of Toronto.
McLeod was born in Scotland and had studied medicine at
the University of Aberdeen. He had also taught at several
universities and institutes in Europe and North America before becoming
professor of physiology at the University of Toronto and also
director of its physiological Laboratory. McLeod was a leading expert
(05:52):
in carbohydrate metabolism at the time, and in nineteen he
had published Diabetes, Its Pathology and Physiology. He had been
trying to identify which part of the nervous system controlled
the liver's glycogen storage functions. Unlike Banting, McLeod knew all
about those earlier attempts to make a pancreatic extract that
could treat diabetes, and he thought there was some kind
(06:14):
of pancreatic secretion that could be the key to an
effective treatment, but he had his doubts about it's ever
being isolated and used. And it wasn't just that McLeod
had doubts about whether it was possible at all to
make a usable pancreatic extract. Those earlier researchers also all
had training and skills and experience that Banting just didn't have.
(06:36):
Mcloud's impression of Banting was that he had a very basic,
textbook level understanding of the pancreas and its role in diabetes,
and really this was pretty accurate. So McLeod was reluctant
to offer Banting the lab space, assistance, materials and animals
that he was going to need to research his idea.
The two men had multiple meetings to talk through the situation,
(06:58):
and then when McLeod finally agreed to let Banting do
some experiments over the summer, Banting actually got a little
nervous about it. Banding still thought that his idea might
lead to a breakthrough, but he also understood that if
he left his practice and his job to pursue an
idea that didn't work out, he would basically have to
start his career over while also trying to pay off
(07:19):
debts from a failed project. On March eighth, one, Banting
and McLeod finally agreed on the terms of the project.
The work would take place over the summer of nine
starting in mid May. Two students, Charles Best and Edward
Clark Noble, would assist Banting. They would divide the summer
between the two of them. These two young men flipped
(07:41):
a coin to see who would take the first shift
with Banting, with Best planning to take the first half
of the project and Noble planning to take the second half.
Best at that point had finished his bachelor's degree in
physiology and biochemistry and was preparing to start medical school.
For about a month, Banting, Best in McLeod all were
together in the lab, with McLeod fine tuning their plan
(08:03):
and process and surgical techniques and instructing them on how
to best prepare an extract. Then in mid June he
left for a vacation in Scotland that he had previously arranged.
We will talk about how Bantings and bests work proceeded
over the summer, which will have more about their animal
experiments after a quick sponsor break. When Frederick Banting and
(08:32):
Charles Best started their experiments on dogs to try to
find a treatment for diabetes, things did not go well.
Their plan was to legate the pancreatic ducts of some
of the dogs, which would cause the assent our cells
to atrophy, but theoretically at least leave the islets of
longer hunts mostly unaffected. By that point, Banting would have
learned that the digestive enzymes were inactive while they were
(08:54):
actually in the pancreas. But this atrophy of the assenter
cells would at least in theory, deuced the amount of
material that needed to be removed from the extract before
it could be safely used. Once enough time had passed
after this legation procedure to allow the asdenter cells to atrophy,
they would euthanize the dog and remove its pancreas, using
(09:15):
it to prepare an extract. Then they'd inject that extract
into another dog whose pancreas had been removed entirely. However,
these surgical procedures could be difficult. It was also summer,
so the facilities where they were working were hot and uncomfortable.
Several of the dogs that they were working with died
of infections or other complications, and they started buying stray
(09:37):
dogs as replacements. It was mid July before they had
a deep pancreatized dog and one with an atrophied pancreas
ready to work at the same time. The process of
preparing a pancreatic extract was also long and complex. It
included chopping the pancreas, chilling it, grinding it up, filtering it,
(09:57):
and warming it back up to body temperature. On July,
they tried injecting their extract for the first time. Although
the sugar levels in the dog's urine did drop, they
rose again pretty quickly. The dog died the next day,
most likely from an infection. Banting and Best kept trying, though.
When Edward Noble came back to the lab to take
(10:19):
over his shift as assistant, he found that the two
of them had worked out this whole rhythm and flow
to their work. At that point, Noble thought that if
he tried to take Best's place, as was previously planned,
he would just become a hindrance to the project. He
would have to learn everything that Best was doing pretty
routinely at that point, so he left Best to it,
although he did come back to the project later on,
(10:41):
which we will get to. In August, Banting and Best
ran out of legated dogs, so they switched to using
the whole pancreas something that, as it turned out, worked
just as well. They kept refining their work and taking notes,
and when McLeod returned to the lab on September one,
they had results. This seemed promising. They were still seeing
(11:03):
some complications, but their extract did seem to be lowering
the glucose levels of deep pancreatized dogs. McLeod, as we
said earlier, was very skeptical about this whole project from
the very beginning, and he was surprised enough at these
results that he questioned whether they were accurate. Banting was
highly insulted by the suggestion, and the two men butted
(11:25):
heads over it. Ultimately, McLeod told them to repeat their experiment.
Apart from taking offense at being questioned about the accuracy
of his work, Banting was also worried about his finances.
He had planned to take the summer to do this research,
but he had not planned for it to continue into
the next academic year. He also thought the facilities where
(11:47):
he'd spent the summer working left a lot to be desired.
For example, he said that they couldn't scrub the floors
thoroughly because if they did, water leaked through the ceiling
of the room below. He thought that was to blame
for some of the infections and the deaths of their
research animals. So Banting asked for a salary and one
for best as well as repairs to the floor of
(12:09):
the lab and an assistant to take care of the animals.
Banting also asked for a biochemist to be added to
the team to help them better refine their pancreatic extract.
McLeod didn't think they were ready for that last step yet,
but he did give Banting and Best retroactive salaries. He
also hired somebody to take care of the dogs and
arranged to have the laboratory floor waterproofed with tar, which
(12:33):
was like the least expensive way to deal with this
water seepage problem. Eventually, Banting and Best tried another source
for their pancreas tissue. After learning that fetal and newborn
calves had proportionally more islet cells than older animals do.
They started buying fetal pancreas from slaughterhouses. They still had
(12:53):
trouble getting enough pancreas for their work, though, so they
ultimately started using the whole pancreas of adult animals, also
purchased from slaughterhouses. In November of one, Banting and Best
published a paper, the Internal Secretion of the Pancreas. Banting
also presented the paper publicly that December in New Haven, Connecticut.
(13:14):
This presentation once again caused tension between Banting and McLeod.
Banting was just not a very good public speaker, and
some of the people who were in the audience on
that day were literally at the top of their field.
He just didn't have the breadth of knowledge to answer
some of the very probing questions that they asked him.
When Banting had trouble fielding questions, McLeod stepped in. He
(13:38):
did have that breadth of knowledge, and he was also
polished and well spoken in his presentation. He also used
the word we a lot, something that wasn't necessarily unusual
considering that the work was happening in his lab ultimately
under his supervision. But Banting felt like McLeod was taking
credit for work that he had not actually done. And
(13:59):
the audience that day was the research director for Eli
Lily Pharmaceuticals, who asked if the company could be involved
in this project, and in McLeod's opinion, once again, they
were not there yet. By the end of though, McLeod
thought the project was promising enough that he finally did
bring on a biochemist, James Bertram Collop, who took a
(14:20):
sabbatical from the University of Alberta at Edmonton to work
on it. McLeod also dedicated the whole lab to the project,
thinking that they were on the verge of a life
saving breakthrough. The extraction method that Collip developed was a
lot more effective but also still very involved. I initially
(14:40):
had like all of the steps written into this outline,
and it went on for paragraphs. He realized that different
pancreatic materials could be extracted at different strengths of alcohol,
and so he developed this method that included multiple extraction steps,
with the results of those extractions being concentrated in centrifu,
huged and precipitated. It went on. He also discovered that
(15:04):
the extracts lowered the blood sugar of rabbits, so they
no longer needed to work with deep pancreatized dogs. Edward
Clark Noble rejoined the project at this point to help
with the studies on rabbits. Running parallel to this work
at the University of Toronto were developments in blood sugar testing,
which made it easier to test their extracts effects on
(15:25):
blood sugar directly, rather than relying on how it affected
glucose levels in the urine. More efficient and effective blood
sugar testing was a huge part of the ongoing development
of insulin. In late December of Banting tried one of
their extracts on a human subject. Dr Joseph Gilchrist had
been one of Banting's classmates and had developed diabetes not
(15:48):
long after they graduated from medical school. This extract did
not work at all, though, and it wasn't because the
extract itself was bad. Even if they had made completely
pure insulin, if taken orally, that would have been digested
in the stomach way before it could have been absorbed
into the bloodstream. In January of the team was ready
(16:08):
for their first attempt at injecting their extract into a
human patient. The patient was Leonard Thompson, who was fourteen
years old and critically ill. He weighed only sixty five
pounds that's about thirty ms when he was admitted to
Toronto General Hospital. He had been on a starvation diet
like we talked about in Part one, which had taken
(16:30):
him down to about four hundred fifty calories per day.
His daily yearine output was about four leaders that's more
than a gallon. A typical amount is more like eight
hundred to two thousand million leaders. And he was also
showing signs of diabetic keto acidosis, which is when the
body starts burning fat instead of sugar for fuel and
(16:50):
as a result, acids start to build up in the
blood stream. So this whole time Banting had felt like
McLeod had been stealing credit for his work, second guessing him,
and undermining him every step of the way. Added to
all of that, Banting could not really control this first
human trial at all. He did not have the background
or the experience that was needed to run a trial
(17:12):
on human subjects. He also did not have the authority
to work with patients at Toronto General Hospital, So when
it came to their first human trial, Banting really insisted
that they use an extract that he and Best had prepared.
They did this on January eleventh. Of This preparation did
lower Leonards blood sugar somewhat, but it did not alleviate
(17:35):
any of his outward symptoms of diabetes. The boy also
developed an abscess at one of the injection sites. Colip,
who was still refining his methods for extraction, really went
into overdrive at this point, finally producing an extract he
thought was pure enough to use. Several days later. They
tried again with this extract on January twenty three of
nineteen twenty two, and this time the results were immediately
(17:59):
and dramatically affected. Leonard's blood sugar dropped significantly, as did
the glucose in his urine, and he also was just
visibly improved. It was obvious to other people that he
was doing better. In the words of Charles Best's notes quote,
daily injections of the extract were made from January to
February fourth, accepting January and February fourth. This resulted in
(18:24):
an immediate improvement. The excretion of sugar became much less,
the acetone bodies disappeared from the urine. The boy became brighter,
more active, looked better, and said he felt stronger. Leonard,
whose condition had been critical when he was admitted, lived
another ten years. After the success, though, the ongoing backbiting
(18:46):
and hostility in the lab became even more dramatic, and
we will get to that. After another sponsor break at
Leonard Tom Sin was getting his first injections of a
working pancreatic extract. The already contentious relationships among the team
(19:07):
from the University of Toronto got even worse. James Callip,
who had not shared the details of his extraction method
with anyone else, threatened to quit the project and patent
it himself. The details here are a little bit sketchy,
but Banting was outraged and he and Collip had a
physical altercation in the lab, with Banting grabbing Collip by
(19:29):
the color of his coat and slamming him into a chair,
and Best writing that he had to restrain Banting with
all of his force. After this, on January two, Banting, Best,
and call Up all signed a memo that none of
them would be seeking a patent for insulin. This was
part of a manufacturing agreement with Connu Laboratories, which is
(19:49):
a public pharmaceutical company that had been established in Canada
during World War One to make diphtheria anti toxin. After
that first successful treatment of Leonard Thompson, six more patients
were treated in February of nineteen two. From there, they
moved quickly into a clinical trial, and at that point
the project largely moved out of Bantings and Best's hands.
(20:12):
As we said earlier, Banting just did not have the
training or experience to run a clinical trial on human subjects,
and he was deeply frustrated by his exclusion, and he
tried to cope, unfortunately by drinking to excess. On March
two of nineteen twenty two, a paper was published in
the Canadian Medical Association journal called Pancreatic Extracts in the
(20:34):
Treatment of Diabetes melitists. It's authors were F. G. Banting, C. H. Best, J. B. Collip, W. R. Campbell, A. A. Fletcher, J.
J R. McLeod, and E. C. Noble. The two names
from that long list of authors that we haven't mentioned
specifically before this point our Campbell and Fletcher, and those
were the doctors who administered the actual injections to the
(20:57):
diabetes patients. On May third, nine two, McLeod presented a
paper called the Effects Produced on Diabetes by Extracts of Pancreas.
It described that extract as insulin, once again from the
Latin route for islands and apparently not related to the
earlier uses of the same term from the same source.
(21:18):
Both Banting and Best refused to go to this presentation.
Between roughly these two papers, between March and May, the
clinical trials of insulin had run into a huge stumbling
block When Connaught laboratories tried to replicate Collips extraction methods.
It just didn't work. Multiple sources described this as Collip
(21:39):
losing the knack for making insulin, or as problems with
translating Collips small scale batches from the laboratory into a
large scale production. They finally did resolve the issues and
started production in mid May of ninety two. For Banting's part,
he believed that Collip had wanted to keep his method
secret for his own benefit, and that consequently he had
(22:02):
not kept good enough records, and that that's why they
were having so much trouble. One patient died during this shortage,
and Banting and call Up had another massive altercation. As
words started to spread about insulin, families started trying to
get their children included in the clinical trials. The most
famous of these patients was Elizabeth Hughes, who was daughter
(22:24):
of former New York Governor Charles Hughes. Her father, Charles
later became Secretary of State in nineteen twenty one and
Chief Justice of the U. S. Supreme Court. Elizabeth had
been born in nineteen oh seven and had developed diabetes
in nineteen nineteen. Elizabeth had been one of doctor Frederick
Allen's patients and had been on a starvation diet before
(22:44):
starting insulin therapy. Alan saw her at a conference later
in nine two, and she was so improved that he
literally did not recognize her. She later wrote. Quote Dr
Allen said, with his mouth wide open. Oh, and that's
all he did, and after starting insulin therapy, Elizabeth lived
until the age of seventy three. Soon there was so
(23:07):
much demand for insulin that cannot labs could not produce
enough on their own, and that is when Eli Lilly
and Company was brought on to increase the output. This
led to yet another challenge, which was trying to standardize
this treatment across two different drug makers who were operating
in two different countries. It wasn't yet possible to measure
(23:28):
the strength of insulin itself. You had to administer a
sample of it to rabbits and then measure the rabbits
blood glucose levels to figure it out. One issue in
this whole process turned out to be because the two
drug makers were using different sized rabbits, with one of
them using rabbits that had been fasted and the other
(23:48):
using rabbits that had been fed normally. He seemed like
such small but important details, very very important details. Uh.
This standardization process ultimately led to the first deaf nition
of a unit of insulin, which was the amount that
it took to lower the blood sugar of a rabbit
weighing two kilograms from zero point one to zero point
(24:11):
zero four five, with that drop happening over five hours
and the rabbit having been fasted for twenty four hours.
Insulin is still measured in units today, but we can
also measure insulin itself now, so today one unit is
equivalent to thirty four point seven micrograms of crystalline insulin.
Throughout the nineteen twenties, Connaught Laboratories, ELI Lily, and numerous doctors, clinicians, researchers,
(24:37):
and others were working on standardizing insulin, with one of
the major contributors being Sir Henry Dale. Sometimes he's described
as being the person who did it, but like there
were a lot of people and entities involved. Another big project,
including most of these same basic entities, was refining the
extraction process and improving the yield of that process over
(24:59):
a few year or as drug manufacturers went from being
able to extract fifteen units of insulin from a kilogram
of pancreas to extracting almost four hundred units per kilogram.
In late nineteen twenty two, George Wilden at ELI Lily
developed a method for isoelectric precipitation of insulin, but the
relationships among banting best McLeod and call up, we're not
(25:23):
nearly as productive. In September of nine two, hoping to
create a definitive account of the discovery of insulin and
put all of the arguing to rest, Colonel Albert Gooderham
asked Banting, Best in mcleoud to each right up their
account of what happened. By that point, coleb had returned
to the University of Alberta at Edmonton, but McLeod wrote
(25:44):
him and asked for his thoughts. This whole process did
not really resolve anything, though. Banting characterized McLeod as constantly
undermining and criticizing him and taking credit for his work,
and he ended his write up with an appendix of
six additional is that he said showed quote a lack
of trust and cooperation on mcloud's part. McLeod characterized his
(26:06):
caution as very reasonable, giving bantings and experience, and he
pointed out that he had frequently taken a lot of
care to give credit to Banting and Best whenever that
credit was due. Best's account was relatively brief and fairly
neutral between the two of them, although Banting, Best, and
McLeod had all agreed not to personally apply for patents
(26:29):
on insulin as part of their agreement with Connent Laboratories.
Patents were needed to ensure quality and safety. This was
a brand new drug that could be life threatening if
made incorrectly, not just because of all the side effects
that we talked about earlier from poorly made extract, but
because of formulation that was too weak or too strong
could be life threatening for patients. At the same time,
(26:53):
the goal was to make insulin widely available as quickly
as possible and for it to be affordable. An in
Culin Committee had been established in early nineteen twenty two
to help coordinate patenting and licensing issues. Numerous patents were
issued on insulin and the process for making it in
the early nineteen twenties. By nineteen twenty six, insulin was
(27:14):
patented in twenty six different countries, and it had become
the standard of care in managing type one diabetes, especially
around the world. The relationship among those men who had
created it was never smooth, though in many ways. Banting
became the face of the discovery. On August nineteen twenty three,
he was on the cover of Time magazine. He received
(27:36):
numerous awards and honors, and he met King George the fifth.
The Banting and Best Chair of Medical Research was established
at the University of Toronto, and Banting was the first
person appointed to it. However, none of that seemed to
outweigh Banting's feelings about another award, which was the nineteen
three Nobel Prize and Physiology or Medicine, which was awarded
(27:59):
to both him and McLeod. Banting was so outraged at
McLeod's inclusion and getting the Nobel Prize that he threatened
to decline the award until somebody pointed out to him
how unfortunate it would be for the very first Canadian
Nobel laureate to refuse the honor. Banting ultimately decided to
(28:19):
give best half of his prize money, and McLeod gave
half of his prize money to call it. The team
also faced criticism from a number of directions in the
early nineteen twenties. Anti vivisectionists objected to the research in general,
and to Banting's admission that they had been buying stray
dogs off the streets when they ran out of research animals,
(28:40):
some of which may have actually been people's pets. Within
the medical community, there were people who criticized the whole
project because even though it had a good outcome, it
had started with Bantings fundamentally incorrect ideas. And then there
was Nicolay Paul Askew, who he talked about briefly in
Part one. He claimed aimed that Banting and McLeod had
(29:02):
stolen his work and that they had only become known
as the people to discover insulin because they had just
made the first commercially viable extract. Poliscue had sent Banting
his papers in ninety one and had asked him to
keep up a correspondence with him, but Banting had never
answered him. Banting and Best had also mischaracterized some of
(29:22):
Poliscue's earlier work in their own writing, something that really
seems to have been because of a mistranslation of a
document that was in French, rather than a deliberate misstatement
on their parts, like trying to cover something up. And
we should also know that there are still people who
make the argument that Polisque should be credited as the
discoverer of insulin, while others point out that he also
(29:44):
published multiple anti Semitic documents and that he helped found
anti Semitic parties that later formed the fascist organization known
as the Iron Guard in Romania. In a strange turn
of events, the one collaborator that Banting was actually on
good turn arms with at the end of his life
was James Collop, who he had shoved into a chair
earlier in this story. By the time Banting died in
(30:07):
nineteen forty, he had fallen out with Best, who he
had previously been close to. That year, being nineteen forty,
Best was scheduled to travel to Europe to act as
a medical liaison during World War Two. He canceled that
trip and Banting took his place, reportedly telling a friend
just before leaving, quote, if they ever give that chair
(30:28):
of mine to that expletive deleted Best, I'll roll over
in my grave. Having made that statement, Banting's flight on
this trip crashed after taking off from Gander Bay, Newfoundland,
on February nineteen forty. Banting survived the actual crash, but
died of his injuries before he could be rescued. In
terms of the other three of those first four contributors,
(30:51):
Charles Best did succeed Banting as the chair of the
Banting and Best Department of Medical Research. He continued to
do groundbreaking work on insta land and he was part
of the development of the drug heperin. He died on
March thirty first, nineteen seventy eight. John McLeod left the
University of Toronto for the University of Aberdeen in ninety eight,
(31:11):
and he died in nineteen thirty five at the age
of fifty nine. James Collup ultimately became the Dean of
Medicine at the University of Western Ontario. He died on
June nineteenth, nineteen sixty five. There have been a lot
of developments in the worlds of endo chronology, diabetes and
insulin since the nineteen twenties. That first preparation made in
(31:33):
nineteen twenty two only lasted for about six hours and
people could have really dramatic spikes and blood sugar as
it wore off. He had to be really careful with it,
so researchers started trying to develop versions of insulin that
would be absorbed more gradually and predictably and would last longer.
Researchers also worked on isolating insulin itself and figuring out
(31:55):
its exact chemical structure. John j Abel crystallized insulin and
nineteen twenty six ten years later, insulin was combined with
the hormone protomine to make a version that was absorbed
more slowly and consistently. In nineteen thirty nine, a version
that combined protomine and zinc was introduced that could last
for up to forty eight hours. Slow acting, buffered lente
(32:18):
insulin's were developed in the early nineteen fifties. Beyond McLeod
and Best, multiple other researchers have been awarded Nobel Prizes
for work that was related to insulin. In nineteen fifty five,
Frederick Sanger was awarded the Nobel Prize in Chemistry for
his work in identifying the amino acids that make up
a molecule of insulin. In nineteen sixty four, Dorothy Mary
(32:41):
Crowfitt Hodgkin was awarded the Nobel Prize and Chemistry quote
for her determinations by X ray techniques of the structures
of important biochemical substances. One of those important biochemical substances
was insulin. Then, in nineteen seventy seven, rosalind Yellow was
one of the recipients of the Nobel Prize in Physiology
Your Medicine Quote for the development of radio immuno assays
(33:04):
of peptid hormones. This was tied to a discovery that
people who got injections of hormones, including insulin, could develop
antibodies to that hormone. Those two decades saw a lot
of other advances in addition to those Nobel prizes. You're
in glucose self test strips were introduced in the nineteen sixties.
In nineteen sixty three and nineteen sixty five, two different
(33:27):
teams each synthesized insulin for the first time. The first
insulin pump was also developed in nineteen sixty three, although
at the time it required a pump the size of
a backpack. Amy's Diagnostics introduced the first blood glucometer in
nineteen sixty nine. The first fully synthetic insulin was introduced
in nineteen seventy five, was made using recombinant DNA rather
(33:51):
than by extracting insulin from animal pancreas. Before this point,
it took an estimated twenty steers or eighty hogs to
get enough insulin for a patient for one year, and
although most people are using synthetic insulince now, animal sourced
insulin is still made today and there are still people
who are using it to manage their diabetes. The ability
(34:12):
to synthesize insulin made it possible for researchers to create
insulin analogs in the nineteen eighties and nineties. These have
slightly different amino acid chains from human insulin, so they
lower blood sugar the way that insulin does, but they
also behave a little bit differently in the body. In
most cases, they're made to be absorbed more quickly or
(34:33):
more slowly than human insulin. Is this research into ways
to improve insulin is ongoing, including attempts to make insulin
that can be administered orally. In the United States, there
have been a lot of headlines about how expensive insulin
has become, and a big reason for that is that
all these refinements and synthetic analogs and other developments, they're
(34:54):
all patented and so drugmakers can set their own price,
and especially with these newer versions, there's just not a
generic alternative available. In general, the lower cost alternatives that
are available we're developed decades ago, so they haven't had
all those tweaks and things like absorption rates that we
just talked about. Using insulin to manage diabetes is a lifelong,
(35:18):
daily process and researchers are still trying to find a
way to treat diabetes directly, rather than using insulin to
manage its effects. This can include pancreatic graphs or transplants,
or finding a way to prevent the body's immune system
from damaging the pancreas in the first place. The introduction
of insulin also made it possible for people with diabetes
(35:39):
to live much longer, so research is ongoing into ways
to treat and prevent the complications that can arise later
in life, including retinopathy, neuropathy, and foot problems. So that
in two parts is insulin? Yeah? Uh, you did some
listener mail on part one? Do you have some more
for part do I do? It is from Ian. Ian
(36:04):
sends a note about Woolworth's lunch counters, and Ian says, Hi, ladies,
thank you for your episode on the lunch counter sit ins.
Although it does feel funny to say thank you for
an episode which essentially involved people being nasty to each
other for something they did not choose, like the color
of their skin. If you want to have lunch at
a Woolworths lunch counter, you can still do so. If
(36:24):
you visit Sydney, Australia. The Woolworths at town Hall Station
still has a lunch counter on the top floor of
its store. It's not quite the same Woolworths though. Many
years ago I got a new workmate who had just
moved from South Africa to Australia. He told me his
wife had worked as a store manager for Woolworths in
South Africa, but that it wasn't the same store as
(36:45):
the one we had in Australia, so I looked it
up out of curiosity. The original woolworth was founded in
eighteen seventy nine and Utica, New York by Frank Winfield Woolworth.
The store name was either Woolworth without an S on
the end, or with and an apostrophe and an S
on the end. It was originally a discount five and
dime store, specializing in selling items five to ten cents,
(37:07):
and grew to become at one time the largest department
store chain in the world. The podcast Useless Information did
a Christmas special last year that talked about how it
popularized Christmas tree decorations in the US. Sadly, changing times
in competition from new stores like Walmart led to its
decline in the original Woolworths department stores were closed and
(37:27):
the parent company focused on its foot locker brand instead.
Woolworths did, however, set up several overseas subsidiaries in Mexico, Germany, Austria, Cyprus, Britain, etcetera.
The German and Mexican subsidiaries still survived, but the British
chain went out of business in two thousand nine. This
was kind of sad, as Woolworths was a British institution.
My mom even worked in one when she was in
(37:49):
high school in England in the nineteen sixties. Meanwhile, back
in some Australian businessmen want to set up their own
woolworth style store. They had one or two ideas for
the name, but they found the name Woolworths had not
been registered in Australia, so they copied the name. Note
this spelling has an S on the end and no apostrophe.
(38:10):
Wolworths Australia started as a department store, but after World
War Two started selling groceries and developed its own supermarket chain. Eventually,
the department stores were rebranded as Big w for Big
Woolworths and continue today, competing with the discount department stores
like Target and Kymart. Woolworth's and its arch rival Coals
are two big supermarket chains in Australia and control something
(38:31):
like eighty percent of the market. It continues on from there,
but the part about the Australian Woolworths was the part
that I really wanted to read because I found that
all very interesting. Thank you so much to Ian for
writing in about that. Something that we didn't really mention
in the episode or in any of the listener mail
at this point is that a lot of the former
Woolworth's buildings have been converted into something like the building
(38:54):
is still standing with the original historic Woolworths facade on
there um. And one that I have been to is
now the Woolworth Walk in Asheville, North Carolina, which is
like an art and studio space that also has a
fifties style lunch counter in there. So if you'd like
to write to us about this or anither podcast or
(39:14):
a history podcast at iHeart radio dot com and then
we're all over social media at missed in History. That's
where you'll find our Facebook, Twitter, Pinterest, and Instagram, and
you can subscribe to our show on Apple podcast The
iHeart Radio app, and anywhere else to get your podcasts.
Stuff you Missed in History Class is a production of
(39:36):
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Hosts And Creators
Tracy V. Wilson
Holly Frey
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