Around the time that Emil von Behring was advancing

the treatment of diphtheria, other scientists

were gaining understanding of diabetes,
another terrible disease.
At the time, diabetes inevitably led to a patient's death.
Doctors knew that sugar made diabetic symptoms worse.
So patients were often prescribed
strict diets of only 800 to 1,000 calories
with minimal sugar.
These diets, however, were not a cure,
and patients would only survive a few extra years at best.
At worst, the patient would die of starvation.
In 1889, Oscar Minkowski and Joseph von Mering
at the University of Strasbourg removed the pancreas from dogs.
They noticed that each of the dogs then developed diabetes.
Based on this observation, it was
concluded that an unknown substance in the pancreas,
which we now know is insulin, was responsible for regulating
sugar levels in the body.
Isolation of insulin proved to be challenging, however.
Several scientists in the early 20th century
made pancreatic extracts that reduced hyperglycemia.
Yet in all cases, toxic reactions to the extracts
halted further experiments.
In 1920, Frederick Grant Banting was
teaching anatomy and physiology at what
is today the University of Western Ontario in Canada.
While preparing for his lectures,
he thought of a new method to prepare pancreatic extracts.
Banting convinced John James Rickard MacLeod,
the head of the physiology department at the University
of Toronto and an authority on carbohydrate metabolism,
to give him lab space and a student-- Charles Herbert
Best-- to pursue his idea.
Banting and Best extracted what they
hoped was insulin from the pancreas of dogs.
When these extracts were administered to diabetic dogs,
the dogs reliably showed a decrease
in their blood sugar levels.
They realized that they would be able to isolate and test
more insulin if they used a larger animal.
So they began using cow pancreases instead.
[MOOING SOUND]
In January of 1922 Banting and Best
prepared an extract that would be used
in the first clinical trial.
It was given to 14-year-old Leonard Thompson,
who was severely diabetic.
The trial was a failure.
There appeared to be no clinical benefit
and young Leonard developed an immunologic response
at the site of the injection.
A second trial would happen later that January.
This time the insulin extract would
be subjected to an additional purification step.
In December of 1921, James Bertram Collip,
a biochemist from the University of Alberta in Edmonton,
had joined the project to work on the purification of insulin.
Banting and Best would prepare another extract and give it
to Collip for further purification.
This purified extract was injected again
in Leonard Thompson.
This time his blood sugar and glucose excretion,
both indicators of diabetes, dropped significantly.
This was the first successful clinical test of insulin
on a human diabetic subject.
And six more patients were treated successfully
shortly thereafter.
For their work in the discovery and isolation of insulin,
Banting and MacLeod awarded the 1923 Nobel Prize in medicine.
Best and Collip were not included on the award,
and Banting and MacLeod each shared half
of the award with them.
Given their clinical success, the researchers
began collaborating with Connaught Laboratories
in Toronto in an attempt to manufacture insulin
on a large scale.
Collip, who developed the insulin purification,
was set to direct the commercial-scale production.
The procedure he had developed, however, no longer worked.
Scaling up from small-scale to large-scale production
was a significant challenge.
Even today, this is one of the main challenges
in modern biomanufacturing.
They turned to Eli Lilly and Company
to help them produce larger quantities of insulin.
They too had difficulty with the purification
until Lilly's chief chemist, George Walden,
noticed that at the right pH the insulin would crystallize
and that those crystals had the highest purity to date.
Eli Lilly began producing large quantities of insulin, which
allowed more than 25,000 diabetic subjects to begin
treatment by the fall of 1923.
This previously untreatable disease
was no longer the death sentence that it once was.
Yet a few key challenges still remained.
First, porcine- and bovine-derived insulins
were not identical to human insulin.
Similar to the anti-toxins produced in horses,
the non-human insulin caused an immunogenic reaction.
In the worst cases, the therapeutic benefit
was completely eliminated.
Second, production of insulin depended on the availability
of animal pancreases.
This supply is largely driven by consumer demand
for pork and beef, not on a diabetic subject's
need for insulin.
In the early 1970s, there became a growing concern
that the world's supply of porcine and bovine pancreases
may not meet the global demand for insulin.
Just as with anti-toxins, these drawbacks
would be important drivers in the search for new ways
to manufacture insulin.
Despite this, the production of insulin from porcine and bovine
sources represented a huge step forward
in the manufacture of protein therapeutics.
It would take another war, however,
to bring about the next advance.
[GUNFIRE SOUNDS]