Today, I'm relaying the story of how Insulin was discovered
and ultimately led to the saving of countless lives. Honestly, this whole
scientific tale has been rather neglected and not given the attention it
deserves.
Insulin is a hormone that in short regulates blood sugar
levels, to allow the body to use energy efficiency. So, if you eat a sugary
meal, your blood sugar levels would increase- but the body needs to get this
sugar out of the blood and to the cells that can actually use it .If the sugar
remains in the blood, blood sugar levels get too high and this results in quite
a bit of damage to blood vessels and nerves, along with kidney damage and eye
damage.
For those with type 1 diabetes, or diabetes mellitus,
Insulin is not produced effectively. This is due to the immune system
attacking the beta cells in the pancreas. The beta cells are located in clumps
of cells called the Islet of Langerhans and are where Insulin is secreted
from. Type 1 diabetes is ultimately an autoimmune disorder and if the
beta cells are damaged, insulin cannot be secreted.
Type 1 diabetes was once known as the sugar sickness, and it
wasn't until the discovery of Insulin that it could actually be treated
effectively. Ultimately, it was a death sentence- and a cruel one.
A person's blood sugar would be dangerously high but there would be no way for
the body to actually use this sugar to generate the energy it needed to keep
going.
As a result, other sources of energy would need to be
press-ganged into service. The body would start frantically breaking down fat
and muscle to get energy. But this would result in a condition called Diabetic
Ketoacidosis (DKA) where the blood would become too acidic. Combine this with
high blood sugar and you end with up life threatening medical emergencies - meaning
that before the 1920s, many of those with type 1 diabetes could not hope to
live for long.
Until Insulin was discovered, one of the only effective
treatments would be the starvation diet. This is pretty much as awful as it
sounds, and it did not hope to actually cure diabetes. It only hoped to prolong
life by severely restricting food intake. This was a desperate attempt to lower
blood sugar with patients often consuming only a few hundred calories per day.
This of course made already ill patients thin and fragile.
With this background established, the story of Insulin can
begin proper. The story of Insulin actually begins in 1869, more than 50 years
before Insulin itself is identified. In Berlin, a medical student by the name
of Paul Langerhans (is this name ringing a bell to anyone yet?) looks down a
microscope at a pancreas. At this stage, the pancreas was known to have some
role in digestion - but not much else. Paul Langerhans noticed some tissue
clumps scattered throughout the pancreas which he referred to as 'little heaps
of cells'. As to what they did... well, that wasn't yet clear- but stay
tuned as their importance will soon be discovered.
20 years later, the story takes us over to the University of
Strasbourg where we encounter Oscar Minkowsi, Joseph von Mering, and several
dogs. After removing the pancreas from a healthy dog, these physicians
discovered sugar in the dog's urine. This allowed for a link between the
pancreas and diabetes to be established for the first time. Sadly, the dog
ultimately would have died from complications of the pancreas being removed.
Before I go any further, I should now mention that experiments on dogs play a
very important role in this story. In the late 19th century and early
20th century, there were no formal animal welfare regulations. It is undeniably
sad that these dogs died and modern standards would result in these experiments
being subject to strict ethical oversight. However, in the context of the time,
these experiments paved the way for insulin and ultimately saved millions of
lives. In short, the sacrifice was not in vain and was in fact
life-transforming.
In 1893, it was then suggested by Edouard Laguesse in 1893
that the little heaps of cells discovered by Paul Langerhans may play a
regulatory role in digestion. He named them as Islets of Langerhans in honour
of their discoverer.
Now the story takes away from Europe, and we head over to
Virginia, USA. In 1903, medical student Eugene Lindsay Opie notices
morphological changes in the Islets of Langerhans in patients with diabetes. He
concludes that Diabetes occurs when the Islets of Langerhans are partly or wholly
destroyed.
The story then lags a little bit with many researchers
attempting to isolate the secretions of the Islet of Langerhans. George
Ludwig Zuelzer had some success in 1906 when he injected pancreatic extracts
into diabetic dogs. He also created an extract called 'Acomatol' which was
derived from calf pancreases and injected into it a comatose dying diabetic
patient. The patient showed some improvement but suffered from side effects and
died once the supply of Acomatol was exhausted.
In 1911 and 1912, Ernest Lyman Scott was working at the
University of Chicago, as a master's student under the supervision of Anton
Carlson. It's not quite clear what his exact role in this story was but
it is known that he worked independently on dogs with disrupted pancreases to
isolate an 'active principle' that had anti-diabetic effects. His 1911
master's thesis suggests that he isolated a protein that had clinical benefits
in diabetic dogs. This protein was likely Insulin. However, this version
of the thesis was not published until 1966. Instead, Anton Carlson published an
edited version in 1912 in Scott's name. This version was arguably more
cautious with softened claims. Carlson was sceptical that Scott had
actually isolated the 'active principle’ and it is also important to note that
Scott's extracts were impure and not adequate for clinical use.
In 1914, Zuelzer was still working to seek a cure for
diabetes. With the help of the company Hoffmann-La Roche, his pancreas extracts
reached a higher level of purification and injected into diabetic dogs. Sadly,
the dogs developed convulsions and unfortunately died. Zuelzer believed
this was due to the preparation not being sufficiently purified. In actuality,
it was most likely caused by an overdose of insulin causing hypoglycaemia.
At Rockefeller University in 1915 Israel Kleiner discovered
similar results to Scott and demonstrated how pancreatic extracts caused
hypoglycaemia -low blood sugar. Crucially, Kleiner's work used blood glucose
measurements, rather than urine sugar which many of the other researchers had
focused on. In a healthy human body, glucose is not found in the urine due to
the kidney reclaiming it, but in diabetes, excess glucose spills into the urine
as the kidney is unable to cope with it all.
In 1916, Nicolae Paulescu made significant strides. He was
successful in significantly normalising blood sugar levels in dogs by injecting
a pancreatic extract.
Unfortunately, the work of Zuelzer, Kleiner and Paulescu was
significantly disrupted by WW1. Kleiner was not able to return to his work, and
in Germany, Zuelzer's lab was turned over to the German military. Paulescu also
had to interrupt his experiments as he was called into service in the Romanian
army -although later returned to this story...
The story doesn't pick up again until 1920 in Canada. For those who read my article last week, you might recall the names Frederick Banting, Charles Best, John Macleod and James Collip.
In spring 1921, Frederick Banting is travelling to Toronto to speak to John Macleod at the University of Toronto. Banting was able to conclude in October 2020 that the islet secretion couldn't be effectively extracted as digestive secretions were breaking it down. Banting realised that blocking the pancreatic duct would lead most of the pancreas to die - but the islets would remain intact. He then reasoned that a pure extract could then be extracted. He had an idea: if the pancreatic ducts of a dog were ligated, and the dog kept alive until the pancreas degraded, a pure extract could then be obtained from the Islets. This is what he travelled to Toronto to speak to Macleod about.
Initially sceptical, Macleod agreed to provide lab space. He
also arranged for two undergrads to assist Banting; Charles Best and Clark
Noble. As Banting only required one assistant, the two flipped a coin to decide
who got to be Banting's lab assistant. Charles Best won and was kept by Banting
for the whole summer. In July 1921, the two were able to extract a secretion
from islets of a dog with a degraded pancreas and injected it into a diabetic
dog. This extract reduced the blood sugar of the diabetic dog by 40% in an
hour. In Autumn 1921, Macleod moved Banting and Best to a better
laboratory began paying Banting a salary from his research grants and helped
them publish their results from the next set of experiments. As the process of
duct-tying dogs and waiting several weeks became time consuming, they started
using the fetal calf pancreases - as these had not yet developed digestive
glands. By December 1921, Insulin had also been extracted from the adult cow
pancreas. The main task now was to purify the secretions. Macleod discounted
all other research to concentrate on this and invited James Collip to help with
the purifications.
Meanwhile, Paulescu returned to his experiments and
published four papers about his work. He was able to conclude that pancreatic
extracts that he called pancrein, reduced blood sugar and urinary sugar, and
that the pancreas secretes an internal hormone responsible for regulating
carbohydrate metabolism.
This was different to the work of Scott, Zuelzer and Kleiner
as his experimental results were much more consistent- and complete He had
conducted a series of controlled experiments, published detailed results and
was the first to conclude that the pancreas produces an anti-diabetic
hormone.
Anyway, back in Toronto...
Things started to move at a rather breakneck speed from
there and on the 11th of January 1922, less than a year after Banting's journey
to the University of Toronto, the story takes us to Toronto General Hospital,
at the bedside of a dying 14-year old diabetic.
Leonard Thompson received the first ever injection of
insulin. However, the extract was impure, and Thompson had a severe allergic
reaction. Over the next 12 days, Collip worked to improve the extract,
and Leonard Thompson received the second ever injection of insulin on the 23rd
of January. This time no side effects were seen.
Things then moved even faster from there. In August 1922,
Elizabeth Hughes, the daughter of American statesman Charles Evan Hughes,
received the third ever injection of insulin from Dr Banting in Toronto. She
became the first American to receive Insulin. At the time of her injection, the
15 year old Hughes weighed 20kg and had been surviving on a starvation diet of
less than 800 calories per day. After receiving Insulin, she recovered quickly
and within two weeks was placed on a 2200-2400 calorie weight gain diet. At the
time of her death in 1981, she had received approximately 42,000 insulin
injection.
Also in 1922, twenty-two year old James D Havens become the
first person in America to receive insulin. He received his insulin from
John Ralston Williams who imported it from Toronto to Rochester. Havens
died at the age of 60 from cancer.
Tensions began to rise between the four co--discovers to the
extent that Collip threatened to separately patent his purification process.
Meanwhile, Macleod and Banting were reluctant to patent their process on
grounds of ethics - but concerns began to rise that a third party could hijack
and monopolize the research, and that safe distribution would be difficult to
guarantee. In the end, the four co-discovers along with John G. FitzGerald, the
director of the public health institution Connaught Laboratories wrote to the
University of Toronto to propose an arrangement. This arrangement ensured that
the production of Insulin would be licensed to reputable pharmaceutical
companies, with strict quality controls- but no one including the discovers
could benefit financially. In short, no one could impose monopolistic pricing.
The discovers symbolically sold their patent to the University of Toronto for 1
dollar in January 1923.
By late 1923, large scale commercial insulin derived from
cow and pig pancreases became available in the United States and Canada.
Honestly, it is insane how fast it all moved. The speed at which the drug was
purified and entered the public domain following its discovery was
extraordinary. Ironically, despite advancements in scientific technology making
protein purification faster and more precise, it would now take so much longer
to actually get lab results into clinical practice. This isn't due to slower
science or reduced research but a reflection of modern safety and ethical
standards.
In 1923, The Nobel Prize Committee awarded the prize to
Frederick Banting and John Macleod. As explained in my article last week,
it is still subject to debate why Paulescu didn't receive the Nobel Prize. He
wrote to the Nobel Prize committee claimed he had discovered Insulin first.
Zuelzer also wrote to the Novel Prize Committee claiming he had done it first.
Some would argue that Scott also deserved to be acknowledged as did
Zuelzer. Ian Murray, a professor of physiology in Glasgow,
vice-president of the British Association of Diabetes and a founding member of
the International Diabetes Federation claimed in 1971 that Paulescu did not
receive the recognition he deserved. A potential reason for this is Paulescu
being a victim of bad luck. Banting and Best did reference Paulescu in
their 1922 paper - but made a mistranslation. Paulescu's papers were
written in French and neither Banting nor Best were particularly fluent. They
claimed that Paulescu had stated injections of pancreatic activity does not
have any effect on blood glucose. Paulescu had actually stated the complete
opposite. This mistranslation even became part of the written evidence
supporting the Toronto group's claim of discovering insulin. (My thanks
to Thomas Annesley, Professor of Clinical Chemistry at the University of
Michigan Medical School for teaching me this).
The work in Insulin continued, with the next task
being to determine its structure and what it actually was.
Michael Somogyi, Edward A Doisy and Philip A Shaffer provided evidence that Insulin was a protein in 1924. This was proven when Hans Jensen and Earl A Evans Jr isolated amino acids phenylalanine and proline in 1935. In 1955, Frederick Sanger characterised the amino acid structure of Insulin-he was awarded the 1958 Nobel Prize in Chemistry for this discovery. This allowed for synthetic insulin to be produced for the first time at the lab of Paynayotis Kasoyannis (University of Pittsburgh) and Helmut Zahn (RWTH Aachen University) in the 1960s. In 1969, Dorothy Hodgkin used X-ray crystallography to determine the entire 3-dimensional structure of insulin. She had previously received the Nobel Prize in Chemistry in 1964 for her work in crystallography.
Hans E Weber was able to discover a precursor to Insulin in
1974. This became an important molecule to study transcription and
translation.
In 1978, another major breakthrough was made by Arthur
Riggs, Keiichi Itakura and Herbert Boyer when a genetically engineered
synthetic human insulin was successfully produced using E. coli. This
biosynthetic human insulin became commercially available in 1982 under the
brand Humulin. Most insulin now produced worldwide is biosynthetic human
insulin. Whilst animal-derived insulin was effective and many lived long
healthy lives whilst taking it, it had slight differences in structure which
could result in immune reactions, some injection-site reactions and some
insulin resistance. The biosynthetic insulin reduced in less immune reactions
and was also purer.
This now brings the story up to now. However, the story is
still not finished. Research is still ongoing to improve many aspects of
Insulin production and delivery. Insulin Degludec, under the brand name
Tresiba, is a long acting insulin designed to act over 42 hours, reducing the
number of injections required. Delivery methods are also being researched along
with 'Smart Insulin' - an insulin that would only activate when blood glucose.
Some research focuses on creating a pancreas using stem cell-derived islet of
Langerhans and using CRISPR to deliver the insulin gene allowing the body to
produce insulin itself.
Some of these developments may seem a bit outlandish and
some - like a stem cell pancreas are still potentially years and years away.
But once, it might have seemed outlandish that a cure to diabetes would even
exist. So many researchers played significant roles in this discovery.
Many of us will know someone with type 1 diabetes or maybe are diabetic
themselves. This life-saving hormone is easily taken for granted but it is
built on decades of experimentation, persistence and sacrifice. The work of
these researchers transformed a fatal disease into a manageable condition. This
article and remembering their contributions is more than a historical exercise-
it's also a way to honour the lives saved and the impact this discovery still
plays.
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