The story of insulin - drug innovation at the speed of life

Yesterday was World Diabetes Day. This year, the occasion is even more significant as it marks 100 years since the discovery of insulin, the hormone that helps the body control blood sugar levels.

In diabetes, blood sugar control is poor, and this results in all sorts of medical issues such as heart disease, stroke, kidney failure and gangrenous limbs. Singapore has one of the highest rates of diabetes in the world, and high rates of kidney failure, limb amputations, and cardiovascular disease that can be attributed to it.

The National Population Health Survey reported that in 2017, 8.6 per cent of Singapore residents had diabetes. And, according to other studies, up to one in three Singaporeans has a lifetime risk of developing this condition.

There are two types of diabetes.

The more common one seen the world over is known as Type 2 diabetes. This is generally considered a disease of "lifestyle", where poor diet, obesity and lack of exercise contribute to a condition known as "insulin resistance", whereby the effect of insulin produced in the body is blunted, resulting in frequent and sustained high blood sugar levels.

This tends to occur in adulthood.

The less commonly seen version is Type 1 diabetes, where insulin-producing cells in the pancreas are damaged and the poor sugar control is a result of the lack of insulin.

This occurs in childhood as a result of an autoimmunity - and in the days before the development of insulin as a treatment, it resulted in severe wasting, dehydration and eventually death.

Children afflicted with this condition, when untreated, suffered slow and agonising deaths. They would be normal one day, and then suddenly present with severe thirst and constant urination, and lose weight and muscle mass.

Over weeks and months, the weight loss progressed, acid built up in the system, breathing became laboured, until the child died, usually within a year of diagnosis. The parents of these children were invariably desperate for a cure, but could only look on helplessly.

In November 1920, three scientists, Sir Frederick Banting, Charles Best and John Macleod, put their minds together to purify extracts of the pancreas that might be used to treat this dreadful, fatal condition.

Experiments started six months later, in May 1921, on dogs.

By November of that year, the team was able to use this extract to successfully treat diabetic dogs that had their pancreas removed.

With this, they moved to further purify the extract for human use, and brought in biochemist John Collip.

On Jan 11, 1922, this purified extract was used to treat a 14-year-old boy with Type 1 diabetes, Leonard Thompson.

The first treatment was a partial success, with blood sugar levels dropping. But this first version suffered from lack of purity and concentration, resulting in an abscess at the injection site, and the blood sugar did not fall far enough.

The next effort a few weeks later with a more purified version produced much improved results.

Type 1 diabetes had turned from a death sentence into a treatable condition.

Subsequently, the universities and scientists involved in this singular breakthrough, understanding their own limitations for large-scale manufacturing, worked with Eli Lilly and other companies to scale up mass production.

Today, insulin for human use is no longer extracted from animal sources, but produced by bio-engineered cells, and it is delivered to tens of millions of people globally every day.

Some of these insulins have been engineered with synthetic modifications that improve their profile when used as an injection.

This is a remarkable story of science, perseverance, collaboration and belief.

The speed at which it progressed from scientific idea to use in patients was unprecedented.

From the concept of injecting an exogenous extract for the control of sugar, to the set-up of experiments, rounds of purifications, and eventual successful trial administration to a human subject, it took not much more than 14 months.

A year later, in 1923, insulin was already in mass production, with enormous improvements in purity and scale, and being delivered into the arms of thousands of patients.

Apart from celebrating the centenary of the achievement, the basis of which has transformed millions of lives, are there lessons to be taken from this story?

Scientific and medical research is messy, as this endeavour is at the forefront of discovering new information and developing new capabilities.

In developing new medicines, one treads the thin line between safety and effectiveness in humans, and sometimes difficult trade-offs have to be made between the two.

Where a disease can cause significant mortality and morbidity, one might be willing to tolerate greater risk or endure higher degrees of side effects.

The classic example here is in many cancers: If the outcome of disease progression is rapid death, many patients and their treating physicians are likely to have a higher tolerance for side effects and risks.

This would not be the case for milder illnesses such as the common cold.

In other words, the risk-benefit calculus for each disease-treatment pair is specific.

Related to this is the further question of how much information is needed before progressing development from one stage to the next, and how fast can one reasonably go.

Again, it is down to the exigencies of the condition.

If effective alternative treatments are available, one could perhaps take a more leisurely approach.

If one were in the middle of a raging pandemic where thousands of people are at risk of dying every day, the notion of waiting for 10 years of safety data for a new vaccine is plainly ludicrous.

The story of insulin is now a hundred years old.

Banting, Best, Macleod and Collip had their fair share of detractors in their day.

At the time, however, knowing that there was no cure for that fatal, debilitating illness, they worked with fortitude and speed, and focused on delivering a transformative medicine as quickly and safely as possible.

When lives are at stake, nothing less will do.

• Dr Danny Soon is chief executive officer of the Consortium for Clinical Research and Innovation Singapore. He is also executive director of the Singapore Clinical Research Institute.