From insulin to Humulin – the story of the first genetically engineered drug
Frederick Grant Banting: via Wellcome Collection
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When you eat, the carbohydrates in your food are broken down into glucose, which travels into your bloodstream. To stop your blood sugar from getting too high, your body releases a hormone called insulin which encourages cells to remove glucose from your bloodstream, helping you maintain normal blood sugar levels.
In people with type 1 diabetes who produce little or none of the hormone insulin, blood sugar levels can become toxically high, causing damage to tissues and organs, and coma or even death in extreme cases. Fortunately, people living with this type of diabetes can control their blood sugar levels by injecting insulin, allowing them to live relatively normal lives, but this wasn’t always the case.
Rewind the clock around a century back to the early 1900s, and the picture was very different. Back then the only available treatment for type 1 diabetes was a highly controlled, low calorie, low carbohydrate diet, which often bought sufferers to the brink of starvation in an attempt to control the disease. As a result, few people with diabetes survived for more than five years after diagnosis.
In the early 1920s, Frederick Banting, a physician working at the University of Toronto under Professor John James Rickard Macleod, knew there had to be a better way. By 1921, the Toronto team had managed to figure out that insulin - or rather, the lack of it - lay behind diabetes. So, Banting figured, why not try and get hold of some of this magical hormone, then give it to the people who didn’t have enough.
First, he had to find a source of insulin - a protein hormone that’s made by special cells in the pancreas, known as beta cells, and released into the bloodstream in response to rising blood sugar levels. Banting and his assistant Charles Best began by extracting insulin from healthy dogs and using it to treat diabetic dogs. Evidently, their initial experiments weren’t amazingly successful because they ended up killing so many dogs that they eventually ran out and had to start buying them on the black market, before moving on to extracting insulin from cows instead.
Eventually, Banting and Best perfected their insulin extraction and purification process with help from biochemist James Bertram Collip, and in January 1922, they injected the first human with animal insulin. Their patient was a 14-year-old boy called Leonard Thompson, who was in the hospital with extremely high blood sugar and severe complications from diabetes. The treatment bought Leonard’s blood sugar levels down to normal, and he lived another 13 years before unluckily dying of pneumonia.
Soon after, the Eli Lilly drug company started large-scale production of animal insulin, making it the first biological drug on the market and saving many lives. Macleod and Banting went on to share the 1923 Nobel prize in physiology or medicine for their work, splitting their winnings with Collip and Best.
Although animal insulin improved the lives of people with diabetes substantially, around 5% of them suffered allergic reactions to the treatment. What’s more, as the demand for insulin grew, so too did the need for animal pancreases to extract insulin from, specifically the leftover organs of cows and pigs that had been slaughtered for meat. It took around 23,500 animals to make one pound or around half a kilo of insulin, so by the 1970s, Eli Lilly was churning through 56 million animal pancreases per year for insulin production and were struggling to meet the demand for the drug.
By the mid-late-1970s, following the birth of recombinant DNA technology - an early form of genetic engineering - several different scientists had come up with the idea of using the technique to produce human insulin in bacterial cells. You can learn more about the history of genetic engineering in episode 23 of series 1 - GMO, OMG! - but it’s quite simple: take the human insulin gene, stitch it into a circle of bacterial DNA known as a plasmid and put it into bacteria. Then grow up the modified bugs in large vats of broth and wait as they pump out pure human insulin, which you can then purify and give to patients.
But there was just one teeny tiny problem. At the time, we didn’t know the DNA sequence of the gene coding for insulin or even which chromosome held the human insulin gene. In fact, all we really knew was the molecular structure of the hormone itself - a protein made of 51 amino acids, strung together in two chains, which was figured out by British biochemist and two-times Nobel prizewinner Fred Sanger in 1955.
The hunt for synthetic human insulin was led by Herbert Boyer, a biochemist and expert in recombinant DNA from the University of California, San Francisco, who teamed up with two scientists from the City of Hope National Medical Center, Arthur Riggs, a geneticist, and Keiichi Itakura, an organic chemist and expert in chemical DNA synthesis.
Together, they decided to work backwards from the structure of the insulin protein to produce a synthetic gene for it, which they could insert into bacteria to make insulin. Although it sounds conceptually straightforward, chemically synthesising DNA was a long and laborious process that involves building a DNA strand one nucleotide, or letter, at a time until the sequence is complete. And because each amino acid of a protein is encoded by three letters of DNA, they needed to create two perfect sequences of at least 63 and 90 DNA letters, in order to build the 21 and 30 amino acid strings that made up the insulin molecule.
Rather than leap straight to insulin, Boyer and his team decided to start small by trying to make an artificial gene encoding somatostatin, a simple and easily detectable 14 amino acid peptide that inhibits growth hormone. In 1976 they applied for a grant to chemically synthesise the somatostatin gene and express it in bacteria, then, if successful, they planned to move on to doing the same process for insulin. Alas, their grant application was rejected, with the reviewers saying their project was too complex and couldn’t possibly be completed in 3 years.
Undeterred, they started working with a ‘business friend’ Robert A. Swanson who was interested in recombinant DNA technologies. Together, Boyer and Swanson founded Genentech, one of the first biotechnology companies. With investment from Genentech in hand, the team pressed on with the project, producing insulin in bacteria for the first time in 1979, three years after their grant rejection. They chemically synthesised DNA, creating two separate synthetic genes coding for each of the two insulin amino acid chains, which were made and purified separately and then combined together to produce the full insulin protein.
Unfortunately, the initial yields of insulin were tiny, so the team at Genentech had to figure out how to get the bacteria to produce around 50 times more insulin to make the process worthwhile. Eventually, they found a way to hi-jack powerful control genes to encourage the bacteria to produce large quantities of insulin. The project was then transferred to Eli Lilly for large scale production. Clinical trials in 1981 proved the safety and effectiveness of this artificial insulin, which they called Humulin. In 1982 it was approved for use in people with diabetes, becoming the first genetically engineered drug and virtually eliminating the problems caused by allergies and impurities in animal insulin.
A few years later, after researchers had successfully located and sequenced the actual proper human gene for insulin, production moved from using the synthetic gene produced by Genentech to using the human gene for proinsulin, a precursor protein that is cut up in the body to make active insulin molecules.
There have been further innovations over the years since the early days. For example, scientists have tweaked the structure of the hormone to create rapid-acting insulins that are absorbed directly into the bloodstream, rather than sitting under the skin where they’re injected and gradually moving into the blood, as well as long-lasting insulin products that keep working over 24 hours. And there are also innovations like Bluetooth insulin pumps and stick-on continuous blood glucose monitors, all of which help to make it easier for people with diabetes to manage their blood sugar levels.
Thanks to advances in diabetes treatments, including synthetic insulins, people with type 1 diabetes can now expect to live for much longer than the typical five years after diagnosis that would have been their lot a hundred years ago, with an average life expectancy of around 80 years.
However, despite the array of life-saving insulin products that are now available, some people with diabetes still face problems being able to access these treatments because of their astronomically high prices. Insulin prices in the US have tripled between 1990 and 2016, with a single vial of modern insulin often costing as much as $300. This is up to ten times more than the consumer cost in many other countries, and - arguably - completely unacceptable for an essential life-saving treatment.
In the UK and many other countries, healthcare systems negotiate the best prices for drugs like insulin. But in the US, insulin producers are free to set their own prices. Medicare, the government health care plan, is banned from negotiating prices. What’s more, continual ‘improvements’ to insulin products have allowed drug companies to maintain their patents on older versions of the hormone, preventing the production of generic products that would drive down prices.
As a result of the price hikes, some people with diabetes are crowdfunding their medication costs or buying insulin on the black market. Another option, especially in pre-pandemic days, was to travel to Canada where drug prices are strictly regulated, and the same vial of insulin costs a fraction of the price - $20 instead of $300. Others are cutting costs by rationing their insulin, a practice that can increase the rates of diabetes side effects such as eye problems and kidney disease, and has been linked to several deaths.
Looking at the situation facing many people living with diabetes in the US right now, I’m sure that Frederick Banting, who refused to put his name on the patent for insulin because it would be unethical for a doctor to profit from a discovery that would save lives, would be turning in his grave right now, along with his co-inventors who sold the patent for $1 because they wanted everyone to be able to afford insulin.
After all, what good is a life-saving innovation, if it’s unfairly priced out of the reach of the people who need it?
References:
The insulin gene is located on chromosome 11 in humans - Nature
The Insulin Gene Is Located on the Short Arm of Chromosome 11 in Humans - Diabetes
Making, cloning and the expression of the human insulin genes in bacteria - Endocrine Reviews
Immunogenicity and Allergenic Potential of Animal and Human Insulins - Diabetes Care
