Drug Hunters: The Evolutionary History of Insulin

In the lazy afternoon, Lao Yang was bored to brush the news. A piece of news suddenly lit up his eyes and made him feel sleepy. The news wrote: CNR Beijing on May 6, at the centenary of the discovery of insulin, the research progress of oral insulin is exciting.

Oral Insulin Capsules (ORMD-0801) are a new development that breaks through many technical difficulties and upends tradition.
Experts at the meeting said the discovery of insulin 100 years ago revolutionized the world of incurable diabetes.
However, the existing insulin administration methods are all injection administration, which have deficiencies such as hypoglycemia, weight gain and poor compliance, thus restricting the use of many patients.
Because of this, in the past century, scholars at home and abroad have never stopped the pursuit of non-injectable insulin.
In the oral administration, buccal mucosa, sublingual, nasal cavity, inhalation, skin and other ways of drug administration have been explored, but the road of exploration is rather bumpy.

Ning Guang, director of the Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and academician of the Chinese Academy of Engineering, said in a speech, “Oral insulin capsules mimic the path of human physiology after insulin secretion, which can be absorbed through the intestinal tract and directly into the liver, which is more in line with the physiological state.
Its appearance can help patients to start insulin treatment as early as possible and improve patients’ compliance, so as to better control blood glucose fluctuations and delay the occurrence and progression of complications. It is of great help to improve the quality of life of patients with diabetes and has a positive impact on the treatment strategy of diabetes.

At present, 36 hospitals in China under the leadership of academician Ning Guang and director Wang Weiqing Ruijin Hospital, oral insulin capsule Ⅲ phase clinical study.”
Among them, the Tianmai Biological Oral Insulin Capsules (ORMD-0801) of Hefei Tianmai Biological Technology Development Co., Ltd. (Tianmai Biological) is currently enrolled in the phase Ⅲ clinical trial project, which has been completed.

As one of the nearly 130 million sugar friends in China, Yang has a love-hate relationship with insulin — he doesn’t inject it and speaks sweetly.
Injections, in Uncle Ge’s words, are “trouble.”
Some people say that taking medicine is also OK. Let’s take a look at the current domestic market share of insulin in hypoglycemic drugs in 2020.

Data source: public data collation

Yes, insulin has become the dominant hypoglycemic drug, accounting for half of all sales.
Now that we are talking about insulin, Yang would like to take a look at its history and context.

Eli Lilly’s founding covenant with insulin in the early 20th century

First, back to Long Long Ago, the story goes back to 1897, when Bayer started selling aspirin and was making a lot of money.
The success of these synthetic drugs has opened the door for pharmaceutical companies to create original synthetic drugs.
With the turn of the 20th century, several pharmaceutical companies in the United States, including Eli Lilly, were among the first to set up research and development teams to search molecular libraries for useful compounds.
Eli Lilly, the third-generation head of the company, was so envious of Bayer’s success in Germany that he decided to get his own company involved.

In 1919, Eli Lilly hired a scientist named Alec Krauss to look for potential new product opportunities.
Kraus began researching which diseases offered the most promise for developing new drugs, and he soon zeroed in on a disease for which there was no cure at the time: diabetes.

As far back as 2000 BC, Indian doctors discovered that ants were particularly fond of the urine of certain patients, and Egyptian manuscripts of the same period also recorded “excessive urine volume” in some patients.
This is the earliest documented case of diabetes.
The Indians called the disease “honey urine” and the Greeks called it “polyuria” because the patient urinated too much.
In 1675, an English doctor added the Latin word “sweet” to the name of the disease.
Today, the disease is known as Ⅰ type diabetes.

When Dr. Kraus joined Lilly, diabetes patients typically died within a year of diagnosis.
More than 4,000 years after honey urine was first recorded, there is still no cure for the disease.
Klaus hopes to change all that.

Fortunately, there is a widely accepted view of which drugs are likely to be effective for diabetes, and this view came about by accident.
In 1889, two European doctors, Josef von Mering and Oskar Minkowski, discovered that dogs’ pancreases secreted a hormone that controls how the animals metabolize glucose, a hormone we know today as insulin.

Based on Mellon and Minkowski’s work, scientists concluded that simply injecting insulin into diabetics could cure the disease.
But the problem was stuck on the extraction, until Frederick Banting came along.

In 1921, on a balmy Toronto summer day, Banting and his young assistant, Charles Best, began the drug hunters’ traditional tool of trial and error. After countless refinements, the experiment progressed, but the purity and mass production of the extract became so puzzling that Eli Lilly stepped in.
Klaus reached out to Banting after hearing him speak at Yale.

With the support of Eli Lilly, a suitable diabetic was quickly found at the Toronto General Hospital in 14-year-old Leonard Thompson for the first human trial. Fortunately, it worked. Thompson received insulin injections, which, though not a cure for diabetes, prolonged his life for another 13 years.
Once diagnosed with diabetes, people were lucky to live for a year. Today, with daily insulin injections, diabetics live an average of only 10 years less than the general population.

Image source: Internet

In 1923, when insulin from Eli Lilly was first released in North America, it didn’t matter whether Banting, Kraus, Eli Lilly or insulin had made a difference. What mattered was that Thompson was saved, and then hundreds of millions of sugar friends.

Top 10 Hypoglycemic Drugs by Global Sales in 2020

Data source: public data collation

Since then, the development of insulin has also gone through the course of animal insulin, human insulin and insulin analogues, which has changed the fate of countless diabetes patients.

Image source: Internet

The first generation of insulin — animal insulin. When Kraus obtained the license for the method of extracting insulin, he quickly mobilized Lilly’s Indiana plant to purchase large quantities of pig and cow pancreases to prepare for mass production of the first generation of insulin.
With a budget of $200,000 ($3 million in today’s dollars), the project was developed on an industrial scale within a month, and with the help of more than 100 scientists, by the end of 1922 Eli Lilly finally had a reliable way to produce animal insulin in good quality and in good quantity.
This period lasted for more than 50 years.

After more than half a century of suffering from allergic reactions to animal insulin, a new opportunity arose in 1972.
Genetically engineered drugs were born after Stanford professor Paul Berg, who studied viruses, performed one of the most important experiments of the 20th century, called recombination.
In 1976, herb, Boyle, professor of biochemistry at the university of California and Robert swanson (VCS) opened in San Francisco “genentech” to research and development production of human insulin, genentech took more than a year to isolate human insulin gene, but the r&d expenses very fast, they need new partners, an injection of new funds
When faced with a choice between Eli Lilly and Squibb, the first company to go was Squibb, but Squibb missed out on one of the most significant changes in drug development history because of its judgment.
When it came to Eli Lilly, not daring to risk losing the entire market, it agreed to partner with Genentech in 1978.
Human insulin was first marketed in 1982.

The third generation of insulin, the insulin analogue, once the door was opened, the code would follow.
In the late 1990s, in the in-depth study on the structure and composition of insulin, humans found that modification of the peptide chain may change the physical and chemical properties and biological characteristics of insulin, so as to develop insulin analogs that are more suitable for human physiological needs than traditional human insulin.
In 1996, Eli Lilly introduced the world’s first insulin analogue, Lyproline.
In 2000, Sanofi (France) launched the first long-acting insulin analogue, insulin glargine.
Today, a variety of insulin analogues produced by different companies continue to emerge.

The domestic dream team and its successors

Back at home, let’s see how our insulin-wielding swordsmen are cutting their way through.

Back in 1958, when the People’s Republic of China was founded less than 10 years ago, economic development and material conditions were relatively backward.
The British chemist Sanger won the Nobel Prize in chemistry that year for completing the entire sequencing of insulin, and the academic journal Nature said in a commentary that year that “the synthesis of insulin will be a distant thing.”
On the other side of the world in developing China, in a small room at the Shanghai Institute of Biochemistry, eight 30-somethings are meeting to discuss “what to study”, led by Wang Yinglai, the institute’s slightly older director.

This is a “dream team” in the field of biochemistry in China.
King should biochemical Dr. Lai is the university of Cambridge, enzyme chemist Zou Chenglu from Cambridge, Cambridge protein experts from Cambridge, nucleic acid experts de-bao wang is the Johns Hopkins university postdoctoral, vitamin experts Zhang Youduan also from Cambridge, protein experts NiuJingYi is the Texas state university, PhD, biochemical experts guang-yu zhou is a doctor at the university of leuven in Belgium,
Shen holds a PhD from the University of Toronto, Canada. Xu graduated from the Department of Chemistry, Southwest Associated University.

At the nine-person conference, the idea of moving into the life sciences and synthesizing proteins generated a lot of discussion.
What scholars in developed countries in Europe and America did not know was that Chinese scientists, with relatively “poor” scientific research facilities, dared to challenge the task of “synthetic insulin”, which seemed impossible at that time.
On December 18, 1958, the Institute of Biochemistry formally confirmed the project of synthetic insulin, and invited Peking University and other units to participate in the research.
After a lot of experimental design, and a lot of trial and error, the Chinese drug hunters finally crystallize bovine insulin on September 17, 1965.

China’s insulin market started late, and there is a gap with foreign technology.
At present, the domestic insulin market is mainly dominated by imported products, with international leaders Novo Nordisk, Sanofi and Eli Lilly ranking the top three, occupying 70% of the domestic market share.
Major domestic insulin manufacturers include Tonghua Dongbao, Ganli Pharmaceutical Co., Ltd., Federal Pharmaceutical Co., Ltd. and Jiangsu Wanbang Co., Ltd.

Said to tonghua dongbao and GanLi pharmaceutical, have to mention is currently the largest GanZhong such as Dr, insulin founder GanZhong such as Dr. Graduated from Peking University department of biology, the early reform and opening up is the second batch of Chinese students by Mr. Deng xiaoping advocated traveled abroad, then he has a doctor’s degree at Michigan state university and in the United States Merck postdoctoral, senior biochemist.
In 1995, he came back to China and wanted to develop the recombinant human insulin project in the field of biological medicine, so he started to produce the second generation of human insulin in cooperation with Li Yikui, one of his former classmates at Peking University and the chairman of Tonghua Dongbao.
By 1998, they had put the second generation of recombinant human insulin on the market, making China the third country in the world to produce and sell recombinant human insulin.
At the time, only Eli Lilly and Novo Nordisk had the same product, and Sanofi had no similar product on the market.

In 1998, Dr. Gan Zhongru established Gan Li Pharmaceutical Co., Ltd. to develop the third generation of insulin.
By October 2005, the third generation insulin analogue was on the market.

So will oral insulin capsules be Generation 4 or Generation 3 +?
That doesn’t matter. What matters is that a new generation of drug hunters is still building magic bullets, dreaming of solving the world’s problems, and vying to be the ultimate terminator.