Recombinant Insulin: The Birth of Biotechnology

Before Biotechnology

For six decades after its 1921 discovery, insulin came from one source: animal pancreases. Pharmaceutical companies processed millions of pig and cow pancreases to extract the hormone that kept diabetics alive. It took about 8,000 pig pancreases to produce one pound of insulin.[1]

This worked, mostly. But there were problems:

• Supply concerns: The number of diabetics was growing faster than the supply of animals
• Immunogenicity: Pig and cow insulin differ slightly from human insulin, causing allergic reactions in some patients
• Purity issues: Animal-derived insulin contained trace contaminants
• Religious/ethical concerns: Some patients objected to pork-derived products

Scientists knew that human insulin would be better. But harvesting it from human pancreases was obviously impractical. The solution would come from an unexpected direction: bacteria.

The Recombinant DNA Revolution

In 1973, Stanley Cohen and Herbert Boyer demonstrated that DNA from one organism could be inserted into another using restriction enzymes (molecular "scissors") and plasmids (circular DNA molecules that bacteria naturally exchange). This was recombinant DNA technology, the foundation of genetic engineering.[2]

Boyer recognized the commercial potential. In 1976, with venture capitalist Robert Swanson, he founded Genentech (Genetic Engineering Technology), the first biotechnology company. Their initial investment: $500 each, totaling $1,000.

"We were trying to do something that had never been done before: make bacteria produce a human protein. Most people thought we were crazy."

The Race to Make Insulin

Multiple teams competed to produce human insulin in bacteria. The challenges were formidable:

• Human insulin is a protein of 51 amino acids in two chains (A and B) connected by disulfide bonds
• Bacteria don't naturally make human proteins
• The gene had to be designed, synthesized, and inserted into bacterial DNA
• The bacteria had to be convinced to read and execute human genetic instructions
• The product had to be purified and folded correctly

Genentech partnered with researchers at City of Hope National Medical Center (Arthur Riggs and Keiichi Itakura) who had expertise in synthesizing DNA. Rather than isolating the natural insulin gene, they would build it from scratch, codon by codon.

Building the Gene

The team chemically synthesized the genes for the insulin A chain and B chain separately. These synthetic genes were then inserted into plasmids and introduced into E. coli bacteria.[3]

On September 6, 1978, Genentech announced success: they had produced human insulin in bacteria. It was the first human protein made using recombinant DNA technology.

From Lab to Pharmacy

Making a few micrograms of insulin in a laboratory was one thing. Producing it at industrial scale was another. Genentech licensed the technology to Eli Lilly, which had the manufacturing expertise and regulatory experience to bring it to market.

The scale-up was challenging:

• Growing enormous quantities of engineered bacteria
• Extracting and purifying the insulin chains
• Ensuring consistent quality and potency
• Proving safety and efficacy to the FDA

In October 1982, the FDA approved Humulin, the first recombinant DNA drug for human use. It was a watershed moment not just for diabetes care, but for medicine itself.[4]

The Biotechnology Industry Is Born

Humulin's approval proved that genetic engineering could produce safe, effective medicines. Investment flooded into biotechnology. Hundreds of companies formed to exploit recombinant DNA technology.

What followed was a parade of life-saving drugs:

• Human growth hormone (1985): No longer extracted from cadaver pituitaries
• Erythropoietin (1989): For anemia in kidney disease
• G-CSF (1991): Boosts white blood cells during chemotherapy
• Factor VIII (1992): For hemophilia, no longer from pooled blood
• Interferons, interleukins, monoclonal antibodies: Entire classes of drugs

Today, the majority of new drugs approved are biologics: large molecules produced using biotechnology.

Evolution of Insulin

Recombinant technology enabled not just human insulin, but improved versions:

By tweaking the amino acid sequence, scientists created insulins with precisely tailored pharmacokinetics, impossible with animal-derived products.

The Ongoing Challenge: Access and Cost

The insulin story has a troubling chapter. Despite being off-patent for decades, insulin prices in the United States skyrocketed, rising over 1,000% between 1996 and 2019. Patients rationed their supplies; some died.[5]

The reasons are complex:

• Continuous "evergreening" with new analog formulations
• Lack of true generic competition (biosimilars face high regulatory hurdles)
• Pharmacy benefit manager rebate structures
• Lack of price regulation in the US

Recent legislation has capped insulin costs for Medicare patients at $35/month, and manufacturers have announced price cuts. But the crisis highlighted how the fruits of scientific innovation don't automatically translate to affordable access.

Beyond Bacteria

Today, most insulin is produced not in bacteria but in yeast (Saccharomyces cerevisiae) or mammalian cells, which can produce the properly folded, full-length protein more efficiently. The principle, however, remains the same: using recombinant DNA technology to produce human proteins in cellular factories.

Research continues into new production methods:

• Plant-based production: Insulin-producing safflower, lettuce, tobacco
• Oral insulin: Protecting the protein from digestion
• Smart insulin: Glucose-responsive formulations
• Cell therapies: Transplanting insulin-producing cells

Legacy

The story of recombinant insulin illustrates both the power and the complexity of translating scientific breakthroughs into human benefit. A $1,000 investment, brilliant science, and entrepreneurial vision created an industry now worth hundreds of billions of dollars and producing medicines that millions depend on daily.

That first successful expression of human insulin in E. coli in 1978 opened a door that can never be closed. We now routinely program living cells to manufacture molecules of our design. The biotechnology revolution that began with insulin continues to accelerate, promising new treatments for diseases once thought untreatable.