A Sweet Invention

Insulin pen used to inject insulin. Wikimedia Commons.

If your lunch or dinner companion pulls out a pen and instead of signing the check jabs her stomach with it, don’t run away: you are seeing the lifesaving fruits of a new science.

Chances are the person has diabetes, and the “pen” provides the insulin that a diabetic’s body can no longer produce. Diabetes sufferers must constantly monitor the amount of sugar in their blood; if levels get dangerously high, they need a shot of insulin. Modern pens with short, thin needles and preloaded cartridges with specific insulin doses are widely available and take away some but not all of the unpleasantness of injection.

A terrifying 25.8 million children and adults in the United States (that’s 8.3% of the population) have either type-1 (an autoimmune disease) or type-2 diabetes, and that number rises each year as the world’s population ages and grows increasingly obese and sedentary.

The ancient Egyptians, when faced with an ailment that caused sufferers to urinate excessively, prescribed a rectal injection of honey, sweet beer, or sea salt. Despite treatment, death always ensued. By the early 20th century calorie-restricted diets existed, but life for a diabetic was still short—and ended in an agonizing slump into a diabetic coma. 

For a disease known for over 3,000 years understanding came late: not until the early 20th century was insulin found to be important in diabetes. In 1921, thanks to a few brave dogs, Frederick Banting, Charles Best, and John Macleod at the University of Toronto were the first to extract insulin, which came from the dogs’ pancreases. The loss of insulin made the dogs diabetic, but they were kept alive by injections of insulin taken from their extracted organs.

Insulin became medically available to diabetics by 1923. The drug at that time was extracted from the pancreases of pigs and cows slaughtered for their meat.

By 1976 Eli Lilly, the leading insulin producer, had become concerned about its ability to provide enough animal insulin as the number of diabetes sufferers increased. At roughly the same time, scientists were developing techniques to manipulate DNA. Recombinant-DNA technology is a way of knitting together DNA fragments—often from two different organisms—to make a new DNA sequence. Concerns about this technology played out in the press: scientists were accused of trying to create monsters, of behaving like Dr. Frankenstein or even God. The scientists themselves worried about accidentally creating rogue DNA. In response to these concerns, in 1976 the National Institutes of Health came up with the first guidelines for use of recombinant-DNA technology, which included the recommendation that certain experiments not be carried out and that all experiments be done in safe, secure labs fitted with biohazard equipment.

By 1978 the race was on to use recombinant DNA to make something useful. The target: insulin.  Three teams entered the contest, including one led by Herbert Boyer, who in 1976 had formed a small company called Genentech.

The Genentech team built from scratch the small, single strands of DNA that coded for human insulin. They then stitched this strand into the DNA of a bacterium: when the bacteria multiplied, each descendant contained the instructions to make human insulin. The other teams were attempting to coax bacteria into producing insulin by stitching in insulin-coding DNA taken from rats.

Genentech won the race by a hair’s breadth.

Ron Wetzel, a structural biologist who joined Genentech in 1978, remembers the skepticism of the scientific community. “There was a lot of excitement about the insulin project,” he said in 2011, “but this was a concept that many people believed would never work. [They] thought that there were barriers built into evolution that would prevent the large-scale commercially feasible synthesis of human proteins in bacteria.”

Synthetic insulin came to market in 1983 after yet more groundbreaking moves—the Food and Drug Administration’s approval of the first genetically engineered drug.

Genentech kicked off a new scientific revolution: the era of start-up biotechnology companies had begun. “There’s a before and there’s an after,” says author Stephen Hall, whose book Invisible Frontiers charts the race between those three groups in the 1970s. And before Genentech life scientists weren’t used to commercializing their ideas.

For diabetics the switch from animal-derived insulin to bacteria-made human insulin was fairly insignificant. The clinical efficacy of human or animal insulin is the same, although pig and cow insulin occasionally provoked minor allergic reactions. More important was the next step in recombinant-DNA technology: insulin analogues.

Insulin analogues are slightly altered versions of human insulin; one or more amino acids are changed to form insulins with different clinical benefits. A fast-acting insulin analogue was developed for mealtimes—when a diabetic needs a quick-acting dose—and a slow-acting analogue for between meals—when a steady, slow supply is required.

No matter the form of insulin, those now jamming that needle in their stomachs will one day be able to toss the pen for a pill. Biotechnologists are working to create a pill form of insulin, one that won’t be broken down by the gut before it gets into the blood (in a healthy body insulin is secreted from the pancreas directly into the bloodstream).

But all recent and future developments are the consequence of those first brave steps taken in the late 1970s. “The legacy is just huge,” says Wetzel of human insulin. “It really was a turning point, both in industry and in medicine.”

Biotech companies and recombinant-DNA technology have given us new drugs, as well as new insect-resistant and herbicide-resistant crops. Thanks to changes in how and where research is done—a direct consequence of the development of human insulin—we can now get our genomes sequenced. In the not-too-distant future our medicine will be personalized to match our individual genetic quirks. The legacy of human insulin is shared by far more than diabetes patients; Stephen Hall wasn’t exaggerating when he said, “It changed everything.”

Katharine Sanderson is a freelance science journalist based in Toulouse, France.

 

Read the PDF of the National Institutes of Health’s original press release for recombinant-DNA technology.

Listen to some of the issues surrounding personalized genome-based medicine.