Insulin Factories

Insulin, the diabetes-treating hormone, is now mass-manufactured from transgenic bacteria that have been engineered to carry and express the human insulin gene. The human insulin saga is of historical interest because it provides one of the first success stories in genetic engineering and also illustrates the broader trials and tribulations of the neophyte GM enterprise.

In the spring of 1976, in Indianapolis, the pharmaceutical giant Eli Lilly convened a national scientific symposium about insulin. For decades, Lilly had purified this pancreatic protein, for human therapeutic purposes, from slaughtered cattle and pigs. When administered by injection, animal insulin enables diabetics to metabolize sugars that otherwise accumulate in their bodies at debilitating and sometimes fatal levels. Lilly had done well in the insulin trade, tallying about $160 million in annual sales to a market of more than 1 million insulin-dependent diabetic sufferers in the United States alone. But Lilly's business charts identified an ominous trend: projected insulin demand someday might outstrip the available supply from farm-animal tissues. Furthermore, as a therapeutic drug, animal insulin was less than ideal because its structure differed somewhat from that of human insulin. This could cause problems, as, for example, when diabetic patients developed antibodies to animal insulin.

The Indianapolis meeting had a stellar lineup of insulin experts as well as leaders in the infant field of molecular biology. The latter included Howard Goodman, known for his pioneering role in the characterization of bacterial restriction enzymes; William Rutter, an expert on molecular functioning in the pancreas; Argiris Efstratiadis, soon to be famous for inventing methods for isolating genes and for synthesizing gene segments in vitro (outside living bodies); and Walter Gilbert, who four years later would receive a Nobel Prize in chemistry for contributions to the experimental manipulation of DNA. This impressive scientific gathering provided an early intellectual spark for genetic engineering research.

Participants came away from the meeting fired by a realization that it might be feasible to isolate the insulin gene from the tangled jumble of DNA in mammalian cells, clone that gene by splicing it into bacteria, and perhaps even coax the GM bacteria to produce human insulin in commercial quantities. Soon, a scientific race began as researchers got caught up in an insulin sweepstakes that promised huge scientific as well as financial rewards to the winners. Major participants in this race were a Gilbert—Efstratiadis team at the University of California at San Francisco, a Goodman—Rutter team at Harvard, Herb Boyer (another noted molecular biologist in California, who a month earlier had co-founded Genentech, one of the world's first genetic engineering companies), and industry scientists at Genentech and Lilly, for example.

Within a year, the University of California group announced a major breakthrough. Using pancreatic cells from a special strain of rats, they had managed to isolate the protein-coding DNA sequence for rodent insulin and insert and amplify it in a bacterium. In other words, they had cloned the rat insulin gene, much to everyone's amazement. About one year later, the Harvard group did them one better by contriving a bacterial strain that expressed (turned on) the rat insulin transgene. In essence, the GM microbes produced a protein of potential use in the treatment of diabetes.

Technically, however, what those GM bacteria actually produced was proinsulin, an insulin precursor molecule. At about that same time, the California and Genentech teams were racing to find ways to align, snip, and girder such precursor molecules so as to get bacteria to make bona fide mammalian insulin. Meanwhile, Genentech and the University of California made independent agreements with Lilly regarding how the technologies might be applied to clone and express the human insulin gene for commercial markets. Finally, in 1982, Lilly began to market genuine human insulin produced by GM methods. Sold under the name Humulin, this was the first biopharma-ceutical product of medical value to be engineered by recombinant DNA procedures. Today, according to Lilly, more than 99% of all insulin used in the United States comes from genetically engineered sources. Total U.S. sales of this drug amount to more than $3 billion annually.

It would be naive to think that this entire research effort was cordial and collaborative. To the contrary, it was often highly competitive and even cutthroat, as recently became apparent during lurid courtroom disclosures in a major lawsuit. For the groundbreaking technologies that its faculty devised during the course of cloning the insulin gene, the University of California won two U.S. patents that Lilly ignored as the company proceeded with marketing human insulin from recombinant bacteria. To tap into some of the windfall profits, the University of California sued Lilly in 1990. This led to an eight-year court battle with squadrons of attorneys representing both sides and charges of misconduct flying back and forth over technical scientific and legislative matters. In the end, a federal judge ruled in favor of Lilly, yet also exonerated all of the participating researchers of any scientific misconduct.

Beyond stiff competition per se, the 1970s were trying times for the genetic pioneers for another reason. Even as researchers began conducting their seminal GM experiments, American society had begun debates over the fundamental merit of any and all genetic engineering. For example, in Cambridge where the Harvard team worked, the city council held heated public hearings that in 1976 precipitated a critical seven-month moratorium on certain kinds of recombinant DNA experiments.

On the national scene, scientists already had debated such matters for several years, one result being a series of research guidelines by the National Institutes of Health (NIH) concerning recombinant DNA procedures. This proved crucial in the insulin case because in 1976 the NIH had not yet certified as safe one of the plasmid cloning vectors (see appendix) that was central to the ongoing insulin research, especially in California. Ambiguities related to this certification process surfaced again in the aforementioned court battle between the University of California and Lilly. Thus, especially in those early years of genetic engineering (but continuing to a lesser extent today), the sociopolitical climate in the United States was a daunting hurdle for basic and applied research on recombinant DNA.

Notwithstanding these several controversies that accompanied development and marketing of GM insulin, the enterprise overall merits recognition as an unequivocal boon, both in terms of producing a valuable medical product and in having pioneered ideas and research approaches that were critical to the broader development of the genetic engineering field.

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