Happy Birthday, Biotechnology

by Greg Conko on October 29, 2007 · 4 comments

So far as I can tell, it’s gotten no attention whatsoever, but today is the 25th Anniversary of the Food and Drug Administration’s approval of the very first ever biotech medical product: Humulin, a recombinant version of human insulin invented by the biotech company Genentech, and marketed by Eli Lilly.

This was a stunning breakthrough because, until Humulin was approved, diabetics used insulin taken from pig and cow pancreases to treat their condition. Using recombinant DNA techniques, Genentech was able to create a product consisting of actual human insulin. FDA completed the review in a remarkably fast five months, at a time when the average review of new medical products was close to three years. CEI adjunct scholar and Hoover Institution fellow Henry I. Miller, who was the FDA medical reviewer in charge of the Humulin dossier, told The New York Times that the speedy review confirmed the ”scientific and commercial viability of” recombinant DNA technology and the biotechnology industry.

Biotechnology has revolutionized the practice of medicine and the pharmaceutical industry. Over the past 25 years, more than 187 biotech medicines have been approved in the United States, and they have been prescribed to an estimated 325 million patients. Over 300 more such biopharmaceuticals are in development. The biotechnology industry has delivered extraordinary medical advancements and has helped to create medicines that treat diseases once thought intractable. Biopharmaceuticals currently are used to treat cancers, stroke, multiple sclerosis, diabetes, cystic fibrosis, and many other diseases. Many forms of cancer that were invariably fatal a decade or two ago have now become treatable and even curable. Other once-fatal diseases have now become manageable conditions for many sufferers thanks to biotech medicines.

Unfortunately, while food biotechnology has the same potential, it has not fared nearly as well. A broad scientific consensus has concluded that rDNA technology (known variously as gene splicing, genetic engineering, and genetic modification) is merely an extension, or refinement, of less-precise breeding techniques that scientists have long used for similar purposes, but it’s use has been hobbled by vast over-regulation in the U.S. and around the world — a phenomenon I have written about at length elsewhere. So, today, let’s celebrate the tremendous success of the medical biotechnology industry, but let us not forget how government has nearly strangled food biotechnology in its crib.

Zev October 30, 2007 at 4:27 am
Maggie Douglas October 30, 2007 at 8:10 am

I'm afraid I must be a party-pooper. The most comprehensive medical review on animal vs. 'human' insulin concluded:

"A comparison of the effects of human and animal insulin as well as of the adverse reaction profile did not show clinically relevant differences." [1]

Where's the "stunning breakthrough"? In fact, this drug established a dangerous precedent, since the claims made at its introduction were not backed by evidence:

"The story of the introduction of human insulin might be repeated by contemporary launching campaigns to introduce pharmaceutical and technological innovations that are not backed up by sufficient proof of their advantages and safety." [1]

Furthermore, Eli Lilly (licensing from Genentech) and Novo Nordisk hold a virtual duopoly on insulin, and both companies have discontinued animal insulin. A recent editorial in a medical journal recounted Novo's introduction of GE insulin:

"Far from responding to the market, a manufacturer now set a new precedent by telling the market what it was going to get. As a result, and within the space of 6 years, the insulin-requiring population of Europe had been changed to a more expensive insulin that it did not really need." [3]

The story of GE insulin is a cautionary tale, not a cause for celebration.

SOURCES:

[1] Richter, B., Neises, G. (2005) “’Human’ insulin versus animal insulin in people with diabetes mellitus.” Cochrane Database of Systematic Reviews, Issue 1 Art. No.: CD003816

[2] Hirst, Jenny (2007) "30 Years of Synthetic Insulin, Are People with Diabetes Getting the Best Deal?" The Insulin Dependent Diabetes Trust. Available: http://www.dri-ft.co.uk/insulin.pdf

[3] Holleman, F. and A. Gale (2007) "Nice insulins, pity about the evidence" Diabetologia 50: 1783-1790.

Scott January 8, 2008 at 10:42 am

I would have to echo Maggie Douglas' comment, and provide a few relevant excerpts from the book "Invisible Frontiers: The Race to Synthesize a Human Gene" by Stephen Hall and James Watson which are worth considering:

As the team noted, in a "Preliminary Communication" published in the British medical journal The Lancet on August 23, 1980, "there seems to be little demonstrable difference between the purified porcine and the genetically synthesized human insulins." But perhaps the more important historical point resided in an unrelated comment. "The experiments described in this paper," Keen's team wrote, "report not only the first use of human insulin produced by recombinant DNA but also, to our knowledge, the first use of any recombinant DNA product in man."

"After all the excitement, all the talk, and all the money," the Economist wondered in 1982, "has it been worthwhile?" Did human insulin represent, as Wally Gilbert suggested to the Cambridge City Council back in 1976, "something which is, in a sense, beyond price"?

A sampling of initial reaction shows, however, that Humulin was greeted more as a technological than a medical breakthrough, and that this sentiment was building even before the drug reached pharmacies. As early as 1980, the British magazine New Scientist reported, "Other big chemical manufacturers predict that Eli Lilly's massive $40 million investment in two plants to make insulin … may be a classic example of backing a loser."

Business Week noted, "Without question, Eli Lilly & Co has gained a place in manufacturing history by being the first company to produce a drug for humans using recombinant DNA technology." But Dr. Henry Miller, medical officer for the FDA's National Center for Drugs and Biologics, told the Washington Post that "the advent of human insulin therapy is not likely to constitute a medical breakthrough for insulin-requiring diabetics." … And the Economist [concluded]: "The first bug-built drug for human use may turn out to be a commercial flop. But the way has now been cleared-and remarkably quickly, too-for biotechnologists with interesting new products to clear the regulatory hurdles and run away with the prizes."

… Art Riggs makes the most impassioned case to the value of genetically engineered insulin. "Human insulin has a very marginal advantage over porcine insulin, and no advantage over the human insulin made by Novo's semi-synthetic process" he admits. "What is a fact is that approximately ten percent of diabetics become allergic to bovine insulin, and even when they're switched to porcine, they still can be in trouble. In 1978, I was told that it was impossible to supply all the world with porcine insulin. Given our present state of technology, it is medically wrong to start any diabetic on bovine insulin, because there's a ten percent chance of an allergic reaction."

"Let me point out to you," Rachmiel Levine said at one point, "that there was really no crying need for human insulin. The refinement of getting human insulin rather than animal insulin has to do with the fact that it differs in chemical structure to a small extent from the ordinarily used pig or beef insulin, and that therefore it has a slight antibody situation so that allergies are more common than with human insulin. But really, the incidence of that is not very severe-insulin allergies or antibody phenomena. It's not severe at all. It occurs. But it wasn't something that cried out for doing something drastically."

Dennis Kleid (of Genentech) vividly recalls the moment when some long-cherished conceits about the uniqueness of genetically engineered insulin began to crumble in his own mind. It came during a trip to Indianapolis in December 1979, when the seasoned hands at Lilly showed the visiting upstart cloners through the insulin plant and explained to them how insulin was prepared the old-fashioned way.

"We were under the impression that it was impure and there was crap in it and stuff like that," Kleid remembers. "But that stuff was crystallized two times in the process. It was incredibly pure stuff. And there were only a few parts per million of contaminants.

That was a real eye-opener. They were not making crap. Maybe they used to. But they certainly, in the last few years were not making it. And they impressed upon us very, very clearly that this [human insulin] was going to be no advantage at all." The newer way of making porcine insulin did not prompt allergic reactions, the biologists were told, and Lilly had enough glands to last for a long time.

As the tour of the facilities continued, the complicated economics of insulin production became clear as well. The Genentech scientists viewed a vault filled with vials of insulin. They were shown a freight car full of frozen pancreases, fresh from the stockyards, 25 cents per gland, shipped by the ton. They were shown where the glands were ground up prior to the extraction and purification of insulin. The recombinant DNA alternative was elegant and less messy, but not necessarily simpler and, more important, no necessarily cheaper, despite all the persistent suggestions, dating back to the ferocious public debates on recombinant DNA, that it might be. …

"With our stuff, he says, "you had to grow these bugs up. You had to expend energy and media to get your starting material from which you extracted the insulin. Then you have to do all this complicated processing. I mean, Lilly's starting material was essentially made with grass in the sun and cows walking around, and it was a by-product of making beef, so their starting material was even cheaper." This was the kind of rude economic awakening that many of the early entrepreneurial biologists experienced. Medical break-throughs did not necessarily follow from scientific breakthroughs.

This is not to diminish all the work-conceptual and technical, basic research and applied-that went into the insulin molecule during the late 1970s. While the marketplace product that emerged in this case may not have revolutionized the care of diabetics, all the techniques discovered and protocols refined and enthusiasm generated by the work have put us well on the way to revolutionizing our understanding of disease, all diseases, and ultimately of how we may cure them.

Of course, the moral to this story is that these promises have (so far) not occurred. What has happened is a story of greed.

What we saw after the advent of human insulin was a burgeoning of biotechnology,

patents and the entrepreneurial riches that might attach to each.

Somewhere along the way, the author (in preceding paragraph) recognized the importance of what had been done, but failed to acknowledge-or perhaps could not even imagine-the succeeding decades that have been marked not by the betterment of mankind, but of the enrichment of corporations that have redefined mission statements to exclude patient welfare.

I should also close by noting that the idea of using 'human' insulin to treat human patients with type 1 diabetes is now known to be seriously flawed. The May 12, 2005 issue of the British science journal Nature, researchers confirmed that the disease begins when the body's immune system reacts to the hormone 'human' insulin, therefore treating patients with a copy of the hormone which caused their disease in the first place vs. porcine insulin, in retrospect, seems to be flawed.

On this anniversary of biotechnology, it should be noted that from an industry perspective, the marketing of synthetic 'human' insulin was highly successful – the choice of the name 'human' insulin was possibly the best marketing strategy in history. It implies that in some way this genetically modified protein is derived from real human beings, not manufactured in a laboratory from yeast or e-coli. However, from a patient perspective, the marketing was misleading and devious, suggesting that animal insulins were being removed from the market and raising fears of shortages of animal pancreases. But above all the marketing made claims of superiority that have never been substantiated.

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