Eli Lilly and Company developed an industrial method to supply enough genetically engineered human insulin (Humulin) to meet the needs of the millions of diabetics worldwide.
Carbohydrates (sugars and related chemicals) are the main dietary food and energy source for humans. Most carbohydrate eaten is polymers of the sugar glucose, like plant starch and its animal equivalent, glycogen. In affluent countries, more than 50 percent of the dietary intake of calories is composed of carbohydrates. In underdeveloped countries, dietary carbohydrate content is even higher, reaching 70 to 90 percent of the caloric intake. Therefore, the appropriate disposition of dietary carbohydrate more than a pound each day is essential to the quality and length of human life. Normally, most dietary carbohydrate is rapidly used (metabolized) to produce the energy needed to run the body. Excess carbohydrate is either converted to fat, for storage, or stored as the glucose polymer glycogen. Body glycogen about a pound in most adult humans is broken down to produce energy when needed. Several diseases of carbohydrate metabolism prevent normal carbohydrate disposition and cause health problems in humans.
Genetic engineering is being used to synthesize large quantities of drugs and hormones such as insulin for therapeutic use.
The most frequently seen disease of carbohydrate metabolism is diabetes mellitus,
Uncontrolled cases of diabetes are very dangerous because they can lead to deterioration of the eyes and eventual blindness, to kidney dysfunction, to severe damage to blood vessels and other cardiovascular problems (for example, atherosclerosis), to a reduced life expectancy, and to coma followed by death. It is these complications that explain why diabetes is the third most common killer in the United States. The basis for most of the problems caused by diabetes is the high glucose levels in the blood. For example, cataracts often form in diabetics, as excess glucose is deposited in the lens of the eye.
Major symptoms of diabetes include continual thirst, excess urination, and large amounts of sugar in blood (hyperglycemia) and urine (glycosuria). In fact, the term “diabetes mellitus” means excessive excretion of sweet urine, and measurement of the glucose content of urine is one way to diagnose the disease. A more reliable test for diabetes, however, is examination of the blood glucose content and its response to glucose intake, the so-called glucose tolerance test (GTT). People given a GTT are first told to fast overnight and then given about one-quarter pound of glucose (dissolved in water) to drink.
Blood glucose levels are measured shortly before glucose administration and every thirty to sixty minutes during the next four to six hours. In nondiabetics, the glucose levels observed during a GTT do not rise above 180 milligrams per 100 milliliters. Furthermore, they drop to about 100 milligrams per 100 milliliters within two hours, as the glucose is assimilated because of pancreatic insulin production. In juvenile-onset diabetics, the blood glucose levels rise much higher and do not drop at normal rates. Furthermore, glucose from the test dose appears in the urine of most such diabetics.
Genetically engineered human insulin.
Until the 1920’s, control of the symptoms and consequences of juvenile-onset diabetes was possible only through the use of diets that severely restricted carbohydrate intake. These diets were only moderately successful. Then Frederick G. Banting
The usual treatment for juvenile-onset diabetes quickly became the routine injection of insulin, isolated by drug companies, from the pancreases of cattle and pigs slaughtered by the meat-packing industry. Most diabetics survive well on the animal insulins. Unfortunately, use of the animal insulins has two drawbacks: First, about 5 percent of diabetics are allergic to animal insulins; they can experience severe allergic reactions. Second, and more important, the world supply of animal pancreases is limited by and dependent on fluctuation of the demand for meat foods. In this respect, it alarmed many that this supply declined sharply from 1970 to 1975, while the number of diabetics continued to increase. Consequently, the search for a better, less limited supply of insulin began.
At that time, study of insulin, from the pancreases of people who donated their bodies to science, showed human insulin to be nonallergenic and thus preferable to animal insulin. Therefore, it became apparent that a suitable means for chemical or biological preparation of human insulin would solve the problems both of insulin allergy and of the fluctuating insulin supply. This endeavor became a major goal of pharmaceutical research. Eli Lilly and Company was the first pharmaceutical house to achieve success, and on May 14, 1982, it filed a new drug application with the Food and Drug Administration (FDA) for the human insulin preparation it called Humulin.
Human, beef, and pork insulins are similar, small proteins
Eli Lilly spokesman Irving Stanley Johnson described the commercial method for producing Humulin (devised in collaboration by scientists at Genentech,
In 1982, genetically engineered human insulin was approved for pharmaceutical use by the FDA and equivalent regulatory agencies around the world. This insulin preparation, marketed under the trade name Humulin, is medically important because it generates a reliable supply of insulin and because it does not contain an allergen. In addition, Humulin manufacture is important because it is a test case proving the industrial viability of recombinant DNA research.
Humulin manufacture guarantees a reliable, easily increased supply of insulin for the growing number of insulin-requiring diabetics around the world. The importance of Humulin availability is best clarified by consideration of problems foreseen in the 1970’s, when slaughterhouse beef and pork pancreases were the sole source of insulin. It became clear then that the supply of available pancreases had plateaued, while the number of insulin-requiring diabetics (4 million cases in industrial nations) was rising steadily. This led to fear that an insulin shortage would occur by 1990; the availability of Humulin ended this fear.
Many members of the biomedical community view the lack of allergic reactions from Humulin as being less important than its promised abundance. They state that this results from the fact that a lack of allergenicity will help probably only the 3 to 4 percent of diabetics who experience severe allergic responses to beef and pork insulin. In contrast, it is stressed that the real treatment problems seen with insulin-dependent diabetics are how to obtain adequate amounts of insulin to serve all of them and how to get the hormone into patients in the most appropriate way. Finally, it cannot be emphasized too strongly that a prime aspect of the importance of Humulin production is the fact that it was the first genetically engineered industrial chemical. It thus began an era wherein recombinant DNA technology could be viewed as a viable source of pharmaceuticals, agricultural chemicals, and other important industrial products. It seems likely that gains from such efforts will produce understanding of cancer and other disease processes, as well as lead to methodologies that will provide adequate amounts of food in a world where productive land areas are decreasing, while population continues to increase.
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Chance, Ronald E., Eugene P. Krieff, James A. Hoffmann, and Bruce H. Frank. “Chemical, Physical, and Biologic Properties of Biosynthetic Human Insulin.” Diabetes Care 4 (March/April, 1981): 147-154. Detailed technical paper describes the chemical, physical, and biological properties of Humulin and shows its chemical, physical, and biological equivalence to insulin isolated from human pancreases. Describes tests that show the biological equivalence of Humulin and pork insulin. -
Johnson, Irving S. “Human Insulin from Recombinant DNA Technology.” Science 219 (February, 1983): 632-637. Description of Humulin development by a vice president of Eli Lilly Research Laboratories. Discusses the basis for commencement of the project, aspects of regulation of recombinant DNA research, preparation and testing of Humulin, and the impact of recombinant DNA research on the pharmaceutical industry. -
Nelson, David L., and Michael M. Cox. Lehninger Principles of Biochemistry. 4th ed. New York: W. H. Freeman, 2004. Later chapters of this excellent college biochemistry text cover aspects of insulin biochemistry and diabetes, including information on diabetes diagnosis and treatment, the pancreas, and the production of insulin. Includes diagrams showing the structure of insulin and the glucose tolerance test. -
Orci, Lelio, Jean-Dominique Vassali, and Alain Perrelet. “The Insulin Factory.” Scientific American 236 (September, 1988): 85-94. Describes insulin biosynthesis, processing, and secretion. Very informative for readers who wish to understand the nature of insulin and provides background for dealing with the concept of insulin as a protein composed of A and B chains that can be taken apart and recombined.
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