Hormones and the Discovery of Insulin

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Hormones and the Discovery of Insulin

Overview

Hormones are chemical messengers secreted mainly by the body's complex network of glands and glandular tissue that comprise the endocrine system. Each hormone has a unique function and travels via the bloodstream to exert influence upon its targeted cells, tissues, or organs. Hormones affect many vital life functions, stimulating certain life processes, while retarding others. Among other functions, hormones regulate reproduction, the body's fluid balance, growth, and metabolism. The nervous system also acts in conjunction with hormones to enable the body to react to sudden internal or external changes in environment.

After almost 50 years of experimentation, the fledgling science of endocrinology (the study of hormones and their effects on the body) exploded in the 1920s with the discovery of the hormone insulin. Insulin, necessary for the regulation of carbohydrate metabolism, offered the first effective treatment for diabetes, a metabolic disorder documented since ancient times. After the discovery of insulin, the isolation and characterization of other hormones led to a new understanding of the body's physiology and new methods of treating disease.

Background

Prior to the 1920s, scientists studied hormones primarily through experimentation with hormone-producing glands. In search of youthful regeneration, French-American physiologist Charles Brown-Sequard (1817-1894) experimented on himself by injecting testicular extracts in 1889. He lived six years afterward, and although he failed to reverse the effects of aging, his glandular extracts attracted attention among scientists. Crude extracts containing iodine and hormones from the thyroid gland were prepared in the late nineteenth century with no correlation recognized at that time for its relevance in the treatment of disease.

In 1902 two British scientists, William Bayliss (1860-1924) and Ernst Starling (1866-1927), first proposed the theory that internal secretions control the functions of the body. By the end of World War I, scientists knew of a relationship between the secretions of the pancreas (an endocrine gland) and diabetes. When that connection was narrowed down to a specific region of the pancreas, the islets of Langerhans, the search was on to find and extract the hormone that lowered the characteristically and abnormally high concentrations of glucose (sugar) in the blood of diabetics.

In 1920, while reading medical journal articles in preparation for delivering a lecture on the functions of the pancreas, Canadian physician Frederick Banting (1891-1941) jotted down an area of interest and potential research—isolation of the secretion that lowers glucose in the blood. Earlier, German physician Charles Minchowsky (1858-1931) suggested that if the pancreas was minced, the fluid extracted, then injected into diabetic animals, it might help control diabetes. Minchowski's efforts failed when the enzymes of the minced pancreas destroyed the insulin before it could be injected. Banting proposed a different approach. By ligating (tying off) the pancreatic duct and allowing the pancreas to degenerate slowly within the animal, Banting reasoned the pancreatic enzymes would not destroy the insulin, and would remain viable in an extract.

Banting approached Scottish physiologist John Macleod (1876-1935) with his proposal. Macleod, an expert in carbohydrate metabolism at the University of Toronto, was initially skeptical, but agreed to provide Banting with laboratory space at the university during the summer break. Macleod also furnished 10 laboratory dogs and a medical student assistant, fellow Canadian Charles Best (1899-1978). In May 1921, the two began their research as Macleod traveled on summer holiday. Banting performed most of the surgeries, first ligating the pancreas of the dog, then later removing it to produce diabetes in the animal. Best performed most of the biochemical tests for measuring sugar in the blood and urine, and occasionally assisted Banting with the surgeries.

By the end of July, the pair had their first conclusive results. After removing the ligated, shrunken pancreas from of the dogs, the pancreas was ground in a mortar with a saline solution, strained, and a small amount was injected into a diabetic dog. The dog's blood sugar levels were significantly reduced, and the dog became more active. After repeating the results with other dogs in the laboratory, Banting and Best were confident they had isolated the anti-diabetic hormone from the islets of Langerhans in the pancreas. They named their discovery "Isletin" and later changed the name to "Insulin" (from the Latin for "Island"). Macleod requested that the pair validate their results by repeating the experiments two more times. Although in the repeated experiments the results varied due to the quality and concentration of the insulin extraction, the discovery of the role and extraction of insulin was confirmed.

Before insulin could be tested on a human it was necessary to eliminate the variations within the extraction. Canadian biochemist James D. Collip (1892-1965) joined the research team in December 1921, and worked to purify the quality and concentration of insulin. When Banting suggested the use of fetal calf pancreas, which contained few digestive enzymes, Collip was able to produce greater amounts of insulin of sufficient purity that the injection site no longer formed an abscess, as did earlier extractions. Collip's efforts had produced insulin in a form suitable for human clinical use.

In January 1922, Leonard Thompson, a 14-year-old patient dying of diabetes in Toronto General Hospital, was the first human to receive insulin. Thompson's blood sugar levels, initially high enough to produce diabetic ketoacidosis and coma, dropped dramatically after insulin was injected. Two weeks were necessary to prepare additional extract, and with a second insulin injection, Thompson's blood sugar levels fell further. After several injections Thompson recovered from his bout with hyperglycemia (abnormally high blood sugar associated with diabetes) and was discharged home from the hospital in May 1922.

Earlier, in February 1922, Banting and Best published their famous paper, "The Internal Secretion of the Pancreas," in the Journal of Laboratory and Clinical Medicine. Ironically, Banting and Best later learned that their original premise was not entirely correct; insulin could, in fact, be obtained from an intact pancreas. Nevertheless, by the spring of 1922, the group produced quantities of insulin sufficiently purified to prove the practical value of insulin in treating diabetic patients. The Eli Lilly and Connaught companies of North America offered laboratory space and assistance to help improve the concentration, stability, and purification of insulin. Soon the supply of insulin dramatically increased, with Connaught as its primary manufacturer.

The 1920 Nobel Prize for Physiology or Medicine was awarded to Banting and Macleod for the discovery of insulin. Banting felt strongly that Best should have been recognized by the Nobel committee as well. Banting shared half of his prize money with Best, and upon learning this, Macleod shared his prize with Collip. For some years afterward the four men privately feuded over the essential nature of each of their roles in the discovery. Macleod's role perhaps caught the attention of the Nobel committee because, as the only member among the group belonging to the American Association of Physicians, only Macleod was eligible to present the paper at the association's meeting. Macleod also presided over another professional meeting where the paper was presented by Banting and Best. On this occasion, Macleod introduced Banting and Best as his assistants, and reporters covering the event gave Macleod heightened credit and publicity. Nevertheless, the contributions of all four men are fully recognized by history and related professional literature.

Impact

Insulin was hailed as a miracle drug and, incorrectly, initially as a cure for diabetes. No longer was diabetic coma assumed a death sentence. At first, insulin was reserved for those suffering the most severe effects of diabetes. Later, as supplies became more abundant and physicians learned the intricacies of insulin dosages and reactions, insulin therapy became standard treatment for diabetics. Before 1920, diabetics were treated with starvation diets of proteins considered easily digested. Insulin enabled diabetics to gain the benefits of a varied diet rich in nutrients.

By 1950 there were an estimated seven million diabetics in the United States alone, many of whom were unaware they had the disease. Armed with simplified lab procedures to detect abnormal blood sugar levels, physicians began to incorporate diabetic screening in their patient's routine health examinations. With insulin available to treat diabetes, victims of one of the world's ancient and deadly diseases were given hope to live longer, more productive lives.

After the discovery of insulin, research on the function of other endocrine glands and their hormone secretions burst into scientific prominence. The discovery of cortisone, an anti-inflammatory hormone released by the adrenal cortex, offered relief for patients suffering from the debilitating effects of rheumatoid arthritis. First tested on humans in 1947, initial results showed the beneficial effects of cortisone were temporary and patients suffered significant side effects. With further research, other hormones with anti-inflammatory properties would eventually become mainstream treatment for many varied ailments, including autoimmune diseases, asthma, and some traumatic injuries.

In 1945 American endocrinologist Fuller Albright (1900-1969) proposed the possibility of "birth control by hormone therapy," an idea that planted the seeds for a subsequent social revolution. After hearing of what became known as "Albright's Prophecy," American Planned Parenthood founder Margaret Sanger (1879-1966), then 70 years old, set out to inspire the development of an oral contraceptive. Sanger and her wealthy American friend Katharine McCormick (1875-1967), also in her seventies, approached research biologist George Pincus (1905-1967) of the Worcester Foundation for Experimental Biology with the task in 1948. Two years later, funded by McCormick, Pincus began the research that led to the introduction of a hormonal oral contraceptive (birth control pill). Ultimately, the birth control pill would lead to the first generation of women able to separate sexuality from reproduction and to plan the size of their families. This new freedom precipitated the sexual revolution of the 1960s, the women's movement of the 1970s, and the influx of women into the workplace.

BRENDA WILMOTH LERNER