On March 29, 1962, President John F. Kennedy met with several leading scientists from around the Americas. One of them was the 74-year-old Argentine physiologist Bernardo Houssay (Figure 1). Nobody discussed it during the meeting, but the research of the older man had been vital to the health of the US leader. Fifteen years earlier, JFK had been diagnosed with a condition called adrenal insufficiency, in which the adrenal glands do not produce enough adrenal hormones. That same year the Argentine Houssay had received the Nobel Prize in Physiology and Medicine for making discoveries important to the understanding of those very hormones.
To diagnose the young JFK, physicians in 1947 had relied on what was called the "ACTH stimulation test," whereby adrenocorticotropic hormone (ACTH) is administered to the patient to see how well it stimulates the adrenal glands to release the important hormone cortisol. Although JFK’s test results showed problems with adrenal gland function, by the late 1950s his results on the same test had normalized. This led doctors to suspect that JFK – Senator Kennedy at the time – did not have Addison disease, a permanent insufficiency of the adrenal glands. Instead, they had attributed the inability of his adrenal glands to respond to ACTH to extreme stress and a bout of malaria that JFK suffered during World War II.
Unresponsive adrenal glands, whether permanent or temporary, could be recognized with certainty only after researchers had learned of ACTH. Especially its synthesis by a gland at the base of the brain called the pituitary and how multiple hormones enable the pituitary and other glands to affect one another in what are called "hormone feedback loops." That understanding rested on the very research for which Dr. Bernardo Houssay (Figure 2) had been awarded his Nobel Prize.
A new area of research
In 1887 the science of endocrinology did not yet exist, but physicians had come a long way since ancient times when Galen of Pergamon had first described the pituitary, a structure deep in the brain, and proposed that it served in draining nasal phlegm. Based on discoveries made since the 18th century, anatomists of 1887 knew of the system of blood vessels connecting the pituitary with a nearby brain structure that we call the hypothalamus (Figure 3). At that time, physicians were distinguishing different types of diabetes (diseases characterized by polyuria, excessive urination) and they knew of a rare disease called acromegaly, characterized by enlarged body parts. 1887 was also the year that Oskar Minkowski discovered that cadavers with acromegaly also showed pituitary enlargement.
Meanwhile, in Argentina José María Ramos Mejía founded the Department of Neuropathology at the University of Buenos Aires, and a few blocks away, on April 10, 1887, Bernardo Alberto Houssay was born to Dr. Albert and Clara Houssay, both immigrants from France. When it comes to Houssay, there is no known story of a coming of age or an unusual childhood event that perked a science interest, except that he was a brilliant student – so brilliant that he was admitted to the University of Buenos Aires School of Pharmacy in 1901 at the age of 14. Three years later he entered medical school and earned his MD in 1911 after completion of a thesis on the physiological effects of pituitary extracts.
As for why he chose the pituitary as a student, years later, upon receiving the Nobel Prize, Houssay explained, "I was attracted to the [pituitary]…because the microscopic picture showed glandular activity and its lesions were accompanied by serious organic disturbances, such as acromegaly, dwarfism, etc."
The years 1890-1920 saw dramatic advances in science and technology throughout the world, and endocrinology was one of many new fields that came to life in this era. As with many other areas of body function, however, understanding the endocrine system built up in a piecemeal fashion and took a long time to come together. Scientists would not know the basics of every gland and the target tissues and roles of their various chemical messengers until well past the midpoint of the 20th century. As Houssay advanced through his career, however, certain pieces gradually came together, and since the pituitary interacts intricately with other endocrine glands, Houssay’s discoveries both influenced, and were influenced by, a growing comprehension of the roles of the other glands.
Emergence of endocrinology depended on animal research
In the final years of the 19th century, scientists started extracting chemical agents from certain body structures. When injected into test animals, these extracted agents produced powerful changes in physiology. The earliest example was the adrenal gland, of which there are two, one above each kidney. Unlike the salivary glands and sweat glands and other structures that anatomists had been calling “glands” because they secreted their products into special ducts, the adrenals appeared to have no ducts at all. In the 1890s, however, researchers extracted an adrenal substance that they named epinephrine. When injected into experimental animals, epinephrine raised blood pressure and made the animals very energetic.
In those days, laboratory animals were paramount to experimental physiology and medicine and they are still vital in our own time. But whereas researchers 100 years ago could essentially do as they wished with animals, today animal welfare laws strictly regulate how non-humans can be used as test subjects. Much of the change happened during the 1950s through guiding principles introduced by researchers W.M.S. Russell and R.L. Burch. The principles are known as the "Three Rs" as they consist of replacement, reduction, and refinement.
Replacement means using any in vitro (test-tube based) or other methods in lieu of animals whenever those methods can provide the same (or more) information that animal models could provide. Reduction means employing those non-animal methods, if not to replace animals entirely, then at least to use fewer animals than could be used without the in vitro method. It also means doing whatever is possible to obtain more information from the same number of animals as well as using smaller animals such as mice and worms to reduce the use of larger animals such as dogs, cats, pigs, and primates that have varying levels of sentience (consciousness and self-awareness). Over the last few years, scientists have made enormous progress in this area. This is because gene editing and other biotechnologies have enabled the advent of humanized mice, which have replaced the need for dogs and pigs in medical research areas.
Finally, refinement concerns the treatment of the animals that actually are used. Therefore, it requires that researchers employ all available methods to alleviate and minimize any potential pain, suffering, or distress. While 100 years ago researchers could practically pull a stray animal from the streets and use it for research, today researchers need to explain what they’re planning to do with an animal, show that they will follow animal welfare regulations, and obtain approval from a governing board to conduct the research.
Will there always be a need for animals in the lab? For the foreseeable future, the answer is probably yes, but we can expect that new technologies will keep the numbers at a minimum, particularly when it comes to the dogs and pigs that were so vital for the pioneers of endocrinology in Houssay’s time.
The discovery of hormones
Seeing the dramatic effects of epinephrine when injected into various animals, researchers at the turn of the 20th century realized that the adrenals must release their epinephrine directly into the blood. That meant that the adrenals and certain other structures such as the thyroid were glands of a different type. Scientists called them endocrine glands (endo meaning within) because secreting products into the blood distinguished them from the glands with ducts that took secretions outside the blood (Figure 4).
Around the same time, researchers also found that various chemicals released in one part of the gastrointestinal tract influenced in other areas of the tract, so they started thinking of the released chemicals as tiny messengers. Based on this perspective, British physiologist Ernest Starling coined the term hormones (derived from the Greek word for "excite" or "arouse") as "chemical messengers which speeding from cell to cell along the blood stream, may coordinate the activities and growth of different parts of the body." Generalizing epinephrine and the gastrointestinal messengers into a common category led physiologists to suspect that there must be numerous other hormones yet to be discovered. Soon after that, the thyroid was found to secrete hormones. In 1915, these were extracted by Edward Kendall of the Mayo Clinic in Minnesota and eventually were made into treatments for people whose thyroid did not function.
That was the thinking during Houssay’s medical school years, and it made hormones a hot topic for budding researchers. There were no medical specialties. Instead, new physicians entered general practice, went for special training to become a leader in surgery, or opted for a research career. Houssay chose the latter partly because his prior pharmacy study provided him with a strong background and also because his medical school research project went very well, though he also did some hospital practice for a couple of years after graduating.
Looking at the pituitary and the thyroid (which is located in the neck, see Figure 5), researchers during the first decade of the 20th century saw no ducts, no secretions exiting the body or entering any body cavity. This made both structures good candidates to study for possible sources of undiscovered hormones. During this thesis research, Houssay invented a way to remove the pituitary, first from a frog and then from a dog. Once achieving that, he could grind down different parts of the pituitary, make extracts and inject those into test animals just as researchers had been doing for more than a decade with epinephrine from the adrenal. Injecting animals with pituitary extracts, he was able to make animals slightly diabetic sometimes, and reduce diabetes other times, depending on which part of the pituitary he ground up and on how much he concentrated the extract. This suggested that something interesting was occurring, but figuring out what it was would take years. That was far more than would be demanded of a medical student. Giving his method for pituitary removal and his finding that pituitary extracts had some effects, the data in his student thesis were substantial. Already by this point, he was not only a medical student but for the last year also Professor of Physiology at the School of Veterinary Medicine, so it was time to move on. He graduated and was awarded a university prize for his thesis.
Over the 1910s, Houssay held appointments at Alvear Hospital, the Laboratory of Experimental Physiology and Pathology in the National Department of Hygiene, and finally at the University of Buenos Aires, where he was Professor of Physiology. Within the university, he also created the Institute of Physiology and served as its Director until 1943. In that year, the rise of the Perón military dictatorship deprived Houssay of his position, because Houssay supported groups calling for democracy. So, he moved to the Instituto de Biología y Medicina Experimental, which was funded privately. He was reappointed at the University of Buenos Aires after the Peronista government was deposed in 1955 and remained there until his death in 1971.
During the course of those six decades, Houssay conducted research studies on the physiology of the circulatory, respiratory, nervous, and digestive systems, but his pituitary research is what made him famous and earned him the Nobel Prize. That research focused specifically on the anterior portion of the pituitary and sprang out of his 1911 medical school thesis. In some instances, the pituitary research connected closely with Houssay’s study of other areas of the body, particularly when it came to the digestive system. The latter system includes the pancreas, which early 20th century physiologists suspected must function both as exocrine and an endocrine gland.
Houssay’s research and diabetes mellitus
The pancreas secretes digestive enzymes through a duct into the small intestine. That made it exocrine, but back in 1889 Minkowski and another researcher had found that removing a dog’s pancreas caused diabetes; the amount of urine from the pancreatectomized (that is, having undergone a procedure to remove the pancreas) animal had increased dramatically along with its thirst. Whenever researchers did this to dogs and other animals, the urine not only increased but it was also sweet; it contained sugar, and so the type of diabetes caused by pancreatectomy was diabetes mellitus. Mellitus means "honey" or "sweet" in Latin, and diabetes mellitus is the most common category of diabetes. It’s the type of diabetes to which most people are referring when they use the word "diabetes" by itself.
During the 1910s, 20s and 30s, much of Houssay’s time went into testing different amounts of the pancreas from lab animals such as rats and dogs and testing how the animals were affected by injection with pituitary extracts. In the animals, he found that one did not necessarily have to remove the entire pancreas. One could make an animal moderately diabetic by removing part of the pancreas and severely diabetic by removing much more of the organ. In the case of moderate diabetes caused by removal of a small portion of the pancreas, Houssay found that injecting the animals with pituitary hormone worsened the diabetes.
The discovery of insulin
In 1916, Romanian Nicolas Paulescu extracted a chemical from pancreas tissue that when injected into diabetic animals eliminated their symptoms. Few researchers noticed his work, but in 1921 Canadians Frederick Banting and Charles Best did almost the same thing. They isolated a pancreatic compound, injected into diabetic dogs and found blood glucose levels dropped quickly from very high to normal. They called the compound "isletin" and later it was renamed insulin.
Both before and after the discovery of insulin, removal of the pancreas provided Houssay and other scientists animal models for studying diabetes mellitus in the lab. Not long after Banting and Best made their insulin discovery in 1921, that hormone became available for research. Houssay thus started testing its effects in his own lab animals while also conducting research on how the insulin and blood sugar levels affected one another. During the 1940s, he started working with a substance called alloxan that produced diabetes as effectively as pancreatectomy, but without any surgery. He surmised, correctly, that the alloxan must destroy those cells within the pancreas that produced the insulin, cells known as islet Beta cells (Figure 5). This provided him an additional experimental model for studying blood sugar and diabetes.
ACTH and cortisol: hormones interact
During the 1930s Houssay wondered whether secretion of insulin from the pancreas into the blood might be modulated by hormones sent out from the pituitary. He tested the idea by treating lab animals with pituitary extracts, just as he had been doing for years, but this time measuring insulin levels. He tried this over and over with different animals with and without different amounts of their pancreas removed. It turned out that the pituitary extract did not decrease insulin levels. By this time, however, a different mechanism for how the pituitary affected blood sugar was presenting itself.
The 1930s was a time when numerous researchers isolated various compounds from the blood. These included an adrenal gland hormone that was not epinephrine. The adrenal gland has two main regions: the medulla and the cortex. Epinephrine (along with two other similar hormones) comes from the medulla, but during the 1930s a team of three researchers – Edward Kendall (the same researcher who isolated thyroid hormones two decades earlier), Tadeus Reichstein, and Philip S. Hench – isolated a hormone from the adrenal cortex. It was called cortisol and when injected into experimental animals, it raised blood sugar. Meanwhile, influenced substantially Houssay’s pituitary extract studies, another researcher, Evelyn Anderston, succeeded in isolating the specific pituitary hormone responsible for the diabetic, sugar-raising effect. Further work demonstrated that the Anderston’s pituitary hormone did not affect either the pancreas or the ability of muscle to absorb sugar from blood. Instead, the pituitary hormone worked by stimulating release of a different hormone: cortisol. In other words, the role of the hormone isolated from the pituitary was to stimulate the adrenal cortex. Thus, it was named adrenocorticotrophic hormone (ACTH).
In parallel with the discoveries of ACTH and cortisol, the 1920s and 30s also brought discoveries and insights in connection with the thyroid. Similar to the adrenal cortex, the thyroid was found to release hormones only in response to another hormone. As with ACTH, the pituitary was also found to be the source of that thyroid stimulatory hormone. Thus, by the 1930s and 40s scientists had an idea that release of hormones from various endocrine glands must depend on stimulatory hormones from the pituitary.
Not only did physiologists anticipate that more pituitary hormones would be discovered in the years to come, but the growing understanding of the role of the pituitary also explained what previously had seemed like an odd combination of symptoms that manifested in patients with certain pituitary tumors. In a condition that neurosurgeon Harvey Cushing started describing in the early 20th century, patients had swollen faces (often called moon faces), fat on the back of the neck and upper back, and excessive body hair. All of this eventually was found to result from excessive levels of cortisol, which can result from a benign adrenal tumor. Many patients, however, also had headaches and other symptoms of compression inside the head, such as double vision. Cushing found an enlarged pituitary (Figure 7) when he x-rayed their heads. With new surgical methods that he invented, he was able to extract the tumors and cure the condition, which came to be known as Cushing disease.
Houssay's work helps affects understanding of ACTH and cortisol
Cushing disease is an excess of cortisol that is caused by an excess of ACTH coming from the pituitary. When patients have high levels of cortisol due to problems in the adrenal gland itself, with no pituitary problem, it is called Cushing syndrome (to distinguish it from Cushing disease). The opposite is deficient cortisol; that’s adrenal insufficiency, which is what JFK had, and when it’s permanent it’s called Addison disease. The work on ACTH and its effects on cortisol rested strongly on the insights that depended ultimately on Houssay’s research. He was granted the Nobel Prize in 1947 for this reason and because of numerous studies elucidating various details connected with the interactions of hormones and their effects on how the body uses sugars. The specific reasons why all of his studies were so meaningful to endocrinology are highly technical, but they are summed up nicely in the conclusion of the Houssay’s own Nobel Prize speech:
Carbohydrate metabolism and other metabolic processes are regulated by the balance maintained between the secretion of several endocrine glands. Diabetes and other metabolic diseases are a disturbance in this endocrine equilibrium. There are still many problems to be solved, but undoubtedly the [pituitary] is one of the most important organs in the regulation of metabolism and the center of the endocrine constellation.
Along with endocrinology, Houssay conducted numerous studies in physiology, pharmacology, digestion, immunology, neuroscience, and the effects of snake and spider venom. Dr. Houssay is the author of over 500 papers and of several books. By his death in 1971, he had received a plethora of awards from scientific organizations including the National Academy of Sciences, Buenos Aires and the London Society of Endocrinology, honorary degrees from twenty-five universities, and honorary professorships from 15 institutions. He was honored by leaders from multiple countries, the meeting with President Kennedy being just one example.
In addition to resting on Houssay’s research, the work on ACTH and cortisol also led researchers in the 1930s and 40s to devise the ACTH stimulation test, which works because glands that are stimulated by the pituitary also feedback to modulate the pituitary itself. When levels of thyroid hormone in the blood are low, the pituitary releases thyroid stimulating hormone (TSH), which stimulates the thyroid to release thyroid hormone, whose level in the blood is now increased. This increased level tells the pituitary to stop secreting TSH, and a similar thing happens with the adrenal gland. If cortisol levels are low, the pituitary senses it and releases ACTH, which then stimulates the adrenals to release cortisol. However, if the adrenal is not working, it won’t respond to ACTH. That’s true whether the ACTH comes from the pituitary or an external source, and that’s the basis of the ACTH stimulation test.
When JFK was given ACTH in the same year of Houssay’s Nobel Prize, his adrenal glands did not respond; his levels of cortisol did not increase. That’s why he was diagnosed with adrenal insufficiency, and once diagnosed he could be treated with injections of cortisol. Those cortisol treatments had kept him alive for all those years. Thus, JFK's state of health was related to the research of Bernardo Houssay, the same man who stood before him at the meeting in 1962.
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