1977 Nobel Prize in Physiology or Medicine — Guillemin, Schally, and Yalow: Hypothalamic Hormones and Radioimmunoassay

What You Will Learn in This Article

You may think that the pituitary gland is the supreme command center of the body, but you will learn about the discoveries of Guillemin and Schally, who revealed that there is another command center above it (the hypothalamus). You will also learn about Rosalyn Yalow, who developed the radioimmunoassay (RIA), which can measure hormones in picogram (10⁻¹² g) units. This article will explain how the discoveries of these three individuals laid the foundation for modern endocrinology and clinical diagnostics.

A Story Different from Common Sense — Another Command Center Above the Supreme Command

Let's set out the background of pituitary hormones. Among humans and other higher animals, the hormones produced and secreted by the anterior lobe of the pituitary gland include thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and growth hormone (GH). As their names suggest, most of them are in charge of regulating hormone synthesis in other endocrine glands of the body.

In other words, the pituitary gland has long been understood as the supreme command center that regulates various other endocrine glands in the body (thyroid, adrenal gland, gonads, etc.). When the pituitary gland sends a signal, the thyroid gland produces thyroxine, the adrenal gland produces cortisol, and the gonads produce sex hormones.

However, there was a crucial unanswered question: Who regulates the pituitary gland itself? The pituitary gland does not randomly secrete hormones at any time, but is regulated according to the body's condition (stress, growth phase, reproductive cycle, etc.). Who sends the regulatory signals to the pituitary gland?

Guillemin and Schally found the answer. The pair discovered the releasing hormones — or releasing-inhibiting hormones — produced by the neurosecretory cells of the hypothalamus, which sits atop the endocrine system as its true supreme command center, and showed that these hormones regulate the secretion of pituitary hormones. This body of work is what earned them their joint Nobel Prize.

The four-step hierarchy: hypothalamus → pituitary gland → target endocrine gland → target tissue. The discovery that the hypothalamus is above the pituitary gland is the key point of this paradigm.

In the language of computer science, this discovery represents the discovery of a new layer in the hierarchical architecture. It is like discovering that there is another regulating component above a component that was previously thought to be at the top of the system. This kind of discovery fundamentally changes the understanding of the system.

The Zeitgeist — A Major Shift in Popular Culture and Technology Consumption

1977 was a period of major shifts in popular culture and technology consumption.

In world history, Star Wars was released on May 25th — a science fiction epic that revolutionized the film industry. In June, the Apple II was released — marking the beginning of the popularization of personal computers (PCs). On August 16th, Elvis Presley died at the age of 41 — a symbolic end to the rock and roll era. In January, the Concorde supersonic airliner began service. In April, Steve Jobs and Wozniak registered Apple Computer.

In Korean history, it was a time when political control was strengthened in anticipation of the presidential election for the re-establishment of the Yushin system. Resistance from young people, students, and opposition groups intensified. In December, the artifacts related to the Baekje Muryeong Tomb in Buyeo were moved to the National Museum.

It was in this era that the Nobel Committee recognized a new layer in the endocrine regulation system. It was the year in which a new layer was discovered in the regulatory hierarchy of the body at a time when the social hierarchy of human society was being reorganized.

The Three Laureates — Guillemin, Schally, and Yalow

Roger C. L. Guillemin (1924– ) is an American physiologist (of French origin). He received his Ph.D. from the University of Montreal (1953), was a professor at Baylor University College of Medicine (1953–1970), and a distinguished professor at the Salk Institute (1970–1989), and a professor at the University of California Medical School (1990– ).

Andrew V. Schally (1926– ) is an American endocrinologist (of Polish origin). He received his Ph.D. from McGill University (1957) and was a professor at Baylor University College of Medicine (1957–1962), and later became the director of the Endocrine and Polypeptide Research Laboratory at the New Orleans Veterans Hospital (1962– ).

Guillemin and Schally independently performed the extremely difficult task of extracting hypothalamic hormones. They cut out the hypothalamus from the brains of hundreds of thousands of sheep to extract a tiny amount of hormone — a laborious task. The two worked independently in their respective laboratories and were in competition with each other. They later shared the Nobel Prize.

Rosalyn Yalow (1921– ) was an American physicist. She received her Ph.D. from the University of Illinois (1945) and later worked as a professor at Hunter College (1946–1950) and as chief of the Radioisotope Service at the Bronx Veterans Hospital (1950–1970).

Yalow was an unusual combination: a woman with a background in physics. She made a major contribution to the application of radiation physics to medicine. The radioimmunoassay (RIA) she developed accounted for half of this award.

Key Discovery 1 — Hypothalamic Releasing Hormones

The hypothalamic hormones identified by Guillemin and Schally:

• TRH (thyrotropin-releasing hormone): Secreted by the hypothalamus and stimulates the secretion of TSH by the pituitary gland. TRH is a very small peptide consisting of only three amino acids. To determine this short sequence, the two independently performed the task of extracting mg quantities of TRH from the brains of hundreds of thousands of sheep.
• GnRH (gonadotropin-releasing hormone): Regulates the release of gonadotropic hormones (FSH, LH).
• GHIH (growth hormone-inhibiting hormone) = somatostatin: Inhibits the secretion of growth hormone. Interestingly, some hypothalamic hormones promote release, while others inhibit — a bidirectional regulation.

The discovery that a simple short peptide can regulate the entire body's hormonal state had a significant impact.

The Guillemin–Schally discovery is now recognized as a groundbreaking achievement in endocrinology — one that first proved that the secretion of anterior pituitary hormones, up to that point considered the top command center of the endocrine system, is in fact regulated at a higher tier by peptide hormones synthesized and secreted in the hypothalamus. This discovery set off an explosive expansion of research into other releasing and inhibiting hormones of the hypothalamus, and to date seven hypothalamic regulatory hormones have been identified — with more expected to be discovered.

Discovery of β-endorphin — beyond TRH and GHIH, Guillemin went on to show that the pituitary gland also produces β-endorphin, a neurotransmitter that relieves pain and elicits feelings of joy and comfort. This substance is similar in effect to opium, and because the body itself evolved to produce it as a survival adaptation, it is also called an endogenous opioid-like peptide.

The discovery that the body produces its own opium had a significant impact. This has had a decisive impact on the understanding of pain relief, euphoria after exercise, and clinical anesthesia.

Key Discovery 2 — Radioimmunoassay (RIA)

Yalow's key discovery, the radioimmunoassay (RIA), is a technology for measuring extremely small amounts of hormones.

The principle of RIA runs as follows. Radioactively labeled hormone and the unlabeled hormone present in the sample compete for the same antibody, and by measuring the degree of that binding competition, then comparing the result against a pre-drawn standard curve based on varying quantities of labeled hormone, one can quantify the amount of hormone in the sample. In other words, the fraction of radioactively labeled hormone that fails to bind to the antibody reflects the amount of hormone that was originally present in the sample. This technique can quantify hormone levels down to the picogram (10⁻¹² g) level, and because it is both exceptionally simple and exceptionally sensitive, it became decisive for the qualitative and quantitative determination of the trace hormones secreted by the pituitary gland.

If there were no technology to quantitatively measure such extremely small amounts, the existence of hypothalamic hormones would have been virtually impossible to confirm. A key perspective is that Yalow's RIA made possible the discoveries of Guillemin and Schally.

The principle of RIA:

• Preparation of antibodies that specifically bind to the hormone to be quantified.
• Radioactively labeled standard hormone and unlabeled hormone in the sample compete for the same antibody.
• If there is a large amount of unlabeled hormone, it will occupy more of the antibody binding sites → less of the labeled hormone will bind to the antibody.
• Measuring the radioactivity of unbound labeled hormone → the hormone level in the sample is calculated.

Remarkably high accuracy. Radioactively labeled signals can be detected with extremely high sensitivity. This is what enables the quantitative measurement of trace amounts of hormones.

Hierarchical Architecture + Disruptive Measurement Accuracy — CS Framework

Discovery of a new layer in the hierarchical architecture. This is common in software as well. When designing a system, you may think that a particular component is at the top level, but later you realize that there is another regulating component above it (e.g., orchestrator, control plane). It was thought to be at the top, but it wasn't — an event that fundamentally changes the understanding of the system.

Disruptive accuracy of measurement tools. There are many things in nature that cannot be known to exist without a tool to measure them. If there were no RIA, hypothalamic hormones would have remained a mystery. New knowledge often requires new tools, and new tools make new knowledge possible. This cycle is the fundamental engine of scientific progress.

The special human story of this award is that Yalow, a woman with a background in physics, received the Nobel Prize in Physiology or Medicine. Yalow was the second woman to win the Nobel Prize in Physiology or Medicine — the first was Gerty Cori (1947). Her physics training made a decisive contribution to medicine. This is an example of how the flexibility of academic boundaries can create great value.

The patience of Guillemin and Schally, who extracted hormones from the brains of hundreds of thousands of sheep, is another key aspect of this award. The two competing laboratories independently performed this seemingly impossible task, which eventually opened the door to the era of hypothalamic hormones.

Summary of Guillemin, Schally, and Yalow in 1977: Guillemin and Schally independently discovered hypothalamic releasing hormones (TRH, GnRH, GHIH, etc.) — establishing a regulatory hierarchy above the pituitary gland. Yalow developed the radioimmunoassay (RIA) — enabling the quantification of hormones in picogram units. Today, it is the theoretical foundation of clinical hormone tests, infertility treatments, understanding of endorphins, insulin quantification, and cancer marker tests.

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