1950 Nobel Prize in Physiology or Medicine — Hench, Kendall, and Reichstein for Cortisone

What You Will Learn in This Article

You will learn how Compound E, an unfamiliar hormone isolated from the adrenal cortex by Mayo Clinic’s Kendall, became known as cortisone through Hench’s pivotal clinical trial, and how this discovery ushered in the steroid era, which we now use extensively for conditions ranging from asthma and autoimmune diseases to post-transplant care and even COVID-19. You will also gain an understanding of its remarkable effects and the principles guiding its cautious use.

Beyond Common Knowledge — The Two Faces of a Powerful Tool

We use the term "steroid" in two extreme ways. In some contexts, it is a "miracle drug," while in others, it is a "drug with frightening side effects." Both expressions are partially true, and their integration reveals the complete picture. Steroids are tools that forcibly manipulate the body's natural regulatory system, and this manipulation can lead to decisive recovery in some situations and serious side effects in others.

The first clear confirmation of the precise nature and clinical power of this tool came from the Mayo Clinic experiments of 1948-1949, and these experiments were recognized with the 1950 Nobel Prize. The fact that three people shared the award is significant. The award reflects a three-stage relay of Kendall's chemical isolation, Reichstein's chemical structure elucidation, and Hench's clinical demonstration. Five years after the Nobel Prize for the three pioneers of penicillin (1945), another laboratory-clinical relay was recognized in the same format.

We can summarize this story in the language of computer science. Our body's inflammatory system is similar to a microservices architecture, with numerous services sending requests in parallel. Infections, tissue damage, and autoimmune reactions each send a request, and nature's rate limiter, cortisol, regulates the intensity of these requests. In most cases, this natural throttle works well, and inflammation occurs only as much as needed and stops at the appropriate time.

The problem arises when this natural regulation fails. In autoimmune diseases, there is a request flood where incorrect requests continue to be sent. In this state, the manager can take the extreme step of significantly strengthening the rate limit, and this is precisely what cortisone injections do. The request flood decreases, but necessary normal requests are also limited, leading to side effects.

The entirety of this story is contained within the 1950 award.

The Zeitgeist — The Year When the Cold War Became a Hot War

1950 was the year of the Korean War. On June 25th, North Korean troops crossed the 38th parallel and launched an invasion, and the United Nations immediately decided to intervene, with UN forces beginning preparations for the Incheon Landing the following month. This was the first time the Cold War had escalated into a large-scale hot war, and the subsequent three years of the war fundamentally changed the geography of the Korean Peninsula and the nature of the global Cold War.

In the United States that same year, Senator Joseph McCarthy began his anti-communist hearings. "McCarthyism" shook the American intellectual community for several years, and many scholars and artists became the subject of ideological scrutiny. It was a time when the political paranoia of the global Cold War was penetrating the social systems of individual countries.

Against this backdrop, the Nobel Prize ceremony was held normally in December in Stockholm. All three recipients attended, and the discovery of cortisone was highlighted as one of the most significant events in human medicine in recent years. The fact that cortisone was already being used in the clinical management of Korean War casualties contributed to the timeliness of the award. Cortisone was establishing itself as a new tool for conditions such as severe shock, severe allergic reactions, and recovery from widespread tissue damage.

When viewed in conjunction with Korean history, in that year, our society was experiencing an unimaginable scale of loss of life and social destruction. A significant portion of those casualties would later become clinical subjects for new drugs, including cortisone, in US field hospitals and domestic hospitals. This year demonstrates how closely the clinical application of a discovery can be linked to geographical and political upheaval.

Kendall — From Thyroid to Adrenal Gland

Edward Calvin Kendall was a biochemist who had already established a firm position in the academic world. In 1914, he was the first in the world to isolate thyroxine, a thyroid hormone in crystalline form, and this single discovery had already established his reputation.

In the 1930s, he turned his attention to the adrenal cortex. It had long been known that dogs that underwent adrenalectomy died within hours. This indicated that the adrenal cortex secreted some substance essential for life, but the nature of that substance was unclear. Kendall's team attempted chemical isolation from bovine adrenal cortex.

His approach was one of mass processing. From a small amount of pure crystals obtained by processing one ton of bovine adrenal cortex, he isolated six different steroid compounds and named them A to F. It was still unclear which of these was responsible for the essential function of the adrenal cortex. Compounds A, B, E, and F remained as candidates, and in particular, Compound E was found to be most potent in reversing the symptoms of adrenal insufficiency in experimental animals.

However, there was a problem: it was impossible to obtain Compound E in large quantities. The amount obtained from bovine adrenal cortex was extremely small, and a much larger quantity was needed for clinical trials. At this point, Kendall's team was in exactly the same situation as the penicillin team had experienced in the early 1940s — they had made a discovery, but they could not scale it up.

Reichstein — Chemistry Completed in Switzerland

Tadeus Reichstein was a Polish-born Swiss chemist. He already had an impressive accomplishment to his name: he had developed the industrial synthesis of vitamin C. Today, the vast majority of commercially available vitamin C is produced by descendants of his synthesis route (Reichstein process).

Reichstein's team conducted research on adrenal cortex steroids independently of Kendall. Their key contribution was the elucidation of the precise chemical structure of several adrenal cortex steroids and the development of partial synthesis routes. They established a route to partially synthesize Compound E from other steroids obtained from nature (e.g., deoxycholic acid obtained from bovine bile) through several steps of chemical reactions.

Why was this partial synthesis so decisive? Because it opened the way to produce cortisone chemically without relying on the large-scale processing of natural materials. Subsequently, Merck expanded Reichstein's route industrially to produce cortisone in quantities suitable for clinical use. Merck played the same role for cortisone that Peoria had played for penicillin.

Hench — The Dramatic Clinical Moment

Philip Showalter Hench was a rheumatologist at the Mayo Clinic, the same institution as Kendall. The two had worked together at the same hospital for over 20 years, but during those 20 years, Hench had quietly been convinced that the adrenal cortex hormones would be beneficial for his patients.

There were two clinical facts that Hench had observed for a long time. First, the symptoms of patients with rheumatoid arthritis were surprisingly alleviated during pregnancy. Second, their symptoms also improved when they suffered from jaundice. Both of these conditions involve significant changes in the body's levels of steroid hormones. Hench maintained the hypothesis that adrenal cortex hormones contain something that suppresses rheumatoid arthritis.

In September 1948, he made a crucial decision. He requested Compound E, of which only a small amount remained with Kendall, and administered it experimentally by intramuscular injection to a 29-year-old woman with rheumatoid arthritis. This patient had been unable to walk and her hands had been severely deformed for four years, to the point that she could not dress herself.

The observations of the following days became a dramatic scene in medical history. Within hours of the first injection, the patient reported that her pain had decreased, and after two days she was able to walk, and after a few days she was dancing in the hospital room. Hench carefully documented this recovery and recorded it in photographs and videos. Each time this video was shown at academic conferences, the audience fell silent — it was the first time they had witnessed firsthand that a seemingly hopeless clinical situation could be reversed by a single injection.

There was one sad aftermath. While the effect of Compound E was remarkable, it required a continuous large supply to maintain the administration. At that time, the existing stock could only treat a small number of patients for a few months. The early cases, including the first patient, gradually returned to their original condition when the drug was discontinued. This was the reason why Reichstein's partial synthesis route and Merck's industrialization were crucial. Between 1949 and 1950, large-scale supply was established, and clinical use subsequently expanded rapidly.

Cortisone's CS Framework — Throttle Inside the Body

Now, let's summarize what cortisone does in the body using the language of computer science.

Various cells in the body send signals to communicate their state. Infected cells release cytokines, damaged tissues release prostaglandins, and activated immune cells release chemokines that call other cells. These signals are inflammation response requests. Each request is necessary in itself, but if they all occur strongly at the same time, it leads to a state of inflammation overload.

Cortisol (the natural adrenal cortex hormone in the human body) is the body's natural response to this overload. Cortisol regulates the transcription of genes in various target cells, suppressing the generation of inflammation-inducing signals. The expression of cytokine genes decreases, the movement of activated immune cells slows down, and the prostaglandin synthesis pathway is inhibited. It is a large-scale rate limit for all inflammation-related services.

Cortisone is a slightly modified form of this natural cortisol. It is converted into its active form (hydrocortisone) in the body and has the same effect. However, it can apply a much stronger rate limit than the natural cortisol rhythm. This is the source of its decisive clinical power.

In autoimmune diseases such as rheumatoid arthritis, in the language of computer science, it is a state in which incorrect requests continue to be sent. The body's immune system mistakes its own joint tissue for an intruder and continues to send attack requests. When cortisone is injected into this overload, the rate limit is extremely strengthened, the overload subsides, and joint symptoms are alleviated. Hench's first patient being able to walk again is a dramatic expression of this mechanism.

Side effects are naturally predictable in this framework. If the rate limit is applied indiscriminately to all requests, necessary requests are also limited. Normal infection defense (a necessary request) is also suppressed, increasing the risk of infection. Bone formation and maintenance (a necessary request) are also suppressed, leading to osteoporosis. The body's normal blood sugar regulation services are also disrupted, leading to diabetes. All these side effects occur because cortisone is not a tool that precisely suppresses only specific services, but a broad-spectrum throttle.

This understanding is the basis of today's clinical principles: "use the minimum necessary dose, for the shortest necessary duration." And, if possible, minimize systemic exposure by using local administration (skin creams, inhalation, intra-articular injections). The reason we repeatedly remind ourselves of this principle whenever we use steroids today is based on the side effects accumulated since 1950.

Today's Cortisone Descendants — An Expanded Toolbox of Throttles

The discovery of cortisone ushered in an explosive expansion of steroid drugs over the following half-century.

Inhaled steroids (budesonide, fluticasone, etc.) have become the standard of care for asthma management. They minimize systemic side effects by local administration and control airway inflammation. Topical steroid creams are the mainstay of management for atopic dermatitis and psoriasis. Intra-articular steroid injections target local joint inflammation. Intravenous high-dose steroids are used in the management of acute exacerbations of multiple sclerosis, optic neuritis, and anaphylaxis emergencies.

One of the essential components of post-transplant immunosuppression is steroids. Most patients undergoing heart, liver, or kidney transplantation take low-dose steroids long-term. This is to prevent rejection (an overload of incorrect requests).

And a crucial moment came in the COVID-19 pandemic. In June 2020, the RECOVERY clinical trial published the results that dexamethasone — a potent synthetic steroid — dramatically reduced mortality in severely ill COVID-19 patients. It was established that a significant portion of the severe COVID-19 was not due to the virus itself but to the body's excessive inflammatory response (cytokine storm), and steroids were reconfirmed as a tool to regulate this overload. The precise counterpart of Hench's 1948 observation was used again in the intensive care units in 2020.

Behind this expansion lies the shadow of steroid abuse. There have been long-standing concerns about the misuse of steroid prescriptions in fields such as otolaryngology, orthopedics, and dermatology, and the problem is particularly acute in developing countries where they are sold without a prescription. A powerful tool requires strong management.

Why It Matters

We can summarize the insights left to us by the 1950 award in three ways.

Scientifically, this discovery established that we can understand the body's natural regulatory systems and manipulate their throttles. Over the following half-century, many Nobel Prizes in endocrinology and immunology have been built on this framework. The question of why our body works so well has expanded into a question about the delicate balance of the various rate limiters in our body.

Clinically, this discovery has provided a powerful tool for a variety of clinical situations, including autoimmune diseases, allergies, post-transplant care, and acute inflammatory overload. Today, many clinical areas of hospitals could not function without this tool. However, the use of this tool must always be done with an awareness of the broad nature of the rate limit.

Philosophically, this story is a clear example of the old principle that powerful tools require powerful restraint. The natural throttle is delicately balanced, and artificially manipulating that throttle disrupts the balance. How carefully we should use this tool is reflected in the dramatic moment when Hench's patient danced again after four years, and that is on the opposite side of that moment.

The relay narrative also runs through this piece. Kendall's chemical isolation, Reichstein's structural elucidation, and Hench's clinical demonstration. They were three people who made different contributions at different times on different continents, but their combination created a single tool. The fact that the flow of penicillin and the flow of cortisone are so similar is not a coincidence — it is a consecutive expression of the fundamental structure that medical science in the late 20th century has taken, with a relay of laboratory, chemistry, and clinical work.

In the year the Korean War began, the Nobel Committee's awarding of this prize may have been inevitable. It was a time when a large amount of acute inflammatory overload was occurring, and the committee recognized the arrival of a tool to regulate that overload. It was a moment when a dark time and a bright tool coincided.

1950 Hench, Kendall, and Reichstein Summary: The award for Kendall's isolation of adrenal cortex steroids, Reichstein's elucidation of the structure, and Hench's clinical demonstration in rheumatoid arthritis. This was a pivotal discovery that ushered in today's steroid era and is also the root of the principle of "use the minimum necessary dose, for the shortest necessary duration."

→ Experience with coding: DevBench — Rate Limiter Simulation → Learn CS concepts: DryBench — Throttling and Service Limits → Previous: 1949 — Hess and Moniz → Next: 1951 — Theiler and yellow fever vaccine