1982 Nobel Prize in Physiology or Medicine: Bergström, Samuelsson, and Vane, Unraveling the 100-Year Mystery of Prostaglandins and Aspirin

What You'll Learn in This Article

You will understand that the answer to why aspirin relieves pain was discovered in 1971. It took 72 years after Bayer began selling aspirin in 1899 for its mechanism of action to be elucidated. We will explore the 25-year journey from Bergström laying the foundation for prostaglandin research, to Samuelsson discovering thromboxane and leukotrienes, and Vane elucidating the mechanism of action of aspirin and prostacyclin. We will also examine the collaborative work between mentors and disciples at the Karolinska Institute, and how the journey of a pharmacist who started his research in a garden shed gifted by his father in England, eventually became the basis for low-dose aspirin for cardiovascular prevention, NSAID analgesics, and asthma treatments.

Beyond Common Sense: Local Signaling in the Body

We often think of hormones when we talk about signaling molecules in the body. These are substances secreted by specific organs, such as the pituitary gland or the adrenal gland, that travel through the bloodstream to the entire body and act on specific target tissues. Insulin, adrenaline, thyroxine, and cortisol are examples of this.

Prostaglandins challenge this conventional wisdom. They are synthesized in almost all cells and only affect neighboring cells where they are released. They do not travel through the bloodstream over long distances but act locally. These substances are called parahormones or, in modern terms, paracrine signaling molecules. They are effective even at very low concentrations.

In the language of computer science, this difference can be compared to global broadcasting vs. local event buses. Hormones send signals to all tissues through the global message queue of systemic circulation. Prostaglandins are local pub-sub messaging, where signals are only transmitted to adjacent components – similar to a sidecar pattern in a microservices architecture. They adjust the state locally without shaking up the entire system.

As the importance of this local signaling becomes clear, it becomes evident that a wide range of physiological regulations, including inflammation, pain, fever, blood clotting, uterine contraction, bronchial constriction, and gastric acid defense, are actually controlled by local signaling of the prostaglandin family.

Even more surprisingly, there is aspirin. This drug has been consumed daily by people for nearly 100 years since Bayer began selling it in 1899. However, why this drug relieves pain and reduces fever, its mechanism of action, remained a mystery until 1971. John Vane discovered the answer: aspirin inhibits the synthesis of prostaglandins. It blocks the enzymes that create pain signals. It took 100 years to find out why a 100-year-old drug works.

In the language of computer science, this is a case of perfect reverse engineering. After using it for 100 years, knowing only the results without the source code, they finally uncovered the internal function call graph. Today, we precisely design analgesics (NSAIDs) that target cyclooxygenase (COX-1/COX-2), the prostaglandin synthesis enzyme. Celecoxib and other COX-2 selective inhibitors are examples of this subsequent refactoring based on reverse engineering.

The Zeitgeist: Localized Conflicts of the New Cold War and the First Year of Korea's 3S Policy

1982 was a year in which superpower proxy wars erupted locally in various parts of the world.

In world history, on April 2, the Argentine military junta invaded the Falkland Islands, prompting the British, under Prime Minister Thatcher, to dispatch a task force to the South Atlantic. After 74 days of intense fighting, the British won on June 14 – marking the resurgence of the Thatcher government and the downfall of the Argentine military junta. In June, Israel invaded Lebanon to launch an operation to drive out PLO forces, putting the Middle East conflict into a new phase. On December 2, the first artificial heart (Jarvik-7) transplant was performed at the University of Utah – patient Barney Clark survived for 112 days. This marked the dawn of the era of artificial organs.

In the cultural landscape, Michael Jackson's Thriller was released on November 30, marking the beginning of the music video era and the restructuring of the pop music industry. On August 12, Sony released its first CD player, the CDP-101, in Japan, marking the beginning of the digital transition of music media.

In Korean history, on January 5, the nighttime curfew was lifted, symbolizing the end of the 37-year curfew that had been in place since the US military government in 1945. On March 18, the Busan Cultural Center arson incident – a student movement that held the United States accountable for the Gwangju massacre. On March 27, the professional baseball league began, marking the first year of the Korean professional baseball league with six teams. In May, the Lee Cheol-hee and Jang Young-ja promissory note fraud scandal erupted, raising questions about the morality of the government. The year marked the full-scale launch of the new military regime's 3S policy (Sports, Sex, Screen) – a period in which political weight was suppressed and public attention was diverted to culture, consumption, and sports.

In this turbulent year, the Nobel Committee recognized those who had solved the 100-year mystery of aspirin. It is symbolic that in a year when international politics fragmented into localized conflicts, local signaling molecules in the body were recognized.

Sune Bergström: The Father of Prostaglandins

Sune K. Bergström (1916-2004) was a Swedish biochemist. He received his Ph.D. from the Karolinska Institute in 1944 and served as the head of the Department of Medicine at the Karolinska Institute from 1963 to 1966. His academic journey began with pure biochemical research, but his later interests expanded to global public health.

The roots of prostaglandin research can be traced back to Ulf von Euler, who won the Nobel Prize in 1970. Euler discovered that a substance extracted from human semen caused smooth muscle to contract in a test tube and rapidly lowered the blood pressure of experimental animals. Because this substance was first extracted from the prostate gland, it was named prostaglandin. The name itself is a fossil that preserves the starting point of the discovery.

Bergström delved into the nature of this substance. In 1957, he and his student Samuelsson purified and isolated PGE1 and PGF1α, prostaglandins that induce smooth muscle contraction, and elucidated the chemical structure of these substances. Crucially, he discovered that prostaglandins are derivatives of unsaturated fatty acids, particularly arachidonic acid. Because arachidonic acid is present in the cell membranes of most cells, this explains why prostaglandins can be synthesized in almost all cells.

Bergström earned the nickname "Father of Prostaglandins" for this achievement. Later in life, he shifted his focus to global public health. Recognizing the role of prostaglandins in uterine contraction and birth control, he turned his attention to tropical diseases and nutritional problems in developing countries. He served as Chairman of the WHO Advisory Committee on Medical Research from 1977 to 1982.

At the time, his colleagues said that there may not be a scientist who started from basic science and reached the global public health arena. Even if he had not received the Nobel Prize for his prostaglandin research, he would have been worthy of the award for his contributions to public health in developing countries. He is a rare figure who has traversed both academic and public spheres.

Bengt Samuelsson: 25 Years with His Mentor, Discovery of Thromboxane and Leukotrienes

Bengt I. Samuelsson (1934- ) is a Swedish biochemist. He received his Ph.D. from the Karolinska Institute in 1961 and worked as a researcher at the Karolinska Institute from the same year until 1996. He also served as a professor at the Royal Veterinary and Agricultural University from 1966 to 1972, and as a professor and director at the Karolinska Institute from 1972. In his later years, he also served on the Nobel Foundation Board for many years.

Samuelsson's academic journey began as Bergström's graduate student. In 1957, at the age of 23, he participated in the purification and isolation of prostaglandins PGE1 and PGF1α with his mentor. For the next 25 years, he worked alongside his mentor to expand the world of prostaglandins.

Samuelsson's main contributions are two.

First, elucidation of the metabolic pathway of arachidonic acid and prostaglandins. He completed the overall metabolic map of how prostaglandins are produced from arachidonic acid in cell membranes and how they are degraded. This became the target map for the development of analgesics and anti-inflammatory drugs.

Second, discovery of thromboxane and leukotrienes. These two substances are part of the prostaglandin family but have distinct and potent biological activities.

Thromboxane plays a key role in the blood clotting process. It is released when platelets are activated, causing other platelets to aggregate and promoting coagulation. Inhibiting this substance is the key to the cardiovascular preventive effect of low-dose aspirin.

Leukotrienes are produced in the lungs and white blood cells, and in the lungs, they contract smooth muscle, narrowing the airways. In the blood, they alter the permeability of proteins in blood vessels and cause allergic and inflammatory reactions. Asthma's characteristic symptoms – wheezing, coughing, chest pain, and shortness of breath – are caused by this substance. Today, leukotriene receptor antagonists, such as montelukast (Singulair), are widely used as asthma treatments, and this discovery is the basis for their development.

John Vane — From a Garden Shed Laboratory Built by His Father to Unraveling the 100-Year-Old Mystery of Aspirin

John R. Vane (1927-2004) was a British pharmacologist. He received his Ph.D. from Oxford University in 1953 and served as a professor at the Royal College of Surgeons of England from 1955 to 1973, followed by his tenure as Chairman of the Wellcome Foundation from 1973 to 1985, and as a professor at Queen Mary University of London's Medical and Dental School from 1986 to 2004.

The story of how Vane embarked on his path as a pharmacologist is particularly memorable. At the age of 12, he received a chemistry set as a Christmas gift, sparking his interest. Initially, he used the kitchen as his laboratory, but an explosion during an experiment forced him to find a new space. Seeing his son's disappointment, his father built a small laboratory in the garden shed. This shed, equipped with a chair, gas, and water, became his first laboratory. In this garden shed, his chemical experiments rapidly expanded into various fields. His father's constant interest and active support guided him toward becoming an outstanding pharmacologist.

Vane's three major achievements are as follows:

1967 — Development of a bioassay for the detection of arachidonic acid. He established a method for detecting arachidonic acid and its biologically active derivatives in the laboratory. This bioassay became a standard tool for research on prostaglandins and related substances.

1971 — Elucidation of the mechanism of action of aspirin. He discovered that aspirin inhibits the synthesis of specific prostaglandins. This discovery had the most significant impact on the entire field. It was the moment when the mechanism of action of a drug that humanity had been taking daily for nearly a century was finally revealed. Aspirin irreversibly acetylates the cyclooxygenase (COX) enzyme, blocking prostaglandin synthesis. It's like shutting down the factory that produces signals for pain, fever, and inflammation.

1976 — Discovery of prostacyclin. This new substance in the prostaglandin family has opposite effects to thromboxane. It dilates blood vessels and inhibits blood clotting. Vane experimentally demonstrated that thromboxane promotes blood clotting, while prostacyclin inhibits it, completing the picture of how the balance between these two substances determines cardiovascular health.

The clinical implications of these discoveries are profound. The principle behind the use of low-dose aspirin for the prevention of cardiovascular disease — aspirin irreversibly inhibits COX-1 in platelets, thereby inhibiting thromboxane synthesis. Meanwhile, the COX in vascular endothelial cells is capable of being resynthesized, allowing prostacyclin production to continue. As a result, the balance between coagulation promotion and inhibition shifts towards inhibition, resulting in a preventive effect against myocardial infarction and stroke.

Organized with a CS Framework — Middleware Interception and Reverse Engineering

If we were to reconstruct these three individuals' discoveries using the language of computer science, it would look like this:

System Architecture: Cells store arachidonic acid, a raw material, in their cell membranes, and when needed, they call COX (cyclooxygenase) or LOX (lipoxygenase) enzymes to produce prostaglandins, thromboxanes, and leukotrienes. This is similar to a factory pattern that generates and delivers various types of signal objects on demand.

Middleware Interception: Aspirin irreversibly blocks the COX enzyme itself. It's like monkey-patching the factory function. As a result, all subsequent prostaglandin-related signals are prevented from occurring. Pain, fever, and inflammation disappear because the signal source is blocked.

Refactoring Case — COX-2 Selective Inhibitors: Subsequent research revealed that COX-1 and COX-2 play different roles. COX-1 maintains homeostasis, such as protecting the gastric mucosa, while COX-2 is mainly involved in inflammatory responses. Aspirin blocks both, leading to the side effect of gastric ulcers. COX-2 selective inhibitors, such as celecoxib, are precise refactoring that blocks only the v2 API. However, it turned out that this refactoring was not completely flawless, as cardiovascular risks emerged as a side effect.

Completion of Reverse Engineering: Aspirin was created in 1897 by Felix Hoffmann at Bayer by adding an acetyl group to salicylic acid and was sold starting in 1899. 72 years later, in 1971, Vane discovered the mechanism, even though only the result was observed without source code. After half a century, we were able to design precise inhibitors that target specific COX isoforms. Observation → mechanism → precise design—this is the sequence of how humans understand nature.

This analogy is not perfect. The lipid signaling system in cells has much more complex feedback regulation than software, and blocking a single enzyme can lead to partial bypasses through other metabolic pathways. However, the raw material-enzyme-signal-receptor structure is remarkably similar to a pipeline architecture.

Academic Impact — The Dawn of Paracrine Signaling and Lipid Mediator Research

The discoveries of these three individuals marked a pivotal milestone in establishing the concept of paracrine signaling molecules. Until then, the main axis of signaling molecules was hormones (endocrine) and neurotransmitters (synaptic). With these discoveries, a third axis, lipid mediators, was established.

The subsequent research in this field expanded explosively. A notable example is Robert Furchgott, Louis Ignarro, and Ferid Murad, who were awarded the Nobel Prize in 1998 for recognizing nitric oxide (NO) as a paracrine signaling molecule, extending the concept of this prize. The research on endocannabinoid system, sphingosine-1-phosphate (S1P) signaling, and the entire eicosanoid landscape are all extensions of this discovery.

In clinical pharmacology, this prize led to an explosion in the development of NSAIDs (nonsteroidal anti-inflammatory drugs). Ibuprofen (developed in 1961, prescribed in 1969), naproxen (1976), celecoxib (1998, COX-2 selective), and rofecoxib (1999, withdrawn in 2004 due to cardiovascular side effects) are all drugs precisely designed to target prostaglandin synthesis. Low-dose aspirin for cardiovascular prevention was established on a large scale in the Physicians' Health Study in 1988 and has been the standard for primary prevention of myocardial infarction for the past 30 years.

In obstetrics and gynecology, prostaglandins are standard drugs for abortion and induction of labor. They soften the cervix and contract the uterus. Conversely, the uterus-contracting inhibitory effect of NSAIDs makes them effective analgesics for women with severe menstrual cramps — subsequent research in this field revealed that menstrual cramps are caused by excessive prostaglandin production in the uterus.

In pulmonology, leukotriene receptor antagonists (montelukast, zafirlukast) are one of the pillars of asthma treatment. They are particularly standard for childhood asthma and aspirin-induced asthma.

The Legacy in Korea and Today

The impact of this legacy in Korea is immediately observable. In the late 1980s, research on prostaglandins and NSAIDs was actively conducted in the pharmacology departments of medical schools at Seoul National University, Yonsei University, and the Catholic University of Korea. Today, the fact that many adult Koreans take low-dose aspirin for cardiovascular prevention is a testament to the clinical establishment of this legacy.

The fact that you can buy 500-won aspirin or ibuprofen at any convenience store in Korea is the ultimate legacy of this Nobel Prize. A drug that was taken for 100 years without knowing why it worked is now a drug that is taken with a precise understanding of its target.

Why is it important?

What these three individuals left behind is the establishment that "signals in the body flow not only through systemic broadcasting but also through local hormone layers."

Bergström laid the foundation for prostaglandin research—the discovery of arachidonic acid-derived lipid mediators. Samuelsson added two powerful active substances, thromboxane and leukotriene, and a metabolic map. Vane completed the answer to the 100-year-old mystery of aspirin and the discovery of prostacyclin, a balancing agent.

The story of how aspirin works, which took 100 years to reveal, symbolizes the nature of science. We often use things knowing only the result, and much later we understand the mechanism. And once we understand the mechanism, precise follow-up designs become possible. Observation first, understanding later, precise design after that — this is the basic rhythm of how humans understand nature.

The flow of research on lipid mediators after this prize continued as follows:

• 1988, with Pannell, Salzmann, and Newsom (although in a different area, visual perception), establishing clinical cardiovascular prevention
• 1998, Furchgott, Ignarro, and Murad — nitric oxide as a paracrine signal, awarded the Nobel Prize, extending the concept of this prize
• 1998, celecoxib approved by the FDA — clinical entry of COX-2 selective inhibitors
• 2000s onwards — endocannabinoid, S1P, and lysophospholipid signaling, and the entire lipid mediator map

The clinical apex of this discovery:

• Low-dose aspirin for cardiovascular prevention — 1988 Physicians' Health Study, standard since then
• Montelukast as asthma treatment — 1998 FDA approval, standard for childhood asthma
• Misoprostol as a standard in obstetrics and gynecology — abortion and induction of labor
• NSAID market — accounts for a large portion of the global analgesic market

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