1943 Nobel Prize in Physiology or Medicine — Dam and Doisy, and Vitamin K

What You Will Learn in This Article

You will understand how an experiment that began with the incidental observation of bleeding in chicks led humanity to discover vitamin K, a hidden essential component of the coagulation system; the story of Dam receiving the Nobel Prize notification in a laboratory in the United States instead of Nazi-occupied Denmark; and how this discovery became the foundation for today’s newborn prophylactic injections and warfarin anticoagulants.

Something Other Than Common Sense — What the Coagulation System Hides

We often think that when we get a wound, it is the platelets that stop the bleeding. This is only half the story. Platelets stopping the bleeding is only the first step in coagulation, and above that, a dozen or so proteins called the coagulation cascade are activated in sequence, and only then does the blood clot properly and seal the wound.

Interestingly, several key factors in this cascade (II, VII, IX, X) must undergo a post-translational modification when produced in the liver to become activated. This post-translational modification requires vitamin K. In other words, the entire coagulation system depends on a single fat-soluble vitamin.

If this vitamin is deficient, all downstream functions of the coagulation cascade fail to compile, resulting in uncontrolled bleeding. The fact that newborns are inevitably in this deficient state immediately after birth is why vitamin K injections are given daily in newborn nurseries today.

This system was discovered in 1943. And once you understand this system, it naturally explains how warfarin, which is taken daily by patients with atrial fibrillation, works. Precisely, it's the opposite — warfarin is a drug that blocks the recycling of vitamin K.

The Landscape of the Time — The System is Reactivated

1943 was the year the Nobel Prize was resumed after a three-year hiatus.

In February, the German 6th Army surrendered in Stalingrad. This was Nazi Germany’s greatest military defeat, with the loss of 330,000 soldiers, and after that, the Eastern Front gradually began to shift westward. In January, Roosevelt and Churchill agreed at the Casablanca Conference to demand the unconditional surrender of the Axis powers. In July, Allied forces landed in Sicily, opening the Italian Front. In September, Italy surrendered. Although Nazi Germany had not yet collapsed, it was the year that the tide of the war decisively turned.

During this period, the fermentation process in Peoria, USA, was completed, and penicillin was first mass-produced for the US military. The Soviet Union’s mobile field hospital system was also expanded. Oxford and Peoria, Mannheim and Chicago, Moscow and New York — laboratories around the world operated in parallel, accumulating humanity’s medical assets explosively.

Against this backdrop, the Nobel Committee in Stockholm reactivated the prize system. The first decision the committee made in 1943 was to award the prize to Henrik Dam and Edward Doisy. This choice was symbolic. Dam was a scientist in Denmark under Nazi occupation, and Doisy was a chemist in St. Louis, USA. The combination of forgotten experiments in occupied Europe and safe chemical discoveries in the United States created a single prize — this combination was the Nobel Committee’s declaration of reactivation.

If we compare it to Korean history, 1943 is the year that Korea’s independence was first explicitly mentioned on the international stage in the Cairo Declaration (November). At the same time that the Nobel Prize was resumed in continental Europe and the hidden component of the coagulation system was recognized, Korea’s independence was first listed somewhere in the cascade of international politics.

Henrik Dam — A Story That Began with Chick Bleeding

Henrik Dam was a quiet biochemist in Copenhagen. The experiment he began in 1929 was originally unrelated to vitamin K. He was studying the cholesterol metabolism of chicks, and for this, he fed the chicks a special diet from which cholesterol had been removed.

A few weeks later, something strange happened. These chicks began to bleed and die. They developed subcutaneous bleeding even without any wounds, and their blood did not clot well even with minor punctures. Initially, Dam thought this was due to vitamin C deficiency (at the time, vitamin C was the only known vitamin related to coagulation). However, even when vitamin C was administered, the chicks’ bleeding did not stop.

What Dam did here was a textbook example of a good scientist. He hypothesized that something was missing from his experimental diet and tested each “something” one by one. Alfalfa leaves, spinach, pig liver, cereal germ — he added various plant and animal materials to the diet of the experimental group. Only when specific materials were added did the bleeding stop. Alfalfa and spinach were particularly effective.

In 1935, Dam named this unknown factor “Koagulationsvitamin (coagulation vitamin)” and decided to call it “K” using the first letter of the German word. However, Dam did not have the ability to determine the exact chemical structure of this vitamin. His laboratory was a small physiology laboratory, and the precise separation and purification of small, fat-soluble molecules required separate, specialized skills.

In April 1940, Nazi Germany occupied Denmark. During this period, Dam was invited by the Rockefeller Foundation in the United States and was at the University of Rochester. Returning to Denmark under Nazi occupation became virtually impossible, and he stayed in the United States for the next five years. He received the Nobel Prize notification at his desk in the laboratory in the United States. Because his homeland was under occupation, he postponed the award lecture until his visit to Stockholm in 1946.

Edward Doisy — Determining the Chemical Structure and Synthesis

Edward Adelbert Doisy was a biochemist at St. Louis University in the United States. He was already famous. He was the first to isolate estrone in crystalline form in 1929, and this sex hormone research had established his position in the academic world.

After Dam announced the existence of vitamin K, several teams jumped into determining its structure. Doisy’s team made a crucial breakthrough. They isolated vitamin K1 from alfalfa and obtained it in crystalline form (1939). Subsequently, they isolated vitamin K2 from fishmeal and showed that K1 and K2 share a naphthoquinone basic skeleton and are distinct compounds. Critically, they also developed a method for synthesizing K1 in the laboratory.

Why is this synthesis important? Chemical synthesis makes it possible to supply large quantities for clinical use. It is much faster and more stable than extracting from natural materials, and inventory can be secured in a predictable manner. The vitamin K injection (phytonadione) used in hospitals today is based on the modification of the synthesis method developed by Doisy’s team during this period.

The stories of Dam and Doisy are also a typical international collaboration model of natural sciences in the early 20th century. The European physiology experiment created observations and concepts, and the American chemical laboratory completed the structure determination and synthesis. This collaboration was a recurring pattern in several Nobel Prizes in the 1930s and 1940s, and the Dam-Doisy combination remains a representative example.

Coagulation Cascade and Linkage Time Dependency

Now, let’s organize what vitamin K actually does in the language of CS.

The coagulation cascade flows roughly like this. When a wound occurs, tissue factor (TF) is exposed. TF activates coagulation factor VII, activated VII activates X, X activates II (prothrombin) to become thrombin, and thrombin converts fibrinogen to fibrin, creating the actual clot. Several auxiliary and inhibitory factors intervene in the meantime to regulate the reaction so that it is limited to the wound site.

Here is the common characteristic of factors II, VII, IX, and X. These factors, when produced in the liver, must undergo a post-translational modification in which a carboxyl group is added to a specific glutamate amino acid residue to become activated. This post-translational modification is called gamma-carboxylation, and the resulting residue is called a Gla residue. The Gla residue must be present for these factors to bind to calcium ions and participate in the coagulation reaction.

And the enzyme that catalyzes this carboxylation reaction (gamma-glutamyl carboxylase) is vitamin K as an essential cofactor. In this reaction, vitamin K becomes an oxidized form (epoxide), and another enzyme (vitamin K epoxide reductase, VKOR) reduces it to recycle.

Now, the CS analogy makes sense. If you view the coagulation cascade as a dependency graph of several functions, II, VII, IX, and X must link an external library at build time (when synthesized in the liver) to become activated. This external library is vitamin K. The linker itself (gamma-carboxylase) is already in the code, but if the library file is missing, the link fails, and the functions remain in a dangling reference state.

Warfarin is exactly the drug that breaks the recycling cycle in this system. When warfarin inhibits VKOR, oxidized vitamin K cannot be reduced, and the linker continues to request new library files. When the stored vitamin K is depleted, the carboxylation of coagulation factors becomes incomplete, and coagulation slows down. This is precisely the desired effect in patients with atrial fibrillation — inhibiting the formation of blood clots that cause stroke.

This analogy breaks down partially here. The library management in actual cells is a dynamic cycle that is continuously recycled, unlike static linking at compile time. However, the core structure of “dependency on external components” is exactly the same.

Why Is It Important?

What Dam and Doisy’s discovery has left for humanity today can be broadly divided into two things.

First, newborn vitamin K prophylactic injection. Newborns have low vitamin K transfer via the placenta, no intestinal bacteria to synthesize K2, and low vitamin K content in breast milk. This deficiency can lead to newborn vitamin K deficiency bleeding (VKDB), which can cause life-threatening intracranial hemorrhage. Since 1961, vitamin K injection has been standardized in the United States and Europe for all newborns immediately after birth, and it has become a standard protocol in Korea since the 1980s. All babies born today are beneficiaries of this prophylactic injection.

Second, the clinical success of warfarin and the anticoagulant series. Warfarin was first developed as rat poison in 1948, but its clinical application was expanded after President Eisenhower’s myocardial infarction in 1954, and it remains one of the standard anticoagulants for patients with atrial fibrillation, deep vein thrombosis, and artificial valves today. DOACs (direct-acting anticoagulants) are partially replacing it, but warfarin’s long-accumulated clinical experience remains irreplaceable. To understand the mechanism of this drug, it is essential to understand the vitamin K recycling cycle.

The story that Dam and Doisy started with chicks and alfalfa is used every day in our hospital’s newborn nursery and cardiology department. It is important to remember that they were the first to discover the hidden external dependency of the coagulation system pipeline.

The fact that the Nobel Committee reactivated the prize system with this discovery is also meaningful. It represents the beauty of laboratory science that quietly continues even in turbulent times. It was the moment when observations and insights that began with a few chicks and a handful of alfalfa were recognized as human medical assets, transcending the turmoil of the world war.

1943 Dam-Doisy Summary: Dam discovered the existence of an essential coagulation factor (vitamin K) through chick bleeding observations, and Doisy determined its chemical structure and developed a synthesis method. This discovery became the theoretical basis for newborn vitamin K prophylactic injections and warfarin anticoagulant therapy.

→ Experience with coding: DevBench — Coagulation system simulation → Learn about CS concepts: DryBench — Dependency management and linking → Previous: 1942 — The boundary between ethics and science → Next: 1944 — Langerhans and the nerve fiber