Scientifically Speaking | A disease in cows, a rat poison, and Dwight Eisenhower
What started as a quest for farmers to save their dying cattle led to one of the most popular anticoagulant drugs in history. Here's the story behind this serendipitous drug
The story of how a mysterious bleeding disease in cattle in North America led to the development of a rat poison, which ended up being one of the most prescribed drugs in medical history is absolutely incredible. One of the early patients prescribed this rat poison was American President and World War II hero, Dwight Eisenhower.
In the 1920s, two veterinary pathologists cracked the mystery of internal bleeding among cattle. What was happening was that cattle were consuming sweet clover hay that was damp and had become a breeding ground for certain kinds of moulds. (Shutterstock)
I have a fascination with how drugs are discovered and how they work. In an earlier column, I recounted how a mouldy muskmelon found by Mary Hunt at an American market in Peoria, Illinois became the source of much of the world’s penicillin, years after its discoverer, Alexander Fleming, gave up hope of using the mould as a practical drug.
But the story of the discovery of a blockbuster drug that has helped patients around the world by preventing pulmonary embolism, deep-vein thrombosis, and stroke is so fantastic that it is hard to believe. A series of events had to occur in a precise order with the main characters playing key roles.
Let me start at the beginning, since this is a story that's best told in chronological order. I’ll reveal the name of the drug in due course.
In the 1920s, in the prairies of North America, farmers noticed that their healthy cattle were suddenly dying of internal bleeding. No one could fathom the cause, but to the farmers, it was a catastrophic problem. These farmers had already been squeezed by the economic hardships of the Great Depression and the loss of cattle amounted to a loss of livelihood.
Two veterinary pathologists, Frank Schofield and Lee Roderick, cracked the mystery. What was happening was that cattle were consuming sweet clover hay that was damp and had become a breeding ground for certain kinds of moulds. In times of prosperity, perhaps damp hay with mould would not be given to cattle, but there was a shortage of other available high-quality feed.
The two pathologists called the bleeding disease the “sweet clover disease”. The only way to save afflicted cattle was by providing them with fresh hay that was uncontaminated or by performing blood transfusions.
A decade after the original outbreak of sweet clover disease, a Wisconsin farmer named Ed Carlson travelled nearly 200 miles in the middle of a blizzard, with one of his dead cows in the back of his truck, to an agricultural experimental station. Carlson had lost a number of his prized cattle in the preceding months. Searching around that night, Carlson found one office building open. It was a serendipitous turn of events that would change the course of medical history.
Carlson deposited a milk can with cattle blood, a hundred pounds of sweet clover, and his dead cow in front of Carl Link, a research scientist who was in his office that night. The blood in the milk can came from a cow with sweet clover disease and so it would not clot.
At the time, scientists knew that the bleeding disorder in cattle was caused by moulds in contaminated hay, but they did not know how it occurred. Link sent Carlson back without much hope, but shortly after, he and his colleagues devised experiments using plasma from rabbits to test clotting with various compounds isolated from contaminated sweet clover hay.
The work was arduous, and it took Link and his colleagues six years to finally be able to figure out the substance in the hay that was causing the bleeding. What the researchers found is a natural substance called coumarin was becoming oxidized in the mouldy hay to become dicoumarol. There was an enzyme in the fungus that was causing coumarins to become linked to form this dicoumarol, and it was this anticoagulant which was causing cattle to bleed to death.
A few years later, while Link was recovering from the after-effects of an earlier infection of tuberculosis, he got the idea of using dicoumarol as a rat killer. His bright idea was that rats that swallowed dicoumarol would die from internal bleeding. But the practical use of dicoumarol as a rat poison was somewhat limited. Dicoumarol proved to be unsuitable for the task, so his team started to work on variations of coumarin.
It's worth pointing out that the development of the rat killer was funded by the Wisconsin Alumni Research Foundation (WARF), which held the rights to the patent for dicoumarol. The acronym WARF would soon become part of the name of the most suitable rat killer found by the team.
A list of 150 different compounds was created. Number 42, which was most suitable was named warfarin. (Fans of Douglas Adam’s The Hitchhiker’s Guide to the Galaxy will nod at the coincidence, since Adam has pointed out that “42” is the answer to life, the universe, and everything). And in 1948, warfarin was promoted as a rat poison.
In 1951, a US army soldier tried to kill himself by taking multiple doses of warfarin. He fully recovered after being treated with vitamin K. It is then that researchers began to realise the full potential of using warfarin, not as a rat killer, but as an anticoagulant drug.
Warfarin had significant advantages over other anticoagulants in use at the time since it was highly soluble in water and could be used as an oral drug. Its effects could also be reversed with vitamin K.
In 1955, after US President Dwight Eisenhower suffered a heart attack, he was given the rat poison, warfarin. He’s certainly not the only patient who benefitted. What started as a quest for farmers to save their dying cattle led to one of the most popular anticoagulant drugs in history. Many patients have benefitted from treatment with warfarin ever since.
Anirban Mahapatra is a scientist by training and the author of a book on COVID-19. He’s writing a second popular-science book
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