How Moldy Hay And Sick Cows Led To A Lifesaving Drug

Aug 29, 2017
Originally published on October 12, 2017 11:43 am

There is a lifesaving drug that owes its existence to moldy hay, sick cows and rat poison.

The drug is called warfarin sodium. It prevents blood clots, and it can be a lifesaver for patients who've had a heart attack or stroke. It's one of the most widely prescribed drugs in the world.

There is rarely a straight line from idea to invention, but the story of warfarin is particularly twisted. It began on a winter day in the mid-1930s when a farmer showed up at a lab at the University of Wisconsin in Madison.

"He apparently showed up in a blizzard, and he had this can of cow's blood with him," says Kevin Walters, a graduate student in history at the University of Wisconsin who has studied the warfarin story.

The blood came from a cow that had eaten sweet clover hay that had some mold growing in it. The farmer said quite a few of his cows had eaten the moldy hay and had fallen ill with what became known as sweet clover disease.

"The cows eat the hay, and a few days later, they die from bleeding internally, because their blood doesn't clot," says Walters.

The lab the farmer showed up at belonged to a chemist named Karl Paul Link. Link was intrigued by the farmer's problem and decided to try to figure what was happening.

"He redirects his laboratory towards this question of what is it in this hay that is making this cows blood thin out," says Walters.

After years of experiments, in 1940, Link and his colleagues concluded that the blood-thinning molecule arises when a fungus that causes the mold reacts with a natural substance in hay called coumarin. The chemists called the overall blood-thinning compound dicoumarol.

"They realize that the dicoumarol is thinning the cows' blood. Therefore, it could also be used as a blood thinner in human patients," says Walters.

Link and his colleagues collaborated with clinicians who tried dicoumarol as a treatment for patients who had life-threatening blood clots, and it worked. It was regularly used for patients at risk for forming blood clots.

But the chemists weren't done. They started making chemical cousins of dicoumarol. One, labeled No. 42, was a particularly potent blood thinner. But Link didn't immediately turn to its potential human uses; apparently, he was interested in building a better mousetrap — literally. He had tried using dicoumarol to kill rodents in the past, but you can counteract its effects with vitamin K, and rats apparently get a lot of vitamin K in their diets. But No. 42 gave him an idea.

"Maybe if we give [No. 42] to rats ... then what happened to the cows will happen to the rats," says Walters, channeling Link all these years later.

It worked. No. 42 became a popular rat poison, and the active ingredient in the poison was named warfarin. The name was coined by Link. It's a mashup of WARF, the Wisconsin Alumni Research Foundation, and coumarin, the chemical found in sweet clove hay.

So how did a rat poison get back to being a drug? Well, like dicoumarol, warfarin prevents blood clots from forming, and in small amounts, a version called warfarin sodium is much easier to use as a human drug than dicoumarol is. It was used to treat President Dwight Eisenhower after he had a heart attack in 1955.

Warfarin sodium went on to become blockbuster drug under the trade name Coumadin.

"And so that's how you get from a sweet clover disease in cows that is causing cows to bleed internally ... to a blood thinner for humans, then a rat poison, and then a more refined, easier-to-take blood thinner called warfarin," says Walters.

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ARI SHAPIRO, HOST:

There's a lifesaving drug that owes its existence to moldy hay, sick cows and rat poison. NPR's Joe Palca brings us the long and twisted story as part of his series on inventions.

JOE PALCA, BYLINE: Warfarin is a drug that prevents blood clots. It can be a lifesaver for patients who've had a heart attack or stroke. The story of its invention begins on a wintry day in the mid-1930s. A farmer shows up at the University of Wisconsin in Madison.

KEVIN WALTERS: He apparently showed up in a blizzard, and he had this can of cow's blood with him.

PALCA: That's Kevin Walters, a graduate student in history at the University of Wisconsin. Walters has researched the warfarin story. The blood the farmer brought with him came from a cow that had eaten a batch of sweet clover hay that had some mold growing in it. The farmer said quite a few of his cows had eaten the moldy hay.

WALTERS: The cows eat the hay, and a few days later, they die from bleeding internally because their blood doesn't clot.

PALCA: The problem became known as sweet clover disease. On that snowy day, the farmer happened to arrive at the lab of a chemist named Karl Paul Link. Link was intrigued by the farmer's dilemma and decided to try to figure out what was happening.

WALTERS: He'd redirect his laboratory towards this question of, what is it in this hay that is making this cow blood thin out?

PALCA: After years of experiments, Link and his colleagues conclude that the blood-thinning molecule arises when the fungus causing the mold reacts with a substance that occurs naturally in the hay. The Chemist called the blood-thinning compound dicumerol.

WALTERS: And they realized that dicumerol is thinning the cows' blood. Therefore, it could also be used as a blood thinner in human patients.

PALCA: So they try it as a treatment for human patients who have life-threatening blood clots, and it works. But the chemists weren't done. They started making chemical cousins of dicumerol, and one, labeled number 42, was particularly potent. Historian Kevin Walters says that gave the scientists an idea.

WALTERS: Maybe if we give it to rats, it will kill rats because then what happened to the cows will happen to the rats with this number 42.

PALCA: And it does. Number 42 becomes a popular rat poison. The name of the active ingredient in the poison - warfarin. And how did a rat poison get to be a drug? Well, just like dicumerol, warfarin does a good job at preventing blood clots. And it turns out that a version of warfarin called warfarin sodium is a much-easier-to-use drug than dicumerol. It was used to treat President Dwight Eisenhower after he had a heart attack. Warfarin becomes a blockbuster drug.

WALTERS: And so that's how you get from a sweet clover disease in cows that is causing cows to bleed internally to a blood thinner for humans, then a rat poison and then a more refined, easier to take blood thinner called warfarin.

PALCA: Invention is rarely a straight line from idea to product, but the invention of warfarin is unusually convoluted. Joe Palca, NPR News.

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