Wisconsin Alumni Research Foundation

Of Rats and Men: Warfarin Becomes World Famous by 1955

Two men in a lab in the 1950s
Karl Paul Link and Mark Stahmann posing in their laboratory sometime in the 1950s. Courtesy UW Digital Collections, Photo ID: S05108

While the era of the Steenbock patents came to a close when WARF dedicated them to the public in 1946,1 Harry Steenbock remained engaged with the foundation into the 1950s, monitoring the actions of the trustees and offering them advice. Meanwhile, a younger generation of foundation management dedicated most of their energy to the newer, lucrative patents of Steenbock’s colleague, biochemistry professor Karl Paul Link.

As the Steenbock patents were winding down, Link and his lab assistants produced a series of inventions that earned the foundation millions of dollars. By the early 1950s, Link had matched Steenbock’s reputation as a scientist of international renown. And, much like irradiated vitamin D in the decades before, the testing, licensing and marketing of the Link patents put dozens of WARF employees to work.2

Although Link’s name tends to be most associated with warfarin, a drug that acts as both a blood thinner in human patients and a poison when fed to rats, he and his lab assistants held multiple patents related to three productive inventions. In scientific terms, Link’s lab isolated a chemical compound, 4-hydroxycoumarin, that prevents blood from clotting in humans and animals. Through experiments on various analogs and synthetic forms of the underlying compound, they derived dicoumarol, warfarin and warfarin sodium.

But a more dramatic story, one that Link enjoyed retelling and that he may have embellished over the years, lay behind the basic science. In 1933, a dairy farmer drove through a blizzard and up to the biochemistry building, carrying a can of cow blood and a bushel of moldy hay. His cows had been dying and he hoped university researchers would figure out why.

Link recognized the symptoms as “sweet clover disease,” a scourge of Wisconsin dairy farmers in those years. After eating spoiled clover hay, the cows’ blood became too thin to clot, causing them to bleed to death from even small wounds. If Link told the farmer to just find better hay, that would only be a short-term fix. So he and his assistants set off to determine the chemical process that caused the disease.

They soon discovered the culprit: a substance in clover known as coumarin that reacts with fungi to produce the anticoagulant dicoumarol. After several years of research and experimentation, Mark Stahmann, a graduate student working for Link, managed to produce a synthetic form of dicoumarol on April 1, 1940. This was no April fool’s joke. Instead, it was 3,3’ methylenebis(4-hydroxycoumarin), the breakthrough that led to all the discoveries that would follow.3

Together, Link and Stahmann filed for a patent and assigned it to WARF. The substance Stahmann had isolated went into clinical trials as a way to prevent blood clots in human patients. From there, Link, Stahmann and their associates continued studying and synthesizing various forms of 4-hydroxycoumarin. Their work continued even through the mid-1940s, when Link had to be admitted to a sanitarium for treatment of tuberculosis.

In fact, his absence may have been a key part of the next big invention. Link believed that one iteration, which the laboratory labeled as analog 42, was too potent to be useful as a blood thinner. But Stahmann, who headed up the lab during Link’s convalescence, realized that small amounts of this stronger analog would have a lethal effect on rodents while posing minimal danger to humans or larger household pets.4 With Link indisposed, Stahmann worked with WARF to patent number 42 in 1945 with Link listed as co-inventor.5

Once he returned to the lab, Link decided this new substance needed a catchy name, rather than just a number. Combining “WARF” with “coumarin,” he came up with “warfarin.” Soon thereafter, in 1947, the Link group filed for a patent on yet another derivative, a water-soluble form that they called warfarin sodium.

Within a decade, each of these three anticoagulants found early success in the marketplace. First, in 1948, dicoumarol saved WARF President George Haight from a blood clot in his lung after gallbladder surgery.6 And, by the early 1950s, warfarin grew to become the world’s safest and best-selling rat poison.

Then, in 1954, warfarin sodium earned approval for human use. Just a few years before, a young army recruit had tried to commit suicide by ingesting a large quantity of warfarin rat poison. Instead, he gave himself the human equivalent of sweet clover disease. Once doctors cured the patient with blood transfusions and doses of vitamin K, they realized that warfarin could be adapted for human use. Subsequent studies confirmed warfarin sodium to be the most suitable form for patients and an even more stable blood thinner than dicoumarol.

Wider renown came in 1955. While visiting his in-laws in Denver, President Dwight D. Eisenhower suffered a heart attack. To ensure a full recovery, his personal physician administered “a drug of the Dicumarol type,” to use the imprecise language of the White House press secretary.

Link later confirmed, thanks to inside information from a Wisconsinite who happened to be stationed at the army hospital in Denver, that the president’s prescription had been for warfarin sodium. From that point forward, the newest and most refined of the Link patents set the medical standard for a safe, reliable blood thinner. Warfarin sodium, often sold under the trade name Coumadin, is still taken by patients and referenced in pharmaceutical ads to this day. Thus a derivative of sweet clover hay, named after WARF, became something of a household word for more than 60 years.7

The success of the Link laboratory could not have come at a better time for the foundation. All of the advertising expertise and legal resources that WARF had developed for the Steenbock patents could now be applied to dicoumarol, warfarin and Coumadin. When all was said and done, the inventions patented by Link and his collaborators earned $16.4 million, or $143.6 million when adjusted for inflation. Those sums paralleled the revenue from irradiated vitamin D, which in the 1930s and 40s had brought in $14 million, or $232.2 million in today’s money.

Those considerable scientific and financial resources would prove crucial as the foundation headed into the turbulent era of the 1960s. To find out more about those challenges, stay tuned for the next installment of Decade by Decade.

Kevin Walters