Wisconsin Book of the Month: ‘Saving Hearts and Killing Rats,’ on the scientist behind warfarin

Jim Higgins

Wisconsin Journal/Sentinel

Wisconsin Book of the Month highlights a book — new, newish or neglected — by a state writer or on a Milwaukee or Wisconsin subject that Journal Sentinel book editor Jim Higgins recommends you read this month. This feature appears in print the second Sunday of each month, and is posted online the preceding Wednesday.

Through years of diligent effort in the laboratory and the field, Karl Paul Link and his team transformed spoiled sweet clover hay into both lifesaving medication and deadly rat poison.

In his new biography “Saving Hearts and Killing Rats: Karl Paul Link and the Discovery of Warfarin” (HenschelHAUS Publishing), veteran Madison journalist and author Doug Moe recounts the steps from hay to medicine while also building up a portrait of Link, a University of Wisconsin-Madison biochemist with a propensity for battling authority.

Without dumbing things down, Moe explains the science for lay readers, who might naturally wonder how the same substance can heal and kill. His portrait of Link also provides the vicarious thrills of riding with the pugnacious professor as he spars with colleagues, the graduate school dean and later UW president, the UW Regents and even the Madison newspaper that covered him so favorably. This includes a hands-on brawl between Link and another professor that may have started in the biochemistry department’s men’s room.

Warfarin, approved since 1954 for medical use in humans as an anticoagulant, was still one of the 100 most prescribed drugs in the U.S. as of 2022, according to industry website ClinCalc.com.

Isolating the anticoagulant

Link was born in 1901 in La Porte, Indiana, the son of a Lutheran minister who died when Link was 12. An excellent student, Link earned bachelor’s, master’s and doctoral degrees at UW-Madison, where he studied what was then called agricultural chemistry. He also won a postdoctoral fellowship to study carbohydrate chemistry with a prestigious scientist in Scotland, with whom he would have a nasty falling out. He returned to UW as a young professor with advanced technical skills and sensitive new equipment.

In 1933 a distressed St. Croix County farmer brought a dead cow, a milk can full of cow’s blood and a hefty portion of spoiled sweet clover hay to UW, wanting to know why cows eating that hay were hemorrhaging to death. For the next six years, Link and his lab assistants searched to isolate what element of the hay was causing the uncontrolled bleeding.

“The team made 10,000 blood coagulation tests. They employed more than 1,000 rabbits, 200 rats and 30 guinea pigs — and used 10,000 pounds of spoiled sweet clover,” Moe reports. In 1939, Harold Campbell isolated the culprit: coumarin, a crystalline solid. Fellow team members Charlie Huebner and Mark Stahmann then synthesized the compound in the lab; the synthetic version was dubbed dicumarol.

While coumarin present in the hay was killing cows, everyone immediately saw the potential of synthetic dicumarol in medicine for treating blood clots in people. After clinical trials succeeded, doctors rapidly adopted the drug. Link and his colleagues worked with the Wisconsin Alumni Research Foundation on the business end; he would spar and joust occasionally with WARF in the years to come.

Consensus took longer on another Link finding: that vitamin K could counteract the effects of dicumarol, making that vitamin a treatment for people who experience excessive bleeding while using the anticoagulant.

When a scientific paper argued for use of dicumarol to kill rats, Link worried: if dicumarol became known as a rat poison, that would ruin its public reputation in human heart medicine. His lab developed a much stronger coumarin variation dubbed Compound 42, which we know today as warfarin — named in part after the UW foundation.

Warfarin was patented in the names of lab researchers Miyoshi Ikawa and Mark Stahmann, and Link. In the years that followed Link and Stahmann fell out bitterly. Stahmann argued that Link minimized his contributions and omitted him from public discussion about warfarin. Stahmann even contended that Link should not be credited as a co-inventor of the compound, even though (Moe writes) “it would have been … unusual not to have Karl, who directed the lab where most of the work was done, as an inventor.”

Moe unpacks this conflict through as many primary sources and documents as he can put hands on. He appears to side with Link, based in part on the scientist’s established history of crediting and supporting his other assistants. Perhaps the break “wasn’t any single episode or point of contention, but rather was cumulative — a mix of ego skirmishes, credit disputes and other disagreements, including but not limited to the patenting of the new coumarin compounds and subsequent research on them as a possible rodenticide, that finally became combustible,” Moe writes.

This history illuminates how assigning credit for scientific discoveries is a complicated — and frequently a negotiated — matter.

Warfarin would go on to be a popular rodenticide; the related compound warfarin sodium is a powerful anticoagulant drug that many humans take today. One of its early recipients was President Dwight D. Eisenhower, who received it after his heart attack in 1955.

Moe also explores the tantalizing rumor that Soviet dictator Joseph Stalin was killed in 1953 by warfarin poisoning.

Link won two Lasker Awards, a major health science prize, for his work on anticoagulants. One of his former students, Stanford Moore, won the Nobel Prize in Chemistry in 1972 for his work on enzymes.

A man who spoke his mind

While Link was still a student, one of his UW professors told him: “Your opinions are stated in a forthright manner. You do not tell me what I would like to hear. You tell me what you think. Retain those qualities as long as you can.”

He did, and not only in scientific matters.

He clashed with the UW Regents, and was censured by that body — primarily for criticizing them in newspaper interviews.

Link also supported leftist student organizations on campus, a challenging stance in the McCarthy and House Un-American Activities Committee era. Link served as the required faculty sponsor for the Labor Youth Group and the John Cookson Karl Marx Discussion Group, not necessarily because he supported their ideas, but because he believed in their right to talk about them.

Moe quotes from a speech Link gave to the scientist’s son’s high school graduating class: “Oppose any form of tyranny over the mind of men. Without freedom of thought and expression, no man is free.”

Moe also cites a description of this scrappy professor from Wisconsin State Journal reporter John Newhouse’s profile of Link:

“Here in Madison, however, we’re used to seeing him needing a haircut, needing a shoe-shine, driving a beat-up station wagon, and getting into fascinating brawls with eminently respectable persons who have impeccable haircuts and wonderfully well-polished shoes.”

Late in the biography, discussing Link’s mood swings and manic moments, Moe suggests the scientist may have suffered from bipolar disorder.

In the years after Link’s death in 1978, efforts were made, unsuccessfully, to have Campus Drive on the UW campus named after him. But visitors to Madison can reflect on his legacy while visiting Elizabeth (Lisa) Link Peace Park on Gilman Street, named after his wife, a dedicated peace activist.

For more information about Doug Moe, visit dougmoe.org.