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A Dead Cow, Moldy Hay and Drug Discovery

Anticoagulants are widely prescribed to prevent strokes and heart attacks. A dead cow and a bale of moldy sweet clover played an important role in their discovery.

There are roughly 20,000 prescription medicines approved for use around the world and in developed countries two thirds of the population takes one or more of them. Then there are all the non-prescription drugs and the various supplements that claim to have some sort of therapeutic effect that vastly outnumber prescription drugs. Obviously, drug development is a gigantic business, which is understandable given that health matters more than anything else in life and drugs promise to help with a wide range of ailments. Today, therapeutic drugs are developed by teams of expert chemists, biochemists, pharmacologists, biologists, physicians and geneticists who have an intricate knowledge of the molecular underpinnings of life. However, that is a relatively recent development whereas the use of drugs goes back thousands of years. The fact is that until about the mid-nineteenth century drugs were discovered mostly by trial and error.  

The first medicinal drug was probably opium, the resin secreted by the opium poppy before it blooms into a flower. Some 5000 years ago Mesopotamians were already cultivating the poppy because they had discovered the pain killing and euphoria inducing effects of its juice. That didn’t come about as a result of any dedicated search for medicinal plants. In all probability, it was the quest for edible plants that resulted in the fortuitous finding that some had an effect other than satisfying hunger. The ancient Chinese, Indians and Egyptians made a number of such chance discoveries, and once it became apparent that some plants had medicinal effects, early physicians were motivated to seek out plants with such properties. Traditional Chinese Medicine, Indian Ayurvedic Medicine and ancient Egyptian medicine made use of numerous plants for all sorts of diseases. Some of these were actually effective. The bark of the willow tree afforded relief from pain, mint countered gastric problems, and wormwood treated malaria. 

Although most modern drugs are the result of systematic research aimed at treating a disease by focusing on some body function such as the release of insulin, or targeting a specific invader such as a virus, bacterium or cancer cell, some discoveries are serendipitous. The classic example is the 1928 discovery of penicillin by Alexander Fleming who noted the anti-bacterial effect of a mold that had drifted into the dish in which he had been culturing staphylococci bacteria. A more recent example is that of sildenafil (Viagra), a drug originally developed for heart disease that was serendipitously found to treat erectile dysfunction. Another chance discovery was that of warfarin, a drug that reduces the ability of blood to coagulate. Under the name Coumadin, it is the most widely prescribed anticoagulant.  

Our story starts in 1933 when dairy farmer Ed Carson knocked on the door of Karl Paul Link, a biochemist at the University of Wisconsin. Carson thought that Link, who had a background in agricultural chemistry, could help with his problem. That problem was presented in the form of a strange cargo that Carson had piled into his truck. There was a dead cow, a bottle of its blood, and a bale of moldy hay. The cows on his farm were bleeding to death, he explained. Could the hay be the problem?  

As it turned out, Carson had come to the right place. Link knew that some twelve years earlier Canadian veterinarian Fran Schofield had looked into an epidemic of cattle hemorrhaging and dying after minor procedures such as dehorning and castration. Schofield had traced the problem to moldy sweet clover by feeding healthy and mold-damaged stalks to rabbits and documenting the outcome. Rabbits fed the moldy hay died from hemorrhaging illness, while the others remained healthy. It seemed that something in the moldy hay prevented blood from clotting. Informed of this, Carson returned to his farm and made sure that any sweet clover hay he fed his animals was free of mold. 

This episode kindled Link’s curiosity and sparked an investigation into the chemistry of sweet clover with hopes of identifying the component responsible for the anticlotting effect. That turned out to be quite a challenge since, like any plant, sweet clover is composed of hundreds of compounds. It took more than five years before one of Link’s students was able to isolate a few milligrams of a compound from moldy clover that had an anticoagulant effect in rabbits. It turns out that the mold plays a critical role. Sweet clover contains coumarin, the compound that is actually responsible for the plant’s sweet smell. It has no anticoagulant effect, but is converted by enzymes in the mold into the anticoagulant that the researchers named “dicoumarol.”  

While dicoumarol was certainly toxic to cattle, Link realized that this cloud might have a silver lining. It was well known that conditions such as heart attacks, strokes and deep vein thrombosis can be caused by blood clots. Dissolving these clots in a timely fashion, or preventing their formation in the first place, had an obvious therapeutic potential. Link patented dicoumarol as an anticoagulant medication and tests in hospitals soon showed that it did indeed work to reduce coagulation, but the compound was unstable, quickly broken down in the body. When a situation like this arises, usually the next step is to tinker with the compound’s molecular structure to come up with a “new and improved” version.  

In subsequent years, over a hundred dicoumarol analogues were synthesized, and one of these proved to be particularly potent as an anticoagulant. Since funding for the research had come from the Wisconsin Alumni Research Foundation (WARF), Link decided to name this compound “warfarin,” from “WARF and “coumarin.”  

When tested in small animals, warfarin proved to be such a potent anticoagulant that when ingested, it quickly caused internal hemorrhage and death. That made it ideal as a rat poison! Curiously, in larger animals the anticoagulant effect was much less, and in 1954, warfarin was approved for humans as “Coumadin.” At first there was hesitancy both by patients and physicians to use the drug on account of its reputation as a rat poison, but that resolved as a result of a widely publicized heart attack. That of President Eisenhower! The President was treated with Coumadin and made a full recovery. If the drug was good enough for the President, then it was good enough for anyone! 

The mechanism by which warfarin prevents blood clot formation was not worked out until 1978. Vitamin K is needed for the synthesis of clotting factors in the blood and warfarin interferes with an enzyme that is needed to convert vitamin K into its active form. This also explains why vitamin K is administered in case of a warfarin overdose and why people who have been prescribed Coumadin, usually because they have risk factors for stroke or heart attack, have to be careful about not overdoing their intake of foods such as kale, spinach, broccoli and seaweed that are high in vitamin K.  

Although warfarin proved to be highly successful in preventing blood clots, its use has to be carefully monitored with regular blood tests to prevent internal bleeding. Some newer drugs, such as apixaban (Eliquis) that do not require regular blood testing and have no dietary restrictions are often prescribed instead of warfarin but are more expensive. Anticoagulants are one of the most widely prescribed drugs in the world and have prevented countless strokes and heart attacks. All because in 1933 a desperate Ed Carson had driven 200 miles in a blizzard with his truckload of a dead cow and moldy sweet clover to ask for help from Professor Karl Link at the University of Wisconsin.  


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