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K is for coagulation

Woody Lane, Ph.D. for Progressive Dairyman Published on 12 December 2016

This is a story of bureaucratic bungling, a Nobel Prize, three brilliant scientists, two countries, moldy hay and rat poison. I am talking, of course, about the discovery of vitamin K.

Before we start, I’ll point out something (a very important something) about a uniquely American feature found in scientific papers from our land-grant universities. The next time you read a scientific article in a research journal like the Journal of Dairy Science or Journal of Animal Science, look at the footnotes at the bottom of the first page.

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Among the usual items acknowledging the funding agencies and listing the authors’ current addresses, look for a footnote with the words “Published with the approval of the Director of the [ ... state ... ] Experiment Station as Publication No. [ ... number ... ].”

Although this type of footnote was more common years ago, you still occasionally see it today. I always thought it was just boilerplate fluff. Until now.

Back to the story. In the 1920s, farmers across the High Plains were coming into their veterinary clinics carrying buckets of blood that wouldn’t clot. They described a strange hemorrhagic syndrome in which their livestock, especially cattle, bled to death from the slightest wounds.

No one knew the cause, but the main commonality between these farms was that the affected animals had been fed moldy hay made from a popular legume called sweet clover (Melilotus alba and Melilotus officinalis).

During this same period, poultry producers reported a strange bleeding disease in their chickens. These producers were beginning to follow the modern practice of raising chickens in wire cages, and they observed that some caged chickens suffered from a hemorrhagic syndrome that kind of resembled scurvy. Again, no one knew the cause.

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Let’s put these reports into historical perspective. The early years of the 20th century comprised a period of explosive growth in scientific technology, especially in nutrition and biochemistry.

Researchers developed powerful laboratory techniques for identifying toxins and other biochemical agents. It was during this period scientists discovered the nutritional factors called vitamins, and vitamin research was all the rage.

These two bleeding syndromes, however, were puzzling, and researchers from many countries raced to discover solutions. In 1929, a prominent Danish biochemist named Henrik Dam published a paper that thoroughly described the bleeding syndrome in chicks.

After additional research, Dam published another paper in 1934 in which he contended no known vitamins were involved in this syndrome. Two Kansas researchers, Romayne Cribbett and John Correll, reached the same conclusion in their 1934 paper “On a Scurvy-like Disease in Chicks.”

Meanwhile, at the University of California – Berkeley, S.F. Cook and K.G. Scott were conducting experiments with chickens, and in 1935 they postulated this bleeding syndrome was caused by some sort of unknown toxin in fishmeal (because feeding meat meal did not cause the problem). Their paper didn’t make the fishing industry happy, but it did seem to point in a logical direction.

At the same time on that campus, a young scientist named Herman Almquist was also working on this bleeding problem in chicks. After earning a Ph.D. in organic chemistry, he had recently joined the division of poultry husbandry in the college of agriculture (yes, Berkeley had an agricultural school back then).

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In a series of brilliant experiments, he demonstrated that this bleeding syndrome involved a “factor” that was soluble in fat and that could be produced by bacterial growth in feedstuffs. He showed he could prevent the bleeding syndrome by adding this factor back into purified diets, even diets containing fishmeal.

Almquist concluded that this preventive factor, which was somehow associated with the clotting process, was a new, yet-undiscovered vitamin.

This was great investigative work, but then he tried to publish it. Remember that footnote I mentioned earlier? Well, the routine procedure for scientists on the Berkeley campus was that, prior to sending their papers to research journals for publication, they submitted their manuscripts to the experiment station director’s office for his “approval.”

But the university administrators had a serious problem with Almquist’s paper; they didn’t agree with his conclusions. They noted that senior scientists on their campus had found a different result (the possibility of a toxin) and also that respected scientists in other institutions had already concluded that no vitamins were involved in this bleeding syndrome.

These Berkeley administrators, in their wisdom, were afraid that Almquist’s outlandish paper would embarrass their institution. They felt so strongly about it that they ordered Almquist to stop submitting research manuscripts until the matter was resolved within the university.

So while Almquist fought to obtain approval from his university administrators, his landmark paper sat on a shelf waiting to be published in a scientific journal.

But the world did not wait for the University of California. In Denmark, Henrik Dam was actively researching the same syndrome, and in 1935, he published a paper in the journal Nature entitled “The Antihemorrhagic Vitamin of the Chick. Occurrence and Chemical Nature,” with essentially the same results as Almquist.

Although Dam and Almquist had both reached the same conclusions about this clotting factor, Dam published his paper first. And since the Germanic term for blood clotting is Koagulation spelled with a “K,” Dam named this factor vitamin K.

In 1943, Henrik Dam was awarded the Nobel Prize for his discovery of vitamin K. Eventually, Herman Almquist won his argument with the university system and published his paper in Nature – a few months after Dam. But the damage was done. Almquist lost out on the Nobel Prize because he couldn’t get his paper published first.

But that’s not the end of my story. Remember that other hemorrhagic problem in cattle fed sweet clover hay? Well, vitamin K is an integral part of the clotting process. Sweet clover naturally contains a compound called coumarin. Although coumarin is harmless, its derivative is not.

When sweet clover is made into hay, and if that hay gets wet so that mold grows on it, the mold converts coumarin into dicoumarol. Dicoumarol interferes with the function of vitamin K, and this interferes with the clotting process. Hence the bleeding syndrome occurs in livestock fed moldy sweet clover hay.

After the discovery of vitamin K, a Wisconsin scientist named Karl Link worked on this hemorrhagic disease of sweet clover and, in 1941, successfully characterized dicoumarol and its anticoagulant properties. His laboratory then synthesized other similar compounds with anticoagulant properties, trying to find a commercial blood-thinning drug.

Because of the financial profit potential of such a compound, the University of Wisconsin was very interested in his work. In fact, like many universities that administer the licenses and royalties from the commercial products of university research, the University of Wisconsin had set up a separate funding organization called the Wisconsin Alumni Research Foundation (WARF).

One compound that Karl Link synthesized from coumarin was particularly effective as an anticoagulant, far more powerful and dependable than dicoumarol. This compound was soon commercialized as a rat poison.

In fact, it has become one of the most widely used rodenticides in the world, as well as a premier anticoagulant drug in human medicine. We know it as Warfarin. But think for a moment about its name. Karl Link had cleverly combined the acronym of his university foundation with the name of the base compound – WARF plus coumarin.

So there we have it. University bureaucrats delay the publication of a breakthrough paper on vitamin K because they wished to avoid institutional embarrassment, and in doing so they deprive a fine scientist of a Nobel Prize.

Years later, after working on a compound linked to vitamin K, another fine scientist in a different state named a rat poison after his university’s funding organization.

Life is filled with little ironies.  end mark

Woody Lane, Ph.D., is a livestock nutritionist and forage specialist in Roseburg, Oregon. He operates an independent consulting business and teaches workshops across the U.S. and Canada. His book, From The Feed Trough: Essays and Insights on Livestock Nutrition in a Complex World, is available online (Woody Lane PhD).

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