Modern doctors and their patients whose lives depend on therapies used routinely in cardiovascular and transplant surgery owe a debt to a handful of coagulation pioneers whose discoveries during the 1920s took place not at medical schools but at the forerunners of the University of Guelph. That's the thesis of a journal review article written by a Canadian transplant surgeon about what he calls a little-known connection between modern clinical medicine and early research in agricultural and veterinary sciences done in Guelph. �The science of agriculture and the science of humans � they're all related,� says Dr. Vivian McAlister, a surgeon at University Hospital in London and a surgery professor at the University of Western Ontario. His paper chase, including an examination of documents held in the McLaughlin Library archives, unearthed work done by several researchers � including two major names in the history of the Ontario Agricultural College and the Ontario Veterinary College � decades before U of G itself was established. McAlister's paper, now before the Canadian Medical Association Journal for review, details how early OAC and OVC studies played a role in the development of anti-clotting agents, specifically vitamin K, heparin and warfarin. More than that, he found that early Guelph researchers pioneered systematic agricultural studies, including the use of controlled trials, a concept that wouldn't catch on in human medicine until later. �They were ahead of medicine,� he says. In his paper, called �Control of Coagulation: A Gift of Canadian Agriculture,� McAlister explains that vitamin K was named in 1935 by a Danish researcher who would later share a Nobel Prize. But that work stemmed from research by a trio of OAC graduate students. William McFarlane had studied dairy science in his native United Kingdom; in Canada, he completed a PhD on poultry in 1932 under the supervision of Prof. William Graham. (McFarlane subsequently left for Edmonton but returned to Guelph as a chemistry professor in Macdonald College.) Along with students William Graham Jr. and Frederick Richardson, McFarlane published a paper in 1930 about experiments on fat-soluble components of chick feed. Working with chicks on a fat-free diet, they noticed persistent bleeding from wounds where the birds' identification tags had been applied. Having ruled out known vitamins and other dietary components, they were left with the possibility that an unknown component prevented blood clotting. Interested mostly in comparing various dietary supplements and chick growth, the trio went no further. But in a 1943 Nobel Prize lecture given by Copenhagen researcher Henrik Dam, they were credited with the initial observation that led to the discovery of vitamin K. Other researchers mistakenly believed that vitamin C was the missing ingredient. Dam found an anti-hemorrhagic factor in other foods and named it vitamin K for �koagulation� in Scandinavian and German spellings. American researcher Edward Doisey extracted, characterized and synthesized vitamin K from alfalfa. McAlister's paper notes that vitamin K soon became available for treating patients who were bleeding or needed surgery. Dam and Doisey shared the 1943 Nobel Prize in Physiology or Medicine. But that was only part of the Guelph connection to the coagulation story � and not even the first part. McAlister says neither Dam nor other vitamin researchers knew that vitamin K antagonists had been studied almost a decade earlier, this time at OVC. Dam had shown how the body uses vitamin K to make prothrombin, a precursor in the chain of biochemical events that leads to fibrin, a vital clotting protein. In his Nobel address, he also mentioned that this chain of events could be disrupted by dicoumarol. This substance interferes with vitamin K metabolism, slowing the production of prothrombin. The precursor to dicoumarol forms in sweet clover that has been spoilt by mould. But nobody knew that back when Francis Schofield, a 1910 OVC graduate and pathologist at the veterinary college, began looking at a bleeding disorder that caused cattle to hemorrhage to death. In 1922, he traced the problem to mouldy sweet clover. He suggested that an anti-thrombin substance in spoilt silage led to uncontrolled bleeding. Two decades would pass before scientists figured out how the process worked. It was researchers at the University of Wisconsin who found that mould oxidized coumarin in clover. Yoked to formaldehyde, coumarin formed dicoumarol, a vitamin K antagonist. Those scientists had uncovered a substance that would become a powerful anticoagulant. A derivative became warfarin, named for the acronym of the Wisconsin Alumni Research Fund. Used originally as a rodent pesticide, warfarin � along with dicoumarol � found use in human medicine, not least after then U.S. president Dwight Eisenhower was treated with it after a heart attack. McAlister's paper also details how Toronto scientists Charles Best, Gordon Murray and Louis Jaques found a cheap, abundant source of purified heparin that could be used in vascular surgery. McAlister says many liver transplant recipients now receive vitamin K, warfarin or heparin during their care. He first uncovered the Guelph connections more than five years ago, when he was preparing a talk on coagulation and hemorrhage control, including a new drug made in Denmark. He already knew about Dam's work there on vitamin K, but he was searching for more information to strengthen the link to Copenhagen. �What I was astonished to see was that Dam credited scientists in Guelph with the preliminary work that allowed him to do his Nobel Prize-winning work.� Curious, he followed up the reference at the McLaughlin Library archives (his paper credits help from archivist Darlene Wiltsie). He sent his review paper to CMAJ about a year ago. Speaking about the early Guelph research, he says: �The most important message is that these are not isolated matters of luck. This was a planned approach arising out of a 19-century decision to have an agricultural and a veterinary college in Guelph supported by the Government of Ontario. That link was, I think, essential to its success. It gave scientists credibility in the community.� That point was underlined when his preliminary research on McFarlane led him to the elder William Graham, for whom the former poultry building on campus is named. Although he had nothing to do with studies of bleeding chicks on fat-free diets, Graham Sr. fostered a climate of inquiry that enabled other researchers, including his son, to thrive, says McAlister. For McAlister, the U of G connection to the story of coagulation is bittersweet. McFarlane and his collaborators knew that a fat-soluble component of the diet was responsible for clotting failure, but they left that research avenue untrodden. �If they had pursued it, they would have figured it out. They would have got the Nobel Prize.� Similarly for Schofield, McAlister says, although for different reasons. Pointing to the range of research papers the OVC scientist wrote on infectious diseases in farm animals, McAlister suggests Schofield might have earned a Nobel, too, if he'd stuck to hemorrhagic factors. Similar sentiments were expressed in a short biography published last year by Douglas Maplesden. He wrote that Schofield's �early discovery of an anticoagulant active via the oral route was one of the most important discoveries of the veterinary profession in the first half of the 20th century. Oral anticoagulants could thereby be developed to poison rodent pests and as human drugs to prevent thrombosis.� More lyrically, David Archibald, a U of G grad and composer/playwright, retold Schofield's story in a musical portrait called Schofield: The Sleepless Tiger. One song, called The Ballad of Mouldy Sweet Clover, ends with the discovery of warfarin in Wisconsin as follows: �. . . when my bones are still and spent/They'll say there lies the man who sent/A million bleedin' rodents to their grave.�