In 1968 in Boston a pathologist examined the case of an infant who had died of a rare inherited disease. Under the microscope its arteries did not look like a baby's. Their walls were thickened, with overgrown fibrous plaques and patches of destroyed tissue: the kind of finding doctors expect in an adult with advanced arteriosclerosis.
The pathologist's name is Kilmer McCully. Instead of closing the report, he went looking for more. In the archives he found a second case: a child who had died back in 1933 of another, different inherited disease. A different defect, a different enzyme, a different decade. But the arteries carried the same damage.
The two diseases have only one thing in common: in both, the blood is flooded with a small amino acid called homocysteine.
Two diseases, one trail
Homocysteine is an intermediate that forms in every cell when the body uses methionine. A healthy body does not let it pile up: it is processed back without a break. In the two children different inherited defects had broken that processing in two different places. The result in both cases is one: permanently high homocysteine.
That is exactly what makes the comparison so strong. If the damaged arteries turned up with only one of the defects, the cause could be anywhere. When two independent defects with one shared biochemical consequence leave the same marks on the vessels, the arrow points at the shared consequence.
In 1969 McCully published the observation in the American Journal of Pathology and took the next, far more uncomfortable step: if extremely high homocysteine destroys the arteries of children in a few years, moderately raised homocysteine may do the same in adults, only slowly, over decades.
The idea that cost a career
The timing for an idea like that was the worst possible. America was in the middle of an epidemic of vascular deaths that peaked in 1955, and the explanation of the day was cholesterol. A hypothesis that part of the answer is an amino acid tied to the B vitamins met an icy reception.
McCully's professional standing collapsed. In 1979 he left Harvard, where he had been since 1965, and in 1981 he started work at a Department of Veterans Affairs hospital. His research went on there, far from the big departments.
The rehabilitation
In the 1990s the data caught up with the hypothesis. Large clinical and epidemiological studies established raised homocysteine as a strong independent risk factor for vascular disease. In 1997 The New York Times told the story under the title "The Fall and Rise of Kilmer McCully", and he himself lived to see the molecule he had paid for with his career in the textbooks and on lab test orders.
The observation from the autopsy table can now be read straight off: the children with the inherited defects had shown in an extreme and fast version something that otherwise runs quietly and slowly.
Where homocysteine goes when everything works
The processing that was broken in the two children runs along several routes at once in a healthy body. One takes homocysteine back to methionine with a methyl group brought by folate, with vitamin B12 as the go-between. The second does the same in the liver with a methyl group from betaine. A third path, dependent on vitamin B6, takes it in another direction and out of circulation.
That is why the level of homocysteine in the blood is read today also as a measure of how those routes are running. McCully himself names a shortage of folate, B6 and B12 among the main dietary causes of its rise.
It has been a long road: from two children born with one broken enzyme each to a routine blood test. Their arteries told in a few years what in everyone else is written over decades.
Sources
- Kilmer S. McCully, Vascular Pathology of Homocysteinemia: Implications for the Pathogenesis of Arteriosclerosis, American Journal of Pathology 56(1), 1969: 111–128.
- Kilmer S. McCully, Homocystinuria, Arteriosclerosis, Methylmalonic Aciduria, and Methyltransferase Deficiency: A Key Case Revisited, Nutrition Reviews 50(1), 1992: 7–12.
- Kilmer S. McCully, Homocysteine, Vitamins, and Vascular Disease Prevention, The American Journal of Clinical Nutrition 86(5), 2007: 1563S–1568S.
- Martina Huemer et al., Guidelines for Diagnosis and Management of the Cobalamin-Related Remethylation Disorders, Journal of Inherited Metabolic Disease 40, 2017: 21–48.
- Michelle Stacey, The Fall and Rise of Kilmer McCully, The New York Times Magazine, 10 August 1997.
