Homocysteine: a matter of time – medical researcher Kilmer McCully

Homocysteine: a matter of time – medical researcher Kilmer McCully – Interview

Patrick Perry

For 26 years, Dr Kilmer McCully remained convinced that the connection he discovered between homocysteine, vitamin deficiency, and heart disease as a young researcher at Harvard would eventually gain credibility.

From Galileo’s observations of planetary movements to Louis Pasteur’s theories about bacteria and disease, scientific discoveries have often been slow to gain acceptance–the discoverer is often scoffed at, ridiculed, dismissed, or worse. Even in the late 20th century, Australian researcher Barry Marshall’s “hunch” that a bacteria, Helicobacter pylori, not stress, caused many ulcers was initially dismissed as ridiculous by many and rejected by others, but is now embraced by the medical community and millions of grateful patients.

Dr. Kilmer McCully is yet another innovative scientist whose research on the connection between homocysteine and heart disease in 1969 remained largely unnoticed for 26 years. Yet he never wavered from his firm belief that a seemingly insignificant amino acid, called homocysteine, might be causing as much as half of all heart disease in humans, even though scientists dismissed his hypothesis as “an offbeat approach and probably wrong.”

Only recently–when studies at Tufts University, the Framingham Study, and the Harvard School of Public Health made international headlines–did the medical community take renewed interest in Dr. McCully’s original hypothesis.

Research into the role of homocysteine in heart disease, cancer, stroke, and other ailments is mushrooming around the world. Now a pathologist at VA Medical Center in Providence, Rhode Island, Dr. McCully attended and was a guest lecturer at the first International Conference on Homocysteine Metabolism, held in County Clare, Ireland.

We spoke with him shortly after his return.

PP: With the recent news about homocysteine and its role in disease, do you feel somewhat vindicated?

KM: I’m not sure that “vindicated” is the word. I feel gratified. I’m gratified that scientists all over the world are beginning to see, to understand, to build on the validity of this approach and to understand the genesis of heart disease. I’m also extremely pleased that the younger generation of scientists and medical investigators is becoming enthusiastic about carrying on this important work.

PP: Are you surprised that your theory is finally being accepted?

KM: I have always felt from the very beginning that it was only a matter of time until the evidence piled up enough so that scientists would become convinced of the importance of this approach to understanding the leading disease of the population. I have felt that throughout all these 26 years. Once enough information was obtained from experimental and clinical areas, this approach would come to be recognized as the best way to understand the genesis of vascular disease in the general population–a comprehensive theory, rather than a piecemeal approach to understanding the disease. In that sense, I’m not surprised. My surprise is that it’s taken so long and that the theory has been relegated to a secondary or minor position in understanding the basic cause of vascular disease; whereas, in my opinion, it’s the only way that a really comprehensive and meaningful understanding of the genesis of this disease can be developed.

PP: When talking about the genesis of the disease, are you talking about homocysteine, as opposed to cholesterol and other factors?

KM: It really isn’t opposed to cholesterol. Blood cholesterol elevation is correlated with susceptibility to heart disease, but of course there are many other factors that have been identified over the years –for example, high blood pressure, smoking, family history with genetic factors, and some dietary correlations. All of these factors have been developed over the years in understanding the genesis of atherosclerosis. In my opinion, the homocysteine theory is capable of illuminating why cholesterol and all of these other factors are important in production of the disease. I’ve never felt that the homocysteine theory excluded, for example, the cholesterol approach.

On the other side of the coin, every doctor knows that there are many, many patients who develop severe, or even fatal, heart disease or other vascular disease, yet they have totally normal cholesterol and normal lipoproteins. That means that something like 85 percent or more of patients who have significant vascular disease have no indication of an abnormality in cholesterol. As a matter of fact, I set up a study of 200 patients who had died at the Providence. VA Hospital. (The study was published in 1990 in the American Journal of Medical Sciences.) I wanted to determine how many actually had abnormal cholesterol values. It turned out that only 10 percent had elevated cholesterol. Among the group that had the severest disease and actually died of vascular disease, the average cholesterol figure for the group was 186, well below the target values advocated for lowering cholesterol levels. So it’s obvious that there are other factors besides cholesterol. I think that everybody knows this. The advantage of the homocysteine approach is that it’s a fundamental chemical theory capable of encompassing many other factors that have been identified over the years.

PP: How did you first discover that homocysteine might play a role in heart disease back in 1969?

KM: This is a long, interesting story. Briefly, I was offered a position at Massachusetts General Hospital in Boston after my pathology residency. While I was there, I had a grant from the National Institutes of Health (NIH) to study basic molecular genetics and molecular biology. I decided at that point that I wanted to get closer to diseases. I began to affiliate myself with the genetics unit, which was examining different types of genetic diseases. In the course of this affiliation, members of the genetics unit presented a fascinating case of a 12-year-old girl with homocystinuria–a new, rare genetic disease in 1968. I had never heard of it before. It turned out that the mother of this patient had told the two pediatricians who had discovered the disease in this patient (Drs. Mary Efron and Vivian Shih) that an uncle of the patient had died in the 1930s and was the subject of a case report published in the New England Journal

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