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News Gram™ April 2004

April 2004 ~ Vol. 10, No. 9

Back in the 1950s, a pathologist at Harvard, Kilmer McCully, came up with some interesting ideas about the cause of heart disease. McCully's theory was simple. He proposed that the amino acid homocysteine was the chief culprit in the formation of artery clogging plaques. If there were a medication to lower the level of this molecule to normal levels, atherosclerosis could be brought under control. It turned out that folic acid, a B-vitamin, was able to lower homocysteine levels - and it didn't cost much more than aspirin.

Great news, right? Well, not exactly. In fact, the reception his work received was icy at best. His colleagues at the time were busy at work trying to determine what the role of cholesterol and other fats in the blood were in the development of heart disease. Behind them were pharmaceutical companies anxious to develop therapeutic agents to combat high cholesterol, thereby lowering the possibility of developing life-shortening plaques in the coronary arteries. To these people, a new theory was not a welcome addition to their scientific work. It was, briefly, a threat.

If coronary artery disease could be defeated with a simple vitamin that lowered blood levels of homocysteine, then the whole edifice housing the established scientific and medical community behind the cholesterol theory would come tumbling down. Never mind that McCully was not trying to destroy anyone's career or stop large companies from making earning profits. All he was after was the truth behind heart disease.

McCully was aware that children who suffered from a rare biochemical abnormality called homocysteinuria, which consists of elevated blood levels of the amino acid, also had fibrous scarring and calcification of the inner lining of their coronary arteries. That was the kind of fact that got him thinking about the possible role of this substance in ordinary heart disease. What he came up with was the idea that homocysteine interferes with the way cells use oxygen, the result of which is the build-up of free radicals, compounds that damage the body and accelerate the changes associated with aging.

It is noteworthy that half of all people who develop coronary artery disease have normal blood cholesterol levels. In McCully's mind, this kind of statistic makes one doubt the theory that cholesterol is the principal agent that damages the lining of coronary vessels. In the department of pathology at Harvard, there was a good deal of support for McCully's research. For five or six years, the chairman of the department helped provide him with the necessary equipment and supplies for him to conduct his research. In 1975, however, things changed dramatically - and for the worse. McCully's chairman retired and his successor was not at all impressed by the homocysteine theory.

McCully's new chairman bluntly informed him that he would offer him no support. His laboratory was removed to another part of the hospital and he was told to look elsewhere for the financial means to continue his work. The Director of the hospital told him that Harvard Medical School did not believe the scientist had proven his theory.

At the end of 1978, McCully left Harvard and took a position at the Providence Veterans Administration Hospital, where he still works. Several years ago his case was presented in the New York Times Magazine. It was shocking. McCully was all but run out of Harvard by his "scientific" colleagues. But the gist of the article was that these people had enormous financial interests in the cholesterol theory and were not going to be undone by the likes of Kilmer McCully.

Over the years, the homocysteine theory has received increasing acceptance until it now sits beside the cholesterol theory. McCully notes that there have been at least 1500 publications on homocysteine and heart disease. And 20-30 new articles are coming out each month.

The lesson of this saga is that there is much more to science than experiments and results. There are all the personalities, interests, idiosyncrasies, economic, political and often religious forces at work. As the stakes increase, the forces on scientific research - from within and without - increase accordingly. The direction of research is often influenced by non-scientific factors. The questions scientists ask can be determined more by these outside forces than their own intuition or curiosity.

One would think these other influences corrupt the mission of science, whether that mission be in physics, chemistry, biology or medicine. On the other hand, we need to recognize that science is a human endeavor - and humans are, well, human. No, it's not fair that science is motivated, directed or changed by outside forces. But we needn't be shocked by this fact either. Were it not for human beings, science wouldn't exist.

Philosophers and historians are interested in the forces that shape the scientific enterprise. The man who opened this whole area of inquiry was Thomas Kuhn, who wrote a famous book, The Structure of Scientific Revolutions. In that book, Kuhn introduced the idea of a "paradigm," i.e., a model within which "ordinary science" is practiced. In McCully's case, the model was the cholesterol theory of cardiovascular disease. McCully threatened the integrity of that model when he introduced the alternative theory that homocysteine was the central offending agent causing this problem. As a result, he engaged the wrath of his colleagues.

Next month: Are we on the right track in the war against Alzheimer's Disease?

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