Hugh Sinclair: An Eccentric and his Theory on Essential Fatty Acids

In her book, “Fine Wines and Fish Oil. The Life of Hugh MacDonald Sinclair,” Jeannnette Ewin, nutritionist from Harvard, tells how she surveyed ”the woebegone collection of papers and memorabilia left by an eccentric old man” and found them interesting. Then, asking whether a biography was warranted, she decided that it was, because so few people of his day considered, as had Sinclair, that nutrition was a legitimate subject for scientific investigation (Ewin 2002, xiii).

According to Ewin, Sinclair was capable “of immense kindness and generosity and brilliant intellectual insights, but [had] an uncanny ability to provoke sheer, irrational rage in the great, the good, the virtuous, and the self-satisfied” (ibid., vii).

For the history of CVD epidemiology, interest in Hugh Sinclair hinges on the hypothesis that exploded upon the scene in his classic editorial in the Lancet in 1956 about the possible role of essential fatty acids in atherosclerosis (Sinclair 1956). Moreover, he was indirectly responsible for a crucial change in the career direction of Ancel Keys from laboratory science to international pursuits in epidemiology.

Sinclair had first been impressed by Keys’s quantitative, multidisciplinary approach to nutrition and human biology during a 1942 wartime visit to Minnesota’s Laboratory of Physiological Hygiene. In consequence, he invited Keys to be visiting professor in Magdalen College at Oxford and this finally took place in 1951. During that Sabbatical year, Keys began his peripatetic observations beyond the laboratory and samples of Minnesota white men, into the worldwide scene of different traditions and rates of heart attack. This unusual deviation from physiology culminated in the Seven Countries Study and the legacy of Keys’s work on cultural and individual variations in habitual diet, blood lipids, and coronary disease.

Dr. Ewin’s biography of Sinclair contains several fascinating notes on Keys and his relations with Sinclair and with essential fatty acids (EFA) (Ewin, 2002, 199):

Dr. Ancel Keys, an American scientist, joined Sinclair’s laboratory in 1950 [actually 1951], and worked there for two years [less than one, actually]. In the beginning the two men were friends, traveling together to scientific meetings and sharing ideas; but rivalry grew with time. Sinclair wrote some years later that while Keys was at Oxford he thought all fats, including corn oil, raised plasma cholesterol levels. This was a matter of real irritation for Sinclair, because he and a member of his growing staff, Dr. V. Basnayake, were showing that a relative deficiency of essential fatty acids caused deposits of cholesterol in avascular tissues, such as the epididymis of the rat. Another matter that irritated Sinclair was the obvious esteem in which Rudolph Peters [Oxford nutrition head] held Keys. Nonetheless, Sinclair and Keys produced interesting work together. ‘Real nutritional deficiency,’ a paper authored jointly by Keys and Sinclair and published in the British Medical Journal in 1952, was one such a piece of collaboration (ibid.,199).

In another paper Sinclair wrote for the British Medical Journal in 1953 he again mentions Keys. ‘Therefore Keys, whom we were fortunate to have working with us for a year at Oxford recently, has been led to suggest that increased dietary fat raises serum cholesterol and produces atherosclerosis: since increased dietary fat will tend to cause obesity it is not surprising that atherosclerosis is commoner in overweight persons.’ At that point, at least, Sinclair didn’t challenge Keys’s views” (ibid.,200).

There was much hoopla surrounding Sinclair’s idea about EFA deficiency and atherosclerosis, in part from the way in which he presented the issue. For example, his letter to the Editor of Lancet starts as follows:

Scant attention seems to be paid by the medical profession and by food administrators to a very important change in the dietaries of the more civilized countries that has been occurring over recent decades with increasing intensity. I refer to a chronic relative deficiency of the polyethenoid essential fatty acids. It is true that the matter was raised in your columns, a year ago, but then no less a person than a professor of nutrition stated that such deficiency rarely, if ever, occurs in man; Professor Yudkin, however, has the disadvantage of not having worked on EFA. Our own experimental work, humble in scope, combines the careful assessment of the literature and has led us to exactly the opposite conclusion. The causes of death that have increased most in recent years are lung cancer, coronary thrombosis, and leukemia; I believe that in all three groups deficiency of EFA may be important. Your readers having stereotyped minds should stop reading at this point” (Sinclair 1956, 381).

Sinclair’s self-described discovery of deposits of cholesterol in the epididymis of rats fed a diet free of fats indicated to him that cholesterol was being synthesized in the body and was accumulating … due to increased permeability and capillary fragility or unusual synthesis or esterification with fatty acids poorly disposed of from tissues. Others reported that the requirement for EFA is five times greater in male than in female animals. All this, mechanisms and epidemiology, seemed to him to fit a picture. [ed. Brian Bronte-Stewart at Cape Town had already shown in feeding experiments that linoleic acid lowers serum cholesterol in man. He became interested in 1956 in testing the hypothesis of essential fatty acid deficiency as relative, contingent upon an excess of saturated fats in the diet. (pers.comm. to Henry Blackburn).]

Ancel Keys, all the while, was holding to his early idea that it was total fat and not the quality of fat that was important in atherosclerosis and coronary disease. Bronte-Stewart came to work for a year with Keys in 1956, further contributing to rupture of the relationship between Keys and Sinclair. Sinclair, who had also found qualitative differences in fatty acid effects on blood cholesterol, was actively challenging Keys’s ideas.

In the last year of his life, Keys was asked about his time with Hugh Sinclair, and, as usually happened on sensitive matters, Keys gave a non-committal answer, diverting to non-essentials, asking his wife:

“Margaret, you remember Lady Place where the Sinclair’s lived?”

“Oh, yes indeed, lovely home.”

That ended the matter. (pers.comm. to H. Blackburn).

Keys was never heard to publicly credit Hugh Sinclair with anything, including his pioneer work among the starving Dutch in 1945 or his supportive role in inviting Keys to Oxford. There, in fact, Keys became so disenchanted during winter, and his dreary chore of lecturing to students and medical audiences, that he escaped to a grander adventure in sunny southern Italy, the one that led eventually to the Seven Countries Study. He never looked back.

Jeannette Ewin refers to details of the estrangement of Keys and Sinclair:

Like George Burr, Ancel Keys, a man well known for holding views on cholesterol that contradicted Sinclair’s, did not attend the First International Conference on Essential Fatty Acids hosted by Sinclair and Oxford University in July 1957. Like Burr’s, his work was nevertheless present in the minds of participants; the thoughts were not always flattering. Unbeknownst to Keys, he was frequently the subject of spiteful jibes in letters between Sinclair and Kinsell, who were both working on different metabolic effects of different fatty acids.

Ignoring discretion during the conference, Sinclair made his feelings toward Keys an open joke. On the afternoon of Tuesday, 16 July, the conference adjourned for a time so members could travel to Stratford-on-Avon to see a performance of Julius Caesar. To remember the occasion, Hugh revised one of Antony’s soliloquies, part of which read:

‘If you have plaques, prepare to shed them now.

You all do know this corn oil; I remember

The first time Larry Kinsell gave a dose;

‘Twas on a summer’s evening, in his ward;

That day we overcame the Keysii’ (Ewin 2001, 227).

The proceedings of the EFA conference at Oxford became a classic in the field of dietary lipids. According to Ewin, this conference, with its apparent confirmation of his views on essential fatty acids, and the 100-odd notables who attended, may have represented the height of Sinclair’s career. Thereafter, labeled an eccentric and forbidden by Krebs, then department head, to carry out research at Oxford, he started a long period on his own in attempts to establish an International Institute of Nutrition.

According to his biographer, Sinclair was a colorful character, a maverick championing unpopular ideas, a passionate gatherer of data but who failed to publish sound scientific work based on these data; and who antagonized members of the establishment of nutrition and medicine by his outlandish expressions, his bluntness, and his sharp wit. He even came in his later years to enlarge upon his reputation for eccentricity. He ended up being honored around the world in nutrition circles and being a popular after-dinner speaker on such subjects as laughter and the food and diseases of Eskimos.

Sinclair’s legacy is in his central responsibility for the idea that EFA are crucial to nutrition and that Omega 3 and Omega 6 are equally important and might be related to a number of diseases including coronary disease and multiple sclerosis (Sinclair, 1990). He and Larry Kinsell made fun of Ancel Keys for holding on to the idea of total fats as the important thing in coronary disease and cholesterol regulation. Sinclair also suggested that the low lung cancer rates in high-smoking Spain and Japan, low areas of coronary disease as well, might be related in some way to a diet high in essential fatty acids. This hypothesis, along with dietary protection from anti-oxidants, is being actively pursued in Japan today.

He was turned down by the Medical Research Council in his later years because of the absence of controls in the studies he had proposed about eating seal meat, fish and coconut in the Pacific Islands and mutton in Patagonia, but nevertheless continued a longstanding collaboration with the Danes, studying Greenland Eskimos. Little has been reported from his Oxford Nutritional Survey, in a cohort, of data on habitual diet and food preparation, environment and social habits, correlated with biochemical measurements in urine and tissues and clinical manifestations, but the data are being looked at, according to Ewin, for findings in pregnant women in regard to the Barker hypothesis of intrauterine conditioning for future disease.

Dr. Ewin summarized Sinclair’s contribution:

His life’s work did not result in any great discovery, nor did it lead to the methodical and irrefutable explanation of any important scientific question. Instead, Sinclair did something very different and–many would agree–more important: he championed unpopular ideas, inspiring others to test and argue their veracity. From his early school days until the end, Hugh McDonald Sinclair’s life was a celebration of the mind, and he invested all that was his in making the enjoyment of knowledge both accessible and acceptable” (ibid., 288) (Henry Blackburn)

References

Ewin, Jeanette and Horrobin, David F. 2002. Fine Wines and Fish Oil: The Life of Hugh Macdonald Sinclair Oxford: Oxford University Press.

Keys A. and H.M. Sinclair. 1952. Real nutritional deficiency. British Medical Bulletin 8: 2262-2264.

Sinclair H.M. 1956. Deficiency of essential fatty acids in atherosclerosis, etc. Letter to the Editor, Lancet 1: 381-383.

Sinclair H.M. 1990. History of essential fatty acids and Omega-6 essential fatty acids. Pathophysiology and roles in clinical medicine. ed. D.F. Horrobin. New York: Wiley-Liss 1-20.

Born in 1910, died in 1990, Sinclair was a fellow of Magdalen College, Director of Oxford Nutrition Surveys from 1941-46; Reader in Nutrition at Oxford 1951-58; visiting professor Food Science University Reading, 1970-80; and Founder and director International Institute of Human Nutrition.