An impression of the Department of Experimental Medicine at Cambridge

An impression of the Department of Experimental Medicine at Cambridge

James R. Robinson

An Impression of the Department of Experimental Medicine at Cambridge (England)

A student of Dr. R. A. McCane, the professor of Experimental Medicine at Cambridge University, England, provides delightful reminiscenses from a personal and professional perspective about the personal style and laboratory conditions which led Dr. McCane to make his many significant contributions to our knowledge of human nutrition and physiology. Dr. Robinson participated as subject and scientist in Dr. McCane’s studies on the effect of rationing on the adaptive capacity of the human.

The Department of Experimental Medicine was set up in 1945 when the University of Cambridge established a Chair of Experimental Medicine. This was a personal chair for Dr. Robert Alexander McCance, C.B.E., F.R.S., limited to one tenure, for so long as the Medical Research Council (MRC) provided his salary. In fact it lasted two decades, until Professor McCance retired in 1966. The Department had really begun in embryo and was already a lusty youngster long before its official date of birth; for Dr. McCance came to Cambridge in 1938, as Reader in Medicine in the Department of the Regius Professor of Physic, John Ryle. He came from King’s College Hospital, London, where he had established a great reputation by his heroic and fascinating studies of experimental human salt deficiency while he was Assistant Physician in Charge of Biochemical Research.(1) He brought with him his life-long collaborator, Dr. Elsie M. Widdowson, who recently described(2) how they met when she was undergoing postdoctoral dietetic training in large-scale cooking at King’s College Hospital and became aware of a white-overalled gentleman who came into the kitchen to cook joints of meat which he was later to analyse as part of an investigation of the effects of cooking on nutrient content. Dr. Widdowson joined him in this enterprise and they made a formidable combination, known affectionately as “Mac and Elsie.” One of their major early achievements was the analysis of a large number of British foods, both as raw materials and also cooked and ready to serve, for their great book of tables, The Chemical Composition of Foods. The first edition(3) was published by His Majesty’s Stationery Office in 1940; two subsequent editions and a reprint with amendments came from the Department of Experimental Medicine in 1948, 1960 and 1967. Paul & Southgate later carried on the tradition and produced a fourth edition in 1978 which included new analyses from the laboratory of the Government Chemist.(4)

STUDIES ON WARTIME RATIONING

I first met Dr. McCance in 1943, shortly after he had migrated to Cambridge. I had consulted Professor Ryle about whether to follow up an honours degree in biochemistry and a Ph.D. in what was really physical chemistry by completing the medical course. Ryle gave his opinion, and then took me through to put the question to Dr. McCance. He gazed at me with his clear blue eyes and said “Oh, of course, you must; – you’ll hate it, but you’ll never regret it;” and then after I’d started he recruited me as a subject for the experimental study of rationing which he was planning in order to find out how the English people might be expected to survive nutritionally if so many ships were sunk that they had only drastically limited food supplies. So I spent several months closely involved with the Department-to-be early in the War.

For the subjects the experiment initially involved adapting to a much more

bulky and flatogenic diet which came to include reheated vegetables for breakfast, a mainly vegetarian lunch in the Department each day, and an evening meal prepared from the strictly rationed foods by a collegue in her home in Cambridge. After a few months, as a test of our fitness on the restricted regime, Dr. McCance and I set out the day after Christmas and rode on bicycles to Langdale in the English Lake District, stopping for our evening meal at two hotels on the way north, where we ate only the vegetables intended to accompany the main course. We brought out scales and weighed and recorded the weights of our servings, to the consternation of the staff and the amusement of other diners. The last half day was on icy roads, but others of the team had gone in advance with Dr. Widdowson by car; they cheered us on with hot drinks half way, and had a fire and hot soup ready to greet us on arrival. The whole fascinating story of this study could not of course be released until after the war.(5) A number of metabolic balance periods were included in the programme, so that an immense amount of analytical work went on behind the scenes, which was not apparent to the subjects at the time; I only came to appreciate the laboratory as a functioning unit when I worked in the established Department for 10 years after being demobilized from the Army, but I do not think the pattern was very different. One important feature that remained was the daily midday lunch. Because of rationing which was introduced during the war, the Department had to be licensed as a catering establishment in order to carry out its researches with experimental diets. The rationing lasted for many years after the war was over; in fact it became more severe, for then we had to share our limited resources with Europeans, including our former enemies! So the lunches continued and provided a meeting point where work in progress and future plans were discussed, and where a stream of local and overseas visitors were entertained and had their brains picked. This was how I came to meet people like Daniel C. Darrow and Homer Smith from the United States, the Indefatigable Professor Borst from Amsterdam, and countless other international figures.

THE FACILITIES

Considering the large output of distinguished publications that emanated from it, the laboratory was remarkably small, modestly equipped and located in a few rooms on the ground floor of the Department of Pathology. There was a large common room which housed a gas stove and where lunches were prepared and eaten. There was also a “big laboratory” of similar size where a handful of technicians carried out the analyses of foodstuffs, end products – including the remains of four human corpses and bodies of experimental animals, blood and other offerings from subjects of experiments and from patients on balance studies in the Professor’s beds in the hospital. The staff included Lois Thrussell, now Strangeways, one of the first research nurses ever to be employed in England. She had to control the balance regime, watch over the patients and ensure that they received all that they were intended to eat (and nothing else!), and then make certain that exact duplicates of the food eaten at each meal, and all other materials required for analysis by-passed normal disposal systems and found their way back to the laboratory complete and uncontaminated! Without these essential safeguards weeks of laboratory work and restrictions imposed on patients or subjects could be wasted.

Most of the metal fittings in the big laboratory were corroded by hydrochloric acid fumes, for organs and dissected portions of corpses were first left to soften in glass tanks in “moderately strong hydrochloric acid,”(6) then heated for several days on boiling waterbaths and finally boiled over a flame until the fat-free parts were dissolved. The electric lights were suspended from metal wires strung across the room, requiring precautions against dust showers when they were moved by sliding them back and forth along the wires; and hundreds of bottles containing acid extracts of tissues and organs and people were stored in what we called “the mine” under the floor of the corridor outside the “big lab” in case analyses needed to be repeated. The only entrance to the Professor’s office was through this “big lab,” so that he kept in touch with the action and could also be warned of the approach of visitors.

I came back in 1947 after 3 1/2 years in the Army, and spent my first year in a room which had housed Professor Ryle’s Secretary. supply was a large aspirator bottle on the window ledge, and my sink a carboy on the floor with a large funnel in its neck. I can remember one morning walking round the “big lab” with a cork in my hand searching in the cupboards for a bottle to fit it. But I had a good (though slow) long beam Oertling analytical balance and a set of Barcroft manometers for metabolic experiments on tissue slices. Two years later, as Assistant Director of Research, I had a laboratory of my own and a single-pan Sartorius balance which speeded things up a great deal. But I still determined sodium by a zinc uranyl acetate procedure, and what was then called “total base” in tissues by a complex process which started with digestion with nitric acid, sulphuric acid and hydrogen peroxide in a boiling tube held over a flame, and took more than a day to complete. This was before the days of flame photometers, but Edward L. Pratt, who was later to become chief of research at the Children’s Hospital in Cincinnati devoted a great part of a sabbatical period he spent in the Department to developing one of the first models to be manufactured in England.

DR. WIDDOWSON – SCIENTIST

I was paid by the University (the other staff were MRC employees) and worked mainly on problems related to the control of the water content of cells, but I attended the weekly ward rounds and took part in discussions of the other work in the Department. The Professor was a great man for ideas. He lived 13 miles away and his daily rides to and from Cambridge on his bicycle in those days when the roads were quite gave him 2 hours every day when he could think, unhindered by visitors or telephones. He also had something of Claude Bernard’s genius in choosing the right animal, devising useful experimental approaches to a problem and a tremendous enthusiasm. He had to go to London too often for continuity in bench work, to attend many meetings and also to use the library of the Royal Society of Medicine, for the Cambridge collections were deficient in many clinical journals, and McCance’s reference lists were characteristic`lly remarkably long and complete. But though the Professor could spend little time in the laboratory, Dr. Widdowson more than made up for any deficiencies in supervision. She also had good ideas, and great laboratory skills; above all she could see exactly what was needed to turn the Professor’s ideas into practical reality. She also had a remarkable capacity to think through the implications of results and ideas and to present them in unusually lucid prose. So she played a large part in the detailed planning of the studies; she directed the laboratory work; and she also took a major share in interpreting the results, which she calculated with the aid of an exceptionally long slide rule. I used to picture her as hanging on to the Professor’s ankles and keeping him close to earth when his head got too high in the clouds.

The Professor’s great skills included writing and editing. It is hard to believe from the polished final versions of his published writings that the first drafts were often written in trains and other odd places on the backs and insides of old envelopes! One of the most important things he taught me was how to write up an investigation. Versions of most of the papers that emanated from the Department during my 10 years there were critically read, redrafted, reread and rewritten, often many times, by all of us, before a final version went to a journal; and one result was that the editing job we had done before they were submitted was often all the editing that was required, and they usually enjoyed a smooth path through to print. And of course all this was before the days of word processors.

Some of the Department’s work arose out of problems of nourishing a nation at war, with special reference to the needs and growth of school children.(7,8) For much of the first 4 years of the Department’s existence Professor McCance and the MRC staff were absent from Cambridge, working as an MRC Unit based in Wuppertal, carrying out nutritional and clinical studies of the postwar German population, especially of malnourished ex-prisoners of war repatriated from Russian camps, which led to the publication of a massive report[9] in 1951. This work required the development of methods for measuring the composition of the body during life; needless to say the techniques were tried out on members of the team, and one unexpected result was that the Professor was found to have a smaller percentage of fat in his body than any of the undernourished prisoners. He had, however, a great deal more muscle! Supplementation of children’s diets in two German orphanages revealed no essential difference in efficacy between white and brown bread under the conditions of the experiment, but the children’s growth depended greatly upon the emotional climates generated by matrons with very different personalities.[10]. Later reviews dealt in detail with the relative merits of brown and white breads.[11,12]

Other work related to the war included studies of motion sickness and its control and of how best to preserve the lives of survivors of shipwrecks floating on water they could not drink; these arose from Professor McCance’s service on a committee of the British Admiralty on Survival at Sea. Sailors were studied on rafts in tropical and in Arctic seas, and in climatically controlled chambers in the Department, on which they left their mark by painting it, and by a parting gift to the Professor of a pair of cycle clips, for they noticed that he tied the bottoms of his trouser legs with string before riding home in the evenings. The energy intakes and needs of cadets in training[13] and of individuals of all ages in civil life were investigated, and overnutrition also came in for its share of attention, with particular emphasis on the various underlying mechanisms.[14]

Some of the Department’s work started from questions raised by things that happened to patients who suffered pain and disability because for one reason or another their bones dissolved and bent under their weight. Reasons included resistance to the biological action of vitamin D, and also hyperparathyroidism, which led to a close liaison with the orthopedic surgeon, who referred many of the patients, and, incidentally, also carried out parathyroid surgery when necessary. Some patients who could not retain potassium were probably victims of aldosteronism before aldosterone had been discovered. These problems led Paul Fourman, who later became Professor of Clinical Investigation at Leeds and wrote a treatise on the metabolism of bone, to embark on an investigation of human potassium deficiency with himself as the principal experimental subject. Another prominent potassium-watcher, J. Russell Elkinton, took time off from the Chemical Section of the Department of Medicine, University of Pennsylvania School of Medicine in Philadelphia, to work in the Department for a few months in 1957, and included some impressions of life in the Department and a delightful character study of the Professor in a recent book.[15]

There was a great deal of work on individual nutrients, particularly the mineral elements, calcium, iron and zinc, and the factors that affect their absorption and utilisation. Complete metabolic studies on calcium took up so much laboratory time and effort that the Professor was sometimes able to lend one or more of his small allocation of hospital beds to other physicians. Bio-chemical investigations included the metabolism of nicotinic acid and its derivatives and the enzyme cholinesterase and its excretion in milk. The need to relate the nutrition of developing young to the demands imposed by their rapid growth led to the use of animal models and detailed measurements of the composition of the body at (and before) birth and of the way it changed right through to old age.[16,17] The different rates of growth of a large number of different species were brought into relation with the compositions of their milks, revealing a “harmony of growth” from rat, cat, dog, pig, man through calf, elephant and hippopotamus to blue whale.[18,19]

Changes in composition of the growing body and in the relative proportions contributed by body fluids, skeleton, lean soft tissues, and fat raised the problem of making measurements at different ages truly comparable[20] and led to several studies of renal function in infancy and even before birth.[21,22] McCance and Widdowson had reviewed mineral metabolism for the Annual Review of Biochemistry in 1944,[23] and the physiology of water and electrolytes remained a central, unifying theme for much later work. The development of the digestive system and factors and mechanisms that control appetite and the intake of food during life were also studied in depth, notably by Gordon Kennedy and Romaine Hervey, whose work using parabiotic pairs of rats to study hypothalamic mechanisms[24] began in the Department; Dr. Widdowson’s landmark study[10] of German orphans had already revealed the importance of influences from above the neck!

Rats were convenient in the laboratory, but the Professor also developed the use of pigs and “piglets” which he reared at his country home, because in many ways that mattered he found pigs more like people than the common laboratory animals were. But the Department of Experimental Medicine used human subjects to a greater extent than many comparable departments. Anyone who entered those doors was almost certain to become a “guinea pig.” Quite apart from ethical questions which had not become fashionable in those days, there were serious doubts about the relevance of animal experiments to human situations, and the question led to frequent lively debates at lunchtime. Dr. Widdowson appropriately gave a paper on the problems and pleasures of human experiments in 1958[25], however, in 1985 she also reviewed the importance of animals for human nutrition in an E. V. McCollum International Lecture which was a Keynote Address at the XIII International Congress of Nutrition.[26]

I emigrated to New Zealand in 1957, and my place was taken by John Walshe, whose distinguished work on the metabolism of copper and its relation to Wilson’s disease might be seen as a fitting extension of the Professor’s early researches on copper. I took with me my wife, who, as Marion Harrison, had come from New Zealand in 1948 to work on the accumulation of heavy metals in the liver for her Cambridge Ph.D. Degree. She measured the average amount of DNA in hepatic cells so that by determining DNA as well as the metals, she could express her analytical results in quantities per cell.[27] BAck in New Zealand, after our children no longer needed her full-time attention, she returned to work on trace elements and became a Professor in the University of Otago with a special interest in selenium in human nutrition. Many old memories were revived (and we also learned some things we had not known before) when Dr. Widdowson came out as a major guest lecturer at a special meeting arranged by the Department of Nutrition and the Nutrition Society of New Zealand in 1989 to mark her retirement.

Although I missed most of the last half, I was still able to watch from afar, and see how over two decades the Department’s emphasis shifted from practical problems of national nutrition and metabolic disease to pioneering work on many aspects of the chemical physiology of the whole span of life, from the foetal period through perinatal events and infancy to old age, in human and many other animal species.[28] And this work, which yielded so many exciting new insights and “made many major contributions of an extraordinarily wide variety to physiological knowledge,”[15] was achieved with a relatively small nucleus of workers, in surroundings which appeared so modestly equipped that one Japanese visitor came back later and pleaded with us to show him the “real” laboratory after the Professor had gone home! We did our best to assure him that he had seen everything, but he did not seem fully convinced. He could not of course see, for they were invisible, the real secrets of the Department’s success. These were the responses of a small but loyal and dedicated staff to Professor McCance’s innovative thinking and intuition and the superb implementation of the research programmes by Dr. Widdowson, who was herself elected a Fellow the Royal Society of London in 1976 and invested with the order of CBE in 1979.

PHOTO : Dr. McCance eats a loaf of bread on an English mountain during the fitness phase of the experimental study of rationing.

PHOTO : Dr. McCance “Mac” on the left and Andrew Huxley, subjects in the rationing study, along with Dr. Elsie Widdowson. Huxley, now master of Trinity College at Cambridge University shared the Nobel Prize in Medicine in 1963 with Sir Alan Hodgkin and Sir John Eccles.

PHOTO : Dr. McCance’s 1972 Xmas card drawn by his daughter Catriona to depict the the total miles he had cycled since 1939.

PHOTO : Drs. McCance and Widdowson attend a meeting in Holland on “Metabolic Processes of of Foetus and Newborn Infants.”

REFERENCES

(A complete bibliography would be longer than the entire article; the following few selected references supply background to some of the main lines of research.)

[1.] McCance RA. Medical problems in mineral

metabolism (Goulstonian Lectures). III. Experimental

human salt deficiency. Lancet

1936;1:823-30.

[2.] Widdowson EM. Research on cooking. In: Kurti

N, Kurti G, eds, But the crackling is superb.

Philadelphia, Adam Hilger, 1988:207-10.

[3.] McCance RA, Widdowson EM. The chemical

composition of foods. Medical Research Council

Special Report Series No. 235. London, His

Majesty’s Stationery Office, 1940.

[4.] Paul AA, Southgate DAT. McCance and Widdowson’s

The composition of foods. Fourth revised

and extended edition of MRC Special

Report No. 297. London, Her Majesty’s Stationery

Office, 1978.

[5.] McCance RA, Widdowson EM. An experimental

study of rationing. Medical Research Council

Special Report Series No. 254. London, His

Majesty’s Stationery Office, 1946.

[6.] Widdowson EM, McCance RA, Spray CM. The

chemical composition of the human body. Clin

Sci 1951;10:113-25.

[7.] Widdowson EM, Alington BK. Middle-class

diets in peace and war. Lancet 1941;2:361-5.

[8.] Widdowson EM, McCance RA. The war and

school boys food. Lancet 1942;2:689-93.

[9.] Members of the Department of Experimental

Medicine, Cambridge, and associated workers.

Studies of undernutrition, Wuppertal 1946-9.

Medical Research Council Special Report Series

No. 257. London, His Majesty’s Stationery

Office, 1951. [10.] Widdowson EM. Mental contentment and

physical growth. Lancet 1951;1:1316-8. [11.] McCance RA, Widdowson EM. Old thoughts

and new work on breads white and brown.

Lancet 1955;2:205-10. [12.] McCance RA, Widdowson EM. Breads white

and brown. Their place in thought and social

history. London, Pitman Medical Publishing

Co. Ltd. 1956. [13.] Widdowson EM, Edholm OG, McCance RA.

The food intake and energy expenditure of

cadets in training. Br/Nutr 1951;4:332-53. [14.] McCance RA. Overnutrition and undernutrition

Lancet 1953;2:685-91; 739-45. [15.] Elkinton JR. Bird on a rocking chair. Occasional

essays from family and professional life. Lincoln,

MA, The Cottage Press, 1988. [16.] Spray CM, Widdowson EM. The effect of

growth and development on the composition

of mammals. Br/Nutr 1951;4:332-53. [17.] Widdowson EM, Dickerson JWT. Chemical

composition of the body. In: Comae CL, Bonner

F. Mineral metabolism, an advanced treatise,

Volume II, The Elements, Part A, Chap 17.

New York: Academic Press, 1964:1-247. [18.] McCance RA, Widdowson EM. Composition

of the body. Br Med Bull 1951;7:297-306. [19.] Widdowson EM. Harmony of growth. Lancet

1970;1:901-5. [20.] McCance RA, Widdowson EM. The correct

physiological basis on which to compare infant

and adult renal function. Lancet 1952;2:860-2. [21.] McCance RA. Renal function in early life. Physiol

Rev 1948;28:331-48. [23.] McCance RA, Widdowson EM. Mineral metabolism

Ann Rev Biochem 1944;13:315-46. [24.] Hervey GR. The effects of lesions in the hypothalamus

in parabiotic rats. / Physiol

1959;145:336-52. [25.] Widdowson EM. Problems and pleasures of

human experiments. Proc Nutr Soc

1958;17:15-20. [26.] Widdowson EM. Animals in the service of

human nutrition. Nutr Today. 1985;20(5):33-40. [27.] Harrison MF. Composition of the liver cell.

Proc R Soc London B 1953;141:203-16. [28.] McCance RA. Food, growth and time. Lancet

1962;2:621-6.

Dr. Robinson retired in 1979 as Professor of Physiology at the University of Otago in Dunedin, New Zealand following a distinguished career in research and teaching. Immediately after completing a degree in Biochemistry and a Ph.D. in Colloid Science at Cambridge University, he served as an experimental subject on Rationing before entering medical school. He spent over 3 years in the Army Medical Corps in Europe and India and 10 years as Director of Research at the London Hospital Medical School.

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