Ear worms brought on by a catchy tune eventually wear off. By contrast, brain worms—questions, problems and ideas—can recur at intervals for years or decades. Why I should have remembered the one recounted here or why I have done nothing to find the answer previously I do not know.
During the academic year 1963-64, Gerald Wiseman (1923-2000), then Reader in Physiology at Sheffield, gave a lecture on shock to second year physiology students, a cohort comprising honours physiologists as well as those of us taking physiology as a subsidiary subject to a different honours course. Physiology in Britain has its roots in human medicine and pre-clinical teaching and even science students had lectures or short courses on topics at the edges of physiology and pathology. Shock or traumatic shock in the early 1960s was still highly topical. The treatment of traumatic shock had advanced during the Second World War. In cities with heavy industry, like Sheffield then, there were numerous industrial accidents.
During that lecture which covered reversible and irreversible shock came my brain worm. Gerald Wiseman explained that as a result of work in Sheffield during the War, a substance released from damaged tissues was thought to be one of the factors responsible for the deleterious effects of shock on the cardiovascular system that can have such a devastating effects on survival. What, I thought—and continued to think—was that substance, and what happened next?
A few weeks ago, I was looking something up in Arthur Chapman’s history of the University of Sheffield published in 1955 when I came across this:
It has long been realized that one of the most serious immediate consequences of severe injury is shock, and at the suggestion of the Medical Research Council a traumatic shock research unit was formed in the Department of Pathology in 1941 to investigate the cause and treatment of shock in major industrial accidents. The discovery by this unit of a substance in muscle which was capable, after injection, of producing a condition resembling traumatic shock aroused widespread interest, and through the active support of the Chief Medical Consultant of the U.S. Army, European Theatre, and the R.A.M.C., American and British experimental physiologists came to Sheffield to assist in the work. Later, at the request of the Medical Research Council and the War Office, investigations were extended to battle casualties. After a preliminary reconnaissance in the battlefields of Holland and Belgium the team was constituted a full R.A.M.C. unit— the British Traumatic Shock Unit 2—and was attached to the 21st Army Group to deal with casualties from the Battle of the Rhine. Working at Casualty Clearing Station level, with its own transport and mobile laboratory, it accompanied the 2nd Army through Westphalia and N.W. Germany, finally to reach Lubeck. Most of its analyses were made in the forward areas, but from time to time material for more specialized tests was flown with members of the team to England. Although the full significance of this work is not yet clear, the observations on the field and in the laboratory are of importance in that they confirm that one causal agent in shock is a substance liberated by extensive damage of muscle.
While this research unit was with the 2nd Army it was able to advise surgeons of many units, both British and American, on the immediate treatment of those wounded a short time before, and to suggest lines of enquiry on the cause of death peculiar to certain battle casualties. After the German surrender the unit went to Louvain to study normal soldiers, and to give lectures to the Faculty of Medicine of the University and to many units of the 2nd Army.
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| Harry Norman Green |
I have just got round to looking up what this was all about. The story begins when Sir Edward Mellanby FRS (1884-1955), then in the once powerful position of Secretary of the Medical Research Council, suggested to Professor Harry Norman Green (1902-1967) of the Department of Pathology in the University of Sheffield that for the war effort he should work on traumatic shock. Green was well known to Mellanby. Indeed Green had been Mellanby’s clinical assistant in Sheffield when the latter was Professor of Pharmacology; they had published together, on vitamin A and carotene. Sheffield was also a bit of a centre of activity for the Mellanbys. Mellanby kept his lab in Sheffield when appointed as Secretary of the MRC until facilities at Mill Hill were built. Sir Edwards nephew, Kenneth Mellanby (1908-1993), did his famous wartime research on scabies there.
Extracts from Green’s obituary* expand on the account in university history and explain the background as well as what happened next:
Traumatic shock is more often thought of as a subject for war-time investigation by physiological rather than pathological departments. However, Green always considered that traumatic shock, being part of the general response to injury, was, with inflammation and cancer, one of the fundamental reactions of pathology. In this work, which occupied him for just over ten years, he adopted the Hunterian view that the changes that occurred in the body after injury might well be part of a defence mechanism. At first the work was clinical in association with Mr (now Sir) Frank W. Holdsworth in the accident service of the Sheffield Royal Infirmary. From an analysis of the shock following industrial accidents they became, like others before them, convinced of the need for the early treatment of the local injury and of the relation between the amount of damaged tissue and the severity of the response. These considerations led to work on the toxicity of a muscle extract first investigated by Dyckerhoff in Germany before the War and shown by him to have two components, one of which was thromboplastin. Dr Marianne Bielschowsky, who had joined the Department in Sheffield with her husband, was able to show that the second factor was adenosine triphosphate.
Adenosine triphosphate (ATP) had been isolated from muscle by Lohmann in 1929, but in 1942 very little was known of its biological role. The finding that ATP could produce a state of shock when given parenterally in large doses, that its activity was potentiated by environmental and other factors and that with thromboplastin it accounted for the toxicity of Dyckerhoff’s muscle extract led to a full- scale investigation of the pharmacological activities of the adenine nucleotides and their possible involvement in traumatic shock. The pharmacological studies and the use of nucleotide shock as a model for traumatic shock proved the more immediately fruitful of these two projects and the results are contained in the book on the “Biological actions of the adenine nucleotides” published with H. B. Stoner in 1950.
The possible involvement of the adenine nucleotides in traumatic shock was a much more difficult problem. Green had no illusions about this, for in the initial experiments he had found that injured muscle contained less ATP than normal muscle…The possibility of causal involvement was obvious and in a war-time environment had to be examined. To do this No. 2 Traumatic Shock Team RAMC [Royal Army Medical Corps] was created with Green in command.
As a professor in uniform Green was not a typical Lieut.-Colonel, even for the RAMC. Nevertheless he generated considerable loyalty in his small band of officers and other ranks, and the Unit achieved quite a lot during the fourteen months of its existence. His success in this venture, despite his inherent shyness, was due to his lack of sense of rank and his way of treating all military personnel as if they were still civilians. Although the prime function of the Unit was to study the effect of injury on the distribution of adenine compounds, the opportunity was taken for collecting other clinical and biochemical data. Most of the observations were made during and shortly after the battle of the Rhine Crossing.
In all this work there was a lot of circumstantial evidence pointing to a role for the adenine nucleotides in traumatic shock. The trouble was that, owing to the crudeness of the analytical tools available, it was not possible to devise experiments that would eliminate the hypothesis. It was not until 1957 that Threlfall and Stoner were able to show satisfactorily that adenine nucleotides left damaged muscle only after they had been deaminated to the non-toxic inosinic acid and inosine. It is now clear that the adenine nucleotides do not play a prime toxic role in the shock accompanying ischaemic limb injury. Nevertheless there are still many unanswered questions concerning the involvement of these compounds in pathological reactions, particularly in those organs where the pattern of breakdown differs from that in muscle. Green’s original decision that the study of the pharmacology of these compounds is worthwhile from a pathological point of view may prove correct.
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| Harry Berrington ('Berry') Stoner |
The co-author of the Green’s obituary was Harry Berrington Stoner (1919-2004), his main collaborator on the traumatic shock project, and who finally demonstrated no linkage between ATP release from damaged muscle and traumatic shock. Stoner, like Green, born in Sheffield and a Sheffield medical graduate, was moved into the MRC Unit by the R.A.M.C. and then into the No. 2 Traumatic Shock Team. Unlike Green, who became more interested in cancer research and moved to Leeds in 1953 as Professor of Experimental Pathology, Stoner retained his interest on research on trauma and remained with MRC. He was head of a unit at the laboratories in Carshalton but then moved as head of a new trauma unit attached to the University of Manchester in 1977.
It is not surprising that by the onset of war in 1939 the MRC was persuaded that release of ATP into the circulation might be responsible for many of the manifestations of traumatic shock. Physiologists and pharmacologists had been studying the effect of chemically similar compounds for the previous ten years or so. ATP had been discovered in 1929 and, in the 1930s, its role in cell energetics established. It is also not surprising that its effect and that of other purine compounds outside the cell, on blood vessels and the nervous system, for example, was the subject of pharmacological research (some I find done by former and then very senior colleagues) in the early decades of the 20th Century. Although that particular line came to nothing (and the meticulous Gerry Wiseman was behind the times in his lecture) these and other studies contributed the background knowledge for the realisation that there is a purinergic signalling system in the body†. ATP is released as an extracellular signalling molecule, independently of its role inside the cell as a a high-energy carrier. Green’s prediction, ‘the study of the pharmacology of these compounds is worthwhile from a pathological point of view may prove correct’, has been vindicated.
Although I now know the answer to my brain worm, there is an intriguing incident I found while searching for information on Harry Green. But that can wait until the next article.
*Bonser GM, Stoner HB. 1968. Harry Norman Green 21 September 1902-16 May 1967. Journal of Pathology and Bacteriology 96, 243-252.
†Burnstock G, Fredholm BB, North RA, Verkhratsky A. 2010. The birth and postnatal development of purinergic signalling. Acta Physiologica 199, 93-147.
Chapman AW. 1955. The Story of a Modern University. A History of the University of Sheffield. Oxford University Press.
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