Sir John Henry Gaddum – 60 years on

Despite 60 years having passed since his death on June 30th, 1965, the work of John Gaddum is no less relevant now than it was then. As a founding member of the British Pharmacological Society, and the first Editor of the British Journal of Pharmacology, Gaddum helped to forge pharmacology as a rigorous, quantitative scientific discipline. 

Gaddum is probably best known amongst pharmacologists for the equation which bears his name. His work, an extension of earlier work by Hill and Haldane, dealt with the competition between two reversible ligands for a single, shared binding site (1). This laid the foundations for the quantitative understanding of competitive antagonism. Schild would go on to extend Gaddum’s work and develop a robust method for estimating the equilibrium dissociation constant for a competitive antagonist (2,3). 

Beyond his work on competitive antagonism, Gaddum made important contributions to a diverse range of pharmacological topics. Some of his early work at the National Institute for Medical Research, London, and the University of Cairo determined the role for acetylcholine as a neurotransmitter in sympathetic ganglia. He also showed that sympathetic nerve fibres exert their effects on target organs through the release of adrenaline or noradrenaline. In collaboration with Ulf von Euler, Gaddum discovered and characterised a novel vasodilatory substance – labelled “P” – in extracts from intestine and brain. The name caught on, and Substance P has since been implicated in inflammation and pain, as well as various other processes, such as emesis and aversive learning. Later work focussed on serotonin, its receptors and the effects of lysergic acid diethylamide (LSD); based on his experiments, Gaddum was the first to postulate that serotonin may be important in the regulation of mood. All of this work depended on Gaddum’s pain-staking development of assays to measure the presence of given chemicals in biological extracts, and methods with which to test their effects [for further details, see (4)]. 

 

Sir John Henry Gaddum (right) with Wilhelm Feldberg (left), and Sir Henry Hallett Dale (middle) circa 1960. Credit: "Lembeck Vorbilder" by Josef Donnerer, Pharmakologisches Institut Graz; Josef Donnerer und Fred Lembeck: The Chemical Languages of the Nervous System; CC BY-SA 3.0 DE
 

An area in which Gaddum’s contributions are most underappreciated is that of controlled clinical trials. In his textbook, Pharmacology (1940), Gaddum outlined the standards required for clinical trials and discussed topics including randomisation and blinding, the proper use of controls and placebos, and the importance of selecting an appropriate outcome measure. In many respects, Gaddum’s discussion of these and other topics relating to clinical trials was well ahead of its time, and is still of use today. In the years following the publication of his textbook, Gaddum would join the Medical Research Council committee which directed a ground-breaking trial of streptomycin for the treatment of tuberculosis (5). 

Outside of his work in academia, Gaddum advised the British Government during the Second World War on treating the effects of chemical weapons, and on the feasibility of contaminating enemy water supplies with capsaicin – the pungent active ingredient in chillis. He also had an interest in conservation and corresponded with Harthoorn, a veterinarian and conservationist, on the use of etorphine for the immobilisation of large mammals, particularly white rhinoceros. This was necessary for the relocation of these animals to game reserves in the hope of protecting them from poaching and the destruction of their habitat. 

After spending much of his career in London and Edinburgh, Gaddum’s final position was as director of the Institute for Animal Physiology in Babraham, Cambridge (now the Babraham Institute). Gaddum was married to Iris Mary Harmer (m. 1929), herself an accomplished physician, specialising in dermatology, and one of the first women to receive a medical degree from the University of Cambridge. They had three daughters, Susan, Ann and Phyllis. Iris lived for 27 years after the death of her husband, and died in 1992, aged 97. 


The plaque commemorating Gaddum at St Peter’s Church, Babraham, Cambridge.


In Gaddum’s obituary, Marthe Vogt wrote that students and colleagues would remember Gaddum
 

not only for his brilliant mind but also his complete lack of prejudice, his willingness to hear all views, his integrity and sense of duty, his kindness and modesty, and the way in which a busy man gave freely of his time to their many needs.

A faded plaque dedicated to Gaddum’s memory can be found on the north wall of St Peter’s Church in Babraham, Cambridge – a subtle and easily-missed tribute to a remarkable life and legacy. 

References
1. Gaddum JH. The quantitative effects of antagonistic drugs. Journal of Physiology. 1937;89(Supp):7–9. 
2. Schild HO. pA, a new scale for the measurement of drug antagonism. Br J Pharmacol Chemother. 1947;2(3):189-206. 
3. Schild HO. pAx and competitive drug antagonism. Br J Pharmacol Chemother. 1949;4(3):277-280. 
4. Feldberg WS. John Henry Gaddum, 1900-1965. Biographical Memoirs of Fellows of the Royal Society. 1967;13:56-77. 
5. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation. Br Med J. 1948;2(4582):769–782.

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