Adolf Bingel's blinded, controlled comparison of different anti-diphtheritic sera in 1918.

With the uptake of serum treatment for diphtheria from the end of the 19th century onwards, deaths from the disease fell dramatically, albeit, less dramatically in countries, such as the UK, in which serum treatment had not been adopted wholeheartedly. The development of serum therapy of humans – in a race between the Berlin Institute for Infectious Diseases and Emile Roux and his colleagues at the Pasteur Institute in Paris – led to the award of the first ever Nobel Prize in physiology or medicine, in 1901, to Emil Behring. This illustrated that there was wide acceptance that anti-diphtheritic serum was effective. The accepted account of the serum’s mechanism of action was that anti-toxins produced by artificially infected animals neutralized toxins released by diphtheria bacteria in infected humans (measured using a method developed by Ehrlich to measure anti-toxin levels in serum). Acceptance of the theory had been reflected in the establishment of ‘healing-serum’ factories all over the western world, using horses (because they are large animals) as ‘anti-toxin producers’. This orthodox explanation of the mechanism of action was challenged by the results of further clinical trials done by Adolf Bingel, a senior physician at the district general hospital of Brunswick, Germany. During a severe epidemic of diphtheria during the winter of 1910– 1911, Bingel had become sceptical of the orthodox view that these specific ‘healing-sera’ were responsible for serum’s anti-diphtheritic effects: variable responses to the anti-toxin serum had prompted him to wonder whether its beneficial effect was due solely to the anti-toxin. Might it not be caused by a non-specific action resulting simply from administering to patients a serum from another species? Bingel was aware of ‘the enormous influences of [foreign] protein from strange [non-human] species’, as manifested in serum disease, and its marked effects on haematological indices. He was at pains to emphasize that he had not the slightest intention of casting doubts on the results of animal research on immunity, but noted that the variable clinical picture of human diphtheria, ‘with its numerous and diverse complications’, was completely different from the ‘experimentally induced infection or intoxication of an animal’, so ‘whether a drug influences a human disease can only be decided in man’. This reasoning of species-specific pathophysiology and therapy were the basis for Bingel’s decision to undertake a study comparing (Behring’s) ‘anti-toxin serum’ with ‘normal serum’, that is, serum derived from horses that had not been infected with diphtheria: ‘If no differences are found, the anti-toxin cannot be the effective agent’. Given the widely acknowledged effectiveness of Behring’s anti-toxin serum, Bingel proceeded cautiously, using alternation to create comparable groups of patients: