On guinea pigs, dogs and men: anaphylaxis and the study of biological individuality, 1902–1939

Stud. Hist. Phil. Biol. & Biomed. Sci. 34 (2003) 399–423 www.elsevier.com/locate/shpsc

On guinea pigs, dogs and men: anaphylaxis and the study of biological individuality, 1902–1939 Ilana Lo¨wy Centre de Recherche Medecine, Sciences, Sante´ et Socie´te´ (CERMES), cite CNRS, 7 rue Guy Moquet, 948001 Villejuif cedex, France

Abstract In 1910, Charles Richet suggested that studying individual variations in anaphylactic responses might both open a way to experimental investigation of the biological basis of individuality and help unify the immunological and physiological approaches to biological phenomena. The very opposite would happen however. In the next two decades, physiologists and immunologists interested in anaphylaxis and allergy experienced more and more difficulties in communicating. This divergence between the physiopathological and immunological approaches derived from discrepancies between the experimental systems used by each of these scientific communities. Trying to develop a point of view that took into account all bodily reactions to stimuli, physiologists thought that individual variations between the laboratory animals they used (mainly dogs and cats) constituted important experimental data. Seeking to develop reproducible studies of infection, immunity and ‘sensitisation’, bacteriologists and immunologists considered that individual variations between the laboratory animals they used (mainly small rodents) constituted ‘noise’ and not a ‘signal’. Each group’s loyalty to the experimental models used in their discipline widened the gap between immunological and physiological explanations of allergies and led to the abandonment of studies on the biological basis of individuality.  2003 Elsevier Ltd. All rights reserved. Keywords: Anaphylaxis; Allergy; Biological individuality; Physiology; Immunology; Experimental systems.

E-mail address: [email protected] (I. Lo¨wy). 1369-8486/$ - see front matter  2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1369-8486(03)00053-0

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1. Introduction: early meanings of anaphylaxis The term ‘anaphylaxis’ was coined by the French physiologist Charles Richet (1850–1935) to describe a biological phenomenon contrary to ‘phylaxis’, which signified protection through immunisation. Shortly after immune phenomena were first described, scientists learned that the activation of immune mechanisms could have undesirable and dangerous effects.1 Anaphylaxis, especially one induced by serotherapy, was seen as a major practical problem and, in parallel, a key theoretical issue. Scientists had hoped that understanding it would open new, highly promising pathways for biological research. This conviction had roots in their view of immunity (and, by extension, of anaphylaxis) as a fundamental physiological mechanism. ‘Humoral and cellular reactions’, a 1910 immunology textbook stated, . . . are not confined to the field of infectious diseases proper but are, to a far greater extent, expressions of physiological events, whether normal or pathological. The dividing line between the physiological and the pathological cannot be biologically drawn with any precision. (Citron, 1910; quoted in Fleck, 1979, p. 58) Following these early descriptions of anaphylaxis, attempts were made to explain this phenomenon in terms of the basic properties of living organisms. Let us begin by examining Charles Richet’s view of anaphylaxis. Richet took special interest in the wide variability of individuals’ responses when they received a second injection of a stimulating substance. His observations led him to develop a new concept: the ‘humoral personality’ constituted an individual’s specific chemical make-up expressed (mainly) in the blood. As such, it paralleled the ‘psychological personality’, that is a person’s psychological make-up expressed (mainly) in the brain. Both these personalities, Richet argued, mirrored the history of interactions between the person’s unique hereditary makeup and his/her unique history of experiences with external stimuli. By studying the person’s highly variable anaphylactic responses, individuality could be evaluated quantitatively and made subject to controlled investigations. For Richet, this provided an experimental approach to a central problem in medicine, namely individuality’s biological basis. Besides, investigating individuals’ reactions to anaphylactic stimuli might help unify the various approaches developed by immunologists, physiologists and neurologists.2 However, research on anaphylaxis and allergies did not take the direction pointed out by Richet. Physiological, neurological and immunological studies of allergies

1 Silverstein’s chapter on the history of allergic reactions bears the title ‘Allergy and immunopathology: The price of immunity’ (Silverstein, 1989, pp. 214–256). With regard to allergies and anaphylaxis, Moulin writes about ‘risking it all’ and sees allergy as a highly dangerous field of inquiry where the usual benefits should be balanced against the occasional dangers (Moulin, 1991, pp. 143–146). 2 Von Pirquet’s 1911 explanation that symptoms of an infectious disease are quite often not directly produced by the invading organism but reflect, instead, the body’s reaction to this organism can be also seen as an attempt to move beyond the usual ‘war metaphors’ used in bacteriology and immunology (Silverstein, 1989, pp. 221–222).

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and anaphylaxis were not unified and did not merge into a single field of research. In fact, the very opposite happened. In the 1910s and 1920s, each professional group focused on a specific set of problems and developed increasingly distinct ways to handle them. As a consequence, immunologists and physiologists had increasing difficulties talking to each other.3 This gap between the physiopathological and immunological explanations of anaphylaxis and allergy were, I shall argue, grounded in major discrepancies between the experimental systems employed by physiologists and by immunologists. Physiologists, especially those interested in physiopathology, tried to work out a broad viewpoint encompassing all reactions to stimuli. For them, individual variations among laboratory animals (mainly dogs and cats) constituted important experimental data. Bacteriologists and immunologists, on the other hand, sought to develop reproducible methods for studying infection, immunity and ‘sensitisation’. For them, individual variations among the animals used in their studies (mainly small rodents such as mice or guinea pigs) were ‘noise’ rather than ‘signal’. Loyalty to these divergent experimental models did much to widen the gap between the immunological and physiological explanations of allergies.4 This gap, in turn, led scientists to abandon earlier attempts to make ‘biological individuality’ (or, in medical terms, ‘idiosyncratic responses’) into a legitimate subject for basic scientific research.

2. Richet and the study of anaphylaxis Trained as both a physician and a physiologist, Charles Richet (1850–1935) combined scientific research with several cultural and political preoccupations. Early in his medical career, he took interest in phenomena on the borderline between the physiological and the psychological spheres, and wrote a doctoral thesis on sleepwalking. As a young scientist at the College de France, he worked with Claude Bernard, Marcel Bertholet and Jules E´ tienne Marey. Thanks, in part, to his family connections (as the son of a famous surgeon, Alfred Richet), he rose fast in academic ranks. Appointed in 1887 as professor of physiology at the Paris Medical School, he would later become a member of the Academy of Medicine and the Academy of Sciences, a president of the Society of Biology and, in 1913, a Nobel Prize Laureate for his work on anaphylaxis. Richet also took an interest in socialism, pacifism and eugenics, supported the development of aviation, and had a longstanding curiosity about psychic and paranormal phenomena (Caroy, in press). As a young man he also wrote several novels and plays. Though abandoning his literary activities in the 1890s, he continued to write essays, in particular on topics in popular science and history (Richet, 1932; Wolf, 1992; Estingoy, 1993, 1996b). Through Vulpian, one of his teachers, Richet drew close to the founding group 3 The ‘incommensurability’ between the practices of these distinct scientific communities was first mentioned by a serologist commenting the difficulty of combining ‘chemical’ and ‘clinical’ views of a disease (Fleck, 1979, pp. 110–111). 4 On scientists’ loyalty to experimental models, see Rheinberger (1997).

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at the Pasteur Institute and turned toward bacteriology and immunology. In 1888– 1890 he experimented with passive immunotherapy, which he called ‘hemotherapy’. After claiming to be able to protect sheep from anthrax and rabbits from sepsis through an immune serum, he tried to apply his method in clinics. His failed attempts at serotherapy for tuberculosis occurred shortly before Behring’s, Kisato’s and Roux’s more successful serotherapy for diphtheria. He later made additional attempts at finding cures for major diseases. He tried to cure tuberculosis by feeding patients with an extract from raw meat (a treatment he named zomotherapy) and, along with Jean He´ ricourt, he developed an anticancer serum that reportedly caused malignacies to temporarily shrink (Richet, 1888–1909). However, Richet always considered his studies of ‘hemotherapy’ to be his major contribution to medical science. Until the end of his life, he continued to lay claim to the discovery of serotherapy (Richet, 1932). Though enthusiastically suppporting the ‘Pasteurian revolution in medicine’, Richet never became a true follower of the ‘Pasteurian method’. Instead, he remained faithful to a physiological way of thinking and experimenting.5 His studies were guided by monism, a belief in the unity of body and spirit. The idea that memories, thoughts and feelings had a material basis was being propagated in France by the philosopher and physiologist The´ odule Ribot (1939–1916), who held the chair of experimental psychology at the College de France from 1989 to 1901. Ribot attempted to incorporate memory into new ideas about biology and physiological psychology. According to him, memory encompassed not only conscious memory but also heredity, instincts and habits—a proposal in line with Richet’s way of thinking (Otis, 1994). Richet’s monist convictions also motivated his strong interest, and, at times, naive belief, in paranormal phenomena (Le Malfan, 2002). He strongly held to the idea that the thoughts, emotions, individual behaviours and social organisation of human beings would ultimately be found to have a physicochemical basis. He also believed that a holistic approach, as exemplified in Cuvier’s notion of ‘organism’, should be used to study life phenomena (Mayer, 1936; Wolf, 1992, pp. 146– 147). Richet’s 1895 essay on general psychology presented human consciousness and intelligence as a direct extension of neuronal responses observable in animals. In his lessons on the organism’s defences, he professed a unified view of such mechanisms, which encompassed chemical reactions, nerve reflexes and conscious actions. The human organism defends itself against external threats, such as extreme temperatures, traumas, parasites, toxins and aggressions, through a vast array of voluntary and involuntary mechanisms, such as medullary and bulbar reflexes, scars, immunity, psychic defenses (fear, disgust, vertigo or pain) and conscious actions. He added that the last of these, however, played a relatively limited role. The living organism’s main defences were anatomical structures and chemical functions: the first were mostly inherited whereas the latter were partially acquired (Richet, 1888–1908, Vol. 3; 1895, pp. 458–573). The perception of the body’s defence mechanisms as entities

5 In 1913 Richet won the Academy of Science’s poetry prize for the best e´ loge for the 100th anniversary of Pasteur’s birth (Richet, 1913b).

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governed by heredity and as physiological adaptations, both embodied in specific chemical structures, may well have oriented Richet’s understanding of anaphylaxis (Mayer, 1936; Roussy, 1945). Richet’s view of anaphylaxis can also be related to his concept of ‘psychical reflexes’ as formulated in 1902. ‘Psychical reflexes’, such as fear, disgust, vertigo or anger, fitted into the fundamental continuum between elementary physiological reactions and complicated expressions of the psyche. We should, he argued, distinguish between ‘generic’ (or ‘organisational’) and ‘intelligent’ reflexes. The former, conditioned by the species’ anatomical and chemical structure, were similar in all animals of the same species, age and sex. In contrast, the latter were not specific to the species but to the individual. ‘Intelligent’ reflexes derived from the person’s memories and capacity to associate ideas. Phenomena such as remembering scary or unpleasant episodes could be described as ‘intelligent’ only insofar as they reflected unique life-events and nonmechanical reactions. We should not forget that the reactions, such as fear or revulsion, set off by such memories were often fully involuntary. In this sense, they formed a perfect bridge between simple reflexes and complex psychological states (Richet, 1888–1909, Vol. V, pp. 373–475). Richet’s study of anaphylaxis was motivated by observations of the physiological effects of toxins. In 1902, Richet and his colleague Portier found that an extract from the tentacles of marine animals had a toxic effect on dogs. First made during a cruise on Prince Albert of Monaco’s yacht, La Princesse Alice, which was equipped for studying marine biology, these observations of the effects of the Physalia extract were followed up in Richet’s laboratory in Paris with an extract from Actinia tentacles. Portier and Richet noticed that some dogs, though having survived the first non-lethal injection of the Actinia poison, succumbed rapidly to a second dose. Furthermore they observed that, whereas death from the poison usually occured slowly and gradually, the dogs that had survived the first injection experienced a dramatic, violent death a short time after the second injection of the same substance (Portier & Richet, 1902a; G. Richet, 1998; Estingoy, 1994, 1996a, pp. 59–71, 1996b). Richet coined the term ‘anaphylaxis’ to describe this phenomenon. Anaphylaxis, he explained, had been observed by chance: the dogs that had survived the first injection were being ‘recycled’ in order to cut costs. This observation was facilitated by the fact that Portier and Richet were not studying ‘dogs’ reactions’ in general but were paying close attention to how individual dogs reacted, carefully monitoring their responses after injections (Portier & Richet, 1902a,b; Richet 1911a,b). Having developed personal relationships with the dogs they were using, Richet and his colleagues saw each animal as having a unique ‘character’ (Wolf, 1992, p. 79). This individualisation of the dogs fell in line with an experimental approach which postulated that physiological reactions, being unique, were incorporated in the individual’s complex ‘constitution’. The decision to work with bigger animals, such as dogs, was also in line with this approach. In the late nineteenth and the early twentieth centuries, several laboratory physiologists were trying to scientifically study and measure emotions in the laboratory (Dror, 1997, 1999). These studies were fitted into a mechanistic understanding of how the body worked. In turn, including the animal’s emotions as a variable in

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physiological studies drew attention to the interrelations between the soma and the psyche, and to the importance of individuality.6 Physiologists noted differences between the ‘constitution’ and ‘temperament’ of laboratory animals, and observed contingent variations in behaviour. Between 1897 and 1904, Pavlov, for instance, investigated the ‘mind of the glands’ and the effects of a ‘capricious psyche’ on gastric and pancreatic secretions (Todes, 2001). He explained that, ‘precisely because of his great intellectual development, the best of man’s domesticated animals—the dog—often becomes the victim of physiological experiments’ (Todes, 1997). We may reasonably assume that Richet’s interest in the links between body and mind might well have influenced his preference for dogs as experimental subjects. Richet’s use of dogs was facilitated by the fact that he and his assistants were the sole occupants of the new laboratory of physiology at the Medical School, a facility with arrangements for keeping up to sixty dogs.7 The dogs in Richet’s laboratory were attributed individual traits and assigned individual names, often borrowed from Greek and Roman mythology or from French literature.8 The detailed description of how individual dogs reacted recalls Richet’s descriptions of how cancer patients responded to anti-cancer serum or tuberculosis patients to raw meat extract. Some dogs were remembered individually. In his memoirs, Richet wrote that the sudden, violent death of Neptune, a ‘magnificent specimen’ who had been in excellent health and of happy temperament, especially affected him (Richet, 1932, p. 102). Neptune was not mentioned in Portier and Richet’s first paper on anaphylaxis. We do learn, however, that Polyphe`me, Matamore, Sganarelle, Araminte, Scaramouche Moutonne and Circe died after receiving 0.15 to 0.25 milligrams of Actinia poison, while Mathurin, Galathe´ e, Pierrot, Diane, Chloralosa and Neptune survived the first injection but succumbed to the second (Portier & Richet, 1902a; Richet, undated, Vol. VI, pp. 62–65). Portier, who soon abandoned anaphylaxis studies, and Richet were the first scientists who considered anaphylaxis to be important, but not the first to observe the sudden death of an animal after a second injection of a ‘sensitising’ (often innocuous) substance. Magendie observed that rabbits died after a second injection of albumin,

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According to Dror (1997), laboratory animals were not merely the ‘right tool for a job’, and mammals such as dog, cats, rabbits and rats were not handled like instruments by scientists in their experiments. We might suppose that several approaches co-exist. Some laboratory organisms (for example, drosophila, frogs, mice or guinea pigs) are mainly viewed as interchangeable tools whereas others (for example, dogs and cats) are often ‘individualized’, and some (for example, rats) are used in both ways. The way a specific organism is used in the laboratory reflects ‘subcultures’ specific to the laboratory. 7 This laboratory, in the 14th arrondissement of Paris, had been built thanks to the efforts of Paul Bruardel, the dean of the Medical School and Richet’s friend. With the help of a few friends (Pinard, Caravalho, Chantemesse), Richet paid for part of the equipment. Kennels were placed in the laboratory’s big garden (Richet, undated, Vol. VI, pp. 65–68). The dogs used in his laboratory (and in all other Parisian laboratories of physiology) were strays provided by the municipality. 8 Richet used similar names in Le savant (1923), a semi-serous, semi-mocking description of various ‘ideal-types’ of scientists. Richet’s illustrious colleagues from the University and the Academy received names such as Simonides, Epistemon, Gildas, Menippe, Alcidas, Archibald, Agathocles, Megaphorus, Ephrastides, Phocidon, Aramis, Eurylas Polyctor and Ephidorus.

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Flexner reported that rabbits succumbed to a second injection of dog’s serum, Koch described a ‘hypersensibility’ to tuberculin, and researchers who were testing the potency of anti-diphtheric serum noticed that the guinea pigs in such tests became sick and occasionally died after several consecutive injections. Richet and Hericourt similarly observed in the 1890s that dogs fell sick following a second and third injection of eel’s serum in much lower doses than the first. Richet affirmed later that he failed to grasp the significance of all this. His earlier studies might have, nevertheless, made him more aware of the possibly cumulative effect of repeatedly injecting foreign substances (Richet, 1911a, pp. 1–12) and helped him to link anaphylaxis immediately to immune phenomena and to the reaction of tuberculous animals to tuberculin. Richet worked exclusively with poisons, and his demonstration of the anaphylactic effect was based on observing the difference between a given substance’s toxic and ‘anaphylactic’ (sensitising) doses. A year after Portier and Richet’s publication, another French researcher, Maurice Arthus, described an anaphylaxis-like effect following repeated injections of innocuous horse serum. Arthus immediately related this finding to serotherapeutical accidents in humans (so-called serum sickness), and to a few cases of human deaths following the injection of horse serum (Arthus, 1903).9 Given this growing recourse to serum therapy, ‘hypersensitivity’ to immune and normal serum soon became an important subject for basic and clinical research (Von Pirquet & Schick, 1905). Laboratory studies of anaphylaxis turned to the links between hypersensitivity and immunity. These two were thought to be closely related: both were induced only after a ‘lag period’ (usually from ten to fourteen days) between the ‘sensitising’ and the ‘activating’ reaction, both were highly specific for the sensitising substance, both could be induced by a very small quantity of foreign protein, and both could be passively transferred through the serum of an immunized or sensitised animal (Rosenau & Anderson, 1906, 1908; Otto, 1906). Scientists failed, however, to display specific antibodies in the serum of sensitised animals. At first, this failure was not a major obstacle to defining anaphylaxis as an immunological phenomenon. In the early twentieth century, scientists were often unable to demonstrate that antibodies were present, and the term ‘antibody’ often referred to a physiological function of the immunised animal’s serum. ‘Specificity’ and ‘passive transfer’ were taken to be convincing evidence that anaphylaxis and immunity were related (Nicolle, 1907). Richet adopted the immunological explanation of anaphylaxis, but continued centering his own experiments on physiological reactions to toxic substances. In 1907, he reported how dogs reacted to mytilo-congestine, a toxic extract from a Mytilus edulis mussel. He showed that dogs sensitised by this toxin (an emetic) usually vomited when injected with a much lower dose than the one that induced vomiting in non-sensitised dogs. He also showed that toxic and sensitising reactions were highly individualised: some dogs were sensitised with very low doses, whereas others

9 Richet showed no interest in studying anaphylaxis induced by non-toxic substances (Richet, undated, Vol. VI, p. 66).

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could not be sensitised with relatively high doses. On the average, Richet argued, the doses causing vomiting in a sensitised dog were significantly weaker than the original emetic doses, and this rule held when testing lethal doses of the same toxin in non-sensitised dogs as compared with the lethal doses in sensitised ones (Richet, 1907, pp. 506–513). For Richet, as for Pavlov and his colleagues, the important point was not the uniformity of physiological phenomena but the fact that, despite the wide variability in individual reactions, a consistent ‘sensitisation’ pattern could be observed.10 For this reason, the results of experiments were interpreted with a ‘dog correction’ factor—a detailed account of the pattern of individual reactions intended to shed light on the circumstances under which some dogs deviated from the expected pattern (Richet, 1907, p. 517). In 1907 Richet tried, for the first time, to provide a physiological explanation of anaphylaxis. A toxin’s ‘anaphylactic effect’ was, he explained, much more rapid and violent than its toxic effect. This rapidity and violence, he argued, might account for the physiological utility of anaplylaxis. From a teleological point of view—which, he added, should guide biological research—anaphylaxis could be seen as a means for inducing a fast reaction to bacterial toxins, especially to weak doses of them. Anaphylaxis could thus be interpreted as an effective defence reaction, but one which could go wrong, especially when sensitising substances were injected in animals (or humans), since this was not a natural way to receive a foreign protein (Richet, 1907, pp. 520–524). Three years later, Richet set forth a different view that focused on the role of anaphylaxis in shaping each individual’s unique pattern of chemical reactions (Krocker, 1999). Richet had first expounded his ideas about the linkage between anaphylaxis and individuality in his presidential speech, ‘Old and new humoral theories’, delivered at the opening of the International Congress of Physiology in Vienna in September 1910. Doctors had remained attached to the Hippocratic humoral theory for several centuries, he said. Only once they started to rely on direct observation and then on experimentation was the ‘old humoralism’ replaced with a ‘new humoralism’, a discipline for studying the chemical structure of body liquids. This new humoralism had its grounds in the ‘chemistry of the imponderables’. In the wake of Lavoiser, traditional chemistry studied compounds that could be easily measured and quantified. In living organisms, however, very small amounts of compounds could set off chemical reactions with major effects. This principle could be seen at work in the way the nervous system acted on secretions, and in the way toxins could have an effect in very weak concentrations. Anaphylaxis, Richet argued, provided especially telling evidence of how a very weak concentration of chemicals could induce intense phenomena (Richet, 1910). Moreover, anaphylaxis shed light on how the individual’s reactions varied owing to the organism’s past encounters with quite small quantities of foreign proteins. The chemistry of the biological functions of the humours

10 Pavlov provided a similar explanation for differences in how dogs responded to foodstuffs (Todes, 1997).

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. . . leads us directly into the region that, up till now, has been almost totally unexplored, i.e., the physiology of the individual . . . we have therefore, every one of us, a psychological individuality. But what has not been sufficiently taken into account is that each one of us also has a humoral individuality. Each of us is differentiated from the rest of mankind not only by our mentality, but also by our chemical constitution.11 Accordingly, major differences in the organism’s reactions originated in minimal chemical changes in the humours (that is, the combined result of heredity and the individual’s biographical history).12 This may be seen as extending Richet’s earlier ideas about how previous excitations ‘leave a trace in the organism, and modify this organism . . . the excitation is gone, but a trace remains’ (Richet, 1891, p. 362). It can also be seen as the extension of his 1902 discussion of ‘intelligent reflexes’ (fear, disgust) to the realm of chemical reactions, and its application to the study of anaphylaxis (Richet, 1888–1909, Vol. V, pp. 373–475). In 1902, Richet thought that the cells in the central nervous system were the only place in the body that could store memories of earlier events and set off involuntary but highly individualised reactions related to these memories. In 1910, he argued that the body humours, too, were able to store memories, and that humoral responses were as individualised as neurological reactions.13 In his 1913 Nobel speech, Richet coined the term ‘humoral personality’ to refer to the each individual’s unique mixture of inherited and acquired traits: We all know what the personality of the psyche is . . . Now, in the light of immunity and anaphylaxis, we can conceive of another personality in juxtaposition to the moral personality, namely the humoral personality, which makes us different from other men owing to the chemical makeup of our humours. This is an entirely new idea. Till now, it was thought, perhaps from a lack of afterthought, that the humours would be chemically identical in persons of the same age, race and sex. But it is not like that at all. Every living being, though highly resembling others of his species, has his own characteristics so that he is himself and not somebody else. (Richet, 1913a, pp. 488–489) Richet proposed opening up a new field of scientific investigation by focusing on individual variations in physiological reactions: ‘After we learn more about general physiology and the physiology of the species, we may, some day, be able to delve

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Richet’s first physiological study was published in 1877. In 1910, he tried to link ‘sensibility’ and ‘sensitivity’ through a ‘chimie des imponde´ rables’. 12 Holding to monism, Richet (1910) stated that ‘irritability of the nerves’ was also a chemical phenomenon: ‘the living being is a chemical mechanism, and perhaps nothing more’. 13 Richet (1910) related his concept of ‘humoral personality’ to studies of anaphylaxis and immunity and to observations of how nerves affect internal secretions, another field of study linking the chemistry of body fluids to the central nervous system.

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into the physiology of individuals, which does not yet exist, not even in the most rudimentary form’ (Richet, 1911b, pp. 195–198, 251, original italics; Lo¨ wy, 1991). In the early twentieth century, anaphylaxis and allergy were seen as important biological phenomena and as mechanisms underlying many pathological events. Richet’s call for inquiry into the ‘physiology of the individual’ derived, we can assume, from the medical orientation of his physiological studies and his lifelong aspiration to abolish the division between physiology and pathology (Richet, 1888).14 Richet established a link between, on the one hand, experimental studies of anaphylaxis and iatrogenic shock that followed the injection of a therapeutic serum and, on the other hand, phenomena observed in clinics, such as the ‘idiosyncratic’ intolerance of foodstuffs or individual differences in reactions to tuberculin (Richet, 1911b, pp. 195–198; 1913a, pp. 487–489). He took special interest in ‘food-related anaphylaxis’, that is the severe symptoms shown by individuals who had become ‘sensitised’ to a specific food. Such sensitisation proved, he argued, that anaphylaxis was not just an artificial result obtained in laboratories or an iatrogenic side-effect of serotherapy, but an important physiopathological phenomenon (Richet, 1911a, 1919; undated, Vol. VI, pp. 68–69).15 A ‘physiology of the individual’, Richet believed, might help physicians treat several pathological conditions, but it was ‘very difficult and barely broached’ (Richet, 1913a, p. 489). Scientists, Richet added in his book on anaphylaxis, had an incomplete understanding of anaphylaxis. They were striving to discover simple chemical explanations and develop all-encompassing theories. In their rush toward a global explanation, they tended to underestimate the practical difficulties in studying highly complex physiological phenomena: In spite of our possession of definite facts on this subject, many key issues remain unclear, even very unclear. Science will end by elucidating these issues, but only if we carefully avoid hasty generalisations. In the history of anaphylaxis and, too, of immunity, we face a huge number of complicated—incoherent, fragmented, isolated, and highly variable—facts. It is much better to view them as such than to attempt to gather everything under a single law and thus confer a false and artificial unity to phenomena that, in nature, are separate and diversified. (Richet, 1911b, p. 256) Richet’s critique pinpointed immunologists’ efforts to uncover the basic rules underlying immunity and anaphylaxis. Such rules, they believed, could be discovered by working with simple, reproducible animal models. The work of Maurice Arthus and

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I am indebted to Charles Richet’s grandson, Prof. Gabriel Richet, for pointing out how important medical goals were to his grandfather’s research. 15 Between 1905 and 1915, descriptions of ‘sensitisation’ to foodstuffs suggested that some proteins, not fully digested in the intestine, could pass intact (or, at least, partly so) into the blood. These studies were abandoned, as most physiologists came to deny the possibility of proteins being adsorbed from the digestive tract. Since the 1970s scientists have once again begun systematically studying the transparietal passage of proteins or protein fragments and its role in immunity (G. Richet, 1999).

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Alexandre Besredka, two French scientists, illustrate the difficulties this approach would encounter. 3. From dogs to rodents: immunology and anaphylaxis Initially trained as a physiologist, Maurice Arthus (1862–1943) specialized in microbiology in the 1880s. After schooling in France and Germany, he taught microbiology at the University of Freiburg in Switzerland. In 1901, he joined the staff of the Pasteur Institute in Lille, an institution devoted to practical applications of bacteriology. In 1903, he described skin necrosis following repeated injections of immune or normal serum; in his experiments, horse serum was injected into rabbits. This necrosis, he explained, was not a local reaction to the serum. Animals receiving repeated intraperitoneal injections of the serum and then a single intradermal injection developed a similar necrosis (Arthus, 1903, 1906, 1909). Arthus claimed that he made these findings by chance. Only afterwards would he link them to Portier and Richet’s results. He proposed to distinguish between two parallel and independent discoveries: the discovery of anaphylaxis following sensitisation by toxins (which might be called the ‘Richet phenomenon’) and the discovery of sensitivity to foreign serum (the ‘Arthus phenomenon’) (Arthus, 1921, p. 7). Richet contested this claim, arguing that Arthus had made his finding while deliberately—following Albert Calmette’s suggestion— trying to reproduce Portier and Richet’s findings in a different experimental system (Richet, 1907, p. 499). Nonetheless, Richet did recognize that Arthus’s observation of an anaphylactic reaction to horse serum signaled a radical change in the status of his and Portier’s findings. The latter were no longer a mere curiosity; they were now seen as having major medical implications. Arthus’s observations would soon be related to accidents in serotherapy, which were a cause of concern for immunologists, clinicians and the makers of therapeutic sera (G. Richet, 1998, p. 263). From Lille, Arthus was appointed to a chair of physiology at the University of Lausanne. Both the bacteriological and physiological approaches would spur his continuing interest in anaphylaxis. His experiments were in between physiology and immunology. While most immunologists interested in anaphylaxis looked only for the presence or absence of an anaphylactic shock (an ‘all or nothing’ approach), Arthus measured the physiological evidence of anaphylaxis, such as faster respiration or modifications in body temperature. However his experiments followed, in the main, a bacteriological/immunological approach. He repeated for several years the same experiments with minor modifications in order to compare the effects of sensitisation by: substance, dose, pattern of injections, and the kinetics of immune and anaphylactic responses in the same animals. He described his experiments as ‘painstaking, labour-intensive, and laden with difficulties’ (Arthus, 1921, p. xxix). His primary goal was not to inquire into the physiological basis of anaphylaxis, even less to investigate individual responses to stimuli, but instead to shed light on the relations between anaphylaxis and immunity. Therefore, he paid no attention to variations within a given species but focused on differences between species. Anaphylaxis in guinea pigs, for example, differed from anaphylaxis in rabbits (Arthus, 1921).

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Alexander Besredka’s research on anaphylaxis (1907–1914) belongs even more firmly to the bacteriological/immunological tradition. Besredka (1870–1940) studied science in Russia and then medicine in Paris. In 1897 he joined Metchnikoff’s laboratory at the Pasteur Institute, where he worked on phagocytosis, bacterial endotoxins, immunisation with ‘sensitised micro-organisms’ (a mixture of living bacteria and immune serum against them), and anaphylaxis. Naturalised as a French citizen, he served in the French army during the World War I. Upon returning to the Pasteur Institute in 1918, he replaced Metchnikoff (who had died in 1917) as head of one of Institute’s departements (‘chef de service’), a position he would hold till his death in 1940. His post-war research focused on ‘local immunity’ and on practical ways to protect animals and humans from infectious diseases. These studies were thought to be quite unorthodox and deviant from the Pasteurian dogma. In contrast, his earlier studies of anaphylaxis and ‘antianaphylaxis’ (desensitisation) became a part of mainstream immunology (Langrange, undated ms.; Delaunay, 1971). Besredka saw himself as the faithful guardian of Metchnikoff’s teachings. His 1921 biography of his former teacher lavishly praised the latter’s ideas. His own focus on cells and ‘local immunity’ was part of the effort to follow up on Metchnikoff’s work (Berczeller, 1943; Nicolle, 1970, 1971; Delaunay, 1971). However this description is inexact. A closer look at Besredka’s concept of ‘cellular immunity’ reveals differences from Metchnikoff’s. For the latter, immunity was mediated by a specific category of cells (the phagocytes), and expressed a specific physiological function—eliminating dead and damaged cells (Tauber & Chernyak, 1991). For Besredka, in contrast, immunity and anaphylaxis reflected a ‘general reactivity’ of all the body’s cells and their capacity to undergo modification in response to external stimuli. Such ‘modified cellular reactivity’ was thought to operate through changes in the chemical structure of cells. This view of immunity was cellular insofar as it focused on cells rather than antibodies in the serum; otherwise, Besredka followed the prevailing chemical, or physicochemical, view of immunity (Besredka, 1934).16 He did, in parallel, faithfully follow the bacteriological ‘experimental style’, according to which laboratory animals were ‘living test tubes’ expected to react identically. During his early work on anaphylaxis, Besredka sought to improve the safety of the administration of therapeutic antisera. He first tried to develop a reliable— homogenous and reproducible—experimental system in which sensitised animals were reliable ‘instruments’ for calibrating and quantifying anaphylactic and ‘antianaphylactic’ stimuli.17 He did not, therefore, pay attention to individual differences between animals; he mentioned them only when he needed to account for difficulties

16 One may notice resemblances between, on the one hand, Richet’s parallel between a ‘humoral personality’ (shaped by immune reactions) and ‘psychic personality’ (shaped by the central nerve system’s reactions) and, on the other, Besredka’s efforts to present immunity as a ‘general cell reactivity’ similar in many ways to the reactivity of nerve cells. 17 Besredka’s experimental methodology was apparently inspired by Ehrlich’s method for calibrating the potency of antidiphtheric sera by measuring the weakest dilution capable of protecting 50% of the animals (LD 50). On the strategies used by researchers to limit variability when working with living organisms, and the consequences thereof on biological knowledge, see Geison & Laubichler (2001).

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in obtaining the same results when repeating experiments or for deviations from expected patterns (Besredka, 1908b, 1910). Along with Edna Steinhardt, Besredka tried to repeat the experiments conducted by Otto in Frankfurt, and by Rosenau and Anderson at the Hygienic Laboratory of the Public Health and Marine Service in Washington, DC. These researchers had found that guinea pigs sensitised with a mixture of diphtheria toxin and antitoxin reacted much more strongly to horse serum than animals sensitised with the serum alone; furthermore, they nearly always succumbed to a subcutaneous injection of the sensitising substance (Rosenau & Anderson, 1906). In Besredka & Steinhardt’s (1907) first experiments, only a quarter of the guinea pigs sensitised with the toxin-antitoxin mixture developed full-fledged anaphylaxis and died. However, when the sensitising serum was injected directly into the brain of sensitised guinea pigs, nearly all the sensitised animals experienced a fatal anaphylactic shock. The intracerebral injection had this effect, Besredka explained, because the sensitised guinea pigs looked healthy but, in fact, had a latent, potentially lethal cerebral lesion.18 Thanks to a reproducible experimental system, Besredka could explore ways of preventing anaphylaxis. His starting point was the finding, made by several scientists, that the onset of anaphylactic sensitivity was significantly delayed in animals that received a second injection of the sensitising substance before the full period (in guinea pigs, twelve days) for the development of anaphylactic sensitivity (Besredka & Steinhardt, 1907). Besredka was able to show that even animals with well-established anaphylactic sensitivity could be ‘desensitised’ with intradermal injections of small doses of the sensitising serum. The site and the timing of the second injection determined the reaction, whether anaphylactic shock or desensitisation. The latter, he argued, was not a new immunization, since it followed very rapidly on the desensitising injection. Besredka thus proposed desensitising patients by a preliminary injection of a small quantity of the antiserum, a method he called ‘subintirant injections’ (Besredka, 1908a,b, 1909). Besredka’s studies led him to the belief that anaphylaxis and antianaphylaxis were essentially identical. The main difference between these two reactions, he proposed in 1908, was their rapidity: anaphylactic shock was merely a sudden, uncontrolled desensitisation. His ‘physical theory of anaphylaxis’ explained all manifestations of anaphylactic shock as a rapid reaction to the sensitising substance in the cells of the central nerve system (Besredka, 1908b). Between 1908 and 1913, he adopted the then dominant view based on the postulate that the reaction to a sensitising substance with ‘antisensibilin’ caused the production of numerous specific ‘anaphylotoxins’ which mediated the manifestations of anaphylactic shock (Besredka, 1910; Besredka & Stro¨ bel, 1911; Besredka, Stro¨ bel, & Jupille, 1913).19 He scarified a con18 This explanation might be related to the finding, made by Besredka along with E´ mile Roux, that an anaesthetised animal did not succumb to an anaphylactic shock (Besredka, 1908b). 19 Richet, too, proposed in 1911 that the reaction of an antigen with a ‘toxicogen’ (a substance that, present in a sensitised animal’s blood, is harmless in the absence of the sensitising compound) causes a third substance, ‘apotoxin’, to be produced, which affects nerve cells (Richet, 1911a, pp. 234–237). See also Rosenau & Anderson (1908).

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siderable number of guinea pigs while trying to use a differential sensitivity to heat in order to dissociate the putative sensitising, desensitising and toxic elements.20 Besredka claimed that he could separate ‘sensibilin’ from ‘anaphylotoxin’ by selectively heating the serum (Besredka & Stro¨ bel, 1911). He failed, however, to obtain stable, reproducible results. From 1917 on, he reverted to his original ‘physical’ theory of anaphylaxis and explained all anaphylactic phenomena by a rapid, chaotic reaction to ‘sensibilins’ in the sensitised cells of the nervous system (Besredka, 1917a,b, 1920). Besredka’s ideas about anaphylaxis served as the starting point for his global theory of immunity.21 All immune phenomena—allergy and anaphylaxis, natural and acquired immunity—were, Besredka explained, different forms of a single physiological mechanism: ‘natura non facit saltus’ (Besredka, 1934, pp. 25–27). The specificity of anaphylactic or immune reactions was not primarily grounded in the chemistry of humoral antibodies. Instead, like the ‘specificity’ of natural immunity, it mainly reflected the receptivity of target cells to pathogenic germs or their ability to react to toxins. The main differences between natural and induced immunity, and between the absence of anaphylactic sensitivity and artificially induced desensitisation, had to do with how the final result —the absence of ‘reactive cells’—was obtained. A naturally immune or non-sensitised animal had no ‘reactive cells’, whereas, in an artificially immunised or a desensitised animal, such cells were intitially present, but were either depleted or inactivated. In immunisation—if the substance conveying protection is an antibody in the serum—protection corresponded to the antibody inactivating ‘reactive’ cells. In antianaphylaxis—if it was admitted that ‘sensibilin’ was an antibody—desensitisation was an inactivation of the antibody, which makes the cells ‘reactive’. The latter thus represents a return to a normal situation (Besredka, 1925).22 Given his conviction that immunity had its basis in the desensitisation of cells, Besredka developed an ‘antivirus’ therapy (Lo¨ wy, 1998), which used filtered supernatants of bacterial cultures for vaccines and for the treatment of chronic infections. His research in the 1920s and 1930s focused on this topic (Besredka, 1928). Although he never went back to studying anaphylaxis, he remained till the end of his life a believer in a unified theory of immunity, which was grounded in the concepts of cellular sensitisation and desensitisation, and which explained anaphylaxis in terms of a direct sensitisation of the central nerve system.23 20 This approach, also used by Maurice Nicolle, for instance, was modelled on Jules Brodet’s studies of ‘alexine’, a substance that, activated by antigen-antibody complexes, precipitates the lysis of bacteria of red blood cells (Nicolle, 1907). 21 Besredka’s endeavour could be seen as a typical example of an ‘attempt to gather everything under a single law’ (Richet, 1911a, p. 256). 22 Besredka’s scepticism concerning the key role of antibodies and his insistence on the ‘modified cell reactivity’ may be related to ‘coloidal’ theories, which set changes in cell reactivity down to reversible changes in the cytoplasm’s physicochemical states (akin to electrical changes in neurons) rather than to the formation of new, stable chemical structures. On colloidal theories in immunology, see Mazumdar (1974). 23 In chapters X and XI of the textbook on immunology that he was writing, Besredka repeated his ideas about identical mechanisms governing natural and acquired immunity as well as anaphylaxis and antianaphylaxis (Besredka’s manuscript, Pasteur Institute Archives, Besredka’s file).

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4. Experimental systems and the study of anaphylaxis and allergy in the 1910s and 1920s In the 1910s and 1920s immune reactions gradually became a field of study separate from physiology. Immunologists focused almost exclusively on interactions between antigens and a single group of proteins in the serum—gamma globulins (later immunoglobulins). Efforts to work out a general theory of the body’s reactivity were abandoned in favour of inquiries into specific chemical reactions between proteins. This chemical turn taken by immunology widened the gap between the (mostly unsuccessful) attempts to discover the specific immunological mechanisms underlying allergy and anaphylaxis on the one hand and, on the other, the (mostly successful) attempts to investigate the nonspecific mechanisms underlying these phenomena. As a consequence, studies of immune reactions became more firmly linked to biochemistry, and studies of anaphylactic reactions to pathology.24 The long divorce between mainstream immunological research and the study of anaphylaxis and allergy was, I would like to suggest, related to the failure to investigate allergy and anaphylaxis with the techniques and methods used in immunology laboratories. Early studies of anaphylaxis can be described as being both chemical and physiological. They sprung from a nineteenth-century approach to physiology which valued simple, elegant experiments for providing immediate answers to specific questions. Richet in particular was said to be proficient in such experimentation. The discovery of anaphylaxis was hailed as an exemplary use of Richet’s approach to physiological phenomena: an immediate grasping of the importance of an unexpected finding and the ability to devise simple experiments for demonstrating a phenomenon’s fundamental characteristics (Mayer, 1936).25 Richet soon assumed that anaphylaxis and immunity were so complex they could not be solved by a single disciplinary approach. Scientists coming from the bacteriological/immunological tradition held a different opinion. For them, the difficulties in working on these phenomena in the laboratory would be solved by the development of the ‘right’ animal model (such as guinea pigs sensitised with antidiphtheric serum) or the ‘right’ experimental system (such as the dissociation between the putative ‘anaphylactic antibodies’ and putative ‘anaphylotoxins’ through their selective inactivation by heat). Besredka, a typical representative of this tradition, explained that anaphylaxis became, between 1906 and 1908, a ‘fertile subject of laboratory investigations’ thanks to the development of a preferential model for this reaction—a guinea pig sensitised by an injection of anti-diphtheric serum mixed with diphtheric toxin, then injected intracerebrally with the sensitising substance (Besredka, 1917a). Thanks to the development of reproducible animal models, the parameters of anaphylactic sensitisation could be quantified. But immunologists would reach limits in

24

On pathology-oriented approaches to immunology in the interwar era, see Keating (1998). Richet himself (unlike Marey) was sceptical about the need for sophisticated laboratory equipment (Richet, 1932, p. 67). 25

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using such models. Although more and more studies were made with different antigens and on different sensitisation patterns, the mechanisms underlying anaphylaxis were not elucidated. The impressive accumulation of experimental data and the parallel development of an increasingly complicated terminology had not brought immunologists any closer to understanding the biological mechanisms underlying anaphylaxis and allergy. Tens of thousands of experiments wherein variable doses of sensitising substances were injected at various intervals into many, supposedly uniform, laboratory animals did not help scientists understand anaphylactic phenomena any better. As E´ mile Roux stated in his preface to Besredka’s 1917 book, accumulating studies of anaphylactic phenomena were mainly adding to the confusion. There was widespread agreement, Besredka explained, about many of the fundamental facts related to anaphylaxis: the nature of sensitising substances, the lag necessary for the appearance of anaphylactic sensibility, and the physiological consequences of injecting a sensitising substance a second time. But no one could explain why the second injection was so dangerous: ‘Here precisely, we see the fundamental breach in the anaphylactic edifice, which each author tries to temporarily mend using the resources of his imagination’ (Besredka, 1917a, p. 120). The persistent failure to demonstrate the presence of ‘reagins’ (the putative allergic antibodies) amplified the difficulty of studying allergy and anaphylaxis in immunology laboratories. This absence of demonstrable sensitising antibodies was an ever growing problem during the interwar period. The difficulty of using standardised immunological methods to study allergies and anaphylaxis contrasted both with the success of using stabilised, codified immunological techniques to investigate the physico-chemical properties of specific antibodies in the serum and with the practical successes achieved in serotherapy and serodiagnosis. In the 1920s and 1930s the vanguard of basic immunological and immunophysical research joined ranks with applied serology thanks to the circulation of ‘boundary objects’—chemically purified antibodies—and ‘boundary techniques’—methods used to produce, isolate and test these antibodies (Jordan & Falk, 1932). Immunological theories transcribed immunological specificity in terms of signaletic rather than trophic interactions, at first between molecules and then, after 1950, between cells. They focused on complementary chemical structures and irreversible pathways, rather than on dynamic interactions and reversible equilibria.26 In parallel, physiological investigations of allergy-related phenomena abandoned the quest to explain the specificity and variability of allergic reactions. Previous interrogations yielded to efforts to shed light on the mechanisms underlying nonspecific manifestations of allergy and anaphylaxis, an issue with practical importance for clinicians (Dale, 1920). Physiologists thus stopped observing how dogs individually reacted and started looking at organs in physiological solutions. Thanks to this ‘semi in vitro model’, similarities could be observed between the physiological evidence

26

On recent speculations about this ‘alternative’ view of immunity, see Kupiec & Sonigo (2000). In 1935, Fleck proposed an ‘ecological’ explanation of the specificity of immune reactions (Fleck, 1979, pp. 61–63).

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of an anaphylactic shock and the activity of beta-imidazolyehthylamine (histamine) on smooth muscles (Schultz, 1909; Dale & Laidlaw, 1911; Beaven, 1976). Meanwhile, researchers who had observed, in the 1910s, that the cells in a sensitised animal quickly freed vasodilators and bronchodilators now began noticing that the histopathological changes in the lungs of a guinea pig suffering from anaphylactic shock resembled those found in individuals suffering from bronchial asthma (Kolmer, 1917; Dale, 1920, 1952). The latter observation linked physiologists’ studies of anaphylaxis to clinical studies of allergy and serum sickness. Physicians came to realize that asthmatic patients often reacted violently to injections of a foreign serum and were over-represented among the victims of fatal anaphylactic shock. Studies of ‘serum sickness’ and of serum-induced anaphylaxis in human beings connected the violent reaction to injecting serum or to an insect sting with the (usually) more benign consequences of a sensitivity to foodstuffs, bacterial substances and drugs. The finding that injecting a foreign serum could set off a large variety of symptoms, ranging from mild ‘serum sickness’ to a lethal shock, provided an appropriate model for the wide scope of ‘anaphylactic’ or ‘allergic’ reactions in people. Clinicians increasingly took up the latter term since it referred to a broader spectrum of patho-physiological symptoms. Their interest in these symptoms in the 1920s and 1930s may be related to the growing importance of a functionalist, holistic approach in medicine. During the interwar period, some physicians argued that effective therapy should be ‘function-regulating’—it should target not the assumed causes of disease but the effects, namely the deregulation of fundamental physiological functions.27 Furthermore, the wide variability of individuals’ allergic reactions (‘idiosyncrasy’) was increasingly taken to be a sign of the variability of the pathological ‘terrain’, which was less often thought to be a potential subject for basic scientific inquiry. In 1919 Roodhouse Gloyne, the British physiologist who translated Besredka’s Anaphylaxie et antianaphylaxie into English, pointed to the growing gap between immunological and physiological studies of anaphylaxis. Immunologists, he explained, viewed anaphylaxis only through their theories and focused exclusively on interactions between antibodies and antigens in either the blood or, in some cases, cells. Their investigations occurred . . . in the No Man’s Land between the biochemist on the one hand, and the bacteriologists on the other . . . The general trend of immunological research at the

27 For instance, Fernand Bezanc¸ on, president of the French Medical Association, explained that physicians had given up the notion of specificity and left the etiologic period behind, and were focusing instead on physiopathological mechanisms. They were no longer expected to provide specific medication for a disease but to administer drugs that would act on the patient’s ‘reactional modalities’ in various stages of the disease (Bezanc¸ on, 1932; quoted by Mendelsohn, 2001, p. 35). On holistic medicine during the interwar period, see Lawrence & Weisz (1998), and on French holism, Weisz (1998). On earlier attempts to develop treatments based on controlling major ‘disease moments’ rather than on etiological causes, see Lo¨ wy (2000), pp. 21–31, 45–67.

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present day appears to be along the lines of physical chemistry, more especially as it relates to the chemistry of colloids. (Roodhouse Gloyne, 1919, p. 130) He regretfully added that immunological studies of anaphylaxis more often than not lead to a dead end. Immunological terminology . . . has become extremely confusing. Most workers had produced theories based upon the interaction of antigen and antibody, and in almost all cases new terms have been coined for the purpose. Many of the new terms presuppose conditions which it is impossible to prove at the present time. (Roodhouse Gloyne, 1919, p. 130) This confusion in immunology contrasted with the progress made by scientists who were working on the nonspecific physiological phenomena underlying anaphylaxis. However, ‘up to the present time the morbid histology of this subject [anaphylaxis] has not produced any great interest amongst workers in immunology’ (Roodhouse Gloyne, 1919, p. 130). The opposite was true as well: physiologists preferred standing aloof from the confusing mess of clinical and immunological studies. They conducted ‘do-able’ investigations into the pathophysiological mechanisms of anaphylaxis under well defined conditions and lost interest in individuality and ‘idiosyncrasy’. The word ‘anaphylaxis’, Henry Dale explained in 1922, was applied to a heterogeneous mixture of phenomena: . . . in our view, this extension and vagueness of nomenclature is regrettable, as being detrimental to the clearness of conception. We confined our attention to the condition to which the name anaphylaxis was first applied . . . the condition of abnormal sensitiveness to the injection of a foreign protein. (Dale & Kellaway, 1922) During the interwar period, the only explicit call for studies of ‘biological individuality’ came from a scientist, Serguei Metalnikov, whose theoretical preoccupations— the attempt to link the ideas developed by Metchnikoff and his school with Ivan Pavlov’s physiological investigations—were distant from those of mainstream physiologists and immunologists.

5. Serguei Metalnikov: studying biological individuality at the margins Serguei Metalnikov (1870–1945) was trained as a zoologist in Alexandre Kovalevsky’s St. Petersburg laboratory and then in Heidelberg and Naples before working in Metchnikoff’s laboratory (1900–1901). In 1902, he went back to Russia, where he was appointed professor at St. Petersburg University in 1907 and head of the St. Petersburg Biological Institute in 1910. In the aftermath of the Russian Revolution, he emigrated to France. In 1919, he joined Felix Mesnil’s laboratory at the Pasteur

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Institute and continued working there until his death (Metalnikov, 1940; Moulin, 1985, 1990). Between 1919 and 1945, Metalnikov’s major subject of research was ‘defence reactions’ in invertebrates. Nowadays, Metalnikov is deemed a pioneer in insect immunity (Brey, 1998). His main experimental model was the bee mite caterpillar, Galleria mellonella. His research had a practical goal—to develop ways of fighting harmful insects. But for Metalnikov, it was also of theoretical importance for understanding the origins of immunity. Investigating how invertebrates reacted to parasites could shed light both on immune responses in higher organisms and on the linkage between the two principal mechanisms whereby animals reacted to the external world: immune and neurological reactions (Metalnikov, 1927). Indeed, the interaction between the immune and central nerve systems lay at the heart of Metalnikov’s scientific interests. This disciple of Pavlov’s school proposed linking immunological and neurological reactions through the concept of a conditioned reflex, and he sought to demonstrate the role of reflexes in immunological reactions. In an exceptional turn away from his usual experimental model (immunity in insects), he examined the role of conditional reflexes in producing antibodies in guinea pigs and rabbits. Metalnikov and his collaborator Victor Chorine claimed that rabbits that had received intraperitoneal injections of a culture broth of killed microbes and that received external stimuli—heating or grating of the skin where the broth was injected—reacted later by increasing the production of humoral antibodies following the sole repetition of the stimulation of the skin, without injection of an antigen. Guinea pigs were similarly ‘conditioned’ to produce haemolysins when their skin was stimulated. Similar results were obtained when the reaction to stimulation of the skin in conditioned animals (either guinea pigs or rabbits) was measured by the arrival of monocytes to the stimulated area. Finally rabbits were conditioned to produce antibodies and increase their white blood cell count upon hearing a trumpet sound (Metalnikov & Chorine, 1926, 1928a,b). Metalnikov’s book (1934) on the role of the nervous system and of biological and psychic factors in immunity presented his views on the connections between the nervous and immune systems. Therein, he also advanced the view that living organisms were unique, endlessly changing entities. Metalnikov exposed his ideas about biological individuality in an essay on reflexes as creative acts. Every action of a living organism, ‘even the least significant produces a modification in the living matter’ (Metalnikov, 1928c, p. 226). There were no two identical organisms and no two identical parts in a single organism. Even two leaves on the same tree differed. Individuality was not a property of stable structures alone; it extended to physiological reactions such as assimilation, secretion and reactions to external stimuli. Even assuming that all external conditions were identical, every such reaction remained individualised because each organism—and also the same organism at different times—reacted differently to the same stimulus. An organism not only inherited properties but also gradually acquired them during its lifetime. Even a unicellular organism’s reactions depended on its previous history: . . . every living organism changes at each moment, and is not exactly the same as it used to be. Its present physiological state depends upon its previous state.

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Every physiological action is determined by previous actions . . . Every manifestation of a living organism is not only a new fact in the life of the universe, but also a creative act, since it participates in the creation of individuality . . . Existence is change. It is a perpetual act of self-creation. (Metalnikov, 1928c, p. 230–231) For Metalnikov, . . . the essence of all vital phenomena is constant variability and the absence of repetition . . . If nothing is lost in the universe, this must also hold for the individuality that bears the traces of all manifestations of life phenomena, whether reflexes or psychic states. These traces, it is true, are replaced with others, but they are not lost; they cannot be lost. (Metalnikov, 1940, p. 53) This extreme individualisation may seem in contradiction with the existence of natural law, but this contradiction was merely apparent. Laws about non-repetitive phenomena could be formulated, but they described only selected aspects: ‘Every vital phenomenon is individual and non-repetitive as a whole, but it possesses characteristics shared with other, similar phenomena’ (Metalnikov, 1928c, pp. 235–236). The non-repetition of vital phenomena was so obvious, Metalnikov thought, that readers not blinded by dogma or routine could . . . not fail to be surprised how little attention biologists pay to this idea. Many scientists who pursue the sole goal of searching for new laws and generalisations have neglected the essence of all vital phenomena and probably of all natural phenomena’. (Metalnikov, 1928c, p. 234) In the 1920s and 1930s, immunologists considered biological individuality to be an obsolete topic. Metalnikov’s outsider status accounts for his interest in this topic. He was an outsider in two senses: as an immunologist with views grounded in Russian neurophysiology and as a scientist studying the esoteric subject of insect immunity. As the founder of a new domain of investigation, Metalnikov developed his own experimental models. He thus escaped form the restraints imposed by existing disciplinary tradition. All this fostered a highly personal point of view on immunity and a peculiar interest in the (then) outmoded topic of biological individuality. His theoretical idiosyncrasy, we suspect, accurately reflected his outsider status in the scientific community. Mainstream science took a very different turn.

6. Conclusion: science and idiosyncrasy The history of allergy is often presented as a belated triumph of the fundamental immunological approach (Silverstein, 1989; Moulin, 1991). Until the 1960s, ‘idiosyncratic reactions’ such as food allergies, sensitivity to inhaled allergens, or anaphylactic reactions to drugs or insect stings were peripheral to mainstream immunological inquiries and were investigated mainly in clinical contexts. With the

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description and purification of ‘reagins’, identified as IgE antibodies in the 1960s, the biological mechanism underlying allergy was reinterpreted as a ‘normal’ antigenantibody reaction, as cell-bound IgE replaced IgM or IgG antibodies in the serum (K. Ishizaka & T. Ishizaka, 1967; K. Ishizaka, 1985). As a consequence, immunological theory became, once again, an appropriate framework for understanding allergy and anaphylaxis, and allergies became a legitimate topic in basic immunological research. The improved understanding of the molecular basis of sensitisation and of the linkage between allergy and immunity did not, however, result in a unification of allergy studies. The latter are still divided into three distinct, loosely connected fields: fundamental immunological research on the antibodies (mainly IgE) and genes coding for them; clinical inquiry with the aim of managing allergies; and epidemiological and environmental studies for preventing allergies (the fight against a ‘toxic environment’). None of these fields deals directly with biological individuality.28 Doctors are now aware of the impact of psychosomatic factors on the manifestations of allergy and asthma, but their understanding of the mechanisms that relate psychological events to physiopathological phenomena—or, to use Richet’s terminology, the psychological and humoral personalities—has not advanced much since 1910. Far from being an exemplary domain for the investigation of individuality or of interaction between the soma and the psyche, the study of allergic phenomena continues to be a highly fragmented field. This paper suggests that it might have been otherwise. The difficulty of developing links between the topics of interest to specialists from various disciplines (biology, pathology and environmental studies) and the disappearance of ‘idiosyncrasy’ as a legitimate subject in basic research reflect to an important extent contingent events. The different ways of ‘framing’ anaphylactic and allergic phenomena has come out of a growing incompatibility between experimental systems employed by immunologists and physiologists in the early twentieth century.29 Anaphylaxis was first displayed in dogs, an animal model especially well adapted to display individual variations among organisms used in the physiological laboratory. Between 1905 and 1920, allergy and anaphylaxis were, however, increasingly defined as an immunological problem, and were investigated in homogenised animal models (guinea pigs, mice) used in the immunology laboratory. The incompatibility between these two kinds of models led to a growing dissociation between immunological studies and patho-physiological investigations. It also led to the gradual abandonment of interrogations of the biological mechanisms underlying ‘idiosyncrasy’. Moreover, physiologists’ answers to the accumulation of esoteric immunological data was to

28

Studies of the role of major histocompatibility complex in diesease deal, on some level at least, with biological individuality. However their medical applications remain limited (Moulin, 1991; Silverstein, 1989). 29 I have borrowed the phrase ‘framing of disease’ from Charles Rosenberg (1992), who discusses the ‘interpretative grid’ for understanding pathological phenomena, including body sensations. Hacking’s idea (1999) that some diseases (mainly mental afflictions) are of a ‘looping kind’—affected by the patient’s familiarity with their diagnosis and prognosis—can be extended to allergies.

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focus on the study of chemical mediators of non-specific manifestations of anaphylaxis and allergy. This in turn consolidated the tendency to abandon studies of biological individuality. The seemingly neutral choice of the ‘right organism’ for the study of allergic reactions and of the right way of using this organism thus had, one may propose, far-reaching consequences. It shaped distinct and non-convergent approaches to experimental studies of allergy and widened the gap between researchers and doctors who treated allergic patients. In the second half of the twentieth century, scientists made major advances in understanding the biological mechanisms underlying allergies, even as physicians and pharmaceutical companies invented methods for relieving the symptoms of people who suffer from urticaria, eczema or asthma. At the same time allergies became a major public health problem with no easy solution in sight. In the early twenty-first century too, many key questions about allergies and anaphylaxis remain, as Richet put it, ‘unclear, and even very unclear’ (Richet, 1911, p. 256).

References Arthus, M. (1903). Injections re´ pe´ te´ es du se´ rum de cheval chez le lapin. CR Socie´ te´ de Biologie, 55, 817–820. Arthus, M. (1906). Sur la se´ ro-anaphylaxie du lapin. Re´ union Biologique de Marseille, session of 19 June, 1143–1145. Arthus, M. (1909). La se´ ro-anaphylaxie. La Presse Me´ dicale, 1 May. Arthus, M. (1921). De l’anaphylaxie a` l’immunite´ . Paris: Masson. Beaven, H. A. (1976). Histamine. New England Journal of Medicine, 294, 30–36. Berczeller, A. (1943). Alexandre Besredka: His theory of immunity. Medical leafs, Pasteur Institute Archives, Besredka file. Besredka, A., & Steinhardt, E. (1907). De l’anaphylaxie et de l’anti-anaphylaxie vis-a`-vis du se´ rum du cheval. Annales de l’Institut Pasteur, 21, 117–127. Besredka, A. (1908a). De l’anaphylaxie se´ rique expe´ rimentale. Bulletin de l’Institut Pasteur, 4, 496–508. Besredka, A. (1908b). Du me´ canisme de l’anaphylaxie vis-a`-vis du se´ rum de cheval. Annales de l’Institut Pasteur, 22, 384–392. Besredka, A. (1909). Du moyen d’empeˆ cher la mort subite produite par les injections re´ pe`tes du sang ou` des microbes dans la circulation ge´ ne´ rale. CR de la Societe´ de Biologie, 67, 266–269. Besredka, A. (1910). Le proce´ de´ des vaccinations subintirantes applique´ aux animaux passivement anaphylactise´ s: L’antianaphylaxie passive. CR de la Socie´ te´ de Biologie, 69, 69–72. Besredka, A., & Stro¨ bel, H. (1911). De la nature des anaphylotoxines. CR Socie´ te´ de Biologie, 71, 599–601. Besredka, A., Stro¨ bel, H., & Jupille, F. (1913). Anaphylotoxine, peptotoxine and pepetone: Leurs rapports avec l’anaphylaxie. Annales de l’Insitut Pasteur, 27, 185–204. Besredka, A. (1917a). Anaphylaxie et antianaphylaxie: Bases expe´ rimentales. Paris: Masson. Translated into English as Anaphylaxis and anti-anaphylaxis (S. Roodhouse Gloyne, Trans.). London: William Heineman Medical Books, 1919. Besredka, A. (1917b). The´ ories de l’anaphylaxie. Bulletin de l’Institut Pasteur, 14, 413–428. Besredka, A. (1920). Anaphylotoxine et anaphylaxie. Annales de l’Institut Pasteur, 34, 334–343. Besredka, A. (1921). L’histoire d’une ide´ e. Paris: Masson. Besredka, A. (1925). Immunisations locales: Pansements spe´ cifiques. Masson: Paris. Besredka, A. (1928). E´tudes sur l’immunite´ dans des maladies infectieuses. Paris: Masson. Besredka, A. (1934). Expose´ des titres et travaux scientifiques. Laval: Imprimerie Barne´ aud.

I. Lo¨ wy / Stud. Hist. Phil. Biol. & Biomed. Sci. 34 (2003) 399–423

421

Bezanc¸ on, F. (1932). Les tendances nosographiques actuelles et la notion de spe´ cificite´ . Presse Me´ dicale, 40, 1549–1551. Brey, P. T. (1998). The contributions of Pasteur school of insect immunity. In P. T. Brey, & D. Huttemark (Eds.), Molecular mechanisms of immune responses in insects (pp. 1–39). London: Chapman & Hall. Carroy, J. (forthcoming). Playing with signatures: The young Charles Richet. In M. S. Micale (Ed.), The mind of modernism. Stanford: Stanford University Press. Dale, H., & Laidlaw, P. (1911). The physiological action of b-imidazoleyethylamine. Journal of Physiology, 41, 318–344. Dale, H. (1920). The biological significance of anaphylaxis. Proceedings of the Royal Society, Series B, 91, 126–146. Dale, H., & Kellaway, C. H. (1922). Anaphylaxis and anaphylotoxins. Philosophical Transactions of the Royal Society of London, Series B, 211, 273–315. Dale, H. (1952). The mechanism of anaphylaxis. In H. Dale (Ed.), An autumn gleaning: Occasional lectures and addresses (pp. 199–211). London: Pergamon Press. Delaunay, A. (1971). Vie et œuvre d’Alexandre Besredka. Bulletin de l’Institut Pasteur, 69, 73–78. Dror, O. (1997). Modernity and the scientific study of emotions. PhD dissertation, Princeton University. Dror, O. (1999). The affect of experiment: The turn to emotions in Anglo-American physiology, 1900– 1940. Isis, 90, 205–237. Estingoy, P. (1993). Charles Richet, 1850–1935: Esquisse biographique et bibliographie. DE´ A d’Histoire, Universite´ de Lyon III. Estingoy, P. (1994). Charles Richet (1850–1935) et la de´ couverte de l’anaphylaxie, Me´ moire de AEU d’Histoire de la Me´ dicine. Universite´ de Lyon I. Estingoy, P. (1996a). Charles Richet et l’anaphylaxie. In Confe´ rences d’histoire de la Me´ decine (pp. 59– 71). Lyon: Universite´ de Lyon I. Estingoy, P. (1996b). Charles Richet et la de´ couverte de l’anaphylaxie: Histoire d’un prix Nobel de me´ decine. MD thesis, Universite´ de Lyon I. Fleck, L. (1979). Genesis and development of a scientific fact (F. Bradley & T. Trenn, Trans.) Chicago: Chicago University Press. First published 1935. Geison, G. L., & Laubichler, M. D. (2001). The varied lives of organisms: Variation in the historiography of biological sciences. Studies in History and Philosophy of Biological and Biomedical Sciences, 32C, 1–29. Hacking, I. (1999). The social construction of what? Cambridge, MA: Harvard University Press. Ishizaka, K., & Ishizaka, T. (1967). Identification of IgE antibodies as a carrier of reaginic activity. Journal of Immunology, 99, 1187–1198. Ishizaka, K. (1985). Twenty years of IgE: From the identification of IgE to regulatory factors in IgE response. Journal of Immunology, 135, i–x. Jordan, E. O., & Falk, I. S. (1932). The newer knowledge of bacteriology and immunology. Chicago: University of Chicago Press. Keating, P. (1998). Holistic bacteriology: Ludwik Hirszfeld’s doctrine of serogenesis between the two World wars. In C. Lawrence, & G. Weisz (Eds.), Greater than the parts: Holism in biomedicine, 1920–1950 (pp. 283–302). Oxford: Oxford University Press. Kolmer, J. A. (1917). Infection, immunity and specific therapy, 2nd edition. London: W.B. Saunders Company. Krocker, K. (1999). Immunity and its others: The anaphylactic selves of Charles Richet. Studies in History and Philosophy of Biological and Biomedical Sciences, 30C, 273–296. Kupiec, J. J., & Sonigo, P. (2000). Ni Dieu ni ge`ne. Paris: Seuil. Lagrange, E., & Besredka, A. (1870–1940). [Undated manuscript]. Pasteur Institute Archives, Besredka file. Lawrence, C., & Weisz, G. (Eds.) (1998). Greater than the parts: Holism in biomedicine, 1920–1950. Oxford: Oxford University Press. Le Malfan, P. (2002). L’e´ pisode de la villa Carmen: Un moment de folie scientifique. In B. Bensaude Vincent, & C. Blondel (Eds.), La science face a l’occulte (pp. 173–200). Paris: La De´ couverte. Lo¨ wy, I. (1991). The immunological construction of the self. In A. Tauber (Ed.), Organism and the origins of the self (pp. 43–75). Dordrecht: Kluwer.

422

I. Lo¨ wy / Stud. Hist. Phil. Biol. & Biomed. Sci. 34 (2003) 399–423

Lo¨ wy, I. (1998). “The terrain is all”: Metchnikoff’s heritage at the Pasteur Institute, from Besredkas “antivirus” to Bardach’s “orthobiotic serum”. In C. Lawrence, & G. Weisz (Eds.), Greater Than the Parts: Holism in Biomedicine, 1920–1950 (pp. 257–282). Oxford: Oxford University Press. Lo¨ wy, I. (2000). ‘The terrain is all’: Metchnikoff’s heritage at the Pasteur Institute from Besredka’s ‘antivirus’ to Bardach’s ‘orthobiotic serum’. In I. Lo¨ wy (Ed.), Medical acts and medical facts, the Polish tradition of practice-grounded reflections on medicine and science, from Tytus Chalubinski to Ludwik Fleck. Krakow: Polish Academy of Sciences. Mayer, A. (1936). Notice ne´ crologique sur M. Charles Richet. CR Acade´ mie de Me´ decine, 51–64. Mazumdar, P. (1974). The antigen-antibody reaction and the physics and chemistry of life. Bulletin of the History of Medicine, 48, 1–21. Mendelsohn, A. (2001). Medicine and the making of bodily inequality in twentieth century Europe. In J. P. Gaudillie`re, & I. Lo¨ wy (Eds.), Heredity and infection: A history of disease transmission (pp. 21–79). London: Routledge. Metalnikov, S., & Chorine, V. (1926). Roˆ le des re´ flexes conditionnels dans l’immunite´ . Annales de l’Institut Pasteur, 40, 893–900. Metalnikov, S. (1927). L’infection microbienne et l’immunite´ chez les mites et les abeilles. Paris: Masson. Metalnikov, S., & Chorine, V. (1928a). Roˆ le des re´ flexes conditionne´ es dans la formation des anticorps. CR Societe´ de Biologie, 99, 142–145. Metalnikov, S., & Chorine, V. (1928b). E´ tudes sur le roˆ le des re´ flexes conditionnels dans l’immunite´ . Zeitschrift fu¨ r Immunita¨ tsforschung, 57, 326–336. Metalnikov, S. (1928c). Le re´ flexe conside´ re´ autant qu’acte cre´ ateur. In Biologia generalis, IV (3–5) (pp. 217–236). Vienna & Leipzig: Emil Haim. Metalnikov, S. (1934). Roˆ le du syste`me nerveux et des facteurs biologiques et psychiques dans l’immunite´ . Paris: Masson. Metalnikov, S. (1940). Travaux du professeur S. Metalnikov, chef de service a` l’Institut Pasteur, mimeo. Pasteur Institute Archives Metalnikov file, doc. 29.056. Moulin, A. M. (1985). Syste`me nerveux et syste`me immunitaire: Rencontres historiques. Neuro-Psy, 4, 19–24. Moulin, A. M. (1990). Death and resurrection of immunology at Pasteur Institute, 1917-1940. In P. A. Cazenave, & G. P. Tolwar (Eds.), Immunology: Pasteur’s inheritance (pp. 53–69). New Delhi: Wiley Eastern Ltd. Moulin, A. M. (1991). Le dernier langage de la me´ dicine. L’histoire de l’immunologie de Pasteur a` Sida. Paris: Presses Universitaires de France. Nicolle, M. (1907). Contribution a` l’e´ tude du phe´ nome`ne d’Arthus. Annales de l’Institut Pasteur, 21, 128–137. Nicolle, P. (1970). Alexandre Besredka: Souvenirs d’un ancien e´ le`ve. An intervention at Pasteur Institute on 11 June, Pasteur Institute Archives, Besredka file. Nicolle, P. (1971). La vie l’oeuvre et la personnalite´ d’Alexadre Besredka. An intervention at the International Symposium on Oral Immunization, Milan, 2–3 April, Pasteur Institute Archives, Besredka file. Otis, L. (1994). Organic memory: History of the body in the late nineteenth and early twentieth century. Lincoln, NE: University of Nebraska Press. Otto, R. (1906). Das Theobald Smitsche Phenomen der Serum Ueberempfindlichkeit. Leuthold Gedenkschrift. Jena: Gustav Fischer. Portier, P., & Richet, C. (1902a). De l’action anaphylactique de certains venins. CR Societe´ de Biologie, 54, 170–172. Portier, P., & Richet, C. (1902b). Nouveux faits de l’anaphylaxie ou sensibilisation aux toxins par des doses reite´ re´ es. CR Societe´ Biologie, 54, 548–551. Rheinberger, H. J. (1997). Towards the history of epistemic things: Synthetising proteins in the test tube. Stanford: Stanford University Press. Richet, C. (1877). Recherches expe´ rimentales et cliniques sur la sensibilite´ . Paris: Masson. Richet, C. (1888). La physiologie et la me´ dicine: Lec¸ on d’ouverture. Paris: Maison Quantin. Richet, C. (1888–1909). Physiologie: Travaux de laboratoire de M. Richet (6 vols.). Paris: Alcan. Richet, C. (1891). Qu’est-ce qu’est la physiologie ge´ ne´ rale? Revue Philosophique, 33, 337–367.

I. Lo¨ wy / Stud. Hist. Phil. Biol. & Biomed. Sci. 34 (2003) 399–423

423

Richet, C. (1895). La de´ fense de l’organisme: Cours de physiologie de la Faculte´ de Me´ decine de Paris. Reprinted in Physiologie: Travaux de laboratoire de M. Richet (Vol. 3, pp. 458–573). Paris: Alcan. Richet, C. (1907). De l’anaphylaxie en ge´ ne´ ral et d’anaphylaxie par mytilo-congestine en particulier. Annales de l’Institut Pasteur, 7, 458–573. Richet, C. (1910). Humorisme ancien et humorisme moderne, La Presse Me´ dicale, 1 October. Translated into English as ‘Ancient humorists and modern humorism’, British Medical Journal, ii, 921–926. Richet, C. (1911a). L’anaphylaxie. Paris: Felix Alcan. Richet, C. (1911b). De l’anaphylaxie alimentaire par la cerpitine. Annales de l’Institut Pasteur, 8, 580– 593. Richet, C. (1913a). Anaphylaxis. Nobel Lecture, 11 December. In Nobel Lectures: Physiology or medicine (Vol. 1, pp. 473–492). Amsterdam and London: Elsevier Publishing Company, 1967. Richet, C. (1913b). La gloire de Pasteur. Paris: Academie des Sciences. Richet, C. (1919). Introduction. In G. Laroche, C. Richet, & F. Saint Girons (Eds.), L’anaphylaxie alimentaire (pp. 1–9). Paris: J. B. Ballie`re et Fils. Richet, C. (1923). Le savant. Paris: Hachette. Translated into English as Natural history of a savant (O. Lodge, Trans.). London & Toronto: J. M. Dent & Sons, 1927. Richet, C. (1932). Souvenirs d’un physiologiste. Paris: J. Peyronnet & Cie. Richet, C. (undated). Me´ moires sur moi et les autres (manuscript). Academy of Medecine Archives, Richet file. Richet, G. (1998). La de´ couverte de l’anaphylaxie: Dix-neuf jour apre`s une note anodine de toxicologie, il est montre´ que l’immunite´ peut eˆ tre pathoge`ne. CR Acade´ mie des Sciences, 321, 261–266. Richet, G. (1999). Les de´ buts de l’anaphylaxie alimentaire. Alimenter: Le journal de l’allergie alimentaire, 4, 3–8. Roodhouse Gloyne, S. (1919). Recent work on anaphylaxis. In A. Besredka (Ed.), Anaphylaxis and antianaphylaxis (pp. 117–130). London: William Heineman Medical Books. Rosenberg, C. (1992). Framing disease. In C. Rosenberg, & J. Golden (Eds.), Framing disease: Studies in cultural history (pp. xiii–xxvi). New Brunswick, NJ: Rutgers University Press. Rosenau, M. J., & Anderson, J. F. (1906). A study of the case of sudden death following the injection of horse serum. Hygienic Laboratory Bulletin, 29, 95. Rosenau, M. J., & Anderson, J. F. (1908). Further studies upon anaphylaxis. Hygienic Laboratory Bulletin, 45, Roussy, G. (1945). E´ loge de Charles Richet. Acade´ mie de Me´ decine, se´ ance du 18 de´ cembre. CR Acade´ mie de Me´ decine, 725–731. Schultz, W. H. (1909). Physiological studies in anaphylaxis: The reaction of smooth muscle of guinea pig sensitized with horse serum. Journal of Pharmacology and Experimental Therapy, 1, 566–572. Silverstein, A. (1989). A history of immunology. San Diego: Academic Press. Tauber, A., & Chernyak, L. (1991). Metchnikoff and the origins of immunology: From metaphor to theory. New York & Oxford: Oxford University Press. Todes, D. (1997). Pavlov’s physiological factory. Isis, 88, 205–246. Todes, D. (2001). Pavlov’s physiology factory: Experiment, interpretation and laboratory enterprise. Baltimore: Johns Hopkins University Press. Von Pirquet, C., & Schick, B. (1905). Die Serumkrankheit. Leipzig: Franz Denticke. Translated into English as Serum sickness. Baltimore: Williams & Wilkins Company, 1951. Weisz, C. (1998). A moment of synthesis: Medical holism in France between the wars. In C. Lawrence, & G. Weisz (Eds.), Greater than the parts: Holism in biomedicine, 1920–1950 (pp. 68–93). Oxford: Oxford University Press. Wolf, S. (1992). Brain, mind and medicine: Charles Richet and the origins of physiological psychology. New Brunswick & London: Transaction Publishers.