Biologics, A History of Agents Made From Living Organisms in the Twentieth Century

Alexander von Schwerin, Heiko Stoff, Bettina Wahrig, Alexander von Schwerin, Heiko Stoff, Bettina Wahrig

• Publisher: Routledge
• Year: 2015
• Edition: 1
• eBook ISBN:
  9781317319085
• Topic: History
• Subtopic: World History
• Index: History

The use of biologics – drugs made from living organisms – has raised specific scientific, industrial, medical and legal issues. The essays contained in this collection each deal with a case study of a biologic substance, or group of biologics, and its use during the twentieth century.

1 Standardization and Clinical Use: The Introduction of the Anti-Diphtheria Serum in Lyon¹

Jonathan Simon

The use of serum to treat diphtheria, a deadly childhood disease, was a groundbreaking therapy in many respects. Its production involved inducing immunity to a specific pathogen in horses (they initially used a culture of the bacteria responsible for diphtheria to induce this immunity, and later replaced this culture with the purified toxin produced by the bacteria) and using the serum separated from the animal’s blood to treat human victims of the disease. While it can be viewed as an extension of the techniques used for vaccination – the manipulation of a living organism (specifically its immune system) to produce a medicament for use in another species – its status as a treatment for a widespread and deadly disease put it in a class of its own.² Furthermore, serum production, starting in 1894, required microbiological techniques and savoir-faire that were beyond the reach of the majority of pharmacists and medical doctors at that time. This is a key reason why, unlike the majority of medicines that were still prepared in the pharmacist’s laboratory according to directions provided by the pharmacopoeia, the serum was produced in relatively large quantities at a small number of specialized facilities.

One particularly challenging element in the serum production process was the evaluation of its therapeutic or immunization potential. The active principle of the serum (if, indeed, there was such a thing as an active principle) did not correspond to any known single component, making it different from a chemical medicine, the potency (and, in principle at least, efficacy) of which could be evaluated by simply weighing the physiologically active compounds. Determining the serum’s efficacy therefore involved the use of a number of experimental animals and a series of protocols that governed the serum being tested, a sample of standardized diphtheria toxin, and often a standard serum as well.³

The particular problems posed by the production and assessment of the therapeutic virtue of this serum opened up a new area of pharmaceutical standardization, which will be the subject of the first part of this essay. I use the term industrial standardization to characterize this process, an approach to the evaluation of the serum that relied on clearly defined and monitored protocols. These were aimed at limiting variability in the production process, so that the units of production and the personnel could be replaced without interrupting or redefining the activity. In a second section, I want to consider the introduction of this medicine into the clinic, using the example of the diphtheria ward at the Charité hospital in Lyon. In this part, after surveying views about diphtheria and its treatment before the introduction of serotherapy, we will see how serum was used in a hospital ward. Behind the apparently haphazard nature of the serum’s clinical use, I want to argue the case for what I term clinical standardization. This alternative form of standardization, while it is predicated on an increasingly consensual vision of what constitutes appropriate treatment, affirms the autonomy of the individual clinician in implementing the accepted therapy, leading to a large diversity in the application of emerging norms.

Anti-Diphtheria Serum, the First Biological?

One reason that this anti-diphtheria serum is of interest, is that in an uncritical history of therapeutics it would, alongside earlier vaccines, qualify as one of the first biological medicines. Looking at present-day European legislation we find the following definition of biologics:

A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and for which a combination of physico-chemical-biological testing and the production process and its control is needed for its characterisation and the determination of its quality.⁴

It is easy to detect the influence of the history of sera in this definition, in particular with the emphasis placed on product testing. The second part of the definition orients us towards the issue of forms of quality control that rely on test organisms. This approach to quality control, termed Wertbestimmung in German, has grown out of the evaluation of the therapeutic sera that appeared at the end of the nineteenth century, first the serum used to treat diphtheria and then the serum to treat tetanus.⁵ The fact that the sera have influenced this modern definition of biologics makes it logical, if not tautological, to consider them among the first biological medicines. Nevertheless, as Jean-Paul Gaudillière argues elsewhere in this volume, why should we not consider all the products derived from natural sources that are not prepared as pure synthetic molecules to be biologics? Interpreting the term this widely would open up the category considerably, and the sera would lose any claim to pioneer status, with homoeopathic remedies having a claim to be considered biological medicines, to take an extreme example. Nevertheless, it seems to me that counting homoeopathic remedies (as well as other traditional vegetable extracts) as biologics would involve a deliberate misinterpretation of the intention of those who drafted the text cited above. The target of the definition is clearly sera (more particularly monoclonal antibodies), hormones, blood products, and other medicines or vaccines of this type. Even this brief reflection on the question shows how indefinite the term ‘biological medicines’ is in principle, however well circumscribed its application might be in practice.

The modern definition of biological medicines serves to recall two important aspects of the history of the serum: its production and its evaluation, two processes that provide an entry-point into the issue of standardization. Indeed, the innovations that sera represented in these areas were tightly bound to the establishment of production, managerial and metrological standards.

Something that all products of biological origin (vaccines, sera and, later, hormones) had in common was the impossibility of defining and isolating an active ingredient uniquely responsible for their therapeutic or prophylactic effects. This would not necessarily have posed a problem had these effects been completely invariant (meaning in the case of diphtheria treatment, the same effect for the same volume of blood serum prepared under similar conditions), but the variability inherent in living beings and their natural products meant that the serum manufacturer could not be sure that a new batch would have a level of efficacy similar to that of an old one. This was the case even when the serum came from the same horse, let alone when it came from a different one. Of course with regard to pharmaceuticals, there are two aspects to this problem of variability: that of the product itself and that of the person receiving the treatment. Although we should bear this in mind when we consider the use of the serum in the clinic, we will leave the second aspect to one side for the moment and concentrate our attention on the first one, the variability of the product. The systems that were developed around the serum in order to master this variability conformed to the logic of what I term industrial standardization.

Diphtheria Serum, Evaluation and Industrial Standardization

In Germany, Paul Ehrlich took the lead in successively developing more sophisticated evaluation procedures that came to depend on a standard dose of toxin. The lethal dose – the volume of toxin (per weight) capable of killing guinea pigs within a fixed amount of time – became the touchstone within a system populated by fluctuating products and animals. Thus, Ehrlich based his comparison of different sera on the lethal dose of toxin, and he increasingly used dried standards to compensate for the variability of these products over time.⁶ In France, where the production and evaluation processes were not subject to the same pressures for innovation as in Germany, Emile Roux and his successor in charge of serum production, Louis Martin, stuck with an early version for evaluating the potency of the serum, using a technique initially developed by Behring himself. This procedure involved injecting guinea pigs with a proportion of their weight of the serum under test (one 1/50,000 of its weight the other 1/100,000) followed by a lethal dose of toxin. If only the first guinea pig survived, the serum was classed as 150 units, and if they both survived this rose to 200.⁷

While the details of the evaluation method differed between the producers in France and Germany, what I want to emphasize for the sake of comparison are the features of ‘industrial standardization’ that were common to both. The idea is to draw out the most significant elements of this type of standardization in order to compare it with the ‘clinical standardization’ that was developed in Lyon (and elsewhere) after the serum became available starting in 1894. In their book on standardization in evidence-based medicine, Timmermans and Berg present four types of standards: design, terminological, performance and procedural.⁸ Although these categories (especially performance and procedural) can account for much of the standardization in this context, I believe it is more useful to think of the industrial standardization of the production of serum in more global terms. Thus, this kind of industrial standardization relies on centralized production with a system of sampling and testing that evaluates the products in terms of both their quality and their efficacy. This system of control is tied to bureaucratic procedures that accompany the process, duplicating it on paper and thereby providing a form of traceability and administrative proof that the production process was carried out according to the established norms and that the finished product conformed to the testing standards.⁹ This documentation also gives unity to a process that can be broken up through the division of labour at various stages of production. Protocols specifying the materials to be used and procedures to be followed allow different specialists to execute the same steps in the production process. The personnel (like the producing units – in this case the horses) can thus be replaced by others, although this does not mean that we can neglect the importance (and variability) of the specialized skills possessed by each individual technician.

These features mark the difference compared with artisanal production, where the individual manufacturer brings his or her skills to bear in the fabrication of each product. While the products of such an industrial system may be no more uniform than those of the artisan, they are nevertheless subject to a different regime of control, where well-defined procedures and systematic checks form the core of what we are calling ‘industrial standardization’. This term, therefore, covers the norms of production, their application and their enforcement, as well as the corollary of the interchangeability of personnel. While it might seem that industrial standardization would require a certain minimum scale of production, this is not a fundamental factor in the present case. For example, the scale of serum production in Lyon was very modest compared to the output of the Pasteur Institute in Paris (two horses versus over one hundred and thirty), and yet the details of production were just as clearly defined.

The Epidemic in Oullins — The Triumph of the Infectious 'Germ'

Having outlined this industrial culture of serum manufacture and the standardization that it implied, I now want to turn to the question of the clinical use of the serum. How was the serum employed once it had been distributed and was no longer under the control of the manufacturers? This section explores the use of the serum in Lyon starting in late 1894, but I also want to expand the perspective to include the place of diphtheria in this city prior to the introduction of serotherapy. This provides relevant context for what I have to say about the issue of standardization in the use of the serum for the treatment of diphtheria in Lyon. Furthermore, I will consider the discussions about serotherapy that took place in medical circles in 1894–5. Nevertheless, in reviewing these debates over the serum that appeared in the medical press, I have found nothing suggesting that the fact that serum was a product taken directly from an animal was of pressing concern for either the patients or the administering doctors. While it might appear surprising from the perspective of the standards embodied in today’s health-care regulations that so little attention was paid to a biological product intended to be injected in large doses into young children, it did not seem to shock the doctors or patients at the end of the nineteenth century.

In Lyon, as we shall see, the debate was displaced onto other issues (in particular, onto debates that pre-dated the introduction of serotherapy and would continue for decades afterwards). As we have argued elsewhere, the justification for the widespread use of this relatively untested product was the gravity of the disease itself.¹⁰ The fact that the disease was so lethal, particularly among children, justified a treatment that could well have been rejected in less drastic circumstances. The important place that the serum occupied relatively quickly, particularly in hospitals, did not, however, prevent criticisms of its use and investigations into its potential dangers for the patients. Thus, Saturnin Arloing, a professor of both veterinary and human medicine in Lyon who oversaw local serum production for the region, conducted a number of tests on animals in order to clarify these risks, in spite of the fact that he was producing the serum. We will return to consider Arloing’s studies and their motivation at the end of this chapter.

To introduce the historical analysis, I want to consider an epidemic of diphtheria that dates from before the introduction of serotherapy in Lyon. This has the advantage of illustrating not only how the medical community viewed diphtheria and its outbreaks, but also the range of treatments that were available in the second half of the nineteenth century. Thus, I will be looking at a description of an outbreak of the disease in the Lyon area in 1888, i.e. shortly before the introduction of the serum and at a time when the microbial nature of the disease was already well established in the medical community – at least among those doctors who kept themselves informed about these developments. Furthermore, doctors, particularly hospital doctors, were increasingly availing themselves of the possibility of detecting the presence of the ‘germ’ responsible for diphtheria by means of the microscopic analysis of throat cultures. Thus, while there was no general agreement concerning any ‘standard’ treatment – a point we will return to later – the means for diagnosing and more generally ‘understanding’ the disease was becoming more consensual.

In September 1888, the first cases of diphtheria appeared in Oullins, an industrial community on the outskirts of Lyon (population c. 8,000). Louis Bard, a young local doctor, gave a full account of the resulting epidemic in the Lyon Médical for 1889.¹¹ This account was presented in the form of an investigation aimed at identifying the cause of the epidemic.¹² Indeed, for all practical purposes, Louis Bard effectively replaced the official inspecteur des épidémies de Lyon, Professor Peroud, investigating the outbreak and conducting a case-by-case analysis in order to shed some light on its origins. He divided the epidemic up into different periods, but was mainly interested in the moment when the first cases appeared, hoping it would provide the answers he sought. In this initial period from September to November 1888, there were twenty-nine cases among children brought to the ...

Table of contents

• Cover
• Half Title
• Title
• Copyright
• Contents
• Acknowledgements
• List of Contributors
• List of Figures
• Biologics: An Introduction
• Part I: Producing Nature
• Part II: The Body Politics of Biologics
• Part III: The Making of Contested Biologics
• Notes
• Index