Seriality and Standardization in the Production of “606”

Hist. Sci., xlviii (2010)

SERIALITY AND STANDARDIZATION IN THE PRODUCTION OF “606”

Axel C. Hüntelmann Bielefeld University

The first major chemotherapeutic agent, the anti-syphilitic Salvarsan, is especially significant because its production in a network linking research laboratory, pharmaceutical industry and the clinic was the prototype for so much biomedical research in the twentieth century. Salvarsan, which originated in Paul Ehrlich’s laboratory as a compound numbered “606”, is also among the most famously serial objects in the history of science, technology and medicine. Ehrlich’s early biographers recounted its production as a planned, linear process. Every stable chemical preparation that exhibited a disinfectant effect against parasites or bacteria received its own number. So chemicals such as 306 (arcacetin) and 418 (arsenophenylglycine) were presented as mere waystations on the path to the production of 606 (arsphenamine). In these heroic tales about a scientific icon and benefactor of humanity, numerical growth correlates with progress and modernity, development and discovery, and illustrates Ehrlich’s dogged will to cure syphilis come what may.1 The story of Salvarsan has also been recounted as a chemist’s history of ingeniously combining and extracting derivatives, separating, purifying and recombining. At first, the numbers represented mere chemical combinations, but these came to embody progress as they grew.2 By contrast, this article will focus on the numbers themselves and the processes lurking behind them. I shall present the scientific object 606 as linked to countless other objects and subjects in a network of structures and procedures within which its status and relations continually changed. Chemical compounds were combined, rejected, purified, dissolved, diluted and their effects evaluated. Stable compounds were produced, dried, vacuum bottled, opened and used. The changes mark the transformation, in laboratory notebooks, medical journals, and the general press from a promising compound to a clinically tested and validated remedy sanctioned by the scientific community and the state. Only once 606 and then Salvarsan were recog- nized in this way could the tortuous process of development come to seem linear.3 In the course of the trials, 606 became the “Ehrlich-Hata-compound” — named also for the Japanese collaborator Sahachiro Hata — that was marketed as Salvarsan and celebrated in a major motion picture as “Dr Ehrlich’s Magic Bullet”. I draw on several publications by Ehrlich, his assistants and collaborators, as well as his personal papers and their notebooks. My interest is in neither the commercial scientist’s relations with the chemical industry and other allies,4 nor the intellectual history of the receptor concept. Both have been well described.5 Instead, I interpret research methods within his Institute for Experimental Therapy (IET) and the Georg Speyer House for chemotherapeutical research (GSH) in terms of standardization,

organization, administration and rationalization. I wish to explore, for this iconic case, the role of serial practices in the standardization and industrialization of scientific methods.6 The first section of the essay introduces the two institutes, both headed by Ehrlich, and their links with industry. I then analyse a range of labour processes, commodity flows and production methods that were organized in extensive series, both temporally and spatially. I discuss the origins and significance of this kind of serial organization. Industrial modernity around 1900 has often been associated with the emergence of serial production systems and continuous throughput. Here the argument is extended from specialist forms of pharmaceutical expertise and the regulated division of labour to serial co-ordination through forms of accountancy and quality control. Seriality in this case was not solely a matter of accelerated production. For through complex links with standardization and surveillance on a genuinely vast scale, it also affected the career of the scientific product and the reputation it acquired.

the iet, the gsh, and their industrial links The interpenetration of science and industry, especially in the chemical and electrical industries of the second Industrial Revolution, meant mass production of science- based, technically complex products and the industrialization of scientific work. Large-scale screening necessitated more specialized training and more highly divided labour than was usual in academic laboratories.7 As research laboratories began to look more like industrial ones, larger experimental settings and arrangements became usual and were regulated according to national standards and norms. These developments led to the emergence of genuinely ‘big’ science.8 A fine example was the new production plant of the bacteriological department of Dyestuff Industries in Hoechst, officially inaugurated in November 1894. A few weeks later theMünchener medicinische Wochenschrift, Germany’s pre-eminent medical weekly, published an enthusiastic report about how serum was made there. The author, a physician who had visited the department a few days earlier, gave an overview of the architecture, spatial arrangement, production process, and work flow. The plant was equipped with the latest devices and designed for large-scale production of diphtheria serum — eighty horses produced serum that was bottled in thousands of phials. The author stressed the organizational aspects of the production and explained the “modern principle” of the division of labour: one worker filled the phials, another sealed them, a third labelled them, and a fourth assigned each phial a number before it was packed. Each step was registered in a database and assigned an operation number that made it possible to trace each phial back to the equine host and the specific day of bloodletting. Via the register, the operation number was linked to other journals for the serum hosts and the test animals, each serum host having its own journal documenting health, temperature, feeding, and bloodletting dates.9 After the state assumed control over diphtheria serum in the spring of 1895, the operation number became the organizational linkage between the local serum producer and the central state-run serum institute. Furthermore, the principle of operation numbers and the various administrative and production techniques became models SERIALITY AND STANDARDIZATION · 437 for the newly-founded state-run serum institute and for other serum producers as well.10 In 1896, Paul Ehrlich was appointed director of the Royal Prussian Institute for Serum Research and Serum Testing in Berlin. The institute’s principal task was serum inspection, but it also conducted basic research on serum therapy and the standardization of serum control. State approval was obligatory for every phial sold on the German market and producers paid a fee to cover the cost of materials and personnel. To promote more research, in 1899 the institute was reorganized, renamed the Royal Prussian Institute for Experimental Therapy, and moved to Frankfurt am Main. Alongside the original Serum Control Department, the institute was subdivided into a Hygiene Department doing bacteriological tests for the city, a so-called Experimental Biological Department conducting research, and a department for Cancer Research. Ehrlich now focused on experimental research, expanding and experimentally fortify- ing his side-chain theory to explain immunological processes and experimenting with dyestuffs and arsenic compounds.11 These experiments were very expensive; the costs for chemicals and test animals increased and the institute’s books recorded frequent deficits. Ehrlich therefore spent much time and energy exploiting his extensive network to acquire dyestuffs and other chemicals from colleagues and industry. Frequent requests for additional funding, including a full-time chemist, came to fruition when, in 1906, the GSH was founded as an independent research institute for chemotherapy. Funded by private donations, the institute was headed by Ehrlich and divided into a Chemical and a Biological Department. In the former, “countless” dyestuffs and arsenic substances were created and modified; in the latter the therapeutic effects of the compounds were systematically screened in animal experiments. The 606th compound created in the Chemical Department was arsphenamine.12 So 606 was developed at the intersection of several transformations: the most rapid phase of German industrialization, the constitution of the pharmaceutical industry, the standardization of different spheres of society, the differentiation of medical disciplines and an increase in biopolitical activities to improve public health in the national “struggle for survival”.13 This involved the foundation of public health insti- tutions, such as the Imperial Health Office, the Institute for Infectious Diseases, and the IET.14 The development, production, and regulation of such therapeutic agents faced problems similar to those in electrotechnics and precision engineering, and these similarly drove institutional innovation between the state, science, and industry. The IET may therefore be likened to the Imperial Physical-Technical Institute, which combined basic research in optics, electricity, and precision mechanics with the testing of devices, technical instruments and materials against national standards.15 As director of the IET and the GSH, Ehrlich had multiple connections to the pharmaceutical, dyestuff and chemical industry, which also produced serum. He was familiar with the production process, and directly engaged in the improvement and standardization of serum and serum testing. Ehrlich’s institutes relied on the fees paid for serum approval, while the pharmaceutical-dyestuff-chemical industry depended on this approval and was keen to exploit the patents generated at the GSH. This suggests a great deal of give and take, and an entire economy of material and expertise.16 438 · AXEL C. HÜNTELMANN

organization by numbers, control by the book In speaking of compound 606, it is crucial to recall that 605 other compounds had already been created. We do not need to trace each step back to the very first chemical, however, but will rather focus on the numerical organization. Why had Ehrlich organized the chemical compounds by number instead of alphabetically, by colours, or by some other systematic order based on the chemical ingredients?17 Numerical organization was nothing new to Ehrlich and his contemporaries. In the 1880s his notebooks and publications were full of numbers assigned to mice in experiments. For example, his “Studies on the cocaine series” ran to mouse number 753.18 In smaller experiments he used characteristics such as brown or white guinea pigs, rabbits with white or speckled marks, and dogs classified by race. Larger animals were sometimes given names.19 It was the increase in scale that demanded numerical organization: organization by specific characteristics was impractical for an array of experiments over a longer period of time, including a large number of experiments involving different laboratory personnel. Ehrlich drew on his experience in serum evaluation. The biological effect of serum could be measured only by the reaction of the injected organism. Testing aimed to transform an undefined, imponderable variable into an objective, quantifiable, comparable factor with a mathematically exact value, an objective criterion for the potency and curative value of a remedy within an organism.20 As an objective criterion, the evaluation of serum had to be independent of local circumstances and of the identity of the tester. All variables, including test animals, bacterial cultures, and technical arrangements, had to be determined and all contingencies eliminated.21 As part of the production, evaluation, and state control of serum, test animals and the serum hosts were each assigned their own laboratory book. Locally, in the production plant, every serum host had a file containing data on weight, temperature, pulse, health, dates of toxin injections, and the immunization units upon bloodletting. A main register linked all the data together. In the event of irregularities or unexpected side effects, the register could be used to trace each step in the production process back to the initial bloodletting, thus allowing irregularities and anomalies to be identified and resolved.22 Different laboratory personnel were involved and supervised at various stages in this documentation process. Each datum entry had to be clear and comprehensible to others further down the chain of production. Numerical codes made this easier.23 Documentation procedures were themselves standardized too. Around 1905–6 the institutes’ organization was reorganized according to rational and numerical criteria. Each morning Ehrlich wrote down the tasks of the staff and laboratory assistants. His personal servant brought the so-called “pads [Blöcke]” to the institute, where they were numbered serially, and copied by his secretary into a so-called “copy book [Kopir-Buch]”, before being passed on to the scientists and assistants.24 The copy book itself contained several “series” listing the correspondence of the director of the IET, the pads for each institute, and personal notes.25 Each pad was assigned a number that was then recorded in the copy book (Figure 1). The copy book allowed SERIALITY AND STANDARDIZATION · 439

Fig. 1. Pads with work instructions concerning the infection of a series of mice (22.12), a test for toxicity (15.5) and a meeting concerning a new experimental setting. Paul Ehrlich Institute. the director to control the work-order and keep track of the work performed. Even after a prolonged absence, he could rapidly assess what had been done. The pads were essential to the institute’s division of labour. After 1900, Ehrlich rarely found the time to conduct laboratory research himself.26 While the Bacteriologi- cal Department and the Department for Serum Control were relatively independent once a work routine and a reporting system had been implemented, the Experimental Biological Department of the IET and both Departments in the GSH were geared to Ehrlich’s needs. But only the Biological and Chemical Department in the GSH were involved in the development of 606, so I shall focus on them. Over time, a division of labour evolved on three different levels. First, dyestuffs and chemicals were supplied by the chemical industry or other collaborators outside the IET/GSH, and by Ludwig Benda, who worked in the laboratories at Cassella & Co and was later employed by the GSH.27 Second, different tasks were assigned to Ehrlich and his assistants and laboratory staff respectively. Aside from his daily administrative work-routine, he mainly spent his time reading the scientific literature, advising, corresponding with other physicians and scientists, and outlining simple experiments based on articles he had read. Inspired by his reading, he wrote up blueprints for experiments in his pads. For example, in a note for Alfred Bertheim, Ehrlich wrote that “in the Chemischen Neuesten Nachrichten I read about a patent acquired by Hoechst which might be interesting. It’s likely possible to oxygenate As=As into AsO using bromate in alkaline solution. As a test, try No. 418 — the quantity of bromide should already be calculated in the article.”28 Other briefings involved requests for bibliographies or thematic reports. For the Biological Department, Ehrlich ordered that a new series of test animals be infected to start a new set of experiments, to breed a new microbial 440 · AXEL C. HÜNTELMANN

strain via animal passage, or to start investigating the lethal dose of a given chemical compound or dye.29 He received reports of the results and in turn proposed chang- ing the experimental setting, continuing the experiment, or terminating it.30 The two departments comprised a third level on which a division of labour evolved: while the Chemical Department created chemical compounds, the Biological Department tested these in vivo and in vitro on different pathogens or strains. Ehrlich coordinated and directed this work.31 The organization of labour within the GSH can best be described as a three- dimensional matrix. In the Chemical Department, chemical compounds were created and modified in countless variations (X-n). Stable or promising compounds were registered in a preparations book (Präparate-Buch).32 Once an interesting compound was found (e.g., 379/418), it was used as a basis to improve solubility, reduce its affin- ity with the organism, or increase its toxicity against the parasite. If the compound generally affected the pathogenic germ, then it was tested in vitro on various strains

of bacteria. For this purpose, several kinds (Y-n) and numerous strains (Y1-m-n1-m) of parasites were bred and stocked. If the compound had an effect on parasites in vitro by either immobilizing, sterilizing, or killing them, then it was tested on various types of laboratory animals (Z-n). In a further step, the therapeutic efficacy of compounds that were able to sterilize pathogenic germs without affecting the test animal had to be proven in clinical trials. This required cooperation with actors outside the GSH. A precondition for these tests was a stable production process in small series at the GSH — or an affiliated pharmaceutical or chemical producer — to guarantee sufficient quantity and quality.33 Ehrlich integrated the therapeutic tests into an institutional framework and coordinated them. Initial clinical trials began by testing for tolerance, i.e., the dosage tolerated by patients. After successfully completing the first trials with closely connected partners, the clinical trials were expanded, incorporating numerous clinicians throughout Europe or even worldwide. Once tolerance had been confirmed, potential side-effects detected, indications and counter-indications identified, and the most effective dosage as well as the form of application standardized, the newly devised therapeutic agent was released, produced on a large scale, marketed, and often regulated by the state.34

chemistry: the series from 418 to 606 Compounds have histories. The history of 606 did not start with 418, but with the failure of 418, or arsenophenylglycine. That compound was able to sterilize trypanosomes in animal experiments, but difficulties and side-effects arose in clinical trials on sleeping sickness in 1908–9. Ehrlich asked Bertheim and Robert Kahn in the Chemical Department to modify the compound by adding to or removing chemical compounds from the arsenobenzene. Since 1906, a range of derivatives had been produced from atoxyl to form acetylatoxyl (306), formylatoxyl acid (310), chloroacetylatoxyl (322), phenylacetyl-atoxyl (325), and bromoacetylatoxyl (367).35 Combinations were formed from successful compounds, as for example with arsenic, acetylacid, phenyl, and halogen compounds. A promising preparation was serially SERIALITY AND STANDARDIZATION · 441 synthesized and reduced from different chemical combinations: tartar emetic was reduced from laevotartaric acid (D-tartaric acid) (490), from a combination of dex- trotartaric acid (L-tartaric acid) and ethylenediamine (491), from piperazine (493), and from lysidine (494) (Figure 2).36 New compounds had been obtained from 418, which was itself a purified form of compound 379: compound 440 was created by the reaction of acetic anhydride with hot 418, while compound 441 was made by boiling 418 in a saturated solution of acetic anhydride and then precipitating with alcohol. Using his pads, Ehrlich instructed his assistants to perform a series of experiments, for instance in May 1909 to combine halogen compounds with azo dyes.37 Experiments varied widely, using different techniques and combining existing compounds in the hope of modifying them.38 Compared with Ehrlich’s series of “suggestions” and the work that followed, the compound number represented only an end-point of a sequence of experiments. In their individual laboratory notebooks, the chemists must have noted the different results that led to successful reductions. For instance, the combination of halogens, including fluorine, chlorine, bromine and iodine, with three sets of different azo dyes, with variations in their preparation and reduction, might have given hundreds

Fig. 2. Page from the “preparations book” showing compounds 539–42. Paul Ehrlich Institute. 442 · AXEL C. HÜNTELMANN

of compounds, but only two were noted in the preparations book in early June: no. 595 (monochlorophenylarsinic acid, resulting from the diazotization of aminophenyl 39 arsinic acid with CuCl2) and no. 596 (iodineaminophenyl arsinic acid) (Figure 2). Since Ehrlich’s pads led to various work schedules and the results were noted in different laboratory books,40 it is difficult to establish which of his pads or series of pads and which instructions initially led to the synthesis of arsphenamine. One note mentions the arrival of the intermediate product nitro-phenylarsinic acid that had been prepared by Benda at Cassella.41 From this point on, we have Bertheim’s retrospective summary of the research path. 3-nitro-4-hydroxy-phenylarsinic acid was combined with sodium hydrosulphite and heated to between 55 and 60oC to reduce the arsenic acid radical to an arseno-group and the nitro-group to an amine. After an initial exploratory analysis, the compound was purified from residues of ash and sulphates, resulting in a 3, 3’-diamino-4, 4’-dihydroxyarsenobenzene, registered as no. 592, and the purified compound later registered as no. 606 in the preparations book.42 In daily laboratory life, the serial compound numbers facilitated internal commu- nication: in the copy books, on the pads, and in laboratory notebooks nobody wrote names that, even by German standards, were complicated and hard to pronounce. While 464 was a dye made from “Tetramethyldiamidobenzhydrol” and “Dimethyl pyrrholphenylarsinsäure” [arsinic acid], 466 was simply the leuco base of 464 while 467 was the reduced form of 466. In words, one wrong letter risked making a new compound and anyone familiar with Ehrlich’s handwriting will understand the implications of that.43 So a compound became a formula and a number. For insiders, the number carried rich information about the substances and their experimental setting, their creation and chemical properties. The preparations book functioned as a catalogue in which all promising compounds were registered.44 In addition, Ehrlich suggested to his assistants that frequently prepared compounds receive a serial number, and that biological characteristics be noted alongside provenance in the delivery book.45

biology: testing 592/606 in animals Compound 592 was later transferred to the Biological Department. There it was tested for toxicity and therapeutic impact, and animal tests were then conducted to establish the proper dosage. But this is to cut a long story short. The compound interacted with several different objects: different types of spirilla (recurrent fever, chicken spirilloses, syphilis) or, to be more exact, various strains of the different types in various different animals.46 Until the spring of 1909, Ehrlich and his assistants had mainly worked on diseases caused by trypanosomes, such as sleeping sickness. One difficulty with trypanosome research was variation: while strains of trypanosome causing sleeping sickness in Togo were susceptible to arsenobenzol compounds, those in the Congo and East Africa often proved resistant.47 So, after consultations with the Biological Department, further research in the Chemical Department was done to develop more effective arsenobenzol preparations. Resistant strains of trypanosomes that were specially bred SERIALITY AND STANDARDIZATION · 443 via animal passages served as indicators for enhanced effectiveness. These highly resistant pathogens acted as so-called therapeutic filters used to differentiate more or less effective compounds. Those that had an initial impact on the pathogens but later caused relapses, were dismissed, whereas compounds that sterilized the pathogens counted as promising and hence were tested in vitro. After relapses and resistances had appeared accidently in clinical trials and in vitro tests, Ehrlich and his assistants tried to re-produce the resistant strains of pathogens systematically in an experimental setting. This gave him several possible ways to increase resistance. Mice that had been infected with pathogens and thus transformed into mice-trypanosome-hybrids (MTH) were given various chemical compounds, but in doses that would not kill the trypanosomes. After relapse, the MTH were repeatedly exposed, so as to increase their resistance to the chemical compound. An alternative way of generating resistance was — mimicking the process of passive immunization — to inject a mouse serum from an animal that had already shown resistance to a certain compound.48 After one strain of trypanosomes acquired resistance to a compound, it was also possible to enlarge the pathogen’s resistance to a second or third compound. The serial process of generating resistance was documented in a specific laboratory book, such as Rea III (Figure 3).49 Trypanosomes were closely related to spirilla and while the clinical trials with 418 showed no progress, Ehrlich decided to cross-check existing compounds for their impact on spirilla. This task was assigned to Sahachiro Hata. When Hata entered the Biological Department of the GSH at the end of March 1909, he started work

Fig. 3. Notebook for strain Rea III showing a table with dates of the reaction of resistant variations of the strain (ranging from “highly mobile” up to “death”) within a certain period of time on two alternative parafuchsin dilutions (compound 508). Paul Ehrlich Institute. 444 · AXEL C. HÜNTELMANN

on recurrent fever. The infected MTH were tested on over 200 existing dyestuff and arsenic compounds, including atoxyl, arsacetin (306), arsenophenylglycine (418), arsenophenol, diaminodihydroxyarsenobenzene (592), and the salpetric salt of 592, i.e. 606 in vitro.50 For example, compound 592 was diluted in alternative solutions and then mixed with blood containing spirilla. An hour later Hata examined the preparation using dark-field microscopy, observing the effects on the spirilla, such as inhibition of movement. In light of the varying experiences with trypanosomes, Hata tried to standardize the in vivo experiments. An African and a European strain of spirilla causing recurrent fever had been reproduced separately. Every two days, the blood of an infected mouse was injected into a healthy one that consequently was transformed into an MTH. By October 1910, the spirilla had passed through 230 animal passages, thus significantly elevating the level of virulence. Hata pointed out that “it was absolutely necessary to generate a uniform infection” in order to achieve comparable results with respect to other compounds in his screening schedule51 and with respect to the same compound over an extended period of time, so as to evaluate the improvement. Comparable results and a “standard” infection were premises for experimental therapy. The severity of infection was first evaluated on the basis of the course of the disease and the number of spirillum bacteria counted under dark-field microscopy.52 Based on his observation that the virulence increased over the time, Hata generated an infection by counting the spirilla. Only blood samples of an infected MTH that contained twenty to thirty spirilla per visual field three days after inoculation were used for reinfection.53 Beyond the standardization of spirilloses and of the mode and technique of generating and evaluating an infection, the mice themselves were also standardized. Given that every mouse had an individual health status54 and reacted individually to the chemical compound, large-scale test series or screenings were designed to compensate individual variation. The problem of individual constitution was dealt with by using uniform test animals of the same weight, health status, sex and age. After compound 592/606 showed positive results and was able to sterilize the pathogens of recurrent fever and chicken spirilloses, the experiments were enlarged on syphilis. Because Hata found it more difficult to cultivate the strains or eliminate individual differences,55 more time was needed to complete the experiments: it took two weeks for the disease to appear and months passed before full-blown symptoms emerged. The very manner in which Hata reported the experiments indicates their small number: while tables of figures summed up the experimental results on recurrent fever (as we shall see in Figure 7), syphilis experiments were reported as single case histories. Nevertheless, the experiments showed compound 592/606 as having a specific effect on the disease. Whereas the control animals died, the treated rabbits were cured and the ulcers regressed and healed; no parasites could be found.56 As a premise for subsequent clinical trials, the biological testing also included the scaling and determination of different degrees of effectiveness. The quantity of a compound that was able to sterilize the spirilla and cure an infected MTH was SERIALITY AND STANDARDIZATION · 445

Fig. 4. Notebook dosis tolerata containing data on toxicity, here for compound 418 and 425, and the dosis tolerata in relation to a general standard weight (kilograms live weight) for mice (Ms), rats (R), guinea pigs (M), rabbits (K), dogs and chicken. Paul Ehrlich Institute.

defined as the dosis efficiens, which ranged between the dosis tolerata and the dosis letalis. The bottom of the scale was defined as thedosis tolerata, the dose of a chemical compound at the transition between no reaction and the first reaction. This was determined as the minimum and starting doses for the clinical trials. From there, increasing doses induced weight loss, reduced agility, hyperactivity, up to the lethal dose or dosis letalis that killed the mouse. Across this range, the dosis effectiva was intended to be as close as possible to the dosis tolerata and as far as possible from the dosis letalis (Figure 4).57 record-keeping and experimental organization Not every experiment can be traced back through the laboratory books. Here I sum- marize the links between institutional structure, seriality and standardization. The division of labour and cooperation between the two departments seems clear. The animal experiments were conducted by laboratory assistants. Hata supervised the labour, based on the groundwork of his colleague Wilhelm Röhl. Many people were involved, and accurate and reliable registration was indispensable. A single mistake, such as the injection of an incorrect strain of parasites into another strain or cross infections, could destroy months of work and corrupt ongoing therapeutic experiments. Consequently, a system of laboratory notebooks was introduced: various journals were used to document the reproduction of different strains of parasites (Figure 3), to assess progress on disease standardization, to determine the dosages (Figure 4), as 446 · AXEL C. HÜNTELMANN

Fig. 5. Fräulein Leupold recording something in a notebook. The stock of notebooks is at the back of the bench on the left. The legend states: “One hundred mice, which were injected for experimental purposes with disease materials of all kinds. In the Ehrlich Institute there are halls that can accommodate 5–6,000 mice.” Berliner illustriere Zeitung, clipping, Rockefeller Archive Center.

well as to follow up on the clinical progress of therapeutic experiments. Depending on the experiments, the collected data included the identification number of the test animal, the dates of infection, the dates on which the compound was injected, and the daily progress of weight or temperature. Many of the notebooks were kept on the shelves beside the test animals (Figure 5), so that everybody in the GSH could keep track. New assistants were instructed in the record-keeping system.58 Just how important the notebooks were became evident when Röhl left the GSH in the autumn of 1909 and took with him one of the guides (Führer). An acrimonious ownership dispute erupted and continued even after he returned it, because several pages had gone missing. Ehrlich went so far as to threaten legal and professional proceedings that could have ruined Röhl’s scientific career.59 The notebooks were used not only to organize daily work, but also to provide the director with a general overview of ongoing work.60 When writing articles, Ehrlich requested that his assistants give him the pads, and that he receive tables and summaries of the experiments and notebooks.61 When Hata arrived in the GSH at the end of March 1909, Ehrlich conferred with him about his work and he sketched out a schedule for screening different dyes and SERIALITY AND STANDARDIZATION · 447 arsenic compounds for spirilloses.62 Beyond this, Ehrlich observed the ongoing research and Hata reported on his progress when Ehrlich visited the Biological Department. Ehrlich addressed numerous pads to his assistants, providing advice,63 detailing instructions, and linking together the different projects. On 26–27 March, he asked Ragnhild Gulbranson and Wilhelm Röhl of the Biological Department if bromine- and chlorine-arsenophenol had been tested only on spirilla or also on trypansomes. A day later he instructed them to start a new experiment on spirilla to find out which compound worked best. The result would be important because Ehrlich had asked Bertheim from the Chemical Department to prepare a larger quantity of arsenophenol and wanted to discover the best combination. On the same day, Bertheim was asked to prepare a batch of the “promising halogenotized phenols”, but to await the results of the biological experiments.64 A few days later Ehrlich reminded Röhl to start experiments on arsenophenol with rats, so that Hata could begin his own experiments on recurrent fever.65 The influence of such large experimental series on the standardization of procedures, especially in the context of creating a standard clinical picture, may seem obvious. But Hata’s work on the reproduction of syphilis underscores the effect of these repetitive practices and the drive to improve them. Originally, two modes of generating syphilis were used in experiments: corneal syphilis was reproduced in eyewash while scrotum syphilis was reproduced in the scrotum of rabbits. But both strains caused problems. While the therapeutic treatment and control of cornea spirilloses were difficult to handle in the eye, scrotum syphilis was easy to handle, but the inoculation of scrotum tissue often resulted in cross-infections. After attempting several series, Hata tried to grow corneal syphilis in the scrotum and vice versa. Both tests showed the same clinical picture and henceforth Hata infected the scrotum of rabbit A with the eye-water of a syphilitic rabbit B to reproduce a more regular infection with easier aseptic technique and fewer cross-infections.66 clinical trials and large-scale production After promising therapeutic results in animals, the experiments were extended to humans. Based on the established dosis tolerata in animals, Ehrlich cooperated closely with Konrad Alt, the director of the mental asylum in Uchtspringe, in experiments designed to establish estimates of tolerable doses for humans. Since 1908 Alt had cooperated with Ehrlich on therapeutic experiments with 418 and had earlier worked with August Wassermann on a diagnostic test for syphilis.67 In September 1909 Ehrlich informed Alt about the effectiveness of the new compound 606 against spirilloses and asked whether he could test the dosage,68 investigate physiological processes, and find an ideal method of application. Alt conducted initial therapeutic tests on patients with tertiary syphilis involving tabes dorsalis and general paralysis of the insane. In March 1910, the results were presented to the scientific community.69 Alt stated that the patients treated with 606 showed no severe side effects and that the compound had a positive effect: ulcers regressed and the so-called Wassermann 448 · AXEL C. HÜNTELMANN

reaction became negative. He defined 0.3 g as the initial therapeutic dosis tolerata efficiens.70 At the same time, Julius Iversen at St Petersburg carried out clinical trials on recurrent fever and concluded that the new compound was also effective against the pathogenic germs.71 In early December 1909 Ehrlich drew Bertheim’s attention to future tasks. He wrote: “I knit the strings for the testing of 606 as tightly as possible.” Clinical trials required large quantities of material and he instructed Bertheim to prepare sufficient material to ensure uninterrupted work. “Demand will become hyperbolic”, he pre- dicted.72 The experience acquired in the production of 418 proved extremely helpful,73 because 606 was similarly difficult to make. The compound had to be synthesized, dried and divided in a vacuum. When arsphenamine interacted with oxygen it was transformed into an arsenic-oxide combination that caused local corrosion and had noxious effects. As with 418, Robert Kahn re-arranged the technical devices to produce large quantities of 606 in the laboratory. For the production process eleven assistants worked under Bertheim’s supervision to maintain the devices and weigh the portions, before sealing and shipping up to 700 ampoules per day.74 Every batch was assigned a unique operation number and information about the production process was collected in a separate book (Figure 6). If complaints about the toxicity, weight, or colour arose, rechecking the series using the production notebooks made it possible to track back, detect the mistake, and optimize the process.75 The Biological Department tested batches produced in the Chemical Department for toxicity and effectiveness. Testing for toxicity functioned like state-run quality control of diphtheria serum at the IET. For one, it was designed to ensure that

Fig. 6. Production of 606, Batch 37. Paul Ehrlich Institute. SERIALITY AND STANDARDIZATION · 449 a compound was harmless and effective when administered to patients, and more generally to safeguard the whole therapeutic approach insofar as side-effects risked discrediting it. The local tissue damage that was reported from treatment with 606 could, in principle, arise from two sources: an error in treatment or an error in the production process. Testing for toxicity was designed to ensure that no phial would be filled with defective material. In response to complaints, Ehrlich could cite test results that confirmed the quality and harmlessness of the preparation so that only an error in treatment or an abnormal response of the patient, such as hypersensitivity, remained as a plausible explanation. As with serum, testing for toxicity made the compound a valid remedy, regardless of its therapeutic efficacy.76 During 1910, members of the GSH continued their work on 606 to make the production process more reliable and to improve solubility and hence therapeutic effectiveness.77 The search for an ideal cure against spirilloses or trypanosome diseases continued into 1910,78 but by April all of the resources of the GSH were focused on the production, organization and testing of 606.79 To improve production, Ehrlich corresponded with Benda and Arthur Weinberg at Cassella and engineers at Hoechst. Ehrlich frequently read and was inspired by the patent literature.80 The experience gained from 418 and 606 contributed to improvements and greater standardization of production. In July Hoechst constructed a large-scale production line for 606. The longer distances that chemical substances had to travel through the conduit pipes caused problems and compromised the quality of the end product. Hence, in the following months, the production procedure had to be optimized in cooperation with Bertheim, Benda and Kahn. By November 1910 Hoechst was able to produce 606 — marketed under the brand Salvarsan — reliably and in large quantities.81 On the basis of claims by Alt, E. Schreiber, J. Hoppe and Iversen82 that 606 had a positive effect on syphilis, other dermatologists started to test it. Because, unlike the Institute for Infectious Diseases in Berlin or the Pasteur Institute in Paris, the GSH had no hospital wing, Ehrlich created a network of clinicians to test the therapeutic effect of various compounds. First he asked clinical colleagues such as his old friend Albert Neisser in Breslau or Wilhelm Wechselmann in Berlin to test the compound.83 His experience with 418 taught him that the shift from animal to human experimentation was difficult and that side-effects or relapses might occur in only one patient in a thousand or only after a long period of time. So Ehrlich planned to test the serum on thousands of patients in the hope of acquiring additional information and assessing the side-effects, relapses, indications and the best form of application.84 One of these clinicians was Heinrich Loeb, a dermatologist at the Mannheim Hospital. In April 1910, Loeb received his first phials of 606 with the proviso that he submit regular reports on his experiences. In their correspondence, Ehrlich discussed the dosage, the application method, possible side-effects and solubility. Ehrlich repeatedly encouraged Loeb to increase the dosage to 0.3 or 0.4 g because a high initial dose would totally eradicate the parasites and prevent relapses. He also pressured Loeb to administer 606 intravenously, which was new to most physicians at the time.85 In June, Loeb gave a public lecture on his experiences and most of the 450 · AXEL C. HÜNTELMANN

Fig. 7(a). The first columns of a table showing the effect of arsphenamine on rats that previously had been infected with recurrent fever. From Sahachiro Hata, “Experimentelle Grundlage der Chemotherapie der Spirillosen”, in Die experimentelle Chemotherapie der Spirillosen (Syphilis, Rückfallfieber, Hühnerspirillose, Frambösie), ed. by Paul Ehrlich and Sahachiro Hata (Berlin, 1910), 1–85, table XVII. SERIALITY AND STANDARDIZATION · 451

Fig. 7(b). The concluding columns of the same table. From these columns a series of 45 rats was included in this experimental setting. 452 · AXEL C. HÜNTELMANN collaborators published their results in medical journals.86 Between September 1909, when the first trials by Alt and Iversen began, and September 1910, when Ehrlich presented his results at the annual meeting of the German Natural Scientists and Physicians in Königsberg, he had already collected over 10,000 case studies for the Ehrlich-Hata Preparation 606.87 Ehrlich also discussed some deaths following injections with 606 and, as a consequence, defined severe affliction of the nervous system and diseases of the heart and blood vessels as counter-indications.88 In a circular to dermatologists and physicians in October 1910, he declared that the experimental phase was complete.89

information and standardization Ehrlich’s cooperation with the clinicians was part of the organizational framework of the GSH. He instructed his staff to send out the phials and upon return the clinical reports were evaluated and translated into tables, and the address lists compiled by his assistants. The information was mainly coordinated by Ehrlich and disseminated in numerous letters to other clinicians, discussing the pros and cons of different applications and indications. Finally, it was inscribed into instruction sheets. Eventually the procedures of knowledge production, the organizational structure, the workflow in the GSH, and the framework of relationships that standardized 606 and hundreds of other compounds themselves became standardized. This reciprocal standardization was not simply a product of the “development” of 606, which had been influenced by the experience acquired in producing earlier compounds. Certain repetitive procedures were standardized, simply to improve production efficiency. For example, instead of labelling the pads with the word “copied”, they were stamped.90 The transmission of information about every single experiment was noted in a standardized way and dissociated from the individual worker, thereby ensuring that every trained staff member could understand the notebooks. But once a system of notifica- tion was established, only very specific information was documented and archived. New staff members were schooled in the documentation system, thus standardizing their own knowledge, observations, and working habits as well.91 The notebooks on production protocol illustrate this standardization of notebook- entries. One notebook (IV) records general data about 418 and its main characteristics, with Benda’s reduction documented in six pages of detailed notes.92 Another notebook (IX) from 1908 describes the production of 418 in combination with quinine in far less detail with reference to a former protocol. Ultimately however, notes and measure- ments were recorded on the consistency of the mash, the dissolution, the filtration, and the end product.93 The notebook for the production of 606 gives no details on quality and little information on quantity (Figure 6).94 The entries are ordered by date from approximately 1908 to 1910 or by a sequence of serial numbers. Routine work and writing duties were also standardized in the letters Ehrlich sent his clinical collaborators. In his first letters to Heinrich Loeb in April 1910, he discussed in detail the application, indications and side-effects. In case of problems, such as side-effects and later relapses, Ehrlich asked for the medical record. In June, SERIALITY AND STANDARDIZATION · 453

Ehrlich sent Loeb and later collaborators offprints of a short article by E. Schreiber with detailed information about the methodology, and in October he sent a general circular to all clinicians who wanted to test 606.95 In his regular correspondence on relapses, Ehrlich developed a standardized form of documentation.96 On the organizational learning curve, information and modes of documentation were also standardized and the presentation of the success of 606 changed: while the results of the experiments on recurrent fever were summarized and presented in tables (Figure 7), the experiments on syphilis were presented as single case histories.97 Without the previous large-scale results from the successful experimental therapy on recurrent fever, the results of the syphilis experiments would have become less valid. Later articles — and Ehrlich’s own — summarized the experiences with 606 that were presented in tables. conclusion This essay has explored the working methods pursued within the GSH and the development of 606. These were industrial-scale experiments, and my analysis has studied their numerical organization. These forms of organization can well be characterized as serial, and the seriality of the production regime was intimately connected with issues of standardization, reliability and control. Decisively, the structure of the seriality developed at the GSH in this case both enabled and was also transformed by the enterprise that generated 606. The transformation of 606 was a process influenced by the structures, frameworks and work-flow organization of the GSH, just as the development of 606 changed and standardized work-flow organization there. As I have mentioned, the work in the IET/GSH involved an elaborate division of labour. The more complex the work became, the more structures were needed that would organize the complexity and coordinate the different tasks. This was a dynamic project of serialization in which techniques of recording, inscription, accountability and comparability all played a role, notably through the material traces of the pads and copy-books produced and exchanged inside the GSH. The GSH clearly illustrates the close links between the written forms of serial data and the serialization of experimental science. The co-operation between different departments, between GSH and IET, between GSH and the pharmaceutical and chemical companies, and the overall coordina- tion that Ehrlich attempted to impose, all made it necessary that notebook entries be comprehensible and unambiguous. The creation of different strains of parasites, numerous compounds, and the use of hundreds or indeed thousands of test animals demanded a system of clear and distinct numerical identification. But more was at stake in these processes of scale and series: large-scale serial techniques of inscription and record-taking had marked effects on the character of animals, chemicals and subjects. In relation to a number, a simple mouse became an information carrier. In combination with a strain-number, the mouse was no longer a mouse, but instead a hybrid form, injected with serum of previously immunized rats or rabbits or dogs that had become immune to a certain disease or resistant to a certain chemical compound. 454 · AXEL C. HÜNTELMANN

A mouse, involved in an experiment, infected with parasites, or injected with a chemical compound, could provide information about the experiment. One, two or even ten mice required no identification number, but long series of mice or rabbits did. The information became valid when numerous mice could be judged to have produced the same information. The more experiments were performed, the more valid they became, because coincidences and individual influences could, at least in principle and often in fact, be resolved, averaged, and managed. When the experiments were expanded into passages, the mouse was identified using the passage number (not the mouse as such, but as part of a group of mice with special characteristics). Seriality was required as a management regime for such large-scale experimental programmes. The scale of these programmes was taken to be indispensable to produce credible and robust commodities and data. In turn, this process of labour organization and management aided the effective serialization of the pharmaceutical industry. Rather than understanding the celebrated 606 as the automatic outcome of a serial process already planned well in advance, we should rather see this enterprise as a means through which, at a critical conjuncture of industrial modernity, seriality also gained much of its authority as a programme of planning, management and experimentation.

acknowledgements The article results from a biography project on Paul Ehrlich that is linked to the Institute for the History of Medicine at Frankfurt University (Head: Udo Benzen- höfer) and funded by the Paul Ehrlich Foundation. For archive research, a travel grant and helpful discussions I express my thanks to the staff of the Rockefeller Archive Center, especially Lee Hiltzik and Darwin Stapelton, and the Paul Ehrlich Institute in Langen, especially Christine Pauli-Klöppinger and Susanne Stöcker, and for helpful suggestions and advice I want to thank Simon Schaffer, Jim Secord and especially Eric J. Engstrom and Nick Hopwood.

REFERENCES

1. Biographies of Ehrlich: Adolf Lazarus, Paul Ehrlich (Vienna, 1922); Martha Marquardt, Paul Ehrlich als Mensch und Arbeiter: Erinnerungen aus dreizehn Jahren seines Lebens (1902–1915) (Stuttgart, 1924); idem, Paul Ehrlich (Berlin, 1951); Gerhard Venzmer, Paul Ehrlich: Leben und Wirken (Stuttgart, 1948); Hans Loewe, Paul Ehrlich: Schöpfer der Chemotherapie (Stuttgart, 1950); Walter Greiling, Im Banne der Medizin: Paul Ehrlich – Leben und Werk (Düsseldorf, 1954); Heinrich Satter, Paul Ehrlich – Begründer der Chemotherapie: Leben, Werk, Vermächtnis (Munich, 1963); and Ernst Bäumler, Paul Ehrlich: Forscher für das Leben (Frankfurt/Main, 1979). Ehrlich was characterized as benefactor of mankind by Albert Neisser at the 82nd Congress of German Scientists and Physicians in Köngisberg in 1910: Albert Neisser, “Moderne Syphilistherapie”, Verhandlungen der Gesellschaft Deutscher Naturforscher und Ärzte, lxxxii (1910), Part 1, 172–82, p. 182. 2. For a chemist’s perspective: Steven Riethmiller, “From atoxyl to Salvarsan: Searching for the magic bullet”, Chemotherapy, li (2005), 234–42. 3. Bruno Latour, Science in action: How to follow scientists and engineers through society (Cambridge, SERIALITY AND STANDARDIZATION · 455

1987); idem, We have never been modern (Cambridge, 1993); idem and Steve Woolgar, Laboratory life: The construction of scientific facts, 2nd edn (Princeton, 1986). See also Gustav Rossler, “Kleine Galerie neuer Dingbegriffe: Hybriden, Quasi-Objekte, Grenzobjekte, epistemische Dinge”, Bruno Latours Kollektive: Kontroversen zur Entgrenzung des Sozialen, ed. by Georg Kneer et al. (Frankfurt/Main, 2009), 76–107, pp. 99–100. 4. Anthony S. Travis, “Science as a receptor of technology: Paul Ehrlich and the synthetic dystuff industry”, Science in context, iii (1989), 383–408; Jonathan Liebenau, “Paul Ehrlich as a commercial scientist and research administrator”, Medical history, xxxiv (1990), 65–78; Timothy Lenoir, Instituting science: The cultural production of scientific disciplines (Stanford, 1997); Anne I. Hardy, “Paul Ehrlich und die Serumproduzenten: Zur Kontrolle des Diphtherieserums in Labor und Fabrik”, Medizinhistorisches Journal, xli (2006), 51–84. 5. John Parascandola, “The theoretical basis of Paul Ehrlich’s chemotherapy”, Journal of the history of medicine, xxxvi (1981), 19–43; Pauline M. H. Mazumdar, Species and specificity: An interpretation of the history of immunology (Cambridge, 1995); Arthur M. Silverstein, Paul Ehrlich’s receptor immunology: The magnificent obsession (San Diego, 2002); Cay-Rüdiger Prüll, “Part of a scientific master plan? Paul Ehrlich and the origins of his receptor concept”, Medical history, xlvii (2003), 332–56; idem et al., A short history of the drug receptor concept (New York, 2008). 6. Daniel P. Todes, Pavlov’s physiology factory: Experiment, interpretation, laboratory enterprise (Baltimore, 2001). 7. Andrew Cunningham and Perry Williams (eds), The laboratory revolution in medicine (Cambridge, 1992); Jean Paul Gaudillière and Ilana Löwy (eds), The invisible industrialist: Manufactures and the production of scientific knowledge (Houndsmills, 1998); Todes, Pavlov’s factory (ref. 6); Bernward Joerges and Terry Shinn (eds), Instrumentation between science, state and industry (Dordrecht, 2001); Sven Dierig, Wissenschaft in der Maschinenstadt: Emil Du Bois-Reymond und seine Laboratorien in Berlin (Göttingen, 2002). 8. Peter L. Galison and Bruce Hevly, Big science: The growth of large-scale research (Palo Alto, 1992). 9. Arnold Eiermann, “Die Einrichtung zur Darstellung des Diphtherie-Heilserums in den Höchster Farbwerken”, Münchener medicinische Wochenschrift, xli (1894), 1038–40. 10. Axel C. Hüntelmann, “The dynamics of Wertbestimmung”, Science in context, xxi (2008), 229–52; idem, “Evaluation and standardisation as a practical technique of administration: The example diptheria-serum”, Christoph Gradmann and Jonathan Simon (eds), Evaluating and standardizing therapeutic agents, 1890–1960 (Basingstoke, 2010), 31–51. 11. Wilhelm Kolle (ed.), “Das Staatsinstitut für experimentelle Therapie und das Chemo-therapeutische Forschungsinstitut ‘Georg Speyer-Haus’ in Frankfurt a. M.: Ihre Geschichte, Organisation und ihre Arbeitsgebiete”, Arbeiten aus dem Staats Institut für Experimentelle Therapie und dem Georg Speyer-Hause zu Frankfurt a. M., xvi (1926), 1–67; idem and Erwin Stilling, “Das Staatliche Institut für Experimentelle Therapie und das Chemotherapeutische Forschungsinstitut‚ ‘Georg Speyer-Haus’ in Frankfurt a.M.”, Forschungsinstitute: Ihre Geschichte, Organisation und Ziele, ii, ed. by Ludolph Brauer et al. (Hamburg, 1930), 57–73; Axel C. Hüntelmann, “Einzigartige Sonderstellung: Das Institut für Experimentelle Therapie und das Georg Speyer-Haus im Deutschen Kaiserreich”, Jenseits von Humboldt: Wissenschaft im Staat 1850–1990, ed. by Axel C. Hüntelmann and Michael C. Schneider (Frankfurt/Main, 2010), 189–215. For the side-chain theory and receptor immunology: Silverstein, Receptor immunology (ref. 5); Prüll, “Part” (ref. 5); idem et al., Short history (ref. 5). 12. Kolle, Staatsinstitut (ref. 11); Kolle and Stilling, Institut (ref. 11); Hüntelmann, Sonderstellung (ref. 11). 13. As a general overview Eric J. Hobsbawm, The Age of Empire: 1875–1914 (London, 1987); Christopher A. Bayly, The birth of the modern world, 1780–1914: Global connections and comparisons (Oxford, 2004); Alison Bashford, Imperial hygiene: A critical history of colonialism, nationalism 456 · AXEL C. HÜNTELMANN

and public health (Basingstoke, 2004); Jürgen Osterhammel, Die Verwandlung der Welt: Eine Geschichte des 19. Jahrhunderts (Munich, 2009). 14. Axel C. Hüntelmann, Hygiene im Namen des Staates: Das Reichsgesundheitsamt 1876–1933 (Göttingen, 2008); idem, Sonderstellung (ref. 11); Annette Hinz-Wessels, Das Robert Koch-Institut im Nationalsozialismus (Berlin, 2008); Marion Hulverscheidt and Anja Laukötter (eds), Infektion und Institution: Zur Wissenschaftsgeschichte des Robert Koch-Instituts im Nationalsozialismus (Göttingen, 2009). 15. David Cahan, An institute for an empire: The Physikalisch-Technische Reichsanstalt 1871–1918 (Cambridge, 1989). 16. On the wider anthropological understanding of economy as a give and take and social exchange see Marcel Mauss, Gift: The form and reason for exchange in archaic societies (London, 1990); Frank Adloff and Steffen Mau (eds), Vom Geben und Nehmen: Zur Soziologie der Reziprozität (Frankfurt/Main, 2005); Stephan Moebius and Christian Papilloud (eds), Gift: Marcel Mauss’ Kulturtheorie der Gabe (Wiesbaden, 2006); Allain Cailleé, Anthropologie der Gabe (Frankfurt/ Main, 2008). 17. As in his thesis: Paul Ehrlich, Gesammelte Werke (henceforth GW), i, ed. by Fred Himmelweit (London, 1956), 65–98. 18. Paul Ehrlich, “Studien in der Cocainreihe”, GW, i (ref. 17), 559–66. 19. See several laboratory notebooks in the Rockefeller Archive Center, Paul Ehrlich Collection 650 Eh 89 (henceforth cited as RAC); a list of dogs in the Prussian Secret State Archive, Berlin (henceforth GStAPK), HA 1, rep. 76 Vc, sekt. 1, tit. 1, no. 18, vol. 2; the tale about the cat siblings “Max and Moritz” in a press-clipping in RAC box 51, folder 8. 20. Theodore Porter, Trust in numbers: The pursuit of objectivity in science and public life (Princeton, 1995). 21. In detail, Hüntelmann, “Dynamics” (ref. 10). 22. The form sheets, tables and data bases in GStAPK, HA I, rep. 76 VIII C, no. 3747; Federal Archive (Bundesarchiv) Berlin, R 86/1646; Paul Ehrlich Institute, Langen (henceforth PEI), Abt. V. 23. Hüntelmann, “Evaluation” (ref. 10). 24. Marquardt, Paul Ehrlich (ref. 1, 1924), 23. 25. See the various series of the “Kopier-Bücher” in RAC. 26. One of many contradictions enshrined in the myth of Paul Ehrlich as “laboratory scientist”. 27. Personal file Benda in Stadtarchiv Frankfurt/Main, V 39, XIIId/4 (48). 28. Ehrlich to Bertheim, Note 11 February 1910, RAC box 33, p. 278. 29. See the different work orders in the Kopierbücher series II (“Blöcke”, work orders) and VI (“Blöcke”, notes GSH) in RAC boxes 7–15, 19, 27–35. 30. Marquardt, Paul Ehrlich (ref. 1, 1924), 57–9, describes his daily circuit through the institutes. 31. Pavlov’s Physiological Institute was similarly organized: Todes, Pavlov’s factory (ref. 6). 32. Preparations book (Präparate-Buch) in PEI. 33. Several reminders to make sure there was enough stock of compound 418 in July 1908 (RAC box 31) and in December 1909 and January 1910 concerning the laboratory production of 606 (RAC box 33). 34. Axel C. Hüntelmann, “1910: Transformationen eines Arzneistoffes – vom 606 zum Salvarsan”, Arzneimittel des 20. Jahrhunderts: 13 historische Skizzen von Lebertran bis Contergan, ed. by Nicholas Eschenbruch et al. (Bielefeld, 2009), 17–51. 35. Preparations book (Präparate-Buch) in PEI. 36. Ibid. The idea of combining tartar emetic with other compounds occurred in December 1907 with a view to substituting ammonia or sodium against lysidine or ethylenediamine piperazine: SERIALITY AND STANDARDIZATION · 457

Kopierbuch GSH Dec. 1907, series VI, no. 3, RAC box 29. 37. 1. Dichloroatoxyl and diverse compounds — such as glyoxalin/imidazole and “Iodol”, 2. Dichloroatoxylic acids, 3. Diazoatoxyl and “Iodol” beside the former work instruction to modify amidophenol and to continue the work on glycine: pad from 21 May 1909, Kopierbuch GSH series VI, no. 5, RAC box 32, p. 296. 38. 452 (boiled with formaldehyde and HCl), 458 (combination of 418 and 446), 459 (reaction of sodium hydrosulphite on 446), 461 (418 and 446 in weak alkaline solution and NaCl): Preparations book (Präparate-Buch) in PEI. 39. Preparations book (Präparate-Buch) in PEI. Derived from earlier experiments and experience, not all combinations had to be carried out. 40. For a complete and detailed ‘reconstruction’ one has to combine the different laboratory books at the Chemical Department and the private work notebooks of the scientists, Ehrlich’s “Blöcke” and work instructions and his personal notes. Finally the working steps, tacit and personal knowledge influenced the experiments, as I note elsewhere. 41. Instructions to Benda, 14 March 1909; notes to Röhl, 2 April 1909, 18 May 1909, Kopierbuch GSH series VI, no. 5, RAC box 32. 42. Alfred Bertheim, “Chemie der Arsenverbindung”, Paul Ehrlich: Eine Darstellung seines wissenschaftlichen Wirkens. Festschrift zum 60. Geburtstage des Forschers, ed. by Hugo Apolant et al. (Jena, 1914), 447–76, pp. 466–8; Paul Ehrlich and Alfred Bertheim, “Über das Salzsaure 3.3’-Diamino-4.4’-dioxy-arsenobenzol und seine nächsten Verwandten”, GW, iii, ed. by Fred Himmelweit (London, 1960), 405–11; idem, Aus Theorie und Praxis der Chemotherapie (Leipzig, 1911); idem, “Schlußbemerkungen”, in: idem and Sahachiro Hata, Die experimentelle Chemotherapie der Spirillosen (Syphilis, Rückfallfieber, Hühnerspirillose, Frambösie) (Berlin, 1910), 114–64, pp. 115–25. 43. Paul Ehrlich’s secretary and biographer, Martha Marquardt, described how new interns or assistants were confused by the information on the “Blöcke” and asked for advice: Marquardt, Paul Ehrlich (ref. 1, 1951), 89–91. 44. Ehrlich and Bertheim, “3.3’-Diamino-4.4’-dioxy-arsenobenzol” (ref. 42); Riethmiller, “Atoxyl” (ref. 2). 45. Memo Ehrlich to Röhl, 25 February 1908, RAC box 30, pag. 199. “Es wäre vielleicht praktisch, wenn wir die diversen häufiger dargestellten präparate wie 418, methylharnstoff laufend numerirt und in das lieferbuch die provenienz respective gewisse biologische eigenschaften separat eintragen wollten.” 46. Sahachiro Hata, “Experimentelle Grundlage der Chemotherapie der Spirillosen”, Chemotherapie, ed. by Ehrlich and Hata (ref. 42), 1–85. 47. Paul Ehrlich, “Über die Schlafkrankheit”, GW, iii (ref. 42), 310–17. On Ehrlich’s work on sleeping sickness: Deborah Neill, “Paul Ehrlich’s colonial connections: Scientific networks and sleeping sickness drug therapy research, 1900–1914”, Social history of medicine, xxii (2009), 61–77; Michael Worboys, “Comparative history of sleeping sickness in east and central Africa, 1900– 1914”, History of science, xxxii (1994), 89–102. 48. On the similarities with passive immunization see Ehrlich’s note to Röhl, 17 May 1908, RAC box 30, p. 443. Ehrlich suggested bleeding the animals that were cured. The serum was stocked, the phial numbered and used for immunization. 49. Ehrlich for instance instructed Röhl (15 January 1908) to start a new notebook on the relapsing strains R, R I, R II. “Weiterführung der Rezidivstämme in der Weise, dass man sie erst 2-3mal durch entsprechend geheilte Tiere passiert und nachher normale Passagen 2–3 zwischenlegt.… Bitte auch ein extra buch für Recidivstämme anlegen.” RAC box 30, p. 51. 50. Note Ehrlich to Hata, 27 March 1909, Kopierbuch GSH series VI, no. 5, RAC box 32. 51. Hata, “Grundlage” (ref. 46). 458 · AXEL C. HÜNTELMANN

52. Ibid., p. 4: – (no spirilloses), + sw (very few spirilloses), + w (few spirilloses: 1 in 10–50 visual fields), + (medium: between 1 spirillium in 10 visual fields up to 10 in one visual field), ++ (10–50 in one visual field), +++ (over 50 in one visual field), ++++ (countless, in masses). On microscopical techniques of observation: Jonathan Crary, Techniques of the observer. On vision and modernity in the 19th century (Cambridge, 1990). 53. Hata, “Grundlage” (ref. 46), 5–11. Hata reflected that the artificially generated disease — a laboratory infection — was different from a ‘natural’ or spontaneous disease and different from the course of the human disease, which was more irregular. The experimental setting was also transferred to rats as test animals for purposes of comparison. 54. Despite all efforts to standardize mice. For the standardization of test animals see Karen A. Rader, Making mice: Standardizing animals for American biomedical research, 1900–1955 (Princeton, 2004); Cheryl A. Logan, “Before there were standards: The role of test animals in the production of empirical generality in physiology”, Journal of the history of biology, xxxv (2002), 329–63. On a planned breeding farm for test animals at the IET in the 1920s: Alexander von Schwerin, Experimentalisierung des Menschen: Der Genetiker Hans Nachtsheim und die vergleichende Erbpathologie 1920–1945 (Göttingen, 2004). 55. The test animal of choice was the rabbit, in which two strains of parasites were bred: eye-syphilis and scrotal syphilis. 56. Hata, “Grundlage” (ref. 46), 68–81. 57. Dosis tolerata and dosis letalis were first introduced by Ehrlich in the context of the evaluation of sera to measure the quality of diphtheria or tetanus toxin: Richard Otto, “Die staatliche Prüfung der Heilsera”, Arbeiten aus dem Königlichen Institut für Experimentelle Therapie zu Frankfurt a. M., ii (1906), 1–86. 58. Carl Browning, for example, introduced his successor Wilhelm Röhl to the system of notebooks: file Röhl, request Ehrlich to Browning, RAC box 3, folder 19. 59. The dispute in RAC box 3, folder 19. A similar case in the laboratory of Richard Kuhn, head of the Kaiser Wilhelm Institute for Medical Resarch, is given in Florian Schmaltz, Kampfstoff-Forschung im Nationalsozialismus: Zur Kooperation von Kaiser-Wilhelm-Instituten, Militär und Industrie (Göttingen, 2005), 387–413. 60. Countless work instructions exist in the “Kopierbücher”, e.g., Ehrlich’s requests to show him this or that notebook or to confer about ongoing work, to dispose of laboratory animals, to request and schedule more chemical compounds: Serie VI of the “Kopierbücher” in the RAC. 61. Several examples such as the request to Morgenroth in June 1903 to return the “Blöcke” and pass over laboratory notebooks so that Ehrlich could sum up the results for an article, RAC box 11. The dispute with Röhl about the notebook was also caused by the fact that Ehrlich actually wanted to write an article (orginally planned with Röhl as a co-author) on chemotherapeutic research that he could not finish without the missing information: RAC box 3, folder 19. 62. Ehrlich to Hata, 27 March 1909, Kopierbuch GSH series VI, no. 5, RAC box 32. 63. Ehrlich to Hata, 1 May 1909, proposition to try the spirilla in vitro with dye stuffs like dimethyl amidomethylene blue or methylene green, Kopierbuch GSH series VI, no. 5, RAC box 32. 64. Ehrlich to Röhl/Gulbranson and Bertheim, 26 and 27 March 1909, Kopierbuch GSH series VI, no. 5, RAC box 32. Another example to Röhl/Gulbranson (on research about 418), 14 March 1909, concerning the increase of resistance against antimony, ibid. Later Röhl was asked to check in old notebooks the protocols about hypersensibility of the atoxyl-strain against 379 and a few days later (24 March 1909) to infect a new series of rabbits with trypanosomes to test the acridinium-combination, ibid. 65. Ehrlich to Röhl, 30 March 1909, ibid. 66. Hata, “Grundlage” (ref. 46), 60–3. SERIALITY AND STANDARDIZATION · 459

67. Konrad Alt, “Das neueste Ehrlich-Hata-präparat gegen Syphilis”, Abhandlungen über Salvarsan (Ehrlich-Hata-Präparat gegen Syphilis), ed. by Paul Ehrlich (4 vols, Munich, 1911–14), i, 67–76, p. 67. On the Wassermann test see Ernst Bäumler, Amors vergifteter Pfeil: Kulturgeschichte einer verschwiegenen Krankheit, 2nd edn (Munich, 1989), 156–67; August von Wassermann, Albert Neisser and Carl Bruck, “Eine serodiagnostische Reaktion bei Syphilis”, Deutsche medizinische Wochenschrift, xlviii (1906), 745–6. 68. The start of the experiments in September 1909 was mentioned in Alt, “Ehrlich-Hata-präparat” (ref. 67), 67. 69. Alt’s speech was given on 3 March 1910: Konrad Alt, “Zur Technik der Behandlung mit dem Ehrlich-Hataschen Syphilismittel”, Abhandlungen, ed. by Ehrlich (ref. 67), i, 17–20, p. 17. As an overview Paul Ehrlich, “Chemotherapie von Infektionskrankheiten”, GW, iii (ref. 42), 213–27, pp. 220–2; Ehrlich, “Schlußbemerkungen” (ref. 42); idem, Theorie und Praxis (ref. 42); idem, “Die Salvarsantherapie: Rückblicke und Ausblicke”, GW, iii (ref. 42), 318–36. 70. Alt, “Ehrlich-Hata-präparat” (ref. 67), 74. 71. Julius Iversen, “Chemotherapie des Recurrens”, Chemotherapie, ed. by Ehrlich and Hata (ref. 42), 90–108; idem, “Ueber die Wirkung des neuen Arsenpräparates (606) Ehrlichs bei Rekurrens”, Abhandlungen, ed. by Ehrlich (ref. 67), i, 343–51. 72. Note Ehrlich to Bertheim, 1 December 1909, Kopierbuch GSH, RAC box 33, p. 34. 73. Bertheim, “Chemie” (ref. 42), 460. 74. Ibid., 468–9. 75. On 8 December 1909 Ehrlich informed Kahn and Bertheim about a complaint concerning a difference in weight. He insisted on ideal quality for human experiments: Kopierbuch GSH, RAC box 33, p. 86. 76. Hüntelmann, “1910” (ref. 34). 77. Alfred Bertheim received, e.g., the instruction to improve the solubility: Ehrlich to Bertheim, 18 January 1910, RAC box 33, p. 207. At the Biological Department, research was forced to deal with the problems of hypersensibility and relapses. 78. Several other compounds were developed after 606, between September 1909 and May 1910 compounds 607–631: Preparations book (Präparate-Buch) in PEI. 79. The experimental work diminished up to spring 1910 in proportion as the production and distribution of arsphenamine increased; after April 1910 mainly arsphenamine was produced: “Kopierbücher” of the GSH, RAC boxes 33f. 80. Numerous examples of “Blöcke” to his assistants: “please read and reproduce this and that patent”; or during an experiment Ehrlich referred to patent literature to motivate his staff, e.g. his note to Robert Kahn, 21 January 1910: “I wish merely to direct your attention to the latest issue of the ‘Chemischen Neuesten Nachrichten’, the Bych Patent, the reduction from acid to aldehyde! Might this also be possible for the anthranil acid?”, RAC box 33. Occasionally Ehrlich corresponded with the Lautenschläger company, a manufacturer of laboratory devices, discussing patents and technical improvements. Likewise he was in touch with Arnold Berliner, former director of the “Allgemeine Electrizitäts-Gesellschaft” in Berlin, a producer of electrical equipment and of light bulbs, who was frequently asked for technical advice, e.g., a request by Ehrlich concerning ice acid solution, 20 April 1905: RAC box 24; or several requests concerning a collodium solution in 1908: RAC box 25. With Berliner, Ehrlich had already cooperated in the context of serum control. For standardization, quality standards and mass production: Günther Luxbacher, Massenproduktion im globalen Kartell: Glühlampen, Radioröhren und die Industrialisierung der Elektroindustrie (Berlin, 2003). 81. Report about the introduction of Salvarsan at the Dye Stuff Industries Hoechst by B. Reuter, Histocom Archive (Hoechst Archive); Bäumler, Paul Ehrlich (ref. 1), 237–8, 241. 460 · AXEL C. HÜNTELMANN

82. Alt, “Ehrlich-Hata-präparat“ (ref. 67); E. Schreiber and J. Hoppe, “Ueber die Behandlung der Syphilis mit dem neuen Ehrlich-Hataschen Arsenpräparat (No. 606)”, Abhandlungen, ed. by Ehrlich (ref. 67), i, 77–83; Iversen, “Wirkung” (ref. 71); idem, “Chemotherapie” (ref. 71). 83. Wilhelm Wechselmann, Die Behandlung der Syphilis mit Dioxydiamidoarsenobenzol (“Ehrlich-Hata 606”) (2 vols, Berlin, 1911–12); an overview given in Albert Neisser, “Einleitender Überblick: Salvarsan und Syphilis”, Paul Ehrlich, ed. by Apolant et al. (ref. 42), 515–40. 84. Ehrlich, “Salvarsantherapie” (ref. 69), 318. 85. Correspondence between Ehrlich and Heinrich Loeb, RAC box 57, folder 6. 86. Heinrich Loeb, “Erfahrungen mit Ehrlichs Dioxy-diamido-arsenobenzol (606)”, Abhandlungen, ed. by Ehrlich (ref. 67), i, 101–5; idem, “Weitere Erfahrungen über ‚606’”, ibid., 106–12. Ehrlich supported his collaborators’ publication of their results to generate a public debate on his compound, cf. Paul Ehrlich, “Die Behandlung des Syphilis mit dem Ehrlichschen Präparat 606”, GW, iii (ref. 42), 240–6, p. 242. Ehrlich edited most of the publications: Abhandlungen (ref. 67); already the bibliography of the 606-literature published by Kurt von Stokar, Die Syphilis- Behandlung mit Salvarsan (Ehrlich Hata 606) nebst einer systematischen Zusammenfassung der bisher veröffentlichten Literatur (Munich, 1911) counted up to the end of 1910 over 260 publications. 87. Ehrlich, “Behandlung” (ref. 86); idem, “Schlußbemerkungen” (ref. 42), chapter C; idem, “Salvarsantherapie” (ref. 69). 88. Ehrlich, “Schlußbemerkungen” (ref. 42), 140–4; idem, “Salvarsantherapie” (ref. 69), 325, 328–9; idem, “Behandlung” (ref. 86), 243; in summary, Wilhelm Wechselmann, Zur Pathogenese der Salvarsantodesfälle (Berlin, 1913). 89. Paul Ehrlich, “Permanent action on Ehrlich’s New Remedy 606”, GW, iii (ref. 42), 342–3; Circular, 25 October 1910 in the correspondence to Heinrich Loeb, RAC box 57, folder 6. On the clinical tests in detail: Hüntelmann, “1910” (ref. 34). 90. Fig. 1; and the stamps in Fig. 4: Dos. Tolerat. 91. John V. Pickstone, Ways of knowing: A new history of science, techology and medicine (Chicago, 2000); the inscription and compilation of information in Friedrich A. Kittler, Aufschreibesysteme 1800, 1900, 3rd edn (Munich, 1995); Marilyn Strathern (ed.), Audit cultures: Anthropological studies in accountability, ethics and the academy (London, 2002). 92. Notebook IV, PEI. 93. Notebook IX (1908), PEI. 94. Notebook 606 T, PEI. 95. Obviously it circulated together with the phials: the circular in RAC box 57, folder 6. 96. The form sheet request on relapses: ibid. 97. The results of the successful treatment of syphilis were presented as medical records, while the results of the series of experiments concerning the recurrent fever were presented in a table: Hata, “Grundlage” (ref. 46). Copyright of History of Science is the property of Science History Publications Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.