Medical History, 2003, 47: 332-356

Part of a Scientific Master Plan?

Paul Ehrlich and the Origins of his
Receptor Concept
CAY-RUDIGER PRULL*

One of the basic theories of twentieth-century scientific medicine is the receptor concept.
It deals with the question of how information can be submitted to the cell. Receptors can be
described as "small, discrete area(s) on the cell membrane or within the cell with which
molecules or molecular complexes (for example, hormones, drugs, and other chemical
messengers) interact" .1 The receptor concept became increasingly important, especially for
pharmacology, as it explained the binding of drugs to cells and drug-effects on specific
tissues and organs.
The origins of the receptor concept stem from the last third of the nineteenth century
and are chiefly connected with two names: Paul Ehrlich (1854-1915) and John Newport
Langley (1852-1925). Remarkably, these two scientists approached the receptor idea on
significantly different routes and from different backgrounds: John Newport Langley,
professor of physiology in Cambridge, was predominantly concerned with the investigation
of the functions of the autonomic nervous system, i.e. of those nerves which regulate, with-
out our conscious influence, the vegetative functions of the body, such as blood-pressure
and respiration. Paul Ehrlich, the Berlin bacteriologist and immunologist, was keen to
examine the relations between bacterial toxins and antitoxins and to support contemporary
efforts to combat infectious diseases. Both mentioned the idea first in 1878, and both
returned to their former approaches only several years later-at the turn of the nineteenth to
the twentieth century. According to our current knowledge about the history of the receptor
concept, the two scientists developed their initial ideas on receptors independently.2
* Cay-Rudiger Prull, PhD, Wolfson Research Institute, 2For current views on the history of the receptor
University of Durham, Queen's Campus, Stockton concept, see Arthur Silverstein, Paul Ehrlich's
University Boulevard, Thomaby, Stockton on receptor immunology: the magnificent obsession, Sdn
Tees TS17 6BH, UK. Diego and London, Academic Press, 2002; John
Parascandola and Ronald Jasensky, 'Origins of the
This paper is a first product of the Wellcome Trust receptor theory of drug action', Bull. Hist. Med., 1974,
funded research project, 'The impact of the receptor 48: 199-220; John Parascandola, 'The development of
concept on twentieth-century pharmacology', which is receptor theory', in M J Parnham and J Bruinvels
being undertaken by Professor Andreas-Holger (eds), Discoveries in pharmacology, vol. 3,
Maehle, Dr Robert Halliwell, and myself. It is my Pharmacological methods, receptors and chemo-
special concern to thank both my colleagues for their therapy, Amsterdam and New York, Elsevier Science
advice and suggestions, and the Wellcome Trust for its Publishers, 1986, pp. 129-56; Max R Bennett, 'The
support. I would also like to thank the Rockefeller concept of transmitter receptors: 100 years
Foundation for a grant to visit the Rockefeller Archive on', Neuropharmacology, 2000, 19: 523-46. On
Center in New York. Langley, see Gerald L Geison, 'Langley, John
Newport', in Dictionary of scientific biography,
' Black's medical dictionary, ed. Gordon New York, Charles Scribner's Sons, 1973, vol. 8,
MacPherson, 39th ed., London, A & C Black, 1999, pp. 14-19; Walter Morley Fletcher, 'John Newport
p. 463. Langley: in memoriam', J. Physiol., 1926,
61: 1-27.

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 Paul Ehrlich and his Receptor Concept
This paper focuses on Paul Ehrlich and the development of his receptor concept between
1878 and approximately 1905, when the concept was brought to a certain conclusion.
The purpose is to deal with a basic problem: as there are two independent approaches
to the subject, one could assume that receptors are "objective" facts of nature and that the
"discovery" of the receptors was somehow "inevitable". This impression contrasts with
the sociological constructivist interpretation of science: discoveries do not neatly corres-
pond to objective entities in nature. They are dependent on the cultural setting, for
example, the social position of the researcher and the local scientific system.3 This
paper will show that the constructivist view can be helpful in understanding Ehrlich's
"discovery" of the receptor concept as the latter emerged from the dual effect of social and
scientific aspects of his biography. This means that although the roots of Ehrlich's ideas can
be traced back to early stages of his career, although his ideas appeared in a logical order and
although he was driven by a leitmotifthroughout his academic life, it was far from clear why
and how he would develop the receptor concept. My analysis provides some insights into
the history of modem medical science and contributes to our understanding of the receptor
concept's position in early twentieth-century medicine. In this context it is not my purpose
to follow up the history of the usage of Ehrlich's concept in pharmacology. By contrast,
I envisage this paper as a contribution to the analysis of the difficult starting position of the
receptor idea. Its birth and its character contain the roots of problems, which caused many
difficulties in the successful introduction of the idea to pharmacology after 1945.
I will first discuss Ehrlich's basic scientific ideas and the traditional views on his aca-
demic life. Then I will go into more detail and take a close look at Ehrlich's career in relation
to his work on receptors. Finally, I will summarize and evaluate my findings.4

The Roots of Ehrlich's Research and the Inevitable Discovery of the Receptors
In any focused analysis of Ehrlich's ideas, the introduction of his receptor concept
appears to be consistently planned and realized. As a medical student at the universities
of Strasbourg and Breslau he concentrated on the staining of histological specimens.
Breslau became especially important: he was influenced above all by the pathologist Julius
Cohnheim (1839-1884), one of the few German pathologists to use animal experimentation
in addition to pathological anatomy.5 Cohnheim's research into pathological function, in
3 For the constructivist view of the history of estate, his laboratory books, his laboratory notes and his
science, see Jan Golinski, Making natural knowledge: correspondence in the Paul Ehrlich Collection,
constructivism and the history of science, Cambridge Rockefeller University Archives at the Rockefeller
University Press, 1998; Timothy Lenoir, Instituting Archive Center in New York (hereafter RUA, RAC).
science: the cultural production of scientific The paper also considers materials from the Archive of
disciplines, Stanford University Press, 1997. the Humboldt-University in Berlin and from the State
4This paper makes use of the printed works of Archive of Prussian Cultural Heritage (Geheimes
Ehrlich between 1878 and 1905, which can be found in Staatsarchiv PreuBischer Kulturbesitz, hereafter GStA
Fred Himmelweit (ed.), with the assistance of Martha PK), Berlin.
Marquardt, under the editorial direction of Sir Henry 5Ernst Baumler, Paul Ehrlich. Forscher fir das
Dale, The collected papers of Paul Ehrlich in four Leben, 3rd ed., Frankfurt am Main, Wotzel, 1997, pp.
volumes including a complete bibliography, vol. 1, 24-30, 31-6; Ernst Jokl, 'Paul Ehrlich: man and
Histology, biochemistry and pathology, vol. 2, scientist', Bull. N. Y. Acad. Med., 1954, 30: 968-75,
Immunology and cancer research; vol. 3, esp. p. 972; Margaret Goldsmith, 'Paul Ehrlich',
Chemotherapy, London and New York, Pergamon in Hector Bolitho (ed.), Twelve Jews, London, Rich &
Press, 1956-60; and of parts of Ehrlich's unpublished Cowan, 1934, pp. 65-81, esp. p. 69.

333
 Cay-Riidiger Priill
contrast to pathological morphology, was accompanied by close contacts with clinicians.
He also influenced many British medical students and contributed in this way to the
introduction of "clinical pathology" into Britain.6 Under his influence, Ehrlich followed
the path of applying laboratory findings to clinical practice and, in fact, became a pioneer of
clinical pathology in Germany.
Ehrlich's basic scientific ideas can be briefly summarized: first, he made a claim for the
routine application of the method of staining to medicine in general and to histology in
particular. Second, he supported the theory that the staining process relied on a chemical
reaction between dye-stuff and cell.7 These two ideas formed the basis or leitmotif of
Ehrlich's side-chain and then receptor theory. As early as 1878 Ehrlich had written in
his dissertation of "a definite chemical character of the cell"8 which was necessary for its
reaction with a dye. In 1897, almost nineteen years later, when he worked on immunological
problems, Ehrlich returned to this point and developed his chemical "side-chain theory".
Certain "side-chains" of the cell were able to bind certain toxins. Because these occupied
side-chains would then become unable to fulfil their physiological functions, the cell would
overcompensate by producing a lot of additional side-chains, which would be released into
the blood-stream, where they acted as antibodies or antitoxins.9 Against this background,
in 1900, Ehrlich introduced the term "receptor" as a designation of the side-chain's func-
tion.10 In 1908, Ehrlich was awarded the Nobel Prize for his work in immunology.
A shift in thinking enabled Ehrlich to apply his concept to drug binding. He first thought
receptors would bind toxines and nutritive substances only. Many drugs could be extracted
from tissues easily and so they seemingly could not be bound firmly to the cell. Therefore
they could not evoke the production of side-chains." Ehrlich's theory allowed-as a future
perspective-drug binding to cells only indirectly, as he proposed that certain chemical
bodies or groups (Korperklassen) with specific binding capacities to specific organs could
be used as "vehicles" (Lastwagen) to carry artificial substances to the site of effect.12 Not
before 1907-with reference to his own work on the effect of dyes on trypanosomes and
6Cay-Rudiger Priill, Medizin am Toten oder am contemporary description of Ehrlich's side-chain
Lebenden? Pathologie in Berlin und in London 1900 bis theory, see Ludwig Aschoff, Ehrlich's
1945, Freiburg, 1999, Habilitation thesis, Basle, Seitenkettentheorie und ihre Anwendung auf die
Schwabe, forthcoming; esp. pp. 389-92; Russell C kunstlichen Immunisierungsprozesse, Jena, Fischer,
Maulitz, 'Rudolf Virchow, Julius Cohnheim, and the 1902, esp. pp. 1-25. See also Bruno Heymann, 'Zur
program of pathology', Bull. Hist. Med., 1978, 52: Geschichte der Seitenkettentheorie Paul Ehrlichs',
162-82. Klin. Wochenschr., 1928, 7: 1257-60; Arthur M
7Conceming Ehrlich and chemistry, see Henry Silverstein, A history of immunology, San Diego
Hallett Dale, 'Introduction', in Himmelweit (ed.), vol. and New York, Academic Press, 1989, esp.
1, op. cit., note 4 above, pp. 1-18, esp. p. 2; Goldsmith, pp.64-6,94-9.
op. cit., note 5 above, pp. 69-70. l°Paul Ehrlich and Julius Morgenroth, 'Ober
... . eine bestimmte chemische Beschaffenheit Haemolysine. Dritte Mittheilung' (Berliner Klinische
der Zelle selbst . . .", in Paul Ehrlich, Beitrage zur Wochenschrift, 1900), in Himmelweit (ed.), vol. 2,
Theorie und Praxis der histologischen Farbung, op. cit., note 4 above, pp. 196-204, English transl.
Thesis, Leipzig University, 1878, in Himmelweit (ed.), pp.205-12.
vol. 1, op. cit., note 4 above, pp. 29-64, English transl.: 1 John Parascandola, 'The theoretical basis of Paul
ibid., pp. 65-98. See the quotation on p. 40 (German Ehrlich's chemotherapy', J. Hist. Med. Allied Sci.,
original); p. 75 (English transl.). 1981, 36: 19-43, esp. p. 28.
9Paul Ehrlich, 'Die Wertbemessung des 12Paul Ehrlich, 'Uber die Beziehung von
Diphtherieheilserums und deren theoretische chemischer Constitution, Vertheilung und
Grundlagen' (Klinisches Jahrbuch, 1897), in pharmakologischer Wirkung', from Internationale
Himmelweit (ed.), vol. 2, op. cit., note 4 above, Beitrage zur inneren Medizin: Festschriftfiur Ernst v.
pp. 86-106, English transl. pp. 107-25. For a Leyden zur Feier seines 70. jahrigen Geburtstages

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 Paul Ehrlich and his Receptor Concept
Langley's notion of "receptive substances"-did Ehrlich accept the binding of drugs to
receptors. 13 For this purpose there would be specific "chemoreceptors". The drug needed to
have a greater affinity to the chemoreceptors of the invading organisms, for example the
trypanosomes, than to the chemoreceptors of the host's body. The concept of "specific
affinity" was applied to the pharmacological realm. Based on early nineteenth-century
investigations of the relationship between chemical composition and physiological action
of certain drugs,14 Ehrlich was now able to explain all the phenomena in connection with the
effect of a chemotherapeutic drug, for example drug resistance, with the help of the receptor
concept. The receptors became the theoretical basis for his subsequent work with the dye
"trypan red" and with the arsenic compound "atoxyl" to combat trypanosome infections,
ending with the discovery of Salvarsan, the first chemotherapeutic substance for the treat-
ment of syphilis, in 1910.15 With this discovery, Ehrlich became one of the most prominent
figures of twentieth-century medicine.16
The development and realization of Ehrlich's theories quickly acquired the appearance
of an unbroken success story, taking three steps in a constituent order: staining-
immunology-chemotherapy.17 Of course, the hypothetical character of the side-chain
and receptor theory was soon acknowledged, but its development within the frame of
Ehrlich' s life and career was described as an undisturbed homogeneous process of maturing,
sometimes as the successive appearance of secretly predeveloped plans. This interpretation
did not remain unchallenged, but it shaped the historiography on Ehrlich's work. 18 Even in
Ehrlich's own time,'9 the side-chain or receptor theory found its place in his celebrated
biography. In 1919, one of his students, Leonor Michaelis, was impressed by the newly
discovered dissertation of the master. It would be "of great value for the recognition of
Ehrlich's scientific development". According to Michaelis, the dissertation foreshadowed
am 20. April 1902, Berlin, Hirschwald, 1902, in promoted by the new scientific optimism of the post-
Himmelweit (ed.), vol. 1, op. cit., note 4 above, war decades, for example, Ernst Witebsky, 'Ehrlich's
pp. 570-95, esp. p. 595. English transl. pp. 596-618, side-chain theory in the light of present immunology',
esp. p. 618. Ann. N. Y. Acad. Sci., 1954,59: 168-81. For the history
13Parascandola, op. cit., note 2 above, pp. 134-41. of research on Ehrlich, see Henry Hallett Dale,
14 See Williamn F Bynum, 'Chemical structure and 'Introduction', in Martha Marquardt, Paul Ehrlich,
pharmacological action: a chapter in the history of 19th London, Heinemann, 1949, pp. xiii-xx; Dale, op. cit.,
century molecular pharmacology, Bull. Hist. Med., note 7 above above; Baumler, op. cit, note 5 above,
1970,44:518-38. pp. 5-9. The serious recent historiography of Ehrlich
'51It is not possible in this paper to give a full account includes mostly papers on specific aspects of his work.
of the history of the application of the receptor concept 17 See, for example, Richard Koch, 'Vorwort', in
to drug binding and pharmacology. See, esp., Martha Marquardt, Paul Ehrlich als Mensch und
Parascandola, op. cit., note 11 above, pp. 21, Arbeiter. Erinnerungen aus dreizehn Jahren seines
30-3, 35. Lebens (1902-1915), Stuttgart and Berlin, DVA, 1924,
16 The best general account of Ehrlich's life is pp. 3-15; Dale, 'Introduction', op. cit., note 16 above,
Claude E Dolman, 'Paul Ehrlich', in Dictionary of p. xvi.
scientific biography, New York, Charles Scribner's '8See, for example, Jokl, op. cit., note 5 above,
Sons, 1981, vol. 3, pp. 295-305. Dolman also gives an p. 974; F Klose, 'Paul Ehrlich und Emil v. Behring.
overview of the literature on Ehrlich up to 1980. Zur hundertjiihrigen Wiederkehr ihrer Geburtstage am
Although eighty-six years have passed since his death, 14. und 15. Marz 1954', Deutsche Med. Wochenschr.,
the writing on Ehrlich remains largely hagiographic 1954, 79: 425-27, esp. p. 425.
(see, for example, Baumler, op. cit., note 5 above) for 19See August von Wassermann, 'Die
several reasons. As Ehrlich was Jewish, all public Seitenkettentheorie', in Hugo Apolant et al., Paul
written testimonies of his life were erased by the Nazi Ehrlich. Eine Darstellung seines wissenschaftlichen
government after 1933. After the war, Ehrlich's estate Wirkens. Festschrift zum 60. Geburtstage des
was not accessible for research until recently. Forschers (14. Marz 1914), Jena, Gustav Fischer,
Furthermore, hagiographic accounts were presumably 1914, pp. 134-50.

335
 Cay-Rudiger Prill
Ehrlich's whole oeuvre.20 Even today, Ehrlich's dissertation is sometimes regarded as the
master plan of a successful research programme.21 Recent papers on his work, which do not
venture extensively into Ehrlich's biography and the circumstances of his life, explicitly or
implicitly defend the view of a continuous path towards the receptors. Anthony S Travis
explains the development of the side-chain and receptor idea as an outcome of Ehrlich's
progressive work on dyes. Considering the "social frameworks" for him means a focus on
Ehrlich's collaboration with the chemical industry. Timothy Lenoir's interpretation lies in
the same direction. It focuses on the position of Ehrlich's research on the side-chains within
the triangle of science, politics, and industry. In 1999, Arthur M Silverstein drew a more
radical conclusion from his analysis of Ehrlich's "receptor immunology". According to
him, the receptor idea had been pursued by Ehrlich from his dissertation onwards for over
twenty years, i.e. up to 1898. In his monograph on Ehrlich's receptor concept, Silverstein's
argument is basically the same.22 The studies of John Parascandola and Ronald Jasensky
aptly describe the ups and downs of the early receptor theory, but do not explore its social,
historical and cultural context.23
A closer look into the development of the concept in the context of Ehrlich's biography
until 1905 shows us the impact of many more factors on the emergence of his idea. In
analysing Ehrlich's development of the receptor theory within the framework of his socia-
lization and academic career, five phases can be detected.

Paul Ehrlich's Scientific Career and the Emergence of his Receptor Concept
(1) Ehrlich as a Clinician, 1878-1888
In 1909, a few years before his death, Ehrlich informed a friend about the most important
aspects of his scientific work. He pointed out that his greatest interest had always been in
active therapeutics and that the combination of his chemical and therapeutic interests could
explain his entire scientific career.24 In 1878, Ehrlich was appointed senior physician at the
First Medical Clinic of the Charite'-Hospital in Berlin. The head of the clinic at this time was
the well-known professor of internal medicine, Friedrich Theodor Frerichs (1819-1885).25
... zur Erkennung der wissenschaftlichen and the growth of knowledge in Germany around
Entwicklung Ehrlichs sehr wertvoll", see Leonor 1900',Minerva, 1988,26: 66-88; ArthurM Silverstein,
Michaelis, 'Zur Erinnerung an Paul Ehrlich: Seine 'Paul Ehrlich's passion: the origins of his receptor
wiedergefundene Doktor-Dissertation', Die immunology', Cell. Immunol., 1999, 194: 213-21;
Naturwissenschaften, 1919, 7: 165-8, esp. p. 165; Silverstein, op. cit., note 2 above.
see also pp. 167-8. 23 Parascandola and Jasensky, op. cit., note 2 above,
21 Maria Luise Eckmann, Die Doktorarbeit Paul pp. 199-220; Parascandola, op. cit., note 2 above,
Ehrlichs und ihre Bedeutungffir die Geschichte der pp. 129-56. Also concentrating mainly on Ehrlich's
histologischen Farbung, Thesis, Hamburg University, ideas, Anne-Marie Moulin, Le dernier langage de la
1959; Liz Marshall, 'Paul Ehrlich. 1854-1915. German me'decine. Histoire de l'immunologie de Pasteur
bacteriologist and immunologist', in Emily J au Sida, Paris, Presses Universitaires de France, 1991,
McMurray (ed.), Kelly Kosek and Roger M Valade Ill esp. pp. 74-97.
(assoc. eds), Notable twentieth-century scientists, 24Dale, op. cit., note 7 above above, p. 9.
New York and London, Gale Research, 1995, vol. 1, 25
Franz Hermann Franken, Friedrich Theodor
pp. 564-7, esp. p. 565. Frerichs (1819-1885). Leben und hepatologisches
22Anthony S Travis, 'Science as the receptor of Werk, Freiburg, Falk Foundation, 1994; M Classen,
technology: Paul Ehrlich and the synthetic dyestuffs F H Franken, D Gericke, 'Friedrich Theodor Frerichs in
industry', Science in Context, 1989, 3: 383-408; Berlin', Deutsche Med. Wochenschr., 1995, 120:
Timothy Lenoir, 'A magic bullet: research for profit 1334-7.

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Frerichs wanted to integrate laboratory research and laboratory diagnostics into clinical
work in the wards, and he therefore supported Ehrlich's staining experiments.26 In the
following years, Ehrlich combined his work in the wards with his work at the laboratory
bench. He performed pathoanatomical studies, examining tissue specimens from the post-
mortem room to gain knowledge about the causes of patient deaths. The application of
staining methods helped to explain the pathologically altered function of the morphological
structures. One example of this research is Ehrlich's study of glycogen in the healthy and in
the diabetic human organism.27
Moreover, Ehrlich worked in the field of clinical pathology when examining body fluids
of living patients. One example is his study of bacteriological problems in the course of
pleuritic exudates (effusions into the pleural cavity) through consideration of the patient
records of women in childbed. The application of different staining methods on microbes
allowed him to identify different infections. These results enabled him to give diagnostic
and prognostic advice.28 Furthermore, in these years under Frerichs, Ehrlich performed the
first biopsies of the liver on humans.29 Finally, he described the so-called Diazo-reaction
(Diazo-Reaktion) in 1883. This was a special urine test to detect bilirubin with the help of
dyes-a clinical test for patients with presumably heavy infections.30
Only occasionally did Ehrlich publish single clinical case histories, which show only a
marginal relation to his scientific work.31 Most of the papers written in these clinical years
are concerned with the application of dyes, especially in animal experiments. In 1882,
Ehrlich examined fluorescent dyes on the eye of the rabbit, hoping to find a method to
diagnose human eye diseases. The effectiveness of the substance as well as possible side
effects were of interest.32 Ehrlich's experiments on blood were especially outstanding.
Following animal experimentation, different dyes were applied and tested on the blood of
sick and healthy patients. Different kinds of white and red blood cells were explored. This
experimental work was then applied to the diagnosis and therapy of blood- and infectious
diseases. Ehrlich became a pioneer in modern haematology.33 Furthermore, Ehrlich's early
co-operation with the bacteriologist Robert Koch (1843-1910) relied on the use of staining

26Travis, op. cit., note 22 above, p. 393. 643-5; idem, 'Die Diazo- und Azomethin-Reactionen',
27Dolman, op. cit., note 16 above, p. 296; Paul draft, probably written in 1900, in ibid., pp. 646-50;
Ehrlich, 'Uber das Vorkommen von Glykogen im idem, 'Uber die Dimethylamidobenzaldehydreaction'
diabetischen und im normalen Organismus' (Zeitschrift (Medizinische Woche, 1901), in ibid., pp. 651-3.
fur klinische Medizin, 1883), in Himmelweit (ed.), 31 See, for example, a case study on phosphorous
vol. 1, op. cit., note 4 above, pp. 103-12. poisoning: Paul Ehrlich, 'Uber einen Fall von
28Paul Ehrlich, 'Beitrage zur Atiologie und Phosphorvergiftung mit symmetrischer Gangraena
Histologie pleuritischer Exsudate', (Charite'-Annalen, pedum' (Charite'-Annalen, 1882), in Himmelweit (ed.),
1882), in Himmelweit (ed.), vol. 1, op. cit., note 4 vol. 1, op. cit., note 4, pp. 526-9.
above, pp. 29-310. 32Paul Ehrlich, 'Uber provocirte
29Franken, op. cit., note 25 above, pp. 59-62. Fluorescenzerscheinungen am Auge' (Deutsche
30Paul Ehrlich, 'Uber eine neue Hamprobe', Medizinische Wochenschrift, 1882), in Himmelweit
(Charite'-Annalen, 1883), in Himmelweit (ed.), vol. 1, (ed.), vol. 1, op. cit., note 4 above, pp. 344-53.
op. cit., note 4 above, pp. 619-29; idem, 33 For an overview, see Paul Ehrlich and A Lazarus,
'Sulfodiazobenzol, ein Reagenz auf Bilirubin' Histology of the blood, Cambridge University
(Zentralblattfiur klinische Medizin, 1883), in ibid., Press, 1900 (rev. transl. of P Ehrlich and A Lazarus,
pp. 630-1; idem, 'Uber die Sulfodiabenzol-Reaction' 'Die Anaemie', in H Nothnagel, Specielle
(Zentralblatt fur klinische Medizin, 1883), in ibid., Pathologie und Therapie, Vienna, Holder, 1898), in
pp. 632-42; idem, 'Nachtragliche Bemerkungen zur Himmelweit (ed.), vol. 1, op. cit., note 4 above,
Diazoreaction' (Charite'-Annalen, 1886), in ibid., pp. pp. 181-268.

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 Cay-Riidiger Prull
as an instrument to serve practical purposes. After 1882, when Koch had demonstrated the
newly found tubercle bacillus, Ehrlich improved Koch's staining method for this microbe.34
Ehrlich used dyes not only to solve problems of diagnosis but also to introduce them as
therapeutic agents. In 1886, the substance thallin was used on rabbits and shortly thereafter
on patients suffering from typhoid fever. The best dosage to combat the fever symptoms was
estimated, particularly at the climax of the disease. Ehrlich was able to give advice on the
clinical use of this substance.35
Ehrlich's profile of daily work enables us to estimate the impact of the receptor concept
on his research at these times. The "side-chain" theory was the outcome of one specific
study-his habilitation thesis (teaching licence) of 1885, which was dedicated to Frerichs.
On the basis of countless animal experiments, Ehrlich wanted to estimate the "oxygen-need
of the organism" (Sauerstoff-Bediirfniss des Organismus). The dyes served him to indicate
the different degrees of oxygen affinity of the various organs. Following the infusion of
dyes, the animals were killed after certain intervals of time, and dissected. The colouring of
the tissues indicated the metabolic activities of the single organs and tissues and enabled
a certain classification. Ehrlich concluded that the inner part of the cell (protoplasm/
Protoplasma) was able to utilize oxygen. According to Ehrlich, the protoplasm had
side-chains, which could bind oxygen. This complex could be burned in the protoplasm
and transformed into energy. His study presented a theoretical basis for his staining meth-
ods, but the side-chain as predecessor of the receptor played no important role in his
discussion of oxygen utilization. Moreover, Ehrlich focused on the organs, the character
of the protoplasm and of the surrounding paraplasm (Paraplasma, more unspecific areas of
the cell, die mehr indifferenten Territorien des Zellenleibes) of the cell.36 The side-chains
are mentioned in Ehrlich's 69-page habilitation thesis (in Himmelweit's edition of the
collected works) only six times and then never again during the period of his work
under Frerichs.37
Ehrlich's major aim was to achieve clinically applicable results. He could influence the
work on the wards when connecting different fields: staining methods, animal experimenta-
tion, clinical work and human therapeutic experiments. This filled Ehrlich's entire working
time. Remarkably, he achieved his aims without any deeper insights into the exact way in
which substances bind to cells. This explains why there was no discussion of the side-chains
in the years after the publication of his habilitation thesis. In 1891 Ehrlich was still calling
himself a "clinician",38 and he had acquired his teaching licence in the field of "practical

34Paul Ehrlich, 'Modification der von Koch 36Paul Ehrlich, Das Sauerstoff-Bedarfniss des
angegebenen Methode der Firbung von Organismus. Einefarbenanalytische Studie
Tuberkelbazillen'(Deutsche Medizinische (Habilitation thesis), Berlin, Hirschwald, 1885, in
Wochenschrift, 1882), in Himmelweit (ed.), vol. 1, Himmelweit (ed.), vol. 1, op. cit., note 4 above,
op. cit., note 4 above, pp. 311-13; idem, 'Referat uber pp. 364 432, esp. p. 415. English transl. on
die gegen R. Koch's Entdeckung der Tuberkelbacillen pp. 433-96.
neuerlichst hervorgetretenen Einwande' (Deutsche 37Ibid., pp. 368, 419, 422, 430 (German
Medizinische Wochenschrift, 1882), in ibid., vol. 1, original).
pp. 322-9. 38 Paul Ehrlich, Zur Geschichte der Granula, repr.
35 Paul Ehrlich, 'Experimentelles und Klinisches from Farbenanalytische Untersuchungen zur
uber Thallin' (Deutsche Medizinische Wochenschrift, Histologie und Klinik des Blutes, Berlin, Hirschwald,
1886), in Himmelweit (ed.), vol. 1, op. cit., note 4 1891, in Himmelweit (ed.), vol. 1, op. cit., note 4 above,
above, pp. 542-51. pp. 166-68, esp. 166.

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 Paul Ehrlich and his Receptor Concept
and clinical medicine" (praktische Medicin und drztliche Klinik).39 And in 1898, when
together with a colleague he published the results of their research on the blood cells, he
pointed out the importance of clinical examination. When describing the place of origin of
the white blood cells, Ehrlich wrote that it would be "hard to avoid errors if one confines
oneself exclusively to animal experiments without supplementing these by clinical experi-
ence ... Not the anatomist, not the physiologist, but only the clinician is in a position to
discuss these problems" .40 And furthermore: why did he not apply his now published idea of
side-chains to the haematological results, even though they were concerned with metabolic
and microbiological problems, such as the effect ofbacterial poisons on white blood cells?41
Ehrlich was mostly devoted to laboratory work but it made sense for him only in connection
with practical medicine: he tried to improve diagnostic techniques and tools to make them
usable even for the untrained physician walking the wards.
These two aims mentioned by Ehrlich later as most important-chemistry as well as its
application to biological problems and practical therapy-could initially be reached without
any detailed knowledge about receptors. Moreover, private as well as professional matters
were developing. In 1883 Ehrlich married, and in 1884 his parents moved from Strehlen in
Upper Silesia to Berlin.42 In the very same year, Ehrlich became a titular "professor".43

(2) The Change of Emphasis, 1889-1895

Ehrlich's situation changed rapidly after Frerichs' death in 1885. Now he worked under
Carl Gerhardt (1833-1902), Frerichs' successor as head of the Second Medical Clinic of
the Charite in Berlin. Gerhardt was mainly interested in clinical work in the wards, not in the
attached laboratories. He focused on the development of clinical diagnostics and on the
organization of empirical studies on patients, and he integrated Ehrlich into the daily clinical
routine. There is enough evidence that this caused Ehrlich severe trouble as he remained a
devoted laboratory worker. He was diagnosed as tuberculous in 1888, resigned and went to
Egypt to recover. Leaving his position in Berlin was a break in his career, particularly
because as, a Jew, he could not obtain a full professorship or employment at a State Institute.
Every step of his scientific career, which was achieved only by troublesome efforts, had to
be maintained if he wished to gain a respected social position.44

39Note, in Acta der Friedrich-Wilhelms- Frerichs' clinic, that practical clinical work did not suit
Universitat Berlin, Habilitationen von 1880-1889, Ehrlich, is one of the rare comments on this topic in
Medizinische Fakultat-Dekanat, No.1342/1, p. 203, the literature. See 'Obituary. Professor Paul Ehrlich',
Archive of the Humboldt University, Berlin. Br. med. J., 1915, ii: 349. For his time with Frerichs, see
4WEhrlich and Lazarus, op. cit., note 33 above, Dolman, op. cit., note 16 above, pp. 296-7.
p. 213. 44Goldsmith, op. cit., note 5 above, pp. 73-4;
41 Ibid., p. 258. Dolman, op. cit., note 16 above, p. 297. For Carl
42Baumler, op. cit., note 5 above, pp. 60, 68. See Gerhardt, see his obituary 'Professor Carl Gerhardt',
Margaret Goldsmith's remark on Ehrlich's life after his Lokal-Anzeiger, 1902, 20: No. 337, Berlin, 22 July
appointment to Frerichs' clinic: "The next seven or 1902, p. 1; in Acta betr. die Anstellung des Geheimen
eight years were one of the most fruitful and satisfying Medicinal Raths und Professors Dr. Gerhardt als diri-
periods of Ehrlich's life", in Goldsmith, op. cit., note 5 girender Arzt und Director der 2. medicinischen
above, p. 71. Universitats-klinik, 1885, Kgl. Charite-Direction,
43 Goldsmith, ibid., p. 72. The view expressed in the No. 437, p. 37, Archive of the Humboldt-University,
British Medical Journal concerning Ehrlich's work at Berlin.

339
 Cay-Radiger Prull
Ehrlich returned to Berlin in 1889.45 He was unemployed and could set up a small
laboratory only with the financial help of his father-in-law. He no longer had any patients.
Now he had to rely solely on his dyes and animal experimentation. Ehrlich turned to
immunological work. The latter was not least inspired by Koch and contemporary ideas
about anti-bacterial treatments, and above all by Koch's assistant Emil von Behring (1854-
1917) who, together with his co-worker Shibasaburo Kitasato (1852-193 1), discovered the
phenomenon of antitoxin in diphtheria and tetanus in 1890.46 Ehrlich was successful in
immunizing mice against the plant poisons, ricin and abrin; he investigated the suggested
hereditary transmission of immunity and its transmission via breast feeding; he got results
on the basic processes of active and passive immunization.47
In 1890, only one year later, the period of private science ended because Koch offered his
former assistant a post as clinical supervisor for scientific studies on tuberculosis at the City
Hospital Berlin-Moabit. Now Ehrlich was able to take up clinical experimentation again, as
he had done during his time with Frerichs, and he again combined it with animal experi-
mentation and histological investigation in the laboratory. Indeed, Koch gave him a small
laboratory and a few assistants.48 Together with a colleague, he explored the best tolerated
dosage of the tuberculin serum and combined therapeutic human experimentation with
histological sputum examinations.49 And he again worked with dyes in analysing the
analgesic effect of methylene-blue. These trials were performed on prisoners at the Imperial
Prison Moabit (K6nigliche Strafanstalt Moabit) and the associated Observation Unit for
Insane Criminals (Beobachtungsanstalt fur geisteskranke Verbrecher). The result was that
the dye methylene-blue was observed to have an effect on certain types of pain, above all on
migraine.50 Methylene-blue was also tested as a therapeutic agent against malaria.5' In
1891, Koch offered him his own laboratory in the newly founded Institute for Infectious
Diseases (Institut fur Infektionskrankheiten). This was a good opportunity for Ehrlich to
start a close co-operation with the bacteriological group working under Koch, which
included Behring, Richard Pfeiffer (1858-1945), and August Wassermann (1866-1925).
Ehrlich's interest in immunology grew enormously. Above all, the ability of the organism to
form substances (i.e. antibodies) to combat specific microbes seemed to be useful in
developing new treatments: the therapeutic sera. From 1891, therefore, Ehrlich worked
chiefly on human immunology. Although the investigation of dyes and clinical tests moved
45Marquardt, op. cit., note 16 above, pp. 27-8; 48Goldsmith, op. cit., note 5 above, p. 76.
Baumler, op. cit., note 5 above, pp. 68-9. 49Dolman, op. cit., note 16 above, p. 297; Paul
46Jonathan Liebenau, 'Paul Ehrlich as a commer- Ehrlich, Paul Guttmann, 'Die Wirksamkeit kleiner
cial scientist and research administrator', Med. Hist., Tuberkulindosen gegen Lungenschwindsucht'
1990, 34: 65-78, esp. p. 66. (Deutsche Medizinische Wochenschrift, 1891), in
47Paul Ehrlich, 'Experimentelle Untersuchungen Himmelweit (ed.), vol. 2, op. cit., note 4 above,
uber Immunitat I. Uber Ricin' (Deutsche pp. 7-12.
Medizinische Wochenschrift, 1891), in Himmelweit 50Paul Ehrlich and A Leppmann, 'Uber
(ed.), vol. 2, op. cit., note 4 above, pp. 21-6; schmerzstillende Wirkung des Methylenblau'
idem, 'Experimentelle Untersuchungen uber (Deutsche Medizinische Wochenschrift, 1890),
Immunitat II. Uber Abrin' (Deutsche Medizinische in Himmelweit (ed.), vol. 1, op. cit., note 4 above,
Wochenschrift, 1891), in ibid., pp. 27-30; idem, pp. 555-8.
'Uber Immunitat durch Vererbung und Saugung' 5 Paul Ehrlich and Paul Guttmann, 'Uber die
(Zeitschriftffir Hygiene und Infektionskrankheiten, Wirkung von Methylenblau bei Malaria' (Berliner
1892), in ibid., pp. 31-44. See, Adolf Lazarus, Klinische Wochenschrift, 1891), in Himmelweit (ed.),
Paul Ehrlich, Vienna and Berlin, Rikola, 1922, vol. 3, op. cit., note 4 above, pp. 9-14.
pp. 34-5.

340
 Paul Ehrlich and his Receptor Concept
into the background, they continued to play a role in his daily work. Diphtheria serum, for
example, was tested on children.52

(3) Ehrlich as a Theorizer, 1895-1905

Ehrlich remained in a dependent position and his fate was again decided by his associa-
tion with Koch and by a sponsor outside the Institute. At the request of Behring, Ehrlich
turned again to investigate theoretical problems of immunity. Behring and the Hoechst
company (Farbwerke Hoechst, near Frankfurt am Main) had difficulties with the production
of the new therapeutic diphtheria serum. Before 1894 it was not possible to make it in
reliable concentrations. As in the case of tuberculin, the challenge was to standardize the
effective dosage. Behring asked Ehrlich for help and, considering the keen competition in
Koch's Institute, one can assume that it was only "the direct request ofBehring, urged on by
an impatient Koch and a cost-conscious Hoechst Company, that would allow Ehrlich to
venture into an area to which his institute colleague had full priority claim". 53 Behring
agreed with Ehrlich that the latter should examine the exact quantitative relations between
diphtheria toxin and antitoxin and develop a method to standardize the application of the
therapeutic serum.54
The research on the diphtheria serum helped to put Ehrlich's scientific career onto a
socially secure basis. In Koch's Institute, Ehrlich never got an official post because of his
Jewish faith.5 When in 1895 the "control station" for therapeutic sera (Controlstationflir
Heilsera) was opened in the Institute, Ehrlich became only the deputy head of the depart-
ment, whereas the responsibility for its work was handed over to Koch's assistants August
Wassermann and Hermann Kossel.56 Eventually, however, the influence of the powerful

52 See the descriptions of the clinical trials in Paul 'Uber Gewinnung, Werthbestimmung und
Ehrlich, Hermann Kossel and August Wassermann, Verwerthung des Diphtherieheilserums' (Hygienische
'Uber Gewinnung und Verwendung des Rundschau, 1894), in ibid., pp. 80-3.
Diphtherieheilserums' (Deutsche Medizinische 55 Goldsmith, op. cit., note 5 above, p. 76. In the
Wochenschrift, 1894), in Himmelweit (ed.), vol. 2, report on the work of Koch's Institute of 1892, Ehrlich
op. cit., note 4 above, pp. 56-60, esp. pp. 57-60; Paul is mentioned only once as a voluntary assistant. See
Ehrlich and Hermann Kossel, 'Uber die Anwendung 'Ueber den Bericht des Koch'schen Instituts fur
des Diphtherieantitoxins' (Zeitschriftfiir Hygiene und Infectionskrankheiten', Leipzig, Thieme, 1892 (off-
Infektionskrankheiten, 1894), in ibid., pp. 61-2. print from Deutsche Medizinische Wochenschrift, No.
3Silverstein, op. cit., note 2 above, p.42. Although 4-7 (1892)), in Acta betr. die Einrichtung und die
Silverstein's monograph on Ehrlich's receptor Verwaltung des (staatlichen) Institutes fur
concept is almost exclusively devoted to the history of Infektionskrankheiten in Berlin, vom Januar 1892 bis
ideas, it gives occasional hints of the importance of Dezember 1898, in GStA PK. I. HA, Rep.76
the social setting for the development of Ehrlich's Kultusministerium, VIII B, No. 2893, pp. 63-75, esp.
career and the receptor concept. p. 71. In the records of Koch's Institute, kept by the
54Baumler, op. cit., note 5 above, pp. 90-3. Berlin Charit6-Hospital for the years 1893 to 1895,
Dolman, op. cit., note 16 above, p.297. For Ehrlich and Ehrlich's name does not appear at all. See Acta betr. das
his early involvement in the development of serum Institut fur Infectionskrankheiten, Kgl. Charite-
therapy against diphtheria, see Ehrlich, Kossel and Direction., No. 2205, 1893-1895, Archive of the
Wassermann, op. cit., note 52 above; Ehrlich and Humboldt-Univerity of Berlin.
Kossel, op. cit., note 52 above; Paul Ehrlich and A 56The Prussian Minister of Science and Education
Wassermann, 'Uber die Gewinnung der Diphtherie- to Robert Koch, 9 Feb. 1895; Bericht uber die
Antitoxine aus Blutserum und Milch immunisirter Thaitigkeit des Kgl. Instituts fur Serumforschung und
Thiere' (Zeitschrift fir Hygiene und Serumprufung zu Steglitz. Juni 1896-September 1899.
Infektionskrankheiten, 1894), in Himmelweit (ed.), Zur Einweihung des Konigl. Institutsfir experimentelle
vol. 2, op. cit., note 4 above, pp. 72-9; Paul Ehrlich, Therapie Frankfurt/M., Jena, Fischer, 1899, in Acta

341
 Cay-Riidiger Prull
and well-known Ministry Councillor in the Prussian Ministry of Science and Education
(Ministerialrat im preuJ3ischen Kultusministerium), Friedrich Althoff (1839-1908), saved
Ehrlich from all the problems and difficulties of his provisional post. Ehrlich and Althoff
knew each other very well and also had private contacts.57 It was Althoff who promoted
Ehrlich's career further and who mainly organized the institutional framework of his
academic life. Ehrlich was grateful, as he believed his academic colleagues judged him
"unusable". 58 A safe social position was a priority and had to be secured. This was so
important that Ehrlich's wife even wrote to Althoff. She was very interested in promoting
her husband's career, and was still trying to secure an independent position for him in 1903,
when the main decisions on Ehrlich's institutional setting had already been made.59 The
challenge of the diphtheria serum brought Ehrlich this independence. At the instigation of
Althoff, he became, in 1896, Head of the new Institute for Serum Research and Serum
Testing (Institut fur Serumforschung und Serumpriifung) in Steglitz in the suburbs of
Berlin.60 Its main purpose was the testing of sera, but it also enabled Ehrlich to focus
on diphtheria research in the laboratory.
The events and outcome described led to Ehrlich's second predominantly theory-oriented
phase of work, and instigated the creation of his "side-chain" and "receptor-theory".
Although relevant as an explanatory tool for his research, the "side-chains" had been
mentioned in only two of his papers between 1885 (the year of the development of his
theory) and 1897.61 In his classical study, 'The assay of the activity of diphtheria-curative
serum and its theoretical basis' (1897),62 Ehrlich now defined the side-chains as a part of an
immunological system. He tried to find a standard dosage for the application of diphtheria
antitoxin. He tested a vast number of diphtheria toxins of different origin on guinea pigs and
discovered two threshold concentrations. The first was a completely neutralized solution of
toxins, which caused no signs of disease when applied to a guinea pig. The second contained
the quantity of toxin that killed a 250-gram animal within four days. The difference between

betr. das Institut fur experimentelle Therapie zu pp. 71-4; Goldsmith, op. cit., note 5 above, p. 74. This is
Frankfurt a.M., vom Februar 1895 bis Dezember not the place to discuss the difficulties between
1900, GStA PK. I. HA, Rep.76 Kultusministerium, Ehrlich and Behring. They are described and analysed
Vc Sekt.l, Tit.XI, Teil H, No. 18, vol.1; pp. 1, in the secondary literature on Ehrlich.
189-203, 203. 6 Goldsmith, op. cit., note 5 above, pp. 77-8.
57For Friedrich Althoff, see Bernhard vom 61 Paul Ehrlich, 'Studien in der Cocainreihe'
Brocke (ed.), Wissenschaftsgeschichte und (Deutsche Medizinische Wochenschrift, 1890), in
Wissenschaftspolitik im Industriezeitalter. Das Himmelweit (ed.), vol. 1, op. cit., note 4 above,
"System Althoff' in historischer Perspektive, pp. 559-66; idem, 'Uber neuere Erfahrungen in der
Hildesheim, Lax, 1991; idem, 'Hochschul- und Behandlung der Tuberkulose nach Koch, insbesondere
Wissenschaftspolitik in PreuBen und im Deutschen der Lungenschwindsucht' (Transactions of the 7th
Kaiserreich 1882-1907: das "System Althoff"', in International Congress of Hygiene and Demography,
Peter Baumgart (ed.), Bildungspolitik in Preufien zur 1891), in ibid., vol. 2, op. cit., note 4 above,
Zeit des Kaiserreichs, Stuttgart, Klett-Cotta, 1980, pp. 13-20.
pp. 9-118. 62Ehrlich, 'Die Wertbemessung des
58Paul Ehrlich to Friedrich Althoff, 27 July 1907, Diphtherieheilserums', op. cit., note 9 above, pp. 86-
in Nachlass Althoff B, GstA PK. VI. HA, Rep. 92, 106; see the English translation on pp. 107-25. The
No. 33, pp. 217-22, esp. p. 219. See also Wolfgang quotations in the following footnotes refer to the
U Eckart, 'Friedrich Althoff und die Medizin', in vom German original. For the impact of this paper on
Brocke, op. cit., note 57 above, pp. 375-404, on Britain, see also H G Plimmer, 'A critical summary of
Ehrlich, see esp. pp. 398-401. Ehrlich's recent work on toxins and antitoxins',
59 See, for example, Hedwig Ehrlich to Friedrich J. Pathol. Bacteriol., 1897, 5: 489-98.
Althoff, 13 Sept. 1903, in Nachlass Althoff B, ibid.,

342
 Paul Ehrlich and his Receptor Concept
the first (neutral) and the final (lethal) solution was called the "single lethal dose" (einfache
letale Dosis).63 Ehrlich's results were far from encouraging, as the concentrations of the
solutions of the different diphtheria toxins varied markedly. Moreover, the solutions were
not stable, but lost their toxicity after a certain period of storage, although the number of
antibody-binding units did not decrease. This meant that the toxic effect did not correspond
with the capacity of the toxin to bind to antitoxin. The only explanation for this phenomenon
was that the toxins themselves had undergone some changes.64 Forced to explain these
results, Ehrlich came back to his "side-chain theory". The toxin was thought to consist of
two parts: a poisonous component, the so-called "toxophore group" (toxophore Gruppe),
and a component that enabled the binding to the antitoxin, the so-called "haptophore group"
(haptophore Gruppe). According to Ehrlich, the toxophore group was not as stable as the
haptophore group and in consequence the toxophore groups successively dissolved. There-
fore, to a certain extent toxins emerged which were able to bind antitoxins, but which no
longer had a toxic effect. Ehrlich called these poisons "toxoids" (Toxoide). Through that
binding capacity to a side-chain of the cell, these toxoids were able to induce the production
of antibodies: the latter were an overcompensated production of side-chains, which were
released into the blood-stream. This meant that chemical processes of specific binding were
combined with biological processes of regeneration. Ehrlich explained the binding mechan-
ism with the analogy that the biochemist Emil Fischer (1852-1919) had used to describe the
effect of enzymes when he wrote about the "key-lock" mechanism.65 With his paper of
1897, Ehrlich expanded his vague and provisional idea of side-chains to a "side-chain
theory". From now on, this theory was the basis of his immunological investigations.
Ehrlich's work became theory-oriented, and immunological studies dominated his research
for the next few years.66

(4) From the "Side-Chains" to the Receptors

In the following years, Ehrlich's side-chain theory became more and more intricate as its
details were studied experimentally. Between 1897 and 1905, these experiments were
carried out with vast effort and extensive use of different animal species and poisonous
substances. Until 1899, this took place in the Steglitz Institut,67 thereafter in the Institute for
Experimental Therapy (Institut fir Experimentelle Therapie) in Frankfurt am Main. The
63 Ehrlich, op. cit., note 9 above, pp. 89-93. reaction and Ehrlich's work, see Pauline M H
64Ibid., pp. 93, 96. See also Lazarus, op. cit., note Mazumdar, 'The antigen-antibody reaction and the
47 above, p. 36. physics and chemistry of life', Bull. Hist. Med.,
65Ehrlich, op. cit., note 9 above, pp. 93-106 1974, 48: 1-21.
(immunological theory), p. 94 (key-lock mechanism); 66 For this period ofEhrlich's work, see Dolman, op.
Heymann, op. cit., note 9 above, p. 1258. Forthe history cit., note 16 above, p. 298.
of the "key-lock" metaphor in molecular biology, see 67For the work done in the Institut fur
Friedrich Cramer, 'Emil Fischers Schlussel-SchloI- Serumforschung und Serumprufung in Steglitz,
Hypothese der Enzymwirkung- 100 Jahre danach', in see Wilhelm D6nitz, 'Bericht uber die
Hans-Jorg Rheinberger, Michael Hagner and Bettina Thatigkeit des Konigl. Instituts fur Serumforschung
Wahrig-Schmidt (eds), Raume des Wissens. und Serumprufung zu Steglitz, Juni 1896-
Reprasentation, Codierung, Spur, Berlin, Akademie- September 1899', Klin. Jahrb., 1899, 7: 359-84.
Verlag, 1997, pp. 191-212. The idea of cellular Donitz remarked that the biological application
regeneration stemmed from Ehrlich's cousin Carl of the chemical theory of the side-chains would
Weigert and was developed in contact with the be the basic idea of all research acitivities of the
latter, see Heymann, ibid. For the toxin-antitoxin Institute.

343
 Cay-Rudiger Prull
latter was set up for Ehrlich by the Prussian State, again with the support of Althoff.68
Ehrlich was able to organize and to co-ordinate experimental studies, and he pushed many
assistants to work hard on their subjects. His right-hand man and coordinator for the
laboratory investigations on the side-chain theory was the bacteriologist Julius Morgenroth
(1871-1924), who had been Ehrlich's assistant in Steglitz since 1897.69 But Ehrlich
continued to be the spiritus rector of the whole project, and he urged his assistants to
perform more and more animal experiments to consolidate his theory. Ehrlich's laboratory
notes show this, as for instance when he demanded: "Please also show me the Pyrodin-
animals", or simply "Where is the ape?"70 Accordingly, the "side-chain theory" devel-
oped. The "toxoids", those poisons capable of cell-binding, were supplemented by the
"toxons" (Toxone) only a year later, in 1898.71 The toxons were also ineffective poisons,
but, in contrast to the toxoids, they were synthesized and released by the microbe itself and
had not lost their toxophore group.
Besides analysing poisons, Ehrlich concentrated on the mechanisms and processes of the
side-chain theory itself. The animal experiments on haemolysis, i.e. the solvent action of
antibodies on red blood corpuscles, seemed to be helpful. This could be compared with
antibodies attacking bacilli. Some studies on haemolysis, published together with
Morgenroth, enabled Ehrlich to improve the side-chain theory decisively. The so-called
"addiment" (Addiment), was responsible for the dissolution of the red blood cells through
binding to an antibody or "immune-body" (Immunkorper), enabling this antibody to bind to
red blood cells and to dissolve them. Consequently, Ehrlich assumed that there were not
only antibodies with one binding group but also antibodies with two binding groups. These
were able to bind the "addiment" as well as the red blood cell. Now Ehrlich compared
haemolysis with the physiological process of nutrition. This increased the impact of his
theory. The addiment could be compared with a digestive ferment. A double-binding side-
chain attached to the surface of a cell could bind both a digestive ferment and "giant
molecules" (Riesenmolekiile), i.e. unprepared nutritive substances. These giant molecules
could be prepared for cellular digestion by the digestive ferment.72 In this way, Ehrlich
opened up the path from the more or less narrow immunological terrain to the understanding
of the general metabolism of the human organism.
The side-chain theory appeared to be a good explanatory model to uncover the deepest
secrets of biological chemistry. In 1899, Ehrlich postulated a countless number of side-
chains, which would adapt to the "constantly changing chemistry" of the body. This
chemistry would be influenced by race, sex, nutrition, energy, secretion and other factors,
and so there was a continuous change taking place in the blood serum. Furthermore, not only
in the case of haemolysis but also in regular conditions, the blood contained immune bodies

68Goldsmith, op. cit., note 5 above, p. 78. 71 Paul Ehrlich, 'Uber die Constitution des
69For the life of Morgenroth, see Baumler, op. cit., Diththeriegiftes' (Deutsche Medizinische
note 5 above, p. 329; D6nitz, op. cit., note 67 above, Wochenschrift, 1898), in Himmelweit (ed.), vol. 2,
p. 360. op. cit., note 4 above, pp. 126-33.
70"Bitte mir auch die pyrodin-thiere zeigen!", 72Paul Ehrlich and Julius Morgenroth, 'Zur
"Wo bleibt der Affe !", see Note, 6 March 1900, Theorie der Lysinwirkung' (Berliner Klinische
p.13; Note, 1900 (no day and month), p. 30, in Zettel Wochenschrift, 1899), in Himmelweit (ed.), vol. 2, op.
Buch I, I Feb. 1900, to 26 Dec. 1900, box 7, series II, cit., note 4 above, pp. 143-9. English transl.
(3)-i, 2, 4, Paul Ehrlich Collection, RUA, RAC. pp. 150-5.

344
 Paul Ehrlich and his Receptor Concept
with two binding sites. Ehrlich called them "interbodies" (Zwischenkorper). Normal blood
also contained addiment, which Ehrlich called "complement" (Komplement).73
Finally, in 1900, Ehrlich and his colleague Morgenroth, in their third paper on haemo-
lysins, introduced the term "receptor": "For the sake of brevity, that combining group ofthe
protoplasmic molecule to which the introduced group is anchored will hereafter be termed
receptor."74 The side-chains as such had played a minor role in Ehrlich's research until this
point in his career. He had concentrated mainly on the relations between poison, addiment,
ferment and complement, less on the character of the side-chain as such. The titles of the
published papers illustrate this. Even the third paper on haemolysins is chiefly about the
classification of the different kinds of complement.75 The fourth report on haemolysins also
deals mainly with complement. Ehrlich and Morgenroth claimed that there were many types
and the constitution of the complement became also more intricate.76
The introduction of the term "receptor" was not merely a new term for an "old idea".77
After having sorted out the meaning of the "side-chains" with the creation of a "side-chain
theory", investigation of the nature of side-chains was inevitable. The new heading stands
for the central position of the side-chains in Ehrlich's new research strand. The "receptors"
and their specificity for certain poisons soon stood in the centre of Ehrlich's immunological
theory.78 In 1901, Ehrlich and Morgenroth, when deepening their research on the general
topic, made some remarks on the "peculiarities of the receptor apparatus". They stated that
there would be a vast number of receptors attached to the red blood cells and that these
receptors could bind to diverse immune bodies and haemotoxins.79 As in the case of the
antibodies or intermediate bodies, the structure of the receptors was analysed and classified.
As complex receptors with two haptophore groups, the intermediate bodies (antibodies
regularly belonging to the immune system) were now called "amboceptors" (Ambocep-
toren).80 This view of receptors saw them as flexible entities, first of all attached to the cell
and binding toxins or immune bodies, but then also doing the same in the blood-stream.8'
But Ehrlich conceded soon that there were receptors which, even in the case of a successive

... standig wechselnden Chemismus", see Paul 77 See the quotation in Silverstein, op. cit., note 2
Ehrlich and Julius Morgenroth, 'Uber Hamolysine. above, p. 80. The introduction of the term "receptor"
Zweite Mittheilung' (Berliner Klinische in 1900 is underestimated by Silverstein, who describes
Wochenschrift, 1899), in Himmelweit (ed.), vol. 2, it merely as a "reminder that the side-chain theory
op. cit., note 4 above, pp. 156-64, esp. p. 162. English holds that antibodies are cell receptors", p. 105.
transl. pp. 165-72, esp. p. 170. 78E Freiherr von Dungern, 'Rezeptorenspezifitat',
74"Wir wollen im Folgenden stets, um eine gros- in Apolant, et al., op. cit., note 19 above, pp. 162-5.
sere Kiirze des Ausdrucks zu ermoglichen, diejenige 79"Eigenthumlichkeiten des Receptoren-
bindende Gruppe im Protoplasmamolekiil, an welche apparates", see Paul Ehrlich and Julius Morgenroth,
eine fremde, neu eingefuhrte Gruppe angreift, allge- 'Uber Hamolysine. Funfte Mittheilung' (Berliner
mein als 'Receptor' bezeichnen". See Paul Ehrlich and Klinische Wochenschrift, 1901), in Himmelweit (ed.),
Julius Morgenroth, 'Uber Hamolysine. Dritte vol. 2, op. cit., note 4 above, pp. 234-45, esp.
Mittheilung' (BerlinerKlinische Wochenschrift, 1900), p. 238. English transl. pp. 246-55, esp. p. 249.
in Himmelweit (ed.), vol. 2., op. cit., note 4 above, 80Ibid., p. 244, German original. Paul Ehrlich and
pp. 196-204, esp. p. 196. English transl. pp. 205-12, the Julius Morgenroth, 'Uber Himolysine. Sechste
quotation is on p. 205. Mittheilung' (BerlinerKlinische Wochenschrift, 1901),
75 Ibid. in Himmelweit (ed.), vol. 2, op. cit., note 4 above,
76Paul Ehrlich and Julius Morgenroth, 'Uber pp. 256-77, esp. p. 272. English transl. pp.
Hamolysine. Vierte Mittheilung' (Berliner Klinische 278-97.
81
Wochenschrift, 1900), in Himmelweit (ed.), vol. 2, Lazarus, op. cit., note 47 above, pp. 41-2.
op. cit., note 4 above, pp. 213-23. English transl.
pp. 224-33.

345
 Cay-Riidiger Prill
overproduction of the cell, would not be released into the blood-stream. Instead they
remained at the surface of the cell. Ehrlich called them "sessile receptors" (sessile Recep-
toren).82 But they remained as only one subspecies. Some receptors were common to
different animal species and could be found in many organs. A receptor could have
many complement binding groups, so mutating to a "triceptor" (Triceptor) or "quadri-
ceptor" (Quadriceptor).83 The step to postulate the existence of the "polyceptor" (Poly-
ceptor), able to bind many complements, was eventually taken in 1905.84 One year before,
in 1904, Ehrlich had divided the receptors according to their ability to bind substances,
distinguishing receptors of first, second and third order.85 All those with two or more
binding sites belonged to the receptors of third order. The blood plasma was filled with
a vast number of receptors, which Ehrlich called "haptines" (Haptine). These haptines
covered all those substances which at the time were not yet identified.86 Finally, he
approached what he called the "pluralistic point of view" (plurimistischer Standpunkt).
This was the assumption of a whole range of different complements, anti-complements,
receptors, and many other substances.87 Because they played a key role in immunology and
in combating microbes,88 as well as in the physiology of nutrition and human metabolism in
general, Ehrlich predicted a great impact of the receptor concept on clinical medicine, and
he assumed that his studies on receptors would "open a new meaningful direction of
biological research".89

(5) The Fight for the Receptors and Lost Alternatives

Ehrlich's experimental methods were refined again and again, for example with the
application of new chemicals. He got confirmation and support from colleagues, but
he could not provide direct evidence for his theory as the receptors were not visible.90
The experimental setting and his exact methods enabled Ehrlich to identify the microcos-
mos of substances only indirectly, from reactions of the blood sera. He knew that his theory
for the present remained only a theory. But because it was based on experimental evidence,
he thought it legitimate to publish the results.91 In 1901, he maintained that the side-chain

82Ehrlich and Morgenroth, 'Uber Hamolysine. 88Ehrlich decided to apply a specific bacterial
Sechste Mittheilung', op. cit., note 80 above, pp. 256, serum to different animal species with a different
258. receptor apparatus. Thus he aimed to produce antibo-
83Ibid., pp. 268, 273. dies against all bacterial receptors of this microbe. He
84Paul Ehrlich and Hans Sachs, 'Uber den thought this a possible way of mapping all receptors of
Mechanismus der Antiamboceptorwirkung' (Berliner this microbe. It could then be combatted effectively
Klinische Wochenschrift, 1905), in Himmelweit (ed.), with a therapeutic serum produced from the mixture of
vol. 2, op. cit., note 4 above, pp. 432-41, esp. p. 434. the produced antibodies. See Ehrlich and Morgenroth,
85 Paul Ehrlich, 'Uber den Receptorenapparat der 'Uber Hamolysine. Sechste Mittheilung', op. cit., note
rothen Blutkorperchen', from Paul Ehrlich (ed.), 80 above, p. 259.
GesammelteArbeiten zurImmunitatsforschung, Berlin, 89 eine neue bedeutungsvolle Richtung der
Hirschwald, 1904, in Himmelweit (ed.), vol. 2, op. cit., biologischen Forschung eroffnet". See Ehrlich, op. cit.,
note 4 above, p. 316-23, esp. p. 317. note 85 above, p. 320. See also Dolman, op. cit., note
86Paul Ehrlich, 'Die Schutzstoffe des Blutes' 16 above, pp. 298-9.
(Verhandlungen der 73. Versammlung der Gesellschaft 90D6nitz, op. cit., note 67 above, pp. 376-84.
der Naturforscher und Arzte, 1901), in Himmelweit 91 Paul Ehrlich, 'Toxin und Antitoxin. Entgegnung
(ed.), vol. 2, op. cit., note 4 above, p. 298-315, esp. auf den neuesten Angriff Grubers' (Miinchener
p. 312. Medizinische Wochenschrift, 1903), in Himmelweit
87Ibid., p. 313.

346
 Paul Ehrlich and his Receptor Concept
theory had "passed the test perfectly".92 The appearance of scientific phenomena that were
inconsistent with his theory were explained by Ehrlich as a result of the highly intricate
conditions of the animal organism. The inconsistencies would serve to deepen the theory
and to promote its success.93 Thus a theory should not be dismissed as soon as any contra-
diction occurred, but should be carefully rethought. Ehrlich saw himself as a pioneer of
a new medicine of the future, and he compared his "side-chain theory" with Rudolf
Virchow's (1821-1902) "cellular pathology", which also had not been successful at once.94
The insecure basis of Ehrlich's theory provoked critics even at an early stage in its
development. The critics and his way of dealing with them led Ehrlich deeper into his
receptor concept. He attributed what he called the "unitarian view" (unitarischer Stand-
punkt) to many of his critics. This attitude stood in sharp contrast to his own "pluralistic
conception" (plurimistische Anschauung). Based on their own experiments, the unitarians
attacked specific points of the side-chain theory and thereby questioned Ehrlich's micro-
cosmos of immunological substances.95 Ehrlich identified one opposing group of scientists
at the Pasteur Institute in Paris: the French immunologist and bacteriologist Emile Roux
(1853-1933), made deputy director in 1895 and since 1904 director of the Pasteur Institute,
his Belgian colleague and co-worker Jules Bordet (1870-1961), and the Russian immu-
nologist and bacteriologist Elie Metchnikoff (1845-1916), who had worked at the
Institute since 1888. The dispute between these three researchers on one side and Ehrlich
on the other began about 1897, and went on for about ten years.96 The most important
conflict was, however, with Jules Bordet. The latter had developed a special theory on the
dissolution ofred blood cells. In 1900, Bordet declared there to be no direct relation between
immune bodies and complement. The red blood cells were merely made sensitive by the
immune bodies-a view rejected by Ehrlich as purely mechanistic. Following that, the cells
were influenced by the complement, which Bordet named "alexine" (Alexin). Furthermore,
Bordet questioned the existence of a variety of immune bodies on the basis of his own
experiments on haemolysis. In one species there was only one alexine, causing both
haemolysis and bacteriolysis.97
Such attacks annoyed Ehrlich considerably, and the example of the Paris trio reveals his
methods of dealing with critics of the side-chain theory. Ehrlich instructed his assistants to
(ed.), vol. 2, op. cit., note 4 above, pp. 368-90, Himmelweit (ed.), vol. 2, op. cit., note 4 above,
esp. p. 383. pp. 84-5.
92" die Probe des Versuchs aufs Beste bestan- 97Ehrlich and Morgenroth, 'Uber Hamolysine.
den". See Ehrlich, op. cit., note 86 above, p. 306. Vierte Mittheilung', op. cit., note 76 above, pp. 214,
93Ehrlich and Morgenroth, 'Ober Hamolysine. 218, 220-3. For Bordet, see Jules Bordet, 'Le
Funfte Mittheilung', op. cit., note 79 above, pp. 234-5. Mecanism de l'agglutination', Annales de L'Institut
94Paul Ehrlich to Veit (this could have been Pasteur, 1899, 13: 225-50; idem, 'Agglutination et
either Gustav Veit or Johann Veit), 22 Jan. 1903, in dissolution des globules rouges par le serum', Annales
Direktor, Ehrlich X, 23 Dec. 1902 to 26 Jan. 1903, box de L'Institut Pasteur, 1899, 13: 273-97; idem, 'Les
22, series V, (3-complete)-1, 2, 4 (2-incomplete), serums hemolytiques, leurs antitoxines et les theories
pp. 169-71, esp. 171, Paul Ehrlich Collection, des serums cytolytiques', Annales de L'Institut
RUA, RAC. Pasteur, 1900, 14: 257-96. See also Aschoff, op. cit.,
95 Ehrlich and Morgenroth, 'Ober Hamolysine. note 9 above, pp. 96-8; Silverstein, op. cit., note 9
Sechste Mittheilung', op. cit., note 80 above, pp. 256-7, above, pp. 99-104, and the detailed analysis of Eileen
English transl. pp. 278-9. Crist and Alfred I Tauber, 'Debating humoral immunity
96See Ehrlich's remark about Roux and Buchner and epistemology: the rivalry of the immunochemists
which seems to have started the dispute about the side- Jules Bordet and Paul Ehrlich', J. Hist. Biol., 1997, 30:
chain theory, Paul Ehrlich, 'Zur Kenntnis der 321-56, esp. p. 329.
Antitoxinwirkung' (Fortschritte der Medizin, 1897), in

347
 Cay-Riidiger Prull
repeat Bordet's experiments, and under the heading "against Bordet" (gegen Bordet) he
gave directions on pieces of paper. The results of the experiments did not lead to a revision of
the side-chain theory, but to its vindication. The newly obtained immunological knowledge
was integrated into Ehrlich's flexible, pluralistic theory.98 In this sense all the contributions
of Ehrlich and his workers served not only to consolidate the side-chain theory but also to
defend it against any objections. Ehrlich had a busy correspondence with colleagues. In his
letters, he reported promptly on his latest findings and dissected the experiments of his
opponents, describing them as failed criticism of the side-chain theory. For example,
Ehrlich reported to a colleague that Metchnikoff was the "real spiritus rector" of the attacks
from Paris, having softsoaped Roux with his "breathtaking personality". It was "such a
shame that such an experimenter and such a clear head as Roux got so deeply into mysticism
and into the Russian fog".99 Ehrlich was friends with many of his opponents, but when it
came to his theory, he unfolded a massive campaign against any critics, in front or behind the
curtain. Ehrlich complained about seemingly disparaging remarks in secondary literature.
Once he tried to urge the editor of the journal Deutsche Medizinische Wochenschrift to stop
the printing of critical remarks by one of his opponents, because his own theory "had gained
full acceptance already". 10 Ehrlich sorted his colleagues into friends and enemies of his
theory. In October 1902, he wrote to William Henry Welch (1850-1934): "I was most
delighted to recognize you as one of the warmest friends of the theory, but even more that
you could achieve such new and fundamental insights with its help". In contrast, he wrote to
a pharmacologist in Halle, Germany, "that every impartial person reading the literature has
to count you as an absolute opponent".'01 Again, Ehrlich related the remark to "the theory",
which occupied him more and more in the years after 1897. This becomes apparent through
other critics of his concept.

98 Two Laborzettel, both 1901, in Zettel Buch II und 35-7; Oswin Gunther, 'Immunitatstheorien. Von der
Carcinom, 25 Dec. 1900 to 21 Sept. 1901, box 8, series Seitenkettentheorie zur FlieBbandtheorie', in Zum 100.
II, (3)-i, 2, 4, pp. 292, 293, Paul Ehrlich Collection, Geburtstage Paul Ehrlichs und zum Wiederaufbau des
RUA, RAC. For some general remarks on the dispute Paul-Ehrlich-Instituts, Arbeiten aus dem Paul-Ehrlich-
between Ehrlich and Bordet, see also Arthur M Institut, dem Georg-Speyer-Haus und dem Ferdinand-
Silverstein, 'Pasteur, Pastorians, and the dawn of Blum-Institut zu Frankfurt a. M., Issue 51, Stuttgart,
immunology: the importance of specificity', Hist. Gustav Fischer, 1954, pp. 68-107, esp. pp. 75-81.
Philos. Life Sci., 2000, 22: 29-41, esp. pp. 37-9; and 1 00, . -. in der ganzen Linie sich anerkennung
the comments of August von Wassermann, op. cit., verschafft haben". See Paul Ehrlich to Rudolf Kobert,
note 19 above, pp. 148-50. Rostock, 1 Dec. 1902; Paul Ehrlich to Albert
99"... der 'wirkliche spiritus rector'; mit seiner Eulenburg, Berlin, 15 Nov. 1902, in Direktor, Ehrlich
'hinreissenden pers6nlichkeit'. Es sei 'jammerschade, IX, 25 Sept. 1902 to 23 Dec. 1902, box 21, series V,
dass ein solcher experimentator und klarer kopf wie (3-complete)-l, 2, 4 (2-incomplete), pp. 434-47,
Roux so in den mysticismus und den russischen esp. 434-7; pp. 376-7, quotation on p. 377, Paul
nebel gerathen musste!"'. See Paul Ehrlich to Carl Ehrlich Collection, RUA, RAC.
Salomonsen, Copenhagen, 24 Feb. 1899, in Copir Buch 101 "Hocherfreulich war es mir, Sie wieder als einen
Im. Ehrlich, 21 Feb. 1899 to 31 July 1899, box 5, series so warmen freund der theorie zu erkennen, noch mehr
I, (3)-1, 2,4, pp. 13-16, Paul Ehrlich Collection, RUA, aber, dass Sie durch diesselbe zu so neuen und fun-
RAC. Metchnikoff's theory of phagocytosis (digestion) damentalen gesichtspunkten gekommen sind"; "dass
of bacilli through leucocytes and the latter's ability to jeder Unbefangene, der die Literatur liest, Sie zu den
produce antitoxin was seen as an attack on the "side- absoluten Gegnern zihlen muss."; See Paul
chain theory" by Ehrlich; see Aschoff, op. cit., note Ehrlich to William H Welch, Baltimore, 20 Oct.
9 above, pp. 28, 42-3, 103-4, 115-17. For some 1902; Paul Ehrlich to Ernst Fuld, Halle, 27 Oct. 1902,
general remarks on the dispute between Ehrlich and in Direktor, Ehrlich IX, ibid., pp. 117-18, 182-7, esp.
Metchnikoff, see Silverstein, op. cit., note 98 above, pp. pp. 182-3.

348
 Paul Ehrlich and his Receptor Concept
Ehrlich's style of dealing with critics of the side-chain theory can also be found in his
controversy with the physical chemist Svante Arrhenius (1859-1927) and his student
Thorvald Madsen (1870-1957), which started in 1903. Ehrlich had to defend his biological
point of view against a physico-chemical interpretation of antitoxin-toxin binding. Arrhe-
nius and Madsen applied basic chemical laws to processes of life, which, according to
Ehrlich, could not be expressed in such rigid formulas. Above all, Arrhenius adopted
Bordet's unitarian point of view on the complement and the haemolysis ofblood. 102 Ehrlich
again carried out experiments and started a letter campaign against Arrhenius.103 In a letter
to Althoff, presumably written in 1904, Ehrlich noted that Arrhenius would be "pushed to
the wall".104
Even more serious was Ehrlich's dispute with Max von Gruber (1853-1927), professor of
hygiene at Vienna from 1887 to 1902 and at Munich from 1902 to 1923. Although giving
him credit for new findings in the field of immunology, Gruber attacked Ehrlich's pluralism
of specific toxines and immune bodies in a very polemical way, as purely speculative with a
nearly total lack of evidence. He did this in several papers on immunology, published
between 1901 and 1903. Again, Ehrlich made tremendous efforts to explain to his academic
friends the weakness of Gruber's criticism. Ehrlich and some colleagues were even evicted
from a train, because the former had complained loudly about the rhetoric of Gruber.105
Ehrlich rejected the hygienists' criticism entirely as "stupid" (blodsinnig) and treated it
as a "quantitene'gligeable". This again led Gruber to point out "that he solely reproaches
him [Ehrlich] for in the course of his theorizing permitting too much fantasy and too
little criticism".106Beyond any judgement on the comments of the "gifted polemicist"
102
Paul Ehrlich to Svante Arrhenius, 1 Jan. 1903, in 105 Claude E Dolman, 'Paul Ehrlich and William
Direktor, Ehrlich X, 1902,23 Dec. to 26 Jan. 1903, box Bulloch: a correspondence and friendship (1896-
22, series V, (3-complete)--, 2, 4 (2-incomplete), 1914)', Clio Medica, 1968, 3: 65-84, esp. pp. 80-1;
pp. 71-9, Paul Ehrlich Collection, RUA, RAC. Svante Max Gruber, 'Zur Theorie der Antikorper. I. Ueber die
Arrhenius and Thorvald Madsen, 'Anwendung der Antitoxin-Immunitat', Munchener Medizinische
physikalischen Chemie auf das Studium derToxine und Wochenschrift, 1901,48: 1827-30, 1880-4; idem, 'Zur
Antitoxine', Zeitschriftffir Physikalische Chemie, Theorie der Antikorper. I. Ueber Bakteriolyse und
1903,44: 7-62; Svante Arrhenius, Quantitative laws in Haemolyse', ibid., pp. 1924-7, 1965-8; idem, Cl.
biological chemistry, London, G Bell, 1915, esp. Freiherr v. Pirquet (Referent: M. Gruber), 'Toxin und
pp. 110-39. For a detailed description of the Ehrlich- Antitoxin', Munchener Medizinische Wochenschrift,
Arrhenius controversy, see Lewis P Rubin, 'Styles in 1903, 50: 1193-6, esp. p. 1194; Max Gruber, 'Toxin
scientific explanation: Paul Ehrlich and Svante und Antitoxin. Bemerkungen zu Ehrlichs "Entgegnung
Arrhenius on immunochemistry', J. Hist. Med. Allied auf Grubers Replik"', Miunchener Medizinische
Sci., 1980, 35: 397-425. Wochenschrift, 1903, 50: 2297; idem, 'Neue Friichte
103 For example, Paul Ehrlich to Paul Heinrich der Ehrlichschen Toxinlehre', Wiener Klinische
Romer, 8 July 1903, in Direktor, Ehrlich XI, 1903, 13 Wochenschrift, 1903, 16: 791-3.
Mar. to 17 July 1903, box 23, series V, pp. 445-8; Paul 106Paul Ehrlich to Paul Heinrich Romer, 8 July
Ehrlich to S J Meltzer, 30 Dec. 1903, in Direktor, 1903, in Direktor, Ehrlich XI, 13 Mar. 1903 to 17 July
Ehrlich XIII, 21 Dec. 1903 to 13 June 1904, box 23, 1903, box 23, series V, pp. 445-8, Paul Ehrlich
series V, pp. 44 6, Paul Ehrlich Collection, RUA, RAC. Collection, RUA, RAC: "... ich mache ihm nur zum
See also further letters of Ehrlich in this file. Vorwurf, dass er bei seinem Theoretisieren zuviel
104Paul Ehrlich to Friedrich Althoff, 12 Sept. Phantasie und zu wenig Kritik walten lasse". See
presumably 1904, in Nachlass Althoff A I, GStA PK. Max Gruber, 'Toxin und Antitoxin. Eine Replik
VI. HA, Rep. 92, No. 258, pp.15-16, esp. pp.22-30. For auf Herrn Ehrlichs Entgegnung', Munchener
the controversy between Ehrlich and Arrhenius/ Medizinische Wochenschrift, 1903, 50: 1825-8,
Madsen, see also Pauline M H Mazumdar, Species and esp. p. 1825.
specificity: an interpretation of the history of
immunology, Cambridge University Press, 1995,
pp. 202-13.

349
 Cay-Ruidiger Prull
Gruber,107 it is evident that he hit Ehrlich on a vulnerable spot. All the inventions of new
terms and substances could not really explain the formation of antibodies. Gruber made one
general remark which explains his attitude best: "Only the conditions which accompany the
processes of life are accessible to our research" .108 Ehrlich, despite his adverse reaction to
Gruber's remarks, published two papers devoted to his opponent in 1903.109
The strongest blow against Ehrlich' s side-chain and receptor theory came from a group of
immunochemists, who attacked the chemical specificity of the concept on unitarian
grounds. The most important of these was the Viennese pathologist and immunologist
Karl Landsteiner (1868-1943). As a student of Gruber in 1896, he became involved in the
dispute with Ehrlich and joined the front-line of Ehrlich's opponents. Landsteiner then
developed the colloid theory of immunology: reactions are influenced by the chemical
constitution of substances, but above all the quantitative relationship is influenced by
physical phenomena such as solubility and temperature. Echoing Gruber's criticism, Land-
steiner attacked Ehrlich's "uneconomical" pluralism, which in his view was loaded with
too many uncertainties. From 1903 onwards, Landsteiner invaded the field of immunology
with his theory.!10 By 1912 "the colloid theory had superseded Ehrlich's, although in the
practice of the serum institutes the old assumption of clear-cut, one-to-one specificity was
essentially unchanged"! l l
All these critics did not lead Ehrlich to rethink his pluralistic attitudes. On the contrary, as
many printed and unprinted sources show, he became more and more obsessed with his
theory in the first years after 1900. Ehrlich always had only a meagre interest in culture and
politics, and there are no hints that he recognized his involvement in the state-oriented and
nationalistic bacteriological research of his teacher Koch.'12 Ehrlich talked incessantly
about his work, painted sketches of the receptors on note-pads, letters, postcards and even
on the floor or tablecloths.'13 And, as we know from the recent contribution of Cambrosio,
Jacobi and Keating, the images themselves fuelled the criticism of their opponents that they
were an attempt by Ehrlich to illustrate invisible structures, whose material existence was
not evident but debated at this time. Bordet made Ehrlich's graphic representations respon-
sible for the success of the side-chain theory, arguing that it was not based on fact but on
107 Michael Hubenstorf described Gruber as a "'Ibid., p. 255.
"gifted polemicist" (begabter Polemiker), see idem, "2 See Paul Weindling, 'Scientific elites and
'Gruber, Max (von)', in Wolfgang U Eckart and laboratory organisation in fin de siecle Paris and Berlin:
Christoph Gradmann (eds), Arzte Lexikon. Von der the Pasteur Institute and Robert Koch's Institue
Antike bis zur Gegenwart, 2nd ed., Berlin and for Infectious Diseases compared', in Andrew
Heidelberg, Springer, 2001, pp. 140-1, esp. 140. Cunningham and Perry Williams (eds), The laboratory
'08"Nur die begleitenden Umstande der revolution in medicine, Cambridge University Press,
Lebensvorgange sind unserer Forschung zuganglich." 1992, pp. 170-88; Christoph Gradmann, 'Money and
See Gruber, op. cit., note 106 above, p. 1827. microbes: Robert Koch, tuberculin and the foundation
109Ehrlich, op. cit., note 91 above; idem, 'Toxin und of the Institute for Infectious Diseases in Berlin in
Antitoxin. Entgegnungen auf Grubers Replik' 1891', Hist. Philos. Life Sci., 2000, 22: 59-79; Heinz-
(Minchener Medizinische Wochenschrift, 1903), in Peter Schmiedebach, 'The Prussian state and micro-
Himmelweit (ed.), vol. 2, op. cit., note 4 above, pp. 391- biological research-Friedrich Loeffler and his
94. For the debate with Gruber, see Silverstein, op. cit., approach to the "invisible" virus', Arch. Virol., 1999,
note 9 above, pp.104-7. For the controversy between 15: Suppl., pp. 9-23; Ragnhild Munch and Stefan S
Ehrlich and Gruber, see Mazumdar, op. cit., note 104 Biel, 'Expedition, Experiment und Expertise im
above, pp. 123-35. Spiegel des Nachlasses von Robert Koch', Sudhoffs
l "O See the detailed analysis in Mazumdar, op. cit., Archiv, 1998, 82: 1-29.
note 104 above, pp. 107-278, esp. pp. 136,216-17,147, 13Marquardt, op. cit., note 17 above, pp. 29, 36,
226. 40-2, 54-5.

350
 Paul Ehrlich and his Receptor Concept
image, which was then wrongly accepted as the picture of real material life. 114 Remarkably
enough, Ehrlich's efforts to consolidate the receptor theory were supported by the realm of
literary fiction. One of the few things Ehrlich did in his leisure hours was to read detective
stories, especially those of Sir Arthur Conan Doyle (1859-1930). These served to stimulate
reflection on his work, for he filled the margins with comments and formulas.' 15 The ideas
of his teacher Robert Koch flooded back in his mind through literature: Conan Doyle was an
admirer of Koch and did not hesitate to travel to Berlin in 1890 to investigate the bacter-
iologist's tuberculin cure. Doyle's fascination with the idea of preventing the invasion of the
empire by microbes shaped the work of his fictional hero Sherlock Holmes. The latter
concentrated explicitly on detecting the "invisible" and subversive threads of life. Doyle
saw both Holmes and Koch as "imperial knights" who saved their empires." 6
The experimental facts and the production of sketches of the actually invisible immu-
nological entities conflated in Ehrlich's work. 1'7 Together both had to ensure the credibility
of the side-chain and receptor theory just as visual (early photography) and functional
(animal experimentation) proof had to demonstrate evidence for Koch's postulation of
living microbes."8 Ehrlich explained that his sketches would be "merely a pictorial
method" and therefore that they did not correspond to reality. 119 But such singular remarks
fade before the extensive use Ehrlich made ofhis pictures to persuade his contemporaries of
the truthfulness of his theory. The images, as well as their conflation with experimental
evidence, were in turn boosted by the criticism of them. The system allowed Ehrlich to
reconstruct and enlarge his receptor concept infinitely as there was no factual resistance.
Therefore, notwithstanding the opposing views, Ehrlich compared himself with a victorious
chess player who cannot finish the game because his defeated opponents do not want to give
up.'20 The intense concentration on the side-chains and the receptors decreased only
gradually until 1905, in parallel with the increase of his cancer research and finally-
from about 1906-with his work on chemotherapy. The impact of Landsteiner's immu-
nological theory on Ehrlich's shift of interests is questionable: in 1906, Ehrlich was still
criticizing colloid chemistry.'2' He thought his own theory complete and he now used it as a
tool to examine other fields of medical research.'22

114Alberto Cambrosio, Daniel Jacobi, and Peter of bacteria', Hist. Philos. Life Sci., 2000, 22:
Keating, 'Ehrlich's "beautiful pictures" and the con- 43-58.
troversial beginnings of immunological imagery', Isis, "9Paul Ehrlich, 'On immunity with special refer-
1993, 84: 662-99, esp. pp. 667-9, 684; Crist and ence to cell life: Croonian Lecture (Proc. Roy. Soc.
Tauber, op. cit., note 97 above, pp. 336-7; 346-53. 1900), in Himmelweit (ed.), vol. 2, op. cit., note 4
"15Marquardt, op. cit., note 17 above, pp. 28-9; above, pp. 178-95, here p. 187.
Dolman, op. cit., note 105 above, p. 81. 120Paul Ehrlich to Friedrich Althoff, Aug. 1903, in
116For Doyle's work and its interpretation see the Nachlass Althoff B, GstA PK. VI. HA, Rep. 92, No. 33,
brilliant analysis of Laura Otis, 'Arthur Conan Doyle: pp. 142-3, esp. p. 142.
an imperial immune system', in idem, Membranes: 121 Crist and Tauber, op. cit., note 97 above, p. 333.
metaphors of invasion in nineteenth-century literature, Crist and Tauber also point out that Ehrlich never
science, and politics, Baltimore and London, Johns abandonded his side-chain theory; see ibid., p. 325.
Hopkins University Press, (1999) 2000, pp. 90-118, 122 For Ehrlich's extremely sensitive reaction to
esp. pp. 91-8. critics, see also the more or less hagiographic account of
117Cambrosio, Jacobi, and Keating, op. cit., note Walter Greiling, Im Banne der Medizin. Paul Ehrlich.
114 above, p. 699. Leben und Werk, Dusseldorf, Econ, 1954, pp. 120-2.
118Thomas Schlich, 'Linking cause and disease Research on chemotherapy was above all carried out in
in the laboratory: Robert Koch's method of super- the Georg-Speyer House, newly erected in 1906. This
imposing visual and "Functional" representations Institute was attached to Ehrlich's Institute. See

351
 Cay-Riidiger Prull
Although he was very enthusiastic about the receptors, there are indications in Ehrlich's
correspondence that he was not entirely satisfied with his situation. Even in the last Berlin
years at the Institute in Steglitz, namely after 1898, Ehrlich was faced with the problem that
as head of a theoretical institute he had no patients.123 The reason for his wish to have
patients was the often repeated intention that "after having worked entirely on questions of
serum therapy for such a long time, I want to turn a bit to my old pet subject again, which is
histological and biological staining"; or, expressed in another way: "After the long period
of immunological magic I am now again getting around to focus again a little bit on the dyes
as my old pet subject ..,, 124 Although predominantly publishing on side-chains between
1897 and 1905 (twenty-eight papers), he did not stop publishing on dye-stuffs and their
clinical application (six papers) as well as on purely chemical problems (two papers).'25
Even in his immunological studies he did not hesitate to draw parallels with staining
processes. Ehrlich was not very keen to work as a physician again, but rather to carry
out the clinical testing of potential drugs. In the following period, he pre-tested dyes on
animals, examined the side effects and thereafter sent them to clinicians with the request that
they perform therapeutic human experiments. Ehrlich ordered the dye stuffs from phar-
maceutical companies. Then he arranged for them to be packed into capsules before handing
them over to physicians. This was meant to simplify the application to patients. 126 The
bottleneck in this system were the patients, and in the following years Ehrlich constantly
begged clinicians to perform therapeutic experiments. The problem forced him to go back to
those he knew well, for example his old friend Albert Neisser (1855-1916), a dermatologist
in Breslau. In 1898 Ehrlich wanted Neisser to administer some of his dyes to patients. These
dyes had already been tested on rabbits and hares, and ha,d been well-tolerated. Ehrlich
recommended a slow increase in the dosage, "first of all in cases of headaches, vague
rheumatic plagues, gonorrhoea and cystitis".127 Neisser was willing to test the dye "bril-
liant blue" on patients. In November 1898, Ehrlich became pushy and urged Neisser to
speed up the trials: "After all, however, it is not so difficult-considering your great
experience with these things-to find the approximate dosage bene tolerata".128 Neisser,
who was then involved in a scandal about his performance of human experiments on

'Das Speyer-Haus in Frankfurt a.M.' (Berliner Anilin- und Sodafabrik, Ludwigshafen, Nov. 15,
Klinische Wochenschrift, 1906), in Nachlass Althoff A 1898; Paul Ehrlich to Nietzki, 24 Dec. 1898, in Copir
I, GStA PK. VI. HA, Rep. 92, No. 258, p. 66. Buch II. Direktor, 11 Nov. 1898 to 21 Feb. 1899,
123Liebenau comments that the Institute in box 4, series I, (3)-l, 2, 4, pp. 69, 242, Paul Ehrlich
Frankfurt gave Ehrlich the opportunity to conduct Collection, RUA, RAC.
"controlled bedside trials". Besides the problem of 125 See Himmelweit (ed.), vols. 1-3, op. cit., note 4
using modem terms and methods anachronistically, it above.
should be remembered that Ehrlich was no longer 126 See especially Ehrlich's letters in Copir
attached to a clinical unit and that he relied on clinical Buch II. Direktor, 11 Nov. 1898 to 21 Feb. 1899,
colleagues to perform therapeutic human experi- box 4, series I, (3)-l, 2, 4, Paul Ehrlich Collection,
mentation. See Liebenau, op. cit., note 46 above, p. 70. RUA, RAC.
124 ... nachdem ich so lange serumtherapeutische 127..*. zunachst bei kopfschmerzen, vagen rheu-
fragen fast ausschliesslich bearbeitet habe, mich wieder matoiden seuchen, gonorrhoe und cystitis." See Paul
etwas mehr meinem alten lieblingsgebiet theorie der Ehrlich to Albert Neisser, no date, in ibid., pp. 93-4.
histologischen und biologischen farbung 128"Schliesslich ist es doch auch wohl nicht gar
zuzuwenden."; "Nach dem langen immunitats zauber zu schwer-bei Eurer grossen ubung in diesen din-
komme ich jetzt wieder dazu, mich meinem alten gen-die ungefahre dosis bene tolerata heraus zu
lieblingsgebiet der farbstoffe wieder etwas bekommen". See Paul Ehrlich to Albert Neisser, 30
zuzuwenden .. .". See Paul Ehrlich to the Badische Nov. 1898, in ibid., p. 128.

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 Paul Ehrlich and his Receptor Concept
prostitutes and children without information and consent, tested several dyes for Ehrlich and
discussed with him the patients chosen.129 Other colleagues were not as helpful as Neisser.
Ehrlich repeatedly requested them to test his substances. Even if the clinician was in
principle prepared to undertake the experiments, Ehrlich had to press forcefully for
tests to be done and the results reported. The system did not work well and from June
1899 Ehrlich showed signs of frustration. He remarked to a colleague that "all these
gentlemen undertake the staining therapy more or less to do me a favour but not out of
deep conviction,. 130
Finally, dye testing appears to have been a futile attempt to restore the old Charite
conditions, where laboratory work and animal experimentation could be linked with
clinical expertise. Ehrlich's favourite style of work was so well-known that in 1899 the
administration of the city of Frankfurt feared that the patients of the city hospitals would be
"used for experimental purposes".'3' But what was left during his first years in Frankfurt
were the merely theoretical studies on the receptors, based on animal trials and test tubes.
Although basically satisfied with his independent position and his working conditions,'32
Ehrlich also detailed the drawbacks when he described his work on the receptors in 1901:
"Because I myself am not in a position to perform such investigations on a large number of
patients, I thought it to be my duty to clarify my point ofview and this way to lay the basis of
the work in a field whose importance for pathology and therapy presumably will be fully
acknowledged only after many years".'33 In 1905, this argument was essentially repeated
when he explained that he had done his work and that "more new and successful work"
could only be done by "specialists, who have the necessary clinical and pathological
material".'34 This did not mean that Ehrlich wanted to become a full clinician: in the
same year, presumably because of responsibilities towards his Institute, he rejected the call

129 Paul Ehrlich to Albert Neisser, 9 Dec. 1898; 7 Ehrlich, 'Das Konigliche Institut fur experimentelle
Jan. 1899, in ibid., pp. 178, 179-80, esp. pp. 180, 299. Therapie zu Frankfurt a.M.', Festschrift zum XIV.
See also Barbara Elkeles, 'Medizinische Internationalen Kongrefifir Hygiene und
Menschenversuche gegen Ende des 19. Jahrhunderts Demographie, Berlin 1907, dargeboten von dem
und der Fall Neisser: Rechtfertigung und Kritik einer PreufJischen Minister der geistlichen, Unterrichts- und
wissenschaftlichen Methode', Medizinhist. J., 1985, Medizinalangelegenheiten, Jena, Fischer, 1907, in
20: 135-48; idem, Der moralische Diskurs iuber das Nachlass AlthoffB, GStA PK. VI. HA, Rep. 92, No. 33,
medizinische Menschenexperiment im 19. Jahrhundert, pp. 244-55, esp. pp. 251-53. His cousin Carl Weigert
Stuttgart and New York, Fischer, 1996, esp. pp. persuaded Frankfurt's administration to agree to
190-206. Ehrlich's and Althoff's plans.
13 ....
. alle diese herren treiben die farbentherapie '32Paul Ehrlich to Friedrich Althoff, 23 Feb. 1900,
eigentlich mehr aus gefalligkeit mir gegenuber, als in Nachlass Althoff B, GStA PK. VI. HA, Rep. 92,
aus innerer uberzeugung." See Paul Ehrlich to Iwanoff, No. 33, pp. 114-15.
Petrowsk, 30 June 1899, in Copir Buch III. Ehrlich, 21 133"Da ich selbst nicht in der Lage bin, derartige
Feb. 1899 to 31 Jul. 1899, box 5, series I, (3)-l, 2, 4, Untersuchungen an einem grosseren Krankenmaterial
pp. 398, 399-402, 403, esp. pp. 398, 399, Paul Ehrlich durchzuflihren, habe ich es fur meine Pflicht gehalten,
Collection, RUA, RAC. die Gesichtspunkte klarzulegen und so die Basis fur die
131 Carl Weigert to Paul Ebrlich, 27 Mar. 1897, in Bearbeitung eines Gebietes zu schaffen, dessen
Nachlass Althoff A I, GstA PK. VI. HA, Rep. 92, No. Bedeutung fiur die Pathologie und Therapie vielleicht
258, pp. 15-16, esp. p. 15. In return for the contributions erst nach Jahren voll gewurdigt werden wird." See
of the city of Frankfurt to the erection of Ehrlich's Ehrlich, op. cit., note 86 above, p. 315.
Institute, Ehrlich had to examine body fluids and organ '34Paul Ehrlich to Friedrich Althoff, 1 Jan. 1905,
specimens from patients of the city hospital. See in Nachlass Althoff B, GStA PK. VI. HA, Rep. 92, No.
Baumler, op. cit., note 5 above, pp. 113-14; Paul 33, pp. 150-6, on p. 153.

353
 Cay-Ruidiger Prull
to become director of the First Medical Clinic in Vienna.'35 But he wanted to be attached to
clinical facilities as a laboratory worker. Ehrlich continued to be dependent on distant
collaboration with physicians in respect of drug trials-for example with his teacher
Koch.'36 And finally it was partly due to the revival of the old idea of the therapeutic
application of dyes, the application of trypan red to trypanosomes, that Ehrlich successfully
developed Salvarsan. In combination with the old ideas, the theoretical work on the side-
chains and receptors had its practical impact.'37

Paul Ehrlich, Pharmacology and the Receptors

Contrary to the current perceptions of Ehrlich's research progression, there was a leit-
motif, but no well developed master plan to lead him directly to the receptors. At the
beginning of his Berlin period, under the clinician Friedrich Theodor Frerichs, Ehrlich
advocated a concept which did not rely on the intricate construction of the side-chain theory
as a predecessor of the receptor concept. Ehrlich's provisional ideas on the theoretical basis
of his work did not play an important role in his objective of these years, namely to achieve
practical therapeutic results. These could be achieved by combining his favourite, chemical
laboratory work, with animal experimentation and therapeutic human experimentation in a
pragmatic way, and there was no need to deepen knowledge of the side-chains. The end of
Ehrlich's career in the clinical context, which was principally caused by the sudden death of
Frerichs, should be considered more seriously as a decisive break in Ehrlich's life than it has
been hitherto. He tried to use the laboratory, his most important work place, as a starting
point to rebuild the old system. Under Koch, he organized and performed clinical trials after
1895. But Ehrlich had to reorientate. He needed to achieve a secure position within the rigid
framework of institutionalized German medicine, which was mainly university based. This
objective was complicated by his Jewish faith, and he had to grasp Behring's and then
Althoffs offers. But Ehrlich remained indebted to the ideas of Julius Cohnheim on func-
tional (experimental) pathology as related to clinical problems.'38 In Germany, where the
older medical disciplines were well established from about 1900, this meant sitting between
the chairs of pathology on one side and clinical disciplines on the other. Although burdened
with problems, Ehrlich made rigorous efforts to initiate the testing of dyes with the help of
clinical colleagues even after he started to work in earnest on the side-chain and receptor
theory. These efforts were not successful, and in this situation the theoretical evidence of his
approach became more important than ever. In his institute, Ehrlich concentrated on con-
structing a comprehensive theory, not only of immunological processes but also of the
human metabolism in general. The final aim continued to be the practical application to
man, based on laboratory research. But at first, Ehrlich was contrained to satisfy himself, the
scientific community and the public with vague assumptions about the future effectiveness
of his concept in modem medicine. The critics of the side-chain and receptor theory, who
raised their voices shortly after Ehrlich had developed his ideas, stimulated the further
135Georg Joannovics, 'Paul Ehrlich 1854-1915', 137Parascandola, op. cit., note 11 above, esp. p. 30.
Wiener Klinische Wochenschrift, 1915, 28: 937-42, See also Ehrlich's papers on chemotherapy, especially
esp. p. 940. the Harben Lectures of 1907, in Himmelweit (ed.),
136 Munch and Biel, op. cit., note 112 above, vol. 3, op. cit., note 4 above.
pp. 13-14. 138Jokl, op. cit., note 5 above, pp. 972-4.

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 Paul Ehrlich and his Receptor Concept
consolidation of his theory, and they dragged Ehrlich more and more into the pluralistic
receptor world. The development of the receptor concept was, therefore, a construction
dependant on the combination of events in his private and public life and in his academic
career. This analysis corresponds with recent biographical research in general historiogra-
phy which has tried to explain the life of scientists on the basis of their social and cultural
environment. 139
This revisionist account of Ehrlich and his receptors helps us to understand why his
receptor theory was not at once generally accepted in pharmacology and it complements the
existing literature on the history of pharmacology.140 Ehrlich's receptor concept was basic
research, hard to understand, and its technical possibilities in his time were limited. But
there are other reasons. Despite his reputation, Ehrlich was no pharmacologist and he did not
agree with the mainstream of pharmacological research. This was devoted mainly to
physical or physico-chemical views of the character of drug-binding. It was based on
the idea of a mechanical connection between dye-stuff and cell. For pharmacologists
such as Walther Straub (1874-1944), one of the most prominent German pharmacologists
in the first half of the twentieth century, such physical properties as solubility and surface
tension played a principal role in the effect of a substance on a cell. Arthur Cushny (1866-
1926), one of the most internationally influential pharmacologists at the turn ofthe century,
at least restricted the impact of structural chemistry in terms of a physico-chemical view. 141
Above all, the doubts of contemporary pharmacologists were fuelled by the theoretical
character of Ehrlich's ideas,142 which could be promoted only with the help of a vast
propaganda apparatus. Although the side-chain theory delivered the basis for Ehrlich's
own research on cancer and chemotherapy,143 and was seen by colleagues as an inspiration
for further work, there was at first no evidence for its usefulness to immunology or phar-
macology in general.'44As a construction, which came into existence as a product of
Ehrlich's social biography, his personality and his scientific career development, the

139Margit Szollosi-Janze, Fritz Haber, 1868-1934. above, pp. 400-7; Cambrosio, Jacobi, and Keating,
Eine Biographie, Munich, Beck, 1998. See above all op. cit., note 114 above, pp. 662-99.
the introduction on pp. 9-22; idem, 'Lebens- 143 Ehrlich saw the side-chain theory as a "unifying
Geschichte-Wissenschaftsgeschichte. Vom Nutzen bond" (einigendes Band) ofthe work of all departments
der Biographie fur Geschichtswissenschaft und in the Frankfurt Institute. See Ehrlich, op. cit., note 131
Wissenschaftsgeschichte', Berichte zur above, p.251. See also 'Paper on the cancer research of
Wissenschaftsgeschichte, 2000, 23: 17-35; Christoph Ehrlich', anonymous, Frankfurt, 7 April 1906, in
Gradmann, 'Leben in der Medizin: Zur Aktualitat von Nachlass Althoff A I, GstA PK. VI. HA, Rep. 92,
Biographie und Prosopographie in der No. 258, pp. 32-8, here esp. pp. 37-8; Lenoire, op. cit.,
Medizingeschichte', in Norbert Paul and Thomas note 22 above, pp. 79-82.
Schlich (eds), Medizingeschichte, Aufgaben, '44See Paul Ehrlich and Hans Sachs, 'Kritiker der
Probleme, Perspektiven, Frankfurt and New York, Seitenkettentheorie im Lichte ihrer experimentellen
Campus, 1998, pp. 243-65. und literarischen Forschung. Ein Kommentar zu den
140 See Parascandola and Jasensky, op. cit., note 2 Arbeiten von Bang und Forssmann' (Munchener
above; Parascandola, op. cit., note 2 above. Medizinische Wochenschrift, 1909), in Himmelweit
141 John Parascandola, 'The controversy over (ed.), vol. 2, op. cit., note 4 above, pp. 448-63; Paul
structure-activity relationships in the early twentieth Ehrlich and Hans Sachs, 'Ist die Ehrlichsche
century', Pharm. Hist., 1974,16: 54-63, esp. pp. 55-6. Seitenkettentheorie mit den tatsachlichen
142This was registered already by contemporaries, Verhaltnissen vereinbar? Bemerkungen zu der II.
see, for example, 'Obituary. Wirklicher Geheimrat Paul Mitteilung von Bang und Forssmann' (Munchener
Ehrlich', Lancet, 1915, i: 525-6, esp. p. 525. It is Medizinische Wochenschrift, 1910), in ibid.,
considered also in the secondary literature on the pp. 464-71; Paul Ehrlich to Friedrich Althoff, 18 Mar.
receptors; see, for example, Rubin, op. cit., note 102 presumably 1907, in Nachlass Althoff B, GstA PK. VI.

355
 Cay-Riidiger Prull
receptors were the final stage of a process spiralling up into the enterprise of theoretical
research. With his propaganda management and his experimental system, Ehrlich was able
successfully to adapt the hypothetical receptor system to every new challenge. The decision
whether to join Ehrlich or to oppose him, whether to be a "pluralist" or a "unitarian", had
parallels with religious profession. One had to believe in "the theory" or to abandon it
totally.145 It was very much shaped by its creator, who tried to increase its credibility
through a combination of persuasion and force. At this point, it could not be foreseen
that the "discovery" of the receptors would become so central to pharmacology, and
biomedicine in general, after 1945.

HA, Rep. 92, No. 33, p. 329. Although the basic idea of William Bulloch, The history of bacteriology, 2nd ed.,
chemical specificity survived in immunology after the London, Oxford University Press, (1938) 1960,
death of the master, this was not true in general for pp. 275-9.
his whole receptor concept. This remained controver- 145 See also August Wassermann, 'Paul Ehrlich',
sial as Ehrlich's mature theory could not be used to Munchener Medizinische Wochenschrift, 1909, 56:
explain the action of the living organism, see 245-7, esp. 247.
Mazumdar, op. cit., note 65 above, pp. 18-21; also

356