Editing Paul Ehrlich (section)

===Serum research===
====Friendship with Robert Koch====
[[File:Robert Koch.jpg|thumb|left|[[Robert Koch]], around 1900]]

When a student in Breslau, Ehrlich was given an opportunity by the pathologist Julius Friedrich Cohnheim to conduct extensive research and was also introduced to [[Robert Koch]], who was at the time a district physician in Wollstein, Posen Province. In his spare time, Koch had clarified the life cycle of the [[anthrax]] pathogen and had contacted [[Ferdinand Cohn]], who was quickly convinced by Koch's work and introduced him to his Breslau colleagues. From 30 April to 2 May 1876, Koch presented his investigations in Breslau, which the student Ehrlich was able to attend.

On 24 March 1882, Ehrlich was present when Koch, working since 1880 at the Imperial Public Health Office (''Kaiserliches Gesundheitsamt'') in Berlin, presented the lecture in which he reported how he was able to identify the [[Mycobacterium tuberculosis|tuberculosis pathogen]]. Ehrlich later described this lecture as his "greatest experience in science". The day after Koch's lecture, Ehrlich had already made an improvement to Koch's staining method, which Koch unreservedly welcomed. From this date on, the two men were bound in friendship.

In 1887 Ehrlich became an unsalaried lecturer in internal medicine (''[[Privatdozent]] für Innere Medizin'') at Berlin University, and in 1890 took over the tuberculosis station at a public hospital in Berlin-Moabit at Koch's request. This was where Koch's hoped-for tuberculosis therapeutic agent [[tuberculin]] was under study; and Ehrlich had even injected himself with it. In the ensuing [[Tuberculin#The tuberculin scandal|tuberculin scandal]], Ehrlich tried to support Koch and stressed the value of tuberculin for diagnostic purposes. In 1891 Koch invited Ehrlich to work at the newly founded  ''Institut für Infektionskrankheiten'' (Institute of Infectious Diseases, which became the [[Robert Koch Institute]])<ref>[http://www.rki.de/EN/Content/Institute/History/history_node_en.html The Robert Koch Institute]. rki.de</ref> at ''Friedrich-Wilhelms-Universität'' ([[Humboldt University]]) in Berlin. Koch was unable to give him any remuneration, but did offer him full access to laboratory staff, patients, chemicals and laboratory animals, which Ehrlich always remembered with gratitude.

====First work on immunity====
Ehrlich had started his first experiments on [[immunization|immunisation]] already in his private laboratory. He accustomed mice to the poisons [[ricin]] and [[abrin]]. After feeding them with small but increasing dosages of ricin he ascertained that they had become "ricin-proof". Ehrlich interpreted this as immunisation and observed that it was abruptly initiated after a few days and was still in existence after several months, but mice immunised against ricin were just as sensitive to abrin as untreated animals.

This was followed by investigations on the "inheritance" of acquired immunity. It was already known that in some cases after a [[smallpox]] or syphilis infection, specific immunity was transmitted from the parents to their offspring. Ehrlich rejected inheritance in the genetic sense because the offspring of a male mouse immunised against abrin and an untreated female mouse were not immune to abrin. He concluded that the foetus was supplied with [[antibodies]] via the pulmonary circulation of the mother. This idea was supported by the fact that this "inherited immunity" decreased after a few months. In another experiment he exchanged the offspring of treated and untreated female mice. The mice which were nursed by the treated females were protected from the poison, providing the proof that antibodies can also be conveyed in milk.

Ehrlich also researched [[autoimmunity]], but he specifically rejected the possibility that an organism's immune system could attack the organism's own tissue calling it "horror autotoxicus". It was Ehrlich's student, [[Ernest Witebsky]], who demonstrated that autoimmunity could cause disease in humans.<ref>{{cite journal|last1=Witebsky|first1=Ernest|title=Chronic Thyroiditis and Autoimmunization|journal=Journal of the American Medical Association|date=27 July 1957|volume=164|issue=13|pages=1439–47|doi=10.1001/jama.1957.02980130015004|pmid=13448890}}</ref><ref>{{cite journal|title=Autoimmunity versus horror autotoxicus: The struggle for recognition|last1=Silverstein|first1=Arthur M.|journal=Nature Immunology|date=1 April 2001|volume=2|issue=4|pages=279–281|doi=10.1038/86280|pmid=11276193|s2cid=10275131}}</ref> Ehrlich was the first to propose that regulatory mechanisms existed to protect an organism from autoimmunity, saying in 1906 that "the organism possesses certain contrivances by means of which the immunity reaction, so easily produced by all kinds of cells, is prevented from acting against the organism's own elements".<ref>{{cite journal|doi=10.1146/annurev-cancerbio-030419-033428|doi-access=free|title=Regulatory T Cells in Cancer|year=2020|last1=Plitas|first1=George|last2=Rudensky|first2=Alexander Y.|journal=Annual Review of Cancer Biology|volume=4|pages=459–477}}</ref>

====Work with Behring on a diphtheria serum====
[[Emil Behring]] had worked at the Berlin Institute of Infectious Diseases until 1893 on developing an [[antiserum]] for treating [[diphtheria]] and [[tetanus]] but with inconsistent results. Koch suggested that Behring and Ehrlich cooperate on the project. This joint work was successful to the extent that Ehrlich was quickly able to increase the level of immunity of the laboratory animals based on his experience with mice. Clinical tests with diphtheria serum early in 1894 were successful and in August the chemical company Hoechst started to market Behring's "Diphtheria Remedy synthesised by Behring-Ehrlich". The two discoverers had originally agreed to share any profits after the Hoechst share had been subtracted. Their contract was changed several times and finally Ehrlich was eventually pressured into accepting a profit share of only eight percent. Ehrlich resented what he considered as unfair treatment, and his relationship with Behring was thereafter problematic, a situation which later escalated over the issue of the valency<ref>In immunology [valency being an expression of the number of antigenic determinants with which one molecule of a given antibody can combine. A polyvalent acts against or interacts with more than one kind of antigen, antibody, toxin or microorganism]. Source: [http://medical-dictionary.thefreedictionary.com/valency TheFreeDictionary].</ref> of tetanus serum. Ehrlich recognised that the principle of serum therapy had been developed by Behring and [[Kitasato Shibasaburō|Kitasato]]. But he was of the opinion that he had been the first to develop a serum which could also be used on humans, and that his role in developing the diphtheria serum had been insufficiently acknowledged. Behring, for his part, schemed against Ehrlich at the Prussian Ministry of Culture, and from 1900 on Ehrlich refused to collaborate with him. Von Behring was the sole recipient of the first Nobel Prize in Medicine, in 1901, for contributions to research on diphtheria.<ref>{{cite book |author=Meyers, Morton A. |title=Happy Accidents: Serendipity in Modern Medical Breakthroughs |publisher=Arcade Publishing |url=https://archive.org/details/happyaccidentsse00meye|url-access=registration |year=2007 |isbn=978-1559708197}}</ref>

====The valency of serums====
[[File:Paul Ehrlich Freiburg.jpg|thumb|Commemorative plaque at the entrance of the anatomy institute of [[University of Freiburg|Freiburg University]] where Paul Ehrlich, as a medical student in the winter semester 1875/76, discovered the [[mast cell]]s]]
Since antiserums were an entirely new type of medicine whose quality was highly variable, a government system was established to guarantee their safety and effectiveness. Beginning 1 April 1895, only government-approved serum could be sold in the German Reich. The testing station for diphtheria serum was provisionally housed at the Institute of Infectious Diseases. At the initiative of Friedrich Althoff,<ref>an influential staff member in the Prussian Ministry of Religious, Educational and Medical Affairs (''Preußisches Ministerium der geistlichen, Unterrichts- und Medizinalangelegenheiten'')</ref> an Institute of Serum Research and Testing (''Institut für Serumforschung und Serumprüfung'') was established in 1896 in Berlin-Steglitz, with Ehrlich as director (which required him to cancel all his contracts with Hoechst). In this function and as honorary professor at Berliner University he had annual earnings of 6,000 marks, approximately the salary of a university professor. In addition to a testing department the institute had a research department.

In order to determine the effectiveness of diphtheria antiserum, a stable concentration of [[diphtheria toxin]] was required. Ehrlich discovered that the toxin being used was perishable, in contrast to what had been assumed, which for him led to two consequences: he did not use the toxin as a standard, but instead a serum powder developed by Behring, which had to be dissolved in liquid shortly before use. The strength of a test toxin was first determined in comparison with this standard. The test toxin could then be used as a reference for testing other serums. For the test itself, toxin and serum were mixed in a ratio so that their effects just cancelled each other when injected into a guinea pig. But since there was a large margin in determining whether symptoms of illness were present, Ehrlich established an unambiguous target: the death of the animal. The mixture was to be such that the test animal would die after four days. If it died earlier, the serum was too weak and was rejected. Ehrlich claimed to have made the determination of the valency of serum as accurate as it would be with chemical [[titration]]. This again demonstrates his tendency to quantify the life sciences.

Influenced by the mayor of Frankfurt am Main, Franz Adickes, who endeavored to establish science institutions in Frankfurt in preparation of the founding of a university, Ehrlich's institute moved to Frankfurt in 1899 and was renamed the Royal Prussian Institute of Experimental Therapy (''Königlich Preußisches Institut für Experimentelle Therapie''). The German quality-control methodology was copied by government serum institutes all over the world, and they also obtained the standard serum from Frankfurt. After diphtheria antiserum, tetanus serum and various bactericide serums for use in veterinary medicine were developed in rapid sequence. These were also evaluated at the institute, as was [[tuberculin]] and later on various [[vaccine]]s. Ehrlich's most important colleague at the institute was the Jewish physician and biologist Julius Morgenroth.

====Ehrlich's side-chain theory====
[[File:Paul Ehrlich Arbeitszimmer.jpg|thumb|Paul Ehrlich around 1900 in his Frankfurt office]]

Ehrlich postulated that cell protoplasm contains structures which have chemical ''side chains'' ([[macromolecule]]s) to which the toxin binds, affecting function. If the organism survives the effects of the toxin, the blocked side-chains are replaced by new ones. This regeneration can be trained, the name for this phenomenon being ''immunisation''. If the cell produces a surplus of side chains, these might also be released into the blood as antibodies.

In the following years Ehrlich expanded his side chain theory using concepts ("amboceptors", "receptors of the first, second and third order", etc.) which are no longer customary. Between the antigen and the antibody he assumed there was an additional immune molecule, which he called an "additive" or a "complement". For him, the side chain contained at least two functional groups.

For providing a theoretical basis for immunology as well as for his work on serum valency, Ehrlich was awarded the Nobel Prize for Physiology or Medicine in 1908 together with [[Élie Metchnikoff]]. Metchnikoff, who had researched the cellular branch of immunity, [[Phagocytosis]], at the [[Pasteur Institute]] had previously sharply attacked Ehrlich.