Paul Ehrlich (; 14 March 1854 – 20 August 1915) was a
Nobel Prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
-winning German physician and scientist who worked in the fields of
hematology,
immunology
Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see the ...
, and
antimicrobial chemotherapy. Among his foremost achievements were finding a cure for
syphilis in 1909 and inventing the precursor technique to
Gram staining bacteria. The methods he developed for staining tissue made it possible to distinguish between different types of blood cells, which led to the ability to diagnose numerous
blood diseases.
His laboratory discovered
arsphenamine
Arsphenamine, also known as Salvarsan or compound 606, is a drug that was introduced at the beginning of the 1910s as the first effective treatment for syphilis, relapsing fever, and African trypanosomiasis.
This organoarsenic compound was the f ...
(Salvarsan), the first effective medicinal treatment for
syphilis, thereby initiating and also naming the concept of
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
. Ehrlich popularized the concept of a
magic bullet. He also made a decisive contribution to the development of an
antiserum to combat
diphtheria
Diphtheria is an infection caused by the bacterium '' Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks more than 10% of those diagnosed with the disease may die. Signs and s ...
and conceived a method for standardizing therapeutic
serums.
In 1908, he received the
Nobel Prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
in Physiology or Medicine for his contributions to immunology.
He was the founder and first director of what is now known as the
Paul Ehrlich Institute, a German research institution and medical regulatory body that is the nation's federal institute for vaccines and biomedicines. A
genus
Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial nom ...
of
Rickettsiales
The Rickettsiales, informally called rickettsias, are an order of small Alphaproteobacteria. They are obligate intracellular parasites, and some are notable pathogens, including ''Rickettsia'', which causes a variety of diseases in humans, and ' ...
bacteria, ''
Ehrlichia
''Ehrlichia'' is a genus of Rickettsiales bacteria that are transmitted to vertebrates by ticks. These bacteria cause the disease ehrlichiosis, which is considered zoonotic, because the main reservoirs for the disease are animals.
''Ehrlichia ...
'', is named after him.
Life and career
Ehrlich was born 14 March 1854 in
Strehlen
Strzelin (german: Strehlen, cz, Střelín) is a town in Lower Silesian Voivodeship in south-western Poland. It is located on the Oława river, a tributary of the Oder, about south of the region's capital Wrocław. It is part of the Wrocław me ...
in the
Prussian
Prussia, , Old Prussian: ''Prūsa'' or ''Prūsija'' was a German state on the southeast coast of the Baltic Sea. It formed the German Empire under Prussian rule when it united the German states in 1871. It was ''de facto'' dissolved by an e ...
province of
Lower Silesia
Lower Silesia ( pl, Dolny Śląsk; cz, Dolní Slezsko; german: Niederschlesien; szl, Dolny Ślōnsk; hsb, Delnja Šleska; dsb, Dolna Šlazyńska; Silesian German: ''Niederschläsing''; la, Silesia Inferior) is the northwestern part of the ...
in what is now south-west
Poland
Poland, officially the Republic of Poland, is a country in Central Europe. It is divided into 16 administrative provinces called voivodeships, covering an area of . Poland has a population of over 38 million and is the fifth-most populou ...
. He was the second child of Rosa (Weigert) and Ismar Ehrlich, the leader of the local
Jewish
Jews ( he, יְהוּדִים, , ) or Jewish people are an ethnoreligious group and nation originating from the Israelites Israelite origins and kingdom: "The first act in the long drama of Jewish history is the age of the Israelites""The ...
community.
His father was an innkeeper and distiller of liqueurs and the royal lottery collector in Strehlen, a town of some 5,000 inhabitants. His grandfather, Heymann Ehrlich, had been a fairly successful distiller and tavern manager. Ehrlich was the uncle of
Fritz Weigert and cousin of
Karl Weigert.
After elementary school, Paul attended the time-honored secondary school Maria-Magdalenen-Gymnasium in
Breslau, where he met
Albert Neisser, who later became a professional colleague. As a schoolboy (inspired by his cousin Karl Weigert who owned one of the first
microtomes), he became fascinated by the process of staining microscopic tissue substances. He retained that interest during his subsequent medical studies at the universities of Wroclaw,
Strasbourg,
Freiburg im Breisgau and
Leipzig
Leipzig ( , ; Upper Saxon: ) is the most populous city in the German state of Saxony. Leipzig's population of 605,407 inhabitants (1.1 million in the larger urban zone) as of 2021 places the city as Germany's eighth most populous, as ...
. After obtaining his doctorate in 1882, he worked at the
Charité in Berlin as an assistant medical director under Theodor Frerichs, the founder of experimental clinical medicine, focusing on
histology
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vi ...
, hematology and color chemistry (dyes).
He married Hedwig Pinkus (1864–1948) in 1883 in the synagogue in
Neustadt (now Prudnik, Poland). The couple had two daughters, Stephanie and Marianne. Hedwig was a sister of
Max Pinkus, who was an owner of the textile factory in Neustadt (later known as
ZPB "Frotex"). He settled in the villa of the Fränkel family on Wiesenerstrasse in Neustadt.
After completing his clinical education and
habilitation at the prominent
Charité medical school and teaching hospital in Berlin in 1886, Ehrlich traveled to
Egypt
Egypt ( ar, مصر , ), officially the Arab Republic of Egypt, is a transcontinental country spanning the northeast corner of Africa and southwest corner of Asia via a land bridge formed by the Sinai Peninsula. It is bordered by the Medit ...
and other countries in 1888 and 1889, in part to cure a case of
tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, i ...
which he had contracted in the laboratory. Upon his return he established a private medical practice and small laboratory in Berlin-Steglitz. In 1891,
Robert Koch
Heinrich Hermann Robert Koch ( , ; 11 December 1843 – 27 May 1910) was a German physician and microbiologist. As the discoverer of the specific causative agents of deadly infectious diseases including tuberculosis, cholera (though the bacteri ...
invited Ehrlich to join the staff at his Berlin Institute of Infectious Diseases, where in 1896 a new branch, the Institute for Serum Research and Testing (''Institut für Serumforschung und Serumprüfung''), was established for Ehrlich's specialization. Ehrlich was named its founding director.
In 1899 his institute moved to Frankfurt am Main and was renamed the Institute of Experimental Therapy (''Institut für experimentelle Therapie''). One of his important collaborators there was Max Neisser. In 1904, Ehrlich received a full position of honorary professor from the
University of Göttingen
The University of Göttingen, officially the Georg August University of Göttingen, (german: Georg-August-Universität Göttingen, known informally as Georgia Augusta) is a public research university in the city of Göttingen, Germany. Founded ...
. In 1906 Ehrlich became the director of the Georg Speyer House in Frankfurt, a private research foundation affiliated with his institute. Here he discovered in 1909 the first drug to be targeted against a specific pathogen:
Salvarsan, a treatment for syphilis, which was at that time one of the most lethal and infectious diseases in Europe. In 1914, Ehrlich was awarded the Cameron Prize of the University of Edinburgh. Among the foreign guest scientists working with Ehrlich at his institute were two Nobel Prize winners,
Henry Hallett Dale and
Paul Karrer
Paul may refer to:
*Paul (given name), a given name (includes a list of people with that name)
* Paul (surname), a list of people
People
Christianity
*Paul the Apostle (AD c.5–c.64/65), also known as Saul of Tarsus or Saint Paul, early Chri ...
. The institute was renamed
Paul Ehrlich Institute in Ehrlich's honour in 1947.
In 1914, Ehrlich signed the
Manifesto of the Ninety-Three which was a defense of Germany's World War I politics and militarism. On 17 August 1915 Ehrlich suffered a heart attack and died on 20 August in
Bad Homburg vor der Höhe
Bad Homburg vor der Höhe () is the district town of the Hochtaunuskreis, Hesse, on the southern slope of the Taunus mountains. Bad Homburg is part of the Frankfurt Rhein-Main urban area. The town's official name is ''Bad Homburg v.d.Höhe'', w ...
.
Wilhelm II
, house = Hohenzollern
, father = Frederick III, German Emperor
, mother = Victoria, Princess Royal
, religion = Lutheranism (Prussian United)
, signature = Wilhelm II, German Emperor Signature-.svg
Wilhelm II (Friedrich Wilhelm Viktor ...
the German emperor, wrote in a telegram of condolence, "I, along with the entire civilized world, mourn the death of this meritorious researcher for his great service to medical science and suffering humanity; his life’s work ensures undying fame and the gratitude of both his contemporaries and posterity".
Paul Ehrlich was buried at the
Old Jewish Cemetery, Frankfurt (Block 114 N).
Research
Hematological staining
In the early 1870s, Ehrlich's cousin
Karl Weigert was the first person to stain bacteria with dyes and to introduce aniline pigments for histological studies and bacterial diagnostics. During his studies in Strassburg under the anatomist
Heinrich Wilhelm Waldeyer, Ehrlich continued the research started by his cousin in pigments and staining tissues for microscopic study. He spent his eighth university semester in Freiburg im Breisgau investigating primarily the red dye dahlia (monophenylrosanilin), giving rise to his first publication.
In 1878 he followed his dissertation supervisor
Julius Friedrich Cohnheim to Leipzig, and that year obtained a doctorate with a dissertation entitled "Contributions to the Theory and Practice of Histological Staining" (''Beiträge zur Theorie und Praxis der histologischen Färbung'').
One of the most outstanding results of his dissertation investigations was the discovery of a new cell type. Ehrlich discovered in the
protoplasm of supposed
plasma cells
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
a granulate which could be made visible with the help of an alkaline dye. He thought this granulate was a sign of good nourishment, and accordingly named these cells
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s, (from the German word for an animal-fattening feed, ''Mast''). This focus on chemistry was unusual for a medical dissertation. In it, Ehrlich presented the entire spectrum of known staining techniques and the chemistry of the pigments employed.
While he was at the Charité, Ehrlich elaborated upon the differentiation of white blood cells according to their different granules. A precondition was a dry specimen technique, which he also developed. A drop of blood placed between two glass slides and heated over a Bunsen burner fixed the blood cells while still allowing them to be stained. Ehrlich used both alkaline and acid dyes, and also created new "neutral" dyes. For the first time this made it possible to differentiate the
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s among the
leucocytes (white blood cells). By studying their granulation he could distinguish between nongranular lymphocytes, mono- and poly-nuclear leucocytes,
eosinophil granulocyte
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s, and mast cells.
Starting in 1880, Ehrlich also studied
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s. He demonstrated the existence of nucleated red blood cells, which he
subdivided into normoblasts, megaloblasts, microblasts and poikiloblasts; he had discovered the precursors of erythrocytes. Ehrlich thus also laid the basis for the analysis of
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
s, after he had created the basis for systematizing
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
s with his investigation of white blood cells.
His duties at the Charité included analyzing patients' blood and urine specimens. In 1881 he published a new urine test which could be used to distinguish various types of typhoid from simple cases of diarrhea. The intensity of staining made possible a disease prognosis. The pigment solution he used is known today as Ehrlich's reagent.
Ehrlich's great achievement, but also a source of problems during his further career, was that he had initiated a new field of study interrelating chemistry, biology and medicine. Much of his work was rejected by the medical profession, which lacked the requisite chemical knowledge. It also meant that there was no suitable professorship in sight for Ehrlich.
Serum research
Friendship with Robert Koch
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
Heinrich Hermann Robert Koch ( , ; 11 December 1843 – 27 May 1910) was a German physician and microbiologist. As the discoverer of the specific causative agents of deadly infectious diseases including tuberculosis, cholera (though the bacteri ...
, 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 Paul Ehrlich was able to attend.
On 24 March 1882, Ehrlich was present when Robert 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
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
Tuberculin, also known as purified protein derivative, is a combination of proteins that are used in the diagnosis of tuberculosis. This use is referred to as the tuberculin skin test and is recommended only for those at high risk. Reliable admi ...
was under study; and Ehrlich had even injected himself with it. In the ensuing
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 Institute of Infectious Diseases (''Institut für Infektionskrankheiten'' – now the
Robert Koch Institute) at ''Friedrich-Wilhelms-Universität'' (now 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
Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an infectious agent (known as the immunogen).
When this system is exposed to molecules that are foreign to the body, called ''non-se ...
already in his private laboratory. He accustomed mice to the poisons
ricin and
abrin
Abrin is an extremely toxic toxalbumin found in the seeds of the rosary pea (or jequirity pea), ''Abrus precatorius''. It has a median lethal dose of 0.7 micrograms per kilogram of body mass when given to mice intravenously (approximately 3 ...
. After feeding them with small but increasing dosages of ricin he ascertained that they had become "ricin-proof". Ehrlich interpreted this as immunization and observed that it was abruptly initiated after a few days and was still in existence after several months, but mice immunized 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
Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...
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 immunized against abrin and an untreated female mouse were not immune to abrin. He concluded that the fetus 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
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
, 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 Ernst Witebsky, also Ernest Witebsky (3 September 1901 in Frankfurt am Main – 7 December 1969) was a German-American immunologist.
Early life and education
Ernst Witebsky was born in Frankfurt am Main.
From 1920 to 1926 Witebsky studied medic ...
, who demonstrated that autoimmunity could cause disease in humans. 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".
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
Diphtheria is an infection caused by the bacterium '' Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks more than 10% of those diagnosed with the disease may die. Signs and s ...
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 synthesized 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 of tetanus serum. Ehrlich recognized that the principle of serum therapy had been developed by Behring and
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.
The valency of serums
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, an Institute of Serum Research and Testing (''Institut für Serumforschung und Serumprüfung'') was established in 1896 in Berlin-Steglitz, with Paul 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 also 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
Titration (also known as titrimetry and volumetric analysis) is a common laboratory method of quantitative chemical analysis to determine the concentration of an identified analyte (a substance to be analyzed). A reagent, termed the ''titrant'' ...
. 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
Tuberculin, also known as purified protein derivative, is a combination of proteins that are used in the diagnosis of tuberculosis. This use is referred to as the tuberculin skin test and is recommended only for those at high risk. Reliable admi ...
and later on various
vaccine
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. s. Ehrlich's most important colleague at the institute was the Jewish doctor and biologist Julius Morgenroth.
Ehrlich’s side-chain theory
He postulated that cell protoplasm contains special structures which have chemical ''side chains'' (today's term is
macromolecules) 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 ''immunization.'' 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
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
, at the
Pasteur Institute
The Pasteur Institute (french: Institut Pasteur) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines ...
had previously sharply attacked Ehrlich.
Cancer research
In 1901, the Prussian Ministry of Finance criticized Ehrlich for exceeding his budget and as a consequence reduced his income. In this situation Althoff arranged a contact with Georg Speyer, a Jewish philanthropist and joint owner of the bank house Lazard Speyer-Ellissen. The cancerous disease of
Princess Victoria, the widow of the German Emperor Friedrich II, had received much public attention and prompted a collection among wealthy Frankfurt citizens, including Speyer, in support of cancer research. Ehrlich had also received from
the German Emperor Wilhelm II a personal request to devote all his energy to cancer research. Such efforts led to the founding of a department for cancer research affiliated with the Institute of Experimental Therapy. The chemist
Gustav Embden
Gustav Georg Embden (10 November 1874 – 25 July 1933) was a German physiological chemist.
Background
Gustav Embden was a son of the Hamburg lawyer and politician George Heinrich Embden. His grandmother Charlotte Heine was a well-known salonn ...
, among others, worked there. Ehrlich informed his sponsors that cancer research meant basic research, and that a cure could not be expected soon.
Among the results achieved by Ehrlich and his research colleagues was the insight that when tumors are cultivated by transplanting tumor cells, their malignancy increases from generation to generation. If the primary tumor is removed, then
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...
precipitously increases. Ehrlich applied bacteriological methods to cancer research. In analogy to vaccination, he attempted to generate immunity to cancer by injecting weakened cancer cells. Both in cancer research and chemotherapy research (see below) he introduced the methodologies of
Big Science.
Chemotherapy
In vivo staining
In 1885 Ehrlich's monograph "The Need of the Organism for Oxygen" (''Das Sauerstoffbedürfnis des Organismus – Eine farbenanalytische Studie'') appeared, which he also submitted as a
habilitation thesis. In it he introduced the new technology of in vivo staining. One of his findings was that pigments can only be easily assimilated by living organisms if they are in granular form. He injected the dyes
alizarin
Alizarin (also known as 1,2-dihydroxyanthraquinone, Mordant Red 11, C.I. 58000, and Turkey Red) is an organic compound with formula that has been used throughout history as a prominent red dye, principally for dyeing textile fabrics. Historic ...
blue and
indophenol
Indophenol is an organic compound with the formula OC6H4NC6H4OH. It is deep blue dye that is the product of the Berthelot's reaction, a common test for ammonia. The indophenol group, with various substituents in place of O''H'' and various rin ...
blue into laboratory animals and established after their death that various organs had been colored to different degrees. In organs with high oxygen saturation, indophenol was retained; in organs with medium saturation, indophenol was reduced, but not alizarin blue. And in areas with low oxygen saturation, both pigments were reduced. With this work, Ehrlich also formulated the conviction which guided his research: that all life processes can be traced to processes of
physical chemistry
Physical chemistry is the study of macroscopic and microscopic phenomena in chemical systems in terms of the principles, practices, and concepts of physics such as motion, energy, force, time, thermodynamics, quantum chemistry, statistica ...
occurring in the cell.
Methylene blue
In the course of his investigations Ehrlich came across
methylene blue, which he regarded as particularly suitable for staining bacteria. Later, Robert Koch also used methylene blue as a dye in his research on the tuberculosis pathogen. In Ehrlich's view, an added benefit was that methylene blue also stained the long appendages of nerve cells, the
axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
s. He initiated a doctoral dissertation on the subject, but did not follow up the topic himself. It was the opinion of the neurologist
Ludwig Edinger that Ehrlich had thereby opened up a major new topic in the field of
neurology
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal ...
.
After mid-1889, when Ehrlich was unemployed, he privately continued his research on methylene blue. His work on in vivo staining gave him the idea of using it therapeutically. Since the parasite family of ''
Plasmodiidae'' – which includes the
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
pathogen – can be stained with methylene blue, he thought it could possibly be used in the treatment of malaria. In the case of two patients so treated at the city hospital in Berlin-Moabit, their fever indeed subsided and the malaria plasmodia disappeared from their blood. Ehrlich obtained methylene blue from the company Meister Lucius & Brüning AG (later renamed Hoechst AG), which started a long collaboration with this company.
The search for a ''chemotherapia specifica''
Before the Institute of Experimental Therapy had moved to Frankfurt, Ehrlich had already resumed work on methylene blue. After the death of Georg Speyer, his widow Franziska Speyer endowed the Georg-Speyer House in his memory which was erected next door to Ehrlich's institute. As director of the Georg-Speyer House, Ehrlich transferred his chemotherapeutic research there. He was looking for an agent which was as effective as methylene blue, but without its side effects. His model was on the one hand the impact of
quinine
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal le ...
on malaria, and on the other hand, in analogy to serum therapy, he thought there must also be chemical pharmaceuticals which would have just as specific an effect on individual diseases. His goal was to find a "Therapia sterilisans magna", in other words a treatment that could kill all disease pathogens.
As a model for experimental therapy Ehrlich used a guinea pig disease
trypanosoma and tested out various chemical substances on laboratory animals. The trypanosomes could indeed be successfully killed with the dye trypan red. Beginning in 1906, he intensively investigated
atoxyl and had it tested by Robert Koch along with other arsenic compounds during Koch's sleeping sickness expedition of 1906/07. Although the name literally means "nonpoisonous", atoxyl does cause damage, especially to the optic nerve. Ehrlich elaborated the systematic testing of chemical compounds in the sense of screening as now practiced in the pharmaceutical industry. He discovered that Compound 418 - Arsenophenylglycine - had an impressive therapeutic effect and had it tested in Africa.
With the support of his assistant
Sahachiro Hata Ehrlich discovered in 1909 that Compound 606,
Arsphenamine
Arsphenamine, also known as Salvarsan or compound 606, is a drug that was introduced at the beginning of the 1910s as the first effective treatment for syphilis, relapsing fever, and African trypanosomiasis.
This organoarsenic compound was the f ...
, effectively combatted "
spirillum"
spirochaete
A spirochaete () or spirochete is a member of the phylum Spirochaetota (), (synonym Spirochaetes) which contains distinctive diderm (double-membrane) gram-negative bacteria, most of which have long, helically coiled (corkscrew-shaped or s ...
s bacteria, one of whose
subspecies causes
syphilis. The compound proved to have few side effects in human trials, and the spirochetes disappeared in seven syphilis patients after this treatment.
After extensive clinical testing (all the research participants had the negative example of tuberculin in mind) the Hoechst company began to market the compound toward the end of 1910 under the name Salvarsan. This was the first agent with a specific therapeutic effect to be created on the basis of theoretical considerations. Salvarsan proved to be amazingly effective, particularly when compared with the conventional therapy of mercury salts. Manufactured by Hoechst AG, Salvarsan became the most widely prescribed drug in the world. It was the most effective drug for treating syphilis until penicillin became available in the 1940s. Salvarsan required improvement as to side effects and solubility and was replaced in 1911 with
Neosalvarsan. Ehrlich's work illuminated the existence of the
blood-brain barrier, although he himself never believed in such a barrier, with
Lina Stern later coining the phrase.
The medication triggered the so-called "Salvarsan war". On one side there was hostility on the part of those who feared a resulting moral breakdown of sexual inhibitions. Ehrlich was also accused, with clearly
anti-Semitic undertones, of excessively enriching himself. In addition, Ehrlich's associate,
Paul Uhlenhuth claimed priority in discovering the drug.
Because some people died during the clinical testing, Ehrlich was accused of "stopping at nothing." In 1914, one of the most prominent accusers was convicted of criminal libel at a trial for which Ehrlich was called to testify. Though Ehrlich was thereby exonerated, the ordeal threw him into a depression from which he never fully recovered.
Magic bullet
Ehrlich reasoned that if a compound could be made that selectively targeted a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity. Hence, a "
magic bullet" (''Zauberkugel'', his term for an ideal therapeutic agent) would be created that killed only the organism targeted. The concept of a "magic bullet" has to some extent been realized by the development of
antibody-drug conjugate
Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...
s (a monoclonal antibody linked to a cytotoxic biologically active drug), as they enable cytotoxic drugs to be selectively delivered to their designated targets (e.g. cancer cells).
Legacy
In 1910, a street was named after Ehrlich in Frankfurt-Sachsenhausen. In
Nazi Germany
Nazi Germany (lit. "National Socialist State"), ' (lit. "Nazi State") for short; also ' (lit. "National Socialist Germany") (officially known as the German Reich from 1933 until 1943, and the Greater German Reich from 1943 to 1945) was ...
, Ehrlich's achievements were ignored while
Emil Adolf von Behring
Emil von Behring (; Emil Adolf von Behring), born Emil Adolf Behring (15 March 1854 – 31 March 1917), was a German physiologist who received the 1901 Nobel Prize in Physiology or Medicine, the first one awarded in that field, for his discovery ...
was stylized as the ideal
Aryan scientist, and the street named after Ehrlich was given another name. Shortly after the end of the war the name Paul-Ehrlich-Strasse was reinstated, and today numerous German cities have streets named after Paul Ehrlich.
West Germany issued a postage stamp in 1954 on the 100th anniversary of the births of Paul Ehrlich (14 March 1854) and Emil von Behring (15 March 1854).
The 200
Deutsche Mark
The Deutsche Mark (; English: ''German mark''), abbreviated "DM" or "D-Mark" (), was the official currency of West Germany from 1948 until 1990 and later the unified Germany from 1990 until the adoption of the euro in 2002. In English, it was ...
bank note, issued until 2001, featured Paul Ehrlich.
The German Paul Ehrlich Institute, the successor to the Steglitz Institute for Serum Research and Serum Testing and the Frankfurt Royal Institute for Experimental Therapy, was named in 1947 after its first director, Paul Ehrlich.
His name is also borne by many schools and pharmacies, by the Paul-Ehrlich-Gesellschaft für Chemotherapie e. V. (PEG) in Frankfurt am Main, and the Paul-Ehrlich-Klinik in Bad Homburg vor der Höhe. The
Paul Ehrlich and Ludwig Darmstaedter Prize is the most distinguished German award for biomedical research. A European network of PhD studies in Medicinal Chemistry has been named after him (Paul Ehrlich MedChem Euro PhD Network).
The
Anti-Defamation League awards a Paul Ehrlich–Günther K. Schwerin Human Rights Prize.
A
crater of the moon was named after Paul Ehrlich in 1970.
Ehrlich's life and work was featured in the 1940 U.S. film ''
Dr. Ehrlich's Magic Bullet'' with
Edward G. Robinson in the title role. It focused on
Salvarsan (arsphenamine, "
compound 606"), his cure for syphilis. Since the Nazi government was opposed to this tribute to a Jewish scientist, attempts were made to keep the film a secret in Germany.
Honors and titles
* 1882 Awarded the title of Professor
* 1890 Appointed Extraordinary Professor at the ''Friedrich-Wilhelms-Universität'' (now Humboldt University)
* 1896 Given the nonacademic Prussian title of a Medical Councillor (''Geheimer Medizinalrat'')
* 1903 Awarded Prussia's highest distinction in science, the Great Golden Medal of Science (which had previously been awarded only to
Rudolf Virchow
Rudolf Ludwig Carl Virchow (; or ; 13 October 18215 September 1902) was a German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician. He is known as "the father of modern pathology" and as the founder ...
)
* 1904 Honorary professorship in
Göttingen
Göttingen (, , ; nds, Chöttingen) is a university city in Lower Saxony, central Germany, the capital of the eponymous district. The River Leine runs through it. At the end of 2019, the population was 118,911.
General information
The ori ...
; honorary doctorate from the University of Chicago
* 1907 Granted the seldom-awarded title Senior Medical Councillor (''Geheimer Obermedizinalrat''); granted an honorary doctorate from Oxford University
* 1908 Awarded The Nobel Prize in Physiology or Medicine for his "work on immunity"
* 1911 Granted Prussia's highest civilian award, Privy Councillor (''Wirklicher Geheimer Rat'' with the predicate "Excellency")
* 1912 Made an honorary citizen of the city of Frankfurt a.M. and of his birthplace Strehlen
* 1914 Awarded the
Cameron Prize for Therapeutics of the University of Edinburgh
* 1914 Appointed full Professor of Pharmacology at the newly established Frankfurt University.
See also
*
Ehrlich's reagent
*
German inventors and discoverers
*
List of Jewish Nobel laureates
References
External links
*
Paul Ehrlich's publications(ordered chronologically, as full-text PDF)
Film Annotations ''Dr. Ehrlich's Magic Bullet''*
Paul de Kruif Paul Henry de Kruif (, rhyming with "life") (1890–1971) was an American microbiologist and author of Dutch descent. Publishing as Paul de Kruif, he is most noted for his 1926 book, ''Microbe Hunters''. This book was not only a bestseller for a le ...
br>
''Microbe Hunters''(Blue Ribbon Books) Harcourt Brace & Company Inc., New York 1926: ch. XII Paul Ehrlich: The Magic Bullet
Paul Ehrlich and Hebrew University of Jerusalem; Chemistry in Israel. Bob Weintraub.*
*
*
Paul Ehrlich Nobel Luminaries – Jewish Nobel Prize Winners, on th
Beit Hatfutsot – The Museum of the Jewish PeopleWebsite.
{{DEFAULTSORT:Ehrlich, Paul
1854 births
1915 deaths
Nobel laureates in Physiology or Medicine
German Nobel laureates
German immunologists
Jewish physicians
People from Strzelin
People from the Province of Lower Silesia
Jewish biologists
19th-century German biologists
Silesian Jews
19th-century German inventors
Jewish German scientists
Members of the Lincean Academy
People from the Province of Silesia
University of Breslau alumni
University of Strasbourg alumni
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Paul Ehrlich Institute people
Humboldt University of Berlin faculty
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Scientists from Frankfurt
Burials at the Old Jewish Cemetery, Frankfurt
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