Paul Ehrlich: Leben, Forschung, Ökonomien, Netzwerke (German Edition)
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Log out of ReadCube. Bacteriology was established in the s as the science of disease germs.
However, experimental explorations in the world of microorganisms had started already in the seventeenth century, and botanists and zoologists in the eighteenth century had tried to structure and classify the world of the invisible living organisms. With the German physician Robert Koch the science of microorganisms moved into the realm of medicine.
Koch identified several bacteria as the causes of infectious diseases and he contributed greatly to the stabilisation of distinct bacterial species. Medical bacteriology promoted laboratory medicine and Louis Pasteur in Paris developed techniques to attenuate microorganisms in order to produce vaccines. Antibiotics became widely available only after the Second World War. Bacteriology has also developed in relation to agriculture, water pollution and biotechnology. First experimental encounters with microorganisms took place using microscopic techniques in the seventeenth century.
A causal linkage between microorganisms and disease was established only in the last third of the nineteenth century. Medical bacteriology developed around the laboratories of Robert Koch and Louis Pasteur and had tremendous effects on public health as well as on conceptions of the body and disease. Robert Koch's bacteriological thought style implied a reductionist approach to infectious disease. Broadly applicable antibacterial therapeutic remedies antibiotics became widely available only in the second half of the twentieth century.
Bacteriology has also developed in relation to agriculture, marine biology, water pollution, bacterial genetics and biotechnologies. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account. If the address matches an existing account you will receive an email with instructions to retrieve your username. Tools Request permission Export citation Add to favorites Track citation. A similar concept had been proposed by John Newport Langley , who predicted that the effect of certain alkaloids on muscle cells were mediated by cell-fixed receptors that can be activated by agonists and blocked by specific antagonists.
This concept turned out to be correct and paved the way to modern pharmacology, advanced immunology and the development of targeting treatment concepts table 2 [ 21 , 22 , 23 ]. Two outstanding talents of Paul Ehrlich should be mentioned in this context of the development of a ligand-receptor concept - his flexibility to adjust and refine his own theories, and his ability to exploit collaborations and new achievements in other scientific disciplines in order to foster and extend his own concepts.
The next logical step was to extend the receptor-ligand concept and to exploit the specific effects of toxic agents with the aim of synthesizing and selecting those drugs that may kill certain microbes or other target cells but spare healthy tissues. Paul Ehrlich approached this concept in two consecutive steps: i by screening for toxic drugs and ii by modifying toxic drugs to be more specific and less toxic.
First, Ehrlich established basic procedures for the chemical synthesis of various drugs and drug derivatives. The donation of Francisca Speyer to the Georg-Speyer-Haus and, thus, to Ehrlich was an essential basis of this work program. In fact, based on these donations, Ehrlich was able to establish a chemical laboratory where chemists and pharmacists synthesized a huge battery of chemical compounds. The head of the laboratory was Paul Karrer, and many patents of arsenic compounds carry his and Ehrlich's name. In a second step, Ehrlich screened pharmacological assays to evaluate and compare the efficacy of all these agents systematically.
In many instances, the structure of an agent had to be modified in order to obtain a safe drug, or a new compound with a similar structure had to be generated. This systematic approach of drug development was a revolutionary concept and formed the basis of modern pharmacology [ 24 , 25 , 26 , 27 ]. In his days, the etiology of cancer remained essentially unknown and no cancer-specific structures molecules had been detected [ 28 ]. Many decades later, however, the seeds sown by Paul Ehrlich led to a new era of targeted anticancer therapies, including small molecule-type drugs directed against molecules responsible for malignant transformation, such as oncogenic kinases or antibody-based drugs directed against various cell surface structures expressed more or less specifically by neoplastic cells.
Although he was able to treat malaria patients with some success, this therapy was not superior to the standard drug quinine. However, the example of methylene blue motivated Ehrlich and his colleagues to further screen for more effective agents. A next important success was the observation made by Paul Ehrlich and his coworker Kiyoshi Shiga that trypan red was therapeutically effective in mice infected with Trypanosoma equinum table 3. Unfortunately, however, the trypanosomes developed resistance. Nevertheless, this observation confirmed the principle value of the screen and provoked even more interest and greater efforts.
As a next step, Ehrlich started to examine organic arsenic derivatives [ 32 , 33 , 34 , 35 ].
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In , his coworker Alfred Bertheim deciphered the chemical structure of Atoxyl as an amino derivative of phenyl arsenic acid. This knowledge opened the door for modifying drug properties by artificially changing its chemical structure. Subsequently, a number of derivatives were synthesized with the aim of enhancing their therapeutic efficacy and of lowering their toxicity [ 9 , 32 , 33 , 34 ]. Finally, by adding substitutes to the amino group of Atoxyl, compound No. Unfortunately, this compound was strongly neurotoxic in mice and could not be developed further.
Finally, a limited set of substances were developed. One of them, arsenophenylglycine No. In , the drug was tested in humans with good results. However, severe hypersensitivity reactions occurred in a subset of patients. Subsequently, the drug was only used to treat patients with severe life-threatening trypanosomiases. The next promising drug Paul Ehrlich developed was arsenophenol, a highly effective agent against trypanosomes. Unfortunately, based on instability and difficulties to purify the drug, its development had to be stopped. Nevertheless, a similar agent was produced by adding a substituent next to the hydroxyl group, compound No.
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This compound was synthesized in However, in a first series of experiments no consistent antimicrobial activity could be demonstrated, and it took until before reassessment of the drug and its pharmacologic activity paved the way to the successful treatment of syphilis. It was a late triumph, but it was a triumph of science and of the visions and theories Ehrlich had propagated, namely that: i the chemical structure of a compound would correlate with specific activity, ii drug efficacy can be improved by proper chemical modification and iii toxicity can be kept under control by creating a magic bullet targeted drug.
Paul Ehrlich had demonstrated that synthesis of specific drugs is achievable. This visionary attitude and his practical abilities to translate these concepts into practical application in patients are the reasons he is considered such an outstanding figure in medical science. In , Fritz Schaudinn and Erich Hoffmann described Treponema pallidum as a causal agent of syphilis. In those days the impact of syphilis on society was comparable to that of AIDS today.
Based on the similarities between spirochetes and trypanosomes, Hoffmann suggested to Ehrlich the idea of applying arsenical compounds to patients with syphilis. As a result, Paul Ehrlich's co-worker Sahachiro Hata reassessed all the arsenicals synthesized until then, and found that compound No.
However, based on the severe hypersensitivity reactions documented in patients receiving arsenophenylglycine, arsphenamine was developed with great caution. On the 19th of April, , at the Congress for Internal Medicine at Wiesbaden, Hata and Ehrlich presented their results obtained with arsphenamine [ 39 , 40 ]. Their announcement at this meeting provoked a huge number of requests, and Ehrlich's institute had to prepare and dispense 65, samples immediately to be forwarded to various hospitals and centers that had initiated clinical trials.
A Short Overview of Paul Ehrlich's Life and Career
Ehrlich's international recognition and popularity increased with the success story of Salvarsan. Over the years it turned out that treatment with Salvarsan was not perfect, as resistance occurred and combination therapy with mercury or bismuth treatment was often necessary to eliminate all spirochetes. The minimum period of treatment with Salvarsan lasted for 18 months and required 20 Salvarsan injections and bismuth injections [ 41 ].
Problems also arose from the galenics of the arsphenamide preparations, mostly because of the water-insoluble nature of the drug. In , the year of Paul Ehrlich's 60th birthday, compound No. This second-generation drug improved overall outcomes and shortened the treatment time of patients with syphilis.
Based on its stability, this agent became the drug of choice for the treatment of syphilis until penicillin was introduced in the early s.
It is noteworthy that oxophenarsine had already been synthesized in Paul Ehrlich's laboratory compound No. Paul Ehrlich's contributions to science undoubtedly paved the way to a new era of medicine, where cellular features and functions were linked to specific molecules, and translational concepts were established based on mechanistic and molecular insights into the pathophysiology of the disease and specific molecular interactions, including drug-target and receptor-ligand interactions.
The seminal contributions of Paul Ehrlich and his colleagues also led to the birth and foundation of modern chemistry, hematology, immunology, chemotherapy, pharmacology and oncology. Finally, the concept of specific drug development and global standardization of diagnostic and therapeutic approaches are based on the seminal work of Paul Ehrlich and his colleagues. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions.
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