The Hematologist

November-December 2015, Volume 12, Issue 6

Paul Ehrlich (1854-1915) and the Birth of Molecular Medicine

Peter Valent, MD Professor Doctor, Department of Internal Medicine I, Division of Hematology & Hemostaseology, Ludwig Boltzmann Cluster Oncology
Medical University of Vienna, Vienna, Austria
Udo Schumacher, MD, DSc, PRCPath, Cbiol, FRSB Professor at The Department of Anatomy and Experimental Morphology, University Medical Center
Medical University of Hamburg, Hamburg, Germany
Fritz Sörgel, PhD, BSc Doctor and Director, Institute for Biomedical and Pharmaceutical Research (IBMP)
University of Duisburg-Essen, Essen, Germany
Hans-Peter Horny, MD Professor of Pathology, Institute of Pathology
Ludwig-Maximilians University, Munich, Germany
Bernd Groner, PhD Director, Georg Speyer Haus
Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany

Published on: October 20, 2015

Authors’ Note: This article is dedicated to the achievements of Paul Ehrlich on the occasion of the 100th anniversary of his death (August 20, 2015).

Between 1850 and 1915, the “new” fields of chemistry, biology, and medicine made revolutionary progress thanks to the seminal contributions of a number of outstanding scientists, including (among others) Louis Pasteur, Robert Koch, Emil Fischer, Rudolf Virchow, and Emil Behring. Inspired by this atmosphere of great discoveries, Paul Ehrlich, born in Strehlen, German Kingdom of Prussia, near Breslau in 1854, became one of the most influential scientists of his time and a pioneer in the fields of hematology, immunology, chemotherapy, and pharmacology.1-3 In his career, Ehrlich connected cellular and molecular theories, discovered and exploited related biological principles, and demonstrated their practical implications. Through this contemporary approach, Ehrlich established the principles of molecular medicine. His vision and concepts not only became tremendously useful after their discovery and experimental validation, but many of them inspired subsequent generations of researchers and are still fundamental and key to theoretical and applied research today (Table 1).1-3

Table. Professor Paul Ehrlich's Initial Theories and Their Influence on Science Since 1915*
Initial TheoryMajor Resulting Concept(s) and Disciplines
Leukocyte differentiation by their dye staining propertiesModern hematology
Leukocyte typing concept
Classification of immune cells
Classification of blood cell disorders
Side chain theoryReceptor-ligand concept
Antibody recognition and diversity
Immunoglobulin receptor theory
Immunostaining reactions and immunoassays
Magic bullet theory (Zauberkugel-Theorie)Experimental pharmacology
Preclinical drug design and drug testing
Target expression profiling
Development of target-specific therapies
Development and application of specific drugsTranslational medicine
Clinical oncology and hematology
Clinical pharmacology and drug validation
Development of anti-infective drugs
Chemotherapy

*Most of Paul Ehrlich's theories had begun to have a great influence on science prior to 1915.

As a student, Ehrlich had already established the principles of modern hematology by describing distinct dye-staining properties of various leukocyte populations.4-6 During his studies, he employed both alkaline and acid dyes but also invented new neutral dyes. Using his dye armamentarium as well as morphology, Ehrlich was able to differentiate most leukocyte subsets from each other and also from other cell types.4-6 He also proposed terminologies for these cells, and in almost all instances, the nomenclature was accurate and was quickly accepted, and in slightly modified form, the same nomenclature is still used today.

Another outstanding talent of Ehrlich was his ability to recognize functional relationships in various cell types. For example, he linked distinct morphologies to certain maturation stages in various hematopoietic lineages; from 1880, Ehrlich studied the red cell in detail and soon detected nucleated red cells in the blood and marrow; a few years later, he described putative maturation stages of red cell precursors that he called “normoblasts,” “megaloblasts,” “microblasts,” and “poikiloblasts.”7

Although his research covered most leukocyte populations, the favorite cell of Ehrlich was the mast cell.6 This highlights the fact that he examined not only blood with great enthusiasm, but other organ systems as well. Although not formally established at that time, he proposed that blood leukocytes have the capacity to enter various tissues by migration – an assumption that was supported by morphologic similarities, such as the striking similarity between tissue mast cells and blood basophils. However, despite this apparent similarity, Ehrlich remained skeptical about the origin of mast cells, and his skepticism was justified: many decades later, mast cells were found to derive directly from hematopoietic precursor cells, but not from blood basophils, monocytes, or a local histiocytic precursor. Thus, mast cells and basophils represent two distinct lineages in the hematopoietic cell system. Despite his interest in mast cells, Ehrlich was also drawn to other cell types, including lymphocytes and connective tissue cells. Additionally, he worked on diverse microbial cell systems and developed a precursor technique to the Gram staining of bacteria.

After his seminal contributions to hematology, and long before “translational research” was coined as a separate discipline, Ehrlich extended his interests and investigated cellular features at the molecular level and their practical applications in medicine. As a first step, he established a theory that proposed the existence of distinct, cell-fixed and membrane-related structures that interact with extracellular material – the so-called “side-chain theory.”8 Today, this theory can be regarded as an important precursor of the “receptor-ligand concept” that has since greatly fertilized the fields of physiology, pathology, immunology, hematology, oncology, and pharmacology, and is still instrumental in science today.1-3 Moreover, this theory formed a solid basis for antibody-based cell typing and diagnostic staining in pathology and laboratory medicine. Finally, this theory provided a basis for the different dye-staining properties of various cell types.

In the later phases of his career, Ehrlich worked intensively in the fields of immunology, pharmacology, and antimicrobial chemotherapy. He made seminal contributions to the development of an antiserum to combat diphtheria and to the approach to standardize methods related to the production of “therapeutic serum.”9 Ehrlich also extended his ideas about distinct recognition-sites and binding (ligand-receptor) interactions. Specifically, he envisioned the possibility to pharmacologically exploit the expression of cell-specific receptors and to develop specific drug therapies and immunotherapies. This would become a global principle applicable to pathogenic microorganisms as well as other cell types, including cancer cells. In a systematic effort to identify drugs capable of specifically killing certain microbes, he developed a first series of specific antimicrobial drugs, the most famous example being arsphenamine (Salvarsan), the first effective agent in the treatment of syphilis.10 He rapidly transferred his observations and findings into clinical practice and thus established the concept of translational medicine. Based on the success of Salvarsan, Ehrlich was also able to popularize his concept of a “magic bullet” (Zauberkugel), a drug specifically targeting a particular pathogen without affecting the host.

Ehrlich also tried to apply his magic bullet concept to anticancer chemotherapy. However, in his days, the etiology of cancer remained unknown, and no cancer-specific structures (molecules) had been detected. Many decades later, however, the seeds planted by Ehrlich and others sprang to life, and we entered a new era of targeted anticancer therapies, employing drugs directed against molecules responsible for malignant transformation, such as oncogenic kinases. These drugs can be regarded as Ehrlich’s Zauberkugel, now known as targeted drugs. Additionally, “immunotherapy” is considered a very promising field in modern anticancer therapy, but it was a part of Ehrlich’s visions already.11 Today, targeted antibodies and antibody conjugates are specifically delivered to cancer cells to inhibit their growth and survival with unprecedented efficacy, and other novel agents can mobilize cytotoxic T cells or natural killer cells to enhance their anticancer activity. All these advances can be traced back to Ehrlich.

During his career, Ehrlich received several honors and awards. Initially, he worked at the Charité in Berlin in association with Robert Koch. He became the Director of the Institute for Serum Research and Evaluation in Berlin in 1896 and Director of the Institute for Experimental Therapy in Frankfurt in 1899. However, despite the brilliance of his discoveries and the awards and honors he received, Ehrlich had to fight many battles to convince the scientific community as well as the public that his concepts and efforts were useful, and the resulting applications beneficial for patients.8 In 1906, Ehrlich was nominated to be the founding Director of the Georg Speyer Haus, where he later established the principles of chemotherapy and developed Salvarsan. In 1908 he received the Nobel Prize in Physiology or Medicine together with Elie Metchnikoff for his work on the basic insights into immunologic defense mechanisms.

In 2015, the Vienna Cancer Stem Cell Club organized an international memorial meeting, with the goal of honoring Ehrlich and his contributions to science, and commemorating the 100th anniversary of his death (August 20, 1915). The authors of this article were members of the meeting faculty. For interested readers who would like more information about Ehrlich’s life and his achievements and contributions to science, please refer to the available literature.1-3,12-16

Photo. "Paul Ehrlich in lab" from Paul Ehrlich Papers: Rockefeller University Archives Record group 650 Eh89 ©. Courtesy of Rockefeller Archive Center.

References

  1. Kaufmann SH. Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nat Immunol. 2008;9:705-712.
  2. Schmalstieg FC Jr, Goldman AS. Ilya Ilich Metchnikoff (1845-1915) and Paul Ehrlich (1854-1915): the centennial of the 1908 Novel Prize in Physiology or Medicine. J Med Biogr. 2008;16:96-103.
  3. Piro A, Tagarelli A, Tagarelli G, et al. Paul Ehrlich: the Nobel Prize in physiology or medicine 1908. Int Rev Immunol. 2008;27:1-17.
  4. Ehrlich P. Beiträge zur Kenntnis der Anilinfärbungen und ihrer Verwendung in der mikroskopischen Technik. Archiv fuer mikroskopische Anatomie. 1877;13:263-278.
  5. Ehrlich P. Ueber die specifischen Granulationen des Blutes. Archiv fuer Anatomie und Physiologie: Physiologische Abteilung. 1879:571-579.
  6. Ehrlich P. Beiträge zur Kenntniss der granulirten Bindegewebszellen und der eosinophilen Leukocythen. Archiv fuer Anatomie und Physiologie: Physiologische Abteilung. 1879:166-169.
  7. Ehrlich P. Ueber einen Fall von Anämie mit Bemerkungen über regenerative Veränderungen des Knochenmarks. Charité-Annalen. 1888;13:300-309.
  8. Ehrlich P. Die Seitenkettentheorie und ihre Gegner. Muenchener medizinische Wochenschrift. 1901:2123-2124.
  9. Ehrlich P. Die Wertbemessung des Diphterieheilserums und deren theoretische Grundlagen. Klinisches Jahrbuch. 1897;6:299-326.
  10. Ehrlich P. Anwendung und Wirkung von Salvarsan.. Deutsche medizinische Wochenschrift. 1910:2437-2438.
  11. Ehrlich P. Referat über die Genese des Carcinoms.. Verhandlungen der Deutschen Pathologischen Gesellschaft. 1908;12:13-32.
  12. Lapage G. Paul Ehrlich. Nature. 1952;169:362.
  13. Sörgel F, Landersdorfer C, Bulitta J, et al. Vom Farbstoff zum Rezeptor: Paul Ehrlich und die Chemie. Nachrichten aus der Chemie. 2004;52:777-782.
  14. Hüntelmann AC. Paul Ehrlich: Leben, Forschung, Ökonomien, Netzwerke. Wallstein Verlag. 2011.
  15. Buchwalow I, Boecker W, Tiemann M. The contribution of Paul Ehrlich to histochemistry: a tribute on the occasion of the centenary of his death. Virchows Arch. 2015;466:111-116.
  16. Paul-Ehrlich-Institut. Publications of Paul-Ehrlich. 2015.

Conflict of Interests

Drs. Valent, Schumacher, Sörgel, Horny and Groner indicated no relevant conflicts of interest. back to top