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Paul Ehrlich and the Early History of Granulocytes

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  • Author: A. Barry Kay1
  • Editor: Siamon Gordon2
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Inflammation, Repair, and Development, National Heart & Lung Institute, Imperial College, London, SW3 2AZ, United Kingdom; 2: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
  • Received 28 April 2016 Accepted 24 June 2016 Published 26 August 2016
  • A. Barry Kay, a.b.kay@imperial.ac.uk
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  • Abstract:

    Paul Ehrlich’s techniques, published between 1879 and 1880, for staining blood films using coal tar dyes, and his method of differential blood cell counting, ended years of speculation regarding the classification of white cells. Acidic and basic dyes had allowed him to recognize eosinophil and basophil granules, respectively, work that was a direct continuation of his discovery of the tissue mast cell described in his doctoral thesis. Ehrlich went on to develop neutral dyes that identified epsilon granules in neutrophils (“cells with polymorphous nuclei”). He also speculated, for the most part correctly, on the formation, function, and fate of blood neutrophils and eosinophils. Before Ehrlich, a number of important observations had been made on white cells and their role in health and disease. Among the most notable were William Hewson’s studies of blood and lymph; the early descriptions of leukemia by Alfred Donné, John Hughes Bennett, Rudolf Virchow, and others; as well as seminal observations on inflammation by William Addison, Friedrich von Recklinghausen, and Julius Cohnheim. Eosinophils were almost certainly recognized previously by others. In 1846, Thomas Wharton Jones (1808-1891) described “granule blood-cells” in several species including humans. The term “granule cell” had also been used by Julius Vogel (1814-1880), who had previously observed similar cells in inflammatory exudates. Vogel, in turn, was aware of the work of Gottlieb Gluge (1812-1898), who had observed “compound inflammatory globules” in pus and serum that resembled eosinophils. Almost 20 years before Ehrlich developed his staining methods, Max Johann Schultze (1825-1874) performed functional experiments on fine and coarse granular cells using a warm stage microscopic technique and showed they had amoeboid movement and phagocytic abilities. Despite these earlier observations, it was Ehrlich’s use of stains that heralded the modern era of studies of leukocyte biology and pathology.

  • Citation: Kay A. 2016. Paul Ehrlich and the Early History of Granulocytes. Microbiol Spectrum 4(4):MCHD-0032-2016. doi:10.1128/microbiolspec.MCHD-0032-2016.

Key Concept Ranking

White Blood Cells
0.96699286
Mast Cells
0.6078044
0.96699286

References

1. Van Leeuwenhoek A. 1674. Microscopical observations from Mr. Leeuwenhoeck, about blood, milk, bones, the brain, spitle, cuticula, sweat, fatt, teares; communicated in two letters to the publisher. Phil Trans 9:121–128. [CrossRef]
2. Lieutaud J. 1749. Elementa Physiologiae, p 82–84. Amsterdam, The Netherlands. (Later translated and quoted in Dreyfus C, 1957, Some Milestones in the History of Hematology, p 11–12, Grune and Stratton, New York, NY.)
3. de Senac JB. 1749. Traite de la Structure du Coeur, de son Action, et de ses Maladies. Jacque Vincent, Paris, France.
4. Hewson W. 1774. Experimental Inquiries, Part I. A Description of the Lymphatic System in the Human Subject and Other Animals, p 30. J. Johnson, London, United Kingdom.
5. Diamantis A, Magiorkinis E, Androutsos G. 2009. Alfred Francois Donné (1801-78): a pioneer of microscopy, microbiology and haematology. J Med Biogr 17:81–87. [PubMed][CrossRef]
6. Thomas X. 2013. First contributors in the history of leukemia. World J Haematol 2:62–70. [CrossRef]
7. Addison W. 1840-1841. Colourless globules in the buffy coat of the blood. Lond Med Gaz 27:524–527.
8. Virchow RL. 1846. Weisses Blut und Milztumoren. Med Zeitung 14:157–163.
9. Rather LJ. 1972. Addison and the White Corpuscles: an Aspect of Nineteenth-Century Biology. Wellcome Institute for the History of Medicine, London, United Kingdom.
10. Von Recklinghausen FD. 1863. Über Eiter- und Bindegewebskörperchen. Virchows Arch Pathol Anat 28:157–197. [CrossRef]
11. Wohlgemuth B, Borte G. 1989. The 150th birthday of Julius Cohnheim. Z Arztl Fortbild (Jena) 83:743–745. (In German.) [PubMed]
12. Gluge G. 1843. Atlas der Pathologischen Anatomie, Mauke, Jena, Germany. (Translated from French by Blanchard and Lea, Philadelphia, PA, 1853.)
13. Vogel J. 1847. The Pathological Anatomy of the Human Body (Day GE, transl). Blanchard and Lea, Philadelphia, PA.
14. Wharton Jones T. 1846. The blood-corpuscle considered in its different phases of development in the animal series. Memoir I. Vertebrata. Philos Trans R Soc Lond 136:63–87. [CrossRef]
15. Schultze MJ. 1865. Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes. Arch Mikrosk Anat 1:1–42. [CrossRef]
16. Brewer DB. 1994. Max Schultze and the living, moving, phagocytosing leucocytes: 1865. Med Hist 38:91–101. [PubMed][CrossRef]
17. Bizzozero G. 1881. Su di un nuovo elemento morfologico del sangue dei mammiferi e sulla sua importanza nella trombosi e nella coagulazione. Osserv Gazz Clin 17:785–787.
18. Ehrlich P. 1878. Beiträge zyr Theorie und Praxis der histologischen Färbung. Doctoral thesis dissertation. University of Leipzig, Leipzig, Germany.
19. Ehrlich P. 1879. Beiträge zur Kenntnis der granulirten Bindegewbszellen und der ecosinophilen Leukocythen. Arch Anat Physiol (Leipzig) 3:166–169.
20. Ehrlich P. 1879. Über die specifischen Granulationen des Blutes. Arch Anat Physiol (Leipzig) 571–579.
21. Ehrlich P. 1900. La Leukocytose. X111e Congres Internationale de Medicine, Paris 1900.
22. Ehrlich P, Lazarus A. 1900. Histology of the Blood, Normal and Pathological (Myers W, transl). Cambridge University Press, Cambridge, United Kingdom.
23. Hirsch JG, Hirsch BI. 1980. Paul Ehrlich and the discovery of the eosinophil, p 3–23. In Mahmoud AA, Austen KF (ed), The Eosinophil in Health and Disease. Grune and Stratton, New York, NY.
24. Hüntelmann AC. 2010. Legend of science. External constructions by the extended “family”—the biography of Paul Ehrlich. InterDisciplines 2:13–36.
25. Wright AE, Douglas SR, Sanderson JB. 1903. An experimental investigation on the role of the blood fluids in connection with phagocytosis. Proc R Soc Lond 72:357–370. [CrossRef]
26. Kay AB. 2015. The early history of the eosinophil. Clin Exp Allergy 45:575–582. [PubMed][CrossRef]
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2016-08-26
2017-11-23

Abstract:

Paul Ehrlich’s techniques, published between 1879 and 1880, for staining blood films using coal tar dyes, and his method of differential blood cell counting, ended years of speculation regarding the classification of white cells. Acidic and basic dyes had allowed him to recognize eosinophil and basophil granules, respectively, work that was a direct continuation of his discovery of the tissue mast cell described in his doctoral thesis. Ehrlich went on to develop neutral dyes that identified epsilon granules in neutrophils (“cells with polymorphous nuclei”). He also speculated, for the most part correctly, on the formation, function, and fate of blood neutrophils and eosinophils. Before Ehrlich, a number of important observations had been made on white cells and their role in health and disease. Among the most notable were William Hewson’s studies of blood and lymph; the early descriptions of leukemia by Alfred Donné, John Hughes Bennett, Rudolf Virchow, and others; as well as seminal observations on inflammation by William Addison, Friedrich von Recklinghausen, and Julius Cohnheim. Eosinophils were almost certainly recognized previously by others. In 1846, Thomas Wharton Jones (1808-1891) described “granule blood-cells” in several species including humans. The term “granule cell” had also been used by Julius Vogel (1814-1880), who had previously observed similar cells in inflammatory exudates. Vogel, in turn, was aware of the work of Gottlieb Gluge (1812-1898), who had observed “compound inflammatory globules” in pus and serum that resembled eosinophils. Almost 20 years before Ehrlich developed his staining methods, Max Johann Schultze (1825-1874) performed functional experiments on fine and coarse granular cells using a warm stage microscopic technique and showed they had amoeboid movement and phagocytic abilities. Despite these earlier observations, it was Ehrlich’s use of stains that heralded the modern era of studies of leukocyte biology and pathology.

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Figures

Image of FIGURE 1
FIGURE 1

Paul Ehrlich in 1878 (from Hirsch and Hirsch [ 23 ]). The first description of the eosinophil appeared in the in 1879. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 2
FIGURE 2

(Left) William Hewson, the Father of Hematology. (Right) Alfred Donné, who introduced the microscope into clinical diagnosis and recorded one of the first descriptions of white cells in leukemia. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 3
FIGURE 3

Alfred Donné’s microscopic images of blood from a patient with leukemia. (Top right) Red and white blood cells from a leukemic patient. (Lower right) “Mucous globules,” or white blood cells, from the same patient. The images were published in the supplement to in 1845 (left). Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 4
FIGURE 4

John Bennett published the first detailed description of leukemia. His illustrations show “colourless corpuscles” in the circulation. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 5
FIGURE 5

Rudolf Virchow and an illustration taken from his volume (7th American edition, Robert M. de Witt, New York, NY, 1856): Fig. 63. A. Pus-corpuscles, a fresh, b after the addition of a little water, c–e after treatment with acetic acid, the contents cleared up, the nuclei which were in process of division, or already divided, visible, at e with a slight depression on their surface. B. Nuclei of pus corpuscles in gonorrhoea; a simple nucleus with nucleoli, b incipient division, with depressions (by many held to be nuclei) on the surface of the nuclei, c progressive bi-partition, d tri-partition. C. Pus-corpuscles in their natural position with regard to one another. 500 diameters. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 6
FIGURE 6

(Left) Julius Cohnheim demonstrated that leukocytes passed through the apparently intact walls of the capillaries by amoeboid movement. (Right) Friedrich von Recklinghausen showed that the amoeboid properties of white cells were the result of both locomotion and contractility. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 7
FIGURE 7

Gottlieb Gluge was possibly the first to describe granular cells, which he referred to as “inflammatory globules.” He proposed that blood corpuscles “metamorphosed” into inflammation globules. The cells shown in the top right panel were believed to represent stages in this process. However, they have the appearance of intact or degranulated eosinophils. Further examples of Gluge’s “inflammation corpuscles” are shown in the middle right and bottom panels. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 8
FIGURE 8

Julius Vogel made extensive drawings of granular cells in inflammatory exudates. The right panels are examples of Vogel’s “pus corpuscles,” which he also refers to as “granular cells” or “Gluge’s compound inflammatory globules.” They bear a striking resemblance to eosinophils. Reprinted from ( 13 ).

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 9
FIGURE 9

Thomas Wharton Jones made an extensive study of granular cells in a wide variety of species. His drawings show coarsely granular cells in the blood of human, horse, and elephant. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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Image of FIGURE 10
FIGURE 10

Max Schultze performed functional studies on finely and coarsely granular cells. The cells were observed on a warm stage at 38°C. Reprinted from ( 16 ), with permission.

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Image of FIGURE 11
FIGURE 11

Paul Ehrlich in 1908. Color plate from ( 22 ). Triacid (orange G, acid fuchsin, and methyl green) was used as a differential leukocyte stain. Reprinted from ( 26 ), with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0032-2016
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