Flemming, Walther

(b. Sachsenberg, Mecklenburg, Germany, 21 April 1843; d. Kiel, Germany, 4 August 1905)

anatomy, cytology.

Flemming’s family was Flemish; his father, C. F. Flemming, had moved from Jüterbog to Mecklenburg to become director of a lunatic asylum there. In this region of Germany, Walther was born and brought up. He was educated at the Gymnasium Fridericianum, where he showed great aptitude for literature and philology, but for his university studies he chose medicine. After one semester at Göttingen he went to Tübingen. There followed a semester of intensive study at Berlin, then at Rostock, where, after a long illness from typhoid fever, he completed his medical studies with his thesis on the ciliary muscles of certain mammals (1868).

His subsequent work as assistant in the department of internal medicine under Thierfelder was shortlived, for in 1869 he was able to return to zoological research, first under his former teacher, Franz E. Schulze, and then as private assistant to Semper in Wurzburg, studying the sensory epithelia of the mollusks. That autumn saw him in Amsterdam, where, under Willie Kühne, he completed a detailed study of the structure and physiology of fat cells. The Franco-Prussian War obliged him to interrupt his studies and join the medical corps reserve at Saarbrucken, in which he remained active until the autumn of 1871. Then he returned to Rostock and presented his Habilitationsschrift, “Über Bindessubstanzen und Gefasswandung bei Mollusken.” Here as a Privatdozent he worked on connective tissue and gave a public lecture on the microscope. Über die heutigen Aufgaben des Mikroskops ... (Rostock, 1872). That year he moved to Prague, where his work flourished and he formed a happy circle of friends among his colleagues. Only bad feeling among the students, two thirds of whom were Czech nationalists, caused him to leave in 1875 for Königsberg. Finally, in 1876, he settled at the small University of Kiel as professor of anatomy and director of the Anatomical Institute, a position he held until his retirement in 1901. Here he carried out the major part of his great work on cell division published in his classic book, Zellsubstanz, Kern und Zelltheilung (Leipzig, 1882). Flemming was a bachelor and for most of his time in Kiel lived with his sister Clara.

In the 1850’s attempts to study the process of cell multiplication were vitiated by inadequate techniques of staining and the poor resolving power of lenses. By the 1860’s it had become certain that before a cell divides the nucleus must first give rise to two daughter nuclei. This appeared to result either from direct fission or from a more indirect process in which dissolution of the mother nucleus was followed by coagulation of two daughter nuclei about two new centers; but the phases of this metamorphosis remained a mystery. It was seen that nucleoli came and went during indirect division, that their number was constant, and that the midpoint of the division process was marked by the appearance of nuclear granules. In the 1870’s these granules were observed to elongate into threadlike structures which split up in some way, yielding the material for two daughter nuclei. It was Flemming’s achievement to observe and interpret the stages correctly, to identify them in a wide variety of tissues, and to give indirect division the name by which it is still widely known—mitosis.

With his background in the study of connective tissues, epithelia, and fat cells, Flemming was wellprepared to attack the problem of cell division. His serious study of this subject would appear to date from 1874 while he was in Prague. His third paper in this field (“Beobachtingen über die Beschaffenheit des Zellkerns,” in Archiv für mikroskopische Anatomie, 13 [1877], 693–717), on the constitution of the cell nucleus, described the use of Hermann’s technique of overstaining followed by differentiation in alcohol. This led him to perceive the thread net (Fadennetz) with associated vacuoles and nucleoli as a constant feature of the living cell. That winter he still held to the direct-division theory of nuclear multiplication and lectured to that effect in Kiel in February 1878, but by the summer he had studied the same cells in living material as well as in fixed. Then he found what he called the Äquatorial-platte (“equatorial plate”) stage (early anaphase), which is so easily missed when working only from fixed material, and realized that what he had called direct division was in fact the indirect process. His lecture and correction appeared in Schriften des naturwissenschaftlichen Vereins für Schleswig-Holstein (Kiel, February and August 1878).

By December 1879 he had investigated all the stages of mitotic division, the results of which appeared in his three famous papers: “Beiträge zur Kenntnis der Zelle und ihrer Lebenserscheinungen” (pts. 1, 2, and 3, 1879–1881). What had been taken for granules Flemming recognized as sections through threads; what hitherto had appeared as a vague and discontinuous process he saw as a continuous metamorphosis from the skein of the mother nucleus to thread loops (chromosomes) and back again to the skeins of the two daughter nuclei. In 1880 he coined the term “chromatin” for the stainable substance of the nucleus; the nonstaining portions he termed “achromatin.” As the cell approaches division, the chromatin separates from the achromatin and becomes organized into a tangled skein (Knäuel) which proceeds to break up into figure-eight wreaths (Kränze), the loops of which open out to give stars (Sterne). At this stage the chromatin is organized with respect to a single center or pole (Flemming’s “monocentric” phase), but this soon goes over to organization around two poles (“dicentric” phase). As the poles move apart, the star figures of chromatin pull apart; and because the arms of the stars have doubled along their length, four V-shaped loops (the chromatids) can be discerned, two traveling toward one pole and two toward the other. This is the equatorial plate stage, from which the barrel stage takes the chromatic loops back to the star, wreath, and skein stages of the nascent daughter nuclei.

Flemming was in error in believing that the chromatin loops arise by fragmentation of a continuous skein and that the loops fuse end-to-end at the close of mitosis to generate a skein once more. Hence it is natural that his terminology has been replaced: wreath by prophase, star by metaphase, equatorial plate by early anaphase, and nuclear barrel by telophase. Although he noted the same number of loops in successive divisions he did not perceive their continuity and individuality. This called for material with much lower chromosome numbers than he used. Flemming’s contribution was to force the data from a wide range of apparently differing division processes into a single framework, to rule out so-called direct division of nuclei by simple fission, and to perceive longitudinal division of chromatin loops as the basis of nuclear multiplication, rather than transverse division as Strasburger believed.

In the summer of 1879 Flemming turned his attention to nuclear division in the testes and concluded that the spermatozoa are formed from cells whose nuclei have arisen by indirect division, the head of the spermatozoon being composed solely of chromatin. He also failed at this time to observe doubled threads in the closing nuclear figures. In 1882, in his book on cell division, he declared this to have been an error, for now he could detect doubled threads.

It was not until 1887 that he succeeded in clarifying the details of indirect division in the spermatozoa. Then he recognized two divisions, the first of which he termed heterotypic, the second homotypic. In the first, the threads formed curious rings and did not appear to double; in the second, doubling occurred and no ring structures were formed, the resulting nuclei having half the normal complement of chromosomes. In fact, doubling takes place in the first, not the second, division.

What Flemming called ring structures were the paired homologous chromosomes (bivalents) that Jansenns described accurately in 1909. The distinction between meiosis and mitosis is of course a deep and subtle one that Flemming, in his desire to unify the data, failed to appreciate. In 1880 he traveled to the zoological station at Naples to study cell division in the formation of the echinoderm egg and established there also indirect division as the mechanism of cell division.

Flemming’s great merit as a theoretician lay in his attempt to find a single process to fit all forms of cell division. History has justified his vision.

In the 1880’s attempts were frequently made to tie down the living substance to a particular class of compounds. Flemming would have none of this, for to him life resided in the whole body of the cell. Yet he took sides in the dispute between those who favored a network structure of protoplasm and those who preferred a filar structure. He belonged to the latter group. Such ideas were of course premature, and none has served as a foundation for later developments.

Among Flemming’s other contributions may be mentioned his work on amitotic division, which he believed to characterize pathological and senescent tissues only; he improved Flesch’s fixative in 1882 by addition of acetic acid to give Flemming’s fluid; he introduced Flemming’s stain (safranine-gentian violet–Orange G) in 1891. In his later years he returned to his earlier studies of connective tissue development and in 1902 wrote a valuable treatise, “Histogenese der Stützsubstanzen der Bindegewebesgruppe,” for O. Hertwig’s Handbuch der vergleichenden und experimentellen Entwickelungsgeschichte der Wirbeltiere.

BIBLIOGRAPHY

I. Original Works. Flemming published 80 papers and two books, all listed in Spee’s obituary notice (below). The majority of his papers appeared in the Archiv für mikroskopische Anatomie und Entwicklungsmechanik, beginning with his doctoral dissertation of 1868 and ending with his paper on rod cells 30 years later. Most important are his “Beiträge zur Kenntnis der Zelle,” pt. 1, 16 (1879), 302–436; pt. 2, 18 (1880), 152–159; and pt. 3, 20 (1881), 1–86. Pt. 2, setting out the details of mitosis, has been translated into English by Leonie Piternick and is in Journal of Cell Biology, 25 (1965), 3–69. Important also are his “Neue Beiträge zur Kenntnis der Zelle,” pt. 1, 29 (1887), 389–463; pt. 2, 37 (1891), 685–751, the first analyzing meiosis and the second introducing the Flemming stain.

Flemming’s first paper on cell division was “Über die ersten Entwickelungserscheinungen am Ei der Teichmuschel,” 10 (1874), 257–292. The first chromatin figures of mitosis are “Studien zur Entwickelungsgeschichte der Najaden,” in Sitzungsberichte der mathematisch-naturwissenschaftlichen Classe der Kaiserlichen Akademie der Wissenschaften71 (1875), pt. 3, 81–212. Major works are Zellsubstanz, Kern und Zellteilung (Leipzing, 1882), and “Histogense der Stützsubstanzen der Bindesubstanzgruppe.” in Handbuch der vergleichenden und experimentellen Entwickelungsgeschichte der Wirbeltiere, 3 vols. (Jena, 1902–1906).

II. Secondary Literature. No biographies and very few obituaries have been published. The present account is based largely on F. von Spee, “Walther Flemming,” in Anatomischer Anzeiger, 28 (1906), 41–59, with portrait and complete bibliography, and on a short note by H. J. Conn, “Walther Flemming,” in Stain Technology, 8 (1933), 48–49, with portrait.

Discussions of Flemming’s work may be found in E. B. Wilson, The Cell in Development and Inheritance (New York, 1896); and A. Hughes, A History of Cytology (London-New York, 1959). Valuable also are W. Coleman, “The Nucleus as the Vehicle of Inheritance,” in Proceedings of the American Philosophical Society, pt. 3, 109 (1965), 124–158; and A. Bolles Lee, The Microtomist’s Vade-Mecum, 3rd ed. (London, 1893).

Robert Olby