Speculation About How Cells Propagate
“Cells propagate themselves through division.” Today this sentence sounds truistic, but at one time it was highly controversial. Long after the cell had been recognized as the fundamental element of all plants and animals, speculations abounded about the mechanisms by which cells continued to proliferate. For example, Matthias Schleiden (Fig. 1), who, in his treatise “Beiträge zur Phytogenesis” (“Contributions to Phytogenesis”) (Fig. 2) published in 1838 established the cellular composition of plants beyond doubt, believed that new cells developed within preexisting ‘mother cells.’ One year after the discovery of the nucleus by the English botanist, Robert Brown, Schleiden attributed a decisive role in the formation of cells to the nucleus, to which he referred as ‘cytoblast.’ Schleiden explained the formation of new cells as follows:
“As soon as the cytoblasts have reached their full size, a delicate, translucent vesicle arises on them, the young cell that sits on the plane cytoblast like the glass on a watch . . . The cytoblasts form freely within a cell in a mass of mucous granules, and the young cells also lie freely within the mother cell and, by flattening off one another, acquire a polyedric outline. Subsequently, the mother cell is resorbed.”1
Matthias Jakob Schleiden (1804-1881).
Figures from the monograph of 1838 of Matthias Jakob Schleiden titled, Beiträge zur Phytogenesis (Contributions to Phytogenesis). The original legend reads in part as follows: “Fig. 1 . . . a The innermost generative mass, composed of gum with admixed mucous granules and cytoblasts. b Newly formed cells still soluble in distilled water. c-e Further development of cells with the exception of cytoblasts, which, under the influence of slight pressure still melt into a formless gelatinous mass. Fig. 2 The generative mass of Figure 1a at higher magnification, gum, mucous granules, the nuclei of cytoblasts, the cytoblasts themselves. Fig. 3 A solitary free cytoblast at even higher magnification. Fig. 4 A cytoblast with a cell forming on it. Fig. 5 The same, at higher magnification.”
The cytoblast was said to arise from formless material (“blastema”) that was thought to condense first into the nucleolus, a structure described first by Schleiden in 1838, and then into the nucleus. It was Theodor Schwann (Fig. 3), who, in his monograph “Mikroskopische Untersuchungen über die übereinstimmung in der Struktur und dem Wachstum der Tiere und Pflanzen” (“Microscopic examinations concerning the identity of structure and growth of animals and plants”) (Fig. 4) published in 1839, extended Schleiden’s discoveries to all living things. This is what Schwann had this to say about the formation of cells: “The initial formation of the nucleolus can be thought of as a kind of ‘crystallization’ from a concentrated fluid. If a fluid is so concentrated that the molecules of the dissolved substance attract one another more strongly than the molecules of that substance and those of the solvent, a part of the solid substance must precipitate.”
Theodor Schwann (1810-1882).
Figure from the monograph of 1839 of Theodor Schwann titled, Mikroskopische Untersuchungen über die übereinstimmung in der Struktur und dem Wachstum der Tiere and Pflanzen (Microscopic Examinations Concerning the Identify of Structure and Growth of Animals and Plants). The original description reads, in part, as follows: “These cells of cartilage are completely embedded in an intercellular substance, which represents their cytoblastema. New cells arise in this cytoblastema, not in already existing cells . . . On one hand, one sees free nuclei which are somewhat smaller than the nuclei of adult cells a and b, on the other hand nuclei which are surrounded by a cell c c, in short, all stages of transition between free nuclei, nuclei surrounded by small cells, and adult cells, so that the development is like that of most cells, and the nucleus is the true cytoblast.”
Those considerations led Schwann to this conclusion: “The entire process of the formation of a cell consists of precipitation, around an initially arising small body (nucleolus), of first one (nucleus), and then, around it, a second layer (cell substance). The different layers grow by intake of new molecules among those already present, by intussusception, and this according to the law that the precipitation is more pronounced in the outer parts of every layer . . . Because of this law, only the outer part of every layer condensates into a membrane (of the nucleus and of the cell).”2
According to Schwann, new cells could form either extracelluarly or within pre-existing “mother cells.” Schwann did not consider the division of cells to be important for propagation of them, although the former phenomenon already was well known. In 1832, Dumortier had described the multiplication through division of the peripheral cells of Conferva aurea.3 In 1835, Hugo von Mohl of Tübingen explained, in his thesis, “über die Vermehrung der Pflanzenzellen durch Teilung” (“About the propagation of cells of plants through division”), how the cells at the periphery (‘end cells’ or ‘branches’) of plants were separated from their mother cell by virtue of “narrowings that projected into the body of the cell. (Fig. 5).” Mohl wrote about the phenomenon in these words: “After having been separated from its mother cell in that way, the branch becomes longer and longer, until it forms a very long cylindrical cell. The latter divides in analogous fashion . . . into two cells arranged on top of each other. Of those, only the end cell becomes larger and later divides, too.”4 Another who in 1837 called attention to the division of plant cells was Franz Julius Ferdinand Meyen (Fig. 6).5 When Matthias Schleiden, one year later, referred to the cytoblast as the starting point of the formation of new cells, Meyen rejected that theory and insisted “that the multiplication of cells through division is a very common phenomenon in lower and higher plants. When, however, cells in the elaborate tissue of higher plants, as well as in lower ones, do not multiply by division, they do not arise from nuclei or so-called cytoblasts, but the new cells form in a condensed mucous mass within older cells, and one can oberve how the mucous mass expands to form a blister whose wall eventually hardens.”6
Figure from the thesis of 1835 of Hugo von Mohl titled, über die Vermehrung der Pflanzenzellen durch Theilung (About the Propagation of Cells of Plants Through Division) showing the formation of dividing walls in the end cells of Conferva glomerata.
Figure from the first volume of the textbook of 1837 of Franz Julius Ferdinand Meyen titled, Neues System der Pflanzenphysiologie (New System of Physiology of Plants) illustrating the formation of transverse walls in cells of Chara vulgaris.
In short, cell division had been recognized as a mechanism for propagation of cells as early as the 1830s, but even proponents of that concept thought of division as only one of several possibilities for how cells might propagate. Among other mechanisms discussed at that time was the formation within cells of new cells by separation of portions of a preexisting cell, a concept advanced by the botanist, Karl Wilhelm von Nägeli of Munich (Fig. 7). Karl Reichert, who worked under Johannes Müller at the Institute of Anatomy of the University of Berlin, observed a furrowing of cells, but attributed that phenomenon to a “de-packaging” of encapsulated cells.3 Most authors of the time adhered to Schwann’s thesis that a new cell formed both intracellularly and extracellularly from a formless ”cytoblastema.” Among the believers was Rudolf Virchow (Fig. 8) who, in 1847, set forth the following general principles: “1. All organization happens through differentiation of formless material, blastema . . . 2. All blastema comes out of the vessels primarily as fluid, exudate . . . 3. All organization begins with the creation of cells.” 7
Karl Wilhelm von Nägeli (1817-1891).
Rudolf Virchow (1821-1902).
The opposing views concerning the propagation of cells were a consequence mostly of lack of adequate histologic techniques and poor quality of microscopes. The maximum resolution of lens of microscopes of that time was approximately 1 µm, the illumination was poor, and stains were not available.3 The examination of findings at the outer limits of visibility was associated inevitably with misperception followed by misinterpretation of fragments of necrotic cells being extracellular nuclei. Rudolf Virchow pointed out in 1847 “that the number of optical deceptions is relatively low and that most of those deceptions are merely logical ones, false interpretations of accurately observed objects.”7
The Greatness and the Forgotten Contributions of Robert Remak
Because of these difficulties that led to deceptions optically and logically, great technical facility in the preparation of specimens was required; great care, patience, and preseverance in order to check observations again and again, and great capability for critical assessment in regard to one’s own conclusions. Hardly any other scientist of the 19th Century marshalled those attributes better than Robert Remak (Fig. 9). Born in 1815 the son of a Jewish trader of small items in Poznan, Remak studied medicine in Berlin, where he was influenced especially by the chairman of the Institute of Anatomy and Physiology, Johannes Müller. Among the illustrious pupils of Müller, such as Theodor Schwann, Jacob Henle, Karl Reichert, and Emil Du Bois-Reymond, Remak remained an outsider, one reason being adherence to his Jewish faith and to his Polish nationality, the other reason being that his scientific findings often were in stark contrast to those considered to be knowledge accepted conventionally. In his doctoral thesis, Remak had described the fibers of the sympathetic nerve system, the axis cylinder of nerves, and the direct connection between nerve fibers and ganglion cells – findings that had been overlooked by famous microscopists who then responded to the ideas of Remak with ridicule, rejecting them out of hand. Once the authenticity of Remak’s work had been recognized, however, those adversaries presented them as their own discoveries. Following graduation, Remak worked for some years as a research assistant in the clinic of Johann Lucas Schönlein. It was there that Remak described the cause of favus, a fungus known today as Trichophyton schönleinii. More important, Remak conducted extensive research in embryology (Figs. 10 and 11) and summarized findings of his own between 1850 and 1855 in the three-volume book, “Untersuchungen über die Entwicklung der Wirbeltiere” (“Studies on the development of vertebrates”). In that work, which is a classic in medicine, Remak described not only the three germ layers of the embryo but demonstrated, using chickens and frogs as his examples, that all organs developed from those three germ layers. In the last years of his life, Remak became a pioneer of galvanotherapy for diseases of muscles and nerves but, once again, earned chiefly criticism and mockery for his important contributions.8,9
Robert Remak (1815-1865).
Figure from the textbook of 1855 of Robert Remak titled, Untersuchungen über die Entwicklung der Wirbeltiere (Studies on the Development of Vertebrates), showing cleavage and division of the cell of an egg.
Figure from the textbook of 1855 of Robert Remak titled, Untersuchungen über die Entwicklung der Wirbeltiere (Studies on the Development of Vertebrates), showing the division of cells of an egg and nuclei of them.
Unlike many other Jewish contemporaries, Remak refused to change his faith in order to be assured of a career. Because he did not convert to Christianity, he never was granted his own research facilities, but was forced to work in the laboratory of Johannes Müller, the clinic of Johann Lucas Schönlein, or in his own private apartment. He earned his living as a general practitioner. When leading positions at universities within and outside Prussia became available, Remak was by-passed routinely. In 1847, Remak’s indefatigable mentor, Alexander von Humboldt, succeeded in inducing the Prussian king to sign a “special dispensation” that, contrary to the then current law, enabled Remak to be promoted to the rank of lecturer (“Privatdozent”), thereby becoming only the second Jewish member ever of the medical faculty of the University of Berlin. The king also instructed his ministers to confer on Remak the next vacant chair at a Prussian university. When, however, a successor was sought for Johannes Müller as chairman of the Institute of Pathology at the University of Berlin, the younger and less distinguished Rudolf Virchow was chosen over Remak.8,9
In the course of his research in embryology, Remak studied intensively the mechanisms of propagation of cells. In 1841, he demonstrated that blood cells of birds and mammals proliferate through division in embryos, and a few years later he showed clearly the division of muscle cells. In 1851, Remak examined larva of frogs and noted “that, after cleavage, all embryonic cells proliferate through division when tissues begin to be formed.” In the following year, he summarized his findings about the proliferation of cells in a comprehensive article titled, “Ueber extracelluläre Entstehung thierischer Zellen und über Vermehrung derselben durch Theilung” (“About the extracellular creation of animal cells and their multiplication by division”) (Fig. 12). By virtue of the ideas expressed in this article of 1852, the concept of cell division as the mechanism of proliferation of cells became established firmly.10
Title page of the article of 1852 of Robert Remak captioned, “Ueber extracellulare Entstehung thierischer Zellen and über Vermehrung derselben durch Theilung” (“About the extracellular creation of animal cells and their multiplication by division”).
Remak began his article with a critique of Schwann’s concept of the formation of cells. He declared that in his experience free nuclei never were found outside cells, as Schwann had postulated, and, instead, averred the following: “For myself the extracellular creation of animal cells has been, since the cell theory has been published, as incredible as the spontaneous generation of organisms.” That Remak’s observations about the division of cells began at an early stage of cleavage of the fertilized egg cell were expressed by him thus: “The division of the cleavage cells starts from the nucleus and, when at the end of cleavage the nucleolus can be recognized from the latter . . . At the lower, white half of the uninjured egg, one can observe by use of a magnifier, in the last stages of cleavage, how the light spot representing the nucleus divides into two spots, how those spots move away from one another, and how the cleavage cell divides in a way that each half is furnished with a light spot (nucleus) . . . Following cleavage, the cells begin to form an embryo by separating themselves into three layers (a sensory, a motoric, and a trophic one) and by proliferating within those layers through division, thus creating the cells that serve as the basis of tissues.”10
In the same article, Remak transferred the observations made by him in the earliest stages of the development of the embryo to neoplastic processes as they occurred in human beings. He opined “that the pathologic tissues, no less than the normal ones, do not arise in an extracellular cytoblastema, but are derivatives and products of normal tissues of the organism.”10 Today this statement sounds obvious, but 150 years ago most pathologists still believed that neoplasms were a consequence of an aberration in organization of formless blastema, a concept advanced most trenchantly by the Viennese pathologist, Karl Rokitansky, and also by Rudolf Virchow. In contradistinction to those pathologists, Remak, in 1854, was able to reinforce the legitimacy of his own thinking about malignant neoplasia when he had the chance to examine two carcinomas of the skin. In an article captioned, “Ein Beitrag zur Entwickelungsgeschichte der krebshaften Geschwülste” (“A contribution to the pathogenesis of cancerous growths”), he described his findings in those malignant neoplasms in these words: “Everywhere I find nuclei within cells, and everywhere I am confronted with changes that indicate a proliferation of cells through division, according to the modus that I have found in normal tissues . . . For those reasons, I believe . . . that pathologic growths do not represent a formation of new tissues, but a transformation of normal tissues, resulting in elements that either remain similar to normal ones in regard to form and composition (homologous) or that deviate from the tissues from which they originate in regard to form and composition through progressive degeneration (heterologous).”11
Remak was not the only scientist who came to recognize the importance of cell division. Already in 1843, the pathologist, Friedrich Günsburg, had described “the proliferation of pathologic cells through the division of their swollen nuclei . . . and the subsequent furrowing of the cell, the actual division of it.”12 In 1846, the anatomist and zoologist, Karl Ernst von Baer (Fig. 13) of St. Petersburg, described devision of cells in the eggs of sea urchins in these lines: “After a period of rest the round nucleus enlarges rather rapidly, shooting out to both sides; while both of its ends swell, the middle becomes thinner and then divides completely, so that two comet-like nuclei result with their tails lying opposed to one another. Then those tail-like extensions are retracted very rapidly into the round or bullous mass, and one sees two nuclei . . . The original nucleus has increased in size already before the division; during division, this process continues so that each of the two new nuclei has approximately the size of the original one . . . Only after the two nuclei have existed next to one another for a while and have moved away from one another even further, one sees a lacing in the yolk, through which the latter falls apart in two halves, each nucleus being surrounded by its own yolk substance . . . In later divisions, in which there is less yolk substance, one sees with great precision that the division of nuclei does not lead to the formation of new cells within a mother cell.” After having told of his findings, von Baer speculated “that the permanent tissues may arise from the original ones by very similar divisions,” and he gave credence to that notion by referring specifically to observations made by Remak.13
Karl Ernst von Baer (1792-1876).
The Lack of Grace of Rudolf Virchow
Although the concept of cell division had been propagated episodically in the 1830s and 1840s, it was the systematic research of Remak in the field of embryology that was the breakthrough. Shortly after publication of Remak’s article about cell division in 1852, critics of that concept became converts to the new doctrine. Virchow, for example, wrote in 1851 that he “still had to maintain, in its entire extent,” the thesis that “new cells develop internally within existing cells – mother and daughter cells.” He advocated the idea that the growth of tumors was caused “primarily by the development of breeding rooms within a mother cell” and attempted to substantiate that notion through a series of drawings (Fig. 14).14 In his definitive article about “Cellular pathology” in 1855, in which he introduced the famous proverb, “Omnis cellula a cellula,” Virchow mentioned cell division only once and in passing, without any hint whatsoever as to its significance biologically. Although Virchow asserted that all cells were derived from other cells, he did not explain, how that came to be.14 Two years later, however, Virchow had become convinced. In an article headed, “Ueber die Theilung der Zellenkerne” (“About the division of nuclei of cells”), he made this statement: “The division of the nucleolus is followed by the . . . division of the nucleus, which may be followed by that of the cell itself.”12
Figure from the article of 1851 of Rudolf Virchow headed, “Die engdogene Zellenbildung beim Krebs” (“The endogenous formation of cells in cancer”). The original legend reads: “Epidermoid cancroid of the lip: 3 large rooms for breeding with endogenous formations and a concentric wall, surrounded by nucleated, flat epidermoid cells that, at the edge, have a striped appearance.”
In the same article, Virchow discussed the contributions of Robert Remak to the elucidation of cell division. Although he acknowledged that “Remak, through his classic examinations about the developmental history of vertebrates, has surely . . . contributed significantly to the establishment of cell division in normal tissues,” he denied Remak any merit concerning the role of cell division in pathologic growths. Virchow did not mention the fact that Remak in his article about cutaneous carcinoma in 1854 had described precisely the “proliferation of cells through division.”11 Instead, he criticized Remak for having referred to carcinomas as tumors of the epithelium, whereas those lesions, in Virchow’s view, were a “heteroplastic growth of elements of connective tissue.” Virchow concluded his article ingenuously with these words:
“Only after the connective tissue had been identified as a permanent germinative tissue, and after the continuity in the development of elements of connective tissue through progressive divisions has been proven empirically for normal and pathologic tissues through a series of detailed studies by myself and my pupils, the concept of cell division could be accepted as generally applicable.”12
In other words, Virchow claimed for himself credit for having recognized cell division as the principle mechanism of propagation of cells – and this on the basis of the idea that carcinomas originated from cells of connective tissue, which not only was unrelated to the issue under discussion but also was dead wrong. Henceforth, Virchow chose to ignore Remak’s contributions entirely. For example, in his famous book of 1858, “Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre” (“Cellular Pathology as Based on Physiologic and Pathologic Histology”), Remak’s name was not mentioned even once.16
That Virchow refrained from deliberately acknowledging Remak’s priority in regard to the concepts of cell division and cellular pathology was probably caused by a particular kind of competition between the two scientists. On two occasions – first when a prosector was sought at the mortuary of the University of Berlin in 1846, and second in 1856, when the chair of pathology became available – Remak and Virchow were the two most promising candidates being considered. Both positions were given to Virchow, a consequence not only of Remak’s being Jewish but of Virchow’s skills as a politician. Virchow, who later became a member for decades of the Prussian and the German parliament, knew how to pull strings and how to show himself in the most favorable light.8 A denigrating reference to the scientific merits of an evident competitor would have been an error unthinkable for a skillful politician and Verchow, of course, did not do that; he simply did not give credit properly.
An Injustice That Deserves to be Set Right After 150 Years
Nothing could reveal the differences between Virchow and Remak more compellingly than a comparison and contrast of their respective articles about cellular pathology. Remak, in his article of 1854 titled, “A contribution to the pathogenesis of cancerous growths,” described his observations by microscopy plainly and accurately, whereas Virchow, in his seminal article of 1855, “Cellular Pathology” advanced practically no new observations but instead issued a political manifesto that could just as well have been presented by him, in similar form, in the Prussian parliament. Because of those differences, Remak has largely been forgotten, whereas Virchow is remembered worldwide as the founder of modern pathology. It is time that inequity be rectified.
Dr. Weyers is co-director of the Center for Dermatopathology in Freiburg, Germany.
1. Schleiden MJ. Beiträge zur Phytogenesis. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin (Müller’s Archiv) 1838;5:37-176.
2. Schwann T. Mikroskopische Untersuchungen über die übereinstimmung in der Struktur und dem Wachstum der Thiere und Pflanzen. Berlin: Reimer, 1839.
3. Cremer T. Von der Zellenlehre zur Chromosomentheorie. Naturwissenschaftliche Erkenntnis und Theorienwechsel in der frühen Zell- und Vererbungsforschung. Berlin, Heidelberg, New York, Tokyo: Springer, 1985.
4. Mohl H. über die Vermehrung der Pflanzenzellen durch Theilung. Inaugural-Dissertation. Tübingen: Fuss, 1835.
5. Meyen FJF. Neues System der Pflanzenphysiologie, vol. 1. Berlin: Haude und Spenersche Buchhandlung, 1837.
6. Meyen FJF. Neues System der Pflanzenphysiologie, vol. 3. Berlin: Haude und Spenersche Buchhandlung, 1839.
7. Virchow R. Ueber die Reform der pathologischen und therapeutischen Anschauungen durch die mikroskopischen Untersuchungen. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow’s Archiv) 1847;1:207-55.
8. Kisch B. Forgotten leaders in modern medicine. Transactions of the American Philosophical Society 1954;44:227-96.
9. Kampe N, Schmiedebach HP. Robert Remak (1815-1865). A case study in Jewish emanzipation in the Mid-Nineteenth-Century German Scientific Community. Year Book of the Leo Baeck Institute 95-129.
10. Remak R. Ueber extracellulare Entstehung thierischer Zellen und über Vermehrung derselben durch Theilung. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin (Müller’s Archiv) 1852;19:47-57.
11. Remak R. Ein Beitrag zur Entwickelungsgeschichte der krebshaften Geschwülste. Deutsche Klinik 1854;6:170-74.
12. Virchow R. Ueber die Theilung der Zellenkerne. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow’s Archiv) 1857;11:89-92.
13. Bär CE. Neue Untersuchungen über die Entwickelung der Thiere. Neue Notizen aus dem Gebiete der Natur- und Heilkunde (L. F. Froriep u. R. Froriep) 1846;39:33-40.
14. Virchow R. Die endogene Zellenbildung beim Krebs. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow’s Archiv) 1851;3:197-227.
15. Virchow R. Cellular-Pathologie. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow’s Archiv) 1855;8:3-39.
16. Virchow R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Berlin: August Hirschwald, 1858.