The history of cell biology in the 1800's: From globules to chromosomes

by Anders Skovly, 2026

Introduction

As we saw in the previous article, The origins of cell- and microbiology, both plant cells and animal blood cells were seen by microscopists in the late 1600s. Despite of this, it would take a long time before anyone got the idea that the “cells” of plants (alternatively called “pores/bubbles/bladders”) were units of structure comparable with animal “blood globules” or “blood corpuscles” (as the blood cells were called early on).

In this text we will review the advance of cell biology through the 1800's, from early misconceptions to the discovery of chromosomes and nuclear division. In writing on this topic I've used John Baker as a guide. Between 1948 and 1955 Baker wrote five articles titled The cell theory: a restatement, history, and critique, Part I/II/III/IV/V, and in 1988 these articles were published together as a book. This book is my main source of information. Therefore, this text has certain similarities with Baker's, covering the same names and discoveries. However, I try to keep the focus on the more curious parts of the history, and where possible I've used primary sources or translations thereof to flesh out the details.

Many of the primary sources are unfortunately only available in German, which I currently cannot read. To be able to gain a more complete understanding of 1800's cell biology, it is clear that proficiency in German is a prerequisite. Still, with the aid of Baker and other works available in english, it has proved possible to reach a fairly good understanding of the topic. With that said, let's begin.

Cells as individual structural units

Today it is known that each plant cell has its own “cell wall”, a layer of cellulose which surrounds the cell. In the early 1800s, however, the general view was that the cell wall was a single continuous object spanning the entire plant, and that the individual cells simply were open spaces within the wall-material. This apparent continuity of the wall can easily be seen in Robert Hooke’s figure of a section of cork, where the material surrounding the cell spaces appears to be continuous throughout the section (this figure was described in the previous article, The origins of cell- and microbiology). For more modern micrographs of the cell wall, see these pictures (where the bright lines represent the cell walls):

Plant cells picture 1
Plant cells picture 2

The fact that the cell wall is not a single continuous material, and that each cell space is surrounded by its own individual wall, was first observed in 1805. Here quoting from Baker (1988):

The first person who clearly demonstrated that plant cells are separable units was G. R. Treviranus. Referring to the globules mentioned by Wolff [...] Treviranus writes (1805, p. 233): ‘I have nowhere seen these little bladders [cells] so clearly as in the buds of Ranunculus Ficaria L. A thin section of this, brought under the magnifying-glass in water, allows itself to be divided by the point of a needle into nothing but little bladders (in lauter blaschen).’

(Treviranus wrote in German, english translation by Baker.)

Additional study on the separateness of plant cells was published by Johann Moldenhawer in his book Contributions to the anatomy of plants (Beyträge zur Anatomie der Pflanzen, 1812). Moldenhawer found that maceration of plant material (i.e. soaking it in water) can cause the material to “dissolve” into separate little sacs (although this didn't work on every type of plant material).

(Baker (1988) translates a short section from page 81 of Moldenhawer’s book. In my opinion that short section was a bit, well, short. Therefore I got a Google-translation of pages 81-83 of Moldenhawer's book. Have a look if you want.)

At least one prominent botanist, Charles-Francois Brisseau de Mirbel, would hold on to the idea of a continuous wall material for many more years. I don't understand why he did this, but anyway, Baker (1988) writes that in 1835 Mirbel admitted that he had been mistaken. At this point, then, it appears to have been a general agreement among the botanists that the cells of plants are not mere spaces in a continuous wall-material, but rather that the cells are individual units with individual walls which are held together in some way.

The globule theory

(Before starting this section, I want first to give a basic explanation of the word “tissue”, if there should be readers who aren't sure what it refers to. This word will appear quite a lot in the text ahead. In animals and plants, not all cells are the same type of cell. In animals, there are muscle cells, fat cells, and many other types of cells. A tissue is basically cells which look similar and function similarly, and are grouped together. For example, many muscle cells grouped together constitute a muscle tissue.)

Another difficulty microscopists faced in the early 1800’s was that while it was possible to see individual blood cells with a microscope, it was not possible to see cells in the solid animal tissues. One reason for this is the fact that animal cells lack a prominent cell wall. In plant tissues, the cell walls give each cell a distinct outline. In solid animal tissues, the lack of cell walls makes it more difficult to see the cells as individual units. For example, take a look at these micrographs of human tissues:

Human cells picture 1 (smooth muscle)
Human cells picture 2 (skeletal muscle)
Human cells picture 3 (some type of cartilage)
Human cells picture 4 (some part of the brain)
Human cells picture 5 (some other part of the brain)

(Note that the cells in these pictures are colored with dyes to improve visibility of the cell structures. Tissues don't look this colorful in their natural state. Also, dyes which are able to color cells were not available until around the mid-1800's.)

While the microscopists of the early 1800’s didn’t see cells in animal tissues, they saw something else: what they called “globules”, which were little spherical objects without any discernible wall around them. Many microscopists came to believe that the muscles, the brain, and other parts of animals were composed of globules, and that the globule represented the elementary part of the animal organism.

Baker (1988) mentions many different examples of people claiming to have seen such glubules. One of them is Everard Home, who in 1818 published On the changes the blood undergoes in the act of coagulation. Home begins by stating that the red globules of the blood in the human body have a measured diameter of 1/1700 inch. (This equals 14.9 micrometer, where a micrometer is a millionth of a meter, or a thousandth of a millimeter). He also says that when these blood globules have “lost their color”, their diameter appear slightly smaller, about 1/2000 inch (12.7 micrometer). Then he explains what he means by saying that the blood globules lose their color:

The colouring substance appears not to be contained in the globules, but only to envelope them: one reason for forming this opinion is, that the separation is very rapidly effected, the colouring substance flowing from all parts of the globule at the same instant, and that to retain the globules in the coloured state it is necessary that a very small quantity of blood only be smeared as thin as possible upon the glass, in order that all moisture may instantly evaporate; they then remain of their full size and colour, perfectly spherical [...] But if a greater quantity of blood be laid upon a glass which retains moisture only half a minute, the colouring matter begins, in a few seconds, to separate and form a circle round the globule, and if the blood is diluted with water, the separation of the colouring matter is instantaneous [...]

Home writes that the globules that have lost their color appear to have an attraction to each other. Once he has seen three of the decolored globules, and once four of them, come together into a short “line”.

Next he mentions that when muscle fibers are first boiled, and then macerated for a long time, the muscle fibers are readily broken down into a mass of globules of the size of those in the blood, deprived of their colour. The accuracy of the appearances that have been described may be depended on; how far they will afford the slightest grounds for an opinion that the [blood] globules are the materials, and the attraction between them the means, by which the single [muscle] fibres are formed, and all the combinations produced that are met with in the structure of muscles, must require farther investigation.

Baker (1988) also mentions the observations of the french microscopist Milne Edwards, who studied many different kinds of animal tissues: connective tissue, muscle, tendons, skin, parts of arteries, veins, and the intestine, and white and gray matter of the brain. Edwards found globules in all these tissues, and Baker comments that In nearly every case he notes that the globules are 1/300 mm. in diameter [3.33 micrometer]. Unfortunately he gives no figures, and it is impossible to guess exactly what he saw. In some cases he may have been looking at nuclei, in others at lipoidal droplets, in others again he may have seen cells; but if he did, it is difficult to account for their uniformly spherical shape and minute and unvarying size.

The “globule theory” came to an end when a new type of microscope, a so-called achromatic microscope, was designed by Joseph Lister. In 1827 Lister, together with a Mr. Hodgkin, published an article called Notice of some microscopic observations of the blood and animal tissues. Here they gave the first correct description of the characteristic double-concave shape of the human red blood cells:

In our examination of these [blood] corpuscles, we have in vain looked for the globular form attributed to them, not only by the older authors Leeuwenhoeck, Fontana, and Haller, but still more recently by Sir Everard Home and Bauer [...] We have never been able to perceive the separation of the colouring matter, which our countrymen have described as taking place in a few seconds after the particles have escaped from the body;

To us the particles of human blood apperars to consist of circular flattened transparent cakes, which, when seen singly, appear to be nearly or quite colourless. Their edges are rounded, and being the thickest part, occasion a depression in the middle, which exists on both surfaces.

Hodgkin and Lister estimate the diameter of the red blood particles to 1/3000 inch, which equals 8.47 micrometer. This is very close to a modern estimate, which gives the average diameter as ≈ 7.81 micrometer. They also estimate the thickness of the red blood particles, which at first seems quite confusing: The thickness of the particles, which is perhaps not so uniform as the diameter of the disks, is on an average to this latter dimension as 1 to 45.

When looking at a modern high-quality micrograph of red blood cells, for example this micrograph, I would estimate the cell diameter as being about 4 to 5 times that of the thickness. So when Hodgkin wrote “1 to 45” I assume this was a typing error, and that he meant to write “1 to 4.5” or “10 to 45”.

After covering their observations on blood they move on to the solid animal tissues:

In proceeding to offer a very short sketch of the result of our inquiries into the microscopic appearances of some of the animal tissues, I do so with one painful feeling, which I shall perhaps be excused from expressing. It is, that I am under the necessity of differing from my excellent and intelligent friend Dr. M. Edwards. It was the knowledge of his talents and address, and of the patience and care with which he made those investigations, which he has related, which induced me to enter into the examination of a question, which I had already regarded as settled in the negative. And though J. J. Lister and myself, in repeating the observations of Dr. M. Edwards, have arrived at widely different conclusions, I am confirmed in the conviction, that he described what he saw, and that he only saw amiss through the imperfection of his instruments. The idea of the globular structure of the different tissues is however by no means peculiar to Dr. Edwards, and to those micrographers to whom I have already frequently alluded.

Hodgkin then lists the observations on muscles, nerves, arteries, and “cellular membrane” (which is what we today call connective tissue, according to Baker (1988)). The microscopic structures of these four tissues he describes as fibrous, with no sight of globules. In the brain and in pus he describes particles of irregular figure and size. Only in milk can he see perfectly spherical globules, although their size varies much from one globule to another. (These milk globules would be the emulsified milk fat.)

Baker (1988) says that many of the globules people had observed were probably the result of small particles, which when viewed with a primitive microscope became surrounded by haloes. These haloes made the particles look like globules. Lister’s improved microscope reduced this halo-effect, which is why he and Hodgkin could see the structures of animal tissues more clearly than their fellow microscopists.

(Here are some photos of Lister's microscope, for anyone interested in having a look.)

The cell theory

“The elementary parts of all tissues [in both plants and animals] are formed of cells in an analogous, though very diversified manner, so that it may be asserted, that there is one universal principle of development for the elementary parts of organisms, however different, and that this principle is the formation of cells.”
– Theodor Schwann, 1839 (translated from German)

In 1838 the botanist Mathias Schleiden published an article called Contributions to Phytogenesis (Beiträge zur phytogenesis), in which he described his idea of how plant cells are formed. Theodor Schwann was inspired by Schleiden's work, and in 1839 Schwann published a book titled Microscopical researches into the accordance in the structure and growth of animals and plants (Mikroskopische Untersuchungen über die Uebereinstimmung in der Struktur und dem Wachsthum der Thiere und Pflanzen). In this book Schwann asserted that the elementary parts of animals develop in a similar fashion to that which Schleiden had described for plant cells.

An english translation of Microscopical researches was released in 1847, which also included a translation of Contributions to phytogenesis attached at the end. This translation of Microscopical researches is the source of the quote above. The book is freely available on Google books. (Alternatively also on biodiversitylibrary.org.)

Schwann's assertion that all tissues are formed of cells has certainly stood the test of time. But apart from this, modern cell theory has nothing in common with Schwann's cell theory. Today's biology holds that the formation of new cells proceeds by way of division of an existing cell into two (or more) smaller cells. Schleiden's and Schwann's idea of cell formation was quite different.

Let's take a closer look at Schleiden's ideas, before moving on to Schwann's.

Schleiden and the development of plant cells

In the earlier 1800’s, microscopists could see little of what was on the inside of cells. As far as I know, the only intra-cellular structures they could see back then were the nucleus and the chloroplasts. The nucleus houses the cell’s chromosomes, but this fact was not yet known at the time of Schleiden and Schwann. (Chromosomes will be described later in this article.) The chloroplasts are little green things which give leaves their green color. They are the sites of photosynthesis (which was also not known at that time).

For pictures of what a nucleus can look like, see for example these pictures:

Plant cells picture 3
Plant cells picture 4

(In the above pictures, the rectangular thing is a cell, the small green things are chloroplasts, and the transparent circular thing is the nucleus. The nuclei have a smaller transparent circle inside of them, and I think these cannot be anything other than the nucleoli, which will be explained shortly.)

Schleiden came to believe that development of a new plant cell generally begins with the creation of a new nucleus from a fluid he calls “gum”. Here quoting from Schleiden’s Contributions to Phytogenesis, on the topic of the nucleus:

It was Robert Brown who first realized the importance of a phenomenon, which, although observed previously by others, had yet remained totally neglected. He found, in the first instance, in a great many of the cells in the epidermis [outermost layer] of the Orchideae, an opaque spot, named by him areola, or nucleus of the cell. He subsequently pursued this phenomenon in the earlier stages of the pollen-cells, in the young ovulum, in the tissue of the stigma, not only in the Orchideae, but also in many other Monocotyledons, and even in some Dicotyledons.

As the constant presence of this areola [nucleus] in the cells of very young embryos and in the newly-formed albumen could not fail to strike me in my extensive investigations into the development of the embryo, it was very natural that the consideration of the various modes of its occurrence should lead to the thought, that this nucleus of the cell must hold some close relation to the development of the cell itself.

The nucleus, he writes, may either look round or oval. Its color is usually somewhat yellow, but sometimes it is almost silvery white, and sometimes most transparent. Its internal structure is in general granulous, without, however, the granules, of which it consists, being very clearly distinct from each other. As an alternative name, Schleiden calls the nucleus a “cytoblast”. (This name is derived from latinized greek and means something like “cell-seed”, ref etymonline/cyto- and etymonline/blasto-.)

Schleiden also describes something within the nucleus, which had gone unnoticed by Robert Brown (possibly because Brown didn't have a sufficiently good microscope): In very large and beautifully developed cytoblasts [nuclei], for example, in the recently formed albumen of Phormium tenax and Chamaedorea schiedeana (pl. I, fig. 5), there is observed (whether sunk in the interior or on its surface, is not yet clear to me) a small, sharply defined body, which, judging from the shadow that it casts, appears to represent a thick ring, or a thick-walled hollow globule. In examples which are not so well developed, only the external sharply defined circle of this ring can be observed, and in its centre a dark point; for example, in the stipes of the embryo of Limnanthes Douglasii, Orchis latifolia (pl. I, fig. 21), Pimelea drupacea (figs. 14, 15). In still smaller cytoblasts it appears only as a sharply circumscribed spot; this is most frequently the case, as in the pollen of Richardia aethiopica, in the young embryo of Linum pallescens, and in almost all Orchidee (fig. 16); or, lastly, only a remarkable small dark point is observed.

This, I think, is a somewhat confusing description. He also says that this “body” can be either darker or brighter than the rest of the nucleus. And each nucleus normally only has one such body, but in some cases he has seen a nucleus with two, or sometimes three such bodies. This body is what is today called the “nucleolus” (being latin for “small nucleus”, ref etymonline/nucleolus). Schleiden illustrates his observations of nuclei and nucleoli in his figures 3, 12, 13, and 14 (below). The nucleoli are shown both as white dots and as black dots with white rings around.

Next Schleiden describes how new cells develops within a plant embryo cell. (I may mention immediately to those who don't know, that Schleiden's description of cell formation is wrong. We return to this later.) At first, he says, the embryo cell contains “gum”, which appears as a somewhat yellowish, more consistent, and less transparent fluid. Next, a quantity of exceedingly minute granules appear in [the gum], most of which, on account of their minuteness, look like mere black points [...] upon which the solution of gum, hitherto homogeneous, becomes clouded, or when a larger quantity of granules is present, more opaque. Single, larger, more sharply defined [kernchen (nucleoli)] next become apparent in the mass (fig. 2, the upper part); and very soon afterwards the cytoblasts [nuclei] appear (fig. 2, the lower part), looking like granulous coagulations around the [kernchen (nucleoli)].

(The english translator translates “kernchen” to “granules” in the above quote, but Baker (1988) states that this is a mistranslation, and that the translator probably misread “kernchen” as “kornchen”, the latter translating to “granules”. The correct english translation for kernchen is “nucleolus”. (And at a later point in the text another occurance of “kernchen” is indeed translated to “nucleolus”.) Schleiden confused this matter by his lack of consistency in naming the object, for when he first describes the nucleolus he does not call it “kernchen”, but rather “körper” (body) and “körperchen” (small body). Then, when he describes cell formation, he suddenly refers to the nucleolus as “kernchen” instead.)

So soon as the cytoblasts have attained their full size, a delicate transparent vesicle rises upon their surface. This is the young cell, which at first represents a very flat segment of a sphere, the plane side of which is formed by the cytoblast, and the convex side by the young cell, which is placed upon it somewhat like a watch-glass upon a watch. In its natural medium it is distinguished almost by this circumstance alone, that the space between its convexity and the cytoblast is perfectly clear and transparent, and probably filled with a watery fluid, and is bounded by the surrounding [granules] which have been aggregated together at its first formation, and are pressed back by its expansion, as I have endeavoured to represent it in figs. 4, 5, 6.

[...] The vesicle gradually expands and becomes more consistent (fig. 1, b), and, with the exception of the cytoblast, which always forms a portion of it, the wall now consists of gelatine [see comment below]. The entire cell then increases beyond the margin of the cytoblast, and quickly becomes so large that the latter at last merely appears as a small body enclosed in one of the side walls [...] The cytoblast is still always found enclosed in the cell-wall, in which situation it passes through the entire vital process of the cell which it has formed, if it be not, as is the case in cells which are destined to higher development, absorbed either in its original place, or after having been cast off as a useless member, and dissolved in the cavity of the cell.

(When Schleiden says that the cell wall now consists of gelatine he is not referring to what we today call gelatine, which is a substance derived from collagen in animals. He describes “vegetable gelatine” as a distinct, perfectly transparent substance, which presents an homogeneous colourless mass when subjected to pressure; when dried it imbibes water and swells; it is not at all affected by tincture of iodine, nor does it ever imbibe it [...] This substance frequently occurs in plants. If this really is a distinct substance found in plants, then I have no idea what it is called today.)

(Later in the text Schleiden also writes that when new cells have grown to fill up their “parent cell”, the parent cell cease to be visible and become absorbed. That is, the parent cell disappears, thus freeing the new cells inside and letting them continue their growth. See Schleiden's figures 23 and 24 above.)

The above-described process was quite detailed, so let’s summarize the essential points. Schleiden says that inside a plant embryo cell, he first sees granules appearing. Then appear somewhat larger objects, the nucleoli. The granules appear to "coagulate" around the nucleoli, thus forming the nuclei. Each embryo cell will then contain multiple nuclei. On the surface of each nucleus a vesicle appears, looking like a part of a bubble. The vesicle-bubble grows bigger and develop into the cell wall of a new cell, leaving the nucleus as an object stuck in the cell wall. Later in cell development the nucleus may disappear. As the multiple new cells in the embryo “parent cell” grow to fill the embryo, the wall of the embryo disappears and the new cells are freed from their parent cell.

After having described the process of cell formation, Schleiden makes the following statement:

I have observed the above-described development of the cells throughout its entire course in the albumen of Chamedorea schiedeana, Phormium tenax, Fritillaria pyrenaica, Tulipa sylvestris, Elymus arenarius, Secale cereale, Leucoji spec., Abies excelsa, Larix europea, Euphorbia pallida, Ricinus leucocarpa, Momordica elaterium, and in the embryonal extremity of the pollen-tube of Linum pallescens, Enothera crassipes, and many other plants.

Without exactly tracing the entire course of the formation of the cells through all its details, I found the cell-nuclei, previous to the appearance of the cells, floating loose in the fluid in very many plants. Finally, I have not met with a single example of newly-developed cellular tissue, the cambium excepted, in which the cytoblasts [nuclei] were wanting. I therefore consider that I am justified in assuming the process above described to be the universal law for the formation of the vegetable cellular tissue in the Phanerogamia [plants that reproduce through seeds].

Later in the text Schleiden states that, as far as he has observed, new cells generally form inside existing “parent cells”. He believes the one exception is the cells formed between the wood and the bark, where he thinks new cells just suddenly appear, fully developed, in the intercellular substance (the substance which is inside of an organism, but outside of its cells):

So soon as the secretion of this organized mass, the wood, takes place, for instance, we suddenly miss the influence of the law of formation, which, until then, had without exception directed the growth of the entire plant in all its parts. Here, so far as we are at present acquainted with the subject, there is no formation of cells within cells, here no expansion on all sides of the originally minute vesicle occurs, there is here no cytoblast upon which the young might be developed; but beneath the outermost layer of cells, which are comprised in the term bark, an organisable fluid is poured out, as it were, into a single, large, intercellular space, which fluid, as it seems, consolidates quite suddenly throughout its entire extent into a new, altogether peculiarly-formed tissue of cells, which are deposited one upon another, the so-called prosenchyma.

(As mentioned earlier, the process of cell formation described by Schleiden is not at all how new plant cells and nuclei actually form. It is clear is that he must have been misinterpreting what he was seeing with his microscope. Baker (1988) writes that Schleiden studied the development of new cells especially in the endosperm and pollen-tube. It may be remarked that he could scarcely have chosen an object of study more likely to lead him astray than the endosperm; for the development of a syncytium [here basically referring to a cell with multiple nuclei], with subsequent division into cells [with a single nucleus each], does in fact bear some resemblance to the supposed [development of new cells inside a parent cell]. The pollen-tube was almost as likely to lead to misinterpretation.)

This concludes our look at Schleiden’s Contributions to Phytogenesis. We now turn to Schwann’s observations and thinking, as presented in his book Microscopical researches.

Schwann's Microscopical researches: introduction

In regard to Schwann, there is a certain detail that should be clarified immediately. In modern biology, the term “cell wall” refers to a relatively thick and stiff outer layer of a cell, readily visible in a light microscope. The term “cell membrane” refers to a relatively thin and flexible outer layer of a cell, not normally visible in a light microscope. Every cell, animal as well as plant, has a cell membrane enclosing the cell contents. A plant cell additionally has a cell wall, made chiefly of cellulose, on the outside of the cell membrane (so that the cell wall is the outermost layer, and the cell membrane is the second-outermost layer, enclosing the cell contents). An animal cell, meanwhile, does not have any cell wall, it only has a membrane.

At Schleiden and Schwann's time, this distinction between wall and membrane was not recognized. They used “cell wall” and “cell membrane” as synonyms for the same object, namely the thick and stiff outer layer that we today only call the cell wall. The thin and flexible outer layer, which we today call the cell membrane, had not yet been discovered. Thus, whenever Schwann uses the term “cell membrane”, keep in mind that this is simply a synonym for the cell wall.

As Schwann states in the preface of his book Microscopical researches, his goal in the book is to demonstrate the connection between animals and plants by proving the similar “laws of development” of their “elementary parts”. He also explains how Schleiden’s description of cell development in plants inspired him to investigate if similar development occurs in animal tissues:

Schleiden communicated the results of his investigations to me, previous to their publication in October, 1837. The resemblance in form, which the chorda dorsalis [aka the notochord, a body structure in the embryos of vertebrate animals], to which J. Müller had already drawn attention, and the branchial cartilage of the tadpole present to vegetable cells, had previously struck me, but nothing resulted from it. The discoveries of Schleiden, however, led to more extended researches in another direction.

In the above-mentioned investigations of Henle, Turpin, and Dumortier, the resemblance which the animal tissues examined (epithelium and the liver or yelk of snails) bore to plants, lay, in the first place, in the circumstance, that their elementary particles grew without [blood] vessels, and in part, free in a fluid, or even inclosed in another cell; and in the second place, in that these elementary particles [...] were furnished with a peculiar wall, like the cells of plants.

[...] The discoveries of Schleiden made us more accurately acquainted with the process of development in the cells of plants. This process contained sufficient characteristic data to render a comparison of the animal cells in reference to a similar principle of development practicable. In this sense I compared the cells of cartilage and of the chorda dorsalis [notochord] with vegetable cells, and found the most complete accordance.

Schwann introduces the concept of “cytoblastema”, which is the substance in which new cells are formed. (It may be said immediately, for the sake of avoiding any confusion, that “cytoblastema” does not exist in modern biology. It is not a real substance.)

He writes that the cytoblastema may be found either inside existing cells, or outside of them, as part of the intercellular substance. There are different types of cytoblastema, which gives rise to different types of cells: In cartilages [the cytoblastema] is very consistent, and ranks among the most solid parts of the body; in areolar tissue [connective tissue] it is gelatinous; in blood quite fluid [...] In animals, the cytoblastema receives the fresh nutritive material from the blood-vessels; in plants it passes chiefly through the elongated cells and vascular fasciculi;

Schwann's observations on cartilage and the chorda dorsalis (notochord)

Let's look at some paragraphs from Schwann's description of cartilage:

The surface of the cartilage, which is represented on the left and lower margin of the figure, (pl. III, fig. 1,) is formed in the first place of intercellular substance [...] This cartilage may, therefore, be described as consisting of intercellular substance, or cytoblastema, in which great numbers of cells are seen [...] Nuclei, around which no cells have yet commenced to be developed, may be observed in the cytoblastema between the cells in some situations; for example, [plate III, fig 1] a and b. These [nuclei in the cytoblastema] likewise contain a nucleolus, and are somewhat less than the nuclei in the smaller cells.

The above observations furnish us with a complete representation of the development of cartilage-cells, and show the accordance of that process with the development of vegetable cells, inasmuch as they exhibit the simultaneous presence in the cytoblastema both of simple nuclei, and of cells containing a nucleus of similar shape and size upon the inner surface of their walls, and which may be observed in all stages of transition, from such as are scarcely larger than the nucleus they contain, to such as are many times its size. Simple nuclei are first present, developed in the cytoblastema. When these have arrived at a certain size, the cell is formed around and closely encompassing them. The cell gradually expands, whilst the nucleus remains lying on a point of the inner surface of [the cell’s] wall. The nucleus, also, increases somewhat in size, but not in proportion to the expansion of the cell.

Schwann continues with an observation of what he considers may be a nucleus in the process of formation:

In the intercellular substance at “e” in the same figure (pl. III, fig.1,) may be seen a small corpuscle, surrounded by a granulous and indistinctly circumscribed mass, the rest of the intercellular substance being smooth and homogeneous . This is, perhaps, a nucleus in the act of formation, the nucleolus of which is already developed; and when the granulous mass surrounding that structure has obtained a defined external boundary, it will form a nucleus. If such be the case, we have here an instance of accordance of the development of the germ itself with the formation of the nucleus of vegetable-cells observed by Schleiden.

Schleiden believed that in plants, the general rule was that new cells developed inside older “parent cells”. The development of new cells outside of older cells, as he believed happened in the area between wood and bark, was an exception to the rule. Schwann sees the situation differently in animals. He thinks the development of new cells more commonly occurs outside of existing cells, in the intercellular substance. But he also mentions cases where he believes new cells to be developing inside existing parent cells. For example, on the topic of the chorda dorsalis, he writes:

Young cells, which float free, form within the cells of the chorda dorsalis, as in plants. They are, however, in the larvae of the frog so transparent, that very favorable light and good instruments are required to see them [...] I have not as yet been able, with certainty, to observe any nucleus, at least not of the characteristic form, in isolated young cells of the chorda dorsalis.

After having presented all his observations on cartilage and the chorda dorsalis, Schwann concludes that both tissues develop from cells which correspond to the cells of plants:

The above detailed investigation of the chorda dorsalis and cartilage, has conducted us to this result, that the most important phenomena of their structure and development accord with corresponding processes in plants, that some anomalies and differences may indeed still remain unexplained, but that they are not of sufficient importance to disturb the main conclusion, viz. that these tissues originate from cells, which must be considered to correspond in every respect to the elementary cells of vegetables.

Some of Schwann's other figures of cartilage and the chorda dorsalis are shown below.

Schwann's observations on other animals tissues

Schwann states that in animal tissues other than cartilage and the chorda dorsalis (notochord), a cell-based structure is generally more difficult to detect. One of the reasons for this is that animal cells come in many different shapes. Another reason is that a structure resembling a cell wall can, for for many types of cells, be difficult or impossible to perceive. When Schwann is in doubt as to whether an “elementary part” of an animal tissue is really a cell or not, he makes the presence or absence of a nucleus the decisive factor: if an elementary part contains a nucleus, it is a cell equivalent to the cells of plants. Here in his own (translated) words:

From these circumstances, many of the cells which now come before us for consideration, have been described as mere globules, or granules, terms which do not express their true signification [...] The most important and abundant proof as to the existence of a cell is the presence or absence of the nucleus [...] More than nine tenths of the globules in question present such a nucleus; in many [globules] the special cell-membrane [wall] is indubitable, in most it is more or less distinct. Under such circumstances, we may be permitted to conclude that all those globules which present a nucleus of the characteristic form and position, have also a cell-membrane [wall], although, from the causes before specified, it may not be perceptible [...] When a globule does not exhibit a nucleus during any one of the stages of its development, it is either not a cell, or may at least be preliminarily rejected, if there be no other circumstances to prove it such. Fortunately, these cells devoid of nuclei are rare.

Schwann proceeds to review many different animal tissues: epithelium, nails, feathers, teeth, the lens of the eye, connective tissue, elastic tissue, muscle tissue, and more. He comments on the similarities that the elementary parts of these different tissues share with the cells of cartilage, chorda dorsalis, and plants. (I won't cover this stuff in any detail, but anyone who is interested can have a look at Section II of Schwann's book, the Microscopical researches.)

(Something I do not understand, is what Schwann is really seeing when he talks about cell walls in cartilage and other tissues. If we look at Schwann's plate III, figure 1 (above), then we see that all the large cells have a thick outer layer, which Schwann calls cell wall. But, as became known later, these thick outer layers do not contain cellulose and are not equivalent to the cell walls of plants. Then, what are these layers made of, and what are their function?

In fact, I'm not even sure that the large irregularly shaped structures in figure 1 are the actual cells. Schwann presents these structures as cells, with the circles inside being the nuclei, and the smaller circles being the nucleoli inside the nuclei. But for all I know, the large irregularly shaped structures may not even be cells. It's possible that the circles inside are the actual cells, with the smaller circles inside those being the nuclei (and nucleoli being invisible). As I have never studied animal tissues with a microscope I am in no position to answer this.)

The cell theory

Having finished his investigation of the development of various animal tissues, Schwann moves on to the topic of “the cell theory”, where he states that:

... The elementary parts of all tissues [in both plants and animals] are formed of cells in an analogous, though very diversified manner, so that it may be asserted, that there is one universal principle of development for the elementary parts of organisms, however different, and that this principle is the formation of cells. This is the chief result of the foregoing observations . The same process of development and transformation of cells within a structureless substance [the cytoblastema] is repeated in the formation of all the organs of an organism, as well as in the formation of new organisms; and the fundamental phenomenon attending the exertion of productive power in organic nature is accordingly as follows: a structureless substance is present in the first instance, which lies either around or in the interior of cells already existing; and cells are formed in it in accordance with certain laws, which cells become developed in various ways into the elementary parts of organisms.

(In the above quote, Schwann used italics for emphasis. In this article, italics are used to indicate a quote, so I changed his italics to bold text in the above quote.)

His thinking now becomes more theoretic as he presents his idea on how a nucleus and a cell is formed:

The formative process of the nucleus may, accordingly, be conceived to be as follows: A nucleolus is first formed; around this a stratum of substance is deposited, which is usually minutely granulous, but not as yet sharply defined on the outside. As new molecules are constantly being deposited in this stratum between those already present, and as this takes place within a precise distance of the nucleolus only, the stratum becomes defined externally, and a cell-nucleus having a more or less sharp contour is formed. The nucleus grows by a continuous deposition of new molecules between those already existing, that is, by intussusception. If this go on equably throughout the entire thickness of the stratum, the nucleus may remain solid; but if it go on more vigorously in the external part, the latter will become more dense, and may become hardened into a membrane, and such are the hollow nuclei.

... When the nucleus has reached a certain stage of development , the cell is formed around it. The following appears to be the process by which this takes place. A stratum of substance, which differs from the cytoblastema, is deposited upon the exterior of the nucleus. (See pl. III, fig. 1, d.) In the first instance this stratum is not sharply defined externally, but becomes so in consequence of the progressive deposition of new molecules.

... Immediately that the cell-membrane has become consolidated, its expansion proceeds as the result of the progressive reception of new molecules between the existing ones, that is to say, by virtue of a growth by intussusception, while at the same time it becomes separated from the cell-nucleus. We may therefore conclude that the deposition of the new molecules takes place more vigorously between those which lie side by side upon the surface of the membrane, than it does between those which lie one upon another in its thickness. The interspace between the cell-membrane and cell-nucleus is at the same time filled with fluid, and this constitutes the cell-contents.

... The fact that many nuclei are developed into hollow vesicles, and the difficulty of distinguishing some of these hollow nuclei from cells, forms quite sufficient ground for the supposition that a nucleus does not differ essentially from a cell; that an ordinary nucleated cell is nothing more than a cell formed around the outside of another cell, the nucleus; and that the only difference between the two consists in the inner one being more slowly and less completely developed, after the external one has been formed around it.

So, such were the ideas of the man who first proposed that all tissues of animals and plants are composed of elementary parts which are fundamentally the same, that is, they are “cells”. Schwann's and Schleiden's ideas of cell formation would come to be discarded by later scientists, but in the years immediately following the publication of the Microscopical researches Schwann's theory became quite prominent.

On the multiplication of plant cells by division

As mentioned previously, new cells do not form according to the Scheliden-Schwann-scheme. Rather, new cells are formed by the division of an existing “parent cell” into new, smaller “daughter cells”.

To a limiting extent, cell division in plant cells and animal cells had both been observed before the publications of Scheliden’s Contributions to Phytogenesis and Schwann’s Microscopical Researches.

For example, multiple botanists in the 1830’s studied filamentous green algae. These are simple microscopic plants where cylinder-shaped cells grow in a chain. (The chain is typically called a filament, but I think “chain” is a more apt word for a long thing composed to smaller things linked together, as is the case with these alga.) One of the botanists who studied filamentous alga was Hugo von Mohl, who described cell division in these alga in his 1835 dissertation On the multiplication of plant cells by division (Ueber die Vermehrung der Pflanzen-Zellen durch Theilung).

In 1851 Mohl released a book on plant cells, and the following year this was translated to english with the title Principles of the anatomy and physiology of the vegetable cell (available on biodiversitylibrary.org). In this book he describes cell division in a filamentous green algae he calls Conferva glomerata (today called Cladophora glomerata). Here are some modern micrographs of this alga:

Conferva (Cladophora) glomerata picture 1
Conferva (Cladophora) glomerata picture 2.

Mohl describes the cell divisions in Conferva as follows. The divisions mostly occur at the end of the cell chains. The cell at the end first grows to twice its initial length. Then, the cell wall in the middle of the cell grows inwards into the cell. Eventually this inward wall growth divides the cell into two smaller cells. Then, the new cell at the end of the chain grows to twice its initial length, and the division process is repeated.

Cells of Conferva sometimes develop a protrusion at their sides. Such a protrusion grows to the length of an entire cell. At the base of this protrusion, the cell wall grows inwards and divides the protrusion off from the main chain. The protrusion has now become a branching cell. The branching cell grows to twice its initial length and divides into two smaller cells, just like the cell at the end of the main chain. The process of growth and division repeats, and the branch becomes longer. The development of a branch cell is shown in the upper-left corner of the image below.

In The Vegetable Cell, on the topic of cell formation in general, Mohl thinks that new plant cells are formed either by division of old cells, or by the formation of “secondary cells” inside existing cells (basically the mechanism that Schleiden had described). He writes:

In [the 1835 dissertation], I sought to demonstrate in the Cryptogamic water-plants [Cryptogamic = propagates without the use of flowers or seeds], that the earlier notion of the necessity of cells originating under the form of very small vesicles was false, and that division of the cells takes place by the formation of partitions, which cut off the contents of the parent-cells into separate portions; but it was not until [1845] that I was able to trace accurately the processes in the formation of [wall partitions]. Before this had happened Schleiden [...] had discovered the free cell-formation, and declared it to be the sole mode of formation of cells, whereby the whole theory of the development of cells was pushed into a false direction, from which it has been chiefly brought back into the right path by Unger and Nägeli, who demonstrated the great prevalence of the process of cell-division.

A little later in the book he adds:

In the Phanerogamia [plants propagating with flowers and seeds], free cell-formation [formation of new cells inside existing cells] occurs only in the embryo-sac, in which both the rudiment of the embryo (the embryonal vesicle) and the cells of the endosperm originate in this way; in the Cryptogamia it occurs only in the formation of spores in the Lichens, and some of the Algae and Fungi.

Thus we see that in the early 1850's, one of the prominent botanists at the time, von Mohl, thought that new plant cells were formed mainly by the division of existing cells. Still, he also believed that the formation of cells inside existing cells (the Schleiden-scheme of development) occured in some cases.

(I don't know when the botanists came to understand that plant cells never develop according to the Schleiden-scheme, and that all the cases mentioned by Mohl as examples of “free cell formation” actually are variants of cell division. But I would think that the improved understanding of chromosomes, which occured in the 1870's and 1880's, must have led to this realization, if it was not reached earlier.)

(From what I know of plant cell division from modern sources, it seems that Mohl’s description of the process of wall partitioning is not completely correct. However, this article isn’t supposed to go into detail on the mechanics of cell division, so I won’t try to elaborate on this here.)

(Baker (1988) has the following to say about Nägeli (who was mentioned by Mohl in the above quote as having demonstrated the prevalence of cell division in plants): One of the most important contributors to our knowledge of cell-division was Nägeli (1844, 1846), but curiously enough, he himself would not allow that most of the processes he was studying constituted cell-division. He restricted the idea of division to “Abschnurung” [constriction], that is to say, to what is called in the present paper “cell-division with constriction of the cell-wall”. In his earlier paper (1844, p. 97) he denied that this process was ever complete: a partition appeared before the constriction had become very deep. He writes of “so-called” cell-division (p. 110). Later, however, he allowed the reality of complete Abschnurung in certain cases (1846, p. 60).)

On the multiplication of animal cells by division

Cell division in animal cells were first seen in fertilized eggs. Prévost and Dumas, in their study of frog eggs in 1824, described the “cleavage-furrows” which appears on the surface of the egg as it is divided into increasingly smaller parts (“blastomeres”). However, it is unclear whether Prévost and Dumas thought that the cleavage-furrows actually divided the egg all the way through, or whether they only divided the surface of the egg.

Then, in 1834, the egg cleavage process was studied by von Baer, who according to Baker (1988) made it perfectly clear that in fact the furrows actually divide the egg into discontinuous parts that are only pressed against one another (1834, p. 487). He used the word “Theilung” [division] to describe the process.

(I don't know what kind of evidence Baer had for saying that the egg was divided into discontinuous parts. The most obvious proof would be if he had been able to separate the different parts from each other, in the same way that Treviranus had separated plant cells from each other in 1805. However, Baker doesn't mention that Baer had been able to do this.)

In 1837, von Siebold saw nuclei and nucleoli in the eggs of nematodes (a kind of worm), as well as nuclei in the blastomeres of these eggs. Baker (1988) comments that these observations represented a considerable step towards the recognition of blastomeres as cells.

Two years later Martin Barry, in a study of rabbit eggs, equated blastomeres with the cells of Schwann's cell theory. Barry, too, had seen nuclei in the blastomeres. But unlike von Baer, Barry apparently didn't think that the blastomeres multiplied by cell division. According to Baker (1988), Barry concluded that two or more “vesicles” (cells) originate within each pre-existing one (1839, p. 363) [...] Barry did not state clearly how he thought that cells multiply [...] He seems to have thought that the nucleus divides or fragments, and that each part of it grows to become a new cell.

Bergmann was the first person who viewed blastomeres as cells while also thinking that they multiplied by division. Baker (1988) quotes Bergmann as writing in 1841 that I may therefore state that the cleavage of the amphibian egg is an introduction to cell-formation in the yolk. Indeed, I would even call it cell-formation, if the first, larger divisions of the yolk could unreservedly be called cells (1841, p. 98). (Bergmann wrote in German, quote translated to english by Baker.)

In an article published in 1842 Bergmann had become more certain that the “larger divisions of the yolk” were in fact cells, and by 1847 Bergmann's view had become generally accepted: blastomeres were cells which multiplied by division. (From this talk about the “larger divisions of the yolk” it is not entirely clear to me whether Bergmann also considered the undivided egg to be a kind of cell, although it seems reasonable to assume that he must have thought so.)

Perhaps the first good description of division in animal non-egg cells was made by Carl Vogt, in his 1842 book titled Investigations on the developmental history of the midwife toad (Untersuchungen uber die Entwicklungsgeschichte der Geburtshelferkroete). Baker (1988) references pages 46-47 of this book, where Vogt gives a description of cells in the notochord of Triturus (a kind of salamander). He comments that it looks like some of the cells in the notochord are undergoing a division process. (Here is the Google-translation of Vogt's pages 46-47.)

Baker (1988) mentions that despite of Vogt’s observation of cells that “appear to be undergoing a division process”, in the very same book (pages 117-120) Vogt wrote about how new cells are formed in a cytoblastema in a similar (but not identical) fashion to what Schwann had proposed in 1839. Indeed, resorting to Google Translate again, one finds that Vogt believes that cells can form in a cytoblastema in three different ways: either the nucleus is formed first and the cell wall is then formed around it, or the cell wall is formed first and the nucleus is later formed inside it, or the wall and the nucleus are both formed at the same time. (Here is the Google-translation of Vogt’s pages 117-120.)

A decade later, in 1852, Robert Remak published an article called On the extracellular origin of animal cells and their multiplication by division (Ueber extracellulare Entstehung thierischer Zellen und über Vermehrung derselben durch Theilung). In this article he argued against the idea of extracellular cell formation in a cytoblastema (cells forming outside of existing cells). He begins by mentioning that none of the renowned plant biologists still believe in extracellular cell formation in plants. Then he talks about how egg cells divide into embryonic cells, which continue to multiply by division as they transform into the cells of different tissues (muscle, blood, etc). He asserts that extracellular cell formation cannot be observed in any kind of tissue, and that consequently, observation supports the idea that new cells always derive from older cells. (Here is the Google-translation of Remak's 1952 article.)

However, Remak didn't believe that cell division was the exclusive mechanism by which new cells could form. In diseased tissue, such as cancer tissue, he thought that new cells could arise inside existing parent cells, without a division process. (It is not clear to me what kind of observations led him to this belief, nor do I know how long it took until biologists realized that cells in pathogenic tissues multiply only by means of division-processes.)

The formation of new nuclei

New nuclei in animal and plant cells are formed by a kind of indirect division process. In this process, the nuclear membrane disappears, the content of the nucleus is divided into two portions which move to opposite sides of the cell, and a nuclear membrane reappears around both portions, thus creating two new “daughter nuclei”. The cell can then divide into two smaller cells, each with their own nucleus. Here is a picture showing the different stages of the nuclear division process:

Composite picture of indirect nuclear division.

(In this composite picture, the picture at the bottom shows a nucleus before the start of nuclear division. As the picture caption inform us, fluorescent dyes are used to color certain cell structures. The nuclear content is colored blue, the nuclear membrane is colored green, and something called alpha tubulin is colored red. The alpha tubulin is involved in the separation of the nuclear content into two portions. The progress of nuclear division is shown by the pictures in a clockwise direction, starting from the bottom picture. Thus in the two pictures on the left we see the nuclear membrane disappear. In the top two pictures we see the nuclear content being separated into two portions. In the two pictures on the right we see a nuclear membrane reappear around both portions. In the last picture (lower right) the cell has almost completed its division process, as is apparent from the thin red strand connecting the two clouds of red alpha tubulin.)

Baker (1988) writes that throughout the 1840’s biologists observed the formation of new nuclei in both plant and animal cells, but they disagreed as to how the formation occured. Some thought that the nucleus of a cell could divide in two by a process where the nucleus was constricted in the middle and pinched in half. Others had the idea that the nucleus would disappear and two new nuclei would somehow appear in its place. In Hugo von Mohl’s 1852 book The vegetable cell, referred to previously, we can get some insight into the thinking among the botanists of the time. Here's a quote:

The second mode of origin of a nucleus, by division of a nucleus already existing in the parent-cell, seems to be much rarer than the new production of them, for as yet it has been observed only in few cases, in the parent-cells of the spores of Anthoceros, in the formation of the stomates, in the hairs of the filaments of Tradescantia, [etc.], by myself, Nageli, and Hofmeister; but it is possible that this process prevails very widely, since, as the preceding statements shew, we know very little yet respecting the origin of nuclei. Nageli thinks that the process is similar to that in cell-division, the membrane of the nucleus forming a partition, and the two portions separating in the form of two distinct cells. I was quite as unable to see such a membranous septum and a membrane on nuclei generally, and the division appeared to me to take place by gradual constriction. According to Hofmeister’s description (“Enstehung des Embryo,” 7) the membrane of the nucleus dissolves, but its substance remains in the midst of the cell; a mass of granular mucilage accumulates around it; this parts, without being invested by a membrane, into two masses, and these afterwards become clothed with membranes and appear as two secondary nuclei (tochter-kerne).

It is still an unsolved question how often the process of division of the nuclei can be repeated, whether it continues indefinitely, or whether after one or more divisions it becomes extinct, and the formation of a new nucleus becomes necessary. In the spores of Anthoceros I found a second division, for in the parent-cell of these a mass was formed, which first parted into two subdivisions, and then each of these divided into two nuclei. Wimmel found the same in the development of pollen-grains (“Zur Entwickelungsgesch d. Pollens.” Bot. Zeit., 1850, 225). In these cases, therefore, a twofold division occurred. But, according to Wimmel, the case is different in the formation of the parent-cell itself, for when one of these cells is about to divide, a new nucleus is formed in it, which becomes divided and gives rise to the development of two secondary cells. When one of these secondary cells is to be divided again, its nucleus takes no part in it but becomes absorbed [it disappears], a new nucleus being formed which divides, [etc.], so that here each nucleus is capable only of one division.

The cell wall

Now we briefly shift topic from the nucleus to the cell wall. In doing so, I want to give a reminder of what was previously said about the cell wall, so I will copy-paste the two following paragraphs from a previous section about Theodor Schwann:

In regard to Schwann, there is a certain detail that should be clarified immediately. In modern biology, the term “cell wall” refers to a relatively thick and stiff outer layer of a cell, readily visible in a light microscope. The term “cell membrane” refers to a relatively thin and flexible outer layer of a cell, not normally visible in a light microscope. Every cell, animal as well as plant, has a cell membrane enclosing the cell contents. A plant cell additionally has a cell wall, made chiefly of cellulose, on the outside of the cell membrane (so that the cell wall is the outermost layer, and the cell membrane is the second-outermost layer, enclosing the cell contents). An animal cell, meanwhile, does not have any cell wall, it only has a membrane.

At Schleiden and Schwann's time, this distinction between wall and membrane was not recognized. They used “cell wall” and “cell membrane” as synonyms for the same object, namely the thick and stiff outer layer that we today only call the cell wall. The thin and flexible outer layer, which we today call the cell membrane, had not yet been discovered. Thus, whenever Schwann uses the term “cell membrane”, keep in mind that this is simply a synonym for the cell wall.

In Mohl's 1852 book The vegetable cell, in the section on the chemical conditions of the cell membrane (referring to what we now call the cell wall), Mohl writes:

The basis of the membranes of all the elementary organs of vegetables consists of neutral hydro-carbons; in almost all cases, and perhaps without exception, of cellulose.

(The word “hydro-carbon” is here used to refer to a carbohydrate: a molecule containing carbon, hydrogen, and oxygen, and no other element.)

Cellulose is colourless, insoluble in cold and boiling water, alcohol, ether, and dilute acids, almost insoluble in weak alkaline solutions, soluble in concentrated sulphuric acid; it is converted into dextrine by dilude sulphuric acid at a boiling heat. When imbued with iodine it becomes coloured indigo blue if wetted with water, this color appears more readily under the conjoined influence of water, sulphuric acid, and iodine. According to Payen, the formula of its composition is C₁₂H₂₀O₁₀. [This is the molecular formula of cellulose. It means that for every 10 oxygen atoms in cellulose, there are 12 carbon atoms, and 20 hydrogen atoms. According to modern sources, this formula for cellulose is perfectly accurate.]

Next, we have Rudolf Virchow's 1859 book Cellular Pathology (Die Cellularpathologie, published in english translation in 1860, available at biodiversitylibrary.org). In this book the following is said about the outer layer of plant and animal cells:

When we speak of ordinary vegetable cellular tissue, we generally understand thereby a tissue, which, in its most simple and regular form is, in a transverse section, seen to be composed of nothing but four- or six-sided, or, if somewhat looser in texture, of roundish or polygonal bodies, in which a tolerably thick, tough wall (membrane) is always to be distinguished [...] The substance which forms the external membrane, and is known under the name of cellulose, is generally found to be destitute of nitrogen.

[...] Vegetable cells cannot, viewed in their entirety, be compared with all animal cells. In animal cells, we find no such distinctions between nitrogenized and non-nitrogenized layers; in all the essential constituents of the cells nitrogenized matters are met with.

From these quotes of Mohl and Virchow, we see that in the 1850's it had become known that the plant cell walls were composed of cellulose molecules, which contain no nitrogen. It had also become known that animal cells have no structure equivalent to the cellulose cell walls of plants.

(The remainder of this section may be a digression, but I felt like including it anyway, so here goes.)

In the previous article The origins of cell- and microbiology, I wrote about how Robert Hooke studied slices of cork and other plant tissues, and described the structures as resembling the cells in a honeycomb. He was the first person to see the cell structure of plant tissue, and the first person to use the word “cell”.

I mentioned in that article that what Hooke meant with the word “cell”, and what we in modern biology mean when we say cell, are not the exact same things. Hooke used “cells” to refer to the spaces within the wall-material. In some plant samples he found the cells to contain air, and in other samples he found the cells to contain juices. See for example this quote from Hooke's 1665 book Micrographia:

But though I could not with my Microscope, nor with my breath, nor any other way I have yet try’d, discover a passage out of one of those cavities into another, yet I cannot thence conclude, that therefore there are none such, by which the Succus nutritius, or appropriate juices of Vegetables, may pass through them; for, in several of those Vegetables, whil’st green, I have with my Microscope, plainly enough discover’d these Cells or Pores fill’d with juices, and by degrees sweating them out; as I have also observed in green Wood all those long Microscopical pores which appear in Charcoal perfectly empty of any thing but Air.

What happens in certain plant tissues, such as cork, is that the cells produce their cell walls, and then the cell's jobs are done and they die. After the cells die, the cell walls are left behind, with spaces where the cells used to be. The purpose of cork, for example, is to protect the surface of the plant, and this protection requires only the thick and rigid cell walls, not the cells themselves. After the cells have degraded, the spaces they used to occupy become filled with air. This air is what makes cork such a lightweight material.

In other cases, the spaces in the cell walls function in the transport of fluid. In these cases the cells produce their walls, then die and disappear, and the spaces they leave behind are filled with “juices”, as Hooke called it.

When we in modern biology talk about cells with the meaning “elementary units of life”, we aren't referring to spaces filled with air or with juices. Rather we are referring to these units which, as we have seen in this article, are capable of growing and multiplying by division, and which contain an internal structure called a nucleus, which also multiply by (indirect) division. So while Hooke was the first person to use the word “cell”, he was not using the word in the modern sense.

It should be mentioned that the above description of cells, as units capable of growing and dividing, and containing a nucleus, is not a universal definition of a cell. For example, a mature human red blood cell does not grow, does not have any nucleus, and is incapable of multiplying by division. Instead, new red blood cells are produced from stem cells in the bone marrow. These stem cells do have a nucleus, and they do have the ability to grow and divide. Bacteria are also considered cells, and they are certainly capable of growth and division, but not a single bacteria has a nucleus.

Chromosomes

Now we return to the topic of the nucleus. The contents of the nucleus are the chromosomes, on which the cell's genes are located. Before nuclear division begins, each chromosome is duplicated into two copies, which are tightly held together. (This duplication process cannot be seen, and I don't know how it was discovered.) When the nuclear division process begins, the chromosomes first “condense”, that is, the chromosomes become shorter and thicker. At the same time, they become visible in the microscope. As the chromosomes are condensing, the nuclear membrane disappears. Additionally, the two copies of each duplicated chromosome become less tightly held together, and it looks as if each chromosome is split into two parts lengthwise. (I will refer to this latter process as “longitudinal splitting”, formally it is called sister chromatid resolution. For some basic details of this process, see the introduction and Figure 1 in Shintomi 2010.)

Here is a picture showing longitudinal splitting of chromosomes (you have to zoom in or open the picture in a new tab in order to see properly).

And here is a set of figures showing the later part of the condensation process and the longitudinal splitting, see figures 1 to 4. (The source for this set of figures will be described below.)

The condensed chromosomes move to the center of the cell, and stay there for some time. Then, the two copies of each duplicated chromosome are pulled apart, and the two copies move to opposite sides of the cell. This produces two groups of chromosomes, both groups containing one copy of every original chromosome. (See the set of figures linked above, figures 5 to 9.)

The separated chromosomes “de-condense”, becoming longer and thinner, and eventually they can not longer be seen in the microscope. At the same time, a nuclear membrane reappears around both groups of chromosomes, forming two nuclei. Because each chromosome has been copied and one copy has been distributed to each of the daughter nuclei, both daughter nuclei contain a set of genes identical to the old nucleus.

Picture showing the condensation, separation, and de-condensation of chromosomes

The different stages of nuclear division are referred to as prophase, prometaphase, metaphase, anaphase, and telophase. In prophase the chromosomes condense. Prophase transitions to prometaphase when the nuclear membrane disappears. In prometaphase the chromosomes move towards the center of the cell. In metaphase the chromosomes are positioned in the center of the cell, where they stay for some time. The longitudinal splitting of the duplicated chromosomes begins in prophase and is complete before the end of metaphase.

In anaphase the chromosomes are pulled apart into two groups, which move to opposite sides of the cell. In telophase the chromosomes de-condense while a nuclear membrane reappears around both chromosome-groups.

(There are in fact two different variants of nuclear division. One variant is called mitosis, and we may think of this as “normal nuclear division”. This is the process described in the preceeding paragraphs. Another variant is meiosis, or “nuclear reduction-division”. Nuclear reduction-division occurs when sperm- and egg cells, and the equivalent cells in plants, are produced from progenitor cells. Normal nuclear division produces all the other cells of animals and plants. The rest of this section concerns normal nuclear division (mitosis). Nuclear reduction-division (meiosis) will not be described in this article.)

Baker (1988) divides the observation of chromosomes into three periods, where the third period is the most interesting one, so I will give minimal coverage to the other two. The first period starts with an observation by Nageli in 1842, where Baker says that Nageli “probably” saw chromosomes. This period lasts until 1870, and Baker sums it up by saying that the descriptions and figures of chromosomes published during this time were “vague and insatisfactory”.

The second period of chromosome observation covers 1870 to 1878, when many microscopists saw the metaphase and anaphase of nuclear division. That is, they saw the condensed chromosomes positioned in the center of the cell, before their separation into two groups. Baker (1988) states that Though the stages of metaphase and anaphase were by this time so familiar, they were not in the least understood.

The third period of chromosome observation covers 1878 onwards, and the two key researchers mentioned by Baker (1988) are Walther Flemming and Carl Rabl. Between 1878 and 1882 Flemming published a number of articles on nuclear division in live cells from salamanders, and in 1882 he also released a book titled Cell substance, nucleus and cell division (Zellsubstanz, Kern und Zelltheilung) where he presents the contemporary state of knowledge on cell- and nuclear division, including his own research.

Flemming was able to see that early in the nuclear division process, the nuclear membrane disappears and the contents of the nucleus condenses into the visually distinct chromosomes (thought he didn’t call them chromosomes, that word came later). He further noticed that each chromosome splits lengthwise into two parts.

He was able to follow the chromosomes as they were positioned in the center of the cell, and as they were divided into two groups which move towards opposite sides of the cell. And he could see that both groups of chromosomes de-condenses, and nuclear membranes forms around both group of chromosomes. Flemming’s descriptions marked the first time someone had followed the chromosomes all the way through the nuclear division process.

According to Baker (1988), Flemming’s most important discovery was that in anaphase, the two parts of a longitudinally split chromosome move to opposite sides of the cell. However, Baker doesn’t specify that Flemming actually saw this happen, he only specifies that Flemming in a 1879 article suggested tentatively that one longitudinal half of each thread [chromosome] might go to each daughter-nucleus. It’s thus not clear if Flemming actually ever saw the separation of the longitudinal parts, or if he just suggested it. (A reading of Flemming's 1882 book would obviously clarify this, but I can't read German.)

Carl Rabl published the results of his work in the 1885 article On cell division (Ueber zelltheilung, available on biodiversitylibrary.org). He found that, in different types of cells from the two species of salamanders he studied, the number of chromosomes was always the same: each cell always had 24 chromosomes. This was the first observation of the fact that in any given organism, the number of chromosomes is identical in all cells of that organism. (Exceptions to this rule include genetic diseases, such as downs syndrome. Exceptions also include certain special cells such as sperm and egg cells, which have a reduced number of chromosomes, as a result of nuclear reduction-division (meiosis)).

While I’m not sure whether Flemming could see the two parts of each chromosome separating to opposite sides of the cell, it is clear from Rabl's figures that he could see this separation. See Rabl's figures on nuclear division below: Figs 5 and 6 in his Plate X, and Figs 6 to 9 in his Plate XII.

(I haven't been able to find a single modern micrograph that actually shows the separation of the two split parts of a chromosome. This is oddly strange, and I can't understand why such a micrograph should be so hard to find, if someone was able to see it clearly in 1885.)

One may wonder what prompted the transition between Baker's three periods of chromosome observation: from the first (“probably”) observation in 1842, until observations of chromosomes being separated into two groups (metaphase and anapahse) in the 1870's, until Flemming and Rabl's more detailed descriptions of chromosomes in the late 1870's and 1880's.

At least a part of the reason why Flemming and Rabl could observe longitudinal splitting and separation of split halves, is related to the fact that they studied salamander cells. Baker (1988) writes that Flemming had already (1877) chosen the salamander (Salamandra maculata) as his cytological research-material, on account of the large size of the cells and nuclei in this animal. [...] Flemming’s choice of organisms with long chromosomes as his research material, both in this early work and later, undoubtedly helped him to elucidate the main features of mitosis. Indeed, it sounds reasonable that the longitudinal splitting and separation would be easier to notice if the chromosomes are relatively long. So perhaps the people who studied cell division before Flemming happened to work with cells with relatively small chromosomes, where longitidinal splitting and separation was not so easy to see.

That still leaves the question of what triggered the advance from the first period to the second period, around the year 1870. It may have come down to advances in microscope technology (I know that the physicist Ernst Abbe was making some microscope-related innovations around this time). It may also have been caused by improvements in methods used to increase the visibility of chromosomes, such as treating the cells with certain acids or other substances before looking at the cells in the microscope. (I don't really know any details here, so I can't say anything with certainty.)

Summary

Now that the article is coming to an end I will try to give a brief summary of everything that has been covered.

In the earliest years of the 1800's, biologists believed that plant cells were nothing but open spaces within a continuous wall-material. They also believed that animal tissues were composed of globules, which were small spherical particles. These ideas met their ends when researchers such as Treviranus in 1805 were able to separate plant tissues into individual cells, and when Lister and Hodgkin in 1827 used a newly invented achromatic microscope to study animal tissues, finding globules nowhere but in milk.

In 1838 Schleiden described his ideas of how plant cells are created: first, a fluid inside an existing cell would form a nucleolus, and a nucleus would form around the nucleolus. Then, the cell wall would form like a small bubble on the nucleus, and this bubble would grow to the size of a fully developed cell.

A year later Schwann applied an essentially similar idea to the creation of the elementary parts of animals. In doing so, he established the idea that animals and plants are composed of elementary parts which develop in a fundamentally similar fashion. That is, both animals and plants are made of cells. Schwann also thought that the cells of animals typically arose outside existing cells, not inside of them, as Schleiden believed to be the case for plants.

By the time of Schleiden and Schwann, cell division in green filamentous alga had already been observed, for example by von Mohl in 1835. Later work by other botanists showed that cell division is widespread also in the larger plants, thought in the early 1850's it was still believed that certain types of plant cells were formed according to the Schleiden-scheme.

Cell division in animals was first seen in egg cells in 1824 by Prévost and Dumas. Bergmann in 1841 was the first person to equate blastomeres (early division products of the egg) with the cells of Schwann, and also to consider that the blastomeres multiplied by a division process.

A decade later, in 1852, Remak wrote of how cell division is the common mechanism for the creation of new animal cells, and how new animal cells never arose outside of existing cells. However, as with the botanists, Remak also believed that there were cases where new cells arose inside of parent cells without a division process.

The fact that there is a major difference between animal and plant cells, in that plants cells had a cellulose wall and animal cells did not, was known in 1858 according to Virchow.

“Normal” nuclear division (mitosis) and chromosomes were first understood in some detail in the early 1880's by Flemming and Rabl. Flemming was able to follow the chromosomes through the nuclear division process, and noticed that the chromosomes were split along their lengths before being pulled apart in the anaphase. He speculated that the split parts of a chromosome were pulled to opposite sides of the cell, so that both daughter-nuclei would contain a longitudinal part of each original chromosome.

It's not certain if Flemming was ever able to see the separation of the longitudinal parts, but apparently Rabl was able to see it. Rabl also found that in different types of cells in the animals he studied (two species of salamanders), the number of chromosomes were always the same: 24. This was the first observation of the fact that in a given species, the number of chromosomes in the nucleus is always the same.

Ending words

The progress of cell biology did not stop with Flemming's and Rabl's discoveries. However, I have to end the article at this point, as this work has taken quite a lot of time, and I now wish to pursue another topic (history of microbiology). In a later article I intend to continue where this one ends, and perhaps look more into the details of cell- and nuclear division. Meiosis, that special type of nuclear division which occurs in egg- and sperm cells and in the equivalent cells in plants, will be covered in that next article. Also covered will be the early research on genetics, which together with the details of meiosis will take us to the chromosome theory of inheritance.

Another topic, which should be covered in a history of cell biology, is the discovery of the cell membrane, that thin and flexible outer boundary layer which is present in all cells. One may say that the main job of the cell membrane is to control which molecules and salts go in and out of the cell. Thanks to Baker (1988) and certain translations of German texts, I've been able to write this article without knowledge of German, but I don't think I could properly cover the history of cell membrane research without being able to read German. So while it seems like an interesting topic, I'm not able to cover it yet.

Bonus section: The origins of certain words

The origin of the word “mitosis”

As mentioned in the text, “normal” nuclear division is called mitosis. One may wonder where such a weird word came from, or what it means, so I wanted to cover its origin. In Walther Flemming’s 1882 book (“Zellsubstanz, Kern und Zelltheilung”) he coins the word “karyomitosis”, which is supposed to mean “filamentous metamorphosis in the nucleus”, or alternatively, “metamorphosis of threads in the nucleus” (german original: “Fadenmetamorphose im Kern”). This in reference to the changes that the chromosomes undergo during nuclear division (i.e. chromosomal condensation and de-condensation).

(Baker 1988 adds that It must be regretted that Flemming was so far influenced by the long chromosomes of the salamander as to choose this word (mitosis), for in very many organisms the metaphase chromosomes cannot by any stretch of the imagination be described as threads. So mitosis (metamorphosis of threads) may not be the ideal term to describe nuclear division in general, but that is the word everyone now uses.)

“Karyo” refers to the nucleus. This word is derived from the latinized greek word “karyon”, which means nut or kernel (ref https://www.etymonline.com/word/karyo-). I’m not sure what “mit” is supposed to refer to, but it possibly derives from a greek word for thread. “osis” refers to metamorphosis.

(Here is a Google-translation of the section from Flemming's book where he discusses the word mitosis)

The origin of the word “chromosome”

The word “chromosome” was coined by W. Waldeyer in an 1888 article in Archiv für mikroskopische Anatomie, volume 32. The article is available on biodiversitylibrary.org. Here follows a Google-translation of the paragraph where Waldeyer discusses various words then in use for chromosomes (page 27):

First and foremost, however, I would like to propose that those things just described by Boveri as "chromatic elements," in which one of the most important acts of karyokinesis, Flemming's longitudinal division, takes place, be given a special technical term: "chromosomes." The name "primary loops" is unsuitable, since we by no means always find a loop shape for these things. "Chromatic elements" is too long. On the other hand, they are so important that a special, shorter name seems desirable. Platner (160) uses the term "karyosomes"; however, since this is too reminiscent of nucleoli, another term would be preferable.

Waldeyer then proposes the word chromosome. This is derived from the latinized greek words “khrōma” and “sōma”, meaning “color” and “body” (ref https://www.etymonline.com/word/chromosome). Thus chromosome means colored body. It is so named because they are strongly colored by certain dyes (however, they don’t have much color naturally, when not dyed).

The origins of the words “prophase”, “metaphase”, “anaphase”, and “telophase”

As Baker (1988) points out, the words prophase, metaphase, and anaphase were first used by Eduard Strasburger in an 1884 article, available on biodiversitylibrary.org (pages 250 and 260). The prefix “pro“ derives from a latin word which can mean “before”, the prefix “meta“ derives from a latinized greek word which can mean “between”, and the prefix “ana“ derives from a latinized greek word which can mean “backwards” (ref etymonline.com).

With prophase, Strasburger referred to the early stage of nuclear division where the chromosomes condense and are split longitudinally into two parts (daughter segments). His metaphase referred to the whole process of separation of the daughter segments into opposite sides of the cell. His “anaphase” referred to the period after separation of the daughter segments until the completion of the two new nuclei. He viewed the late stage of nuclear division (decondensation of the chromosomes and re-formation of the nuclear membranes) as being a reverse of the early stage of nuclear division (condensation of the chromosomes and disappearance of the nuclear membrane). We can therefore understand why he used the word anaphase, where “ana” can be taken to mean “backwards”, as in “going in reverse”.

The word “telophase” was first used by Heidenhan in 1894. The prefix “telo” derives from a latinized greek word which can mean “completion”. Near the completion of nuclear division the two new nuclei (and also microscopic structures called centrosomes which are involved in the separation of chromosomes), move to new positions within the cell, and these movements are what Heidenhan used to define telophase.

In modern biology the phases of nuclear division are defined somewhat differently. Anaphase is now the phase where the two copies of each chromosome separate to opposite sides of the cell. Using the word “anaphase” to refer to this event seems inappropriate , as the separation of the chromosome copies is not a reverse of anything that happens earlier. But I guess this doesn’t matter, especially since most people won’t know that “ana” means “ backwards” anyway.

References

Home
(1818): On the changes the blood undergoes in the act of coagulation. Available on biodiversitylibrary.org

Hodgkin, Lister
(1827): Notice of some miscroscopic observations of the blood and animal tissues. Available on biodiversitylibrary.org

Shintomi, Hirano
(2010): Sister chromatid resolution: a cohesin releasing network and beyond. Paid article

Google-translations

Flemming
(1882): Zellsubstanz, Kern und Zelltheilung. Available on biodiversitylibrary.org. Google-translation from pages 375-376:

I do not insist on the terms "indirect and direct cell division," which are used and defined above (pp. 194 and 343). I only transferred them from the nucleus to the cell for the sake of convenience, which is certainly not unavoidable. They undoubtedly have the flaw that "indirect and direct" refers only to processes at the nucleus, while there are cases where the cell body divides or begins to divide without simultaneous division of the nucleus (budding in protists, capillaries, and anthoceros). These would then either have to be included under "cell division without nuclear division" or considered as special, modified forms of indirect division.

I am not at all satisfied with the terms "indirect and direct nuclear division," which I myself recommended, as they are long and say little about the nature of the division. For the time being, they serve their purpose, as the work of other researchers demonstrates. The same applies to the term karyokinesis (Schleicher) for indirect nuclear division or the metamorphosis involved. It is already so widely used that I have employed it extensively here for the sake of clarity. However, it is capable of improvement, since firstly, it only denotes "movement in or around the nucleus," and such movement also occurs in direct nuclear division; secondly, it says nothing about the precise form of the movements or the parts being moved.

I would therefore suggest replacing it with karyomitosis, which succinctly expresses: "filamentous metamorphosis in the nucleus." Indirect nuclear division (or cell division) could then be called simply mitoschisis, and direct division perhaps holoschisis, or, where one wishes to specifically emphasize that filamentous metamorphism in the nucleus is absent, amitotic division.

Instead of the long term "nucleus division figures," one could then use the shorter term "mitosis."

Historically, Mayzel's suggestion, "typical nucleus division," deserves precedence for what is referred to indirectly in this book. I would prefer the name mitosis only because "typical nucleus division" reveals nothing further about the nature of the process, whereas "karyomitosis" already expresses that a special process occurs in the nucleus's fibrous tissue.

Moldenhawer
(1812): Beyträge zur Anatomie der Pflanzen. Available on Google books. Google-translation from pages 81-83:

The extremely delicate double walls of the cellular components are also revealed in the same way. But maceration, if carried out with due care, also breaks down the cellular substance into separate, independent tubes. A cellular substance that is too delicate, too tightly bound, woody, or even dried out is less suitable for this purpose, because in these cases the tubes are either destroyed along with the bond, or yield too easily to maceration, or cannot be clearly revealed. But the cellular substance of several tree barks and herbs disintegrates sooner or later, depending on the strength of the connection, into individual closed vesicles, which show absolutely no trace of injury, such as would be revealed by irregularly interrupted, jagged walls in the case of the violent tearing of one and the same continuous tissue. Even in their fresh state, the rows of vesicles of the inner cellular substance of the younger leaves of the common leek (Allium cepa) can very easily be divided into individual, almost spherical vesicles, which are closed all around without any detectable crack or opening and show not the slightest injury, although, just like all the other vesicles of the cellular substance, they appear, when viewed in the cross-section of the leaf, to have common walls with the neighboring vesicles. This separation is less easily accomplished in the somewhat firmer, outermost rows of tubules bordering the epidermis, which are not round but compressed laterally. The size, clarity, and roundness of the cells so favor the above experiment that it alone could resolve the dispute. With almost equal ease, even in delicate segments, such as the ripe fruit of the garden pumpkin, the individual large, water-clear tubules that constitute the outer cellular substance of this fruit can be detached one by one and, along with the granular precipitates they contain—which only emerge after the tubule is forcibly opened—examined in water as floating, durably sealed, undamaged vesicles from all sides.

The reasons given so far also explain why the results of these experiments vary considerably in the same stem. In the stem of the common celandine, for example, the results are not as good. The innermost tubes usually dissolved into a semi-transparent mucus along with their connection; they also collapsed too much and were so difficult to handle that nothing could be seen with the necessary clarity. But the firmer, cellular substance closest to the vascular bundles, and even the somewhat more distant substance closer to the axis of the stem, soon broke apart into individual rows of tubes, like those from the bark of the common elder (Table V, figs. 14, 16) or those from the pith of the corn stalk (Table III, figs. 14, 15). These soon separated into their individual tubes under the lens when I examined them with a fine brush. Even when I could easily examine them from all sides while they were floating in water, they showed not the slightest trace of damage. During continued maceration in water, this separation occurs without any further aids. However, without us being permitted to employ an artificial process, the naturally occurring cellular substance occasionally draws our attention to these double walls. Where three cells abut each other, one sees, especially when they are somewhat larger, a small free space between their angles in cross-section, where the walls of each cell are separated from one another. The cells here again assume their arched curvature, and that small space is therefore enclosed by three inwardly curved circular segments. But also in delicate longitudinal sections, one sees, particularly strikingly in the outer bark of annual elderberry branches, between the vertical rows of tubules, sometimes very small, sometimes considerably large free spaces where the walls of the cells are not connected, but more or less separated from one another.

Remak
(1852): Ueber extracellulare Entstehung thierischer Zellen und über Vermehrung derselben durch Theilung. Available on biodiversitylibrary.org. Complete Google-translation:

In plant physiology, the extracellular origin of cells is considered an apocryphal topic. It was already disputed by Schleiden (Müll. Arch. 1838, pp. 162, 163) in opposition to Mirbel's statements, and according to the comprehensive presentations of Hugo von Mohl (Wagner's Handw. der Phys., Vol. IV, Part 2, p. 211) and Alexander Braun (on rejuvenation in nature, Leipzig 1851, p. 243), it lacks substantiation. Rather, the investigations of Mohl, Nägeli, Unger, Hofmeister, Braun, Schacht, and others show that plant cells form from other cells or within other cells, either through division of the entire cell (excluding the cell membrane) or from aliquot divisions of the cell's protoplasm [contents] (so-called free cell formation). Even for the cambium, whose origins were previously unknown, the investigations of my esteemed friend Schacht will show that cell proliferation here also occurs through the progressive division of embryonic cells.

The extracellular origin of cells was introduced into animal physiology by Schwann, coinciding with the creation of the cell theory for the animal kingdom. Schwann knew (Mikr. Unt. p. 44) that, according to Schleiden's observations in plants, young cells always develop within the mother cells. Nevertheless, he maintained (Mikr. Unt. p. 45) that while the formation of young cells within older ones is often observed in animals, it is not the norm and does not occur at all in many tissues. Rather, Schwann considered the basis of animal tissues to be a formless cytoblastema located within or outside of already existing cells (p. 194), in which the cells are supposed to form either as nucleus-less vesicles or around a previously formed nucleus (p. 204).

If Schwann's extracellular origin of animal cells were proven, the difference between animals and plants with regard to development, despite their similar cellular composition, would be almost greater than their similarities. Plants (we can only speak of multicellular plants here) would consist entirely of appropriately defined and appropriately interacting parts (cells), both in their developed state and during development. In contrast, the animal organism would be, during its development, a complex of a number of such parts (cells) and a formless substance not appropriately divided into parts. Plant cells would be structures that arise from cells and possess only the ability to generate cells. Animal cells would be formed precipitates, comparable to crystals, of a formless substance and would share with the latter the ability to form similar precipitates.

Despite these theoretical difficulties, the extracellular origin of cells has found widespread application in animal physiology and pathology. Many physiological and pathological anatomical texts refer to a formless (extracellular) cytoblastema and free (extracellular) nuclei as the precursors of cells.

Initially, investigations into cleavage (of the fertilized egg) were unfavorable to the extracellular origin of animal cells. Schwann had hypothesized (Mikrosk. Unt. p. 62) that during cleavage, two cells develop within the yolk, each of which then gives rise to two new cells, and so on. This hypothesis, which did not postulate a division of the yolk as Henle assumed (Allg. Anat. p. 176), was contradicted by earlier observations from Quatrefages and Dumortier. The investigations of Bergmann, Bagge, Vogt, Kölliker, Bischoff, Reichert, Coste, Warneck, and others have shown that cleavage consists of a progressive division of the yolk, from which the embryonic cells arise. Reichert endeavored (in his work "The Developmental Life of Vertebrates," Berlin 1840) to attribute the multiplication of cells in several organs to the formation of daughter cells and demonstrated the transition of embryonic cells into tissues (epithelium, blood cells, muscle fibers). Some of Schwann's statements, on which he based the extracellular origin of cells, were corrected. Kölliker (in his work "Mikr. Anat.," 1850, Vol. II, p. 350) argued against the occurrence of free nuclei in embryonic cartilage. He states (p. 349) that the cartilage cells of the frog larva's head arise from yolk cells through endogenous cell formation, assuming that free cell formation does not yet occur at this stage. Elsewhere (ibid., Plate I, Fig. 3), he shows that no free nuclei are present in the deeper epidermal layer, contrary to Schwann's assumption. In the field of pathological anatomy, J. Müller's investigations (on the structure of morbid tumors, Berlin 1840) already taught that endogenous cell formation is a very widespread phenomenon.

Since the advent of cell theory, I myself considered the extracellular origin of animal cells as improbable as the equivocal [spontaneous] generation of organisms. From these doubts arose my observations on the multiplication of blood cells by division in embryos of birds and mammals*) and on the longitudinal division of the striated muscle fibers (primitive muscle bundles) arising from cell elongation in frog larvae (Fror. N. Notes 1845 Septbr. No. 768). Since then, I have continued these observations in frog larvae, in which it is possible to trace the development of tissues back to cleavage. However, it was only in the spring of this year (1851) that I succeeded in determining that all embryonic cells arising from cleavage multiply by division upon their transition into the tissues, and that the division of blood cells and elongated muscle cells that I had previously observed were only isolated links in this series of interconnected phenomena. In the following sentences, I will summarize those results obtained so far that appear to be significant for the problem of the extracellular origin of cells.

Cleavage consists of the yolk (the protoplasm of the egg cell) dividing into nucleated cells through a systematically progressing process. At the earliest stages of cleavage, this division is unilateral, progressing from the outside inwards; later, it is partly unilateral and partly omnilateral, as in plant cells. In the upper half of the yolk, it occurs suddenly, while in the lower half it occurs gradually.

Even at the third cleavage stage, large nuclei and double enveloping membranes are visible. The inner surface of these membranes is covered with fine granules and small yolk sacs, indicating their origin from the protoplasm. In the four sections of the upper half of the egg where I observed these membranes, the outer membrane was brown, due to dark granules, while the inner membrane, located between the outer membrane and the coarse-grained protoplasm, was white. These characteristics distinguish the membranes of the earliest stages from those of later stages, which show no granule covering.

The division of cleavage cells is evident from the nucleus and, when (at the end of cleavage) the nucleolus is distinguishable, from the latter. At the earliest stages, two, at the end of cleavage also three, four, six, and in rare cases even eight daughter nuclei appear, enclosed by a mother nuclear membrane (Kölliker). On the lower white half of the intact egg, at the last stages of cleavage, it can be observed with the aid of a magnifying glass how the light spot forming the nucleus (Bergmann) divides into two spots, how these move apart, and how the cleavage cell then cleaves in such a way that each half is provided with a light spot (nucleus).

At the earliest stages of cleavage, both membranes of the cleavage cells participate in the pinching off of the cell following nuclear division: a separation of daughter cells, as observed by Reichert in Strongylus aurieularis, is not discernible. Towards the end of cleavage, however, one finds within the egg cleavage cells in the process of pinching off, equipped with simple membranes and enveloped by common membranes (mother membranes), whose participation in the pinching off cannot be demonstrated. This is the first example of so-called endogenous cell formation, which is based on the fact that, after nuclear division, the protoplasm [cell contents] divides along with the inner membrane (primordial tube), without any part of the outer membrane (cell membrane). Since these divisions, as my observations teach *), occur in the upper half of the egg by sudden constriction, while the cleavage cells of the lower half are not well suited to these observations due to the delicacy of their membranes and the large size of their yolk sacs, it may not be noticeable that the different stages of constriction are never readily observable in the cells of the fragmented egg.

Whether the constrictions of the cleavage cells mentioned here are preceded by a spontaneous division of the protoplasm corresponding to the division line, I must leave undecided. What is certain is only that the protoplasm is not inactive during these constrictions; rather, it exhibits an activity corresponding to the purpose of division by the fact that the yolk sacs, which show a layered structure, break down into smaller pieces by furrows that do not always run parallel to a margin.

I could not observe that nuclei disappear and new ones form in cleavage cells, as Reichert observed in Strongylus; rather, the nucleus of a cleavage cell appears as the parent structure of the nuclei destined for the divisions. Since it is unlikely that a fluctuation in the formation laws should occur during cleavage, the consequence of these observations, beginning with the third stage of cleavage, leads to the assumption of a primitive nucleus belonging to the first cleavage cell, from which the nuclei found in the embryonic cells arising from cleavage are to be considered descendants. Indeed, Johannes Müller recently made the important discovery in the yolk of the snail (Natica), which is produced in such a remarkable way in the abdominal cavity of a holothurian (Synapta digilata), that the germinal vesicle does not disappear but is used for the formation of the light spots (nuclei) of the cleavage cells. (Monthly Report of the Academy of Sciences 1851, Sept. 1851, p. 640, 641). It is not likely that other animals behave differently in this respect.

Neither free nuclei nor intercellular substance are found between the embryonic cells arising from cleavage. Rather, the entire protoplasm of the egg cell is contained within the protoplasm of all embryonic cells, just as the nuclei of the latter appear only as descendants of a primitive nucleus of the first cleavage or embryonic cell, in whose formation the egg cell membrane (the yolk sac) does not participate.

After cleavage, the cells that arise from it begin their activity in the formation of the embryo by separating into three layers (a sensory, a motor, and a trophic layer) and, within these layers, through progressive division, preparing themselves to form the cells that serve as the basis for tissues. The division of embryonic cells appears earliest in the primordium of the brain and spinal cord (the medullary plate); here, too, it originates from the nuclei and results in a fragmentation into small cells, which soon form inextricable connections with one another, just as in the chick. It is most easily traced in the primordium of the spine, not in the notochord, but in the so-called protovertebrae. As I have already mentioned, in the frog, the latter only distinguish elongated muscle cells that occupy the entire length of the so-called protovertebra. If one examines the caudal portion of the proto-vertebral column, which is not yet divided into vertebrae, during the period when the tail is emerging, one always finds a large number of yolk cells undergoing division. However, even in the already separated proto-vertebral vertebrae, longitudinal division of the elongated muscle cells from which they are composed is observed. The nuclei therefore show division both transversely, for the purpose of longitudinal cell division, and longitudinally, to form the large series of nuclei by which the secondary muscle cell (primitive muscle bundle), already containing striated and contractile tissue, is distinguished. The division of embryonic cells originating from the nucleus can be just as easily traced in the middle layer of the wall of the cranial visceral cavity. This division is of particular interest because it exhibits the greatest irregularities, which evidently correspond to the different purposes of the division process. One finds individual large cells dividing into several smaller ones, which bear no resemblance to one another in shape. One cell may be round, another multi-pronged, and a third spindle-shaped or stalked, emerging from the division as if the mother cell had been cut with a knife into nucleated pieces of unequal shape. The divisions of the cells in the subcutaneous tissue (connective tissue) behave similarly, soon assuming the familiar star-shaped form. Here, divisions originating from the nucleus can still be observed in the cells even when they no longer touch each other but already exhibit numerous, network-like extensions. In the trophic layer (the analogue of the intestinal gland layer in birds), the progressive division of the cells can be traced in the network-like interconnected cylinders that form the basis of the liver cells. This phenomenon is particularly striking in the base of the columnar epithelium of the intestinal tract: in the large cells densely filled with yolk sacs, which border the intestinal cavity, the nucleus elongates transversely, so that it occupies almost the entire width of the cell; the latter then divides by longitudinal furrows (similar to muscle cells) into several, usually six, cylinders, each of which immediately contains a nucleus originating from the parent nucleus. These cylinders gradually lose their yolk sacs and, as the intestine increases in length, continue to multiply by simple division originating from the nucleus. I have also observed multiplication by division in the cells of the epidermis, which consists of two layers (an outer pigmented layer and an inner white layer), in the region of the emerging tail.

How the membranes of embryonic cells behave during the divisions mentioned here, and how they participate in the division of their contents, are questions I reserve for a more detailed discussion. At this point, my purpose is merely to draw attention to the finding that in the primordia of the most diverse tissues, progressive division of existing cells can be observed, but nowhere can the appearance of extracellular nuclei or extracellular cells be observed. This applies particularly to the so-called hyaline intercellular substance of cartilage, which, according to my observations, arises almost without doubt from the fusion of depositional layers of the outer cell membranes (mother cell membranes). All cartilage cells, as can most easily be seen at the base of the skull, are descendants of embryonic cells that multiply by division, while nuclei or cells never form in the parietal substance (intercellular substance).

The statement that animal cells, like plant cells, originate solely intracellularly seems to me a thesis grounded in a long series of reliable observations, against which recourse to vague perceptions is not permissible. If, in individual cases, it is not possible to trace tissues, which appear in form to be equivalents of cells, back to embryonic cells, then the interpretation that the subtlety of their constituent parts imposes limits on the investigation is permissible. We have an instructive point of reference for this interpretation in the developmental history of secondary vascular structures. Primary vascular structures are solid cylinders composed of embryonic cells, whose cortical cells form the vessel walls, while their axial cells transform into blood cells. While the latter multiply by visible division, secondary vascular structures exhibit developmental processes that, at first glance, seem to defy any cell theory. Thread-like extensions of the vessel walls (of the primary vessels) of immeasurable fineness appear; these threads thicken, become hollow, nuclei appear in the walls of the new cylinder, and when it has become permeable to blood cells, it does not differ significantly from the vessel from which it originated as a thread-like, seemingly homogeneous or structureless extension. Nevertheless, the interplay of these phenomena shows that this fine thread is equivalent to many cells, that highly complex formation processes, entirely beyond our observation, must occur within it to produce a product identical to the primary vessel wall. The origin of nerve fibers can also be cited here. As far as observations allow, they do not form through the fusion of cell rows, as Schwann presumed, but rather in the tail of frog larvae, where threads of barely measurable diameter (probably cell extensions) can be seen, which gradually thicken and transform into one or more nerve fibers and their sheaths. Here, too, a number of transformations apparently remain outside the scope of observation due to the imperfections of our tools.

These findings are as closely related to pathology as they are to physiology. It can hardly be disputed that pathological tissue forms are merely variants of normal embryonic developmental types, and it is unlikely that they should possess the prerogative of extracellular cell origin. The so-called organization of plastic exudates and the earliest history of the formation of pathological tumors require further examination in this regard. Based on the confirmation of my long-standing doubts, I venture to suggest that pathological tissues, like normal tissues, do not originate in an extracellular cytoblastema, but are rather derivatives or products of normal tissues within the organism.

Vogt
(1842): Untersuchungen uber die Entwicklungsgeschichte der Geburtshelferkroete. Available on archieve.org. Google-translation from pages 46-47:

Besides this regular arrangement, however, another peculiarity distinguishes the vertebral compartment of the triton under investigation. If one examines the notochord of an older larva, which already has developed forelegs and where the hind legs are beginning to sprout, the regular arrangement of disc-shaped cells has disappeared in most of the [core]. The cells are extremely large, clearly nucleated, and mostly of a dodecadic or similar shape. They no longer occupy the entire diameter of the cylinder, but are usually arranged so that two or three cells located within the same transverse diameter of the notochord belong together, are approximately the same size, and thus correspond in their arrangement to a previously existing disc-shaped cell. If one now follows the notochord further into the tail, one can still see the original disc-shaped cells, where each cell occupies a transverse diameter of the notochord, but here and there discs appear that are composed of two cells separated in the middle. If one proceeds further towards the tip of the tail, one sees pointed extensions projecting into the cell at many points, while at the same time the intercellular substance appears to have increased in mass. These extensions of the intercellular substance projecting into the cells look exactly as if the cell membrane is bending inwards; that is, as if the cell is undergoing a division process. At such a point, the intercellular substance also seems to follow the inward bend, and one finds many discs formed from two adjacent cells, where the two middle cell walls appear like two curved lines whose convex surfaces face each other, and where it seems as if two indentations from both sides, thus viewed from a physical perspective, have divided the cell in two, forming a ring-shaped constriction.

Same book as above, Google-translation from pages 117-120:

Some things about cells in general

Should the preceding results of my investigations prove to be correct, some not insignificant conclusions can be drawn from them regarding the origin and development of cells, which would likely contradict some laws previously accepted. I have already alluded to this in the individual sections, but I will now attempt to give a brief overview of what I have only hinted at there.

Cell Formation. Regarding the manner of this formation, there is almost only one prevailing opinion, and, if not explicitly, then tacitly, the following statement has been accepted to date: "In the cell germinal material, cytoblastem, a nucleus first forms, around which the cell then develops as a heterogeneous circumposition and encloses the nucleus." Let us remain with this expression of cell genesis, since, as far as nucleoli are concerned, there seems to be some uncertainty about them and their prior formation before the nucleus. Moreover, they are and remain quite invisible in many cells and can only be detected in very few cases. Why, then, form a general rule from the minority of observations and present the majority as exceptions or developmental stages? Admittedly, with regard to nucleoli, observing their formation is the most difficult aspect, which can probably be abandoned, and the confusion of such free nucleoli with cell contents, molecular bodies, etc., is a serious concern. Not only is it easy to distinguish, but a distinction is almost impossible. There are so many cell structures with clearly defined nuclei, so many bright and transparent nuclei, that a nucleolus within them could not escape observation if it were truly present. Even Schwann, who relies so heavily on Schleiden's discoveries and considers them almost irrefutable truths, even Schwann expresses himself only very uncertainly and inconsistently about nucleolus and their role in cell formation, and it is clear that observation of animals has confirmed his ideas, which he inherited from plants, in very few cases. As for myself, I know of nucleolus only from a few cells of bats and fish; by far, in most structures, however, I have never seen nucleolus at any stage of cell life. However, wherever I observed nucleoli, such as in the cartilage cells of batrachians and the embryonic cells of salmonids, I could only interpret them as later cell forms, as vesicles within the nucleus that destroyed the nucleus through their own development and gradually, or at least probably, developed into cells. In my opinion, therefore, nucleoli are not at all involved in cell origin, but are merely a later developmental stage of individual cell types. Least of all can they be considered a universally occurring structure.

The nucleus is a different matter. It is almost always present, almost always clearly visible, regardless of the cell's stage of life, and can therefore be considered a universally occurring, and thus characteristic, cell structure. However, the varying structure of the nucleus in different cells seems to indicate that its formation and development are not the same in all cells, but rather modify according to the individuality of each cell. Consider the difference between the nucleus of a chordal cell, particularly that of a fish, which, pale and barely discernible, requires exceptionally favorable lighting and great familiarity with the microscope just to be seen, and that of a cartilage cell or ganglion, where it must be obvious to even the most inexperienced observer! Sometimes it appears as a solid, or at least semi-solid, body with a granular appearance, sometimes as a hollow, thin-walled, elastic vesicle. Sometimes its contours are sharp and distinct, in other cases indistinct and disappearing. While it cannot be denied that many of these variations are only caused by later developmental phases, many undoubtedly exist from the beginning, and most cells are characterized by a particular shape or internal structure of the nucleus, which, admittedly, is more readily observed than depicted with a pen or pencil. Both, therefore—the formation of the nucleus in general, compared across different cells, and its divergent development in individual cells, to which we will return later—already suggest that there is no general type underlying the formation of nuclei, but rather that this formation varies depending on the nature of the tissues. The present investigations provide the factual evidence for this.

The pre-existence of the nucleus prior to the cell wall, and thus its origin as a cytoblast, appears to be the case in the connective cells of the yolk. There, we demonstrated how, most likely, the impetus for cell formation propagates from the germinal vesicles, the nuclei of the primitive egg cell, the blastocyst, within the yolk sac, and that this occurs in the connective layer specifically in such a way that the germinal vesicles embed themselves in the connective layer, and each then surrounds itself with a cell membrane within which the germinal vesicle functions as a nucleus. With the further spread of cell formation in the connective layer, the originally vesicular nucleus always seems to form first, and the cell wall is deposited around it. For the yolk nucleus, however, the pre-existence of the cell nuclei could not be proven, and it had to remain doubtful whether the nucleus truly arose before the cell, or perhaps afterward. Indeed, Reichert's observations even seemed to tip the scales in favor of the latter view. However, in the case of bivalve-shaped cells, Schwann's method of cell formation, which was the only one he had assumed, was demonstrable, although here too the peculiar case occurred that nuclei which had previously been enclosed in a cell surrounded themselves anew with cell membranes after the destruction of that cell.

A second, in my opinion indisputable, fact is the formation of the nucleus after the cell wall, and thus the pre-existence of the cell. However much this mode of origin directly contradicts the previous one, it seems to be confirmed by the development of both chordal cells and the subordinate cartilage cells. With regard to the latter, doubts may still be raised, since here the nuclei appear so soon after cell formation that one must seize precisely the opportune moment to find cells without nuclei. In the case of chordal cells, however, the mode of cell wall formation, its slow development, and the late appearance of the nuclei, particularly in fish, safeguard against any possible error. Yes, in fish this later formation of the nucleus seems to be so common that initially, when I limited my investigations to them and had not yet extended them to batrachians, I was led to believe that the nucleus was always a later development and should only be considered as a young cell arising within an older mother cell. Of course, observations in batrachians had to correct me; nevertheless, it remained clear that there were cells in which the nucleus was not the determining factor in cell formation. This relationship was confirmed anew in the blood cells of batrachians, where the nucleus also arises later.

Finally, a third modification of cell formation is that where the nucleus and cell membrane arise simultaneously. Admittedly, this is the area where an error can most easily creep in, since a cell membrane, if it tightly enveloping the nucleus, might not be recognized as such; however, this necessary flaw in observation could only be countered in the case of tissue where one sees free nuclei and might claim that the cell membrane is already formed around them, but is not visible due to its close attachment. However, this objection is irrelevant in the primary cartilage cells of the alytes, for which I postulate this type of cell formation, since I have never seen free nuclei in their cytoblastema, but only molecular bodies or semi-cylindrical stearin plates, which were always easily distinguishable from the granular, grayish nuclei of the cartilage cells. Wherever I observed a primary cartilage cell nucleus, I always found it surrounded by a lighter-colored cell cavity bounded by a cell membrane; I never saw a free nucleus in the primary cartilage blastema. Likewise, I never saw a primary cartilage cell without a nucleus, which could have indicated nucleic epigenesis; rather, the presence of both structures, nucleus and cell, was always interdependent; I never found one of them alone. I also always observed a more or less significant lighter space, a cell cavity, between the nucleus and the membrane, and I therefore believe that both arise simultaneously, with the cell membrane originally forming at a certain distance around the nucleus.