The cell in development and inheritance (1900) 2

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Wilson EB. The Cell in Development and Inheritance. Second edition (1900) New York, 1900.

Cell development and inheritance (1900): Introduction | List of Figures | Chapter I General Sketch of the Cell | Chapter II Cell-division | Chapter III The Germ-cells | Chapter IV Fertilization of the Ovum | Chapter V Reduction of the Chromosomes, Oogenesis and Spermatogenesis | Chapter VI Some Problems of Cell-organization | Chapter VII Some Aspects of Cell-chemistry and Cell-physiology | Chapter VIII Cell-division and Development | Chapter IX Theories of Inheritance and Development | Glossary

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Chapter Ii Cell-Division

"Wo eine Zelle entsteht, da muss eine Zelle vorausgegangen scin, ebenso wie das Thier nur aus dem Thiere, die Pflanze nur aus der Pflanze entstehen kann. Auf diese Weise ist, wenngleich es einzelne Punkte im Korper gibt, wo der strenge Nachweis noch nicht geliefert ist, doch das Princip gesichert, dass in der ganzen Reihe alles Lebendigen, dies mogen nun ganze Pflanzen oder thierische Organismen oder integrirende Theile derselben sein, ein ewiges Gesetz der continuirlichen EntwicMung besteht."

Virchow.

Cellular pathologic, p. 25, 1858.

The law of genetic cellular continuity, first clearly stated by Virchow in the above words, has now become one of the primary data of biology, and the advance of research is ever adding weight to the conclusion that the cell has no other mode of origin than by division of a preexisting cell. In the multicellular organism all the tissuecells arise by continued division from the original germ-cell, and this in its turn arises by the division of a cell preexisting in the parent-body. By cell-division, accordingly, the hereditary substance is split off from the parent-body; and by cell-division, again, this substance is handed on by the fertilized egg-cell or oosperm to every part of the body arising from it. 2 Cell-division is, therefore, one of the central facts of development and inheritance.

The first two decades after Schleiden and Schwann (^o-'fjo) were occupied with researches, on the part both of botanists and of zoologists, which finally demonstrated the universality of this process and showed the authors of the cell-theory to have been in error in asserting the independent origin of cells out of a formative blastema.* The mechanism of cell-division was not precisely investigated until long afterward, but the researches of Remak C41), Kolliker ('44), and others showed that an essential part of the process is a division of both the nucleus and the cell-body. In 1855 {I.e., pp. 174, 175), and again in 1858, Remak gave as the general result of his researches the following synopsis or scheme of cell-division. Cell-division, he asserted, proceeds from the centre toward the periphery. It begins with the division of the nucleolus, is continued by simple constriction and division of the nucleus, and is completed by division of the cell body and membrane (Fig. 24). For many years this account was accepted, and no essential advance beyond Remak's scheme was made for nearly twenty years. A number of isolated observations were, however, from time to time made, even at a very early period, which seemed to show that cell-division was by no means so simple an operation as Remak believed. In some cases the nucleus seemed to disappear entirely before cell-division (the germinal vesicle of the ovum, according to Reichert, Von Baer, Robin, etc.); in others to become lobed or star-shaped, as described by Virchow and by Remak himself (Fig. 24,/). It was not until 1873 that the way was opened for a better understanding of the matter. In this year the discoveries of Anton Schneider, quickly followed by others in the same direction by Btitschli, Fol, Strasburger, Van Beneden, Flemming, and Hertwig, showed cell-division to be a far more elaborate process than had been supposed, and to involve a complicated transformation of the nucleus to which Schleicher ('78) afterward gave the name of karyokincsis. It soon appeared, however, that this mode of division was not of universal occurrence; and that cell-division is of two widely different types, which Van Beneden {'76) distinguished as fragmentation, corresponding nearly to the simple process described by Remak, and division, involving the more complicated process of karyokinesis. Three years later Flemming ('79) proposed to substitute for these the terms direct and indirect division, which are still used. Still later ('82) the same author suggested the terms mitosis (indirect or karyokinetic division) and amitosis (direct or akinetic division), which have rapidly made their way into general use, though the earlier terms are often employed.

2 Cf. Introduction, p. 10.

• For a full historical account of this period, see Remak, Untersuchungen uber die Entwuklung der IVirbelthiere, 1855, pp. 164-180. Also Tyson on the Cell-doctrine and Sachs's Geschichte der Botanik.

Modern research has demonstrated the fact that amitosis or direct division, regarded by Remak and his immediate followers as of universal occurrence, is in reality a rare and exceptional process; and there is reason to believe, furthermore, that it is especially characteristic of highly specialized cells incapable of long-continued multiplication or such as are in the early stages of degeneration, for instance, in glandular cpithelia and in the cells of transitory embryonic envelopes, where it is of frequent occurrence. Whether this view be well founded or not, it is certain that in all the higher and in many of the lower forms of life, indirect division or mitosis is the typical mode of cell-division. It is by mitotic division that the germcells arise and are prepared for their union during the process of maturation, and by the same process the oosperm segments and gives rise to the tissue-cells. It occurs not only in the highest forms of plants and animals, but also in such simple forms as the rhizopods, flagellates, and diatoms. We may, therefore, justly regard it as the most general expression of the " eternal law of continuous development' ' on which Virchow insisted.

Fig. 24. — Direct division of blood-cells in the embryo chick, illustrating Remak's scheme. (Remak.) a-e. Successive stages of division ; f. cell dividing by mitosis.

A. Outline of Indirect Division or Mitosis (Karyokinesis)

In the present state of knowledge it is somewhat difficult to give a connected general account of mitosis, owing to the uncertainty that hangs over the nature and functions of the centrosome. For the purpose of the following preliminary outline, we shall take as a type mitosis in which a distinct and persistent centrosome is present, as has been most clearly determined in the maturation and cleavage of various animal eggs, and in the division of the testis-cells. In such cases the process involves three parallel series of changes, which affect the nucleus, the centrosome, and the cytoplasm of the cell-body respectively. For descriptive purposes it may conveniently be divided into a series of successive stages or phases, which, however, graduate into one another and are separated by no well-defined limits. These are: (1) The Prophases, or preparatory changes; (2) the Metaphase, which involves the most essential step in the division of the nucleus ; (3) the Anaphases, in which the nuclear material is distributed ; (4) the Telophases, in which the entire cell divides and the daughter-cells are formed.

1. Prophases

(a) The Nucleus. As the cell prepares for division, the most conspicuous fact is a transformation of the nuclear substance, involving both physical and chemical changes. The chromatin-substance rapidly increases in staining-power, loses its net-like arrangement, and finally gives rise to a definite number of separate intensely staining bodies, usually rod-shaped, known as chromosomes. As a rule this process, exemplified by the dividing cells of the salamander-epidermis (Fig. 1) or those of plant-meristem (Fig. 2), takes place as follows. The chromatin resolves itself little by little into a more or less convoluted thread, known as the ^r/;/(Knauel)or spireme, and its substance stains far more intensely than that of the reticulum (Fig. 25). The spireme-thread is at first fine and closely convoluted, forming the "close spireme." Later the thread thickens and shortens and the convolution becomes more open ("open spireme"). In some cases there is but a single continuous thread ; in others, the thread is from its first appearance divided into a number of separate pieces or segments, forming a segmented spireme. In either case it ultimately breaks transversely to form the chromosomes, which in most cases have the form of rods, straight or curved, though they are sometimes spherical or ovoidal, and in certain cases may be joined together in the form of rings. The staining-power of the chromatin is now at a maximum. As a rule the nuclear membrane meanwhile fades away and finally disappears, though there are some cases in which it persists more or less completely through all the phases of division. The chromosomes now lie naked in the cell, and the ground-substance of the nucleus becomes continuous with the surrounding cytoplasm (Fig. 25, D, E,F).

Fig. 25. — Diagrams showing (he prophases of mitosis. A. Resting cell with reticular nucleus and true nucleolus ; at c the attract] on -sphere containing Wo ce nlro somes. B, Early prophase ; the chromatin forming a continuous spireme, nucleolus still present; above, the amphiasier (a). CD. Two different types of later prophases. C. Disappearance of the primary spindle, divergence of the oentrosomes to opposite poles of the nucleus (examples, some plant-cells, cleavage-stages of many eggs). D. Persistence of the primary spindle (to form in some cases the " central spindle"), fading of the nuclear membrane, ingrowth of the astral rays, segmentation of the spireme- thread to form the chromosomes (examples, epidermal cells of salamander, formation of the polar bodies). E. Later prophase of type t'i fading of the nuclear menbrane al the poles, formation of a new spindle inside the nucleus : precocious splitting of the chromosomes (the latter not characteristic of this type alone). J-'. The mitotic figure established; t.f. the equatorial plate of chromosomes. ( Cf. Figs, at, xj, 3a, etc)

The remarkable fact has now been established with high probability that every species of plant or animal has a fixed and characteristic number of chromosomes , which regularly recurs in the division of all of its cells ; and in all forms arising by sexual reproduction the number is even. Thus, in some of the sharks the number is 36 ; in certain gasteropods it is 32 ; in the mouse, the salamander, the trout, the lily, 24 ; in the worm Sagitta, 18 ; in the ox, guinea-pig, and in man 2 the number is said to be 16, and the same number is characteristic of the onion. In the grasshopper it is 12; in the hepatic Pallavicinia and some of the nematodes, 8 ; and in Ascaris, another thread-worm, 4 or 2. In the crustacean Artemia it is 168. 3 Under certain conditions, it is true, the number of chromosomes may be less than the normal in a given species; but these variations are only apparent exceptions (p. 87). The even number of chromosomes is a most interesting fact, which, as will appear hereafter (p. 205), is due to the derivation of one-half the number from each of the parents.

The nucleoli differ in their behaviour in different cases. Net-knots, or chromatin-nucleoli, contribute to the formation of the chromosomes ; and in cases such as Spirogyra (Meunier, '86, and Moll, 'gs) or Actinosphcerium (R. Hertwig, '99), where the whole of the chromatin is at one period concentrated into a single mass, the whole chromatic figure thus appears to arise from a "nucleolus." True nucleoli or plasmosomes sooner or later disappear ; and the greater number of observers agree that they do not take part in the chromosome-formation. In a considerable number of forms {e.g. during the formation of the polar bodies in various eggs) the nucleolus is cast out into the cytoplasm as the spindle forms, to persist as a " metanucleus " for some time before its final disappearance (Fig. 104). More commonly the nucleolus fades away in situ, sometimes breaking into fragments meanwhile, while the chromosomes and spindle are forming. The fate of the material is in this case only conjectural. An interesting view is that of Strasburger ('95, '97), who suggests that the true nucleoli are to be regarded as storehouses of " kinoplasmic " material, which is either directly used in the formation of the spindle, or, upon being cast out of the nucleus, adds to the cytoplasmic store of " kinoplasm " available for future mitosis.

7 The spireme-formation is by no means an invariable occurrence in mitosis. In a considerable number of cases the chromatin-network resolves itself directly into the chromosomes, the chromatic substance becoming concentrated in separate masses which never form a continuous thread. Such cases are connected by various gradations with the " segmented spireme."

8 Flemming believes the number in man to be considerably greater than 16.

9 For a more complete list see p. 206.

(b) The Amphiaster. Meanwhile, more or less nearly parallel with these changes in the chromatin, a complicated structure known as the amphiaster (Fol, '77) makes its appearance in the position formerly occupied by the nucleus (Fig. 25, B-F). This structure consists of a fibrous spindle-shaped body, the spindle, at either pole of which is a star or aster formed of rays or astral fibres radiating into the surrounding cytoplasm, the whole strongly suggesting the arrangement of iron filings in the field of a horseshoe magnet. The centre of each aster is occupied by a minute body, known as the ccntrosomc (Boveri, '88), which may be surrounded by a spherical mass known as the centrosphere (Strasburger, '93). As the amphiaster forms, the chromosomes group themselves in a plane passing through the equator of the spindle, and thus form what is known as the equatorial plate.

The amphiaster arises under the influence of the centrosome of the resting cell, which divides into two similar halves, an aster being developed around each while a spindle stretches between them (Figs. 25, 27). In most cases this process begins outside the nucleus, but the subsequent phenomena vary considerably in different forms. In some forms (tissue-cells of the salamander) the amphiaster at first lies tangentially outside the nucleus, and as the nuclear membrane fades away, some of the astral rays grow into the nucleus from the side, become attached to the chromosomes, and finally pull them into position around the equator of the spindle, which is here called the central spindle (Figs. 25, D t F; 27). In other cases the original spindle disappears, and the two asters pass to opposite poles of the nucleus (some plant mitoses and in' many animal-cells). A spindle is now formed from rays that grow into the nucleus from each aster, the nuclear membrane fading away at the poles, though in some cases it may be pushed in by the spindle-fibres for some distance before its disappearance (Figs. 25, 32). In this case there is apparently no central spindle. In a few exceptional cases, finally, the amphiaster may arise inside the nucleus (p. 304).

The entire structure, resulting from the foregoing changes, is known as the karyokinetic or mitotic figure. It may be described as consisting of two distinct parts ; namely, 1 , the chromatic figure, formed by the deeply staining chromosomes ; and, 2, the achromatic figure, consisting of the spindle and asters which, in general, stain but slightly. The fibrous substance of the achromatic figure is gener

Fig. 26. — Diagrams of the later phases of mitosis.

G. Metaphase; splitting of the chromosomes {e.p.). n. The cast-off nucleolus. H. Anaphase ; the daughter-chromosomes diverging, between them the interzonal-fibres (/./.), or central spindle ; centrosomes already doubled in anticipation of the ensuing division. /. Late anaphase or telophase, showing division of the cell-body, mid-body at the equator of the spindle and beginning reconstruction of the daughter-nuclei. J. Division completed.

ally known as archoplasm (Boveri, '88), but this term is not applied to the centrosome within the aster.

2. Metaphase

The prophases of mitosis are, on the whole, preparatory in character. The metaphase, which follows, forms the initial phase of actual division. Each chromosome splits lengthwise into two exactly similar halves, which afterward diverge to opposite poles of the spindle, and here each group of daughter-chromosomes finally gives rise to a daughter-nucleus (Fig. 26). In some cases the splitting of the chromosomes cannot be seen until they have grouped themselves in the equatorial plane of the spindle ; and it is only in this case that the term " metaphase " can be applied to the mitotic figure as a whole. In a large number of cases, however, the splitting may take place at an earlier period in the spireme-stage, or even, in a few cases, in the reticulum of the mother-nucleus (Figs. 54, 55). Such variations do not, however, affect the essential fact that the chromatic network is converted into a thread 1 which, whether continuous or discontinuous, splits throughout its entire length into two exactly equivalent halves. The splitting of the chromosomes, discovered by Flemming in 1880, is the most significant and fundamental operation of cell-division ; for by it, as Roux first pointed out ('83), the entire substance of the chromatic network is precisely halved, and the daughter-nuclei receive precisely equivalent portions of chromatin from the mother-nucleus. It is very important to observe that the nuclear division always shows this exact quality, whether division of the cell-body be equal or unequal. The minute polar body, for example (p. 238), receives exactly the same amount of chromatin as the egg, though the latter is of gigantic size as compared with the former. On the other hand, the size of the asters varies with that of the daughter-cells (Figs. 58, 175), though not in strict ratio. The fact is one of great significance for the general theory of mitosis, as will appear beyond. ••

3. Anaphases

After splitting of the chromosomes, the daughterchromosomes, arranged in two corresponding groups, 2 diverge to opposite poles of the spindle, where they become closely crowded in a mass near the centre of the aster. As they diverge, the two groups of daughter-chromosomes are connected by a bundle of achromatic fibres, stretching across the interval between them, and known as the interzonal fibres or connecting fibres. z In some cases these differ in a marked degree from the other spindle-fibres ; and they are believed by many observers to have an entirely different origin and function. A view now widely held is that of Hermann, who regards these fibres as belonging to a central spindle, surrounded by a peripheral layer of mantle-fibres to which the chromosomes are attached, and only exposed to view as the chromosomes separate. 4 Almost invariably in the division of plant-cells and often in that of animal cells these fibres show during this period a series of deeply staining thickenings in the equatorial plane forming the cell-plate or mid-body. In plantmitoses this is a very conspicuous structure ( Fig. 34). In animal cells the mid-body is usually less developed and sometimes rudimentary, being represented by only a few granules or even a single one (Fig. 29). Its later history is described below.

1 It was this fact that led Flemming to employ the word tnitosis (tdroi, a thread).

2 This stage is termed by Flemming the dyaster, a term which should, however, be abandoned in order to avoid confusion with the earlier word amphiaster. The latter convenient and appropriate term clearly has priority.

3 Verbimiungsfasern of German authors ; filaments rcunissants of Van Beneden.

Cf. p. 105.

4. Telophases

In the final phases of mitosis, the entire cell divides in two in a plane passing through the equator of the spindle, each of the daughter-cells receiving a group of chromosomes, half of the spindle, and one of the asters with its centrosome. Meanwhile, a daughter-nucleus is reconstructed in each cell from the group of chromosomes it contains. The nature of this process differs greatly in different kinds of cells. Sometimes, as in the epithelial cells of Amphibia, especially studied by Flemming and Rabl, and in many plant-cells, the daughter-chromosomes become thickenfid^jcpntorted, and closely crowdecTto lofrnlTdaughtcr-spireme, closely similar to that of the mother ^nucleus (Fig. 29); this becomes surrounded by a membrane, the^threads give forth branches, and thus produce a reticular "nucleus. A somewhat similar set of changes takes place in the segmenting eggs of Ascaris (Van Beneden, Boveri). In other cases, as in many segmenting ova, each chromosome gives rise to a hollow vesicle, after which the vesicles fuse together to produce a single nucleus (Fig. 52). When first formed, the daughter-nuclei are of equal size. If, however, division of the cell-body has been unequal, the nuclei become, in the end, correspondingly unequal — a fact which, as Conklin and others have pointed out, proves that the size of the nucleus is controlled by that of the cytoplasmic mass in which it lies.

The fate of the achromatic structures varies considerably, and has been accurately determined in only a few cases. As a rule, the spindle-fibres disappear more or less completely, but a portion of their substance sometimes persists in a modified form {e.g. the Nebenkern, p. 163). In dividing plant-cells, the cell-plate finally extends across the entire cell anjd splits into two layers, between which appears the membrane by which the daughter-cells are cut apart. 1 A nearly similar process occurs in a few animal cells, 2 but as a rule the cell-plate is here greatly reduced and forms no membrane, the cell dividing by constriction through the equatorial plane. Even in this case, however, the division-plane is often indicated before division takes place by a peculiar modification of the cytoplasm in the equatorial plane outside the spindle (Fig. 30). This region is sometimes called the cytoplasmic plate, in contradistinction to the spindle-plate, or mid-body proper. In the prophases and meta l Cf. Strasburger, '98. a Cf. Hoffmann, '98.

phases the astral rays often cross one another in the equatorial region outside the spindle. During the anaphases, however, this crossing disappears, the rays from the two asters now meeting at an angle along the cytoplasmic plate (Fig. 31). Constriction and division of the cell then occur. 1

The aster may in some cases entirely disappear, together with the centrosome (as occurs in the mature egg). In a large number of cases, however, the centrosome persists, lying either outside or more rarely inside the nucleus and dividing into two at a very early period. This division is clearly a precocious preparation for the ensuing division of the daughter-cell, and it is a remarkable fact that it occurs as a rule during the early anaphase, before the mother-cell itself has divided. There are apparently, however, some cases in which the centrosome remains undivided during the resting stage and only divides as the process of mitosis begins.

Like the centrosome, the aster or its central portion may persist in a more or less modified form throughout the resting state of the cell, forming a structure generally known as the attraction-sphere. This body often shows a true astral structure with radiating fibres (Figs. 8, 49); but it is sometimes reduced to a regular spherical mass which may represent only a portion of the original aster (Fig. 7).

B. Origin of the Mitotic Figure

The nature and source of the material from which the mitotic figure arises form a problem that has been almost continuously under discussion since the first discovery of mitosis, and is even now but partially solved. The discussion relates, however, almost solely to the achromatic figure (centrosome, spindle, and asters) ; for every one is agreed that the chromatic figure (chromosomes) is directly derived from the chromatin-network, as described above, so that there is no breach in the continuity of the chromatin from one cell-generation to another. With the achromatic figure the case is widely different The material of the spindle and asters must be derived from the nucleus, from the cytoplasm, or from both ; and most of the earlier research was devoted to an endeavour to decide between these possibilities. The earliest observers ('73-75) supposed the achromatic figure to disappear entirely at the close of cell-division, and most of them (Butschli, Strasburger, Van Bencden, '75) believed it to be re-formed at each succeeding division out of the nuclear substance. The entire mitotic figure was thus conceived as a metamorphosed nucleus. Later researches ('75— '85) gave contradic 1 See p. 318. Cf. Kostanecki, '97, and Hoffmann, '98.

tory and apparently irreconcilable results. Fol ('79) derived the spindle from the nuclear material, the asters from the cytoplasm. Strasburger ('80) asserted that the entire achromatic figure arose splitting of the spireme, appearan t •'. ihe astral rays disinnpriiasler and

Fig. 37. — The prophases of alama/idra. (MEVFS)

A. Early segmented spireme; tf ruction-sphere. II. Longitiidinr .migration of ilie sphere, C. Early centra] spindle. D. Chromn Sl .nies jn the form ired, amphiaster enlarging, manllefil.ns lievrloping.

from the cytoplasm, and to that view, in a modified form, he still adheres. Flemming ('82), on the whole, inclined to the opinion that the achromatic figure arose inside the nucleus, yet expressed the opinion that the question of nuclear or cytoplasmic origin was one of minor importance. A long series of later researches on both plants and animals has fully sustained this opinion, showing that the origin of the achromatic figure does in fact differ in different cases. Thus in Infusoria the entire mitotic figure is of intranuclear origin (there are, however, no asters); in echinoderm eggs the spindle is of nuclear, the-.asters of cytoplasmic, origin ; in the testis-cells and some tissuecells of the salamander, a complete amphiaster is first formed in the cytoplasm, but to this are afterward added elements prol>ably derived from "the linin-network ; while in higher plants there is some reason to believe that the entire achromatic figure may be of cytoplasmic origin. Such differences need not surprise us when we reflect that the achromatic part of the nucleus (linin-network, etc.) is probably of the same general nature as the cytoplasm. 1

Many observers have maintained that the material of the astral rays and spindle-fibres is directly derived from the substance of the protoplasmic meshwork, whether nuclear, cytoplasmic, or both ; but its precise origin has long been a subject of debate. This question, critically considered in Chapter VI., will be here only briefly sketched. By Klein (78), Van Beneden ('83), Carnoy ('84, '85), and a large number of later observers, the achromatic fibres, both of spindles and of asters, are regarded as identical with those of a preexisting reticulum which have merely assumed a radiating arrangement about the centrosome. The amphiaster has, therefore, no independent existence, but is merely an image, as it were, somewhat like the bipolar figure arising when iron filings are strewn in the field of a horseshoe magnet. Boveri, on the other hand, who has a small but increasing following, maintains that the amphiastral fibres are not identical with those of the preexisting meshwork, but a new formation which, as it were, "crystallizes anew " out of the general protoplasmic substance. The amphiaster is therefore a new and independent structure, arising in, or indirectly from, the preexisting material, but not by a direct morphological transformation of that material. This view, which has been advocated by Druner ('94), Braus C95), Meves ('97, 4, '98), and with which my own later observations (*99) also agree, is more fully discussed at page 318.

In 1887 an important forward step was taken through the independent discovery by Van Beneden and Boveri that in the egg of Ascaris the centrosome does not disappear at the close of mitosis, but remains as a distinct cell-organ lying beside the nucleus in the cytoplasm. These investigators agreed that the amphiaster is formed under the influence of the centrosome, which by its division creates two new "centres of attraction " about which the astral systems arise, and which form the foci of the entire dividing system. In them are centred the fibrillar of the astral system, toward them the daughter chromosomes proceed, and within their respective spheres of influence are formed the resulting daughter-cells. Both Van Beneden and Boveri fully recognized the importance of their discovery. "We are justified," said Van Beneden, " in regarding the attraction-sphere with its central corpuscle as forming a permanent organ, not only of the early blastomeres, but of all cells, and as constituting a cell-organ equal in rank to the nucleus itself ; and we may conclude that every central corpuscle is derived from a preexisting corpuscle, every attractionsphere from a preexisting sphere, and that division of the sphere precedes that of the cell-nucleus."

1 In the case of echinoderm eggs, I have found reason ('95, 2) for the conclusion that the spindle- fibres are derived not merely from the linin-substance. but also from the chromatin. Despite some adverse criticism, I have found no reason to change my opinion on this point. The possible significance of such a derivation is indicated elsewhere (p. 302).

Fig. a8. — Metaphase a (DBJiSKB.)

E. Metaphase. The continuous central spindle-fibres Outside them ihe thin layer of contractile mantle-fibres al which only two are shown. Centrosomes and asters. F. Transverse section through the mitotic figure showing the ring of chromosomes surrounding the central spindle, the cut fibres of the latter appearing as dots. G. Anaphase ; divergence of the daughter-chromosomes, exposing the central spindle as the interional fibres; contractile fibres (principal cones of Van Beneden) clearly shown. H. Later anaphase (dyaster of Flemming) ; the central spindle fully eiposed to view; mantle-fibres attached to the chromosomes. Immediately afterward the cell divides (see Fig. 29) .

1 Boveri expressed himself in similar terms regarding the centrosome in the same year ('87, 2, p. 153), and the same general result was reached by Vejdovsky nearly at the same time, 2 though it was less clearly formulated than by either Boveri or Van Beneden.

All these observers agreed, therefore, that the achromatic figure arose outside the nucleus, in the cytoplasm ; that the primary impulse to cell-division was given, not by the nucleus, but by the centrosome, and that a new cell-organ had been discovered whose special office

Fig. 15. — Final ph /. Epithelial cull I

from the lung- chromosomes ai [he p "mid-body"' or /.viiichtnkSrptr M tr r-cell (lung) immediately after divisio

of each; mid-body a single granule

cells. [Fl.F.l spindle, the cell-body divif of the disappearing spindl ig, the cei

n the middle of tl

was to preside over cell-division. "The centrosome is an independent permanent cell-organ, which, exactly like the chromatic elements, is transmitted by division to the daughter-cells. The centrosome represents the dynamic centre of cell." 3

That the centrosome docs in many cases, especially in embryonic cells, behave in the manner stated by Van Beneden and Boveri seems at present to admit of no doubt ; and it has been shown to occur in many kinds of adult tissue-cells during their resting state ; for example in pigment-cells, leucocytes, connective tissue-cells, epithelial and endothelial cells, in certain gland-cells and nerve-cells, in the cells of some plant-tissues, and in some of the unicellular plants and animals, such as the diatoms and flagellates and rhizopods. On the other hand, Van Beneden's conception of the attraction-sphere has proved untenable ; for this structure has been clearly shown in some cases to disintegrate and disappear at the close or the beginning of mitosis l (Fig. 27).

'S8, pp. 151.

Boveri, '87, ;

Whether the centrosome theory can be maintained is still in doubt ; but evidence against it has of late rapidly accumulated.

In the first place, it has been shown that the primary impulse to cell-division cannot be given by fission of the centrosome, for there are several accurately determined cases in which the chromatin-elements divide independently of the centrosome, and it is now generally agreed that the division of chromatin and centrosome are two parallel events, the nexus between which still remains undetermined. 2

Secondly, an increasing number of observers assert the total disappearance of the centrosome at the close of mitosis ; while some very convincing observations have been made favouring the view that centrosomes may be formed de novo without connection with preexisting ones (pp. 213, 305).

Thirdly, a large number of recent observers (including Strasburger and many of his pupils) of mitosis in the flowering plants and pteridophytes agree that in these forms no centrosome exists at any stage of mitosis, the centre of the aster being occupied by a vague reticular mass, and the entire achromatic figure arising by the gradual grouping of fibrous cytoplasmic elements (kinoplasm or filar plasm) about the nuclear elements. 8 If we can assume the correctness of these observations, the centrosome-theory must be greatly modified, and the origin of the amphiaster becomes a far more complex problem than it appeared under the hypothesis of Van Beneden and Boveri. That such is indeed the case is indicated by nothing more strongly than by Boveri's own remarkable recent experiments on cell-division (referred to at page 108).

1 Cf. p. 323. 2 Cf. p. 108. • Cf p. 82.

C. Details of Mitosis

Comparative study has shown that almost every detail of the processes described above is subject to variation in different forms of cells. Before considering some of these modifications it may be well to point out what we are at present justified in regarding as its essential features. These are : (1) The formation of the chromatic and achromatic figures ; (2) the longitudinal splitting of the chromosomes or spireme-thread ; (3) the transportal of the chromatin-halves to the respective daughter-cells. Each of these three events is endlessly varied in detail ; yet the essential phenomena are everywhere the same, with one important exception relating to the division of the chromosomes that occurs in the maturation of certain eggs and spermatozoa. 1 It may be stated further that the study of mitosis in some of the lower forms (Protozoa) gives reason to believe that the asters are of secondary importance as compared with the spindle, and that the formation of spireme and chromosomes is but tributary to the division of the smaller chromatin-masses of which they are made up.

I. Varieties of the Mitotic Figure

(a) The Achromatic Figure, The phenomena involved in the history of the achromatic figure are in general most clearly displayed in embryonic or rapidly dividing cells, especially in egg-cells (Figs. 31, 60), where the asters attain an enormous development, and the centrosomes are especially distinct. In adult tissue-cells the asters are relatively small and difficult of demonstration, the spindle large and distinct ; and this is particularly striking in the cells of higher plants where the asters are but imperfectly developed. Plant-mitoses are characterized by the prominence of the cell-plate (Fig. 34),. which is rudimentary or often wanting in animals, a fact correlated no doubt with the greater development of the cell-membrane in plants. With this again is correlated the fact that division of the cell-body in animal cells generally takes place by constriction in the equatorial plane of the spindle; while in plant-cells the cell is usually cut in two by a cell-wall developed in the substance of the protoplasm and derived in large part from the cell-plate.

In animal cells we may distinguish two general types in the formation of the amphiaster, which are, however, connected T>y~intermediate gradations. In the first of these, typically illustrated by the division of epithelial and testis-cells in the salamander (Flemming, Hermann, Druner, Meves), a complete amphiaster is first formed in the cytoplasm outside the nucleus, while the nuclear membrane is still intact. As the latter fades away and the chromosomes appear, some of the astral rays grow into the nuclear space and become attached to the chromosomes, which finally arrange themselves in a ring about the original spindle (Figs. 27, 28). In the completed amphiaster, therefore, we may distinguish the original central spindle (Hermann, '91) from the surrounding mantle-fibres, the latter being

1 Cf. Chapter V.

attached to the chromosomes, and being, according to Hermann, the principal agents by which the daughter-chromosomes are dragged apart. The mantle-fibres thus form two hollow cones or half-spindles, separated at their bases by the chromosomes and completely surrounding the continuous fibres of the central spindle, which come into view as the "interzonal fibres" during the anaphases (Fig. 28). There is still considerable uncertainty regarding the origin and relation of these two sets of fibres. It is now generally agreed with Van Beneden that the mantle-fibres are essentially a part of the asters, i.e. are simply those astral rays that come into connection with the chromosomes — wholly cytoplasmic in origin (Hermann, Driiner, MacFarland), or in part cytoplasmic, in part differentiated from the lininnetwork ( Flemming, Meves). Driiner ('95), Braus ('95) (salamander), and MacFarland (Pleuropkyllidia, '97') believe the central spindle to arise secondarily through the union of two opposing groups of astral rays in the area between the centrosomes. On the other hand, Hermann C91), Flemming ('91), Heidenhain ('94), Kostanecki ('97), Van der , Stricht ('98), and others believe the central spindle , to exist from the first in the form of fibres stretching between the diverging centrosomes ; and Heidenhain believes them to be developed from a special substance, forming a " primary centrodesmus," which persists in the resting cell, and in which the centrosomes are embedded. 1 MacFarland's observations on gasteropod-eggs C97) indicate that even nearly related forms may differ in the origin of the central spindle, since in Pleurophyllidia it is of secondary origin, as described above, while in Diaulula it is a primary structure developed from what he describes as the "centrosome," but which, as shown at page 314, is probably to be regarded as 1 </ P- 3'5

an attraction-sphere surrounding the centrosomes, and is perhaps comparable to Heidenhain's " centrodesmus."

In the second type, illustrated in the cleavage of echinoderm, annelid, in ol hi scan, and some other eggs, a central spindle may be formed, — sometimes already during the anaphases of the preceding mitosis (Figs. 99, 155), — but afterward disappears, the asters moving

F'e

31. —The middli

■pha

tetol n

Miosis in the fin

il cleavage of

the .-.

ticarii-egg.

[BOVERJ.]

-losing prophase,

the

ng. B. Met;

Aphas.

-.; equatorii

.1 plate e*a

lished

spill; *,

the equatorial plate, viewed

rn/a.

r, showing

the four chr

tes. (.'. Early anapha;

daughter-chi

>mej (polai

■ body at

■ld<).

D. Uler anapha

se ; p. b. second polar body.

(Fc

a preceding stager

isce

Fig, 90;

lor later stages Fig. 145.)

to opposite poles of the nucleus. Between these two poles a new spindle is then formed in the nuclear area, while astral rays grow out into the cytoplasm. There is strong evidence that in this case the entire spindle may arise inside the nucleus, i.e. from the substance of the linin-network, as occurs, for example, in the eggs of echinoderms (Fig. 25, E), and in the testis-cells of arthropods. In other cases, however, a part at least of the spindle is of cytoplasmic origin, since the ends of the spindle begin to form before dissolution of the nuclear membrane, and the latter is pushed inwards in folds by the ingrowing fibres (Figs. 25, C, 99). 1 In some cases, however, it seems certain that the nuclear membrane fades away before completion of the spindle {first maturation-division of Thalassema, Chatopttnts), and it is probable that the middle region of the spindle is here formed from the Unin-network. In most, if not all, mitoses of the second type the chromosomes do not form a ring about the equator of the spindle, but extend in a flat plate completely through

[Swingle.] e. B. Initial formation t D. Early anaphase ; nucli

A. Early prophase with single aster : spindle. C. Divergence of the daughterstill intact.

its substance. Here, therefore, it is impossible to speak of a "central spindle." It is nevertheless probable that the spindle-fibres are of two kinds, viz. continuous fibres, which form the interzonal fibres seen during the anaphases, and half-spindle fibres, extending only from the poles to the chromosomes. It is possible that these two kinds of fibres, though having the same origin, respectively corre ' Cf. Plainer ('86) on Arien and l.tpUopttrn, Watasc ('91) on I.olige, Braus ('95) on Trilon, and Griffin ('96, '99) on Thalnmma. Erlanger ('97, 5) endeavours to show that in the mitosU of emhryonic cells in the cephalopoda (.SV/1V1), where the inpushing of the membrane wai previously shown by Watase, the entire spindle arises from the nucleus.

spond in function to those of the central spindle and to the mantlefibres. It seems probable that the difference between the two types of spindle-formation may be due to, or is correlated with, the fact that the nuclear transformation takes place relatively earlier in the first type. When the nucleus lags behind the spindle-formation the centrosomes take up their position prematurely, as it were, the central spindle disappearing to make way for the nucleus.

It is in the mitosis of plant-cells that the most remarkable type of achromatic figure has been observed. In some of the lower forms (Algae), mitosis has been clearly shown to conform nearly to the process observed in animal cells, the amphiaster being provided with very large asters and distinct centrosomes, and its genesis corresponding broadly with the second type described above (Figs. 32, 33), though with some interesting modifications of detail. 1 Swingle (*97) describes in Stytopocaulon a process closely similar to that seen in many animal cells, the minute but very distinct centrosomes being surrounded by quite typical cytoplasmic asters, passing to opposite poles of the nucleus, and a spindle then developing between them out of the achromatic nuclear substance (Fig. 32). In the flowering plants and pteridophytes, on the other hand, mitosis seems to be of a quite different type, apparently taking place in the entire absettce of centrosomes. Guignard ('91, 1, '92, 2) clearly described and figured typical centrosomes and attraction-spheres both irj the ordinary mitosis (Fig. 34) and in the fertilization of the higher plants, giving an account of their behaviour nearly agreeing with the views then prevailing among zoologists. Although these accounts have been supported by some other workers, 2 and have recently been in part reiterated by Guignard himself ('98, 1), they have not been sustained by some of the best and most careful later observers, who describe a mode of spindle-formation differing radically from that seen in thallophytes and in animals generally. 3 According to these observations, begun by Farmer and Belajeff, and strongly sustained by the careful studies of Osterhout, Mottier, Nemec, and others, the achromatic figure is almost wholly of cytoplasmic origin, arising from a fibrillar material (" kinoplasm " or il filar plasm," of Strasburger), which at the beginning of mitosis forms a net-like mass surrounding the nucleus, from which fibrillae radiate out into the cytoplasm. As the nuclear membrane fades, these fibrillae, continually increasing, invade the nuclear area, gather themselves into bundles, converging to a number

1 See especially Swingle ('97) on Sphaeelariacea, Strasburger ('97) on Fucus, Mottier ('98) on Dictvota ; cf. also Harper ('97) on Erysiphe and Peziza.

2 Cf. Schaffher ('98), Fulmer ('98).

8 See Osterhout ('97) on Equisetum, Mottier ('97, I, '97, 2) on Lilium, Lawson ('98) on Cobaa, Nemec ('99) on Allium, Debski ('97, '99) on Chara ; also Belajeff ('94) and Farmer ('95).

DETAILS OF MITOSIS 83

of centres (without centrosomes), and thus give rise to an irregular multipolar figure (Figs. 36, 133). This figure finally resolves itself into a definite bipolar spindle which is devoid of centrosomes, and in the earlier stages also of asters, though in the later phases somewhat irregular asters are formed. On the basis of these observations Mottier * proposes to distinguish provisionally two well-defined types of mitosis in plants which he designates as the " thallophyte " and the " cormophyte " types. The latter seems wholly irreconcilable with the "process observed in animal-cells ; for the whole course of spindleformation seems diametrically opposed in the two cases, and should the cormophyte-type be established it would, to say the least, greatly restrict the application of the centrosome-theory of Van Beneden and Boveri. Only future research can definitely determine the question. There can be no doubt that the descriptions of Guignard and his followers do not rest upon pure imagination ; for it is easy to observe at the spindlepoles in some preparations {e.g. sections of roottips of Allium, Lilium, etc.) deeply stainingbodies such as these authors describe, "centrosomes" seem, however, to be of quite asier; inconstant occurrence ; and the careful studies of Osterhout, Mottier, and Nemec seem to give good ground for the conclusion that they have no such significance as the centrosomes of lower plants or of animals. It should nevertheless be borne in mind that true centrosomes (" blepharoplasts ") have been demonstrated in the spermatogenic divisions of some of the vascular cryptogams, and that analogous bodies occur in the corresponding divisions of the cycads (p. 175). We should therefore still hold open the possibility that centrosomes may occur in the vegetative mitoses of the higher plants, their apparent absence being possibly due to lack of stainingcapacity or similar conditions rendering their demonstration difficult.*

Fig. 33. -M

These [ HARPEft -J

A. Resting B. Early prophi

lingua, Rrysipht.

1 aster. C. Later prophase ; am . indie forming. D. Spindle «  Daughter-nucleus after division; spore-rr brane developing from astral rays.

1 Menlit of the plan

l,p. 183.

. may here be made of the barrel-shaped truncated spindles described i . In Basidiebelus, Fairchild ('97) finds spindles of this type, having a

84 CELL-DIVISION

A no less remarkable mode of spindle-formation, which is in a certain way intermediate between the cormophyte-type and the usual animal type is described by Mead ('97, '98, 1) in the first maturationdivision of Chmtopterus. Here the completed amphiaster is of quite typical form, and the centrosomes persist for the following mitosis ; yet Mead is convinced that the amphiaster is synthetically formed by the union of two separate asters and centrosomes (Fig. 1 50) which

interzonal fibres stretching between them, and thi poles- B. Laler stage, showing the cell-plate at the eqi spiremes (dispireme-suge of Flemming). C. Division c resting cell. D. Ensuing division in progress; the uppei

the lily as described by Gwr.NARD.

ve daughter-chromosomes on each side, the

Ircady dot »r 01 the spindh pitted : double

have no genetic connection, arising independently dc novo in the cytoplasm. 1 Improbable as such a conclusion may seem on a priori grounds, it is supported by very strong evidence, 2 and, taken together

and nearly parallel fibres, each of which terminates in a dec-ply staining granule. Neatly similar spindles hove heen described by Slrashurger ('So) in Spirtgyra, and in the embryosac of Monotrof>a. It is not impossible that such spindles may represent a type intermediate between the "cormoptyte" and " thallophyte " tvpes of Mot tier.

1 Cf. p. j°6.

1 I have had the privilege of examining some of Mead's beautiful preparations.

DETAILS OF MITOSIS 85

with the facts described in plants, it indicates that the forces involved in spindle-formation are far more complex than Van Beneden's and Boveri's hypothesis would lead one to suppose. 1

The centrosome and centrosphere appear to present great variations that have not yet been thoroughly cleared up and will be more critically discussed beyond." They are known to undergo extensive changes in the cycle of cell-division and to vary greatly in different forms (Fig. 152). In some cases the aster contains at its centre nothing more than a minute deeply staining granule, which doubtless

Rj. 36.— Division olsporc-moilicr-cells in AV"'M /J "". 5hl > win BSpii>dle-(ormation. [Ostf.rhout.] A. Early prophase, " kinoplasmic " fibrillin the cytoplasm. II. Multipolar fibrillar figure invading (he nuclear area, after disappearance of the nuclear membrane. C Multipolar spindle. D. Quadripolar spindle which finally condenses into a bipolar one.

represents the centrosome alone. In other cases the granule is surrounded by a larger body, which in turn lies within the centrosphere or attraction-sphere. In still other cases the centre of the aster is occupied by a large reticular mass, within which no smaller body can be distinguished (e.g. in pigment-cells); this mass is sometimes called the centrosome, sometimes the centrosphere. Sometimes, again, the spindle-fibres are not focussed at a single point, and the spindle

1 See p. 876 for the peculiar spinrlles, devoid of asters, observed during the maturation of the egg in certain forms. Cj. also Morgan's experiments on the artificial production of asters

86 CELL-DIVISION

appears truncated at the ends, its fibres terminating in a transverse row of granules (maturation-spindles of Ascaris, and some plant-cells). It is not entirely certain, however, that such spindles observed in preparations represent the normal structure during life.

b. The Chromatic Figure. — The variations of the chromatic figure must for the most part be considered in the more special parts of this work. There seems to be no doubt that a single continuous spireme-thread may be formed (cf. p. 113), but it is equally certain that the thread may appear from the beginning in a number of distinct segments, i.e. as a segmented spireme, and there are some cases in which no distinct spireme can be seen, the reticulum resolving itself directly into the chromosomes. The chromosomes, when fully formed, vary greatly in appearance. In many of the tissues of adult plants and animals they are rod-shaped and are often bent in the middle like a V (Figs. 28, 131). They often have this form, too, in embryonic cells, as in the segmentation-stages of the egg in Ascaris (Fig. 31) and other forms. The rods may, however, be short and straight (segmenting eggs of echinoderms, etc.), and may be reduced to spheres, as in the maturation-stages of the germ-cells. In the equatorial plate the V-shaped chromosomes are placed with the apex of the V turned toward the spindle (Fig. 28), while the straight rods are placed with one end toward the spindle. In either case the daughterchromosomes first begin to move apart at the point nearest the spindle, the separation proceeding thence toward the free portion. The V-shaped chromosomes, opening apart from the apex, thus give rise in the early anaphase to < >-shaped figures ; while rod-shaped chromosomes often produce a- an d JL-shaped figures (the stem of the JL being double). The latter, opening farther apart, form straight rods twice the length of the original chromosome (since each consists of two daughter-chromosomes joined at one end). This rod finally breaks across the middle, thus giving the deceptive appearance of a transverse instead of a longitudinal division (Fig. 52). The <>shaped figures referred to above are nearly related to those that occur in the so-called heterotypical mitosis. Under this name Flemming ('87) first described a peculiar modification of the division of the chromosomes that has since been shown to be of very great importance in the early history of the germ-cells, though it is not confined to them. In this form the chromosomes split at an early period, but the halves remain united by their ends. Each double chromosome then opens out to form a closed ring (Fig. 37), which by its mode of origin is shown to represent two daughter-chromosomes, each forming half of the ring, united by their ends. The ring finally breaks in two to form two U-shaped chromosomes which diverge to opposite poles

DETAILS OF MITOSIS 8 7

of the spindle as usual. As will be shown in Chapter V.,the divisions by which the germ-cells are matured are in many cases of this type; but the primary rings here in many cases represent not two but four chromosomes, into which they afterward break up.

Pig- 37

daughter-chromosomes join and dividing ; the swellings spindle-pole. D. Diagram Ihe contractile mantle-fibres

ltypical mitosis in spermatocytes of the salamander. [FLEMMWG.] ngs. each of which represents

ndtoend. B. The rings ranged a am the ends of the chromosomes, c. mesa: rmann) showing the central spindle, asters, an

hcd to the rings (one of the latter dividing).

2. Bivalent and Plnrivalent Chromosomes

The last paragraph leads to the consideration of certain variations in the number of the chromosomes. Boveri discovered that the species Ascaris mcgalocephala comprises two varieties which differ in no visible respect save in the number of chromosomes, the germ-nuclei of one form (" variety bivalens " of Hertwig) having two chromosomes,

88 CELL^DIVISION

while in the other form (" variety univalens ") there is but one. Brauer discovered a similar fact in the phyllopod Artemia, the number of somatic chromosomes being 168 in some individuals, in others only 84 (p. 281).

It will appear hereafter that in some cases the primordial germcells show only half the usual number of chromosomes, and in Cyclops the same is true, according to Hacker, of all the cells of the early cleavage-stages.

In all cases where the number of chromosomes is apparently reduced (" pseudo-reduction " of Riickert) it is highly probable that each chromatin-rod represents not one but two or more chromosomes united together, and Hacker has accordingly proposed the terms bivalent and plurivalent for such chromatin-rods. 1 The truth of this view, which originated with Vom Rath, is, I think, conclusively shown by the case of Artemia described at page 281, and by many facts in the maturation of the germ-cells hereafter considered. In Ascaris we may regard the chromosomes of Hertwig's "variety univalens" as really bivalent or double, i.e. equivalent to two such chromosomes as appear in "variety bivalens." These latter, however, are probably in their turn plurivalent, i.e. represent a number of units of a lower order united together; for, as described at page 148, each of these normally breaks up in the somatic cells into a large number of shorter chromosomes closely similar to those of the related species Ascaris himbricoidcs, where the normal number is 24.

Hacker has called attention to the striking fact that plurivalent mitosis is very often of the heterotypical form, as is very common in the maturation-mitoses of many animals (Chapter V.), and often occurs in the early cleavages of Ascaris ; but it is doubtful whether this is a universal rule.

3. Mitosis in the Unicellular Plants and Animals

The process of mitosis in the one-celled plants and animals has a peculiar interest, for it is here that we must look for indications of its historical origin. But although traces of mitotic division were seen in the Infusoria by Balbiani ('58— '6i), Stein C59), and others long before it was known in the higher forms, it has only recently received adequate attention and is still imperfectly understood.

Mitotic division has now been observed in many of the main divisions of Protozoa and unicellular plants ; but in the present state of

1 The words bivalent and univalent have been used in precisely the opposite sense by Hertwig in the case of Ascaris^ the former term being applied to that variety having two chromosomes in the germ-cells, the latter to the variety with one. These terms certainly have priority, but were applied only to a specific case. Hacker's use of the words, which is strictly in accordance with their etymology, is too valuable for general descriptive purposes tobe rejected.

DETAILS OF MITOSIS 89

the subject it must be left an open question whether it occurs in all. In some of the gregarines and Heliozoa, the process is of nearly or quite the same type as in the Metazoa. From such mitoses, however, various gradations may be traced toward a much simpler process, such as occurs in Ameeba and the lower flagellates ; and it is not improbable that we have here representatives of more primitive conditions. Among the more interesting of these modifications may be mentioned : —

1. Even in forms that nearly approach the mitosis of higher types

Fig. 38. — Mitotic division in Infusoria. [R. HM A-C. Macronucleus of Spirothona, showing pole-plates. D-H. Successive stages i division of the micronucleus of Parametrium. D. The earliest stage, showing reticulum. G. lowing stage ("sickle-form '*) with nucleolus. E. Chromosomes and pole-plates. F. Late phase. H. Final phase.

the nuclear membrane may persist more or less completely through every stage {Noetiluca, Euglypha, Actinospltarium).

2. Asters may be present (Heliozoa, gregarines) or wanting (Infusoria, Radiolaria).

3. In one series of forms the centrosome or sphere is represented by a persistent intranuclear body (nucleolo-centrosome) of considerable size, which divides to form a kind of central spindle {F.ngkna Am<eba, Infusoria ?).

4. In a second series the centrosome or sphere is a persistent

go

CELI^DIVISION

extranuclear body, as in most Metazoa (Helioeoa, Noctiluca, Paramceba).

5. In a few forms having a scattered nucleus the chromatin-granules are only collected about the apparently persistent sphere or centrosome at the time of its division, and afterward scatter through the cell, leaving the sphere lying in the general cell-substance ( Tctramitus).

6. The arrangement of the chromatin granules to form chromosomes appears to be of a secondary importance as compared with

Fig. 39- — Mitosis in the rhii

In this form the body is surrounded by a

cell-body. The latter therefore divides by a

(the initial phase shown ai A) . the nucleus

afte rward wanders out into the bud.

A. Early prophase ; nucleus near lower < somes. B. Equatorial plate and spindle foi

phase, spindle dividing ; after division of the

C D

)pod, Euglypha. [Schewukoff.] firm shell which prevents direct constriction of the process of budding from the opening of the shell meanwhile divides, and one of the daughter-nuclei

ainmg a

higher forms, and the essential feature in nuclear division appears to be the fission of the individual granules.

Wc may first consider especially the achromatic figure. The basis of our knowledge in this field was laid by Richard Hertwig through his studies on an infusorian, Spirochona { '77), and a rhizopod, Actinotpharium ('84). In both these forms a typical spindle and equatorial plate are formed inside the nuclear membrane by a direct transformation of the nuclear substance. In Spirochona (Fig. 38, A~C) a

DETAILS OF MITOSIS

9'

hemispherical "end-plate" or "pole-plate" is situated at either pole of the spindle, and Hertwig's observations indicated, though they did not prove, that these plates arose by the division of a large " nucleolus." Nearly similar pole-plates were somewhat described by Schewiakoff ('88) in Euglypha (Fig. 39), and it seems clear that they are the analogues of the centrosomes or attraction-spheres in higher forms. In EugUna, as shown by Keuten, the pole-plates, or their analogues, certainly arise by division of a distinct and persistent intranuclear body ("nucleolus" or "nucleolo-centrosome") which elon

P1R.40. A. Preparing for divisioi rounded by a group of chrc spindle. C. Later stage. D. The nuclear division completed.

gates to form a kind of central spindle around which the chromatin elements are grouped (Fig. 40); and Schaudinn ('95) described a similar process in Amceba. Richard Hertwig's latest work on Infusoria ('95) indicates that a similar process occurs in the micronuclei of Parametrium, which at first contain a large "nucleolus" and afterward a conspicuous pole-plate at either end of the spindle (Fig. 38, D-H). The origin of the pole-plates was not, however, positively determined. A corresponding dividing body is found in Ceratium (Lauterborn, '95), and as in the Infusoria the entire nucleus transforms itself into a fibrillar spindle-like body.

92

CELL-DIVISION

Still simpler conditions are found in some of the flagellates. 1 In Ckilomonas the sphere may still be regarded as intranuclear, since it lies m the middle of an irregular mass of chromatin- granules, though the latter are apparently not enclosed by a membrane. Nuclear division is here accomplished by fission of the sphere and the aggregation of the chromatin-granules around the two products. In Tetramitiis, finally (Fig. 16), the nucleus is represented by chromatingranules that are scattered irregularly through the cell and only at the time of division collect about the dividing sphere.

■m.

'. *-' - --■■.

"PTyi

•'.is?'

granule" (een V. Prophases of mitosis. E. Budding to foim s G. Swarm-spores preparing for division

Fit- 41

A. Spharaitr**, ; regelate rays. ft-G. Atuntkocystis. B F. Swarm-ipoies, devoid of origin of

In a second series of forms, represented by Noctilnca (Ishikawa, '94, '98), (Calkins, '98, 2), Paramceba (Schaudinn, '96, 1), Actinophrys and Aeantliecystis (Schaudinn, '96, 2), and the diatoms (Lauterborn, '96), the sphere lies outside the nucleus in the cytoplasm and the mitosis is closely similar to that observed in most Metazoa. This is most striking in the Heiiozoa, where the centrosome persists through the vegetative condition of the cell as the " central granule," to which the axial filaments of the pseudopodia converge. Schaudinn ('96, 2) shows that by the division of this body a typical extranuclear amphiaster and central spindle are formed (Fig. 41), while the chromatin passes through a spireme-stage, breaks into very short rod-shaped chromosomes which split lengthwise and arrange themselves in the equator of the spindle, while the nuclear membrane fades away. Noctiltua (Fig. 42), as shown by Ishikawa and Calkins, agrees with this in the main points; but the nuclear membrane does not at any period wholly disappear, and a distinct centrosome is found at the centre of the sphere. The latter body, which is very large, gives

Fig. 4J- — Mitosis in NecMuca. [CaLKINS.J A. Prophase; division of the sphere to form the central spindle; chromosomes converging (o the nuclear pole. B. Late anaphase, in horiiontal seciion. showing centrosornes ; the crntral spindle has sunk into the nucleus; nuclear membrane still intact except at the poles. C. Early anaphase; man de-fibres connected with the diverging chromosomes. D. Final anaphase (which is also the initial prophase of the succeeding division of spore-forming mitosis) ; doubling ol centrosome and splitting of chromosomes.

rise by a division to a fibrillated central spindle, about which the nucleus wraps itself while mantle-fibres are developed from the sphere-substance and become attached to the chromosomes, the nuclear membrane fading away along the surface of contact with the central spindle (Calkins). Broadly speaking, the facts are similar in the diatoms (Surirella, t. Lauterborn), where the central spindle, arising by a peculiar process from an extranuclear centrosome, (sphere ?) sinks into the nucleus in a manner strongly suggesting that observed in Noctiluca.

In the interesting form Paramceba, as described by Schaudinn ('96, 1), the sphere (" Nebenkorper "), which is nearly as large as the nucleus, divides to form a central spindle, about the equator of which the chromatin-elements become arranged in a ring (Fig. 43); but no centrosome has yet been demonstrated in the sphere. Paramccba appears to differ from Englena mainly in the fact that at the close of division the sphere is in the former left outside the daughter-nucleus and in the latter enclosed within it. 1 The connecting link is perfectly given by Tetramitus, where no morphological nucleus is formed, and the sphere lies in the general cell-substance (p. 92); and we could have no clearer demonstration that the extra- or intranuclear position of sphere or centrosome is of quite secondary importance. As regards the formation of the spheres (pole-plates) Actinosphcerium (Figs. 44, 45) seems to show a simpler condition than any of the above forms, since no permanent sphere exists, and Brauer ('94) and R. Hertwig ('98) agree that the pole-plates are formed by a gradual accumulation of the achromatic substance of the nucleus at opposite poles.

A distinct centrosome (centriole ?) in the interior of the sphere has thus far only been observed in a few forms (Noctiluca, Actinospharium\ and neither its origin nor its relation to the sphere has yet been sufficiently cleared up. Both Ishikawa ('94) and Calkins ('98, 2) somewhat doubtfully concluded that in Noctiluca the centrosomes arise within the nucleus, migrating thence out into the extranuclear sphere. With this agree R. Hertwig's latest studies on Actinosphcerium C98), the spindle-poles being first formed from the pole-plates (themselves of nuclear origin), and the centrosomes then passing into them from the nucleus. Hertwig reaches the further remarkable conclusion that the centrosomes arise as portions of the chromatinnetwork extruded at the nuclear poles (Fig. 45), first forming a spongy irregular mass, but afterward condensing into a deeply staining pair of granules which pass to the respective poles of the spindle. It is a remarkable fact that these centrosomes are only found in the two maturation-divisions, and are absent from the ordinary vegetative mitoses where the spindle-poles are formed by two cytoplasmic masses derived, as Hertwig believes, from the intranuclear plates. Schaudinn ('96, 3) likewise describes and clearly figures an intranuclear origin of the centrosome in buds of Acanthocystis (Fig. 41), which are derived by direct division of the mother 1 Cf. Calkins, '98, 1, p. 388.

DETAILS OF MITOSIS 95

nucleus with no trace of a centrosome. In this same form, as described above, the ordinary vegetative mitoses are quite of the metazoan type, with a persistent extranuclear centrosome.

The history of the chromatin in the mitosis of unicellular forms shows some interesting modifications. In a considerable number of forms a more or less clearly marked spire me-stage precedes the formation of chromosomes (diatoms, Infusoria, dinoflagellates, Euglypha); in others, long chromosomes are formed without a distinct spiremestage {Noctiluca). It has been clearly demonstrated that in some cases these chromosomes split lengthwise, as in Metazoa {Noctiluca,

Pig. 43.— MilMit in Ann

AI (he left, amceboid phase, showing nucleus a of division in the swarm-spores.

>a. [SCHAUDINN.] " NebenkOrper." Al (he tight, lour stages

diatoms, Actinophrys, probably in Euglypha) ; but in some cases they are stated to divide transversely in the middle (Infusoria according to Hertwig, Ceratium according to Lauterborn). These chromosomes appear always to arise, as in Metazoa, through the linear arrangement of chromatin-granules (Noctiluca, Actinosph&rium, Euglena), which themselves in many cases arise by the preliminary fragmentation of one or more large chromatin-masses (e.g. in Noctiluca or Actinosphartum). In other forms no such linear aggregates are formed, and direct fission of the chromatin-granules appears to take place without the formation of bodies morphologically comparable with the chromosomes of such forms as Noctiluca. This is apparently the case in Tetramitus, and Achromatium, other forms having a distributed

96 CELL-DIVISION

nucleus, 1 and in such forms as Chilomonas and Traehelomonas, where the granules are permanently aggregated about a central body. Too little is known of the facts to justify a very positive statement ; but on the whole they point toward the conclusion that in the simplest

^:>V

ase ; above and below the rcticu lar cytoplasmic masses in which Ihe rs afterward develop. B. Later stage of the nucleus. D. Mitotic figure in the metaphase, ving equatorial plate, intia-nuclear spindle, and pole-plates (p.p.). C. Equatorial plate, ed en fare, consisting of double chromatin -granules. E. E^rly anaphase. F. C Later anales. H. Final anaphase. /. Telophase; daughter-nucleus forming, chromatin In loop-shaped ads; outside the nuclear membrane Ihe centrosome. already divided, and the aster. J, later e; the daughter-nucleus established; divergence of the centrosomes. Beyond this point the

types of mitosis no true chromosome-formation occurs, thus sustaining Brauer's conclusion that the essential fact in the history of the chromatin in mitosis is the fission of the individual granules. 3

'The f«  n Atkram,

1 For speculations on the historical

of the individual granules is carefully described anil figured by SchcwiakoH

DETAILS OF MITOSIS

97

4. Pathological Mitoses

Under certain circumstances the delicate mechanism of cell-division may become deranged, and so give rise to various forms of pathological mitoses. Such a miscarriage may be artificially produced, as Hertwig, Galeotti, and others have shown, by treating the dividing cells with poisons and other chemical substances (quinine, chloral, nicotine, potassic iodide, etc.). Pathological mitoses may, however,

Kg. 45. — Mitosis in Attinotpharium. [R. Hertwig. A. Encysted form, with resting nucleus; ( B. prophase of division of the encysted form, : and spindle without centrosomes. C. Earlier extrusion of chromatic substance to form the and aster.

occur without discoverable external cause ; and it is a very interesting fact, as Klebs, Hansemann, and Galeotti have especially pointed out, that they are of frequent occurrence in abnormal growths such as cancers and tumours.

The abnormal forms of mitoses are arranged by Hansemann in two general groups, as follows : ( 1 ) asymmetrical mitoses, in which the chromosomes are unequally distributed to the daughter-cells, and (2) multipolar mitoses, in which the number of centrosomes is more than

gg CELL-DIVISION

two, and more than one spindle is formed. Under the first group are included not only the cases of unequal distribution of the daughterchromosomes, but also those in which chromosomes fail to be drawn into the equatorial plate and hence are lost in the cytoplasm.

Klebs first pointed out the occurrence of asymmetrical mitoses in carcinoma-cells, where they have been carefully studied by Hansemann and Galeotti. The inequality is here often extremely marked, so that one of the daughter-cells may receive more than twice as much chromatin as the other (Fig. 46). Hansemann, whose conclu

— Pathological

A. Asytnmctiical mitosis with unequal

bulion of the chromosomes. C, Quadripolai

F. Trumcleatc cell resulting. V

sions are accepted by Galeotti, believes that this asymmetry of mito- \ sis gives an explanation of the familiar fact that in cancer-cells many » t of the nuclei are especially rich in chromatin (hyperchromatic cells), \ while others are abnormally poor (hypochromatic cells). Lustig and , Galeotti ('93) showed that the unequal distribution of chromatin is correlated with and probably caused by a corresponding inequality in 1 the centrosomes which causes an asymmetrical development of the amphiaster. A very interesting discovery made by Galeotti ('93) is that asymmetrical mitoses, exactly like those seen in carcinoma, may be artificially produced in the epithelial cells of salamanders (Fig. 47) by treatment with dilute solutions of various drugs (antipyrin, cocaine, quinine).

DETAILS OF MITOSIS

99

Normal multipolar mitoses, though rare, sometimes occur, as in the division of the pollen-mother-cells and the endosperm-cells of flowering plants (Strasburger); but such mitotic figures arise through the union of two or more bipolar amphiasters in a syncytium and are due to a rapid succession of the nuclear divisions unaccompanied by fission of the cell-substance. These are not to be confounded with pathological mitoses arising by premature or abnormal division of the centrosome. If one centrosome divide, while the other does not, triasters are produced, from which may arise three cells or a trinucleated cell. If both centrosomes divide, tetrasters or polyasters are formed. Here again the same result has been artificially attained by chemical stimulus {cf. Schottlander, '88). Multipolar mitoses are

Pig. 47. — Pathological [Galeotti.J

A. Asyi after treatment with 0.5 % potassic iodide solution.

of salamander caused by poisons, ilh 0.05% antipyrin solution, ft. Tripolar mitosis

also common in regenerating tissues after irritative stimulus (Strobe); but it is uncertain whether such mitoses lead to the formation of normal tissue. 1

The frequency of abnormal mitoses in pathological growths is a most suggestive fact, but it is still wholly undetermined whether the abnormal mode of cell-division is the cause of the disease or the reverse. The latter seems the more probable alternative, since normal mitosis is certainly the rule in abnormal growths ; and Galeotti's experiments suggest that the pathological mitoses in such growths may be caused by the presence of deleterious chemical products in the diseased tissue, and perhaps point the way to their medical treatment.

i formed in polyspcrmic fertilization of the egg are, o>

CELl^DIVISION

D. The Mechanism of Mitosis

We now pass to a consideration of the forces at work in mitotic division, which leads us into one of the most debatable fields of cytological inquiry.

I. Function of the Amp/ii aster

All observers agree that the amphiaster is in some manner an expression of the forces by which celldivision is caused, and many accept, in one form or another, the first view clearly stated by Fol, 1 that the asters represent in some manner centres of attractive forces focussed in the ccntrosome or dynamic centre of the cell. Regarding the nature of these forces, there is, however, so wide a divergence of opinion as to compel the admission that we have thus far accomplished little more than to clear the ground for a precise investigation of the subject; and the mechanism of mitosis still lies before us as

if dividing eggs

problems of cytology.

{a) The Theory of Fibrillar Contractility. — The

Fig. 48. — Slightly schematic fig of Aicarii, illustrating Van beneile [Van Beneden and Julin.]

A. Early anaphase; each chromosome has divided one Q f tnc most fascinating into two. II. Later anaphase during divergence of the daughter-chromosomes. a,e. Antipodal cone of a; rays; <\s. cortical zone of the ai tract ion-sphere; i. ir zonal filircs stretching between the daughter-chro

f.i. principal cone, forming one-half of the contractile view that has taken the

spindle (the action 01 these fibres is reenforced by that of ^trnno-pct no lfl on recent

the antipodal cone) ; ).«. subequatorial circle, to which Strongest noia on rect.ni

Ihe astral raysare attached. research IS the hypothesis

of fibrillar contractility. First suggested by Klein in 1878, this hypothesis was independently put forward by Van Beneden in 1883, and fully outlined ".'•."--.'■" 73.P- 473

THE MECHANISM OF MITOSIS IOI

by him four years later in the following words : " In our opinion all the internal movements that accompany cell-division have their immediate cause in the contractility of the protoplasmic fibrillae and their arrangement in a kind of radial muscular system, composed of antagonizing groups " {i.e. the asters with their rays). " In this system the central corpuscle (centrosome) plays the part of an organ of insertion. It is the first of all the various organs of the cells to divide, and its division leads to the grouping of the contractile elements in two systems, each having its own centre. The presence of these two systems brings about cell-division, and actively determines the paths of the secondary chromatic asters " (i.e. the daughter-groups of chromosomes) " in opposite directions. An important part of the phenomena of (karyo-) kinesis has its efficient cause, not in the nucleus, but in the protoplasmic body of the cell." l This beautiful hypothesis was based on very convincing evidence derived from the study of the Ascaris egg, and it was here that Van Beneden first demonstrated the fact, already suspected by Flemming, that the daughter-chromosomes move apart to the poles of the spindle and give rise to the two respective daughter-nuclei. 2

Van Beneden's general hypothesis was accepted in the following year by Boveri ('88, 2), who contributed many important additional facts in its support, though neither his observations nor those of later investigators have sustained Van Beneden's account of the grouping of the astral rays. Boveri showed in the clearest manner that, during the fertilization of Ascaris, the astral rays become attached to the chromosomes of the germ-nuclei; that each comes into connection with rays from both the asters ; that the chromosomes, at first irregularly scattered in the egg t are drawn into a position of equilibrium in the equator of the spindle by the shortening of these rays (Figs. 90, 147); and that the rays thicken as they shorten. He showed that as the chromosome splits, each half is connected only with rays (spindlefibres) from the aster on its own side ; and he followed, %tep by step, the shortening and thickening of these rays as the daughter-chromosomes diverge. In all these operations the behaviour of the rays is

1 '87, p. 280.

2 *83, p. 544. Van Beneden describes the astral rays, both in Ascaris and in tunicates, as differentiated into several groups. One set, forming the " principal cone," are attached to the chromosomes and form one-half of the spindle, and, by the contractions of these fibres, the chromosomes are passively dragged apart. An opposite group, forming the " antipodal cone," extend from the centrosome to the cell-periphery, the base of the cone forming the "polar circle." These rays, opposing the action of the principal cones, not only hold the centrosomes in place, but, by their contractions, drag them apart, and thus cause an actual divergence of the centres. The remaining astral rays are attached to the cell-periphery and are limited by a subequatorial circle (Fig. 48). Later observations indicate, however, that this arrangement of the astral rays is not of general occurrence, and that the rays often do not reach the periphery, but lose themselves in the general reticulum.

CELL-DIVISION

precisely like that of muscle-fibres ; and it is difficult to study Boveri's beautiful figures and clear descriptions without sharing his conviction that "of the contractility of the fibrillar there can be no doubt." '

Very convincing evidence in the same direction is afforded by pigment-cells and leucocytes or wandering cells, in both of which there is a very large permanent aster (attraction-sphere) even in the resting cell. The structure of the aster in the leucocyte, where it was first discovered by Flemming in 1891, has been studied very carefully by Heidenhain in the salamander. The astral rays here extend throughout nearly the whole cell (Fig. 49), and are believed

B A

basichromalin (chromatin proper).

by Heidenhain to represent the contractile elements by means of which the cell changes its form and creeps about. A similar conclusion was reached by Solger ('91) and Zimmermann ('93, 2) in the case of pigment-cells (chromatophores) in fishes. These cells have, in an extraordinary degree, the power of changing their form and of actively creeping about. Solger and Zimmermann have shown that .the pigment-cell contains an enormous aster, whose rays extend in every direction through the pigment-mass, and it is almost impossible to doubt that the aster is a contractile apparatus, like a radial muscular system, by means of which the active changes of form are produced (Fig. 50). This interpretation of the aster receives additional support through Schaudinn's ('96, 3) highly interesting dis

THE MECHANISM OF MITOSIS 103

covery that the " central granule " of the Heliozoa is to be identified with the centrosome and plays the same rdk in mitosis (Fig. 41), In these animals the axial filaments of the radiating pseudopodia converge to the central granule during the vegetative state of the cell, thus forming a permanent aster which Schaudinn's observations prove to be directly comparable to that of a leucocyte or of a mitotic figure. There is in this case no doubt of the contractility of the rays, and a

4i!Sfe»

r^Pr

m

m

Fig. 50. — Pigment-cells and asters from the epidermis of fishes. [ZlMMEKM 1. F.ntire pigment-cell, from BIcnnius, The central clear space is Ihe central ma: 1 which radiate the pigment-granules; two nuclei below. B. Nucleus (n) and a ion of Ihe pigment, showing reticulated central mass. C, Two nuclei and as

strong, if indirect, argument is thus given in favour of contractility in other forms of asters. 1 The contraction-hypothesis is beautifully illustrated by means of a simple and easily constructed model, devised by Heidenhain ('94, '96), which closely simulates some of the phenomena of mitosis. In its simplest form the model consists of a circle, marked on a flat surface, to the periphery of which are attached at equal

1 For an interesting discussion and development of the contraction-hypothesis see Watue, '94.

CELt^DIVISIQN

intervals a series of rubber bands (astral rays). At the other ends these bands are attached to a pair of small rings (centrosomes) fastened together. In the position of equilibrium, when the rays are stretched at equal tension, the rays form a symmetrical aster with the centrosomes at the centre of the circle (Fig. 51, A). If the connection between the centrosomes be severed, they are immediately dragged apart to a new position of equilibrium with the rays grouped in two asters, as in the actual cell (dotted lines in Fig. 51, A). If a round pasteboard box of suitable size (nucleus) be inserted between two of the rays, it assumes an eccentric position, the cell-axis being formed by a line passing through its centre and that of the pair of small rings (rf. the epithelial cell, p. 57), and upon division of the aster it takes up a position between the two asters. In a second form of the models the circle is formed of two half rings of flexible steel, joined is (mainly from by hinges ; the divergence of the small rings

■ position of ihe ray* upon sever- ; s here accompanied by 1 (V^Mod^s*i(hfl?xibio n hi U n ^d an elongation and partial d, constriction of the model

THE MECHANISM OF MITOSIS 105

in the equatorial plane ; and if, finally, the hinge-connection be removed, each half of the ring closes to form a complete ring. 1

Heidenhain has fully worked out a theory of mitosis based upon the analogy of these pretty models. The astral rays of the cell ("organic radii ") are assumed to be in like manner of equal length and in a state of equal tonic contraction or tension, the centrosome forming the common insertion-point of the rays, and equilibrium of the system being maintained by turgor of the cell. Upon disappearance of the nuclear membrane and division of this insertion-point, the tension of the rays causes divergence of the centrosomes and formation of the spindle between them, and by further contraction of the rays both the divergence of the daughter-chromosomes and the division of the cell-body are caused. A new condition of equilibrium is thus established in each daughter-cell until again disturbed by division of the centrosome. 2 In some cases (leucocytes) the organic radii are visible at all periods. More commonly they are lost to view by breaking up into the cell-reticulum, without, however, losing their essential relations.

No one who witnesses the operation of Heidenhain's models can fail to be impressed with its striking simulation of actual cell-division. Closer study of the facts shows, however, that the contraction-hypothesis must be considerably restricted, as has been done by the successive modifications of Hermann ('91), Driiner('95), and others. Hermann, to whom the identification of the central spindle is due, pointed out that there is no evidence of contractility in the central spindle-fibres, which elongate instead of shorten during mitosis ; and he concluded that these fibres are non-contractile supporting elements, which form a basis on which the movements of the chromosomes take place. The mantle-fibres are the only contractile elements in the spindle, and it is by them that the chromosomes are brought into position about the central spindle and the daughter-chromosomes are dragged apart.* Drliner ('95) still further restricts the hypothesis, maintaining that the progressive divergence of the spindle-poles is caused not by contraction of the astral rays (" polar fibres "), as assumed by Heidenhain (following Van Beneden and Boveri), but by an active growth or elongation of the central spindle, which goes on throughout the whole period from the earliest prophases until the close of the anaphases. This view is supported by the fact that the central spindle 1 In a modification of the apparatus devised by Rhumbler ('97), the same effect is produced without the hinges.

2 Cf. p. 57. For critique of this hypothesis, see Fick ('97), Rhumbler ('96, '97), and Meves ('97, 4).

• Belajeff ('94) and Strasburger ('95) have accepted a similar view as applied to mitosisin plant-cells.

106 CELL-DIVISION

fibres are always contorted during the metaphases, as if pushing against a resistance ; and it harmonizes with the facts observed in the mitoses of infusorian nuclei, where no asters are present. This view has been accepted, with slight modifications, by Flemming, Boveri, Meves, Kostanecki, and also by Heidenhain. A nearly decisive argument in its favour is given by such cases as the polar bodies, or the mitosis of salamander spermatocytes as described by Meves ('96, '97, 3), where the spindle-poles are pushed out to the periphery of the cell, the polar astral rays meanwhile nearly or quite disappearing (Fig. 1 30). This not only strongly indicates the push of the central spindle, but also shows that the assumption of a pull by the polar rays is superfluous. But beyond this both Driiner and Meves have brought arguments against contractility in the other astral rays, endeavouring to show that these, like the spindle-fibres, are actively elongating elements, and that (Meves, '97, 3) the actual grouping of the rays during the anaphases is such as to suggest that even the division of the cell-body may be thus caused. A pushing function of the astral rays is also indicated by infolding of the nuclear membrane caused by the development of the aster as described by Platner, Watas£, Braus, Griffin, and others. 1 The contraction-hypothesis is thus restricted by Driiner and Meves to the mantle-fibres alone, though many others, among them Flemming and Kostanecki, still accept the contractility of the astral rays.

(b) Other Facts a fid Theories. — Even in the restricted form indicated above the contraction-hypothesis encounters serious difficulties, one of which is the fact urged by me in an earlier paper C95), and subsequently by Richard Hertwig ('98), that in the eggs of echinoderms and many other dividing cells the daughter-chromosome plates, extending through the whole substance of the spindle, wander to the extreme ends of the spindle — a process which demands a contraction of the fibres almost to the vanishing point, while in point of fact not even a shortening and thickening of the fibres can be seen (Fig. 52). Moreover, in these cases, no distinction can be seen between central spindle-fibres and mantlefibres, and we can only save the contraction-hypothesis by the improbable assumption that fibres indistinguishably mingled, and having the same mode of origin, structure, and staining-reaction, have exactly opposite functions. The inadequacy of the general theory is sufficiently apparent from the fact that in amitosis cells many

1 Cf. p. 68. It should be pointed out that the originator of the pushing theory was Watase ('93), who ingeniously developed an hypothesis exactly the opposite of Van Beneden's, assuming both astral rays and spindle-fibres to be actively elongating fibres, dove-tailing in the spindle-region, and pushing the chromosomes apart. This hypothesis is, I believe, inconsistent with the phenomena observed in multiple asters and elsewhere, yet it probably contains a nucleus of truth that forms the basis of Druner's conception of the central spindle.

~w •

THE MECHANISM OF MITOSIS

divide without any amphiaster whatever. In Infusoria mitosis seems to occur in the entire absence of asters, although the cells divide by constriction, and the analogy with Heidenhain's model entirely fails.

E

F

Fig. 53. — The later stages of

mitosis

in the egg of the

ea-urchin

Toxopstustti (A-D, X

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A. Melaphase; daughter

^hr

es drawing apart

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-chromosomes separating

C. Late ai

a phase ; daughter

mes lying near the spi

die

f« 

les. D. Final anaphase

ghter

hromosomes con

vesicles. E. Immed

,,,1.

after division, ihe asters un

ivid

ed ; th

ppeared.

F. Resting 3-cell stag

the

In Figs. A and /' the ce

f intensely staining granules, wilt

C

and D elongates at right

IE'

spindle-axis. I

/■'the ce

ntrosome appears as a s

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T

he connection between D

nd Fis not

definitely determi

In Euglypka, according to Schewiakoff (Fig. 39), division of the cellbody appears to take place quite independently of the mitotic figure. Again, a considerable number of cases are now known in which during the fertilization of the egg a large amphiaster is formed, with

IO& CELL-DIVISION

astral rays sometimes extending throughout almost the entire egg, only to disappear or become greatly reduced without the occurrence of division, the ensuing cleavage being effected by a new amphiaster or by the recrudescence of the old. 1 For these and other reasons we must admit the probability that contractility of the astral fibrillae, if it exists, is but the expression or consequence of a more deeply lying phenomena of more general significance. The subtlety of the problem is strikingly shown by Boveri's remarkable observations on abnormal sea-urchin eggs ('96), which show (1) that the periodic division of the centrosome and formation of the amphiaster may take place independently of the nucleus ; (2) that the spindle, as well as the asters, is concerned in division of the cell-body ; and (3) that an amphiaster without chromosomes is unable to effect normal division of the cell-body. The first and third of these facts are shown by eggs in which during the first cleavage all of the chromatin passes to one pole of the spindle, so that one of the resulting halves of the egg receives no nucleus, but only a centrosome and aster. In this half perfect amphiasters are formed simultaneously with each cleavage in the other half, yet no division of the protoplasmic mass occurs? The second fact is shown in polyspermic eggs, in which multipolar astral systems are formed by union of the several sperm-asters (Figs. 53, 101). In such eggs cleavages only occur between asters that are joined by a spindle. Normal cleavage of the cell-body thus requires the complete apparatus of mitosis, and even though the fibres be contractile they cannot fully operate in the absence of chromatin.

We may now turn to theories based on the hypothesis, first suggested by Fol in 1873, that the astral foci {i.e. centrosomes) represent dynamic centres of attractive or other forces. It should be noted that this hypothesis involves two distinct questions, one relating to the origin of the amphiaster, the other to its mode of action ; and we have seen that some of the foremost advocates of the contraction-hypothesis, including Van Beneden and Bovcri, have held the centrosomes to be attractive centres. Apart from the movements of the chromosomes, the most obvious indication that the centrosomes are dynamic centres is the extraordinary resemblance of the amphiaster to the lines of force in a magnetic field as shown by the arrangement of iron-filings about the poles of a horseshoe magnet — a resemblance pointed out by Fol himself, and urged by many later writers, 3 especially Ziegler ('95)

1 Cf. p. 213.

2 This result is opposed to Boveri's earlier work on Ascaris (p. 355), and is modified by Ziegler ('98), who observed in a single case that an irregular cleavage occurred in the enucleated half after two or three divisions of the centrosome. On the other hand, it is supported by Morgan's convincing experiments on the eggs of Arbacia (p. 308).

8 Cf the interesting photographic figures of Ziegler ('95). A still closer simulacrum of the amphiaster is produced by fine crystals of sulphate of quinine (a semiconductor) sus

THE MECHANISM OF MITOSIS

IO9

and Gallardo ('96, '97). It is impossible to regard this analogy as exact ; first, because it is inconsistent with the occurrence of tripolar astral figures ; second, as Meves has recently urged ' the course of the astral fibres does not really coincide with the lines of force, the most important deviation being the crossing of the rays opposite the equatorial region of the spindle, which is impossible in the magnetic or electric field. We must, however, remember that the amphiaster is formed in a viscid medium, that it may perform various movements, and that its fibres probably possess the power of active growth. The

Pi J. S3- — Division of dispermic eggs in sea-urchin eggs, schematic. [Bovi A. C, E, Eggs before division, showing various connections of the asters.

tag division in 1 lie three respective cases, showing cleavage only between ccnli

Ipindlc.

physical or chemical effect of the centres, through which the amphiaster primarily arises, may thus be variously disturbed or modified in later stages, and the crossing of the rays is therefore not necessarily fatal to the assumption of dynamic centres. Biitschli ('92, '98) has, moreover, recently shown that a close simulacrum of the amphiaster, showing a distinct crossing of the rays, may be produced in an artificial alveolar structure (coagulated gelatine) by tractive forces cen pended in spirit! of turpentine (a poor conductor) between two electric poles. This experiment, devised by Faraday, has recently been applied by Gallardo {'96, '97) to an analysis of the mitotic figure. ' '96, p. 371.

1 1 o CELL-DI VISION

tring in two adjacent points. This result is obtained by warming and then cooling a film of thick gelatine-solution, filled with air-bubbles, and then coagulating the mass in chromic acid. Such a film shows a fine alveolar structure, which assumes a radial arrangement about the air-bubbles, owing to the traction exerted on the surrounding structure by shrinkage of the bubbles on cooling. The amphiastral simulacra are produced about two adjacent bubbles, — a " spindle " being formed between them, and the " astral rays " sometimes showing a crossing like that seen in the actual amphiaster (Butschli is himself unable to explain fully how the crossing arises). The protoplasmic asters are maintained by Butschli to be, in like manner, no more than a radial configuration of the alveolar cell-substance caused by centripetal diffusion-currents toward the astral centres. 1 The most interesting part of this view is the assumption that these currents are caused by specific chemical changes taking place in the centrosome which causes an absorption of liquid from the surrounding region. " The astral bodies are structures which, under certain circumstances, function in a measure as centres from which emanate chemical actions upon protoplasm and nucleus ; and the astral phenomena which appear about the centrosomes are only a result incidental to this action of the central bodies upon the plasma." 2 Through centripetal currents thus caused arise the asters, and they may even account, in a measure, for the movements of the chromosomes. 8 This latter part of Biitschli's conception is, I believe, quite inadequate ; but the hypothesis of definite chemical activity in the centrosome is a highly important one, which is sustained by the staining-reactions of the centrosome and by its definite morphological changes during the cycle of cell-division.

More or less similar chemical hypotheses have been suggested by several other writers. 4 Of these perhaps the most interesting is Strasburger's suggestion, 6 that the movements of the chromosomes may be of a chemotactic character, which I suspect may prove to have been one of the most fruitful contributions to the subject. Beside this may be placed Carnoy's still earlier hypothesis ('85), that the asters are formed under the influence of specific ferments emanating from the poles of the nucleus. Mathews ('99, 2) has recently pointed out that there is a considerable analogy between the formation of the astral rays and that of fibrin-fibrils under the influence of fibrin-ferment, adding the suggestion that the centrosome may actually contain

1 Caraoy ('85) and Platner ('86) had previously held a similar view, suggesting that not only the spindle-formation, but also the movements of the chromosomes, might be explained as the result of protoplasmic currents.

2 '92, 1, p. 538.

• '92, 2, p. 160 ; '92, 3, p. IO.

4 Cf. the first edition of this work, p. 77, also Ziegler ('95). * '93, 2.

THE MECHANISM OF MITOSIS I 1 1

fibrin-ferment. Attention may be called here to the fact, now definitely determined by experiment, 1 that cell-division may be incited by chemical stimulus. In most of the cases thus far experimentally examined the divisions so caused are pathological in character, but in others they are quite normal, as shown in Loeb's remarkable results on the production of parthenogenesis in sea-urchin eggs by chemical stimulus, as described at pages 215 and 308. While these experiments by no means show that division is itself merely a chemical process, they strongly suggest that it cannot be adequately analyzed without reckoning with the chemical changes involved in it.

R/sntn/. A review of the foregoing facts and theories shows how far we still are from any real understanding of the process involved either in the origin or in the mode of action of the mitotic figure. The evidence seems well-nigh demonstrative, in case of the mantle-fibres and the astral rays, that Van Beneden's hypothesis contains an element of truth, but we must now recognize that it was formulated in too simple a form for the solution of so complex a problem. No satisfactory hypothesis can, I believe, be reached that does not reckon with the chemical changes occurring at the spindle-poles and in the nucleus ; and these changes are probably concerned not only with the origin of the amphiaster, but also with the movements of the chromosomes. In cases where the centrosome persists from cell to cell we may perhaps regard it as the vehicle of specific substances (ferments ?) which become active at the onset of mitosis, and run through a definite cycle of changes, to initiate a like cycle in the following generation ; and it is quite conceivable that such substances may persist at the nuclear poles, or may be re-formed there as an after-effect, even though the formed centrosome disappears. 2 In this consideration we may find a olue to the strange fact — should it indeed prove to be a fact — that the centrosome may divide, yet afterward disappear without discoverable connection with the centrosomes of the succeeding mitosis, as several recent observers have maintained. 8 When all is said, we must admit that the mechanism of mitosis in every phase still awaits adequate physiological analysis. The suggestive experiments of Butschli and Heidenhain lead us to hope that a partial solution of the problem may be reached along the lines of physical and chemical experiment. At present we can only admit that none of the conclusions thus far reached, whether by observation or by experiment, are more than the first naive attempts to analyze a group of most complex phenomena of which we have little real understanding.

1 See pp. 306, 308. 2 Cf. p. 215. * Cf. p. 213.

CELIrDI VISION

2. Division of the Chromosomes

In developing his theory of fibrillar contractility, Van Beneden expressed the view — only, however, as a possibility — that the splitting of the chromosomes might be passively caused by the contractions of the two sets of opposing spindle-fibres to which each is attached. 1 Later observations have demonstrated that this suggestion cannot be sustained ; for in many cases the chromatin-thread splits before division of the centrosome and the formation of the achromatic figure — sometimes during the spireme-stage, or even in the reticulum, while the nuclear membrane is still intact. Boveri showed this to be the case in Ascaris, and a similar fact has been observed by many observers since, both in plants and in animals.

Fig. 54. — Nuclei in the spirente-stage,

A. From (he endosperm of the lily, showing irue nucleoli. [FLEMHINC]

B. Spermatocyte of salamander. Segmented double spiremc-ihread composed of chromomeres and completely split. Two cenirosomes and central spindle at 1. [Hermann.]

C Spiremc-thread completely split, with six nucleoli. Endosperm of Fritillarin. [Ki.f.m The splitting of the chromosomes is therefore, in Boveri's words, " an independent vital manifestation, an act of reproduction oh the part of the chromosomes."*

AH of the recent researches in this field point to the conclusion that this act of division must be referred to the fission of the chromatin-granules or chromomeres of which the chromatin-thread is built. These granules were first clearly described by Balbiani ('76) in the chromatin-network of epithelial cells in the insectovary, and he found that the spireme-thread arose by the linear arrangement of these granules in a single row like a chain of bacteria. 3 Six years later Pfitzner ('82) added the interesting discovery

1 '87, p. 279.

1 '88, p. 1

•See '81, p. 638.

THE MECHANISM OF MITOSIS

"3

that during the mitosis of various tissue-cells of the salamander, the granules of the spireme-thread divide by fission and thus determine the longitudinal splitting of the entire chromosome. This discovery was confirmed by Flemming in the following year ('82, p. 219), and a similar result has been reached by many other observers (Fig. 54). The division of the chromatin-granules may take place at a very early period. Flemming observed as long ago as 1881 that the chromatin

Pig. SS- — Formalism of chromosomes and earl;

logonia of Asiarii mtgalocephafa, var. bivaltni. [I

A. Very early prophase; granules of the nucli

thread. E. Spireme-threail divided into two parts. F. Spii

ng of the thrum;

"j

ti ['ilium already

ivided. B. Spire

D. Shortening of

segmented into four

thread might split in the spireme-stage (epithelial cells of the salamander), and this has since been shown to occur in many other cases ; for instance, by Guignard in the mother-cells of the pollen in the lily ('91). Brauer's recent work on the spermatogenesis of Ascaris shows that the fission of the chromatin-granules here takes place even before the spireme-stage, when the chromatin is still in the form of a reticulum, and long before the division of the centrosomc (Fig. 55). He therefore concludes ; " With Bovcri I regard the splitting as an

1 1 4 CELL-DIVISION

independent reproductive act of the chromatin. The reconstruction of the nucleus, and in particular th£ breaking up of the chromosomes after division into small granules and their uniform distribution through the nuclear cavity, is, in the first place, for the purpose of allowing a uniform growth to take place; and in the second place, after the granules have grown to their normal size, to admit of their precisely equal quantitative and qualitative division. I hold that all the succeeding phenomena, such as the grouping of the granules in threads, their union to form larger granules, the division of the thread into segments and finally into chromosomes, are of secondary importance ; all these are only for the purpose of bringing about in the simplest and most certain manner the transmission of the daughter-granules (Spalthalften) to the daughter-cells." l " In my opinion the chromosomes are not independent individuals, but only groups of numberless minute chromatin-granules, which alone have the value of individuals." 2

These observations certainly lend strong support to the view that the chromatin is to be regarded as a morphological aggregate — as a congeries or colony of self-propagating elementary organisms capable of assimilation, growth, and division. They prove, moreover, that mitosis involves two distinct though closely related factors, one of which is the fission of the chromatic nuclear substance, while the other is the distribution of that substance to the daughter-cells. In the first of these it is the chromatin that takes the active part ; in the second it would seem that the main rdle is played by the amphiaster.

E. Direct or Amitotic Division

i. General Sketch

We turn now to the rarer and simpler mode of division known as amitosis ; but as Flemming has well said, it is a somewhat trying task to give an account of a subject of which the final outcome is so unsatisfactory as this ; for in spite of extensive investigation, we still have no very definite conclusion in regard either to the mechanism of amitosis or its biological meaning. Amitosis, or direct division, differs in two essential respects from mitosis. First, the nucleus remains in the resting state (reticulum), and there is no formation of a spireme or of chromosomes. Second, division occurs without the formation of an amphiaster; hence the centrosome is not concerned with the nuclear division, which takes place by a simple constriction. The nuclear substance, accordingly, undergoes a divi 1 *93» PP- 2 °3» 2°4» 2 t-'-f P- *>5

DIRECT OR AMITOTIC DIVISION

us

sion of its total mass, but not of its individual elements or chromatingranules (Fig. 56).

Before the discovery of mitosis, nuclear division was generally assumed to take place in accordance with Remak's scheme (p. 63). The rapid extension of our knowledge of mitotic division between the years 1875 and 1885 showed, however, that such a mode of division was, to say the least, of rare occurrence, and led to doubts as to whether it ever actually took place as a normal process. As soon, however, as attention was especially directed to the subject, many cases of amitotic division were accurately determined, though

olicaHy dividing

follicular epithelium of the

very few of them conformed precisely to Remak's scheme. One such case is that described by Carnoy in the follicle-cells of the egg in the mole-cricket, where division begins in the fission of the nucleolus, followed by that of the nucleus. Similar cases have been since described, by Hoyer ('90) in the intestinal epithelium of the nematode Rhabdonema, by Korschelt in the intestine of the annelid Ophryotrocka, and in a few other cases. In many cases, however, no preliminary fission of the nucleolus occurs ; and Remak's scheme must, therefore, be regarded as one of the rarest forms of cell-division(l).

2. Centrosome and Attraction-sphere in Amitosis

The behaviour of the centrosome in amitosis forms an interesting question on account of its bearing on the mechanics of cell-division. Flemming observed ('91) that the nucleus of leucocytes might in some cases divide directly without

1 1 6 CELL-DIVISION

the formation of an amphiaster, the attraction-sphere remaining undivided meanwhile. Heidenhain showed in the following year, however, that in some cases leucocytes containing two nuclei (doubtless formed by amitotic division) might also contain two asters connected by a spindle. Both Heidenhain and Flemming drew from this the conclusion that direct division of the nucleus is in this case independent of the centrosome, but that the latter might be concerned in the division of the cell-body, though no such process was observed. A little later, however, Meves published remarkable observations that seem to indicate a functional activity of the attraction-sphere during amitotic nuclear division in the " spermatogonia " of the salamander. 1 Krause and Flemming observed that in the autumn many of these cells show peculiarly lobed and irregular nuclei (the "polymorphic nuclei " of Bellonci). These were, and still are by some writers, regarded as degenerating nuclei. Meves, however, asserts — and the accuracy of his observations is in the main vouched for by Flemming — that in the ensuing spring these nuclei become uniformly rounded, and may then divide amitotically. In the autumn the attractionsphere is represented by a diffused and irregular granular mass, which more or less completely surrounds the nucleus. In the spring, as the nuclei become rounded, the granular substance draws together to form a definite rounded sphere, in which a distinct centrosome may sometimes be made out Division takes place in the following extraordinary manner: The nucleus assumes a dumb-bell shape, while the attraction-sphere becomes drawn out into a band which surrounds the central part of the nucleus, and finally forms a closed ring, encircling the nucleus. After this the nucleus divides into two, while the ring-shaped attraction -sphere ("archoplasm ") is again condensed into a sphere. The appearances suggest that the ringshaped sphere actually compresses the nucleus and cuts it through. In a later paper ('94) Meves shows that the diffused "archoplasm" of the autumn-stage arises by the breaking down of a definite spherical attraction-sphere, which is re-formed again in the spring in the manner described, and in this condition the cells may divide either mitottcally or amitotically. He adds the interesting observation, since confirmed by Rawitz ('94), that in the spermatocytes of the salamander the attraction-spheres of adjoining cells are often connected by intercellular bridges, but the meaning of this has not yet been determined.

It is certain that the remarkable transformation of the sphere into a ring during amitosis is not of universal, or even of general, occurrence, as shown by the later studies of Vom Rath ("95, 3). In leucocytes, for example, the sphere persists in its typical form, and contains a centrosome, during even* stage of the division ; but it is an interesting fact that during all these stages the sphere lies on the concave side of the nucleus in the bay which finally cuts through the entire nucleus. Again, in the liver-cells of the isopod Porcellio* the nucleus divides, not by constriction, as in the leucocyte, but by the appearance of a nuclear plate, in the formation of which the attraction sphere is apparently not concerned. 3 The relations of the centrosome and archoplasm in amitosis are. therefore, still in doubt ; but, on the whole, the evidence goes to show that they take no essential part in the process.

3. Biological Significance of Amitosis

A survey of the known cases of amitosis brings out the following significant facts. It is of extreme rarity, if indeed it ever occurs in embryonic cells or such as are in the course of rapid and continued

1 % QI. p. 62S.

2 Such a mode of amitotic division was tirst described by Sabatier in the Crustacea ('89), and a similar mode has been observed bv Carnov and Van iter Stricht.

DIRECT OR AMITOTIC DIVISION \\J

multiplication. It is frequent in pathological growths and in cells such as those of the vertebrate decidua, of the embryonic envelopes of insects, or the yolk-nuclei (periblast, etc.), which are on the way toward degeneration. In many cases, moreover, direct nuclear division is not followed by fission of the cell-body, so that multinuclear cells and polymorphic nuclei are thus often formed. These and many similar facts led Flemming in 1891 to express the opinion that so far as the higher plants and animals are concerned amitosis is " a process which does not lead to a new production and multiplication of cells, but wherever it occurs represents either a degeneration or an aberration, or perhaps in many cases (as in the formation of multinucleated cells by fragmentation) is tributary to metabolism through the increase of nuclear surface." l In this direction Flemming sought an explanation of the fact that leucocytes may divide either mitotically or amitotically (/. Peremeschko, Lowit, Arnold, Flemming). In the normal lymph-glands, where new leucocytes are continually regenerated, mitosis is the prevalent mode. Elsewhere (wanderingcells) both processes occur. "Like the cells of other tissues the leucocytes find their normal physiological origin (Neubildung) in mitosis ; only those so produced have the power to live on and reproduce their kind through the same process/' l Those that divide amitotically are on the road to ruin. Amitosis in the higher forms is thus conceived as a purely secondary process, not a survival of a primitive process of direct division from the Protozoa, as Strasburger ('82) and Waldeyer ('88) had conceived it.

This hypothesis has been carried still further by Ziegler and Vom Rath C91). In a paper on the origin of the blood in fishes, Ziegler ('87) showed that the periblast-nuclei in the egg of fishes divide amitotically, and he was thus led like Flemming to the view that amitosis is connected with a high specialization of the cell and may be a forerunner of degeneration. In a second paper C91), published shortly after Flemming's, he points out the fact that amitotically dividing nuclei are usually of large size and that the cells are in many cases distinguished by a specially intense secretory or assimilative activity. Thus, Riige ('90) showed that the absorption of degenerate eggs in the Amphibia is effected by means of leucocytes which creep into the egg-substance. The nuclei of these cells become enlarged, divide amitotically, and then frequently degenerate. Other observers ( Korschelt, Carnoy) have noted the large size and amitotic division of the nuclei in the ovarian follicle-cells and nutritive cells surrounding the ovum in insects and Crustacea. Chun found in the entodermic cells of the radial canals of siphonophores huge cells filled with nests of nuclei amitotically produced, and suggested ('90) that the multiplication of

1 '91. 2, p. 291.

1 1 8 CELL-DIVISION

nuclei was for the purpose of increasing the nuclear surface as an aid to metabolic interchanges between nucleus and cytoplasm. Amitotic division leading to the formation of multinuclear cells is especially common in gland-cells. Thus, Klein has described such divisions in the mucous skin-glands of Amphibia, and more recently Vom Rath has carefully described it in the huge gland-cells (probably salivary) of the isopod Anilocra ('95). Many other cases are known. Dogiel ('90) has observed exceedingly significant facts in this field that place the relations between mitosis and amitosis in a clear light. It is a wellknown fact that in stratified epithelium new cells are continually formed in the deeper layers to replace those cast off from the superficial layers. Dogiel finds in the lining of the bladder of the mouse that the nuclei of the superficial cells, which secrete the mucus covering the surface, regularly divide amitotically, giving rise to huge multinuclear cells, which finally degenerate and are cast off. The new cells that take their place are formed in the deeper layers by mitosis alone. Especially significant, again, is the case of the ciliate Infusoria, which possess two kinds of nuclei in the same cell, a macronucleus and a micronucleus. The former is known to be intimately concerned with the processes of metabolism {cf. p. 342). During conjugation the macronucleus degenerates and disappears and a new one is formed from the micronucleus or one of its descendants. The macronucleus is therefore essentially metabolic, the micronucleus generative in function. In view of this contrast it is a significant fact that while both nuclei divide during the ordinary process of fission the mitotic phenomena are as a rule less clearly marked in the macronucleus than in the micronucleus, and in some cases the former appears to divide directly while the latter always goes through a process of mitosis. These conclusions received a very important support in the work of Vom Rath on amitosis in the testis ('93). On the basis of a comparative study of amitosis in the testis-cells of vertebrates, mollusks, and arthropods he concludes that amitosis never occurs in the sperm-producing cells (spermatogonia, etc.), but only in the supporting cells (Randzellen, Stutzzellen). The former multiply through mitosis alone. The two kinds of cells have, it is true, a common origin in cells which divide mitotically. When, however, they have once become differentiated, they remain absolutely distinct ; amitosis never takes place in the series which finally results in the formation of spermatozoa, and the amitotically dividing " supporting-cells " sooner or later perish. Vom Rath thus reached the remarkable conclusion that " when once a cell has undergone amitotic division it has received its deathwarrant ; it may indeed continue for a time to divide by amitosis, but inevitably perishes in the end." l

1 '91. P- 33*.

SUMMAR Y AND CONCL USION 1 1 9

There is, however, strong evidence that this conclusion is too ♦extreme. Meves ('94) has given good reason for the conclusion that in the salamander the nuclei of the sperm-producing cells (spermatogonia) may divide by amitosis yet afterward undergo normal mitotic division, and Preusse ('95 ) has reached a similar result in the case of insect-ovaries. Perhaps the most convincing evidence in this direction is afforded by Pfeffer's ('99) recent experiments on Spirogyra. If this plant be placed in water containing 0.5 to 1.0% of ether, active growth and division continue, but only by amitosis. If, however, the same individuals be replaced in water, mitotic division is resumed and entirely normal growth continues. This seems to show conclusively that amitosis, in lower forms of life at least, does not necessarily mean the approach of degeneration, but is a result of special conditions. Nevertheless, there can be no doubt that Flemming's hypothesis in a general way represents the truth, and that in the vast majority of cases amitosis is a secondary process which does not fall in the generative series of cell-divisions.

F. Summary and Conclusion

All cells arise by division from preexisting cells, cell-body from cell-body, nucleus from nucleus, plastids (when these bodies are present) from plastids, and in some cases centrosomes from centrosomes. The law of genetic continuity thus applies not merely to the cell considered as a whole, but also to some of its structural constituents.

In mitosis, the usual and typical mode of division, the nucleus undergoes a complicated transformation, and, together with some of the cytoplasmic material, gives rise to the mitotic figure. Of this, the most characteristic features are the chromatic figure, consisting of chromosomes derived from the chromatin, and the achromatic figure, derived from the cytoplasm, the nucleus, or from both, and consisting of a spindle, at each pole of which, as a rule, is a centrosome and aster. There is, however, strong evidence that both these latter structures may in some cases be wanting, and the spindle is therefore probably to be regarded as the most essential element.

The chromosomes, always of the same number in a given species (with only apparent exceptions), arise by the transformation of the chromatin-reticulum into a thread which breaks into segments and splits lengthwise throughout its whole extent. The two halves are thereupon transported in opposite directions along the spindle to its respective poles and there enter into the formation of the two corresponding daughter-nuclei. The spireme-thread, and hence the chromosome, arises from a single series of chromatin-granules or chromomeres which, by their fission, cause the splitting of the thread.

1 20 CELI^DIVJSION

Every individual chromatin-granule therefore contributes its quota to each of the daughter-nuclei, but it is uncertain whether they are persistent bodies or only temporary structures like the chromosomes themselves.

The spindle may arise from the achromatic substance of the nucleus, from the cytoplasmic substance, or from both. When centrosomes are present it is they, as a rule, that lead the way in division. About the daughter-centrosomes as foci are formed the asters and between them stretches the spindle, forming an amphiaster which is the most highly developed form of the achromatic figure. When centrosomes are absent, as now appears to be the case in the higher plants, the spindle is formed from fibrous protoplasmic elements that gradually group themselves into a spindle.

The mechanism of mitosis is imperfectly understood. Experimental studies give ground for the conclusion that the changes undergone by the chromatic and the achromatic figures respectively are parallel but in a measure independent processes, which are however so correlated that both must cooperate for complete cell-division. Thus there is strong evidence that the fission of the chromatin-granules, and the splitting of the thread, is not caused by division of the centrosome or the formation of the spindle, but only accompanies it as a parallel phenomenon. The divergence of the daughter-chromosomes, on the other hand, is in some manner determined by the spindle-fibres. There are cogent reasons for the view that some of these fibres are contractile elements which, like muscle-fibres, drag the daughter-chromosomes asunder ; while other spindle-fibres act as supporting and guiding elements, and probably by their elongation push the spindle-poles apart. The adequacy of this explanation is, however, doubtful, and it is not improbable that the centrosome or spindle-poles are centres of chemical or other physiological activities that play an essential part in the process and are correlated with those taking place in the chromatin. The functions of the astral rays are likewise still involved in doubt, the rays being regarded by some investigators as contractile elements like muscle-fibres, by others as rigid supporting fibres, or even as actively pushing elements like those of the central spindle. It is generally believed further that they play a definite part in division of the cell-body — a conclusion supported by the fact that the size of the aster is directly related to that of the resulting cell. On the other hand division of the cell-body may apparently occur in the absence of asters (as in amitosis, or among the Infusoria).

These facts show that mitosis is due to the coordinate play of an extremely complex system of forces which are as yet scarcely comprehended. Its general significance is, however, obvious. The effect of mitosis is to produce a meristic division, as opposed to a mere massdivision, of the chromatin of the mother-cell, and its equal distribution to the nuclei of the daughter-cells. To this result all the operations of mitosis are tributary ; and it is a significant fact that this process is characteristic of all embryonic and actively growing cells, while mass-division, as shown in amitosis, is equally characteristic of highly specialized or degenerating cells in which development is approaching its end.

Literature

Aaerbach, L. — Organologische Studien. Breslau, 1874.

Van Beneden, E. — Recherches sur la maturation de 1'oeuf, la fecondation et la

division cellulaire : Arch, de Bw/., IV. 1883. Van Beneden and Neyt. — Nouvelles recherches sur la fe*condation et la division

mitosque chez TAscaride me'galocephale : Bull. Acad. roy. de Belgique, III. 14,

No. 8. 1887. B0Yeri,Th. — Zellenstudien: I. Jena. Zeitschr., XXI. 1887; II. Ibid. XXII. 1888;

III. Ibid. XXIV. 1890. Drnner, L. — Studien uber den Mechanismus der Zelltheilung. Jena. Zeitschr.,

XXIX., II. 1894. Brlanger, R. von. — Die neuesten Ansichten Uber die Zelltheilung und ihre Mechanik :

Zobl. Centralb., III. 2. 1896. Id. — Uber die Befruchtung und erste Teilung des Ascariseies : Arch. mik. Anat.,

XLIX. 1897. Flemming, W., '92. — Entwicklung und Stand der Kenntnisse uber Amitose :

Aferkel und Bonnets Ergebnisse, II. 1 892. Id. — Zelle. (See Introductory list. Also general list.) Pol, H. — (See List IV.)

Heidenhain, H. — Cytomechanische Studien: Arch.f. Entwickmech., I. 4. 1895. Id. — Neue Erlauterungen zum Spannungsgesetz der centrirten Systeme : Morph.

Arb., VII. 1897. Hermann, F. — Beitrag zur Lehre von der Entstehung der karyokinetischen Spindel :

Arch. mik. Anat., XXXVII. 1891. Hertwig, R. — Uber Centrosoma und Centralspindel : Sits.-Berg. Ges. Morph. und

Phys. Munchen, 1895, Heft I. Kostanecki and Siedlecki. — Uber das Verhalten der Centrosomen zum Protoplasma :

Arch. mik. Anat., XLVIII. 1896. Hark, E. L. — (See List IV.)

Meres, Fr. — Zell teilung : Aferkel und Bonnets Ergebnisse, VI. 1897. Reinke, F. — Zellstudien : I. Arch. mik. Anat., XL1II. 1894 ; II. Ibid. XLIV. 1894. Strasburger, E. — Karyokinetische Proble me : Jahrb. f. Wiss. Botan., XX VIII. 1 895 . Strasbnrger, Osterhout, Mottier, and Others. — Cytologische Studien aus dem Bonner

Institut: Jahrb. wiss. Bot., XXX. 1897. Waldeyer. W. — Ober Karyokinese und ihre Beziehungen zu den Befruchtungsvor gangen: Arch. mik. Anat., XXXII. 1888. Q.J.M.S., XXX. 1889-90.

1 See also Literature, IV., p. 231.

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Cell development and inheritance (1900): Introduction | List of Figures | Chapter I General Sketch of the Cell | Chapter II Cell-division | Chapter III The Germ-cells | Chapter IV Fertilization of the Ovum | Chapter V Reduction of the Chromosomes, Oogenesis and Spermatogenesis | Chapter VI Some Problems of Cell-organization | Chapter VII Some Aspects of Cell-chemistry and Cell-physiology | Chapter VIII Cell-division and Development | Chapter IX Theories of Inheritance and Development | Glossary

Wilson EB. The Cell in Development and Inheritance. Second edition (1900) New York, 1900.

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