General Physiology: An Outline of the Science of Life

(74) regarding "organ-forming germ-regions." Roux ('95) and Weismann ('92, 2) are the latest defenders of this view, which affirms that different areas are present in the egg, which in continued division are transferred to different cells, and each one of which affords the material for the development of very definite tissues and organs. In other words, the rudiments of the different parts of the body of the adult organism exist, separate from one another, in different parts of the egg. The chief supports of this view are the results of the experiments that Roux has performed upon the frog's egg, in which he observed that after artificial destruction of one of the first two cleavage-cells, from the other at first only halfembryos developed, i.e., embryos in which one half of the body was wholly wanting, this half being capable of development later by " post-generation," as Roux expresses it. In contrast to this is the view of another class of experimenters, especially Pfliiger ('83, '84), O. Hertwig ('92, '93), and Driesch ('92, 93), who deny the existence of organ-forming germ-regions, and believe that the differentiation of the homogenous egg-cell into the various kinds of cells is brought about solely by the influence of external factors upon the various substances contained in the egg. Thus, in eggs like that of the frog, which contain substances of different specific gravities — in the frog's egg there is a white substance that is richer in yolk and a pigrnented substance that is richer in protoplasm — gravity acts in such a manner as to lead to polar differentiation, so that the heavier substance comes to lie below, the lighter above, and, when the egg is turned, the substances move correspondingly.

At the first division of the frog's egg, the polardifferentiated cell becomes divided by a vertical groove into two equal halves, each of which contains white substance and black substance equally. But when Pfliiger put frogs' eggs into an abnormal position and fixed them there, the eggs in cleavage frequently segmented into two unequal parts, one of which contained pre-eminently the light, the other the dark mass; nevertheless, normal larvas developed. The contents of the egg can, therefore, not be so differentiated beforehand, that from each part certain organs only can develop ; on the contrary, the different areas in the egg must be wholly similar as regards development. The fact observed by Hertwig speaks a priori in favour of this view, namely, that even single small pieces of the ovum, if they are capable of life and are fertilized, develop into whole individuals. Moreover, in opposition to the observations of Roux, Driesch discovered in the eggs of sea-urchins that from each of the first two, four or eight cleavage-cells, when he had isolated them from one another by shaking, complete individuals always developed, which were distinguished from normal ones by their small size only; this fact has since been confirmed by numerous observers upon various species of animals, among others by O. Hertwig upon

Roux's own object, the frog's egg. That definite parts or organs of the embryo do not develop from single cleavage-cells arising by the division of the ovum, Driesch and Hertwig were able to show by continuing in a different way the experiment performed by Pfliiger. They, like Pfluger, clamped frogs' eggs between two glass plates in such a way that the cells arising in division were able to arrange themselves in one plane only instead of in a spherical mass, so that they were abnormally placed with reference to one another. Notwithstanding this, completely normal embryos developed from them. From this fact the conclusion must necessarily be drawn that the individual cells arising in cleavage do not represent definite rudiments of organs, and that no organforming germ-regions can be present in the ovum.

To summarise briefly the contrasts that are expressed in these two wholly opposed theories, the idea of Weismann and Roux is essentially the old, more or less clearly expressed doctrine of preformation of the time of Haller, in somewhat modern garb, while the view of Pfluger, Hertwig, and Driesch represents the standpoint of the doctrine of epigenesis of Caspar Friedrich Wolff, which Haeckel, more than all others, has constantly maintained with great persistence in the later embryology. As thus contrasted, the two doctrines are incompatible with one another. There can be no doubt that the facts are adverse to such a very minute preformation of organ-forming germ -regions in the egg, as especially Weismann and De Vries ('89 ) have assumed. The two facts, first, that small pieces of an egg-cell and isolated halves and quarters, formed in cleavage, produce a normal, complete organism of a correspondingly small size; and, secondly, that, when the cleavage-cells are displaced, animals develop with their organs in a completely normal position, — these facts prove that the different parts of the egg-cell must be of absolutely equal value in the production of the cells, tissues and organs proceeding from them, and that we are not justified in speaking of a localized preformation of definite rudiments in the egg ; it makes no difference whether we assume 10, 100, or 1000 rudiments, as Roux does, or several billions.1 While, further, the

1 Since Roux has protested against being reckoned among the preformationists, where he has been placed not only by myself, but by many (I think most) investigators belonging to his special field, in order to do him no injustice I ought not to leave his protest unmentioned. But, at the same time, I must say that upon the basis of his own work I have not been able to alter my foregoing judgment and to accept his explanation. Since, as Roux himself acknowledges, " there are at present few authors who know my [his] views clearly," in order to give the reader the opportunity of an independent judgment concerning them, I will quote his own words, in which his standpoint is stated. In Virchow's Archiv, vol. cxiv, 1888, as well as in the Verhandlungen der anntomischen Gesellschaft auf der sechsten Versamrrdung in Wien, 1892, Roux summarises the results of his experiments and speculations, and explains that "cleavage divides quantitatively the part of the germinal material that accomplishes the direct development of the individual, especially the nuclear material, and, by means of the arrangement thus made of the various separate materials, determines at once the position of the later

theory of Weismann and Roux seeks in the egg the causes of the origin of differentiated daughter-cells from the cleavage, the idea of Pfluger and Hertwig finds the causes pre-eminently in factors acting from outside upon the cells. While, according to the one view, cells divide into unlike products from internal causes, according to the other, external factors essentially produce the unlikeness in continued division. Doubtless both views are correct in this respect, and here is a point where a reconciliation is possible.

From the above-developed idea of the mechanism of the development and reproduction of the individual cell upon the basis of the metabolic changes arising because of growth, it is evident that internal and external causes of form-changes cannot be separated from one another. The whole process of producing and changing form is a compromise, a correlation of factors lying within and without the cell. Because the cell as a result of the characteristic quality of its living substance has the property of taking in substances from the outside and of giving out substances to the outside, the elementary vital process, the metabolism, represents a compromise between the internal and the external factors, without which the life of the cell is impossible. But, since with otherwise uniform external conditions the cell grows as a result of the composition of its living substance, the relations with the external factors become changed, so that the latter now act in a manner different from before. Thus, at every moment of time a different compromise is effected between the cell and the medium, between the internal and the external factors, the expression of which is the change, the development, and finally, the reproduction of the cell. Hence it is clear that the change of the cell, or the variation of the products of its division, is not dependent solely upon its internal character, or the external factors; development and reproduction are an expression of changes in the metabolic relations between cell and medium, conditioned by growth.

The fundamental distinction between a single free-living cell and an egg-cell developing into a cell-community consists wholly in the fact that the daughter-cells arising by the division of the unicellular organism become separated from one another immediately after the division, while in the development of the egg-cell the daughter-cells that arise in segmentation remain in connection with one another. In the unicellular organism, therefore, the correlation between cell and medium always passes through the same short cycle of changes ; in the division of the egg-cell, however, this correlation changes in an entirely new way with each of the almost innumerable divisions. Hence it happens that,

differentiated organs of the embryo." " His's principle of organ-forming germregions is here applicable ; it has been here demonstrated that gastrulation is a mosaic work." From this the reader who is familiar with the ideas of preformation and epigenesis will easily be able to decide for himself in how far Roux is a preformationist and in how far not. while the unicellular organism needs to undergo either a scarcely perceptible development or only a short cycle of changes, the egg-cell must pass through an exceedingly long series of formchanges up to the development of the multicellular organism. As growth in the multicellular organism gradually ceases, the cells undergo constantly fewer form -changes, and many tissue-cells, e.g., the ganglion-cells, many of which do not grow at all in the adult organism, remain apparently wholly unchanged, neither dividing nor differentiating further. In reality, however, as has been seen elsewhere,1 general development never ceases wholly until the time of death, but the later changes occur so very slowly and are relatively so slight, that they are perceived only within long intervals of time. In this apparently stationary condition the tissue-cells are similar to those unicellular organisms that have no perceptible development : in both, the correlation between the internal and the external factors changes imperceptibly, in the tissue-cells proceeding slowly, and in the unicellular organisms being slight and constantly returning to its starting-point. In neither are essential changes of form observed.

From these considerations it appears how incorrect it is, from the fact that the small egg is differentiated into a cell-structure of astonishing complexity, to deduce the idea that the living substance of the former in comparison with that of every other cell, either every unicellular organism or every tissue-cell, must be distinguished by an inconceivably delicate and complex structure. This idea, which is met with very frequently, is only an unrecognised relic of the doctrine of preformation and, as has been seen, is both unnecessary and unjustified ; for the development and differentiation of the cell-community from the egg are based solely upon the correlation between the living substance of the cells and the external factors, which is continually changing with the continual growth and division of the cells. Growth is the cause of all development, both of the individual cell and of the whole cell-community, and this fundamental fact can scarcely be expressed better than in the words of the old master of embryology, Karl Ernst von Baer ('28), who thus stated the most general result of his studies upon the embryology of animals : " The developmental history of the individual is the history of the growing individuality in all its relations"

A summary of the above considerations regarding the mechanics of development leads to the following view. The developing cell, like every cell, represents a drop of living substance, which is characterised by a very definite metabolism. This metabolism is the expression of the correlation existing between the medium with its individual factors upon the one side, and the cell with its manifold internal differentiations upon the other. By the growth

of the cell, the correlation between it and the medium necessarily changes, because the relation of the surface and the mass of the living substance is gradually altered. As a result of this there is also a change in the metabolism. In other words, there is in the growing cell a continual succession of different metabolic conditions forming a very gradual transition, every succeeding condition resulting necessarily from the preceding one. Since here, as everywhere else in the physical world, form is among other things a function of matter, it is thus made clear that with a change of metabolism the form of the cell under certain circumstances will also change, and thus a continual succession of different form-conditions goes hand in hand with the succession of different metabolic conditions, in other words, there is a development. It follows from this that the development of the cell is a real epigenesis in the sense of Caspar Friedrich Wolff, i.e., a succession, of constantly new forms, and not a more distinct appearance of already preformed, but hitherto imperceptible, structural differentiations of the living substance. According to the extent of the changes in the correlation between medium and cell the change of form will be expressed in one case less, in another case more strongly ; it will be most pronounced where, as in the development of the cell-community of plants aitd animals from the egg, the cells dividing as a result of growth remain in connection with one another and act upon one another, in other words, where the relations between cell and medium change rapidly and continually.

Special importance has been attached elsewhere to the fact that living substance possesses the essential properties of a liquid. In the production of form another factor, namely, structure, plays an important role. Since at first sight it might appear as if structure and a liquid state are mutually exclusive, it will be advantageous to examine briefly this question.1 If by structure there is understood a definite mutual relation of the smallest particles of which a substance is composed, the fundamental requisites of the inauguration of structure are the mutual attraction and grouping of definite particles. We can speak of structure only where certain particles attract one another and become grouped. This requirement is fulfilled not merely in solid bodies, but in a certain measure in liquids, for in liquids also, as cohesion shows, the individual parts attract one another. The difference in the structure of liquids and solids is in reality a gradual one, depending wholly upon the degree of consistency ; imperceptible transitions exist between the two states. The difference between them consists essentially in the fact that

the more solid a body is, the less its molecules are in motion. Motion is least in the hardest bodies, and greatest in the thinnest liquids ; in the latter the intensity of the motion is almost equal to that in gases, which, as is well known, is so great that the molecules repel one another. Between the two limits of very thin liquids and very hard bodies the solidity of the structure varies, becoming greater the harder the body is. There is, in fact, a certain molecular structure in every simple solution. If, e.g., a crystal of pure salt be put into a vessel containing distilled water, after some time it dissolves, and the molecules of the salt become scattered by diffusion uniformly throughout the liquid, so that in every volume of the latter, even the most minute, the same percentage of salt molecules is contained. In other words, an attraction between the molecules of the salt and those of the liquid takes place, and about every one of the former is grouped a certain number of the latter. The only difference as regards this grouping or structure between the mobile liquid and the solid body is that, during the active molecular motion in the liquid, molecules are continually being drawn away from their groups and replaced by others, so that the structure is continually being destroyed and reformed ; while in the solid body, where the motion of the molecules is slight, the structure can exist for a long time undisturbed. This continual reformation of structure in the liquid is, however, of fundamental importance to living substance, for only where there is a possibility of continual outgo and income of molecules can a metabolism exist, and without this living substance is inconceivable.

But this continual change of molecules does not hinder the continual appearance of differentiations of form in certain places resulting from molecular and atomic groupings in the living substance. Just as a stream of water or a gas flame can maintain a very definite form, although at no two successive moments do the same molecules produce that form, so living substance, in spite of its liquid nature, can show certain continual differentiations of form, which exist so long as the causes for the definite grouping of the molecules and atoms remain the same.

This consideration is of great importance, for it enables us to understand the general phenomena of the construction of form in living substance. The apparent paradox that living substance, although its components are undergoing continual change, can possess in many cases a constant and often extraordinarily complex form, is at once explained. Let us imagine a cell that possesses various kinds of differentiations, for example, the flagellate infusorian Poteriodendron^hich besides its nucleus is provided with a flagellum and a contractile myoid-fibre (Fig. 263). In each of its individual differentiations the particles are arranged in a specific manner, in the nucleus differing from that upon the surface of the protoplasm, in the flagellum differing from that in the myoid-fibre. Never-

theless, from all these individual differentiations atoms and groups of atoms pass out continually in definite directions, and into them new atoms and molecules enter continually, so that the structure is continually being destroyed and rebuilt. There is, therefore, a continual stream of matter which ramifies into the various differentiations in an extremely complicated way and possesses a very different composition in its different parts. This stream of matter is the expression of the complex metabolic relations between the individual parts of the cell-body, and it is the direct condition of the very definite and peculiar form of the cell in question. The structure is able constantly to re-establish and maintain itself, only when certain atoms are at the necessary place at the right time. If the stream of matter ceases, the molecules disintegrate, and the definite grouping is dissolved. So long, however, as the stream of

matter is uninterrupted, the individual molecules and atoms take up by attraction the necessary particles, and the structure continues to exist. If the stream of matter changes in the direction and composition of its particles, the form of the cell and its differentiations must change also, and there is a development. We have already found the comparison of vital phenomena with a flame very pertinent in many respects. This simile is also adapted to make clear in an especially striking manner, the relation between form-construction and metabolism. The butterfly figure of a gas-flame has a very characteristic differentiation of form. At the bottom immediately above the slit in the burner, there is complete darkness; above it there is a blue zone, only

feebly luminous ; and above that upon each side the bright luminous surface is extended out on both sides like the wings of a butterfly. This peculiar form with its characteristic differentiations, which continues to exist so long as the position of the gas-cock and the surrounding conditions are not changed, depends solely upon the fact that in the individual parts of the flame, the grouping of the molecules of illuminating gas and oxygen is very definite, although the molecules themselves change at every interval. At the bottom of the flame the molecules of illuminating gas are pressed together so closely that the oxygen necessary for their combustion cannot come in between them, and as a result of this there is here complete darkness. In the bluish zone some molecules of oxygen are combined with those of illuminating gas, and the result is a feeble light. In the large

FIG. 263. — Poteriodendron. A single individual of a colony. The cell-body, fastened upon a myoid-fibre, sits in a bellshaped cup and contracts its flagellum. flat flame, however, the molecules of illuminating gas are in such a numerical relation to those of the oxygen of the air that active combustion takes place. The change of the substance of the flame through the incoming gas and the surrounding air is, however, so regulated, that at the same place the same kinds of molecules constantly come together in the same number. As a result, the same form of flame with its differentiations is maintained continually. But if the stream of matter be altered by letting less gas pass out, the form of the flame also changes, because now the mutual position of the molecules of illuminating

FIG 264 — Stentor Rceselii. A, Cut across at*. B and C, The two pieces have become regenerated into complete Stentors. The clear extended mass in the interior is the nucleus. gas and of oxygen is changed. It is thus seen that such a flame, even in its details, presents exactly the same conditions that we have found to be important in the construction of the cell-form. Another interesting group of phenomena of form-construction is at once clear from this point of view, namely, the phenomena of regeneration. If a cell — best an infusorian cell that is provided with very characteristic differentiations of its surface, such as the delicate Stentor Rceselii — be cut into two pieces, so that each contains a part of the nucleus and hence possesses the value of a cell, in a short time, as has been seen elsewhere,1 each of the two

pieces regenerates the parts lacking in it. The wounds close, and the lower part of the cell at once arranges its substance so that a new peristome appears with the characteristic spiral of cilia and a mouth-opening, while the upper part becomes extended so that a new foot-piece is developed, with which the new Stentor attaches itself. Thus, in a short time by the deposition of particles FIG. 265.— Silicious spicules of sponges. /, Scheme of the production of a quadriradiate spicule between four vascular spaces. (After F. E. Schulze.) //, Various forms of silicious spicules.

from the interior of the body at the place of the wound, a complete Stentor is developed from each piece (Fig. 264). This fact of regeneration is now very easily understood. Since in the process of differentiating organised cell-forms every particle attracts and holds fast other specific particles and upon the withdrawal of the latter in metabolism, at once attracts and holds corresponding particles again, so in regeneration the particles existing at the wound, which are separated from their neighbours by the cut,

FIG. 2(56. — Scheme of the production of various skeletal forms by the excretion of skeletal substance into the walls of a vacuolar system. (After Dreyer.) must immediately attract and attach to themselves corresponding particles, if they are obtainable. Since, however, in such a division of the body metabolism experiences no fatal disturbance, the necessary particles are still, as formerly, brought in by the stream of matter, and can attach themselves to the others as the peculiar quality of each one demands. But if the metabolism has

been irremediably injured in the division, regeneration is no longer possible, because the necessary molecules and atoms are no longer produced and brought to the necessary place, Hence it is a universal and fundamental fact that non -nucleated pieces of a cell, i.e., pieces into which a fatal disturbance of metabolism has come, do not regenerate lost parts, although under certain circumstances they are able to live for days. One phenomenon, which some years ago appeared very puzzling, is approximately explained by the fact of structures in the cellprotoplasm. This is the formation of very regular silicious and calcareous skeletons, especially in the delicate Radiolaria, Foraminifera, and sponges. F. E. Schulze, ('87) called attention to the fact that the formation of triradiate and quadriradiate spicules

"Fio. 267.— Silicious skeletons of Radiolaria. (After Haeckel.) A, Dorataspis. £, Theoconus. (Fig. 265, //), which play so great a role in the silicious and calcareous skeletons of sponges, must take place when several spherical bodies are in contact with one another and a skeletogenous substance, such as calcium carbonate or silicic acid, is excreted into the fine spaces between them (Fig. 265, /). Lately Dreyer ('92) has extended the same idea to several special examples, and has shown how various and often extremely complex skeletal parts, especially in the Radiolaria, may easily be traced to the excretion of skeletogenous substance in the protoplasmic walls of a vacuolar layer (Fig. 266). Thus, according to the form of the vacuoles, the thickness of their walls, the place at which the secreted skeletal substance is deposited, and its quantity, a great variety of skeletal forms must result, and are actually realised in the richly varied forms of the radiolarian

skeleton. Thus the fact, which previously seemed so wonderful,, that the simple protoplasmic masses of rhizopod cells, while continually engaged in streaming and forming pseudopodia, are able to construct such astonishingly regular, complicated, and delicate skeletons, is at once understood from the fact that the protoplasm of these cells possesses in a certain body-zone a vacuolar or honeycomb structure. According to the form, the position and the extent of this vacuolar layer and its vacuoles, the effusions, which result from the excretion of skeletal substance between the vacuoles and form the skeleton, must vary extraordinarily (Fig. 267). Doubtless a role similar to this of the vacuolar structure of the protoplasm in the formation of many radiolarian skeletons is played by the structure of protoplasm, as well as by the form and the mutual pressure of the individual cells, in the formation of the skeleton in other organisms.

There finally remains a brief examination of the mechanics of hereditary transmission. The conditions of hereditary transmission are simplest in the lowest unicellular organisms ; for example, in Amoeba, apart from an increase in the size of the body, no distinct development is observable. Here, where the reproduction of the organism takes place simply by the division of the cell into two halves, the process of the transmission of all the characteristics of the mother-cell to the two daughter-cells is at once comprehensible. The living substance of the mothercell with its characteristic metabolism and its peculiar vital phenomena, continues to live independently in the daughter-cells ;. it is no wonder, therefore, that the separate pieces, when living under the same external conditions, possess exactly the same characteristics that the undivided cell possessed. But this-' simplest case of inheritance exhibits very clearly the essential factors of the phenomenon, just as all vital phenomena in general are to be seen and understood most clearly where they appear in* their simplest form, i.e., in the simplest cells. It is seen here that the transference of the characteristics of the ancestors to the descendants, takes place by the transference of substance which possesses the characteristics of the ancestors. In order that this substance may possess all the characteristics of the latter, it must be a complete cell with all the essential cellconstituents. The characteristic peculiarities of the mother-cell are the expression of its metabolism. If, therefore, the peculiarities of the mother-cell are to be transmitted to the daughtercells, its whole metabolism must be transmitted. But this is possible only when a certain quantity of all the essential constituents, i.e., of the protoplasm and nucleus of the mother-cell, passes over to-

the daughter-cell, for otherwise the metabolism of the latter would not be able to continue, and the cell would necessarily perish. In fact, it is seen not only in unicellular organisms, but everywhere in organic nature, that hereditary transmission takes place without exception by means of the transference of a complete cell with nucleus and protoplasm. If by hereditary transmission there is understood the transference of the peculiarities of the ancestors to the descendants, and if the peculiarities of an organism are merely the expression of its physical relations to the external world, the conclusion is absolutely unavoidable, that in hereditary transmission the living substance, with its peculiar metabolic relations, must be transferred. But this is only possible when all the essential parts of the metabolic chain are transferred, the protoplasm as well as the nuclear substance, in other words a whole cell.

However logical and obvious this simple conclusion is, and however completely it is confirmed by actual facts, it has really never been clearly drawn on the part of morphology, which thus far has been almost the sole department of biology to deal with the problem of heredity. As has been seen, among the morphologists, especially in connection with the views of O. Hertwig, Strasburger, Weismann, Boveri and others, the view has become very wide-spread, that the hereditary transmission of parental characteristics to the offspring is mediated by the transference of nuclear substance only, by means of egg- and sperm-cells, and the nuclein of the cell-nucleus has been specially termed the " hereditary substance." Only a few morphologists, like Rauber, Bergh and Haacke, have thus far expressed themselves against this view; but, as our previous presentation of the subject has shown,1 the grounds upon which it rests, are not able to withstand rigid criticism. For the physiologists, moreover, the view is conceived somewhat too morphologically, for it takes no account of the most essential factor of life, metabolism. The physiological mode of thought will hardly be able to adapt itself to the idea of a single hereditary substance, which is localised somewhere in the cell and transferred in reproduction. A substance that is to convey the characteristics of a cell to its descendants, before all else must be capable of life, i.e., must have a metabolism, and this is impossible without a connection with other substances necessary to cellmetabolism, i.e., without the integrity of all essential cell-constituents.