General Physiology: An Outline of the Science of Life

These very acute cases in infusorian cells, which interest every observer who sees them for the first time, are not well-adapted to a study of the more delicate protoplasmic processes, since, with the protoplasm already very granular, it is difficult to decide how far the granular material of the disintegrating masses consists of the preformed granules, and how far it is formed directly as such by the process of death. In this respect many Rhizopoda, such as the marine Hyalopus Dujardinii (Fig. 141, I), which are completely hyaline and absolutely free from granules, are extraordinarily suitable. If one of the smooth, clear pseudopodia be cut off by a knife under the microscope, it begins gradually to undergo granular disintegration from the place where it was cut (Fig. 141, // and III}. Then, either very soon or in the 1 Of. Verworn ('96, 1).

course of a few hours, the time varying according to the thickness and size of the piece, there is seen in place of the transparent protoplasmic mass, a collection of small granules and globules, between which lie isolated, larger, round droplets of hyaline protoplasm (Fig. 141, ///, D, &), and sometimes one or more faint, round, transparent bubbles (Fig. 141, ///, D, a\ all being loosely held together by a very delicate viscous mass. There is no doubt that this collection of granules and globules has arisen by the transformation of a mass of living substance that originally was wholly clear. In the study of this process with stronger magnifying powers an interesting fact appears. In the normal life of the cell a characteristic difference in the behaviour of the protoplasm of the pseudopodia of the Hyalopus during the phase of expansion and that of contraction may be recognised. While during the former, i.e., extension, the protoplasm appears completely homogeneous, during the latter it assumes the typical alveolar structure of Btitschli,1 and, if the contraction becomes very strong, as after stimulation, the protoplasm becomes uneven and knobbed upon the surface (Fig. 141, Fand VI). Exactly the same phenomenon appears in the development of granular disintegration. The protoplasm begins to assume the alveolar structure ; then the alveolar walls are gradually drawn together in uneven and lumpy masses ; they burst here and there, and become rounded off into small globules and droplets ; these are held together in a loose, granular heap merely by the viscous liquid of the burst vacuoles, which frequently flows together into a large, viscous drop (Fig. 141, IV). Thus, granular disintegration depends upon a supramaximal contraction.

This fact is of great interest, for, if the histolytic processes be followed comparatively in different cells, it is found to be a common law that all elements, the contractility of which can be clearly expressed, arid hence especially all naked protoplasmic masses, such as Rhizopoda, protoplasmic drops from tissue-cells, contractile fibrillse, muscle-fibres, etc., without exception die in the phase of contraction. Amoeba and leucocytes (Fig. 142) in necrobiosis, as in every contraction, assume a more or less completely spherical form (Fig. 142, B). Khizopoda possessing long

FIG. 140.— Granular disintegration. 7, Piece of a Spirostomumdisin from the wounded place. //, Pelomyxa disintegrating as the result of overstimulation upon one side. FIG. 141.— Hyalopus (Gromia) Dujardinii, granular disintegration. /, Whole individual ; numerous pseudopodia are extended from the egg-shaped, membranous shell ; at the left they are being drawn in. II and ///, 'Pseudopodia cut off; granular disintegration is developing; the globules and droplets of protoplasm are held together simply by a loose, viscous connectingmass ; between them lie scattered larger droplets of hyaline protoplasm (///, D, b), and viscous globules (///, D, a). IV, Pseudopodium which has been cut off at a, and from that point on is undergoing granular disintegration, highly magnified ; at a the granular disintegration is completed, the globules are separated ; at b disintegration is beginning, being ushered in by the formation of vacuoles ; between these two points occur all transition-stages. V, Opening of the shell of Hyalopus, with extended pseudopodia ; three have been stimulated at the place indicated by the arrow and have assumed an irregular contour. VI, Place of stimulation of a pseudopodium strongly magnified ; vacuoles are shown, the protoplasm of whose walls is irregularly contracted. Comparison with IV shows the agreement of the two.

pseudopodia draw in the latter and become lumpy, or the threadlike pseudopodia become varicose and disintegrate into small globules (Fig. 143). Bits of protoplasm from the interior of cells that have a constant form, e.g., plant-cells or tissue-cells, or even from free-living cells, always become rounded into spherical drops (Fig. 34, a, p. 94). Contractile fibrillse and muscle-fibres pass into rigor mortis, i.e., they contract for the last time (p. 133), and only when the rigor has passed away, when death is completed, do

they become again passively extended by the action of elastic elements. In brief, it is found everywhere that protoplasm whose contractility can in any way be expressed dies in the condition of contraction. It would be of value to determine, by a comparative investigation of necrobiotic phenomena, still other peculiarities common to histolytic processes. As Israel ('97, 1, 2) has rightly emphasised very recently in his researches upon the death of the cell, especially the kind of death and the duration of necrobiosis should be studied. Only through the comparative history of death can an understanding of necrobiotic phenomena, which is now largely wanting, be hoped for in time, and with it will come an advance in our knowledge of the vital process itself.

In contrast to simple histolytic phenomena, metamorphic processes are very clearly characterised by the fact that the metabolism of the cell does not merely come gradually to a standstill, but is previously turned into a perverse course, in such a way FIG. 143. — Necrobiosis of a non-nucleated protoplasmic mass of Orbitolites ; a, the protoplasmic mass has put out still normal pseudopodia ; b, the pseudopodia are becoming varicose and partly drawn in ; c, the protoplasm of the pseudopodia that are not drawn in has disintegrated into drops and globules.

that substances which in the normal cell are either not manufactured at all or appear only as intermediate stages, are produced in quantity as a result of the disturbed metabolism, and accumulate within the cell until the latter perishes. The forms of metamorphic processes that are most frequent, best known, and for physiology most important, are fatty degeneration, or fatmetamorphosis, mucous degeneration, amyloid degeneration, and calcification.

To consider first the phenomena of fat-metamorphosis, we must avoid confounding these with apparently similar processes, viz., the deposition of fat or fatty infiltration in fattening, obesity, etc. In these latter also there is a great accumulation of fat in the cells in question, but this fat has not arisen by a disturbance of the metabolism of the cells themselves ; on the contrary, it or its constituents has entered into the cells from the outside and has there been deposited. If much fat or materials from which fat can be formed be introduced into the body in the food, such fat becomes deposited by preference in certain parts within the cells, as in the cells of the subcutaneous connective tissue, and thus arises corpulency, the panniculus adiposus. Of course it is not impossible that in many cases of corpulency fat arising pathologically within the body also enters into the cells of the subcutaneous connective tissue and is there deposited. But even here there is always a fatty infiltration of the cells from the outside. In contrast to this, in fat-metamorphosis fat is formed within the cell itself at the expense of its living substance, and there accumulates until the cell is permeated with innumerable, large or small proplets and dies. Such fat-metamorphosis, which ends with the death and disintegration of the cell, occurs in certain places in the healthy body as a normal phenomenon ; thus, it is present in the cells of the lacteal glands at a time when they are secreting milk, when a woman is nursing. It is found that at this time in the lobes of the mammary glands microscopic fat-droplets appear in the protoplasm of the older cells (Fig. 144) ; these gradually increase in number, while the protoplasm gradually dies, and the cell finally becomes a round droplet, full of small milk-globules.

The dying protoplasm gradually disintegrates, the fat-globules become free, and the whole mass, i.e., the fat-globules in their liquid, becomes secreted as milk, milk being nothing more than an emulsion of the fat of butter in a solution of salts, proteids, sugar, etc. The younger gland-cells succeed the older, fattydegenerated and disintegrated cells, and pass through the same changes, and thus the process of milk-formation continues long and uninterruptedly. What occurs as a normal process in the cells of the lacteal glands occurs under pathological conditions in much greater extent in very various tissues, and leads almost always to incurable and fatal losses, since as a rule no reparation is made by the younger cells. " The production of milk," says Virchow (71), "in the brain instead of in the lacteal glands, constitutes a form of brain-softening. The same process that in one place affords the happiest and sweetest results, in another induces a painful and bitter wound." Such fatty degenerations appear especially in long-continuing, chronic

diseases, such as tuberculosis, heart-diseases, kidney-diseases, etc., in the kidney, heart, liver, blood-vessels, etc. (Fig. 145) ; and their causes always lie in disorders of nutrition, especially in a disturbance of the process of taking in oxygen through the blood. If, e.g., insufficient oxygen is carried to the cell, or if for other reasons its capacity of receiving oxygen is diminished, the fat, which probably in most cells appears in traces, is not burned, i.e., oxidised, as happens normally, but is stored up and accumulates in quantity. For this reason also in habitual drinkers and after phosphorus-poisoning, where as a result of the ingested alcohol or phosphorus the income of oxygen is diminished, a considerable fat-metamorphosis of the tissues, especially of the liver-cells, always takes place : and pathology recognises a whole series of cases where fat-metamorphosis can be traced to the same causes. It is highly probable that in all processes of fatmetamorphosis the fat originates from the decomposition of

FIG 144. — Fat-metamorphosis in the formation of milk in the lobes of the lacteal glands. (After Virchow.) FIG. 145. — Fat-metamorphosis of cardiac muscle-cells ; the granules in the cells consist of fat. (After Ziegler.) proteid. It is known that in the decomposition of the proteidmolecule both nitrogenous and non-nitrogenous complexes of atoms appear. Moreover, it has been seen,1 that fat can be formed from proteid ; and Leo ('85) has shown in the case of fat-metamorphosis after phosphorus-poisoning that the fat originates within the body. Since now, thirdly, it has been found that the excretion of urea is considerably increased after phosphorus-poisoning, the conclusion is justified that after phosphorus-poisoning proteid is decomposed in greater degree, and that the non-nitrogenous complex of atoms that arises during the decomposition is the fat deposited in the cells, while the nitrogenous portion is transformed into urea and given off to the outside. The origin of fat, at least in all fat-metamorphoses, must be regarded as wholly analogous.

The phenomena of mucous metamorphosis form a complete counterpart to those of fat-metamorphosis. As in the latter fat, so in the former mucus, is formed from, the living substance of the cell. In many cases the mucus that appears contains genuine mucin, in others it consists of mucinoid substances, but it is always a compound of proteid with some kind of carbohydrate.1 It is seen, therefore, that in mucous metamorphosis the origin of the mucus lies in the proteid. Mucous metamorphosis occurs also normally in the healthy body, especially in the cells of the mucous membranes of the respiratory and intestinal tracts, as well as of the urogenital system. In the formation of mucus by these mucous cells under normal conditions the whole cell never perishes, but a part only of its protoplasm is transformed into mucus. Almost always mucous cells are cylindrical cells ; their basal part contains the nucleus, and their upper end bounds the free surface of the mucous membrane. It is always the upper, free end of the cell-

FIG. 146.— Mucous cells. A, Three isolated mucous cells ; B, seven mucous cells united. The three at the left are full, the four at the right are empty. (After Schiefferdecker.) body, the protoplasm of which is transformed into mucus, swelling up into a transparent mass containing separate protoplasmic granules ; each mass, having no boundary, unites with the mucous masses of the neighbouring cells into a coherent mucous covering. The process is a continual one and is increased by certain external influences. The lower part of the cell-body containing the nucleus continues to live (Fig. 146), and constantly shoves upward new masses of mucus-forming substance, or mucigen, which become transformed into mucus in proportion as they move along. A complete transformation of the whole cell-body into mucus, accompanied by the death of the cell, occurs in many lower animals upon strong external stimulation ; the phenomena of this process are very remarkable. They are most remarkable in certain forms of sea-cucumbers, or holothurians, belonging to the Echinodermata,, plump animals, whose bodies are covered by a tough, brown, leather-like skin and resemble a cucumber. If Holothuria Poll, e.g.,.

which lives in the Mediterranean Sea, be brought into the air, the thick, hard skin begins gradually to liquefy into a viscous mucus, and after a few hours becomes completely softened. If small pinholes be bored through an excised piece of the skin this mucous liquefaction, as Semper ('68) showed, can be rapidly induced ; around each hole the cells begin at once to swell up and disintegrate, and the whole piece is changed finally into a thick liquid mass, which, when touched, can be drawn out into glistening threads. Many species of the holothurian genus Stichopus are said to transform their skin in a very short time into a thick mucus. It would be extremely interesting to investigate both chemically and microscopically this wholly unique case of a sudden mucous metamorphosis of so solid and tough a structure as is the holothurian skin. Krukenberg ('82) alone has made a partial study of it. The mucous metamorphosis of epithelium-cells, leucocytes, etc., which

occurs in the human body, especially in intense catarrhs, is well known : in these cases the cells in question die with a swelling and transformation of their living substance into mucus (Fig. 147). In the phenomena of amyloid metamorphosis, in contrast to the FIG. i47.-Mucous-metamorpho8ed ceils. /, processes hitherto considered, a Leucocytes ; ii, ciliated cells. (After substance is formed which, so far .substance, which glistens like wax or lard — which probably has conferred upon the disease in question the name of waxy or lardaceous degeneration — was first termed by Virchow amyloid substance, because with iodine staining it behaves like plant-amylum .and cellulose, under certain conditions being coloured blue by the iodine. Later it was recognised as a proteid-like body, for it contains nitrogen and gives certain proteid reactions ; hence, for the present it is classed in the comprehensive group of albuminoids. Its behaviour with the aniline colour, methyl violet, is very characteristic; with it it takes on a beautiful ruby-red colour, while healthy tissues are coloured blue. By its character as an .albuminoid, amyloid substance points plainly to its origin. It can be derived only from the proteids of the cell, and, although thus far nothing is known in detail concerning its origin, it may safely be considered as a metamorphosed proteid, which is excreted to the outside by the cell and stored up. It never seems to be stored within the cell itself, it is always found rather in the connective substances cementing the cells, especially in the walls of the small blood-vessels (Fig. 148). But, in proportion as the cells secrete it, they die, whether as the result of perverse metabolism, the

product of which is the amyloid substance, or because passively they are torn apart, pressed upon, asphyxiated and killed by the substance accumulating in masses. Amyloid metamorphosis is a secondary phenomenon of disease, appearing especially in connection with long-existing, chronic diseases, such as tuberculosis, longcontinued suppurations, etc., in the abdominal organs, especially the spleen, liver, kidneys and lymphatic glands. This indicates that nutritional disturbances of the tissues, very gradually developed and profound, cause the cells to be put into the condition where their proteid changes gradually into amyloid substance. Beyond what has been stated, amyloid metamorphosis remains still one of the most enigmatical among the metamorphic processes, although it is wide-spread and possesses great importance in pathology.

Finally, calcification is in a certain sense a counterpart to amyloid metamorphosis ; for, as in the latter amyloid substance, so in the former lime-salts are formed by the cells, and are either excreted to the outside or deposited in the dying cell-substance itself. The formation of bone in the normal body is analogous to the former. Large skeletal bones develop from a cartilaginous basis; the cartilage-cells excrete into the groundsubstance calcareous salts, especially calcareous phosphate and carbonate ; particles of these press gradually upon one another blend FlG.148._Amyloi(;7e^nerationof the

together, and thus form the SOlld bony capillaries of the liver ; the cells Substance, in Which the bone-Cells masses stored up between them. continue to live as so-called bonecorpuscles. This process, which appears absolutely necessary in the development of the vertebrate organism, occurs also under pathological conditions, especially when in old age or after certain diseases the cartilaginous discs in the joints ossify. In these cases the same phenomena are present, excepting that, as a rule, the cells by which the lime-salts are excreted later die. Besides this ossification, there occurs also under pathological conditions a true calcification of the cells themselves, in which the lime-salts become stored within the dying cell, until finally the living substance has wholly disappeared and its place is taken by a cemented calcareous mass. This happens in the walls of the arteries (Fig. 149, A), so that they become brittle and afford an opportunity for haemorrhages ; if the latter take place in the brain they constitute apoplexies, or so-called paralytic strokes. Further, in certain brain-diseases the ganglion-cells of the brain become calcified, and there are

found, e.g., in the brains of idiots, " petrified " ganglion-cells in the true sense of the word (Fig. 149, B). Besides the forms of metamorphic processes here presented, pathology recognises others, such as pigment-atrophy, hyaline degeneration, colloid metamorphosis, etc., at the basis of which there is always the same principle, namely, that the metabolism of the cells takes a perverse course, and forms substances that normally are formed either not at all or only in slight quantity, the final result being the death of the cell. But in the cases

FIG. 149.— Calcification of cells. A, Calcified cells in the wall of a blood-vessel. B, Calcified ganglion-cells from the brain of an idiot. (After Ziegler.) mentioned these substances and their genesis are much less known than in the metamorphic processes that have been discussed ; hence it does not appear necessary in this place to go into them more fully. In general, metamorphic processes, especially the genesis of the substances that arise in them and the disturbances of normal metabolism upon which they rest, need greater elucidation ; naturally this will come in proportion as the knowledge of metabolism in general becomes extended.

The causes that lead to death are as manifold as are its phenomena. We have already touched here and there upon some of the special causes, but it is impossible to treat these in every individual case. It is necessary, however, to go somewhat more fully into the general causes, because with them is joined the interesting question whether death is for all living organisms the dira necessitas that it is for mankind — in other words, whether there are organisms whose bodies are immortal.

If we start from the fact that life can only arise, and, moreover, must arise, as soon as a certain complex of conditions is fulfilled, the causes of death in their general form are evident ; for death must then take place so soon as the general conditions of life disappear. In accordance with the distinction between external and internal conditions of life, a distinction must also be made between external and internal causes of death, according as death is due to the removal of the external or of the internal vital conditions.

To examine, first, the external causes of death, the fact does not require detailed consideration that withdrawal of oxygen, water and food-stuffs, and, further, exceeding the necessary limits of temperature and pressure, lead to death, except in the case of organisms that under certain conditions pass into the state of apparent death. But these do not include all the external causes of death. All these conditions may be fulfilled and yet death be brought about by the action of external causes. Hence we must reckon among the external conditions of life the absence of such influences as are destructive to living substance, especially chemical and electrical influences.

The chemical influences that produce fatal effects are the poisons, and they are innumerable. All chemical substances that come into chemical relation with any of the essential constituents of living substance so that the mechanism of metabolism thereby suffers disturbance, cause death, sometimes after very brief, sometimes after long-continued action, death following very rapidly or constituting the end of long, necrobiotic changes. If, e.g., mineral acids or metallic salts act upon the living substance of a cell, the cell inevitably dies, because all proteid is precipitated or chemically combined by these substances so that metabolism must cease. Other substances that are poisonous to all living substance are the anaesthetics (chloroform, ether, alcohol), the vapours of which by continued action finally bring all vital phenomena to a standstill, whether in plants, animals or unicellular forms.1 To what change of the living substance this peculiar effect of anaesthetics is due is for the present wholly unknown ; and the same must be said of the great majority of poisons that act, some upon all living substance, and some upon certain cells only.

Like poisons, electricity in great intensity also acts harmfully to living substance by producing chemical changes in it. It is well known that chemical compounds in solution can be decomposed by a galvanic current. The compounds of living substance are likewise decomposed by strong galvanic currents, so that the living substance is killed and disintegrates. Thus, external causes of death are superficially clear and distinct, although the details of their actions are still largely unknown.

It is entirely different, however, with the internal causes of death. They are still very obscure. Many investigators believe that there are no internal causes of death that are based upon the properties of living substance, and they explain the appearance of death in old age in people who have never been ill by the gradual accumulation of small, imperceptible disturbances during the whole life. This is the most frequent explanation of the phenomenon. But it appears very insufficient. Johannes Mliller ('44) was not satisfied with it. . In the chapter upon the Mortality of Organic Bodies in his handbook, he says : " The question why organic bodies perish, and why organic force passes from the parts producing it into the young, living products of the organic body while the old parts die, is one of the most difficult in all general physiology. We are unable to answer this question, but can merely present the associated phenomena. It is insufficient to answer that inorganic influences gradually wear away life, for then the organic force would be obliged to begin its diminution at the beginning of the individual. Yet it is well known that at the time of puberty organic force is still so complete that it multiplies itself in the formation of germs. There must, hence, be a very different and deeper-lying cause that conditions the death of individuals, while assuring the transmission of organic force from one individual to another and in this way its immortality." Many such objections may be made. Were the view correct that death is brought about by the summation of the actions of external injuries, it would be expected that a man who lives very regularly and avoids as much as possible all harmful things would necessarily live much longer than one who lives irregularly and exposes himself to many hardships.

But, even if such a difference in the duration of life should occur, in many cases it would always be minute, for the oldest men have not lived much beyond 120 years, and not all of these persons have followed an especially regular course of life. Another circumstance comes in. In all men, without exception, whether during their life they have been exposed to the greatest or the least dangers, whether they have been often or never ill, or whether they have had this or that disease, the same phenomena of old age finally appear, consisting of atrophic processes of almost all organs. With special reference to the last circumstance Cohnheim (77-'80) rightly indicates another explanation in saying : " The constancy with which, no matter whether many or few, and especially what pathological phenomena have occurred in the life of an individual, a more or less pronounced atrophy appears in all organs of his

body in old age, in my opinion speaks very evidently for the idea that the conditions of senile atrophy, so to speak, are physiological." Minot ('90, '91) also adopts the same standpoint in his researches upon growth and the phenomena of old age. In fact, when man is considered not as something completed and unchangeable ; when, rather, his whole development is observed, and it is seen how, although living always under the same external conditions, he changes gradually after birth ; how even in childhood many organs, such as the thymus glands, normally atrophy, although not the slightest injuries from the outside act upon them ; and how later in all women even in the prime of life the sexual organs degenerate, etc., etc., — it can no longer be doubted that senile atrophy, which leads finally to death from the feebleness of old age, is simply the end of the long developmental series that man, like every animal, must pass through during his individual life. In reality there is no standstill in the life of the organism. As the adult organism develops gradually from the small egg-cell without the slightest change of its external vital conditions, as is the case in many animals living in the water, so it develops also, although at a different rate, gradually farther to a senile, and finally to a dead, organism. The egg-cell is the beginning, death in old age the natural end of an unbroken development, the cause of which lies in the peculiar composition of the living substance of the egg-cell. It would, hence, be more correct, in place of the current view that death is conditioned by the continual summation of external causes, to believe that the causes of so-called natural death exist in the living organism itself.

This view is justified at once if the history of death be considered, not simply with reference to mankind, but comparatively. The fact that the idea of death as an end-result of the developmental series appears so late in the history of science is closely associated with the prevalent view, that man, when grown, has finished his development and exists for years and decades in a stationary condition. This view is thoroughly false, and is due simply to the fact that man's development takes place much more slowly during his adult life than during his embryonic and youthful stages. In reality, development never ceases. Changes are seen clearly enough when the conditions of the adult are compared at long intervals of time. Although no new organs are formed in the meantime, the man of thirty years is a different being from the man of forty years, the man of forty from the man of fifty and sixty. A stationary condition is never present ; celldivision, upon which from the egg-cell on all development depends, takes place in adults and even in old men, although it becomes constantly slower and slower. What is difficult to recognise in man is shown at once by a glance at the relations that prevail