General Physiology: An Outline of the Science of Life

This important fact shows that in every form of living substance there must exist an extraordinary inclination toward a specific sequence of processes. This sequence is continually present in slight degree and finds its expression in the spontaneous vital phenomena; but the slightest stimuli of all kinds augment the discharge of the processes always in the same characteristic sequence for each specific variety of living substance, just as the nitroglycerine molecule can always be made explosively to disintegrate into the same constituents by mechanical, galvanic, or thermal influences.

The principle of the specific energy of sense-substances in animals provided with sense-organs, as discovered by Johannes Miiller,1 has, therefore, general application. All living substance possesses specific energy in Miiller's sense; within certain limits wholly different stimuli call forth in the same form of living substance the same phenomena, while, conversely, the same stimulus in different forms produces an effect wholly different and characteristic for every form.2

THE principle which the early civilised races with their mythical ideas poetically personified and represented as the cause of all life in the world, lies at the foundation of all vital phenomena according to the scientific knowledge of to-day. Among most people this principle has found expression in its original form in the allegory of the shifting contest between two hostile forces. These forces are life and death, which the ancient Egyptian personified in the forms of Horus and Typhon ; bloom and decay, which the German clothed in the legends of Baldur and Loki ; Ahriman struggling with Ormuzd, by which the Persian represented the interchange of the good and the evil in life ; God striving with the Devil, in which the Christian of the middle ages perceived the all-creating positive element in its opposition to the all-destroying, " ever-denying spirit " ; and, finally, they are recognised in the ever-alternating processes of becoming and passing away, of building up and breaking down, which control every living being and every vital event.

We have already recognised in the continual construction and destruction of living substance or, in brief, in unbroken metabolism, the real vital process, upon which the physical phenomena of life are based. We have become acquainted with these phenomena, have investigated the conditions under which they make their appearance, and have determined the changes that they experience under external influences. We must now endeavour to construct a bridge between the vital phenomena and the vital process, and, so far as the present condition of our knowledge allows, derive the former mechanically from the latter ; the investigation of the mechanism of life forms the nucleus of the science that deals with the physical phenomena of life.

As previous treatment of this subject has shown,1 our knowledge of the individual events in the metabolism of living substance is unfortunately thus far very meagre. Investigation of the mechanism of the physical phenomena of life is necessarily still far from complete, and progress can be made only slowly. An essential advance in this direction can be expected only from the detailed study of the processes in the cell, for the cell is the place where the vital process itself has its seat, and where all vital phenomena occur in their simplest form. Not until the physiology of organs, which is able to explain only the gross performances of the complex cell -community, develops into cell-physiology, can we hope essentially to enlarge our knowledge of the more delicate mechanism of life. Thus far only the first steps have been taken in this direction.

If, therefore, we attempt to form, so far as possible upon the basis of oar present knowledge, a picture of the vital process in living substance, it can be only a sketch in which the most general elements are indicated in gross outline. Notwithstanding this, some kind of a picture of the vital process is necessary for further systematic investigation. It has been seen in a previous chapter that, in general, the characteristic of living organisms in comparison with those dead or apparently dead consists in their metabolism, the expression of which constitutes the vital phenomena. It is necessary to go a step beyond this general fact.

It will be recalled that in the determination of the chemical compounds that constitute living substance investigation deals exclusively with the dead cell. For the completion of a picture of living substance two questions now remain to be answered, viz. : first, do the chemical compounds which are found in the dead cell occur as such in the living cell ? and, second, are there in the living cell still other compounds which are not present in the dead cell, which, in other words, are bound up inseparably with the life of the cell ?

The first of these questions is relatively easy of answer. A careful comparison especially of the solid bodies that may be found as reserve-substances for a time unchanged in the living cell, with the corresponding substances of the dead cell shows that there occur in the living cell proteids, carbohydrates and fats, in other words, the three chief groups of organic compounds, and likewise the products of their decomposition ; in brief, there occur all the essential substances that are found in the dead cell.

There remains only the question whether, in addition, compounds exist in the living substance which are destroyed at death and hence are not to be found in the dead cell. A comparison of the chemical behaviour of living and dead cell-substance forces us to assume the existence of such compounds. Physiological chemistry has shown that between the two kinds of substance very essential chemical differences exist, which prove that living substance experiences in dying pronounced chemical changes. A wide-spread difference between the two consists in their reaction. The reaction of living substance is almost without exception alkaline or neutral and with death changes usually to acid. Further, certain proteids that are in solution in living cell-substance, as, e.g., the myosin of muscle, experience very remarkable changes. In death they coagulate and pass into the solid state, which is very unfit for further chemical transformations. Physiological chemistry has shown similar changes in death in great number. All these facts prove that in the death of living cell-substance certain chemical compounds undergo transformations ; hence substances exist in it which are not to be found in dead cell-substance.

The fact that these chemical compounds are only present in the living substance and are decomposed with death necessitates the conclusion that the vital process is associated very closely with their existence. At all events an important property belonging to them is their great inclination toward transformation, which is for life an indispensable element. When it is borne in mind how few causes are able to produce death, how almost all chemical substances that are at all soluble in water enter into chemical relations with living cell-substance, while dead cell-substance usually behaves wholly indifferently to the same influences, it must be said that the substances that distinguish living from dead cell-substance possess a very loose constitution.

This conclusion is still more obvious when the fact of metabolism is considered. Metabolism shows that the living cell-substance is being continually broken down and reformed, this process being made possible by the continual giving-off and taking-in of material. In contrast to this, under favourable conditions, dead cell-substance is capable of preservation for an extraordinarily long time without its excreting more than a trace of the material that living cell-substance gives off continually. Hence, in contrast to the former, the latter must be distinguished by the possession of complexes of atoms that have very great tendency toward chemical transformations and are continually undergoing self-decomposition. The great lability of these complexes depends upon the fact that

their transformation can be considerably augmented by slight influences from the outside, as the excitation of metabolism by stimuli clearly shows. Since, however, metabolism constitutes the real vital process, it is seen at once that life depends directly upon the existence of these labile complexes of atoms. We are, therefore, justified in examining these significant substances more in detail and investigating their nature somewhat further.

In searching after them we can best start from the decompositionproducts excreted in metabolism. It is here found that among other substances, such as carbonic acid, water, and lactic acid, which contain only the elements carbon, hydrogen and oxygen, compounds also occur that contain nitrogen. The non-nitrogenous decomposition-products may possibly be derived from the decomposition of carbohydrates, fats, etc. ; but those containing nitrogen can come only from the transformation of proteids or their derivatives, for these are the sole bodies containing nitrogen that are present in all living substance. This important fact directs attention first to the proteids.

That this is the right path becomes at once clear when the facts concerning the proteids are recalled that have been mentioned in the course of the previous considerations. These facts show without doubt that the proteids stand at the centre of all organic life. It is an important fact that in all cases where large quantities of reserve-substances, such as fat, starch, and glycogen, are not accumulated in cells, the proteids constitute by far the largest part of the organic compounds of living substance. This proves that they must play a significant role in the life of the cell. The dominant position of the proteids among the chemical compounds of living substance, however, is at once attested by the fact that they are the only substances that can be found in every cell without exception. It is a further fact that of all the more important substances in the cell the proteids and their compounds present the highest complexity in chemical composition, they comprise the largest number and variety of atoms in their molecules. The known chemical relations of the non-nitrogenous organic substances, especially the carbohydrates and fats, to the proteids are in harmony with this dominant position of the latter in living substance ; for, so far as their history is known, those substances either are consumed in building up the proteid molecule, or are derived from the transformations of the latter. The former is, of course, shown most clearly by plants, in which all organic compounds are manufactured synthetically out of simpler inorganic substances. In the cells of the green plant occurs the synthesis of the first organic product, starch, out of carbonic acid and water. This carbohydrate constitutes the organic basis from which the proteid molecule is developed synthetically in a complex and still partly unknown manner with the help of nitrogenous and sulphur-

containing salts taken from the earth. Regarding fat, it is known that it can serve for the construction of carbohydrate by transformations in the plant ; the carbohydrate then gives off in turn the material for the formation of proteid, for in the seeds of Pceonia, which are filled with fatty oils, all oil disappears, e.g., after long exposure to the air, and starch appears in its place. It is thus seen most clearly in the plant how different substances serve for the construction of the proteid molecule; but the animal demonstrates best the fact that the most important non -nitrogenous groups of atoms in living substance, especially carbohydrates and fats, can be derived from the decomposition of the proteid molecule.1 Thus, the fact that fat can be derived from proteid has been demonstrated by Leo in his experiments on phosphorus poisoning in frogs, and by Franz Hofmann in his experiments on the nutrition of the larvae of flies with blood freed from fat. Further, Claude Bernard and recently Mering have proved upon dogs whose bodies were freed from glycogen by fasting, that after the feeding of proteid glycogen is again manufactured in great quantity, in other words, that this carbohydrate rfan be derived from the transformation of proteid. Finally, Gaglio has established the fact that the lactic acid in the body is derived from the transformation of the proteid molecule, since the quantity of it in the blood is dependent solely upon the quantity of proteid that is eaten. Regarding the nitrogenous excretory products of the body, it is evident that they can be derived only from the transformation of proteids and their compounds, since no other nitrogenous bodies are present among the essential organic compounds of living substance.

But the most striking proof of the fact that all substances, both non-nitrogenous and nitrogenous, that are essential to the life of the cell, can be derived by chemical transformation from proteids, is afforded by one of the most significant facts of physiology, namely, the possibility that carnivora are capable of maintaining their life upon pure proteid and, as Pfliiger ('91) has recently shown, possess great capacity for doing work. Nothing demonstrates better than this fact the controlling position of the proteid molecule in the vital process.

Hence, not only does it follow from the fact of metabolism that very labile complexes of atoms exist in living substance, with the presence of which life is inseparably associated, but it is the proteids whose presence constitutes the general, essential condition and focus of life. If we endeavour to harmonize these two facts, the unavoidable necessity arises of assuming in living cell-substance, besides the known proteids that occur also in dead substance, certain other proteids or compounds of proteids, that are present in life only and terminate life with their decomposition.

Dead proteid, as it is found in the dead egg of the fowl, or as it is stored in quantity in living egg-cells in the form of vitellins, is able to exist for an extraordinarily long time without undergoing the slightest decomposition, if protected from bacteria. Certain proteids or proteid compounds of living substance, however, are continually undergoing spontaneous decomposition, even when the living substance is under wholly normal conditions, and, as is shown by the products that are given off, the slightest action of stimuli increases the decomposition. A long time ago Pfliiger (75,1), as has been seen elsewhere,1 called attention to this important difference between the proteid in dead and that in living cellsubstance in his valuable work upon oxidation in living substance, and distinguished clearly between living proteid and dead proteid. The fundamental difference between the two consists in the fact that the atoms of the dead proteid molecule are in a condition of stable equilibrium, while the living proteid molecule possesses a very labile constitution.

Pfltiger's assumption of living proteid, which distinguishes living cell-substance from dead and in the loose constitution of which lies the essence of life, is necessitated. But this substance must be of essentially different composition from dead proteid, although, as follows from the character of its decomposition-products, certain characteristic atomic groups of the proteids are contained in it. The great lability that distinguishes it from other proteids, can be conditioned only by an essentially different constitution. Further, critics will rightly object to the terming of this hypothetical compound a " living proteid molecule, " for there is a certain contradiction in calling a molecule living. The word " living " can be applied only to something that exhibits vital phenomena. Hence, the expression " living substance " is well justified, for vital phenomena may be observed in living substance as a whole. But a molecule cannot exhibit vital phenomena, at least as long as it exists as such ; for if any changes appear in it it is no longer the original molecule ; and, if it continues unchanged, vital phenomena are not present in it. The latter, which are based upon chemical processes, can be associated only with the construction or the destruction of the molecule in question ; and thus the application of another name to the compound that is at the focus of life is doubly justified. In order to distinguish this body, therefore, from dead proteid and to indicate its high significance in the occurrence of vital phenomena, it appears fitting to replace the term " living proteid" with that of liogen.

The expressions "plasma molecule," "plasson molecule," " plastidule," etc., which Elsberg ('74) and Haeckel (76) have employed, and the conceptions of which are comprised approximately in the expression " biogen molecule," are less fitting in so far as they easily give the impression that protoplasm is a chemically unitary body, which consists of wholly similar molecules ; such a view must be expressly rejected. Protoplasm is a morphological, not a chemical conception.1

Extremely little is known concerning biogens, and this facb should not be concealed. Since the constitution of the proteids themselves, i.e., substances that can be investigated chemically at any moment, is not at all known, it is readily understood that we possess much less knowledge concerning the biogens, the composition of which can only be inferred from their decompositionproducts. It can be maintained of them only that they are extraordinarily labile, and this property gives to them a certain similarity to explosive bodies. Pfliiger ("75, 1) has employed certain facts in a most ingenious manner for the purpose of obtaining conclusions regarding certain characteristics of biogens, which make intelligible the great lability of the biogen molecule in comparison with the molecule of dead proteid.

The starting-point of Pflliger's discussion is a comparison of the decomposition-products that arise spontaneously and continually in the oxidation of living proteid, such as in respiration, with those that are obtained by the artificial oxidation of dead proteid. This demonstrates the important fact that the non-nitrogenous decomposition-products in the two cases agree essentially, while the nitrogenous products possess not the slightest similarity. " It follows from this that, as regards its hydrocarbon radicals, living proteid is not essentially different from the proteid of food." The important difference between the two consists rather in the arrangement of the nitrogenous groups of atoms. If, however, the nitrogenous decomposition-products of living proteid be examined, such as urea, uric acid, creatin, etc., as well as the nuclein bases, adenin, hypoxanthin, guanin and xanthin. it is found that, in contrast to the nitrogenous products that appear in the oxidation of dead proteid, some can be artificially prepared from cyanogen compounds, while others contain cyanogen (CN) as a radical. Hence it is highly probable that the carbon and the nitrogen are combined in the biogen molecule into cyanogen, a radical that is wanting in dead proteids.

Thus there is presented a very fundamental difference in the constitution of biogens and that of dead proteids ; this explains also the great lability of the biogen molecule, for cyanogen is a radical that contains a great quantity of internal energy, all its compounds possessing strong inclination toward decomposition. This fact enables us to understand the process of respiration, for when in the biogen molecule two atoms of oxygen come into the vicinity of the very labile cyanogen radical, by reason of the active intramolecular vibrations of the carbon and nitrogen atoms in cyanogen the carbon atom will unite with the oxygen to form the very stable molecule of carbonic acid. In fact, cyanogen is very

easily combustible, and in its combustion yields carbonic acid. Thus, Pfiiiger believes that the continual taking-in of oxygen and giving-out of carbonic acid on the part of living substance depends upon the presence of the cyanogen radical, and that the intramolecular oxygen is the essential condition of the tendency of living substance to decompose. In these considerations we find a basis for an idea of the manner in which the formation of a biogen molecule takes place in an animal cell out of the ingested food. By the co-operation of the biogens already present, the atoms of the dead proteid molecule introduced in the food undergo in the cell a rearrangement, in such a manner that an atom of nitrogen always unites with an atom of carbon to form the cyanogen radical with the loss of water. The changes that necessarily appear at the same time in the other groups of the proteid molecule are for the present wholly unknown, but, if we may judge from the essential agreement in the non-nitrogenous decomposition-products of the living and of the dead proteid, they do not appear to be of fundamental importance. By the intramolecular addition of inspired oxygen the biogen molecule finally arrives at the maximum of its power of decomposition, so that only very slight impulses are required to bring about the union of the atoms of oxygen with the carbon in the cyanogen. The material of the non-nitrogenous groups of atoms afforded by the explosive decomposition of the biogen molecule can easily be regenerated by the residue of the biogen molecule from the carbohydrates and fats that are present in the living substance and contain such groups ; in fact, it has been seen that these substances are consumed in the building-up of proteid. " Probably this is the essential significance of these satellites of the proteid molecule, " as Pfliiger very fittingly terms the carbohydrates and fats. If, finally, the living substance dies, the labile cyanogen-like compound of nitrogen passes over again into the more stable condition of the ammonia radical with the absorption of water, the nitrogen uniting with the hydrogen of the water. Thus we have again the stable compounds of dead proteid, such as serve for food.

These are, in brief, some of the essential features of the abbreviated path followed by the food in the construction of the biogen molecule in the animal cell. The much longer path, which in the plant cell leads from the ingestion of the simplest inorganic compounds through the synthesis of the first carbohydrate and on to the construction of the biogens, is for the present much more obscure. Notwithstanding the facts that the views here developed have been confirmed by experiment only in part, and that they contain many large gaps, which can be filled only slowly, they afford at least a basis for an understanding of the fundamental processes in living substance. The metabolism of living substance, upon which all

life is based, is conditioned by the existence of certain very labile compounds, which stand next to the proteids and on account of their elementary significance in life are best termed biogens. To a certain degree the biogens are continually undergoing spontaneous decomposition, just as is the case with other organic bodies, e.g., prussic acid. But this decomposition is much more extensive, if even slight external stimuli act upon the living substance. We must imagine that by reason of the extremely active intramolecular vibration of the atoms, which is the cause of the labile condition, certain atoms, partly spontaneously and partly as a result of external commotions, come under the influence of others for which they possess greater affinity than for their original neighbours, and in this manner more stable groupings of atoms arise as independent compounds. In this respect the biogens can be compared to explosive substances, the atoms of which possess likewise very labile equilibrium and which upon receiving violent shocks explode, i.e., rearrange their atoms into more stable compounds ; e.g., nitroglycerine or trinitrate of glyceryl, which is employed for making dynamite, is decomposed by mechanical impulses or electric shocks into water, carbonic acid, nitrogen and oxygen : 2C3H5(O NO^a = 5H2O + 6C02 + 6N + O.

But, in contrast to other explosive bodies, we must evidently ascribe to the biogens the peculiarity that in decomposition the whole molecule is not destroyed, but that certain groups of atoms, which are formed by rearrangement, are split off, while the residue is again built up into a complete biogen molecule at the expense of the materials found in its vicinity, just as in the manufacture of concentrated sulphuric acid l the nitrous acid formed from nitric acid by the withdrawal of oxygen is rebuilt into nitric acid with the aid of the oxygen of the air. The substances still present in the living substance in addition to the biogens are merely " satellites " of the biogen molecule, and either serve for its construction or are derived from its transformations. Thus far no substances have been made known in living matter, which can stand in any nearer or more remote relations to the biogens. Nevertheless, from the variety in the decomposition-products that are excreted by different kinds of cells in metabolism, it must be concluded with great probability that biogen molecules have not in all cells exactly the same chemical composition, but that there are various biogen bodies, and even that the biogens not only of different cells, but of the various differentiations of the same cell, such as exoplasm, myoids or contractile fibres, musclefibril^, cilia, etc., have different constitutions, although they agree in essential structure. The biogens, therefore, are the real bearers of life. Their continual decomposition and reformation constitutes the life-process, which is expressed in the manifold vital phenomena.

Now that we have become acquainted with the simplest schematic expression of the elementary vital process in the construction and destruction of biogens, we must consider more in detail certain metabolic relations that result from these, and we must define certain conceptions which are important in clarifying our ideas upon metabolism. It will be recalled that two phases are distinguished in metabolism, assimilation and dissimilation. By assimilation is understood the capacity of living substance to construct its like continually from the ingested food-stuffs ; by dissimilation, the capacity to decompose continually into the products excreted by it. In accordance with the above considerations, this conception can be formulated more exactly as follows : assimilation comprises all those transformations that lead up to the construction of biogens, dissimilation all those that extend from the decomposition of biogens down to the complete formation of the excretion-products.

Such an exact definition of these two fundamental conceptions of the theory of metabolism is necessary, for, when we glance at the history of the theory, we find that they have been employed with very different meanings. Assimilation, which originally signified in a very general sense the formation of living substance in the organism out of non-living food, has been employed by botanists in a very special way. Plant physiology in large part still means by assimilation exclusively the synthesis of starch from water and carbonic acid in the chlorophyll-bodies of the green plant-cell. This narrow conception has gradually been widened in animal physiology, and the term has been employed not only for the synthesis of the first organic product, but also for the construction out of the ingested food-stuffs of the more complex compounds of living substance, especially those that are characteristic of every form of cell, the proteids. In contrast to this latter use, Ewald Hering ('88) has conceived the word in a narrow sense, and in a small but suggestive work has sharply separated assimilation from growth. By the former he understands only the qualitative chemical change of particles already present ; in other words, the completion of the particles up to the maximum of their constitution ; under growth, on the other hand, he includes not qualitative changes, but only a quantitative increase of the particles present. In addition to this Hering has created the conception of dissimilation and placed it beside that of assimilation, finding between dissimilation and atrophy a difference corresponding to that between assimilation and growth ; the qualitative change associated with the separation of certain substances from the particles present he terms dissimilation, and the quantitative diminution of the particles, atrophy

But this sharp separation of assimilation and dissimilation on the one side, and growth and atrophy on the other, can scarcely be maintained, at least in so far as the former are conceived to be based upon purely qualitative, the latter upon purely quantitative changes of living substance. The formation of living substance takes place only with the help of living substance already present. Only where such substance already exists can new masses of it be formed. This is true even of the plant-cell, in which the living substance is produced in great measure from purely inorganic materials. It must be concluded from this that in growth the biogen molecule attracts to itself from the food the elements necessary for the formation of living substance and combines them chemically, and, therefore, it is changed qualitatively in growth. The general tendency of proteids, and likewise of the cyanogen-containing groups of atoms hypothetically present in the biogeri molecule, to polymerisation, as Pfliiger has already emphasised, allows us to understand this growth by chemical union. On the other hand, atrophy is only conceivable as taking place by means of chemical decomposition, that is, by a qualitative change of the living particles. But even if we can, and must, distinguish the regeneration of certain parts of the biogen molecule from the reformation of whole biogen molecules, and, likewise, the separation of single groups of atoms from the complete decomposition of the molecule, chemical changes are always present, which are directed to either the construction or the destruction of complete biogen molecules. Regeneration is only a part of the process of the formation of a new biogen molecule, and, likewise, the splittingoff of certain groups of atoms is only a part of the phenomenon of decomposition.