THE GENERAL EFFECT OF STIMULATION
_Contents_: Various examples of the effects of stimulation. Metabolism
of rest and metabolism of stimulation. Metabolic equilibrium.
Disturbances of equilibrium by stimuli. Quantitative and qualitative
alterations of the metabolism of rest under the influence of stimuli.
Excitation and depression. Specific energy of living substance.
Qualitative alterations of the specific metabolism and their relations
to pathology. Functional and cytoplastic stimuli. Relations of the
cytoplastic effects of stimuli to the functional. Hypertrophy of
activity and atrophy of inactivity. Metabolic alterations during
growth of the cell. Primary and secondary effects of stimulation.
Scheme of effects of stimulation.
In the foregoing lectures we have had occasion to touch more or less
often on the subject of the effects of the stimuli. This was the
case, however, only when it appeared necessary to obtain a systematic
knowledge of the stimuli and the differentiation of the individual
factors. We will now proceed to consider the effect of stimulation in a
more systematic manner. The conditional method of observation, however,
will remain our guide.
We have already pointed out the relations between the conception of
stimulation and that of vital conditions, now we will consider that of
the effect of stimulation with that of vital processes. Nevertheless,
the _effect_ of stimulation being a manifestation of the vital process
is not, therefore, in opposition to the latter as such. Hence the
question presents itself as to the connections between vital process
and the effect of stimulation.
When we study the motile flagellate infusorium _Peranema_ swimming
undisturbed in water, we observe that the swimming movements are
absolutely regular in character. The elongated cell body remains
unaltered in shape. The long flagellum is extended in a perfectly
straight line in the axis of the body and only the extreme end lashes
with regularity through the water (Figure 8, A). There is majestic
grace in this perfect uniformity of motion. The picture suddenly alters
the moment the _Peranema_ is influenced by the slightest jar. The whole
flagellum at once executes a few violent movements (Figure 8, B), the
body draws together, soon stretches itself again and swims immediately
after, in another direction, with the same majestic calm as before.
[Illustration: Fig. 8.
_Peranema._ A--Swimming in non-stimulated condition. B--Mechanically
stimulated at the end of the flagellum.]
Another instance. A number of fertilized eggs of the sea urchin are
placed in a watch glass in sea water. The temperature of the water
should correspond with the mean temperature in which the animals live
in the sea, averaging about 15° C. The eggs begin to form grooves and
to develop slowly by progressive division. In another glass we observe
a second sample of fertilized eggs of the same kind and under the same
conditions, but in this case we increase the temperature to 25° C. The
increased temperature brings about a decided increase of segmentation
and the same stage of development is reached in less than half the
time. The increased temperature, therefore, increases the development.
Further we take a third sample of the same urchin eggs in a watch glass
with sea water of 15° C. and add a little sea water mixed with ether.
The development of the eggs now comes to a standstill. The narcotic has
produced an inhibition of development.
To quote another instance. _Bacterium phosphorescens_ having been bred
upon a putrid fish are exposed in the culture fluid to the air. In the
dark the bacteria give forth a phosphorescent light. Then the culture
fluid containing the bacteria is put into a glass receptacle, which can
be rendered air-tight and all oxygen excluded. After a short time the
light formation ceases completely. The absence of oxygen has here had
a depressing effect and it is only after air has been again introduced
that light is once more produced.
Lastly, an example from the group of mammals may be cited. The
metabolism of a dog in complete rest is examined for a prolonged length
of time and we ascertain the values of the oxygen consumption, the
carbon dioxide production, and the nitrogen elimination in the urine.
Under the same nutritive conditions the animal is then allowed to
work from time to time in a treadmill. During these working periods
impulses of excitation are continually conducted to the muscles from
the nervous system. It is now found that under the influence of the
constantly recurring stimuli the quantity of nitrogen in the urine has
only very slightly augmented, whereas the consumption of oxygen and the
production of carbon dioxide has markedly increased.
What conclusions can be drawn from these instances of response to
stimuli, of which any number could still be quoted? They show us, first
of all, that a state or process existing under given conditions, is
altered by the influence of the stimulus. This is a fact, however,
which could be expected from the beginning and is self-evident, for
stimuli are alterations in the vital conditions, and when these are
altered the state of the system or the happenings thereof must also
alter. The question with which we are here more closely concerned,
however, is a somewhat more detailed characterization of the state
or process itself, as well as that of alterations produced by the
influence of the stimulus. The instances of response to stimuli already
cited furnish us with information in both kinds.
In all these examples, the living processes occur with equal constancy
and unaltered rapidity, provided a stimulus is not operative. Here,
however, the gradual alterations, the result of development, must
not be overlooked. An excellent example of this is seen in the eggs
of sea urchin, where the development is readily perceptible. In all
these instances, however, the condition is immediately changed by the
influence of the stimulus. The previous state of constancy in the vital
process is disturbed. The rapidity of its course is changed, being
either increased or decreased, and the specific vital manifestations
concerned are, therefore, augmented or diminished. We will now study
the vital process with the methods of chemical investigation and
consider the problem from the standpoint of metabolism. It may be
noted here, that other methods, such as the transformation of energy
or changes of form of the living system, would serve equally well as
indicators for this purpose. In every instance there is a uniformity
of the processes; the difference, however, is in the nature of the
indicators and the terms used. The methods and the terms used in
chemical investigation and description reach proportionately much
deeper than those employed when the transformation, energy or the
variations of form of the organisms are studied, and permit of the
finest differentiation of the processes. The atomistic terminology
is, for this reason, preëminently fitted for the description of vital
processes. When we study the vital process metabolically, we can, as
shown in the above-mentioned instance, divide the processes into a
_metabolism of stimulation_ in contradistinction to a _metabolism of
rest_.
The comprehension of _the metabolism of rest_ demands a closer
consideration. On closer observation we must say that this much-used
conception is merely an abstraction nowhere realized in a strict sense.
In truth, there is nowhere in nature a metabolism of rest. No cell
exists which in a mathematical sense remains for even two successive
moments under absolutely the same external conditions. If we imagine
a single living cell of the simplest kind living in a fluid nutritive
medium, and if we suppose its body and surroundings so magnified that
the single molecules and atoms were respectively of the size of cannon
and rifle balls, the boundary between cell and medium would represent
a battlefield, on which a heavy bombardment is constantly taking
place. The rain of shot of food and oxygen molecules penetrating into
the cell from the medium, would produce an explosion in the existing
ammunition depots, now at one point, now at another, creating great
breaches through which new masses of shot would reach the interior.
The fragments of these exploding molecules would be flung out here
and there into the medium and would stem, now at this, now at that
point the besieging masses of shot. In this wild confusion on the
whole boundary line between cell and medium there can be no question
of rest or even equilibrium at any point. The human mind, superior to
the material world as we may deem it, is yet always dependent upon
the results of experience, and even in its highest flights cannot
become wholly emancipated from the concrete objects. For this reason
it is of great purport to conceive processes whose dimensions cannot
be observed even microscopically, as enlarged and transformed to that
method of expression most familiar to the human mind, namely, in the
field of optical presentation. This method is of great help in aiding
our understanding, and likewise here, even in the resting state, the
cell is constantly exposed to local effects of stimulation, now at one
point, now at the other. The conception of the metabolism of rest is,
therefore, in a strict sense fiction.
Nevertheless, the conception of the metabolism of rest as an
abstraction can be of value provided always that it is strictly
and definitely limited. It must, for instance, not be applied to
short periods of time. The continued local and temporary responses
to stimulation constitute a mean value which, although composed
of numberless small sub-threshold responses, we can still call a
metabolism of rest. Weak stimuli have, however, as already seen,
the property, provided their influence is constant, of effecting an
adaptation to the stimulus on the part of the living organism, so
that the stimulus becomes a vital condition for this state of the
organism. Hence the continued existence of a vital process resulting
from the constant action of stimulation is made possible. That which
we are in the habit of calling metabolism of rest, would, therefore,
be metabolism of stimulation, but one that is characterized by a
constantly existing metabolic equilibrium.
This “_equilibrium of metabolism_” distinguishes the metabolism of
rest from that form which is developed in response to temporary
stimulation, in that every temporary stimulation has the effect that
it disturbs the existing metabolic equilibrium for a longer or shorter
time. This disturbance of the equilibrium of metabolism can in contrast
to the metabolism of rest be termed “_metabolism of stimulation_.”
In this, but only in this sense, can these two conceptions be placed
in opposition and used to characterize the processes in the living
organism. The conception of the metabolism of stimulation must always
stand in relation to that of an equilibrium of metabolism characterized
by a constantly existing metabolism of rest, just as the conception
of stimulus can likewise only be defined relatively to that of vital
conditions.
Nevertheless, the conception of the equilibrium of metabolism requires
a somewhat more accurate definition before we can feel justified in
using this term. Definitions are always trite, nevertheless they
are the basis of all our thinking and a definite understanding is
impossible unless we first clearly fix their contents. The history of
theology and philosophy even to the most recent times furnishes a long
line of instances in which the most eminent minds, for the want of
fixed definitions of the conceptions which they made use of, failed to
find a mutual basis for their ideas. Without a sharp definition every
conception is a mere word, which each individual, according to his
personal experiences and views, endows with a different meaning. To
such conceptions we may apply Mephisto’s ironical comment to his pupil:
“Mit Worten lässt sich trefflich streiten,
Mit Worten ein System bereiten.”
The natural sciences, if they are to retain their reputation for
exactness and precision, require the strictest and clearest definitions
of all conceptions. If we seek to penetrate more deeply into the
varied happenings in concrete conditions, we must reconcile ourselves
to dry pedantic definitions. In the case of that of the equilibrium
of metabolism indeed we have before us one of the most important
conceptions in physiology.
The justification to speak of an equilibrium of metabolism arises from
investigations of metabolism in mammals. The classical experiments of
the previous century, as is well known, have shown that in the adult
mammal receiving a necessary quantity of nourishment and in a state of
rest, the intake and outgo of the constituent elements are the same.
The carbon, hydrogen, nitrogen, oxygen, sulphur, phosphorus, etc.,
taken in during a lengthened period in the form of food and respired
air, appear again in equal quantity, in other combinations, in the
products of excretion of the organisms. Calorimetric experiments
likewise show an equilibrium of the consumption and elimination of
energy. If there thus exists an equilibrium of metabolism for the
whole cell community, it is clear that the same must also apply
to the individual cell, that is, for all living substance. The
quantitative relations of the foodstuffs taken _in_, and the excreted
metabolic products given _off_, are, however, merely a standard of the
metabolism. We know that the former are used to build up new living
substance and that the latter represent the result of disintegration
of that previously existing living substance; for we find, as in the
case of the plant, complicated protein combinations, which are built up
from comparatively simple constituents of the food and are again broken
down into comparatively simple substances. And so the building up and
breaking down processes form the two great processes of metabolism,
which with _Hering_[41] we can briefly call “_assimilation_” and
“_dissimilation_.” In the terms assimilation and dissimilation are
comprised the sum of _all_ processes of construction and disintegration
in the living organism. It is apparent that equilibrium of metabolism
occurs when assimilation and dissimilation are equal. The formula A : D,
that is, the relation of the sum of all assimilation to the sum
of that of all dissimilative processes, is a factor of fundamental
importance in the study of the course of the vital processes, for upon
its value depends individual vital manifestation, and, in fact, the
continuation of life. I have, therefore, designated the formula A = D
“_Biotonus_.” The equilibrium of metabolism would then be characterized
by the biotonus[42] of a living organism being equal to _one_. This
would be the metabolism of rest of a system, whilst its metabolism of
stimulation would consist in an alteration of the _biotonus_. But is
this state of living substance strictly speaking ever realized?
[41] _E. Hering_: “Zur Theorie der Vorgänge in der lebendigen
Substanz.” In Lotos, Bd. 9, Prag. 1888.
[42] _Max Verworn_: “Allgemeine Physiologie. Ein Grundriss der Lehre
vom Leben.” V. Aufl. Jena 1909.
In considering the nature of the equilibrium of metabolism one factor
has been disregarded which must be taken into account at every point;
this is growth. Growth changes, although varying more or less, are
never absent during the life of the organism. An equilibrium of
metabolism never exists in a strictly mathematical sense, and here
again we are working with a conception which is faulty, because it is
an abstraction, originating from experience with rather too restricted
boundaries. But an error of which one is aware is not dangerous.
In mathematics we also consciously reckon with errors, without the
result being altered. In the before mentioned cases the equilibrium of
metabolism was maintained, because the investigations involved only a
short time in an adult mammal. In the adult mammal the growth processes
occur very slowly, so that alterations within a relatively short time
are not demonstrated.
If it were possible to subject the adult mammal to metabolic or
calorimetric experiments, extending for years, it would be found that
the intake would be qualitatively and quantitatively different at the
end of the investigation and that the same would apply to the outgo.
In the growing egg cell this takes place with much more rapidity. In
the organism which rapidly grows, it can be seen at once that the
quantity of the outgo of the products of disintegration cannot be equal
to that of the intake of foodstuffs. If biotonus were equal to one,
the organism could not grow. Equilibrium of metabolism can only be
understood when we take into consideration a period of time in which
the alterations in growth take place with such imperceptible slowness
that the resultant error is inconsiderably minute. This period of
time is of greatly varying length in different living organisms and
this fact must be taken into account in every living form. Only with
this restriction can we justify the use of the term “equilibrium of
metabolism.” Then, however, its use is of great value.
The _metabolism of stimulation_ is then a disturbance of the metabolism
of rest, that is, a disturbance of the equilibrium of metabolism
through the effect of stimuli.
The question here follows: Is there a _constancy of this interruption
of the equilibrium of rest produced by the stimulus_ which can be
formulated into a general law? To begin with, the number of possible
responses are greater than the variety of forms of living substance,
for every living organism with its specific properties can undergo
alteration in its metabolism in various directions. Thereby results an
infinite number of manifold reactions to stimuli. However, in answer to
the question, in which direction the change in the specific metabolism
of rest in response to a stimulus takes place, we find a comparatively
simple scheme of general reaction. All phenomena can change in their
rapidity as well as in their nature. That is quantitatively and
qualitatively. In this way the specific vital process of an organism
can be altered by the stimulus, on the one hand, in its rapidity; on
the other, in the manner of its action.
The majority of all temporary responses to stimuli consist in
_alterations of rapidity of the vital process_, and form either a
quickening or retardation of its course. The former is manifested in a
strengthening or an increase, the latter in a decrease or repression
of the specific action of the living organism. The stimuli have the
same effect as in the case of the catalysers in chemical processes.
According to _Ostwald’s_[43] well-known definition of catalysis
a catalyser is a substance which, without appearing in the final
product of a chemical reaction, alters its rapidity. This group of
reactions can, therefore, be referred to as “_catalytic stimulation and
response_.” When the response consists in _increase_, we speak, in a
physiological sense, of an excitation, and when there is decrease in
the vital processes, we speak of a depression.
[43] _Ostwald_: “Ueber Katalyse.” Verhandl. d. Ges. Deutscher Naturf.
und Aerzte zu Hamburg 1901.
The conception of _excitation_ and _depression_ are purely empirical.
They are terms for real things, referring, in fact, simply to
alterations in rapidity of life process, which can be as readily
observed as the process itself. I wish to lay particular stress on
this fact, for the reason that _Cremer_[44] has recently made the
extraordinary statement that I have introduced hypothetical processes
into the definition of the conception of excitation. I have always
considered excitation as merely an increase or change of intensity of
the specific actions of a living system, and as such is an established
process without a _trace_ of the hypothetical element.[45] If, however,
the excitation process is to be regarded as something _absolute_,
as a mysterious state _sui generis_, which is entirely independent
and totally unlike the metabolism of rest, then, of course, it would
appear utterly incomprehensible and would be without purpose. As an
_absolute_ process excitation is merely a meaningless word. Excitation
and depression are _relative_ conceptions and can only acquire meaning
when the process which is excitated or depressed is more closely
defined. This is the specific vital process of a given organism, and
the two conceptions only have meaning in relation to it. The conception
of the vital process, however, is one directly gained from experience.
However complex or difficult to analyze the process may be, it still
is as little hypothetical as that of the combustion of carbon into
carbon dioxide, or the revolving of the earth around the sun. It can
be looked upon as something positive and real. Quite another question
is the manner in which we are to consider the mechanism of the vital
process. In analyzing this mechanism we cannot, at least in the
present state of our knowledge, entirely dispense with hypothesis. But
these hypotheses are in no way involved in the _definition_ of the
process of excitation. If we look upon every excitation or depression
produced by a stimulus as an alteration in rapidity in the specific
vital process of a given organism, we are thereby expressing the same
fact which _Johannes Müller_ has termed “_specific energy_.” We give,
however, the doctrine of specific energy a more general application
in so far as it comprehends not only the increase but likewise the
decrease of activity in response to stimuli. _Johannes Müller’s_
doctrine of specific energy of the living substance at all times has
been the subject of most animated discussion. When I refer here to the
specific energy of living substance, it is with the knowledge that
_Johannes Müller_ did not use this expression of “living substance” in
this connection. He was already acquainted, however, as we have seen,
with the fact of the existence of the specific energy of all living
structures. For appertaining to the muscle he says: “This is universal
in all organic reaction.” The reason why the doctrine of _sense energy_
has become of importance in the discussion of the specific energy of
the living substance, is in consequence of the theoretical interest,
resulting from its connection with the nature of the specific energy
of our _sense substances_. The controversies on this subject are still
far from settled.[46] Indeed, according to the special philosophical
standpoint taken by an observer, the existence of a specific energy of
the senses is acknowledged or disputed. For any one acquainted with
the general physiological reaction to stimuli, such a discussion is
wholly without purport. The sense substances have as a matter of course
in common with all living substances their specific energy, that is,
the influence of stimuli can produce an increase or decrease of their
specific vital processes. “Specific energy” of “sense substance” in
this sense is like that of all other living substances, a fact. In that
the psychical capability of these sense substances, in which we include
not only the peripheral, but also the central portion, are dependent
upon their specific vital processes, it must be self-evident that the
excitation and the suppression of sense sensation can be brought about
by adequate and inadequate stimuli, no matter what one may think of
the relations between physical and psychical phenomena.
[44] _Cremer_: “Die allgemeine Physiologie der Nerven.” In Nagels
Handbuch der Physiologie des Menschen. Bd. IV, Braunschweig 1909.
[45] In the first edition of my “_General Physiology_” in 1895 I
have sharply and clearly defined it as such, stating in formulating
the general law of stimulation: that every excitation is an increase
either of individual parts or the whole of vital phenomena,
depression every decrease in the individual part or the whole of
vital phenomena.
[46] Compare: _Rudolf Weinmann_: “Die Lehre von den specifischen
Sinnesenergien.” Hamburg 1895.
Further: _Eugen Minkowski_: “Zur Müllerschen Lehre von den
specifischen Sinnesenergien.” In Zeitschrift f. Sinnesphysiologie,
Bd. 45, 1911.
The only debatable question is that concerning the limits of the
validity of the doctrine of the specific energy of living substances.
This question will involve our attention when we have analyzed somewhat
more closely the happenings in the living substance taking place under
the influence of stimuli. We will, therefore, return later on to a
more detailed consideration of the last question. Nevertheless, we
will here refer to a fact which, upon a superficial observation, seems
to restrict the validity of the conception of the specific energy of
living substance.
In contrast to those reactions to stimuli, which consist merely in the
changes of a rapidity of the specific vital process, are another group
of reactions in which the influence of stimuli leads to qualitative
alterations in the specific vital process. In these instances, the
influence of the stimulus directs the metabolism of rest into new
channels, so that chemical processes occur in the cell, which under
ordinary circumstances do not take place. This group of reactions,
which I wish to term “metamorphic stimulation and response,” are
chiefly observed where weak stimuli act continuously upon the living
substance. These are essentially weak chemical stimuli, which last
for a prolonged period or frequently reoccur in the life of the cell
community. Examples of this are found in the continual ingestion of
alcohol and other poisons by the human being, or in the formation of
metabolic products of bacteria, etc. The majority of _chronic_ diseases
belong to this group of reactions; disease being simply response to
stimulation. Disease is life under altered vital conditions and altered
vital conditions are stimuli. This simple and self-evident fact shows
the immense importance which the knowledge of the general laws of the
physiology of stimulation has for pathology. The pathologist, who
does not wish to confine his observations to a purely superficial
symptomatology or a merely histological morphology, must seek above
all to penetrate as deeply as possible into the nature of the general
reactions to stimulation in the living organism. It is the essential
point which meets him everywhere. In spite of their great interest
for pathology, however, it is just these qualitative alterations of
the normal vital process produced by continuous stimulation which
have up to now been least analyzed. In this field we expect much from
pathological investigation which alone has the immense amount of
material at its command. This will take place only when pathology adds
to the almost exclusively histological direction of investigation, that
also of experimental physiology. It is true that the problems of the
qualitative alterations of a vital process by chronic stimulation are
much more complicated than those of the rapid responses to temporary
stimuli, consisting simply in mere alterations of rapidity of the
specific vital process. An understanding of the nature of the former
can only be expected when a deeper knowledge of the latter is gained,
for, as will be seen presently, there is the closest relation between
the two groups.
The reactions to catalytic stimuli of short duration, which produce
merely an alteration of rapidity in the specific phenomena of a living
organism, show on a closer analysis the interesting fact, that it is
not always the _entire_ metabolic processes of the cell which are
perceptibly quickened, but that only certain constituent processes
of the same are affected by the action of excitation. This is the
_more_ noticeable, as, considering the close correlation which all
the individual links of the chain of metabolism bear to each other,
it is to be expected that the alteration in rapidity of _one_ would
be followed at once by a corresponding change in all the others. An
example of the case in question, in which a special constituent process
may be predominately affected, is that of the specific activity of a
muscle which is repeatedly stimulated by nervous impulses. Since the
classical investigation of _Fick_ and _Wislicenus_[47] on themselves,
and of _Voit_[48] on the dog, we know that the nitrogen metabolism is
practically unaltered by the functional use of the muscle and there is
a remarkable increase only in the breaking down of the nitrogen-free
groups of the living substance. Sufficient importance has not as yet
been attached to this knowledge. This fact not only has a particular
interest for the much-discussed question of the source of muscle
energy, but also affords a deeper insight into the metabolic activity
of the living substance. It shows us that we must not imagine a purely
linear linking of the individual constituent metabolic processes,
but rather, at least at certain points, a branching formation, the
individual members spreading in various directions. An alteration in an
individual member can occur without an immediate change in the other
branches. This _would not_ be the case if there were only a linear
connection of the constituent processes, for the breaking of a single
member of the chain would be followed by a change in all the following
members.
[47] _Fick und Wislicenus_: “Ueber die Entstehung der Muskelkraft.”
Vierteljahresschrift d. Züricher Naturforschenden Gesellschaft. Bd.
10, 1865.
[48] _Voit_: “Ueber die Entwicklung der Lehre der Quelle der
Muskelkraft and einiger Theile der Ernährung seit 25 Jahren.”
Zeitschrift f. Biologie Bd. VI, 1870.
Derselbe: Physiologie des allgemeinen Stoffwechsels u. d. Ernährung.
In Hermanns Handbuch d. Physiologie, Bd. VI, 1881.
It shows us, further, that certain branches are more labile than
others. In the case referred to here, the branches of this system,
which bring about the nitrogen metabolism, are relatively _firm_ and
_stable_, the branches, which are disturbed by the stimulus producing
functional activity of the muscle, are particularly _labile_. I should
like in passing to call here your attention to the fact that as is
well known, _Ehrlich_,[49] in another field involving other conditions
and other experiences and considerations, has arrived in analogous
manner at his “side chain theory.” In order to have an expression for
those stimuli which involve rapid alteration of the labile constituent
processes and which are connected with the specific action of the
particular organism, I have called them “_functional stimuli_,” and
contrasted with them the “_cytoplastic stimuli_.” In the latter the
alterations produced include all the constituent processes extending
even to the stable processes of nitrogen changes, and sometimes extend
to complete disintegration and rebuilding of living substance.[50] To
the first group belong all adequate stimuli within certain limits of
duration and intensity, and the greater part of inadequate stimuli of
brief duration so long as they do not exceed a certain intensity.
To the latter group belong in general all the stronger adequate and
inadequate stimuli of prolonged duration; such as extreme temperature,
the stronger electric currents, constant alteration in the supply of
food, water, oxygen, the prolonged or stronger influence of extraneous
chemical matter, etc.
[49] _Ehrlich_: “Das Sauerstoffbedürfniss des Organismus. Eine
farbenanalytische Studie.” Berlin 1885. Compare further: _L.
Aschoff_: “Ehrlich’s Seitenkettentheorie und ihre Anwendung auf die
künstlichen Immunisierungsprozesse. Zusammenfassende Darstellung.”
Zeitschr. f. allgemeine Physiologie, Bd. I, 1902.
[50] _Max Verworn_: “Die Biogenhypothese. Eine
kritisch-experimentelle Studie über die Vorgänge in der lebendigen
Substanz.” Jena 1905.
Considering the close correlation of the individual part processes it
would appear very strange, however, if a single one of these could
undergo an alteration of its rapidity without the course of the rest
of the processes being in the least influenced. One cannot comprehend
such _absolute_ independence of a process brought about by functional
stimulation from all the other constituent processes, particularly when
this is of prolonged duration and involves to a considerable extent
the alterations in rapidity, for the individual constituent processes
are dependent in a high degree upon the quantity of the particular
chemical substances of which the living system is composed. The cycle
of the individual constituent processes of this system is determined in
the most delicate manner in its rapidity and extent, by the relative
quantities of the individual substances. Associated with an alteration
in the rapidity of an individual constituent process, there would also
be a relative alteration quantitatively of the substances. And with the
increase in the _quantity_ of the disintegration products, and also the
increase of the substances for their replacement, there would result,
during this time, an alteration in the amount of interaction of the
molecules of the other constituent processes, so that these processes
secondarily suffer an alteration in rapidity which is perceptible after
long continued involvement of the functional part of metabolism.
In fact, in the previously mentioned case of the functional stimulation
of the muscle, the proof has been furnished that a long-continued
increase of the functional metabolism is followed, although to a
less extent, by an increase in the entire cytoplastic metabolism.
_Argutinski_ showed this on himself in 1890 in _Pflüger’s_ laboratory.
He found, namely, that after the exertion of a long walk in a hilly
district, a considerable increase of nitrogen excretion in the urine
took place, which extended over the succeeding two or three days. This
increase of the nitrogen metabolism in its totality is not nearly as
great as that of the breaking down of nitrogen-free substances, but
it is, nevertheless, present and shows us that functional metabolism
cannot experience a lasting excitation without being followed by
secondary results in the entire cytoplastic metabolism. This fact
is even more strikingly illustrated in the alteration of the entire
volume of a living organism as produced by the lengthened duration
of functional stimulation. It has been long known, that the muscle
as the result of frequent functional excitation by means of adequate
nerve impulses, that is, prolonged activity, is considerably increased
in size, whereas in the absence of such it loses more and more in
volume. A hypertrophy of activity, produced by functional stimuli, and
the atrophy of inactivity, the result of the discontinuance of the
functional excitation, is universal and can be observed in the various
tissues of our body. We see it, for example, in the glands; we see
it in the skin and we see it in the elements of the nervous system.
_Berger_,[51] for instance, established the fact that the ganglion
cells of the optic lobe in the cerebrum of newborn dogs only reach
their full development when functionally excitated by adequate light
stimuli (Figure 9, B), coming from the eye, whereas they remain in the
embryonic state when these light stimuli are eliminated. (Figure 9, A.)
The cytoplastic increase of volume of the neurons under the influence
of functional stimuli is a fact of fundamental importance for the
entire happenings of the nervous system and forms the physiological
basis for reinforcement of reflexes, which, in its turn, is essential
for all acts of memory and intelligence. For the increase in volume of
the ganglion cell body is, when functionally activated, accompanied at
the same time by an increase of specific capabilities and the intensity
of discharge. Its excitation impulses can, therefore, be conducted
through a greater number of neurons, with which it is connected, than
would be the case if development of the volume of the ganglion cell
increased to a less extent.
[51] _Berger_: “Experimentell-anatomische Studien über die durch
den Mangel optischer Reize veranlassten Entwickelungschemmungen im
Occipitallappen des Hundes and der Katze.” Arch. f. Psychiatrie, Bd.
33, 1909.
[Illustration: A
B
Fig. 9.
A--Undeveloped ganglia cells in the optic lobe of a dog, the eyes of
which have been sewn up immediately after birth. B--Fully developed
ganglia cells in the same region of a normal dog of the same age.
(After _Berger_.)]
The increase in volume under the influence of stimuli further shows
the relation between the group of those solely catalytic effects
of stimulation consisting in mere alterations of rapidity of the
specific vital process, and that of the metamorphotic effects of
stimulation, which manifest themselves in qualitative alterations of
the vital process. Simple observation shows us that a qualitative
change of individual constituent processes must necessarily result
from the increase of volume of a cell, and that considering the close
correlation of all the individual processes a profound alteration of
the entire metabolism must be produced. I have already at another
place[52], [53] treated these conditions more in detail and will,
therefore, only briefly refer to them here. If we study the growth of a
ball-shaped cell, we find that the surface then increases as a square,
and the volume as the cube. It therefore follows that, by progressive
volume increase, the conditions for the interchange of substance with
the surrounding medium must become more and more unfavorable for
those cell portions situated in the interior, whereas those at the
exterior are at much greater advantage. This must lead to a constantly
increasing difference of the rapidity of the metabolic processes
between the peripheral and central portions. Accordingly, the intricate
interworkings of the individual constituent processes, the rapidity of
action of all which is intimately connected, are, therefore, followed
by corresponding alterations in the entire metabolism. Sooner or later
a stage is reached in which the individual constituent processes become
so limited that certain metabolic products, which previously were
broken down as soon as formed, can be no longer eliminated and remain
in the cell acting as foreign bodies. In this way the relative quantity
of the individual cell substances become more and more altered, and
as the course of chemical processes occurs in accordance with the
law of mass action, the whole metabolism is directed into another
channel, so that finally new constituent processes take place, which
were formerly not possible. These in their turn produce deep-seated
alterations of the relations of the cell to its surrounding medium,
etc. Hence this mere increase of volume of the cell in growth forms
the source of an infinite mass of alterations in the activities of
cell metabolism, which we briefly term its “_development_,” and which
by constant progression, leads either to a process of cell division,
and with this to a correction of existing disorder, or finally to
irreparable disturbances ending in death. In this way an inseparable
relation exists between increase of volume and the development of
living substance. We have seen, however, that the catalytic reactions
of stimulation, which at first only produce an alteration of rapidity
of the individual constituent processes, if of prolonged duration
or of frequent recurrence, secondarily effect a change of volume of
the entire living organism. One can, therefore, hardly reject the
conclusion that seeing the close interworkings of the individual part
process of metabolism, every change of rapidity of a single member,
if of prolonged duration or of frequent occurrence, must finally lead
to qualitative alterations of the entire metabolism. In consequence
there results an important dependence between catalytic stimulation and
metamorphic reaction. Indeed, it is not unlikely that the metamorphic
reactions, which are especially seen in the continued effect of weak
stimuli, result from alterations of rapidity, which the individual
members of the vital processes have primarily undergone from this
influence.
[52] _Max Verworn_: “Die cellularphysiologische Grundlage des
Gedächtnisses.” Zeitschrift f. allgemeine Physiologie, Bd. VI, 1907.
[53] _Max Verworn_: “Allgemeine Physiologie.” V. Aufl. 1909, pages
649–671.
It is perhaps expedient to cite a concrete instance in illustration.
A simple example is furnished by asphyxiation. If oxygen is withdrawn
from any living organism, the result is a depression of its oxydation
processes. Here there is primarily only a change in rapidity,
especially a retardation of oxydation processes. The metabolism,
however, proceeds, the disintegration of living substance continues,
although at a slower rate, but produces an accumulation of other
products. Whereas formerly during the existence of a sufficient supply
of oxygen an oxydative disintegration of nitrogen-free groups into
carbon dioxide and water took place, both of which could easily be
eliminated from the cell, the anaërobic disintegration furnishes only
complex products, having a higher carbon content, such as lactic acid,
fatty acids, aceton, etc. These, being more difficult to excrete from
the cell, accumulate. These asphyxiation products have in their turn a
depressing effect and so on. In this way the whole metabolism is forced
into a wrong course. The accumulation of fat in those tissue-cells
with an insufficient blood supply, as we have seen in the case of the
fat metamorphosis, is doubtless brought about in the same manner by
relative oxygen insufficiency. The fatty acids accumulate as products
of an incomplete combustion and combine with glycerine to form neutral
fats. In like manner it may be that the accumulation of amyloid
substance in amyloid metamorphosis, of lime salts in arteriosclerosis,
etc., is produced by a primary depression of the individual constituent
processes of the particular cells.
The relation here described, of the catalytic stimuli to the production
of the metamorphic processes, leads us to the distinctions between
primary and secondary effects of stimulation. Should the general fact
be established, which has up to now only been pointed out in individual
cases, that all the metamorphic processes are merely secondary results
of primary alterations in rapidity of individual metabolic constituent
processes, _then the primary reactions of every stimulus would consist
purely in the excitation or depression of the directly concerned
constituent_. Whether or not, as may be assumed, this primary effect
of stimulation applies to _all_ stimuli, is a question which only the
future can answer.
The metamorphic processes are not, however, the only secondary effects
of stimulation. The influence of long-continued excitation of the
functional constituent processes upon the entire cytoplastic metabolism
can be looked upon as a secondary response. Therefore, they may be
considered as a _secondary_ effect of stimulation which, in contrast to
this _primary excitation_, may be called the _secondary excitation_.
Further: While the secondary excitation and metamorphic processes
are generally produced by the continued existing effects of weak
stimulation, we also observe as the result of a stimulus of short
duration or frequently repeated at brief intervals, but otherwise
not exceeding the physiological limits of intensity, a secondary
effect, which plays a very important part in the activity of the
organism. I refer to fatigue. Here a secondary depression is developed
in connection with the primary excitation, for fatigue of a living
organism must be characterized as a depression of activity. This case
shows that we have to distinguish between a _primary depression_,
as for example, produced by temperature reduction, withdrawal of
food, deficiency of oxygen, etc., which occurs as a direct effect of
stimulation, and _secondary depression_, which as in fatigue is an
_indirect_ result of primary excitation.
After the cessation of a briefly catalytic stimulus, not exceeding the
physiological limit of intensity, another secondary result is observed,
which is of the greatest importance for the continued existence of the
living substance. The catalytic stimulus brings about a disturbance of
the equilibrium of metabolism, which after cessation of the stimulus is
reestablished by the living substance. In other words: recovery takes
place. This fundamental principle has been known for a long time as
the result of observation. If a skeletal muscle of our body has been
activated for a prolonged period by nerve impulses, until it has become
completely fatigued and incapable of work, a recovery takes place on
the cessation of these impulses and the muscle is again capable of
action. Likewise, as the result of strong mental activity during the
day, we are mentally fatigued in the evening; recovery, however, occurs
during the night, which results from the removal of the source of
activity. The next morning finds us refreshed. This restitution occurs
in every cell, and the return of its former capability of action,
which had disappeared under the influence of stimulation, shows that
compensation has taken place of the metabolism of rest, disturbed
by the effects of the stimulus. _Hering_[54] has aptly termed this
restitution as “_the internal self-regulation of metabolism_.” All
recovery after disease is based on this self-regulation. The physician
simply provides, by means of therapy, for the possibility of its taking
place. Healing itself is brought about by the organism. “_Natura sanat,
medicus curat._”
[54] _Ewald Hering_: “Zur Theorie der Vorgänge in der lebendigen
Substanz.” In Lotos, Bd. 19, Prag. 1888.
Finally, a third kind of secondary effect of stimulation claims
our interest. This is the _secondary extension of the result of
stimulation_ from the part of a living organism directly and primarily
affected by the stimulus, to the surrounding structures. All living
substance has the capability of conducting an excitation, which is
produced locally through a catalytic stimulus, to a neighboring part,
not directly affected by the stimulus. It finds its highest development
in the nerve, but in no living structure is it completely absent. This
capability has been frequently termed “_conductivity of stimulation_.”
It is more precise, however, to speak of conductivity of excitation,
for it is not the primary influencing external stimulus which is
conducted in the living substance, but the excitation which it has
produced. I have intentionally considered only the excitating effects
of stimulation, and not those of the depressing reactions, as only
excitations, not depressions, are conducted by the living substance.
These questions, however, demand a closer analysis. Here we were
concerned only with a survey of the general effects of stimulation. If
I, therefore, once more summarize the results which have been gained,
this is most clearly demonstrated by the following scheme:
PRIMARY EFFECTS OF STIMULATION
Excitation Depression
Functional Cytoplastic Functional
SECONDARY EFFECTS OF STIMULATION
Secondary excitation Secondary depression
Conduction of excitation, Metamorphic processes, Self-regulation of
metabolism
This, however, is simply a scheme, like all other schemes, having for
its purpose a superficial survey of the subject.
It brings to some extent order into the overwhelming mass of manifold
effects of stimulation but tells us nothing of the mechanism and
genesis. Our further task must, therefore, be a more thorough analysis
of this field.