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YALE UNIVERSITY
MRS. HEPSA ELY SILLIMAN MEMORIAL LECTURES
IRRITABILITY
SILLIMAN MEMORIAL LECTURES
PUBLISHED BY YALE UNIVERSITY PRESS
ELECTRICITY AND MATTER. _By_ JOSEPH JOHN THOMSON, D.SC., LL.D., PH.D.,
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THE INTEGRATIVE ACTION OF THE NERVOUS SYSTEM. _By_ CHARLES S.
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Physiology in the University of Liverpool_.
_Price $3.50 net; postage 25 cents extra._
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F.R.S., _Macdonald Professor of Physics, McGill University_.
_Price $3.50 net; postage 22 cents._
EXPERIMENTAL AND THEORETICAL APPLICATION OF THERMODYNAMICS TO
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_Price $1.25 net; postage 10 cents extra._
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the John Innes Horticultural Institution, Merton Park, Surrey, England_.
_Price $4.00 net; postage 25 cents extra._
STELLAR MOTIONS, WITH SPECIAL REFERENCE TO MOTIONS DETERMINED BY MEANS
OF THE SPECTROGRAPH. _By_ WILLIAM WALLACE CAMPBELL, SC.D., LL.D.,
_Director of the Lick Observatory, University of California_.
_Price $4.00 net; postage 25 cents extra._
THEORIES OF SOLUTION. _By_ SVANTE AUGUST ARRHENIUS, PH.D., SC.D., M.D.,
_Director of the Physico-Chemical Department of the Nobel Institute,
Stockholm, Sweden_.
_Price $2.25 net; postage 14 cents extra._
IRRITABILITY, A PHYSIOLOGICAL ANALYSIS OF THE GENERAL EFFECT OF STIMULI
IN LIVING SUBSTANCE. _By_ MAX VERWORN, M.D., PH.D., _Professor at Bonn
Physiological Institute_.
_Price $3.50 net; postage 20 cents extra._
IRRITABILITY
A PHYSIOLOGICAL ANALYSIS OF THE GENERAL
EFFECT OF STIMULI IN LIVING SUBSTANCE
BY
MAX VERWORN, M.D., PH.D.
_Professor at Bonn Physiological Institute_
WITH DIAGRAMS AND ILLUSTRATIONS
[Illustration]
NEW HAVEN: YALE UNIVERSITY PRESS
LONDON: HENRY FROWDE
OXFORD UNIVERSITY PRESS
MCMXIII
COPYRIGHT, 1913
BY YALE UNIVERSITY PRESS
First Printed May, 1913, 600 Copies
THE SILLIMAN FOUNDATION.
In the year 1883 a legacy of eighty thousand dollars was left to the
President and Fellows of Yale College in the city of New Haven, to be
held in trust, as a gift from her children, in memory of their beloved
and honored mother, Mrs. Hepsa Ely Silliman.
On this foundation Yale College was requested and directed to establish
an annual course of lectures designed to illustrate the presence and
providence, the wisdom and goodness of God, as manifested in the
natural and moral world. These were to be designated as the Mrs. Hepsa
Ely Silliman Lectures. It is the belief of the testator that any
orderly presentation of the facts of nature or history contributed
to the end of this foundation more effectively than any attempt to
emphasize the elements of doctrine or creed; and he therefore provided
that lectures on dogmatic or polemical theology should be excluded from
the scope of this foundation, and that the subjects should be selected
rather from the domains of natural science and history, giving special
prominence to astronomy, chemistry, geology, and anatomy.
It was further directed that each annual course should be made the
basis of a volume to form part of a series constituting a memorial
to Mrs. Silliman. The memorial fund came into the possession of the
corporation of Yale University in the year 1901; and the present volume
constitutes the ninth of the series of memorial lectures.
PREFACE
The lectures on irritability here published were held at the University
of Yale in October, 1911. When the authorities of that University
honored me by an invitation to give a course of Silliman memorial
lectures, I accepted with the more pleasure as it furnished me with
the opportunity of summarizing the results of numerous experimental
researches carried out with the assistance of my co-workers during
the course of more than two decades in the physiological laboratories
of Jena, Göttingen and Bonn, to unite therewith the results obtained
by other investigators and thus present a uniform exposition of the
general effects and laws of stimulation in the living substance. I have
long entertained this plan and this for the following reason:
The physiologist, the zoölogist, the botanist, the psychologist,
the pathologist, have to deal, day in, day out, with the effects of
stimulation on the living substance. No living substance exists without
stimulation. In the vital manifestations of all organisms the interplay
of the most varied stimuli produces an enormous and manifold variety of
effects. Experimental biological science employs artificial stimulation
as the most important aid in the methodic production of certain effects
of stimulation. The number of researches in which special effects
of stimulation are treated is endless. Nevertheless the systematic
investigation of the effects of stimulation have, curiously enough,
been strangely neglected. Although countless results of individual
effects of stimulation have been studied, the attempt has never been
made to establish a general physiology of the laws of stimulation
and consider it as an independent problem. This circumstance induced
me to systematically investigate the general laws of the effect of
stimulation. In the fifth and sixth chapters of my book on general
physiology the results of these studies are recorded for the first
time. Since then, especially during our own researches on the general
physiology of the nervous system, a great number of new facts of
importance for the general physiology of the effects of stimulation
have been obtained. All these results I have endeavored to combine and
elucidate in the following lectures.
The text of the lectures in its present form was written in German in
1911. The English translation was made by my wife, with the help of
our friend, Dr. Lodholz of the University of Pennsylvania, who also
undertook the reading of the proofs. We wish here to thank him once
again and express our deep appreciation of the great sacrifice of
time and labor involved in this task. I am likewise much indebted to
Dr. Julius Vészi for his assistance unstintingly given, especially in
obtaining a number of curves. Finally, I wish to take this opportunity
to render warmest thanks to the authorities of Yale University, and
especially to President Hadley and Professor Chittenden, as well as
to my special colleagues, for the hospitality and cordial reception
extended to me in New Haven and for the pleasant hours I was privileged
to spend in their midst.
MAX VERWORN.
Bonn.
Physiological Laboratory of the University.
CONTENTS
I
_Contents_: Introductory. Earliest period. _Francis Glisson_ as
founder of the doctrine of irritability. _Albrecht von Haller._ The
vitalists. _Bordeu_ and _Barthez_. _John Brown’s_ system. _Johannes
Müller_ and the specific energy of living substance. _Rudolf
Virchow’s_ doctrine of the irritability of the cell. Discovery of
the inhibitory effects of stimulation. _Weber_, _Schiff_, _Goltz_,
_Setschenow_, _Sherrington_. _Claude Bernard_ studies on narcosis.
Tropisms. _Ehrenberg_, _Engelmann_, _Pfeffer_, _Strassburger_,
_Stahl_. _Semon’s_ speculations on mneme. 1
II
_Contents_: Principles of scientific knowledge and research. Origin
and meaning of the conception of cause. Cause and condition.
Criticism of the conception of cause. The conditional point of view.
Conception of cause. The conditional point of view applied to the
investigation of life. Conception of vital conditions. Definition of
the conception of stimulation. 18
III
_Contents_: The quality of the stimulus. Positive and negative
alterations of the factors which act as vital conditions. Extent of
the alteration in vital conditions or intensity of the stimulus.
Threshold stimuli, sub-threshold, submaximal, maximal and
supermaximal intensities of stimulus. Relations between the intensity
of stimulus and the amount of response. The _Weber_ and _Fechner_
law. All or none law. Time relations of the course of the stimulus.
Form of individual stimulus. Absolute and relative rapidity in the
course of the stimulus. Duration of the stimulus after reaching its
highest point. Adaptation to persistent stimuli. Series of individual
stimuli. Rhythmical stimuli. The _Nernst_ law. 39
IV
_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. 65
V
_Contents_: Indicators for the investigation of the process of
excitation. Latent period. The question of the existence of
assimilatory excitations. Dissimilatory excitations. Excitations of
the partial components of functional metabolism. Production of energy
in the chemical splitting up processes. Oxydative and anoxydative
disintegration. Theory of oxydative disintegration. Dependence
of irritability on oxygen. Experiments on unicellular organisms,
nerve centers and nerve fibers. Restitution after disintegration by
metabolic self-regulation. Organic reserve supplies of the cell.
The question of a reserve supply of oxygen of the cell. Metabolic
self-regulation as a form of the law of mass effect, and metabolic
equilibrium as a condition of chemical equilibrium. Functional
hypertrophy. 87
VI
_Contents_: Only processes of excitation are conducted, not
processes of depression. Conduction of excitation in its two extreme
instances. Conduction in undifferentiated pseudopod protoplasm of
rhizopoda. Conduction of excitation with decrement of intensity
and rapidity. Conduction of excitation in the nerve. Rapidity of
conduction. Conduction of excitation without decrement. Relation
between irritability and conductivity. Conduction of excitation with
decrement of the nerve after artificial depression of irritability by
narcosis. Theory of the decrementless conduction of the normal nerve.
Proof of the validity of the “all or none law” in the medullated
nerve. Theory of the process of the conductivity of excitation.
Theory of core model (Kernleiter). Electrochemical theory of
conduction based on the properties of semi-permeable surfaces. 118
VII
_Contents_: Conception of specific irritability. Alteration of
specific irritability during and after excitation. Refractory
period in various forms of living substance. Absolute and relative
refractory period. Curve of irritability during refractory period.
Dependence of the duration of the refractory period on the rapidity
of the course of the metabolic processes in the living substance.
Dependence on temperature. Dependence on supply of oxygen. Theory of
refractory period. Refractory period as basis of fatigue. Fatigue as
a form of asphyxiation. Alterations of irritability and the course
of excitation in fatigue. Recovery from fatigue. The rôle played by
oxygen in recovery. Fatigue as an expression of the prolongation of
the refractory period conditioned by the relative want of oxygen.
Fatigue of the nerve. 154
VIII
_Contents_: Examples of effects of interference of stimuli in
unicellular organisms. Interference of galvanic and thermic
stimuli in Paramecia. Interference of galvanic and thermic stimuli
and narcotics. Interference of galvanic and mechanical stimuli.
Interference of galvanotaxis and thigmotaxis in Paramecia and hypotin
infusoria. Real or homotop interference, apparent or heterotop
interference. The two effects of homotop interference of excitations:
Summation and inhibition of excitations. Theory of the processes of
inhibition. _Hering-Gaskell_ Theory. Inhibition as an expression
of the refractory period. Individual possibilities of interference
of two stimuli. Interference of an excitating and a depressing
stimulus. Interference of two depressing stimuli. Interference of two
excitating stimuli. Analysis of the interference of two excitations.
Interference of two single stimuli. Conditions upon which the
result of interference is dependent. Heterobole and isobole living
systems. Intensity of the two stimuli. Interval between the stimuli.
Specific irritability and rapidity of reaction of the living system.
Latent period. Interference of single stimuli in a series. General
scheme of the development of the effect of interference. Summation
and inhibition. Apparent increase of irritability. Conditions of
summation. Tonic excitations. Conditions of inhibitions. Various
types of inhibition. Interference of two series of stimuli. Relations
in the nervous system. Peculiarities of the nerve fibers. Conversion
of the nerve by relative fatigue from an isobolic into a heterobolic
system. 189
IX
_Contents_: Necessity of cellular physiological analysis of toxic
depressions by pharmacology. Apparent variety of processes of
depression. Depression of oxydative disintegration as the most
extended principle in the processes of depression. Asphyxiation,
fatigue, heat depression, as a consequence of restriction of
oxydative disintegration. Narcosis. Theories of narcosis. The
alteration of specific irritability and conductivity in narcosis.
Depression of oxydative processes in narcosis. Asphyxiation of
living substance when oxygen is present during narcosis. Persistence
of anoxydative disintegration in narcosis. Increase of the same by
stimuli. Depression by narcosis as a form of acute asphyxiation.
Hypothesis on the mechanism of depression of oxygen exchange by
narcotics. Possibility of combining the facts with the observations
of _Meyer_ and _Overton_. 235
IRRITABILITY
CHAPTER I
THE HISTORY OF THE SUBJECT
_Contents_: Introductory. Earliest period. _Francis Glisson_ as
founder of the doctrine of irritability. _Albrecht von Haller._ The
vitalists. _Bordeu_ and _Barthez_. _John Brown’s_ system. _Johannes
Müller_ and the specific energy of living substance. _Rudolf
Virchow’s_ doctrine of the irritability of the cell. Discovery of
the inhibitory effects of stimulation. _Weber_, _Schiff_, _Goltz_,
_Setschenow_, _Sherrington_. _Claude Bernard_ studies on narcosis.
Tropisms. _Ehrenberg_, _Engelmann_, _Pfeffer_, _Strassburger_,
_Stahl_. _Semon’s_ speculations on mneme.
Irritability is a _general_ property of living substance but not
exclusively so. Irritable systems also exist in inanimate nature. What
characterizes living substances is not irritability as _such_, but
an irritability of a specific type. The irritability of the living
system can, therefore, not be studied alone, but as the properties of
a living system are dependent upon each other, so this property must
be considered with the others possessed by a living substance. In this
sense irritability presents a problem of fundamental physiological
importance. For if we could analyze the irritability of living
substance to its essence, then the nature of life itself would be
fathomed. The analysis of irritability of living substance offers us,
therefore, a path to the investigation of life and herein lies the
importance of the study of irritability.
I wish to follow this path toward the knowledge of the vital processes
and to endeavor to show in these lectures what information the analysis
of irritability and that of the effect of stimuli can give us of the
mechanism of the processes in living substance. Before doing so,
however, I wish to consider somewhat more in detail the question as to
how we have arrived at the conception of the nature of irritability.
To the thinkers both in the field of physiology and medicine of
ancient and mediæval times the conception of irritability was quite
foreign. Even a comprehension of the nature of stimuli had not yet
begun to crystallize from vague impressions of the various influences
of different agents on the human being. Nevertheless they knew of
such influences of the most varying kinds upon the human body. The
ancients already possessed a materia medica, founded on the real or
supposed influence of various mineral, vegetable and animal substances
upon the organism. It was also known that heat and cold, light and
darkness had an effect upon disease. They likewise believed in the
influence of certain factors upon the health of man, which in reality
have no effect whatsoever, as the stars and the magnet. But neither
in ancient nor in mediæval times was the state of knowledge reached
wherein generalizations were made from these agents, which had a real
or supposed action upon the organism, and to combine these to a general
conception of stimulation.
The conception of stimulation and irritability cannot however be
separated.
The founder of the doctrine of the irritability of living substance
is _Francis Glisson_ (1597–1677), member of the _Collegium Medicum_
in London and at the same time Professor in Cambridge. It is a fact
also not altogether without interest, that _Glisson_ at the same time
was in a certain sense a forerunner of those who interpreted nature
from a physical standpoint. _Glisson_ as an anatomist and physiologist
was an excellent observer and experimenter, but the most prominent
trait of his character was his inclination to philosophic observation
and analysis of nature. His “_Tractatus de natura substantiæ
energetica_”[1] must, therefore, be considered as the chief work of
his life. In this voluminous book _Glisson_ develops an entire system
of natural philosophy, which in accord with the character of the
philosophy of that time is unfortunately of an absolutely speculative
nature and which had hardly emancipated itself from the scholasticism
of the preceding period of thought. When the ideas of _Glisson_ are
isolated from the wilderness of scholastic phraseology, the system
is somewhat as follows. The basis of all existence, “_substance_,”
has according to him two general properties, its “_fundamental
subsistence_,” that is, the essence of its being, and its “_energetic
subsistence_,” that is, the essence of its activity. To these are added
the properties possessed in specific cases, that is, its “_additional
subsistence_.” The energetic subsistence forms the basis of all life.
Life is therefore present not only in organic nature, but in all
nature which is characterized by the union of the general energetic
subsistence with the special additional subsistence of an animal and
vegetable nature. In other forms of life in nature the energetic
subsistence is combined with other special forms of the additional
subsistence. The universal essence of all life, that is the energetic
subsistence, has only three fundamental faculties: the “_appetitiva_,”
the “_perceptiva_” and the “_motiva_.” The _modus_ is the result
of a “_perceptio_,” but the “_perceptio_” is not thinkable unless
the object has the “_appetitus_” to receive the external influence.
_Glisson’s_ doctrine of irritability is based on this conception, which
he develops in a second work already begun before the “_Tractatus de
natura substantiæ_,” but not finished until later and only published
after his death. In this “_Tractatus de ventriculo et intestinis_,”[2]
_Glisson_ dwells in detail on the physiological properties of
animal structures and develops for the first time his conception
of irritability in the chapter “_De irritabilitate fibrarum_.” The
“irritability” manifests itself in the appearance of the alteration of
movement, which is brought about by external influences on the animal
structure, for: “_Motiva fibrarum facultas nisi irritabilis foret,
vel, perpetuo quiesceret, vel perpetuo idem ageret._” The fundamental
factor of this irritability _Glisson_ attributes to the “_perceptio_,”
which he distinguishes as a “_perceptio naturalis_, _sensitiva_ and
_animalis_.” The want of clearness produced here by _Glisson’s_
artificial distinctions and mode of expression is in part removed
if we endeavor to transfer his meaning into our present methods of
thought. This distinction would then simply point out the different
means by which the stimuli can reach the irritable structures. The
“_Perceptio naturalis_” is that which today we should call “direct
response” to stimulation, that is, the excitation of the fiber by
artificial stimuli applied directly to the tissue. _Glisson_ shows
here, that the intestines and muscles in the body immediately after
death and even when removed from the body can be stimulated to movement
by means of corrosive fluids or cold. The “_Perceptio sensitiva_”
is, according to _Glisson_, the excitation of the fibers by external
stimuli which act on the intact body as a whole by way of the sensory
nerves. The “_Perceptio ab appetitu animali regulata_” finally is the
excitation by inner stimuli proceeding from the brain. The _Perceptio
naturalis_ is possessed by all parts of the body, even the fluids,
the bones and the fat. All of them are irritable. But a “vitale” and
a special “animal” irritability they do not possess to a perceptible
degree. These forms of irritability belong only to the special parts
of the body. Here, however, the distinctions made by _Glisson_, are
quite vague and contradictory. In his “_Tractatus de ventriculo et
intestinis_” _Glisson_ sharply distinguishes the “_sensatio_” from the
“_perceptio_.” The perceptio in itself is not a sensation, for although
individual organs of the body are irritable, as they all possess a
“perceptio,” they are not in themselves sensitive. The “_sensatio_,”
the sensation, only arises when the external “_perceptio_” of the
individual organs combine through the nerves with the internal
“perceptio” of the brain. “_Nisi enim percepto externa ab interna simul
percipiatur, non est cognitio sensitiva completa._” Sensitivity is,
therefore, a special faculty, that is only based upon irritability.
[1] _Franciscus Glissonius_: “Tractatus de natura substantiæ
energetica seu de vita natura ejusque tribus primis facultatibus
perceptiva, appetitiva, motiva,” etc. Londini M D C L XXII.
[2] _Franciscus Glissonius_: “Tractatus de ventriculo et intestinis
cui præmittitur alius de partibus continentibus in genere et in
specie de iis abdominis.” Amstelodami M D C L XXVII.
I have treated the views of _Glisson_ somewhat in detail for on the one
hand this seemed to me to be only due to the founder of the doctrine
of irritability, and on the other we have here for the first time,
although in somewhat vague and little worked out form, the discovery
of a general property of all living substance, and its fundamental
importance for the life of the organisms. One might, therefore, in
a _certain_ sense, date from _Glisson_ the beginning of general
physiology, and all the more so, because _Glisson_ from the very
first connected the irritability of the living substance through its
possessing universal energy with the phenomena in nature generally,
just as we do today two hundred years after, on the basis of the modern
teachings of energy.
It might appear strange that a teaching of such fundamental importance
as that of _Glisson’s_ theory of irritability was not at once accepted
on all sides and further developed. There were two reasons, however,
which prevented this. Firstly, _Glisson_ did not devote himself to his
post of teacher at the University of Cambridge with any particular
zeal and so consequently did not establish a school of his own, to
further work out and develop his ideas. Secondly, his doctrines were
so speculative and difficult to understand, his differentiations and
definitions so artificial and labored, that it required the greatest
effort to penetrate to his fundamental conceptions and so it happened
that _Glisson’s_ theory of irritability received attention only at a
comparatively late date. Even then, of his speculative theories hardly
more than the name “doctrine of irritability” was adopted. Since the
middle of the eighteenth century this name, however, was destined to
lead to excited controversies.
The first attempt to give _Glisson’s_ expression “irritability” a more
concrete meaning was made by _Haller_ (1708–1777)[3]. Unfortunately,
though, he confined this conception solely to muscles, in that he
understood by the term irritability “the capability of the muscles to
contract, when stimulated, as the result of vital force (_vi viva_).”
He, therefore, applied the term “irritability” to that which we today
refer to as “contractility.” On the other hand he applied the term
contractility solely to a property possessed by other living and
dead animal as well as vegetable matter, elasticity, that is, the
capability to resume its original form after distortion. He makes a
sharp distinction between “irritability,” which manifests itself by a
contraction of the muscles after stimulation by its own vital force
(_vi viva_), and the “sensitivity,” which is possessed only by the
nervous system. “_Sola fibra muscularis contrahitur vi viva; sentit
solus nervus et quæ nervos acciperunt animales partes._” By confining
the conception of irritability to a single living substance, the
muscle, _Haller’s_ theory represents a great regression in comparison
to the correct fundamental thoughts of _Glisson_. This unfortunate
use of the term of “irritability,” “contractility” and “sensitivity”
has opened wide the gates to confusion and misunderstanding. This
confusion was still further augmented by the fact that the vitalistic
school of Montpelier confused the idea of vital force with that
of irritability. In the works of _Bordeu_ (1722–1776) these views
are comparatively clear, if one bears in mind that he substitutes
_Glisson’s_ term of “_irritability_” with that of “_sensitivity_.” He
assumes a “_sensibilité générale_” or a common property of all living
structures, both solid and fluid. Besides this, each different part
has according to him its “_sensibilité propre_.” Here in place of the
clear conception of irritability we find one of more or less mythical
nature possessing traces of _Stahl’s_ “anima.” Nevertheless we observe
here the idea that all living organisms possess in common a capability
to respond to stimuli. Even though _Bordeu’s_ differentiation of the
“sensibilité propre” and the “sensibilité générale” is too artificial
and the coexistence of both not justifiable, his discussion of the
“sensibilité propre” shows that he is already on the track of the
characteristics of the effect of stimuli which only later under the
name of “specific energy” was clearly recognized as a fundamental
property of all living substance. On the other hand the celebrated
pupil of _Bordeu_, _Barthez_ (1734–1806), accepted the existence of
a meaningless vital principle, the “_principe vitale_,” governing
all vital manifestations. The two forms of vital force of all living
substances, the “_forces sensitives_” and the “_forces motrices_,”
were according to his views manifestations of this vital principle.
He differentiates the “_force sensitive_” into a “_sensibilité avec
perception_” and “_sensibilité sans perception_,” using the term
sensibility in the sense adopted by _Bordeu_ and which today we, with
_Glisson_, call irritability.
[3] _Albrecht v. Haller_: “Elementa Physiologiæ corporis humani.”
Tomus IV. Lausannæ M D C L XVI.
In this way serious thinkers of that time trifled with the words
irritability, sensitivity, contractility, perception. This led to
futile conceptions, which equalled the phantasies of the worst period
of speculative philosophy and which in no way led to progress. Hence it
is easy to understand that numerous attempts were made in those days
to reconcile in some way these different conceptions. An explanation,
which was the beginning of further development, came from England in
the works of _John Brown_ (1735–1788),[4] a man who was as talented
as he was dissolute. _Brown_ was an independent thinker, not without
genius, whose knowledge in practice and theory, however, was limited.
This combination in his mentality enabled him to observe the problems
somewhat differently than through the glasses of the usual conceptions
of that time. In direct opposition to his teacher _Cullen_ (1712–1790),
one of the leading minds in the medical school of Edinburgh, who
considered irritability only as an effect of sensibility and pronounced
the latter a specific property of the nervous system, _Brown_ took the
standpoint that all living substance, vegetable as well as animal, in
contrast to lifeless matter, possessed a fundamental property which he
designated as excitability, that is to say, the capability of being
stimulated to specific vital manifestations through external factors
or “stimuli,” in which sensitivity and indeed all mental processes
as well as movement are interpreted as specific effects, which the
“stimuli” produce on the irritable organs. This was an important
advance and from a wilderness of trifling conceptions his observations
led to a clearer knowledge of this subject. But _Brown_ went even
further. In his so-called “theory of irritation,” he has presented
a whole system of responsivity to stimulation, which in the first
chapters of his chief work he expounds with wonderful clearness. The
fundamental principles here established must be accepted even today.
The essential basis of this “theory of irritability” which he worked
out especially for his doctrine of disease, and which has also played
an important part in pathology, is the following: Every living, that
is, excitable system, is continually influenced by stimuli. The stimuli
consist of either external factors, such as heat, food, foreign matter,
poisons, etc., or inner factors which result from the influence of
the activity of one organ upon another. Only as a result of the
continual action of stimuli is life maintained, in that the stimuli
produce continual “excitement” in the irritable substance. The degree
of irritability differs in various plants, animals, in different
structures of the body, and even in the same individual at different
times under different circumstances. The strength of the “excitement”
depends on the one hand upon the degree of irritability, and on the
other upon the strength of the stimulus. The irritability itself is
influenced and changed by the action of the stimuli. If the stimuli are
too strong and are of prolonged duration, the irritability diminishes
as a result of exhaustion; if weak stimuli act during a prolonged
time, the irritability increases. The healthy organism has a mean
degree of irritability. Disease occurs when this state is altered by
_strong_ stimuli or by an _absence_ of stimulation. Disease and health,
therefore, differ not qualitatively but only quantitatively. It is here
seen that we have the first attempt at a systematic interpretation
of the effects of stimulation, and it is astonishing how sharply and
successfully _Brown_ has pointed out the foundations of this important
field. He has in this way not only amply compensated for the great
setback in the history of the teaching of irritability produced by
the confusions of conceptions created by _Haller_ and the vitalists,
but also placed the whole of the physiology of stimulation on a firm
foundation upon which it is possible to build further. Though it is
true that many of his special theories, in particular those on nature
and the origin of disease, are quite erroneous, still a just critic
must judge work in relation to the period in which it was written, and
I question if at the present day the science of medicine does _not_
contain teachings which in a hundred years will also prove untenable.
[4] _John Brown_: “Elementa medicinæ.” 1778. English translation.
London 1778.
_Johannes Müller_ (1801–1858) then added an important stone to the
building up of our knowledge of irritability. This was the clear
recognition of the _specific energy_ of living substances. We have
already found the germ in _Bordeu’s_ term “_sensibilité propre_” or
“_sensibilité particulière_.” _Brown_ was also of the opinion that
different living objects possessed different types of irritability and
that excitation of their special functions was not dependent upon
the _kind_ of stimulus acting upon them. _Johannes Müller_, grasping
the idea hidden in this presentation, transformed it into a clear
and fundamental conception. Already in the work written in his early
years treating of optical illusions he says:[5] “It is immaterial by
which means the muscle is stimulated, whether by galvanism, chemical
agents, mechanical irritation, inner organic stimuli or sympathetic
response from quite different organs; to every means by which it is
stimulated and an effect produced, it responds by movement. Movement
is, therefore, the _effect_ and the _energy_ of the muscle at the same
time.” “Thus it is throughout with all reactions in the organisms.”
“The sensory nerve, responding to any stimulus of whatever kind, has
its specific energy; pressure, friction, galvanism and inner organic
stimuli produce in nerves of sight that which is peculiar to them,
light sensation; in the nerves of hearing, that which is peculiar to
them, sound sensation; and in the nerves of touch, touch sensations.
On the other hand, everything which affects a secretory organ produces
change of the secretion; that which affects the muscle, movement.
Galvanism is not superior to any other methods, of whatever kind,
which can bring about stimulation.” And in his handbook of physiology
_Johannes Müller_[6] formulates the law of specific energy for the
sensory structures briefly in the following words: “The same external
factor produces different sensations in the different senses according
to the nature of each sense, namely, the sensation of the particular
sensory nerves; and the reverse: the characteristic sensations peculiar
to every sensory nerve can be produced by several internal and external
influences.” This doctrine of the specific energy of the sense
substance possesses an importance which extends far beyond the domain
of the physiology of stimulation, for it forms the basis on which the
whole theory of human knowledge must be built up, no matter how it may
be constructed in detail.
[5] _Johannes Müller_: “Über die phantastischen
Gesichtserscheinungen. Eine physiologische Untersuchung mit
einer physiologischen Urkunde des Aristotles über den Traum, den
Physiologen und den Arzten gewidmet.” Coblenz 1826.
[6] _Johannes Müller_: “Handbuch der Physiologie des Menschen für
Vorlesungen.” Coblenz 1837.
As _Johannes Müller_ already clearly emphasizes, it is here not
the question of a law confined to the sense substance, but one that
applies to all living substances. Every living substance has its
“specific energy,” that is, its characteristic vital phenomena and
this is produced by stimuli of the most varied kind. This doctrine
received an extension of inestimable value for its future development
by the great discovery of _Schleiden_, that the cell is the elementary
building stone of the plant organism. Subsequently _Schwann_ at the
instigation of _Schleiden_ made further investigations and found that
this discovery applied also to the animal organism. Irritability
having been recognized as a general property of living substance,
it followed that, after the foundation of the cell doctrine, every
cell must possess irritability and have its own specific energy. It
now became necessary to study the manifestations of irritability of
the cells in their specific form. Strange to say, this was done at
an earlier date in pathology than in physiology. Indeed, since the
time of _Brown_ the study of irritability was furthered far more by
pathology than by physiology. The chief reason for this is probably the
great practical interest that the investigation of disease possesses,
_Brown_ having already quite correctly ascribed the existence of
disease to the relations of the organism or its parts to stimuli.
_Rudolph Virchow_ then, after the establishment of the cell doctrine,
arrived at the momentous conclusion, that disease must be considered as
reactions of the body cells to stimuli. In his epoch-making “Cellular
pathologie,”[7] he has carried out this idea in a classical manner.
By irritability _Virchow_ understands “a property of the cells, by
virtue of which they are set into activity, when affected by external
influences.” There are, however, _various_ kinds of actions which
can be brought about by external influences. But essentially there
are three kinds. The effects produced are functional, nutritive,
formative. The result of excitation, or if one will, of stimulation of
a living part, can, therefore, according to circumstances, be either
merely a functional process, or there can be a more or less intense
nutritive activity produced without the function being necessarily at
the same time activated, or finally, it is possible that a process of
formative change may occur which produces new elements in greater or
less numbers. _Virchow_ touches here for the first time upon a question
of extraordinary moment, the important bearings of which have only
now begun to be recognized and seriously considered. We now know, for
example, that the functional excitation can be separated to a certain
degree from the cytoplastic excitation of the muscle. If the muscle is
acted upon by functional stimuli, the excitation takes place mainly in
the form of functional metabolism, nitrogen-free substances are broken
down in increased quantities, whereas cytoplastic metabolism, which
produces more profound alteration in the living substance, and which
goes so far as to bring about a breaking down and building up of the
nitrogen containing atom groups, is hardly at all increased. It would
be an error, however, to look upon these different kinds of metabolism
as quite independent. Considering the close correlation which all the
phases of metabolism bear to each other, this idea cannot well be
entertained. If, however, we question in what manner, for instance,
the functional and the cytoplastic metabolism are linked together, we
have a problem before us which does not belong to the past, but to the
present and future. Indeed, _Virchow_ seems already to have felt that
a sharp division between the different phases and parts of functional
metabolism in the cell does not exist, for he says: “It is true
that it cannot be denied that, especially between the nutritive and
formative processes and likewise between the functional and nutritive,
intermediate gradations occur.” Still they differ essentially in
their characteristic action and in the internal alterations which
the stimulated part undergoes, depending on whether it functionates,
nourishes itself, or is the seat of special growth. Disease consists of
the influence of stimuli upon these physiological processes. The law
of the specific energy of living substance is as clearly expressed in
functional disease as it is in the physiological effects of stimuli.
The pathological disturbance of function is purely quantitative,
“nowhere is there a qualitative divergence.” The function exists or
it does _not_ exist. If it is present, it is either strengthened or
weakened. This gives the three fundamental forms of disturbance:
absence, weakening and strengthening of the function. No function
other than the physiological, even under the greatest pathological
alterations, exists in any _structure_ of the body. “The muscle does
_not_ perceive, the nerve moves no bone, the cartilage does not think.”
In this way _Virchow_ rediscovered in the domain of pathology the
law that his great teacher, _Johannes Müller_, had already clearly
established in the field of physiology. But this law can no longer be
applied to all pathological disturbances of the nutritive and formative
activities of the cell. Here processes occur which do not consist of
a quantitative change of the normal phenomena, but in the appearance
of wholly foreign states, as in the case of amyloid degeneration or
heteroplastic tumors. The question today and for the future arises,
therefore, as to where the limits of the validity of the law of the
specific energy of living substances are to be placed, a question
closely connected with the other before mentioned, of the relations
between functional and cytoplastic metabolism.
[7] _Rudolph Virchow_: Die Zellularpathologie in ihrer Begründung auf
physiologische und pathologische Gewebelehre. 1 Aufl. Berlin 1858–4
Aufl. 1871.
By means of cell pathology _Virchow_ has laid the foundations upon
which our modern medical attitude is built and which must remain
essentially forever the basis of all future medical thought. Certain
critics, lacking in appreciation of the interrelations between things
and ignoring the safer and established knowledge, have considered,
in view of the unfoldings of the researches on immunity and of serum
therapy, that the time of cell-pathology was _passed_ and must be
replaced by the humoral-pathological teaching. These ultramodern
critics, however, have here completely ignored the fact that, on the
one hand, the life of our body is built up from the life of all of the
contained cells, for life in our body exists only in the cells; and on
the other, a fact not considered by them is that the components of the
body fluids originate from vital activity of the cells either directly
or indirectly. No result, indeed, of present serology can alter in the
least degree the fact that every disease represents only a disturbance
of the physiological processes of cell life of the organism and the
harmony in their combined workings. Indeed the more recent observations
of serology and chemotherapy are so little opposed to cell-pathology
that they are in fact only possible when based on the latter. They are
only comprehensible then from the unfoldings of cellular pathology.
Until quite recently all those effects of external factors on the
living substance which consist in excitation, that is, in an increase
of their specific vital processes, have always stood in the foreground
of all researches and observations on irritability. It was gradually,
however, more and more recognized that the depressing influence of
stimuli played a great rôle in the vital process of the organism.
_Brown_ was acquainted with exhaustion produced by stimuli, and the
discussion of “asthenic” diseases, in which the irritability was
reduced, occupied an important place in his pathology. That, however,
in the normal activities of the organism such depression or lessening
of vital manifestation could result from the influence of stimulation,
first became clear after the brothers _Weber_[8] in 1846 discovered the
inhibitory effects of the galvanic stimulation of the vagus upon the
heart.
[8] _Eduard Weber_: “Muskelbewegung.” Article in Wagner’s
Handwörterbuch der Physiologie, Bd. 3. Braunschweig 1846.
Since then the inhibitory processes in nerves have been frequently
investigated by _Schiff_ (1823–1896), _Goltz_ (1834–1901) and others,
who gave us a theory concerning the same. Only a small number of
inhibitory processes were known at that time, as for instance the
inhibition of the croak reflex of the frog, or the inhibition of
the grasp reflex during copulation of these animals through skin
stimuli, and a few other cases. They regarded the inhibitory nervous
processes as a special state, of which the inhibition of the heart
through the vagus was the best illustration. Further, the Russian
physiologist _Setschenow_ succeeded by directly stimulating certain
parts of the central nervous system, especially the optic lobes of
the frog, in producing inhibition. It was, therefore, frequently
assumed, as _Setschenow_ did, that in the brain there exist special
inhibitory centers, just as there are motor centers. This view was
later shown to be untenable. It is only quite recently, and especially
since _Sherrington_ has shown that inhibition plays a part in all
antagonistic muscle movements, that we have obtained a broad and more
thorough understanding of the inhibitory processes in the life of the
organism, and a physiological explanation of this important group of
activities of the central nervous system. This inhibitory effect of
stimulation, brought about by the involvement of the central nervous
system in the normal organism, was studied side by side with the
depressing effects of stimulation. _Claude Bernard_ (1813–1878)[9]
first discovered that the excitation of all living substance could
be depressed or totally suspended through the influence of certain
anæsthetics, such as ether or chloroform. By a series of experiments,
as simple as they were convincing, the French scientist showed that
irritability could be depressed in mimosa leaves, the growth of
germinating plant seeds and the ferment action of yeast cells stopped,
likewise the disintegration of the carbon dioxide in the cells of the
green leaf, as well as the development of the egg cells, and also the
movements of the animal organism and the sensations of man. By this
means he recognized that not only does all living protoplasm possess
irritability, but that it can also by means of certain substances
be put into the condition of “anæsthesia,” a state dependent upon
a change of the protoplasm, which he termed “semi-coagulation.”
Finally, besides the more apparent processes of excitation and those
less so, belonging to the group of inhibition and depression, in
the last century the knowledge of the subject was greatly increased
by the addition of another group, which recently in consequence of
various reasons has met with particular interest. These being effects
of stimuli on the direction of movements of motile organisms, it
became more and more recognized that these curious manifestations of
irritability, which appeared to have such a surprising likeness to
the mysterious attraction and repulsion in the sphere of electricity
and magnetism, occur universally in the vegetable as well as in
the animal world. These movements are of the greatest biological
importance for the obtaining of food, propagation, protection against
disease, etc. Botanists have long known of the geotaxis of the roots
and stems of plants, the heliotaxis of their leaves and flowers
and of the thigmotaxis of their tendrils. Likewise the phototaxis
of freely moving protistæ had been often observed, especially by
_Ehrenberg_[10] of Berlin, well known for his researches on infusoria.
Then _Engelmann_, _Pfeffer_, _Strassburger_, _Stahl_, and many others
discovered and studied more carefully the facts concerning chemotaxis,
thigmotaxis, rheotaxis, geotaxis, phototaxis, etc., of bacteria, motile
spores, rhizopoda, and so on. The question arose if one should regard
this singular behavior of the unicellular organisms as an expression
of conscious sensations, discrimination or will. This view was as
determinedly denied on the one hand as it was accepted on the other.
Whilst even today certain scientists still consider the reactions of
the unicellular organisms as a manifestation of conscious sensation,
discrimination or will, others look upon them as unconscious reflex
reactions of cell organism, taking place as purely mechanically as
the spinal cord reflexes of vertebrates. This divergence of opinion
would have practically no value for the development of our knowledge
of irritability had not here, as in the case of the relations between
the mental and physical processes in man, the view been entertained
with more or less fervor, that at some stage or other in the chain
of the purely physiological processes of responsivity, an intangible
factor had been introduced which was considered as the essential
“cause” of the peculiar reactions to stimuli. It is not here the
place to enter into the question if, and in what degree, animal
psychology may be a field of scientific research. Even if one looks
upon conscious processes as effects of stimulation, in both lower
animals and in man, in no case should one assume them to be factors
of an essentially different nature, interrupting the chain of the
mechanical reactions; neither should one consider the particular
characteristic responses observed in unicellular organisms as effects
of non-mechanical “causes.” As a result, a mysticism, in reality quite
foreign to it, would be introduced into physiology. As a matter of fact
the physiological investigations for the tropic reactions of stimuli,
which have been carried out in great number since the end of the
eighties, have shown more and more clearly that this peculiar behavior
of unicellular organisms towards unilateral stimuli is produced by a
comparatively simple mechanism. The analysis of this shows a difference
in the intensity of the exciting or depressing effect produced by the
stimulus. The stimulus exerts its influence unequally upon the specific
activity of the motor elements of different parts of the surface of the
cell body. This difference in response causes the axis of the freely
moving organism to assume a different direction in which to move. It
is _compelled_ to move in a definite direction and so, in this field,
the apparently mysterious attraction and repulsion of living organisms
toward stimuli has, by means of the most simple analysis, been robbed
of its mystical character.
[9] _Claude Bernard_: “Lecons sur les phénomènes de la vie communs
aux animaux et aux végétaux.” Paris 1878.
[10] _Ehrenberg_: “Die Infusionstiere als vollkommene Organismen.”
Leipzig 1838.
Finally, I should like to touch briefly upon a view of the irritability
of living substance which has recently been brought forward by
_Semon_.[11] It assumes the proportions of a whole system and is
proclaimed as a basis for the comprehension of organic phenomena. It
originated with an idea which _Hering_[12] developed many years ago
and which later was accepted by _Haeckel_,[13] namely that heredity
is a species of memory of the living substance. _Semon_ attributes to
living substance, in contrast to non-living, a “_Mneme_.” By “_Mneme_”
he understands the capability of living substance to assume, through
the influence of a stimulus, a permanently altered condition. The
latent alteration resulting from the stimulus he terms “_Engramm_.”
These “_Engramms_” can later, however, not only be activated by the
reapplication of the original stimulus, but also by other stimuli,
so that the state of excitation once brought about by the original
stimulus reappears. _Semon_ calls the reproduction of the state of
primary excitation by a later stimulus “_Ekphorie_.” A great number of
other new word formations, such as “_chronogene Engramme_,” “_phasogene
Ekphorie_,” “_mnemische Homophonie_,” “_mnemisches Protomer_” and
countless others are supposed to serve for the better understanding
of a series of special facts, chiefly in the domain of the processes
of heredity. That which is termed “_Mneme_” and “_Engramm_” is not
further analyzed. _Semon_ expressly declines to discuss the kind of
alterations in which the physical or chemical nature of an “_Engramm_”
consists. Hence physiological analysis has not been advanced in any way
by _Semon’s_ new formation of words applied to long-known facts. With
a series of new expressions the originator of the “_Mneme doctrine_”
deceives himself, as well as a number of his readers not endowed with
the critical faculty, into supposing that he has achieved a serious
analysis. Of such, however, there is not a trace. As can be conceived,
this way of treating the manifestations of life has met with no further
attention from the physiological side. For indeed, what physiologist
would consider that the fact of muscle responding by a contraction
to an induction shock, or to any other stimulus, is sufficiently
analyzed by the explanation that we have the “_Ekphorie_” of a state of
excitation that was once previously produced by an original stimulus
of some unknown kind, and of which the living substance of the muscle,
in consequence of its “_Mneme_,” has retained a latent “_Engramm_”?
Here the deep gulf is apparent which exists between the demands of
a physiological analysis and the futile explanation of the mneme
doctrine. Physiological investigation must reject such a manner of
treating its problems.
[11] _Semon_: “Die Mneme als erhaltendes Princip im Wechsel des
organischen Geschehens.” Zweite verbesserte Auflage, Leipzig.
[12] _Ewald Hering_: “Uber das Gedächtniss als allgemeine Function
der organischen Materie.” Wein 1876.
[13] _Ernst Haeckel_: “Die Perigenesis der Plastidule oder die
Wellenzeugung der Lebenstheilchen.” Berlin 1876.
With this the history of the doctrine of irritability enters into its
present phase of development. To future research remains then the
problem of further analyzing irritability, this common property of
living substance, and finally rendering it into its simplest chemical
and physical components. This last goal can only be approached very
gradually, step by step. With the analysis of irritability we shall
investigate life itself. In the following lectures it will be my
endeavor to show how far, with our present knowledge, we can penetrate
by this path into the great secret.