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MRS. HEPSA ELY SILLIMAN MEMORIAL
LECTURES
ORGANISM AND ENVIRONMENT AS ILLUSTRATED
BY THE PHYSIOLOGY OF BREATHING
SILLIMAN MEMORIAL LECTURES
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ORGANISM AND ENVIRONMENT AS ILLUSTRATED BY THE
PHYSIOLOGY OF BREATHING. By JOHN SCOTT HALDANE, M.D.,
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ORGANISM AND ENVIRON
MENT AS ILLUSTRATED
BY THE PHYSIOLOGY
OF BREATHING
BY
JOHN SCOTT HALDANE, M.D., LL.D., F.R.S.
Fellow of New College, Oxford
NEW HAVEN: YALE UNIVERSITY PRESS
LONDON: HUMPHREY MILFORD
OXFORD UNIVERSITY PRESS
MDCCCCXVII
COPYRIGHT, 1917
BY YALE UNIVERSITY PRESS
First published, February, 1917
Second printing, January, 1918
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 de-
signed 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 Memorial Lectures.
It was the belief of the testator that any orderly
presentation of the facts of nature or history con-
tributed to the end of this foundation more effectively
than any attempt to emphasize the elements of doctrine
or of creed; and he therefore provided that lectures
on dogmatic or polemical theology should be excluded
from the scope of this foundation, and that the sub-
jects 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 Cor-
poration of Yale University in the year 1901 ; and the
present volume constitutes the thirteenth of the series
of memorial lectures.
17
PREFACE
Yale University did me the great honour of inviting
me to deliver the Silliman Lectures for 1915. Owing
to the war I was unable to give the lectures in the ap-
pointed year ; and I must first of all thank the Univer-
sity for permitting me to postpone them till the present
time.
The subject of the full lectures, as they will, I hope,
before long appear in book form under the imprint of
the Yale University Press, is the Physiology of Breath-
ing. Much of the material contained in them is, how-
ever, of a technical character, hardly suited for public
lectures. With the approval of the President, I have
therefore delivered the following four public lectures
confined to points of more general interest, the nature
of which is indicated by the title.
JOHN SCOTT HALDANE.
New Haven, October, 1916.
CONTENTS
PAGE
PREFACE vii
I. THE REGULATION OF BREATHING .... 1
Introduction.
The problem presented by the co-ordinated main-
tenance of reactions between organism and environ-
ment—Vitalistic and Mechanistic attempts at explana-
tion.
The elementary facts relating to breathing.
The respiratory centre and the blood.
Alveolar air and the exact regulation of its CO2
percentage.
Apnoea and hyperpnoea.
Varying frequency of breathing.
Physiological effects of varying pressures of gases.
Effects of deprivation of CO2.
Effects of air of confined spaces and mines.
Effects of breathing compressed air in diving and
tunnelling.
Influence of the vagus nerves in breathing.
Co-ordination of the responses to central and periph-
eral nervous stimuli, so that the respiratory apparatus
acts as a whole.
II. THE READJUSTMENTS OF REGULATION IN
ACCLIMATISATION AND DISEASE . . .27
The gases of the blood.
Oxyhaemoglobin and the conditions of its dissocia-
tion.
The combinations of CO2 in the blood and their
dissociation.
Effects of oxygenation of haemoglobin on the disso-
ciation of CO0.
x CONTENTS
Exact physiological regulation of the blood-gases.
Evidence that CO2 acts physiologically as an acid.
Investigations of the reaction of blood.
Extreme delicacy of the physiological regulation of
the blood reaction.
Regulation of the blood-reaction by the lungs, liver,
and kidneys.
Effects of want of oxygen on the breathing.
High balloon ascents, CO poisoning, and mountain
sickness.
Acclimatisation to oxygen want: — the Anglo-Ameri-
can Expedition to Pike's Peak in 1911.
Acclimatisation effects of oxygen want on the
breathing.
Acclimatisation effects on the haemoglobin percent-
age and blood-volume.
Acclimatisation effects on active secretion inwards of
oxygen by the lungs.
Factors in acclimatisation to want of oxygen.
III. REGULATION OF THE ENVIRONMENT, INTER-
NAL AND EXTERNAL 61
Further analysis of oxygen secretion by the lungs.
Secretion of oxygen by the swim-bladder.
Secretion in other glands.
Analogy between secretion and cell-nutrition.
The circulatory regulation of carriage of oxygen
and CO2.
Regulation by vaso-motor nervous control.
Evidence that this control depends upon the metabo-
lism of the tissues.
Evidence that the heart's action in pumping blood
depends on the same conditions.
Part played by contraction of the veins.
The blood as a constant internal environment.
Regulation of this internal environment by the kid-
neys.
CONTENTS xi
Regulation by other organs.
Regulation after bleeding and transfusion.
Regulation of the external environment
In reality the constancy of the internal or external
environment is a balance between disturbing and re-
storing influences, each of which persists.
The ordinary idea of "function" in an organ is mis-
leading.
"Causes" and "stimuli." Physiology as an endless
maze of causes.
IV. ORGANIC REGULATION AS THE ESSENCE OF
LIFE. INADEQUACY OF MECHANISTIC
AND VlTALISTIC CONCEPTIONS ... 89
Examination of mechanistic interpretation of regula-
tion of the environment.
Difference between an organism and a machine.
Life endures actively and develops.
In life the whole is in the parts and the past is in the
present. Organism, environment, and life-history can-
not be separated.
For biology life and not matter is the primary reality.
The true aims and methods of biology.
Biology an exact experimental science.
Relation of physiological to physical and chemical
investigation of organisms.
The limitations of existing physical and chemical
conceptions.
Inadequacy of vitalism.
Vitalism the inevitable accompaniment of attempted
mechanistic interpretations of life.
Individual life as part of a wider life.
The limitations of biological conceptions.
Science and religion.
INDEX . 123
I
THE REGULATION OF BREATHING
Animal physiology deals with the activities ob-
served in living animals, including men; but under
certain limitations. It deals in the first place with
all the activities which are unconscious, such as diges-
tion, circulation of the blood, secretion, or the growth
and maintenance of the tissues. It deals, also, with
the unconscious element in conscious action. I may,
for instance, breathe consciously, or move my pen in
writing, or hear the noise which it makes; but of the
details involved in any of these acts I have no direct
consciousness. They are only revealed by experi-
mental physiology. Physiology deals, also, with the
sensations, impulses, and instincts of all kinds which
appear in consciousness ; but does not deal with the
meaning and conscious control which are attached to
them. It does not deal with this meaning and con-
scious control for the very good reason that the facts
relating to them cannot be combined with the other
material of physiology into a homogeneous sys-
tem of scientific knowledge. If, however, the mean-
ing and conscious control attached to sensation and
instinct are disregarded, the latter can be treated as a
part of physiology, and are so treated by physiologists.
When the activities included as physiological are
2 ORGANISM AND ENVIRONMENT
regarded as a whole, it is evident that in the case of
any given organism they are co-ordinated in such a
way that the life of the organism tends to maintain
itself as a whole, or at any rate to fulfil its character-
istic life-history. This applies not less to the reactions
between the organism and its environment than to
those between the parts of the organism. In the
inorganic world as ordinarily observed and inter-
preted we find no such co-ordinated maintenance.
How are we to understand its presence in the organic
world? This is of course a very old question; but I
wish to reconsider it in these lectures in the light,
more particularly, of the very rapid advances which
have been made during the last few years in the
physiology of breathing.
We are familiar with two opposing theories as to
the nature of the co-ordination. One of these is that
known as vitalism, which assumes that within the
living body there is constantly at work a special influ-
ence, the so-called "vital principle," which guides the
blind physical and chemical reactions which would
otherwise play havoc with the organism. The other
is that the body is a very complex and delicate
mechanism, so arranged as to bring about the co-
ordination. According to one school this mechanism
is the result of natural selection, though according
to another its origin must be sought in special creation.
I hope to be able to convince you that neither the
vitalistic nor the mechanistic theory of the relation
between organism and environment is tenable, and
REGULATION OF BREATHING 3
that we must look to a more thorough and direct
interpretation.1
Breathing is a form of physiological activity which
goes on whether we are conscious of it or not. Only
by a great effort can we suspend it for 30 or 40 sec-
onds, and any hindrance to breathing is violently
resisted. Although in the seventeenth century Mayow
came very near to discovering the chemical changes
in air during breathing, it was not till the latter half
of the eighteenth century that these changes were
understood. Black found that what we now call
carbon dioxide is given off in breathing, and Priestley
found that what we now call oxygen disappears as
such. Lavoisier put these and many other facts
together, and showed that just as in ordinary com-
bustion of carbonaceous material, so in connection
with respiration, oxygen combines with carbon and
hydrogen to form carbon dioxide and water, and to
liberate heat. Hence breathing is a process in which
the essential factors are the conveyance of oxygen into
the body, and the removal from it of carbon dioxide.
Breathing can thus be compared to the supply of air
to a fire and the carrying off by the air of the products
of combustion.
Subsequent investigation showed that the oxidation
xlt has been suggested to me that if a convenient label
is needed for the doctrine upheld in these lectures the word
"organicism" might be employed. This word was formerly
used in connection with the somewhat similar teaching of
such men as Bichat, von Baer, and Claude Bernard. Cf.
G. Delage, L'Heredite, Paris, 1903, p. 435.
4 ORGANISM AND ENVIRONMENT
process does not occur to any appreciable extent in
the lungs, but in the living tissues of the body gener-
ally. Oxygen is taken up by the blood in the lungs,
and thence carried by the circulation to every part of
the body, the blood yielding its oxygen to the tissues
in passing. Similarly the carbon dioxide formed is
carried by the blood from the tissues to the lungs,
where it is given off to the air breathed.
But another still more important point, often
entirely missed in popular accounts of physiology, has
appeared clearly. Within wide limits the oxidation
process is practically independent of the abundance in
supply of either oxygen or food material to the body.
The amount of oxygen in the air breathed, or carried
by the blood to the tissues, may be increased greatly
without increasing the rate of oxidation; and even
after long starvation the consumption of oxygen per
unit of body weight remains about the same. The
oxidation process is thus evidently very closely regu-
lated. In the burning of a fire there is no such regu-
lation unless it is artificially brought about. Although
increase in the breathing does not cause increase in the
rate of oxidation, yet it is evident that increase in
breathing and in the rate of circulation accompanies
increase in the rate of oxidation, as for instance during
muscular exertion. Here again we have regulation
coming in, but this time it is regulation of the air
supply.
To account for the regulation the vitalistic theory
presupposes the activity of the "vital principle'* as a
regulating agent which controls the consumption of
REGULATION OF BREATHING 5
oxygen and regulates the air-supply, thus playing the
part of a stoker who regulates the supply of both
fuel and air to a furnace. On the mechanistic theory
the regulation is automatic, and due to the working of
a mechanism connected with the fire. The latter
theory is of course the orthodox one at present. It
is not, however, these theories which I wish to discuss
in these lectures, but the character of the facts which
each of the two theories is an attempt to explain.
When the true character of these facts is realised it
seems to me that the old and ever recurring contro-
versy between mechanists and vitalists disappears.
It has been known for more than a century that
breathing is dependent on the integrity of a very small
area of the brain in the medulla oblongata. When this
area, known as the respiratory centre, is destroyed
all signs of co-ordinated breathing efforts disappear.
Severance of the nervous connections between this
centre and the various respiratory muscles paralyses
these muscles ; but so long as any connections are left
respiratory efforts continue, and do so after severance
of the connections between the centre and the higher
parts of the brain. The action of this centre came to
be regarded as automatic, inspiratory and expiratory
impulses being alternately discharged from the centre
down the motor or efferent nerves leading to the
inspiratory or expiratory muscles, but no afferent
impulses being required to liberate these rhythmic dis-
charges. It was also found about the same time that
any interference with the supply of properly aerated
blood to the centre causes greatly increased activity
6 ORGANISM AND ENVIRONMENT
of the centre. A further very significant fact, ob-
served originally by Hook in the seventeenth century,
but forgotten and rediscovered by Rosenthal in 1875,
is that if the blood in the lungs is over-aerated by
artificial ventilation, the breathing stops for a time, the
condition known as apnoea being established. It
seemed, therefore, that just as increased breathing, or
hyperpnoea, is due to defective aeration of the blood,
so apnoea is due to excessive aeration. This interpre-
tation of apnoea was soon challenged, as we shall see,
but was firmly established by an ingenious experiment
of Fredericq. He crossed the circulation of two
animals, so that the blood coming from the lungs of the
first animal passed to the respiratory centre of the
second, and vice versa. It was then found that when
excessive artificial ventilation was applied to the lungs
of the first animal the second became apnoeic, or vice
versa ; while great hyperpnoea in the first animal was
produced by the stoppage of the breathing in the
second.
When aeration of the blood is defective in the
lungs two changes in the arterial blood occur. On
the one hand its content in oxygen becomes less, and
on the other hand it becomes more highly charged
with carbon dioxide. Blood which is not aerated
with oxygen has a dark purple tint, contrasting with
the bright scarlet of fully aerated blood. This dif-
ference in colour is due to the fact that haemoglobin,
the substance which gives blood its colour and is
contained in the red blood corpuscles, is the substance
which carries nearly the whole of the oxygen, and
REGULATION OF BREATHING 7
changes colour from a dark purple to bright scarlet
when it takes up oxygen. The oxygen is taken up in
the form of a weak chemical combination, the com-
pound having the property of being stable only in
presence of a certain concentration of free oxygen,
and dissociating rapidly as the concentration of oxygen
falls. The function fulfilled by haemoglobin as a car-
rier of oxygen from the lungs to the tissues is thus
readily intelligible, as well as the difference in colour
between arterial and venous blood. Substances in the
blood combine to form similar readily dissociable com-
pounds with carbon dioxide, but no change in colour
is associated with this process.
Both deficiency of oxygen and excess of carbon
dioxide in the air were found to produce increase in
the breathing, and till recently the respective parts
played by oxygen and carbon dioxide in regulating
the breathing were by no means clear, and opinions
on the subject were divided. I was myself led to
investigate the whole subject through observations on
the effects of air vitiated by respiration or by the gases
met with in coal-mines and other confined spaces.
When air highly vitiated by respiration or combus-
tion of carbonaceous material is breathed the amount
of air inspired or expired is increased. The increase
is due to the carbon dioxide in the air ; for when this
is removed there is no increase .unless the deficiency of
oxygen is extreme. The effect produced on the breath-
ing by carbon dioxide in the inspired air increases out
of proportion to increase in the percentage of the car-
bon dioxide. This fact suggested that in ordinary
8 ORGANISM AND ENVIRONMENT
breathing the ventilation of the lungs is such as to
keep the percentage of carbon dioxide approximately
constant in the air which is in close contact with the
blood in the small airspaces or alveoli inside the lungs.
If this is so, it is clear that the nearer the percentage of
carbon dioxide (CO2) in the inspired air approaches
that in the lung alveoli the greater will be the quantity
of air which must be breathed in order to keep the
lung air normal in composition.
The matter was investigated a few years ago by
Mr. Priestley and myself. We found that a sample
of the alveolar air could easily be obtained by catch-
ing the last parts of a deep breath expired through a
tube, and that for any individual under normal condi-
tions, the percentage of CO2 in this air remains prac-
tically constant during rest. On the other hand the
percentage of oxygen in the inspired and alveolar air
could be varied within wide limits without affecting
either the amount of air breathed or the percentage of
CO2 in the alveolar air. It was only when the oxygen
percentage fell very low that the breathing was
increased. The percentage of CO2 in the alveolar air
is not quite the same in different individuals, but the
average is 5.6 per cent for adult men.
When air containing different percentages of CO2
was breathed it was found that the volume of air
breathed was increased to such an extent as to keep
the percentage of CO2 in the alveolar air as nearly nor-
mal as possible. Nevertheless there was always a
very slight increase in the alveolar CO2 percentage
with each increase in the breathing. For an increase
REGULATION OF BREATHING 9
of 100 per cent in the ventilation of the lungs over
the normal resting ventilation there was an increase
of about 0.2 per cent in the CO2 percentage in the
alveolar air. Very accurate methods of sampling and
gas analysis were of course needed in order to detect
these differences. When the percentage of CO2 in the
inspired air reaches about the normal percentage in the
alveolar air there is extreme panting. With higher
percentages a point is soon reached where the CO2
begins to produce abnormal effects, culminating in
loss of consciousness. The breathing then quiets down
to a large extent, and this quieting down of the breath-
ing, as observed in animals, led formerly to a misinter-
pretation of the effects of CO2 on the breathing.
If the breathing is by voluntary effort forced for a
time, so as to reduce the percentage of CO2 in the
alveolar air, a period of apnoea results. This effect
depends entirely on the reduction of the percentage of
CO2 in the alveolar air, for if the inspired air con-
tains about 5 per cent of CO2 it is impossible to pro-
duce apnoea by forced breathing, since under these
conditions it is impossible to reduce the alveolar CO2
percentage below normal. Careful observations by
Douglas and myself showed that it is only necessary to
reduce the alveolar CO2 percentage by 0.2 per cent in
order to produce apnoea. It thus appears that a rise
of about 0.2 per cent in the alveolar CO2 percentage
is sufficient to double the breathing, while a fall of
0.2 per cent produces cessation of breathing.
We are now in a position to understand, up to a
certain point, how the breathing is regulated. The
10 ORGANISM AND ENVIRONMENT
quantity of CO2 brought to the lungs by the blood
is constantly varying in accordance with varying
states of bodily activity. For instance during the
exertion of walking at a moderate rate the quantity
of CO2 brought to the lungs is three or four times
what it is during rest. If the breathing did not
increase correspondingly, the percentage of CO2 in
the alveolar air would rise, and loss of consciousness
would result. But with the slightest rise in the alveo-
lar CO2 percentage the breathing begins to increase,
and thus keeps down the alveolar CO2. When, there-
fore, the production of CO2 is three times what it is
during rest, the breathing is also increased to nearly
three times what it is during rest. The alveolar CO2
percentage rises, it is true; but only by 0.4 per cent.
This slight rise produces, as we have seen, an increase
of 200 per cent in the breathing, so that the increase
in breathing is almost proportional to the increase in
the production of CO2. Analysis of the alveolar air,
and determination of the CO2 produced and volume
of air breathed during rest and work show that this
explanation works out in practice, provided that no
disturbing causes come in.
As the oxygen percentage in the alveolar air runs
parallel with the CO2 percentage, it is evident that
regulation of the oxygen percentage is involved in
regulation of the CO2 percentage. The net result is
that both the percentage of oxygen and that of CO2
in the alveolar air are very constant, in spite of great
changes in the amount of oxygen consumed and CO2
given off by the body.
REGULATION OF BREATHING 11
There is no doubt that it is through the blood that
slight changes in the CO2 percentage of the alveolar
air affect the respiratory centre. The effects of these
changes are equally rapid and marked when all the
nervous connections between the lungs and the respir-
atory centre are severed.
To most persons it must come as a surprise that the
breathing is so exactly regulated. Common observa-
tion shows us that the breathing is often more or less
interrupted temporarily, and varies in frequency or
depth at different times, as if the regulation were only
rough. We also know that breathing is under volun-
tary control, and there is a popular idea that by spe-
cial forms of training in breathing we can improve
the aeration of the blood and the supply of oxygen to
the body.
If samples of the alveolar air are taken it is found
that they only give a constant percentage of CO2 if
the breathing is quite regular at the time, and they
are taken at the same phase of the respiratory act —
say at the end of inspiration or of expiration. Ac-
tually the percentage is varying distinctly from
moment to moment round the average; and it is only
the average that is constant. If, moreover, the per-
centage of CO2 in the air inspired is suddenly
increased, it takes some little time before the breath-
ing increases to the new average. There is thus a
considerable lag between changes in the alveolar CO2
percentage and the response of the respiratory centre.
This lag may be in either direction. If, for instance,
the breathing is voluntarily held for a short time,
12 ORGANISM AND ENVIRONMENT
there follows excessive breathing; and if the alveolar
air be then analysed it will be found that the CO2
percentage has fallen below normal. The breathing
is, as it were, making up for lost time.
This is easy to understand. Not only does it take
an appreciable time for the blood to flow from the
lungs to the respiratory centre, but both the blood
and the lymph surrounding the tissue elements in the
respiratory centre have a large capacity for absorbing
CO2. They saturate and desaturate somewhat slowly
when brought into connection with varying concen-
trations of CO2 in the alveolar air. Consequently the
respiratory centre only responds gradually to these
variations. Were it not so the breathing would be
very jerky, and it would be difficult to interrupt it in
speaking or singing or swallowing. Momentary varia-
tions in the alveolar CO2 percentage have thus no
appreciable influence on the breathing, and it is only
the average that counts. But this average is regu-
lated with an accuracy which is extraordinary.
It is evident that the average percentage of CO2
in the alveolar air can be kept constant either by
shallow and frequent or by deep and infrequent
breathing. We can voluntarily set the breathing to
very different frequencies, letting the depth take care
of itself. For instance we can breathe three times or
fifty times a minute. If, however, samples are taken
of the alveolar air when once these different rates
have been properly established, it is found that the
average percentage of CO2 is sensibly the same.
Increased frequency is compensated for by diminished
REGULATION OF BREATHING 13
depth, and vice versa. It is an entire mistake to judge
of the amount of air breathed by the mere frequency
of the breathing. With very rapid and shallow
breathing only a little of the pure inspired air clears
the air-passages and enters the lungs. The very rapid
and shallow breathing of a dog in hot weather does
not over-ventilate its lungs, and is only designed to
promote evaporation from its tongue, and consequent
cooling, since a dog sweats with its tongue, and not
with its skin.
If the breathing is obstructed, so that considerable
effort is needed to draw in and expel air, as in breath-
ing through a partially closed tap, there is still no
appreciable rise in the alveolar CO2 percentage. The
breathing is less frequent ; but it is also deeper, and the
fundamental regulation is practically undisturbed.
It was shown by Paul Bert that the physiological
actions of CO2 and various other gases depend upon
the pressure which they exercise. This pressure de-
pends on the number of molecules of the gas present
in a given volume. For instance, 5 per cent of CO2
present in dry air at the normal sea-level pressure of
760 millimetres of mercury has a pressure of 760 X
%00 — 38 mm., and exercises the same pressure as 1.0
per cent of CO2 in air at 380 mm. barometric pressure.
It also contains the same number of molecules in a
cubic centimetre. The air in the lung alveoli is satu-
rated with aqueous vapour at the body temperature,
and this vapour has a pressure of 47 mm., which must
be allowed for in calculating from an analysis the
pressure of CO2 in alveolar air. As already seen the
14 ORGANISM AND ENVIRONMENT
average percentage of CO2 in the alveolar air of adult
men is 5.6. This is calculated for dry air. Allowing
for the moisture present the pressure of CO2 with
normal barometric pressure is (760 — 47) X 5<%oo —
39.9, or, in round numbers, 40 mm.
On observing the alveolar CO2 percentage at
increased or moderately diminished atmospheric pres-
sure we found, just as might be expected from Paul
Bert's experiments, that it is the pressure, and not
the percentage, of CO2 which remains constant. The
percentage is only constant if the barometric pressure
remains the same. At five atmospheres' pressure the
percentage of CO2 in moist alveolar air during rest
is only a fifth of what it is at normal pressure. At
any one position on the earth's surface the changes
in barometric pressure from day to day are so slight
that the corresponding changes in the alveolar CO2
percentage are not very noticeable; but with con-
siderable changes in altitude, or in the case of workers
in compressed air, these changes may of course be
very great.
We thus reach the provisional conclusion that the
breathing is so regulated as to keep the pressure or
concentration of CO2 in the alveolar air constant
within narrow limits. The slightest increase in con-
centration of CO2 causes an increase in the breathing
which almost completely neutralises the increase in
concentration. The slightest decrease in the con-
centration of alveolar CO2 causes a compensating
diminution in breathing. To put the matter some-
what differently, the respiratory centre reacts with
REGULATION OF BREATHING 15
enormous delicacy towards the slightest changes, up-
wards or downwards, in the concentration of CO2 in
the alveolar air in contact with the arterial blood
which supplies the centre.
It is of the highest significance that a slight change
in the downwards direction is sufficient to suspend
natural or involuntary breathing. CO2 was formerly
regarded as merely a "waste product," the getting rid
of which as rapidly and completely as possible could
only be a physiological advantage. It has turned out,
however, that the presence of a certain concentration
of CO 2 is essential to the continuance of breathing.
This brings us at once into connection with a series
of investigations independently initiated by Professor
Yandell Henderson of Yale, and afterwards carried
on side by side with the Oxford investigations. His
work was at first concerned mainly with the effects of
concentration of CO2 on the circulation, and he found
that undue removal of CO2 from the blood has the
most disastrous effects on the circulation, producing
symptoms similar to those observed in the surgical
condition known as "shock." He found that when
CO2 is removed from the body in undue quantity by
excessive artificial ventilation of the lungs, the heart
and circulation gradually fail, and death results. To
this subject I will return later; but I am referring to
it now in order to emphasise the point that the pres-
ence of CO2 in a certain concentration in the arterial
blood is just as necessary to life as, say, the presence
of oxygen. An environment of CO2 is apparently as
essential as an environment of oxygen.
16 ORGANISM AND ENVIRONMENT
The effects in man of undue deficiency or undue
excess of CO2 can easily be observed. By forced
breathing we can greatly reduce the alveolar CO2
percentage and also the quantity of CO2 in the arte-
rial blood. The effects of continued forced breathing
are very marked. These are "swimming" of the head,
abnormal sensations of "pins and needles," loss of
sensibility, contractions of various groups of muscles,
and gradual loss of consciousness. By breathing dur-
ing rest air containing 6 per cent or more of CO2, or
a less percentage during exertion, we can observe the
effects of undue excess of CO2 — headache, giddiness,
and often rapid loss of consciousness. Breathing is
so regulated as to avoid these and other ill effects of
excess or deficiency of CO2. In other words the main-
tenance of breathing is but one manifestation of the
co-ordinated bodily activities of which the outcome is
the maintenance of bodily activity and structure as a
whole. Breathing is a manifestation of life and there-
fore possesses its characteristic features.
It is evident that the mechanistic school of physi-
ologists can point to the new facts with regard to the
regulation of breathing as a confirmation of their
principles. For the respiratory centre may be re-
garded as a mechanism which reacts in a very sensi-
tive manner to slight changes in the concentration of
CO2. There is thus no mystery about the regulation
of breathing — no need to invoke the presence of
factors which are not physical or chemical. The
respiratory centre is, in fact, typical of other bodily
mechanisms. The delicacy of their reaction is due
REGULATION OF BREATHING 17
to the delicacy of their mechanism, and not to the
interference of some mysterious guiding influence
such as the so-called "vital principle."
But the vitalists can equally find confirmation in
the new facts. They can lay stress on the extreme
delicacy of the regulation, and the fact that in man
this delicate regulation is maintained, day after day,
and year after year, in spite of all kinds of changes
in the external environment, and in spite of the
metabolic changes constantly occurring in all living
tissues. These facts preclude the hypothesis that
the respiratory centre is a permanent structure so
stable that it is unaffected by changes in environment.
The regulation, if it be a mechanism, is utterly mys-
terious from the physical and chemical standpoint,
and necessitates the assumption that a special guiding
influence is present, such as does not exist, so far as
we know, in the inorganic world. The more delicate
and definite the physiological regulations which the
advance of experimental physiology is constantly dis-
covering, the stronger the case for vitalism.
I have tried to put the case fairly on both sides ;
for both sides have always appealed to me strongly,
and I have been utterly unable to accept the one-
sided mechanistic arguments which have been put for-
ward by many leading physiologists in recent times,1
or the equally onesided vitalism of the vitalistic
minority.
1 As an example of these I may perhaps refer to Sir
Edward Schafer's Presidential address to the British Asso-
ciation in 1911.
18 ORGANISM AND ENVIRONMENT
Some of the immediate practical applications of the
new knowledge with regard to the regulation of
breathing are perhaps of sufficient interest to be men-
tioned shortly. The air of all sorts of confined spaces
is apt to be vitiated by the presence of CO2 ; and along
with the excess of CO2 there is usually a deficiency of
oxygen, since the vitiation is due to processes of oxi-
dation, in which oxygen is used up in proportion as
CO2 is formed. In the air of ordinary rooms CO2
is formed and oxygen used up by respiration and by
the burning of illuminants. The natural ventilation
of an ordinary room is, however, so considerable that
it is very seldom that the percentage of CO2 in the
air exceeds 0.5 per cent. What effects will the gaseous
impurity in such air have? Clearly none that are
appreciable. The breathing will be very slightly
deeper, so as to keep the alveolar CO2 percentage con-
stant ; but the increase in breathing will be less than a
tenth, and such an increase is totally unappreciable
subjectively. The slightly increased breathing will
also keep the oxygen percentage in the alveolar air
from falling, so that the diminished oxygen percent-
age in the air will be of no account. We must thus
seek elsewhere than in the gaseous impurities of the
air of rooms for the causes of the discomfort felt in
crowded rooms.
In mines and other underground spaces the propor-
tion of CO 2 often goes much higher, and may reach
about 3 per cent in places where a light will still burn.
With 3 per cent of CO2 in the air the breathing is
doubled. This effect becomes just noticeable during
REGULATION OF BREATHING 19
rest; but during any exertion the effect is not merely
noticeable, but very trying. During moderate work
in pure air the breathing is three or four times what
it is during rest; but when air containing 3 per cent
of CO2 is breathed the increase is to 6 or 8 times the
amount of air breathed during rest in pure air. Pant-
ing is thus very severe, and hinders all hard work.
Constant employment on hard work such as mining
in air of this composition is apt to produce in the lungs
the condition known as emphysema, and thus to cause
premature disablement. The ventilation of a mine
ought, therefore, to be at least sufficient to prevent
the CO2 percentage from exceeding about 1 per cent,
where no other gaseous impurities than CO2 are to
be found.
One of the most interesting examples of the effects
of CO 2 is that which occurs in diving with the ordi-
nary diver's equipment. The diver is supplied with
air by a pipe through which air is pumped down to
him. The air passes into his helmet, and escapes into
the water by a valve situated at the side of the helmet.
The deeper he goes the greater is of course the pres-
sure at which this air must be supplied ; and the com-
position of the air which he breathes in the helmet
will of course depend on the amount of air supplied
to him and on the rate at which he vitiates this air.
During work, for instance, he may produce four or
five times as much CO2 as during rest, so that he will
need correspondingly more air during work.
Supposing that the diver is working at a depth of
22 fathoms, or 132 feet, the air supplied to him will
20 ORGANISM AND ENVIRONMENT
have a total barometric pressure of five atmospheres.
If, now, the rate of supply, as measured by the strokes
of the pump, is such as would keep the percentage of
CO2 in the air of the helmet at not more than 2 per
cent during work, this quantity of air would suffice
to keep him comfortable if he were at or near the sur-
face. But if the same quantity of air is supplied to
him at 22 fathoms, or five atmospheres' pressure, the
effect of 2 per cent of CO2 will, as we have seen, be
the same as that of 5 X 2 = 10 per cent of CO2 at
surface. Hence if the diver exerts himself he will not
merely pant excessively, but rapidly lose conscious-
ness. It used to be a common occurrence for divers
to lose consciousness in this way; and the fact that
British naval divers were so commonly unable to do
any work at considerable depths led to an investiga-
tion of the whole subject in the light of the new knowl-
edge available, and to the laying down of regulations
which now make work quite easy at the greatest depths
required. The air supply to a diver ought evidently
to be increased in direct proportion to the increase in
the atmospheric pressure at which he works.
A diver is in no danger from want of oxygen, since
the pressure of oxygen in his helmet and in his alveo-
lar air is always far higher than in pure air at surface.
It is almost always from oxygen want that a man
dies who is asphyxiated by vitiated air in mines; but
a diver may die from CO2 poisoning in the presence
of abundance of oxygen.
I must now turn to another line of investigation in
relation to the regulation of breathing. In 1868
REGULATION OF BREATHING 21
Hering and Breuer discovered that if expiration is
prevented by blocking the outlet of air at the end of
an inspiration, particularly if the lungs are well dis-
tended, rhythmic breathing efforts are interrupted.
There is a long pause, during which there is nothing
but expiratory effort; and only after this long pause
is there an effort at inspiration. Similarly if inspira-
tion is blocked at the end of expiration there is a long
interval in which only inspiratory effort is observed.
The rhythmic activity of the respiratory centre is
interrupted in either case.
They also discovered that if the vagus nerves, which
proceed from the medulla oblongata in the brain, and
supply branches to the lungs, are cut, these effects are
no longer produced. Rhythmic inspiratory and expi-
ratory efforts continue, quite regardless of whether
the lungs are inflated or deflated. Clearly, therefore,
impulses proceeding up the vagus nerves from the
lungs are concerned in the regulation of breathing.
When these nerves are cut or frozen across the
breathing immediately becomes less frequent, but
deeper, and acquires a well-marked dragging char-
acter.
Hering and Breuer interpreted their observations as
signifying that with the vagus nerves intact disten-
tion of the lungs excites the nerve-endings with the
result that impulses which stop or inhibit inspiration,
and excite expiration, pass up the nerves. On de-
flation of the lungs to a certain point during expira-
tion a corresponding process occurs which inhibits
expiration and excites inspiration. Thus the disten-
22 ORGANISM AND ENVIRONMENT
tion of the lungs during inspiration is the immediate
cause of expiration, and the deflation on expiration is
the immediate cause of inspiration. Subsequent inves-
tigation by various other observers confirmed in the
main these conclusions. The regulation of breathing
thus appeared to be an automatic process dependent,
so long as the vagus nerves are intact, on the effects
of alternate distention and deflation of the lungs.
Until recently, also, many observers concluded from
their experiments that apnoea is the summed effect
of frequently repeated over-distention of the lungs,
and has nothing to do with chemical changes in the
blood. The majority believed that there is both a
"chemical" and a "vagus" apnoea. The continued in-
spiratory or expiratory effort which accompanies con-
tinuous deflation or inflation of the lungs cannot
properly be called apnoea, however.
I have already referred to the evidence showing that
there is certainly no such thing as an apnoea due to the
mere summed effects of repeated distention of the
lungs, such as occurs in panting. The apnoea which
follows forced breathing or excessive artificial ventila-
tion of the lungs is due to reduction in the amount of
CO2 in the alveolar air and arterial blood, and to no
other cause. Were it the case that repeated unusual
distention of the lungs tends to cause apnoea we should
have a physiological arrangement exactly suited to
defeat the whole physiological end of increased breath-
ing. It seems extraordinary that the extreme improba-
bility of this should not have weighed more heavily
with the authors of the "vagus" theory of apnoea.
REGULATION OF BREATHING 23
The theory that the breathing is regulated merely
by the effects of alternate distention and collapse of
the lungs is also quite plainly absurd in view of what
is now known about the part played by the carbon
dioxide pressure in the alveolar air and arterial blood.
The observations of Hering and Breuer and of others
who have made experiments along the same lines are
none the less significant, however. Mr. Mavrogorato
and I have found that the main facts, apart from the
effects of section of the vagus nerves, can best be
observed and analysed in man. The subject breathes
through a wide bored tap which can be opened or
closed at any moment ; the nose is clipped ; and a pres-
sure-gauge is connected between the mouth and the
tap so as to show the inspiratory or expiratory pres-
sure.
When the tap is closed at the end of inspiration it
will be noticed on the gauge that there is expiratory
pressure, slight at first, but afterwards increasing more
and more rapidly, till at last, after an interval occupy-
ing the time of several normal respirations, there is a
sudden inspiratory effort. The natural tendency of the
respiratory centre to discharge alternate inspiratory
and expiratory impulses thus breaks through the
prolonged expiratory effort. Similarly, if the tap is
closed at the end of inspiration there is a prolonged
and increasing expiratory effort. If, now, apnoea
is produced by forced breathing before the experiment,
there is inspiratory or expiratory pressure as before ;
but it is a very long time before this pressure begins
to increase. On the other hand if air containing CO2
24 ORGANISM AND ENVIRONMENT
has been breathed before, so that the breathing is
naturally increased, the inspiratory or expiratory pres-
sure mounts up very rapidly, and is soon broken by
an inspiratory effort. If the tap is closed midway
in inspiration, long-continued inspiratory pressure,
gradually increasing, is shown on the gauge, just as
if the interruption had been at the end of expiration ;
and similarly there is long-continued expiratory pres-
sure if expiration has been interrupted midway.
If we put together the human observations and the
results obtained in animals with the vagus nerves
intact and divided, it appears that the effect of disten-
tion of the lungs is to stop inspiratory and initiate
expiratory discharge of the respiratory centre, while
deflation of the lungs stops expiratory and initiates
inspiratory discharge. Both inspiratory and expira-
tory discharges continue until they are again stopped
by distention or deflation. The result is that the dis-
charges from the centre are directly co-ordinated with
actual inflation or deflation of the lungs. This is
brought about through the vagus nerves. The degree
of energy of the inspiratory or expiratory discharges
depends, however, on the action of CO2 in the blood
upon the centre.
The degree of inflation or deflation necessary to
inhibit inspiration or expiration and initiate expiration
or inspiration depends quite clearly also on the chemi-
cal stimuli acting on the centre through the blood:
for the breathing is far deeper when the pressure of
CO2 in the alveolar air and arterial blood is higher.
We can thus understand how it is that when the fre-
REGULATION OF BREATHING 25
quency of breathing is varied voluntarily or involun-
tarily, the depth naturally adjusts itself in such a way
that the average alveolar CO2 pressure remains sensi-
bly constant: for the least lowering of alveolar CO2
pressure enables the Hering-Breuer inhibitory effect
to become effective within narrower limits of inflation
and deflation, while the least raising of alveolar CO2
pressure has the opposite effect. We can also explain
a very interesting phenomenon recently discovered
independently by Yandell Henderson in America and
Liljestrand, Wollin and Nilsson in Sweden. When
artificial respiration is performed on a conscious sub-
ject by Schafer's or any of the other usual methods,
air enters and leaves the chest in just about the normal
amount, although the subject carefully refrains from
himself making any breathing efforts. If the rate
of artificial respiration is increased there is no increase
in the air entering the chest per minute : for the breaths
become shallower. If, finally, apnoea is produced by
previous forced breathing, and artificial respiration
is then applied, hardly any air enters the chest. The
Hering-Breuer inhibition comes into play with the
slightest inflation or deflation of the lungs, and the
breathing is, as it were, jammed.
When the vagi are cut, an animal can still regulate
its breathing so as to keep the alveolar CO2 pressure
constant ; for the depth of the drawn-out respirations
depends on the alveolar CO2 pressure. But, as might
be expected, the regulation breaks down easily under
any strain, as was recently shown by Scott. The
26 ORGANISM AND ENVIRONMENT
breaths cannot follow quickly enough the requirements
which are easily met by an animal with intact vagi.
In the regulation of breathing we have thus a strik-
ing instance of the co-ordination between the actions
of two different nervous stimuli. The influence of the
peripheral stimuli acting through the vagus nerves is
dependent upon the action of the central stimuli, and
vice versa. This interdependence is characteristic of
the effects of nervous stimuli and indeed of all phys-
iological stimuli. As an outcome of the interdepend-
ence in the present case, the breathing organs work
as a whole, the discharges from the respiratory centre
being correlated with the actual movements of the
lungs.
Even after the vagi and nearly all other nervous
connections to the respiratory centre are severed, alter-
nate inspiratory and expiratory discharges from the
centre continue in their proper order. The inspiratory
discharge seems during its continuance to inhibit ex-
piratory discharge, and vice versa. Here, also, we see
the co-ordination which is inherent in all physiological
activity, and which manifests itself even in the be-
haviour of an isolated heart or strip of muscle, but far
more strikingly in the case of the nervous system, even
after great mutilation, or in the case of the chemical
activities of any living part of the body.
II
THE READJUSTMENTS OF REGULATION IN
ACCLIMATISATION AND DISEASE
We have seen that under ordinary conditions the
regulation of breathing is dependent on very small
variations in the degree to which the arterial blood
leaving the lungs is saturated with CO2, and that a
normal CO2 pressure of about 40 mm. is maintained
in the alveolar air of the lungs during rest. Never-
theless this normal pressure may become altered. Thus
if the oxygen percentage or pressure in the lung air
becomes very low in consequence of great deficiency
in the oxygen percentage of the air breathed, or from
the barometric pressure being very low, as at great
altitudes, the breathing is increased and the alveolar
CO2 pressure falls. A similar fall occurs after mineral
acids have been taken, or in diseases in which abnor-
mal quantities of acid are discharged into the blood,
or after severe muscular exertion. To understand
how the breathing is affected under these various con-
ditions, and on what the normal conditions of breath-
ing ultimately depend, it is necessary to consider the
blood, and particularly the gases contained in it.
When a liquid is brought into intimate contact with
a gas the liquid takes up the gas in solution until a
point is reached at which equilibrium or saturation
occurs. At this point as many molecules of gas are
being given off from the liquid as enter it, and the
28 ORGANISM AND ENVIRONMENT
pressure of the gas leaving the liquid is thus equal
to the gas pressure outside. If, as in the lungs, a
mixture of gases is in contact with the liquid, the
pressure of each of the gases in the liquid becomes,
if no interference to their passage inwards or out-
wards occurs, equal to the pressure of the correspond-
ing gas in the gas-mixture. This holds good even
if the liquid contains substances which form well-
defined compounds with the gas; but in the latter
case the amount of gas which the liquid has to take
up before equilibrium occurs may be very large. ' If no
such chemical combinations occur the volume of gas
taken up by the liquid is in ordinary cases directly
proportional to the pressure of the gas.
As we have already seen, the red corpuscles of the
blood contain a coloured albuminous substance,
haemoglobin, which enters into chemical combination
with oxygen. The compound, oxyhaemoglobin, has
the remarkable property of dissociating freely as the
pressure of oxygen in the surrounding liquid falls,
and re-forming as it rises. The oxyhaemoglobin thus
acts as a reservoir of oxygen, enabling the blood to
take up or give off far more oxygen with varying pres-
sures of oxygen than water would take up or give off,
and thus to act as a very efficient carrier of oxygen
from the lungs, where the oxygen pressure is high, to
the capillary vessels of the body tissues, where it is
low in consequence of the constant consumption of
oxygen. Human blood saturated in the lungs is capa-
ble of giving off about 18 cc. of oxygen per 100 cc. of
blood, whereas water would only give off about 0.3 cc.
READJUSTMENTS OF REGULATION 29
To understand the oxygen supply to the body, and the
connection between oxygen supply and breathing, it is
evidently necessary to understand the circumstances
under which oxygen is taken up or given off by the
haemoglobin of the blood. These circumstances can
* 0
4
13 M IS l«
FIG. 1. Thick line — dissociation curve of oxy haemoglobin
in blood in the presence of 40 mm. pressure of CO2.
Thin line — the dissociation curve of oxyhaemoglobin
in blood within the body.
be investigated outside the body, provided that we
are able to reproduce outside the body the conditions
which obtain within it. Until recently, failure to
appreciate the importance of this led to great error.
The dissociation of oxyhaemoglobin with fall in the
pressure of oxygen can best be represented graphically
by a curve; and Figure 1 represents the law of dis-
30 ORGANISM AND ENVIRONMENT
sociation of human oxyhaemoglobin under the condi-
tions so far known to exist in circulating human blood,
including the rise of CO2 pressure as the blood passes
the capillaries. It will be seen that the curve has a
very peculiar shape, with a double bend, which is of
great physiological significance. At the steep part of
the curve oxygen will evidently come off freely with a
comparatively slight fall in oxygen pressure. The
haemoglobin is thus admirably adapted for maintain-
ing the oxygen pressure approximately constant within
the pressures corresponding to the steep part as the
blood passes through the capillary vessels of the body.
So far as we know the circulation is never, under
normal conditions, so slow that the oxygen pressure
in the body capillaries falls below the steep part of the
curve, and is seldom so rapid as to bring the oxygen
pressure above the steep part. The oxygen pressure
in the alveolar air is normally about 100 mm., or 13
per cent of an atmosphere, which corresponds to the
flat upper part of the curve.
The general form of the dissociation curve of the
oxyhaemoglobin in blood was discovered a few years
ago by Bohr of Copenhagen. He and his pupils also
found that the curve is much affected, not only by
temperature, but by the pressure of CO2 in the blood.
In the absence of CO2 the curve (as represented in the
figure) shifts to the left, so that oxygen is given off
much less readily. For a specified amount of oxygen
to be given off in the absence of the CO2 normally
present in circulating blood, the pressure of oxygen
would require to be lowered to about half the pressure
READJUSTMENTS OF REGULATION 31
otherwise needed. Excess of CO2, on the other hand,
facilitates the dissociation, so that the giving off of
CO2 to the blood in the body capillaries helps to make
the curve steeper and so facilitates the oxygen supply
to the tissues.
The curve is not at all of the shape which would be
expected on purely chemical grounds from what is
known of other substances which dissociate in a similar
manner. It was discovered by Barcroft and his pupils
that the inorganic salts present along with the haemo-
globin in the red corpuscles determine this peculiar
form. When the haemoglobin is freed from these
salts its dissociation curve has the form which would
have been expected on chemical grounds — namely, that
of a rectangular hyperbola. With this form of curve
the oxyhaemoglobin would be wholly unsuited for
performing the work which it actually performs in
the body. The action of the salts is almost certainly
connected with their power of causing the haemoglo-
bin molecules to become aggregated into groups. Bar-
croft also found that it is in virtue of its action as
an acid when in solution that CO2 affects the dissocia-
tion curve. Alkalies shift the curve to the left, while
acids shift it to the right; and the changing position
of the curve is an extraordinarily delicate index of
small changes in the reaction of the blood.
Both the plasma and the corpuscles of blood contain
substances which enter into chemical combination with
CO2; and these combinations dissociate with fall in
the pressure of CO2, and re-form with rise, just as
oxyhaemoglobin dissociates and re-forms. The whole
32 ORGANISM AND ENVIRONMENT
of the combined CO2 can be removed from blood by
exposing it to a vacuum, just as the whole of the loosely
combined oxygen can be removed. A strong acid
does not liberate any more. This is a very remarkable
fact ; for we cannot remove the CO2 from xa sodium
carbonate solution by means of a vacuum, and sodium
is certainly combined with CO2 in blood. Blood con-
tains an excess of alkali which is not combined with
any strong acid, and must be in part combined with
CO2. The explanation lies in the fact that haemoglo-
bin and other albuminous substances present in the
blood are capable of acting as very weak acids and so
partially preventing the CO2 from combining with the
available alkali. When the pressure of CO2, and
therefore its "mass influence" is reduced, more and
more of it is driven out of combination, until with
the CO2 pressure at zero none is left.
From 100 volumes of human arterial blood about
50 volumes of CO2 as gas are given off to a vacuum,
and average venous blood contains only about 4 vol-
umes more. The relations between pressure of CO2
and the volume of CO2 absorbed by human blood were
recently investigated by Christiansen, Douglas and
myself, and Figure 2 represents the results graphically.
We found that blood takes up considerably more CO2
at a given pressure of the gas when the oxyhaemoglo-
bin is dissociated than when it is present as oxyhaemo-
globin. The oxyhaemoglobin thus acts as if it were
a more acid substance than dissociated or reduced
haemoglobin. The relation between pressure of CO2
and its absorption by the blood in the living body is
READJUSTMENTS OF REGULATION 33
^
0-"
^"^
-. — •
^
^
*|f»VA
y
^~
-""
, '
— '
1
^
^
r
^
•^
Jen
^
s
'/
t
^-
^'
p°
0^
"?
/f
•"
j
X
V
^
^
^/
x
X
/V
«1 40
,o'
/
/
/
SO
nx
y
g"
AJ
/
/
|
2
4 10
/^
?
10 20 30 40 50 60 70 60 90 100 110 <2
«JWu*e of CO, i* tH4H 3Ca
FIG. 2. Lower curve — absorption of CO2 by blood in pres-
ence of air and CO2. Upper curve — absorption of COs
by blood in presence of hydrogen and COa. The line
A-B represents the absorption of CO2 within the body.
therefore represented by the thick line starting at 40
mm. which is the pressure of CO2 in arterial blood.
This line rises steeply, so that far more CO2 can be
taken up by the blood with a given rise of CO2 pres-
sure than would be the case if oxyhaemoglobin and
reduced haemoglobin had the same effect on the ab-
sorption of CO2. It follows also that when the venous
blood reaches the lungs and suddenly becomes oxy-
genated, the pressure of CO2 in the blood suddenly
rises. In this way much more CO2 is given off than
would otherwise be the case considering the existing
34 ORGANISM AND ENVIRONMENT
pressure of 40 mm. in the alveolar air. In other words
the oxygenation of the venous blood in the lungs helps
to turn out the CO2 — a fact long ago suspected by
Ludwig, but of which the only evidence that could
be obtained was negative until new and rapid methods
of blood-gas analysis were introduced by Barcroft
and myself.
As regards the carriage of both oxygen and CO2
it is thus the case that the blood is of such a nature
that the pressures of these gases in the blood leaving
the tissues may vary but little in spite of the varying
amounts of gas carried. With respect to oxygen, a
glance at the dissociation curve of oxy haemoglobin
shows that it matters but little to the saturation of the
blood with oxygen whether the oxygen pressure in the
alveolar air is a little higher or a little lower. With
respect to CO2, however, variations in the alveolar
CO2 pressure will make a distinct difference to the
CO2 pressure in the blood leaving the tissues, so that
it is intelligible that what governs the breathing is
normally the CO2 pressure, and not the oxygen pres-
sure in the arterial blood.
A further point about the curves for both oxygen
and CO2 is that for any one individual they are ex-
traordinarily constant from day to day and month to
month. Under normal conditions no difference can
be detected in them, just as with the gas pressures in
the alveolar air. The significance of this constancy
is unmistakable; and to a mechanist who pointed out
that the taking up and giving off of gases by the blood
is a purely chemical and physical matter, a vitalist
READJUSTMENTS OF REGULATION 35
might well retort by asking what regulates all the
complex conditions concerned in the process — the for-
mation and marshalling of haemoglobin and salts in
the corpuscles, and the astoundingly delicate balance of
the various substances which are concerned in the
carriage of CO2.
Nevertheless the regulation of both the breathing
and the carriage of gas by the blood can be disturbed,
either temporarily or for long periods; and it is only
by studying these disturbances that we can get further
insight into the regulation. It has already been men-
tioned that when mineral acids are administered the
breathing increases, so that the alveolar CO2 pressure
necessarily falls, while the amount of CO2 in the
arterial blood may be diminished in acid poisoning
to a small fraction of what it normally is. The
administration of alkalies has a similar effect in the
opposite direction. Slighter effects of a similar kind
can be brought about, at least temporarily, by mere
changes in diet. In diabetes a condition sometimes
occurs in which a great excess of organic acid is
formed in the body; and this also is accompanied by
great increase in the breathing and fall in the alveolar
CO2 percentage. A temporary effect in the same
direction follows exposure to want of oxygen, or
excessive muscular exertion. It was known that expo-
sure to great want of oxygen leads to the production
of lactic acid in the body, and that excessive muscular
exertion must have the same effect, since the amount
of work done excludes the possibility of the circula-
tion being able to supply the muscles with the oxygen
36 ORGANISM AND ENVIRONMENT
required to keep up the work. These considerations
led me to the conclusion that it is probably in virtue
of its acidity that dissolved CO2 (H2CO3 or carbonic
acid) affects the respiratory centre, and that other
acids will therefore have a similar effect, and will thus
help CO2 to excite the centre. This theory explains
why less CO2 in the alveolar air is sufficient to excite
breathing under the various conditions just referred
to.
At the time, however, there was no means available
of accurately measuring the slight alkalinity of the
blood. The old method of adding standard acid till
an indicator changed colour was not only very rough,
but also fallacious in principle. The blood is only very
slightly alkaline, yet quite a large quantity of acid can
be added to it before it becomes acid. It is full of so-
called "buffer substances," which are capable of com-
bining with acids or alkalies, but are not themselves
very definitely acid or alkaline. Thus the amount of
acid which has to be added to blood to change its
reaction is a measure of the buffer substances rather
than of the alkalinity of the blood. According to
modern ideas the acidity or alkalinity of a solution
depends on the relative concentrations in it of hydro-
gen and hydroxyl "ions." This concentration can be
measured directly by the electrometric method, but the
difficulties in applying the method to blood were very
great.
In 1912, however, Hasselbalch of Copenhagen suc-
ceeded in obtaining reliable results ; and he and Lunds-
gaard published curves showing graphically the rela-
READJUSTMENTS OF REGULATION 37
tions between hydrogen ion concentrations and CO2
pressure in blood. A difference in CO2 pressure which
would be sufficient to double the breathing, or to cause
apnoea, produced a difference in hydrogen ion concen-
tration which was just measurable by the method, so
the method is very rough as compared with the deli-
cacy of discrimination by the respiratory centre. By
varying the diet from alkaline to acid-producing
Hasselbalch succeeded in producing a variation of
several millimetres in the alveolar CO2 pressure. He
then found that with the blood saturated with CO2 at
the existing alveolar CO2 pressure the hydrogen ion
concentration as measured was sensibly the same on
either diet ; whereas if the blood was saturated in both
cases at the same CO2 pressure the hydrogen ion con-
centration was markedly different on the two diets.
The difference in alveolar CO2 pressure was thus just
sufficient to keep the hydrogen ion concentration, in so
far as it could be measured by the electrometric
method, constant in the two samples of blood, although
there was presumably a slight difference as indicated
by the difference in the breathing. Other similar ex-
periments had a similar result, and there seems now
to be no doubt that it is true that what the respiratory
centre responds to is hydrogen ion concentration, and
not mere CO2 pressure.
The delicacy of the response of the respiratory
centre to change in the reaction of the blood is very
extraordinary ; but what is still more marvellous is the
fact that in spite of this delicacy the alveolar CO2
pressure is so steady during rest. The respiratory
38 ORGANISM AND ENVIRONMENT
centre is responsible for neutralising, by getting rid
of excess of CO2, the changes in hydrogen ion concen-
tration which would occur in the blood if the excess
of CO2 were not got rid of ; but its action in regulating
the breathing does not explain why, apart from the
disturbing influence of CO2, the reaction of the blood
remains so marvellously constant, as shown by the
constancy during rest of the alveolar CO2 pressure.
Acid-forming and alkali- forming substances are con-
stantly being taken into the body in more or less irreg-
ular quantities. For instance the sulphur in albumin-
ous food is oxidised to form sulphuric acid, and the
phosphorus to form phosphoric acid; while on the
other hand the organic acids contained as salts in
vegetable foods are oxidised to CO2 and thus intro-
duce alkaline carbonates into the body. Acid or
alkaline secretions, such as the gastric or pancreatic
juice, are also being formed at intervals. Yet the
reaction of the blood hardly varies even when tested
by such an exquisitely sensitive indicator as the res-
piratory centre, while no other indicator shows any
variation.
It is thus evident that to understand the physiology
of breathing we must consider the regulation of the
blood alkalinity. Two means are already known by
which the blood-reaction is regulated. One of these
is by regulation of the formation of ammonia in the
body. It was discovered by Schmiedeberg of Strass-
burg and his pupils that when mineral acids are ad-
ministered to dogs or to men the amount of ammonia
salts eliminated in the urine increases greatly, at the
READJUSTMENTS OF REGULATION 39
expense of the normal elimination of urea. Urea
CO(NH2)2 is a nitrogenous body of neutral reactions
in the form of which by far the greater part of the
combined nitrogen passing through the body is elimi-
nated. In acid poisoning the combined nitrogen goes
more and more into the form of ammonia (NH3),
which, in virtue of its alkaline reaction when in solu-
tion, combines with acids and thus neutralises them.
Even under average normal conditions in man the
quantity of ammonia eliminated in the urine is about
sufficient to neutralise the large quantity of sulphuric
acid formed by the oxidation of the sulphur of
albuminous substances ; and with an alkaline diet this
ammonia practically disappears from the urine. In
the Strassburg laboratory it was also discovered that
ammonia salts are converted into urea in the liver.
We have now every reason to believe that ammonia
is formed in large quantities in the intestine by the
breaking down under ferment action of albuminous
compounds. This ammonia is carried straight to the
liver by the portal circulation, and there converted
under ordinary conditions almost entirely into urea.
But the liver appears to leave unconverted any am-
monia needed to regulate the reaction of the blood,
and the minutest deviations in reaction serve to regu-
late this process. Hence in the ratio between ammonia
and total combined nitrogen in the urine we have a
valuable index of any tendency towards acidity or
alkalinity of the blood, though the composition of the
alveolar air is a still more direct index.
Another known means of regulation is by the kid-
40 ORGANISM AND ENVIRONMENT
neys. Human urine is usually acid in reaction, though
it is separated from the alkaline liquid, the blood. As
shown clearly by L. J. Henderson of Harvard, the
urine, like the blood, contains "buffer" substances, so
that the slight acidity of the urine is an index of the
separation of much acid from the blood. But the
reaction of the urine, and therefore the separation of
acid by the kidneys, varies from hour to hour, and
depends on whether the diet is more or less acid
forming or alkali forming. In herbivorous animals,
which live on an alkali- forming diet, the reaction of
the urine is normally alkaline; and in man the urine
also becomes alkaline when alkalies are administered.
It seems evident, therefore, that the kidneys, as well as
the liver, are constantly regulating the alkalinity of
the blood, and doing so with an accuracy which no
means of direct physical or chemical measurement
enables us to measure, but which is shown by the great
constancy of the alveolar CO2 percentage. Neverthe-
less, we can be quite certain that it is in response to
the stimulus of very slightly altered reaction in the
blood that the regulating activity of the liver and
kidneys comes into play: for by such means as acid
poisoning we can make the stimulus so strong that
direct measurements can detect it.
It has been rightly pointed out by L. J. Henderson
that the blood, and the body as a whole, are so full of
so-called buffer substances that a considerable amount
of acid or alkali might be added without any measur-
able disturbance of the blood alkalinity being produced.
This is certainly true, and very important, but the
READJUSTMENTS OF REGULATION 41
disturbances which physiology has to deal with are far
more minute than those which are appreciable by
chemical methods, so that exact regulation of the
reaction of the blood is indispensable.
We have seen above that the composition of the
blood is so regulated that not only is its reaction
practically constant, but the volume of CO2 taken up
by a given volume of blood at a given pressure of CO2
remains also the same under ordinary normal condi-
tions. It is easy, however, to disturb this regulation
temporarily. One means of doing so is by violent
muscular exertion. Douglas and I found that a few
minutes after violent exertion the volume of CO2
taken up by a given volume of human arterial blood
was reduced to about half. An hour later, however,
the blood was again normal. The reduction was
probably due to excessive discharge of lactic acid into
the blood: for not only was the resting alveolar CO2
pressure diminished, but Ryffel succeeded in showing
that after similar violent exertion the proportion of
lactic acid in the blood and urine is greatly increased.
RyfTel showed also that this excess disappears in about
an hour, which is the same time, as we had observed,
that the alveolar CO2 pressure requires to rise again to
normal after a violent exertion. It is clear, however,
that the capacity of the blood for taking up CO2 can-
not depend merely on its reaction, and must depend on
the presence in regulated amount of all the various sub-
stances including albuminous substances, which enter
into chemical reaction when CO2 is present. Their
amount must therefore be regulated — probably by the
42 ORGANISM AND ENVIRONMENT
endothelial cells which line the capillary blood-vessels.
Here, then, we have another delicate regulation con-
nected with breathing.
We must now turn to the respiratory regulation of
oxygen supply. Normally, as we have seen, it is the
CO2 pressure in the blood, and ultimately the reaction
of the blood, which seems to regulate the breathing.
Under normal conditions there is always a sufficient
reserve of oxygen in the alveolar air to saturate the
haemoglobin of the blood to about the full normal
extent, even if, from any cause, the oxygen percent-
age falls distinctly below normal. We can thus under-
stand how it is that even if the oxygen percentage in
the air breathed is reduced from 20.9 per cent, as in
pure air, to as little as 14 or 15 per cent, which
instantly extinguishes any ordinary flame, the breath-
ing is not sensibly affected at the time, and the alveolar
CO2 percentage is undisturbed although the alveolar
oxygen percentage has fallen from 14 to 7 or 8. When,
however, there is a further reduction in the oxygen
percentage the breathing begins to increase, and
the alveolar CO2 pressure consequently falls. The
face and lips also begin to have a bluish or lead-
coloured tinge, showing that the blood is not properly
oxygenated in the lungs ; and if such air is breathed for
a considerable time headache and nausea come on. If
there is only 6 or 8 per cent of oxygen in the air
breathed intense panting is at once produced, accom-
panied by rapidly increasing dizziness, mental fail-
ure, and other alarming symptoms, as well as marked
blueness or leaden colour of the face.
READJUSTMENTS OF REGULATION 43
On studying more closely the effects of breathing
air very deficient in oxygen we found that the alveolar
CO2 pressure still regulates the breathing; but the
regulation is, as it were, set at a lower level. The
great panting produced at first by want of oxygen is
due to the fact that owing to the large reserve of CO2
in the blood and lymph the alveolar CO2 cannot be set
at once to the new level without evident panting.
When once the reserve of CO2 has been got rid of, the
breathing diminishes, while the blueness and other
symptoms increase. If the oxygen percentage or pres-
sure in the air is only diminished gradually there is no
evident panting, although there is still some increase in
the breathing, as shown by the lower alveolar CO2
pressure. The formidable symptoms come on without
the warning given by panting. Nevertheless apnoea
can still be produced easily enough by forced breathing
sufficient to reduce the alveolar CO2 pressure further,
even though the face is blue all the time, and con-
sciousness fails before there is any desire to breathe.
It was through attending too exclusively to want of
oxygen as a cause of the "venosity" of the blood that
so many mistakes were made by physiologists as to
the causes of apnoea, and the general physiology of
breathing.
The action of gradually developing want of oxygen
is very insidious, until dangerous effects develop with
dramatic suddenness. These effects have been
repeatedly observed by balloonists, as well as in mines.
Nothing illustrates the effects better than the experi-
ences of the well-known meteorologist Glaisher and his
44 ORGANISM AND ENVIRONMENT
assistant Coxwell in a famous ascent from Wolver-
hampton in 1862. The balloon gradually reached a
height of 26,000 feet, at which the oxygen pressure in
the air was reduced to two fifths of the normal.
Glaisher then first noticed that he could not read his
instruments properly. Shortly afterwards his legs
were paralysed, and then his arms, though he could
still move his head. Then his sight failed entirely, and
afterwards his hearing, and he became unconscious.
Coxwell meanwhile endeavoured to pull the rope of
the valve, but found that not only his legs, but also
his arms were paralysed. He succeeded, however, in
seizing the rope with his teeth, thus opening the
valve. As the balloon descended Glaisher, about seven
minutes after he lost consciousness, began to hear
Coxwell's voice again, and then to see him, after which
he quickly recovered. The balloon had probably
reached a height of about 30,000 feet.
In another famous high ascent from Paris the three
observers, Tissandier, Sivel and Croce-Spinelli, were
provided under Paul Bert's direction with bags of
oxygen to breathe from if they felt any ill effects.
Though the oxygen would have saved them they were
all paralysed before they realised their danger; and
only Tissandier survived. The balloon, as shown by
a self -register ing barometer, had reached a barometric
pressure of 263 millimetres, corresponding to a height
of 30,000 feet, so that the pressure was reduced to
nearly a third of the normal.
The insidious effects of want of oxygen are per-
haps still more strikingly illustrated in the case of
READJUSTMENTS OF REGULATION 45
carbon monoxide poisoning. This gas (CO) is the
poisonous constituent of ordinary lighting gas; and
poisoning with it is extremely common in America
on account of the high percentage of carbon monoxide
in the carburetted water gas used extensively as a
substitute for the old-fashioned coal gas still supplied
in England. I discovered about twenty years ago that
CO poisoning is also the cause of nearly all the deaths
in great colliery explosions and fires, and a source of
extreme danger to rescuers.
Claude Bernard found that CO enters into combina-
tion with haemoglobin, just as oxygen does, but forms
a far more stable compound. In presence, therefore,
of sufficient CO the oxygen-carrying power of the
haemoglobin is suspended, and death must result from
want of oxygen. It was supposed that CO has also a
direct poisonous action on the nervous system. That
this is not so I succeeded in showing by placing ani-
mals in compressed oxygen before giving them CO.
In the compressed oxygen sufficient oxygen goes into
ordinary physical solution in the blood to enable
the animal to dispense with oxyhaemoglobin as an
oxygen carrier; and the animal remains unharmed
although its blood and tissues are saturated with
CO. Animals which do not employ haemoglobin as
an oxygen carrier live for weeks quite comfortably in
an artificial air composed of 80 per cent of CO and
20 per cent of oxygen. CO is not oxidised in the
living body, and apart from its one fatal property of
combining with haemoglobin it is a physiologically
indifferent gas.
46 ORGANISM AND ENVIRONMENT
In CO poisoning there is usually only a small per-
centage of CO in the air, and as the haemoglobin of
the blood has a large capacity for CO it takes a con-
siderable time for enough CO to accumulate in the
blood to cause dangerous symptoms. These symp-
toms, however,, come on in exactly the same insidious
manner as those from oxygen want arising in any
other way. The headache, nausea, etc., of CO poison-
ing are the same as those of mountain sickness, and
the more remote nervous, cardiac, and other after-
symptoms of CO poisoning or serious oxygen want
produced in any other way are due to damage result-
ing from oxygen want, and to no other cause. The
oxygen want produces not merely temporary func-
tional effects, but structural changes in the cells of
nervous and other tissues.
As CO in small but extremely dangerous propor-
tions in air cannot be detected by smell or by a lamp,
I introduced, as a test for it, the use of a small warm-
blooded animal, such as a mouse or canary. A small
animal has an enormously greater respiratory ex-
change and circulation rate than a man; and in con-
sequence its blood becomes saturated with CO far
more quickly. By watching the animal a miner can
tell in good time whether he is in a dangerous atmos-
phere, though in the long run the animal is not more
sensitive to CO than the man. The provision of small
animals for testing purposes at mines in Great Britain
was made obligatory by recent legislation.
Yandell Henderson discovered that after excessive
artificial respiration on animals the breathing does
READJUSTMENTS OF REGULATION 47
not return. The animal dies of want of oxygen, or
failure of the circulation, without making any effort
to breathe. Hence if we reduce the CO2 pressure
of the blood low enough no amount of oxygen want
will excite the respiratory centre. Oxygen want is
thus not by itself an adequate stimulus to the respira-
tory centre; but it helps the action of CO2, or if we
like to put it otherwise, causes the respiratory centre
to react in presence of a degree of blood alkalinity
which would be too high to excite it under normal
conditions.
Although a slight, or even a considerable, deficiency
in the oxygen pressure of the air breathed produces
no immediate effect on the breathing, yet a long-con-
tinued deficiency has a very distinct effect; and the
study of the effects of a long-continued deficiency has
furnished, I think, one of the most interesting chap-
ters in recent physiology. To observe the effects of
long-continued deficiency it is only necessary to go
to places at high altitudes, where the barometric pres-
sure is low, but where men nevertheless live under
perfectly healthy conditions. The Anglo-American
expedition to Pike's Peak in 1911 had for its object
the careful study of these effects.
On going to a very high altitude the breathing is
increased at once, and the alveolar CO2 pressure falls
correspondingly ; but if the altitude is only very mod-
erate there is at first no effect on the breathing, just
as happens when air containing a moderately reduced
percentage of oxygen is breathed in the laboratory
for a short time. After some days, however, it will
48 ORGANISM AND ENVIRONMENT
be found that the alveolar CO2 pressure has fallen,
which shows that the breathing is deeper. This fall
reaches a certain amount, depending on the altitude,
and then ceases. On the subject's return to sea level
the alveolar CO2 pressure does not at once return to
normal again, but may take many days, or even some
weeks, to do so. Figure 3 shows graphically the aver-
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FIG. 3. Alveolar pressures of oxygen and CO2 and per-
centages of haemoglobin in the blood of persons ac-
climatised to altitudes from sea level to 14,000 feet,—
barometric pressures from 760 to 45 0 mm. of mercury.
READJUSTMENTS OF REGULATION 49
age results of measurements of alveolar CO2 pressure
made by Miss Fitz Gerald, in connection with the
Pike's Peak Expedition, on persons residing perma-
nently at different altitudes. It will be seen that the
alveolar CO2 pressure diminishes regularly with alti-
tude, starting from sea level. That this diminution
is a response to the diminished alveolar oxygen pres-
sure there can be no doubt. If the barometric pres-
sure is kept steady, and the oxygen pressure is dimin-
ished by lowering the percentage of oxygen, the re-
sults are precisely the same, so far as can be judged by
the available observations; and, as was first clearly
pointed out by Paul Bert, practically all the physiologi-
cal disturbances produced by low barometric pressures,
or high altitudes, are due to lowering of the oxygen
pressure.
From Figure 3 it is pretty evident that if the oxygen
pressure is raised above the normal value at sea level,
the alveolar CO2 pressure will rise still higher. That
this is actually the case has recently been shown by
Hasselbalch and Lindhard, who have confirmed in a
steel chamber many of the Pike's Peak results, and
have added further observations of their own. It
appears from their results that the alveolar CO2
pressure does not rise much higher after the normal
oxygen alveolar oxygen percentage has been exceeded ;
but the fact that there is a rise is of great interest, as
showing that even the "normal" alveolar CO2 pressure
depends on the existing alveolar oxygen pressure.
What is the significance of the fall in alveolar CO2
pressure at low barometric pressures? It might be
50 ORGANISM AND ENVIRONMENT
thought that the teleological significance at any rate is
clear enough, since lowering of alveolar CO2 pres-
sure means raising of the oxygen pressure, thus com-
pensating to some extent for any want of oxygen
caused by the lowered oxygen pressure. But there
may be no evident signs of want of oxygen, and lower-
ing of alveolar CO2 pressure is in itself a very dis-
turbing influence, as has already been shown. When
we first observed the persistent lowering of alveolar
CO2 pressure in connection with shorter experiments
in a steel chamber we thought that lactic acid must
have been formed in consequence of oxygen want, and
that the persistence of the lowered alveolar CO2
pressure after the experiment was due to lactic acid
remaining in the body. But further observations by
Boycott and Ryffel failed to confirm this theory ; and
the persistence observed after longer observations in
the chamber, and stays in the Alps, was far too great
to justify the lactic acid theory. As already men-
tioned the excess of lactic acid produced by muscular
work disappears from the blood within about an hour.
Barcroft meanwhile found on the Peak of Teneriffe
that the dissociation curve of the oxyhaemoglobin in
human blood was displaced to the right if the deter-
mination is made in presence of 40 mm. pressure of
CO2 (that of the alveolar air at sea level), but was
normal if made in presence of the existing lowered
alveolar CO2 pressure. From this it could be con-
cluded that there is no appreciable change in the
reaction of the arterial blood within the body at the
higher altitude. The lowered alveolar CO2 pressure
READJUSTMENTS OF REGULATION 51
just compensated sensibly for diminished alkalinity
of the blood. This we confirmed on Pike's Peak at a
higher altitude.
As a result of the whole of the Pike's Peak and
previous experiments we came to the conclusion that
the point of alkalinity to which the kidneys, etc., regu-
late the blood is altered in the direction of slightly
diminished alkalinity, so that, assuming the reaction
of the respiratory centre to alkalinity to be steady, the
alveolar CO2 pressure has to be kept lower in order
to preserve the balance. The very slight diminution
of alkalinity required to account for the increased
breathing is so small as to be at present beyond the
range of measurement, as already explained. Hassel-
balch and Lindhard have more recently published the
results of electrometric measurements of the arterial
blood alkalinity which show a sensibly unaltered
reaction after acclimatisation to lowered barometric
pressure in a steel chamber, with the alveolar CO2
pressure much reduced.
It thus appears that the regulation of the alkalinity
of the blood by the kidneys and liver is dependent on
the oxygen pressure of the air. The change in envi-
ronment has altered the setting of the regulator. This
is a very striking example of the intimate connection
between internal physiological regulation and external
environment; but we have now to consider other
instances.
It has long been known that the percentage of
haemoglobin and relative number of red corpuscles
increases at high altitudes. Figure 3 represents the
52 ORGANISM AND ENVIRONMENT
results of Miss Fitz Gerald's observations on the
haemoglobin percentages in persons permanently living
at different altitudes. These observations were all
made by the colorimetric method of determination
which I introduced a few years ago, and with a care-
fully standardised instrument. It will be seen that
just as the alveolar CO2 rises with fall in the baro-
metric pressure, so the haemoglobin percentage rises.
It appears also that in an atmosphere with a higher
oxygen pressure than air at sea level a decrease in the
haemoglobin percentage below what is termed "nor-
mal" would occur. Here also, then, the setting of the
regulation of haemoglobin percentage is altered by
change in environment.
Using the carbon monoxide method of Lorrain
Smith and myself, we found that on going to a high
altitude not only the percentage amount, but also the
total amount of haemoglobin in the blood is increased.
The* total volume of the blood seems to diminish
at first, thus raising the concentration of haemo-
globin; but after a few days the volume of the blood
increases above normal. The regulation of total
haemoglobin, concentration of haemoglobin, and blood
volume are thus all dependent on the oxygen pressure
of the air breathed.
I now come to what was the most striking result of
the expedition. In the lungs the blood is separated
from the alveolar air by an extremely thin membrane
consisting of the "protoplasm" of flattened epithelial
cells. Do these cells play any active part in the gaseous
exchange between the air and the blood? Or does
READJUSTMENTS OF REGULATION 53
the gas simply pass through them by ordinary diffu-
sion? This question has been debated ever since a
suggestion that they may play some active part was
made by Ludwig forty or fifty years ago.
By means of an apparatus known as the aeroto-
nometer, Pfliiger and his pupils compared the pressure
of CO2 in the blood with that in alveolar air, and
found it to be about the same. The aerotonom-
eter was then improved by Bohr of Copenhagen,
an old pupil of Ludwig. His results seemed to show
that sometimes there is a lower pressure of CO2, and
a higher pressure of oxygen in the arterial blood than
in the lung air, in which case an active secretion of
oxygen inwards, and of CO2 outwards, must be
assumed. Fredericq then got results in favour of the
simple diffusion theory. Last of all Krogh of Copen-
hagen improved the aerotonometer still further, and
obtained results which again favoured the diffusion
theory.
Meanwhile Lorrain Smith and I attacked the prob-
lem by a new method, which was suggested to me by
the study of CO poisoning, and which eliminated cer-
tain sources of very serious error in the aerotonometer
method of measuring the arterial oxygen pressure.
When blood is saturated with a mixture containing
both oxygen and CO the haemoglobin combines partly
with CO and partly with oxygen in perfectly definite
proportions depending on the relative pressures of
the two gases, although in consequence of the far
greater affinity of CO for haemoglobin the pressure
of oxygen must be about 300 times greater than the
54 ORGANISM AND ENVIRONMENT
pressure of CO if the haemoglobin of human blood
at body temperature is to be divided equally between
the two gases. Clearly, therefore, if the pressure of
CO is known, and also the percentage saturation of
the blood after equilibrium has occurred, the pressure
of oxygen can be calculated very exactly. We there-
fore breathed an exactly known small percentage of
CO until the blood ceased to take up any more CO.
We then determined the percentage saturation of the
haemoglobin with CO, and the pressure of CO in the
alveolar air. From these data we calculated the pres-
sure of oxygen in the blood leaving the lungs. CO, as
already mentioned, is, apart from its action on haemo-
globin, a physiologically indifferent gas like nitrogen or
hydrogen. It is not oxidised in the body, and it
appears to pass freely by simple diffusion, like nitro-
gen or hydrogen. We could therefore assume that it
diffuses freely into the blood and finally reaches a
pressure which is the same in the blood of the lungs
as in the alveolar air.
In the human experiments we reached the appar-
ently unmistakable result that the oxygen pressure in
the blood leaving the lungs is considerably higher than
in the alveolar air, and that there is therefore active
secretion inwards. Experiments with animals showed,
further, that when the percentage of CO was in-
creased so as to produce symptoms of oxygen want
the evidence of active secretion became much more
striking.
On repeating the human experiments at a later date
we could not get the same results. Douglas and I then
READJUSTMENTS OF REGULATION 55
improved the method further, and found that both
in animals and in ourselves we got results wholly con-
sistent with the diffusion theory, provided that the
percentage of CO was kept very low. If sufficient
CO was given to produce symptoms of oxygen want
we got active secretion. We also got active secretion
if oxygen want was produced in a group of muscles
by fatiguing work. Nevertheless the human experi-
ments gave on the whole a much less striking result
than the former ones, and we could not at the time
see any reason for this.
The apparent acclimatisation to oxygen want in
mountaineers or persons living at high altitudes then
attracted our attention, and in conjunction with Yan-
dell Henderson the Pike's Peak Expedition (in which
he, Douglas, Schneider and I participated, while Miss
Fitz Gerald made observations at neighboring mining
camps and towns) was planned. When we reached
the summit of Pike's Peak (14,100 feet) we were all
more or less blue in the lips, as were other newcomers.
We then suffered in various degrees for two or three
days from mountain sickness, after which the blueness
entirely disappeared, although our alveolar oxygen
pressures remained nearly the same as while the blue-
ness was present, and our haemoglobin percentages
had not as yet risen appreciably. After this we made a
number of determinations of the arterial oxygen pres-
sure, and each one without exception showed a consid-
erably higher pressure of oxygen in the arterial blood
than in the alveolar air. On the other hand, when we
breathed during the experiment air rich in oxygen, so
56 ORGANISM AND ENVIRONMENT
as to bring the alveolar oxygen to about the normal at
sea level, the difference between arterial and alveolar
oxygen pressure almost disappeared. We then deter-
mined the arterial oxygen pressure in a newcomer who
was still blue, but did not become mountain-sick till
some hours later. It was very little above the alveolar
oxygen pressure; but three days later when he was
acclimatised and well, his arterial oxygen pressure was
as high as our own. The mean result was that on
Pike's Peak, after acclimatisation, the arterial oxygen
pressure was during rest only about 13 mm. lower than
at sea level, but was 35 mm. higher than the alveolar
oxygen pressure. The complete absence of any blue-
ness after acclimatisation was thus easily intelligible.
The lungs were actively secreting oxygen into the
blood, even during rest. Nevertheless the blueness
reappeared temporarily during prolonged muscular
exertions, as in a long climb. The lung epithelium
could thus apparently be fatigued by the extra work
thrown upon it.
As already seen, the lung epithelium is at all times
capable of actively secreting oxygen inwards if the
requisite stimulus arising from oxygen want in the
tissues is present. But at high altitudes this capacity
is greatly increased, and secretion goes on continuously
after acclimatisation. The stimulus, moreover, is
essentially the same stimulus as produces the changes
in the regulation of blood alkalinity and in the haemo-
globin of the blood. The stimulus is want of oxygen
in some form ; but how does the want of oxygen act ?
The haemoglobin of the arterial blood must, after
READJUSTMENTS OF REGULATION 57
acclimatisation, be practically as fully saturated as
usual ; and considering the increase in the haemoglobin
percentage the amount of oxygen in the arterial blood
must be greater than normal. The oxygen consump-
tion during rest was the same on Pike's Peak as at
sea level, and the circulation rate, so far as our tests
could determine it, was about the same.1 Hence the
oxygen pressure in the capillaries of the body would
be somewhat higher than usual, and our unusually
rosy color seemed to confirm this.
The most probable explanation as to how oxygen
want produces these effects is that there is some sub-
stance which normally undergoes almost complete oxi-
dation in the lungs at each round of the circulation.
At high altitudes it escapes past the lungs in abnormal
quantity in consequence of the lowered oxygen pres-
sure, and probably also of the longer time required by
the blood in the lungs to reach its full oxygen pres-
sure. There are many facts pointing to the assump-
tion that such a substance exists and that its presence
in the blood is the source of various phenomena accom-
panying oxygen want.
The increase in the capacity of the lung epithelium
to secrete oxygen is comparable to the increased
efficiency produced in almost any organ by increased
use. This increased capacity suggests the probable
explanation of why in the original human experiments
of Lorrain Smith and myself we obtained much more
1 By more accurate tests Krogh and Lindhard have re-
cently shown definitely that there is no alteration in the
circulation rate after acclimatisation in a steel chamber.
58 ORGANISM AND ENVIRONMENT
striking results than in the later experiments of Doug-
las and myself. The earlier experiments were very
long ones, and we were frequently exposing ourselves
to oxygen want for many hours at a time. We had
probably thus both become more or less acclimatised,
so that our lung epithelium reacted very promptly to
the slight oxygen want produced by the CO. In no
other way can I explain the fact that we were able to
breathe with complete impunity percentages of carbon
monoxide which in subsequent isolated experiments
were found to produce severe symptoms. The same
criticism applies to my own early experiments as to
the effects of definite percentages of CO. I was
breathing CO every day often for hours, and doubt-
less had become highly acclimatised to want of oxy-
gen, so that I underestimated the effects of CO on
ordinary unacclimatised persons.
The part played by the lung epithelium in acclimati-
sation to want of oxygen makes it possible to under-
stand how mountaineers have succeeded in reaching
such great heights as they have. In his recent explora-
tions in the Himalayas the Duke of the Abruzzi
reached the height of 24,600 feet, the barometric pres-
sure being only 312 mm. An unacclimatised person at
this pressure is rapidly disabled completely; but the
Duke's party did not suffer at all from mountain sick-
ness or other serious physiological inconvenience.
Dr. Filippi, a member of the expedition, in his account
of it expresses the opinion that there is no such thing
as mountain sickness due to rarefaction of the air. He
was entirely deceived by the influence of acclimatisa-
READJUSTMENTS OF REGULATION 59
tion, just as I was in the case of CO poisoning. On
rereading Glaisher's account of his balloon expe-
riences I was much interested to see that though he did
not clearly understand the cause of mountain sickness
he was quite convinced that repeated ascents produced
acclimatisation. I have recently found that the effects
of acclimatisation can easily be observed at ordinary
atmospheric pressure in a closed chamber in which the
oxygen percentage has been greatly reduced. An
acclimatised person remains of a normal colour, and
has no unpleasant symptoms, while an unacclimatised
person soon becomes blue in the face, and may faint.
In acclimatisation to high altitudes there are evi-
dently three factors — the increased activity of the
lung epithelium in absorbing oxygen, the increased
breathing, and the increased percentage of haemo-
globin. Of these the last raises the oxygen pressure
in the capillaries of the body, the second diminishes
the fall in alveolar oxygen pressure, and the first
raises the arterial oxygen pressure much above the
alveolar oxygen pressure, whereas at sea level the
arterial oxygen pressure is no higher, as a rule, than
the alveolar oxygen pressure. The teleological sig-
nificance of these changes seems clear, and a vitalist
would naturally point to this as evidence of the inter-
ference of the vital principle. But we must analyse
the facts further.
Ill
REGULATION OF THE ENVIRONMENT,
INTERNAL AND EXTERNAL
We must now attempt to analyse the meaning of
the fact that the pressure of oxygen may be, and at
high altitudes always is, higher in the arterial blood
than in the alveolar air. The layer separating the
blood from the alveolar air in the lungs appears under
the microscope as an extremely thin layer of moist
albuminous material made up of flattened cells. In
such a layer gases are soluble, just as they are in
water ; and it seems natural that the membrane should
take up a gas in contact with it till it is saturated, and
give it off on the other side if the gas pressure is lower
there. During rest at sea level this is in fact what
happens with oxygen, as well as with every other gas
which has been tested. The gas passes so readily that
complete equilibrium between the gas pressure in the
alveolar air and that in the blood has occurred before
the blood leaves the lungs ; and the gas pressure in the
arterial blood is thus equal to that in the alveolar air.
For CO2 and nitrogen this has been shown by the
aerotonometer and other methods: for oxygen it has
been shown by the carbon monoxide method, the aero-
tonometer method being unreliable for oxygen.
But at high altitudes the moist albuminous material
62 ORGANISM AND ENVIRONMENT
suddenly reminds us that it is alive : for it begins to do
something which at once recalls living things when it
delivers oxygen at a higher pressure than that at
which it receives it. The passage of oxygen molecules
is accelerated in the inward direction, and this accel-
eration applies to them alone, and not to other mole-
cules, so it is selective. It does not occur in a non-
living membrane, and its presence is evidently depend-
ent, firstly upon the peculiarities of the living mem-
brane, and secondly upon the presence of a special
stimulus acting on the membrane. We know, also,
that the specific peculiarities of living tissues depend
upon the maintenance of their external environment.
Hence we can say that the acceleration depends, not
only upon the factors just mentioned, but upon the
integrity of the general environment of the mem-
brane— in more familiar words, upon its nutrition,
temperature, etc., and upon the regulated removal of
so-called waste products.
Active secretion of oxygen is not a new phenomenon
in physiology. It is now over a century since the
famous physicist Biot made the discovery that the gas
in the swim bladder of deep sea fishes is nearly pure
oxygen. The pressure of oxygen in sea water is only
about a fifth of an atmosphere, and is doubtless less
than a tenth of an atmosphere in the blood circulating
outside the walls of the swim bladder. Yet inside the
swim bladder the oxygen pressure in the case of deep
sea fishes may be 100 atmospheres or more. It was
shown in 1877 by Moreau that fishes secrete just
sufficient oxygen into their swim bladders to bring
REGULATION OF ENVIRONMENT 63
their specific gravity equal to that of the water at
whatever depth they may be, or even to counterbal-
ance the effects of a float or weight attached to them.
I have in my library Lud wig's copies of Moreau's
papers. They are an interesting clue to what was
passing through his mind in suggestions he made as
to the possibility of oxygen secretion in the lungs. It
was discovered by Bohr that the oxygen secretion in
the swim bladder is, like salivary secretion, under
nervous control ; and Dreser found that oxygen secre-
tion can be excited by pilocarpin, a drug which also
excites secretion in other glands.
The cells in the wall of the swim bladder which
secrete the oxygen are columnar, and arranged like
the cells of many other secreting glands, whereas the
lung epithelium is extremely thin. Nevertheless the
elementary structure of the lung is glandular, just as
in the case of the swim bladder; and both lung and
swim bladder are developed as outgrowths of about
the same part of the alimentary canal. Before the
lungs expand at birth the lung epithelial cells are cubi-
cal, and similar to those of other secreting glands.
That the secreting cells should be thicker in the swim
bladder is natural considering the enormously greater
pressure against which the cells have to secrete.
The pressure difference against which oxygen can
be secreted in the lungs is evidently quite limited. This
is shown by measurements of the oxygen pressures in
the blood in CO poisoning, when the stimulus to secre-
tion is pushed up to what is presumably a maximum.
If there were no limit the secretion of oxygen would
64 ORGANISM AND ENVIRONMENT
afford complete protection, similar to that produced,
as already described, when the oxygen pressure of
the arterial blood is greatly raised by placing the ani-
mal in compressed oxygen. The pressure difference
against which oxygen can be secreted in the lungs is
also dependent on the pressure of oxygen in the alveo-
lar air. When this becomes very low the pressure dif-
ference is diminished; and the flow of oxygen may be
actually reversed if the alveolar oxygen pressure is
low enough. A similar reversal seems to occur in the
case of the swim bladder; and sometimes the air in
the swim bladder seems to be utilized as a store of
oxygen, drawn upon when the blood is insufficiently
oxygenated by the gills. Possibly the active secretion
current is reversed in direction.
Let us now compare the secretion of oxygen with
that of other substances by other secreting glands. In
the case of the kidney, various salts and crystalloid
substances, particularly urea, are actively secreted by
the gland cells, so that their concentration in the
urine is far greater than in the blood. For instance
there is usually about ten or fifteen times as much
urea in a given volume of urine as in the same vol-
ume of blood, and when the kidneys secrete sugar
there may be twenty or thirty times as much sugar
in the urine as in the blood. Here then we have other
cases of the flow of one kind of molecules being accel-
erated in one direction. In the kidney secretion we
also see that the acceleration may be in either direc-
tion, and that it depends upon the molecular concen-
trations in the liquids on the two sides of the secreting
REGULATION OF ENVIRONMENT 65
cells. We cannot by any means force up indefinitely
the concentration of a substance in the urine; and if
the concentration in the blood of a constituent of urine
falls below a certain point, the secretion of that con-
stituent ceases. If, for instance, the concentration of
sodium chloride in the blood falls below normal, sodium
chloride disappears at once from the urine, though it
is still abundant in the blood. Sugar is not secreted
at all by the kidneys unless its concentration in the
blood exceeds the normal. In both these cases the
acceleration is in the opposite direction to secretion,
so that the passage of these substances is actively
prevented.
The secretory action of the kidneys is strikingly
dependent in other ways on the environment of the
secreting cells. Their activity is easily abolished by
want of oxygen, for instance, or by minute doses of
various poisons, and may be increased by the admin-
istration of various drugs.
When we look at other cases of secretion we find
that often enough some one or other of the sub-
stances secreted is not present as such in the blood,
but is formed in the secreting cells. Instances of this
are the formation and secretion of hippuric acid in
the kidney, of urea, bile acids and pigments in the
liver, or of casein and milk-sugar in the milk glands.
The constituents or precursors of these substances
are taken up from the blood, and their combination or
decomposition takes place in the secreting cell. The
resulting substances are then accelerated outwards
from the secreting cell to the duct, while their precur-
66 ORGANISM AND ENVIRONMENT
sors are accelerated inwards from the blood into the
cell.
The step from secretion to the processes which we
commonly designate as cell nutrition or cell respira-
tion is only a short one. The microscopic study of
secreting cells shows that the substances secreted, or
their immediate precursors, are often stored up
for some time until the moment for their discharge
comes. This storage is comparable to ordinary
growth. In his famous book on Secreting Glands,
published in 1830, Johannes Miiller expressed the
opinion that secretion and growth are merely different
aspects of one kind of activity; the sole difference
being that in secretion the product is removed, while
in growth it remains. Muller was a vitalist, and his
ideas on secretion were for the time swept away by
the whirlwind of mechanistic speculation which passed
over physiology about the middle of the last century ;
but in the main he was right. We now know that even
in ordinary nutrition nothing remains still and inactive.
Living structure is really alive and full of molecular
activity: it is the expression of the directions and
velocities which this activity takes. Substances are
constantly being taken up from and given off to the
environment; and even when these substances do not
seem to be used up in adult nutrition, as for instance in
the case of inorganic salts, there is a constant molec-
ular interchange between the cell and its environ-
ment. This is proved by the fact that, as was first
shown in particular by Sidney Ringer, the tissues are
REGULATION OF ENVIRONMENT 67
extremely sensitive to the slightest changes in the
concentrations of inorganic salts in their environment.
Cell-secretion, cell-respiration, and cell-nutrition are
clearly only different aspects of the same whirl of
molecular activity. Where secretion or nutrition seems
to be stationary, there is in reality only a balance
between ingoing and outcoming molecular streams.
Instances of this occur when the kidney is not secret-
ing chlorides, or when no oxygen is passing into or
out of the swim bladder, or when all external activity
is latent, as in a dry seed. The apparent stand-still is
similar to that in a blood corpuscle in a test tube of
blood half saturated with oxygen, when the stream of
oxygen molecules entering the corpuscle is balanced
by the stream leaving it. The unstable oxyhaemo-
globin molecules in the blood corpuscle are constantly
losing oxygen molecules and as constantly regaining
others, so that the half saturation of the blood cor-
puscle with oxygen represents the average of the
gains and losses of the haemoglobin molecules. This
we can understand. But what conception can we form
of the molecular streaming in the living cell and the
strange co-ordination which the different molecular
streams exhibit? I have tried to indicate how this
problem, which will be followed up in the next lecture,
rises directly out of the fact of oxygen secretion. But
meanwhile we must follow further various other facts
relating to respiration.
The evidence existing at present is strongly against
the theory of active secretion of CO2 outwards by the
lung epithelium. Krogh's experiments gave very defi-
68 ORGANISM AND ENVIRONMENT
nite results on this point. In any case we should
hardly expect to meet with active secretion of CO2,
considering that the breathing is regulated by the CO2
pressure in the arterial blood, and that the oxygen
supply to the lungs is dependent on this regulation.
During very excessive muscular work it seems to be
the oxygen supply to the body that first begins to fail.
This is indicated by the fact that in very hard work the
alveolar CO2 percentage begins to fall, and may even
become lower than during rest.
The delicate and exactly regulated organization by
which CO2 is removed from the blood in the lungs,
and oxygen supplied, would quite clearly be of little
service to the body if there were not also a regulation
of the circulation of blood so as to keep the removal of
CO2 from the body tissues and their supply of oxygen
correspondingly steady. We must now, therefore,
consider what is known as to the circulatory regula-
tion. Knowledge on this subject is unfortunately still
very fragmentary, mainly because physiologists have
failed to appreciate the delicacy of organic regulation,
or have even lost sight of it altogether when investi-
gating various matters of detail.
The blood brings to the tissues the various sub-
stances required for their normal life, and removes
from them substances which are then carried to other
tissues or to secretory organs. It is also a carrier of
heat. The carriage of oxygen and CO2 is thus only
one of its many functions. Hence we must not expect
that the circulation will be solely regulated with refer-
ence to the carriage of these gases. Bernard noticed
REGULATION OF ENVIRONMENT 69
that during active secretion of saliva by a salivary
gland the venous blood issuing from the gland was of
a bright red colour, owing to quickening of the circu-
lation ; and Barcrof t found that owing to the quantity
of liquid and CO2 abstracted from the blood during
salivary secretion the absolute quantity of oxygen in
a given volume of the venous blood may be greater,
while that of CO2 may be less, than in the arterial
blood. As one constituent or another assumes greater
or less importance in the exchange between blood
and tissues we must expect the circulation to vary
accordingly, and there is no doubt that it does so
vary. The gaseous exchange is, however, every-
where of such immediate importance that we may be
sure that the circulation is to a large extent regulated
with reference to the gaseous exchange.
The flow of blood through any part of the body
depends partly on the difference in blood pressure be-
tween arteries and veins, and partly on the resistance
to the flow of blood from the arteries through the
capillaries to the veins. Now the difference between
the pressures in the main arteries and veins at any
given body level is nearly constant. This is so because,
if we neglect such part of the pressure as is accounted
for by the mere height above or below the heart, the
pressure in the larger arteries is high, and nearly con-
stant, while that in the veins is so low as to be insigni-
ficant in comparison with the arterial pressure. Hence
it is through variations in the resistance that variations
in the rate of flow are brought about. But variations
in the resistance depend almost entirely, so far as we
70 ORGANISM AND ENVIRONMENT
know, on variations in the calibre of the small arteries,
caused by variations in the degree of contraction of
the circular muscular coat with which they are pro-
vided. It was discovered by Bernard that the muscu-
lar coat is under the control of the nervous system
through the vaso-motor nerves supplying the arteries.
It is apparently, therefore, by these nerves that the
rate of blood flow is controlled, though it may be that
there is also some non-nervous means of control, due
to the direct local action of chemical stimuli.
But how are the vaso-motor nerves themselves
excited? It is known that there is a centre in the
medulla oblongata in connection with afferent nerves
by the excitation of which a widespread reflex aug-
mentation or inhibition of the impulses which are con- '
stantly passing from the centre to the arteries is
brought about. When this centre is destroyed or its
connections severed there is also a great general fall
in arterial blood pressure owing to dilatation of the
arterioles. But the action of this centre does not
explain the local regulation of blood flow in different
organs in accordance with local requirements. That
such local regulation occurs is known from observa-
tions of the local blood flow; it is known, also, that
there are subordinate nerve centres controlling local
blood supply, the response of these centres being to
afferent impulses passing to the centres along locally
distributed nerve-fibres. The afferent nerve-endings
are apparently excited by excessive accumulation of
products of metabolism or by deficiency of the sub-
stances used up. It may be that the products of
REGULATION OF ENVIRONMENT 71
metabolism act directly on the walls of the small
arteries, but it is somewhat difficult to imagine how
this could be brought about.
Be this as it may, there is no doubt that in some way
the blood flow through different parts of the body is
regulated in accordance with the requirements of each
part, so that during extra activity in any part there is
a correspondingly greater blood flow. Measurements
of the circulation through various organs have been
recently carried out, in particular by Barcroft and his
associates, in connection with simultaneous measure-
ments of the oxygen consumption in these organs.
The general parallelism between increased oxygen
consumption and increased rate of circulation is evi-
dent from these measurements.
To measure the circulation rate of the body as a
whole by direct means is impossible without opera-
tive procedures which hopelessly disturb the physio-
logical conditions. Indirect methods have, however,
been introduced recently. One of these is to measure
in the lungs by a rapid method the gas pressures of
the whole venous blood entering the lungs. From the
gas pressures the gas contents can be calculated, as
already seen, and a comparison of the venous with the
arterial gas contents gives a direct measure of the
ratio between oxygen consumption or CO2 produc-
tion and blood flow. If the amount of oxygen being
taken up and CO2 given off at the time is known,
the blood flow itself can also be calculated. Using this
method in man both Dr. Boothby of Boston and I
have found that the blood flow increases proportion-
72 ORGANISM AND ENVIRONMENT
ately with the consumption of oxygen or production of
CO2. Accordingly the differences in gas contents be-
tween arterial and venous blood vary far less than does
the rate of metabolism. To judge from observations
on myself, the venous gas pressures are practically
constant during rest. The differences in gas pressures
between the two kinds of blood differ only slightly
with great differences in the consumption of oxygen.
The gross regulation of the circulation is of such a
nature as to keep the venous gas pressures nearly
steady, while regulation of breathing keeps the arte-
rial gas pressures nearly steady. Hence although the
pressure of oxygen is lower, and that of CO2 higher,
in the venous than in the arterial blood, yet in each
case the pressure is relatively steady. How the pecul-
iar forms of the dissociation curves of oxyhaemoglobin
and of the compounds which CO2 forms in the circu-
lating blood contribute toward this result has been
explained in the previous lecture.
The rate of the total circulation depends of course
on the amount of blood pumped round by the heart;
and it might seem at first as if the heart were the
prime regulator of the circulation. This mistake has,
in fact, been made by many physiologists through
failure to look at physiological knowledge as a whole.
Under normal conditions the heart simply maintains
the pressure in the large arteries by pumping more, or
less, blood according to the rate at which the blood-
vessels allow blood to escape. It is thus the state
of contraction of the blood-vessels in the various parts
of the body that governs the rate of circulation.
REGULATION OF ENVIRONMENT 73
The heart itself could not act as the prime regu-
lator of the general circulation rate without pro-
ducing great variations in the arterial blood pressure,
so as to drive the blood at varying rates through
the resistance of the arterioles. These great variations
do not normally exist, as is easily shown by measure-
ments of the blood pressure. Nor would primary
regulation of the blood flow by the heart be of much
use, since any regulation brought about in this way
would apply to all parts of the body alike, whereas the
increased or diminished requirements for blood are
purely local, according as one part or another of the
body is in a state of greater or less functional activity.
The heart is known to be provided with two sets of
nerve fibres through which its action is controlled, and
which reach it as branches of the vagus and the sym-
pathetic nerves. The vagus fibres, when excited, exer-
cise an inhibitory action, reducing both the frequency
and the strength of the heart beats. The very signifi-
cant discovery of this inhibitory action was made
known by the brothers Weber in 1845. Excitation of
the sympathetic fibres, discovered by von Bezold in
1862, increases the frequency and strength of the
heart beat.
The inhibitory influence of the vagus fibres is at
once increased reflexly if the blood pressure in the
aorta (the great artery leaving the heart) rises, and
diminished if it falls. As an additional preventive to
excessive arterial blood pressure there is a further
nervous connection through which excessive rise of
blood pressure causes reflex dilation of the arteries
74 ORGANISM AND ENVIRONMENT
of the intestinal area, so that the pressure is relieved.
The accelerator or augmentor nerve fibres are, ac-
cording to recent investigations by Bainbridge, brought
reflexly into action by rise in the pressure in the great
veins opening into the heart.
It is clear also that the amount of blood pumped
by the heart must depend on the supply of venous
blood, and there is experimental evidence, first
brought by Yandell Henderson, that fall in venous
blood pressure may actually limit the heart's output
of blood, so that the frequency of the heart beats is
no measure of the rate of circulation, just as the
frequency of breathing is no measure of the amount
of air breathed. In this connection the state of con-
traction or relaxation of the walls of the veins is a
factor of great importance. Yandell Henderson's
observations, part of which are not yet published,
though communicated to me verbally, seem to indi-
cate that contraction of the peripheral veins dams
back blood in the capillaries. Less blood passes on
to the great veins and the pressure in them becomes
insufficient for the adequate filling of the heart.
The immediate causes of contraction of the walls
of the veins are not yet exactly known ; but the obser-
vations of Yandell Henderson on the influence of the
pressure of CO2 on the circulation are extremely sig-
nificant. When the body is greatly impoverished in
CO2 by excessive artificial respiration the circulation
fails, apparently from an inadequate supply of blood
to the heart. The simplest explanation of the facts
seems to be that the tonic contraction of the walls of
REGULATION OF ENVIRONMENT 75
the veins is dependent inversely on the pressure of CO2
in the blood. Accordingly deprivation of CO2 leads
to contraction of veins, with resulting congestion
of capillaries and a decrease in the volume of the
blood in active circulation equalling that induced by
haemorrhage. On the other hand, any condition, such
as muscular work, which is accompanied by increased
pressure of CO2 and diminished oxygen pressure in
the blood leads to dilation of the veins, and consequent
increased rapidity in return of blood to the heart,
with increase of venous blood pressure. What part,
if any, the nervous system plays in this process, or
what other substances beside CO2 are of influence,
there are as yet no data to enable us to decide. From
the circulatory phenomena in asphyxia due to breath-
ing air deprived of oxygen (when there seems to be
a great increase of both arterial and venous blood
pressure) we may, however, infer that want of oxygen
is one such factor.
The state of tonic contraction of the unstriped
muscle such as is found in the walls of blood vessels
depends, doubtless, on many other conditions besides
nervous control. Recent investigation shows that one
of the most interesting of these conditions is the supply
to the blood of adrenalin, a specific product of the
activity of the suprarenal glands. This discovery
illustrates in a striking way the interdependence of
different parts of the body — a subject to which I shall
presently return.
When we review what is known as to the regulation
of the circulation it is evident that it is not primarily
76 ORGANISM AND ENVIRONMENT
the heart, or the nervous system, which is the regu-
lator, but the metabolic activity of the body as a whole.
The blood circulates at such a rate as is sufficient to
keep its composition approximately constant at any
part of the body, and the rate of flow seems to be
greater or less at any one part in proportion as the
causes tending to disturb the composition of the blood
are greater or less at the same part. Among the chief
of these causes is consumption of oxygen and libera-
tion of CO2. Hence the circulation rate is to a large
extent determined by the activity of the latter pro-
cesses, and varies, just as the breathing varies, in such
a way as to keep the gas pressures in each part of the
body approximately constant.
This is not an isolated fact in physiology. Claude
Bernard pointed out in 1878 in his Legons sur les
phenomenes de la vie that the blood is a fluid of re-
markably constant composition, and practically pro-
vides a constant internal environment for the living
cells of which the body of a compound organism is
made up. He seems to have been led to this conclu-
sion by his well-known studies on the sugar of the
blood. While still under the influence of the old ideas
of the blood as a very variable liquid he began his
investigations under the expectation that the amount
of sugar in the blood would vary in proportion to the
sugar absorbed by the intestine, and would disappear
when no sugar or other food was taken. To his
astonishment, however, he found sugar still abun-
dantly present in the blood during starvation, and that
any increase which he could produce in the blood
REGULATION OF ENVIRONMENT 77
sugar, by feeding with sugar or sugar-forming mate-
rial, was slight. If sugar was introduced in very large
quantities it was simply excreted in the urine. He
then discovered the part played by the liver in regu-
lating the concentration of sugar in the blood, and he
soon saw that other conditions of life are similarly
regulated. This led him to express the opinion that
"all the vital mechanisms, varied as they are, have
only one object, that of preserving constant the con-
ditions of life in the internal environment."
Bernard's teaching has been to a large extent for-
gotten or obscured in masses of unconnected detail,
but in reality has been strikingly confirmed by the
progress of physiology since his time, and not merely
in connection with the physiology of respiration. Let
us look at some of the facts.
I will refer first to the regulation of the amount of
water in the blood, since this is a subject which Dr.
Priestley and I have quite recently been investigating.
It is well known that when large quantities of water
are drunk an increasing secretion of urine follows.
This increased secretion is evidently the expression
of what may be called metaphorically the effort of
the body to rid itself of unnecessary water. We made
a study of the water excretion by the kidneys on the
same lines as we had followed in studying the regula-
tion of breathing.
The increase in secretion of urine a short time after
drinking a large quantity of water is very remarkable,
the increase being usually to about twenty-fold or
more, so that as much urine may be secreted in an hour
78 ORGANISM AND ENVIRONMENT
as is usually passed in twenty-four hours. The urine
consists of nearly pure water, containing only what
are relatively speaking traces of the ordinary urinary
constituents. Now this fact in itself is very remark-
able. The blood plasma contains a considerable
amount of sodium chloride, and usually there is more
sodium chloride in the urine than in the blood plasma ;
but in the urine secreted after water drinking there is
hardly any sodium chloride. The sodium chloride is
held back, while the water passes in large quantities.
What we wished, however, to investigate specially
was the change in the blood to which the increased
secretion was a response. One would naturally look
for evidence of dilution of the blood by the water ; and
dilution would be shown by a diminution in the
percentage of haemoglobin, since this can be measured
with great accuracy and none of the haemoglobin is
excreted or destroyed. There was, however, no
diminution in the haemoglobin percentage during the
period of most rapid excretion of the urine. Evi-
dently the blood was not diluted, in spite of the fact
that sometimes a volume of liquid exceeding that of
the whole of the blood had been carried by the blood
from the intestines to the kidneys in the course of
a few hours.
Dr. Priestley then determined the electric con-
ductivity of the blood serum, as this gives a very
sensitive measure of the concentration of salts in the
blood. The result was that there was a very slight
but constant diminution of the conductivity during the
extra secretion. This proved that though the blood
REGULATION OF ENVIRONMENT 79
was not diluted as a whole there was a very slight
diminution in the proportion of salts to water. Some
of the salts had presumably passed from the blood
into the water contained in the intestine, with the
result of decreasing very slightly the percentage of
salts in the blood. The enormous extra secretion of
water was the response of the kidney to this very
slight change. At the end of the extra secretion the
conductivity had returned to normal.
When, instead of pure water, a dilute solution of
sodium chloride in water was drunk, there was again
an enormously increased secretion of urine. This was
accompanied by an easily measurable dilution of the
blood, and the slightly increased conductivity showed
that not only water but also salt was in slight excess
over the other constituents. Both water and salt pass
out in the urine, though at first very little of the salt
goes, indicating that the excretion of the extra water
is a process independent of the excretion of the extra
salt.
After prolonged sweating, so as to deprive the body
of much water, the urine becomes very scanty and
concentrated. But in this case the blood may not
become measurably more concentrated, even though
the body has lost by sweating a quantity of water
nearly equal in weight to the whole of the blood.
The regulation of the proportion of water in the
blood can thus be placed side by side as regards deli-
cacy with the regulation of its reaction and compo-
nents : its pressures of CO2 and oxygen, its percentage
of sugar, urea, salts, and albuminous substances. Had
80 ORGANISM AND ENVIRONMENT
we the means of determining the innumerable other
substances present in blood we should doubtless dis-
cover a similar delicacy of regulation.
All parts of the body seem to participate in this
regulation. We have already seen how this is so in the
case of breathing, circulation, and the activities of the
kidneys and liver. Recent investigations reveal the
same thing in connection with such organs as the
thyroid, suprarenal and pituitary glands. The regu-
lation of the blood temperature in warm-blooded ani-
mals is one of the most striking instances. During
muscular exertion the heat production in the body
may be increased six or eight fold, but the tempera-
ture of the arterial blood is only increased by a quite
insignificant amount, as increase in the skin circula-
tion and in the evaporation of moisture from the body
compensates for the increased production of heat;
while if the external temperature is varied the effects
on the body temperature are also compensated by
changes in the skin circulation and evaporation, and
by variations in the heat-production of the body. The
regulation is through the central nervous system, and
is exactly comparable to the respiratory regulation of
the blood.
The phenomena observed after bleeding or transfu-
sion of blood are of great interest in this connection,
and have recently been studied in some detail by
Boycott and Douglas, using the new method available
for determining the total haemoglobin and total blood
volume in the body during life. After bleeding the
total blood volume in the body is very rapidly recov-
REGULATION OF ENVIRONMENT 81
ered. The capillary walls seem to take up the liquid
and solid material required, and this material is at the
same time reconstituted so as to produce blood plasma
of normal composition. But the regeneration of the
lost red corpuscles is a much slower process, so that the
new blood is at first very deficient in corpuscles, and
several weeks may be needed for their complete regen-
eration. If, however, the bleeding is repeated at inter-
vals the process of regeneration of corpuscles becomes
faster and faster, so that frequent re-bleedings can
be easily borne by the animal. Similarly, if blood is
transfused from one animal to another the liquid part
of the injected blood is rapidly eliminated, but not the
red corpuscles. Hence for a considerable time the
blood is abnormally rich in corpuscles. If, however,
the transfusion is several times repeated the excess of
corpuscles disappears more and more rapidly. The
capacity of both the blood-forming and the blood-de-
stroying process is thus increased by use. Young red
corpuscles are known to be formed in the bone-mar-
row, while the products of destruction of red cor-
puscles are found in the liver and excreted in the bile.
The capacity for formation or destruction of corpus-
cles is thus associated with the physiological activity
of these parts of the body, but this activity is evidently
regulated with great exactitude.
If we look, not merely at the internal, but also at the
external activities of an organism Claude Bernard's
generalisation seems still to hold. The co-ordinated
activities of the senses and muscular system are mainly
directed to the end of providing for nutrition. Behind
82 ORGANISM AND ENVIRONMENT
and controlling these activities are the instinctive ex-
citatory or inhibitory impulses, which we know as
hunger, thirst, satiety, discomfort and comfort. These
impulses may be regarded as expressions of the many-
sided activities which are all directed towards keeping
the internal and external environment constant.
On examining the forms which vitalism has taken
we find that the vital principle has been commonly
regarded as an influence which resists the tendencies
of physical and chemical influences to produce disin-
tegration of the body structure. The great chemist
Liebig, for example, looked at the oxidation processes
in the body from this point of view, and regarded the
vital force as something protecting the structure of the
body from becoming the prey of oxidation.
But let us examine the whole matter more closely.
It is quite evident that the activities of the various
parts of the body are not merely in the direction of
maintaining the internal environment constant, but
also in the direction of disturbing it. The muscles by
their activity may be engaged in obtaining nutriment
for the body, but they are also consuming this nutri-
ment wholesale. The kidneys are not merely remov-
ing superfluous or harmful material from the blood,
but they, too, are consuming oxygen and other sub-
stances, and producing CO2 and other metabolic
products. This is also true even of the lungs and the
respiratory centre, for the respiratory centre is vio-
lently excited by the products of its own oxidation
if its blood supply is checked. Now when we examine
those activities which tend to disturb the internal
REGULATION OF ENVIRONMENT 83
environment we find that they are no less persistent
than the activities which maintain its constancy. The
muscles still continue to consume oxygen and form
heat, even though they are for the time at rest, and
though all loss of heat from them is prevented. The
kidneys still absorb oxygen when they are not secret-
ing. In a sense, too, they are still secreting, even when
there is no external sign of secretion, for the absence
of external secretion is only the expression of an equal
balance between constant intake and constant output
of material. When the muscles and sense-organs are
not at work on the getting of food, or in other con-
servative processes, they seem to employ themselves
otherwise — for instance in what we know as play.
No physiological facts are more significant than
those relating to the persistence of the fundamental
metabolic phenomena. In Liebig's time it was observed
that the excretion of urea rises and falls with the
amount of nitrogenous food consumed, although dur-
ing starvation there is still a certain minimum excre-
tion of urea. This was interpreted as signifying that
all superfluous nitrogenous food simply falls a prey to
oxygen, and is wasted. When, however, the facts
were further investigated it was found that within
wide limits the oxidation in the body does not increase
or diminish with increase or diminution of the nitrog-
enous food consumed. Even after long starvation
the oxygen consumption per unit of body weight is
practically undiminished during rest. When more
nitrogenous food is consumed in the body and oxidised
to urea, less fat or carbohydrate is consumed.
84 ORGANISM AND ENVIRONMENT
Rubner showed that nitrogenous food, fat, and car-
bohydrate are substituted for one another as material
for oxidation in exact proportion to the energy which
they yield in the body. The sum of this energy per
unit of body weight remains constant during rest,
whether food is given or withheld. Even when loss of
heat is prevented as far as possible, the oxidation pro-
cesses in the body remain sensibly constant in spite of
prolonged deprivation of food. The diminished oxida-
tion of nitrogenous material during starvation depends
simply on the fact that the body stores its energy-
forming material mainly as fat, and consequently uses
up mainly fat during starvation. When all the fat
is exhausted there is again, before death from starva-
tion, a great increase in the oxidation of nitrogenous
material. This latter fact adds new emphasis to the
persistence of the oxidation processes.
The internal environment which is maintained so
constant is in reality the expression of a balance be-
tween activities which disturb and activities which
restore it. When we speak of "the function" of an
organ and regard this function as what it does to
restore the internal environment we are thinking in
terms of an imperfect and misleading conception of
what that organ is, and what an organism is: for we
are thinking of only one side of its activities to the
exclusion of others which are just as important. To
put this into philosophical language we are thinking
abstractly, or regarding only a part of the reality we
are dealing with. We can speak more correctly of
REGULATION OF ENVIRONMENT 85
the function of a part of a machine : for this part
does nothing else than fulfil its function, provided the
machine is assumed to be perfect and stable. In a
living organ however we are dealing with something
of which the functions, if we speak of functions, are
endless, since the activities are endless, constantly
seeming to grow in number as we investigate further.
Its true function, to the eye of a physiologist, is to
maintain these endless activities in balance with the
endless activities of other organs, and not merely to
perform one specified action.
It is evident that the balancing of molecular activi-
ties on which the maintenance of the internal environ-
ment depends is centred in the bodies of the cells
which make up the living tissues. The composition
and volume of the blood are the outcome of their
joint active or passive influences. We are thus brought
back to the problems of cell-secretion, cell-respiration,
cell-nutrition, cell-movement, cell-heat-production —
problems which, as we have already seen, are only
different aspects of one problem — that of what may be
called cell-metabolism. Living cells are the nodal
points of the molecular and ionic streams of which
one outcome is the constant internal environment.
The living cells are the seat of the molecular or ionic
accelerations or retardations which manifest them-
selves in secretion, and of the main chemical changes
which express themselves as metabolism in its varied
outward forms. When we concentrate attention ex-
clusively on some one detail of cell-metabolism we
86 ORGANISM AND ENVIRONMENT
necessarily lose sight of the co-ordination which ex-
presses itself in the persistence or constancy of cell-
structure and of the internal environment. But the
co-ordination is plain when we look at the phenomena
as a whole, and becomes more and more detailed the
more we penetrate towards the living tissue elements.
The phenomena of breathing have turned out to be
the outward expression of one side of the co-ordinated
activities which we lump together under the name of
metabolism. Our conception of breathing depends,
therefore, on the ideas we can form of this
metabolism.
At the conclusion of this lecture let us glance at
what may be called physiological causation. All physi-
ological activities seem to be in response to external
or internal causes or "stimuli." Physiologists speak
of a "stimulus" rather than a "cause," since the word
"stimulus" expresses the fact that other external con-
ditions determine the response besides the stimulus
itself. The response depends, not merely on the
strength of the stimulus, but on the "excitability" of
the responding tissue. In other words the response
may be partially or wholly inhibited or greatly in-
creased by varying conditions in the environment of
the tissue. The character or direction of the response
may also depend on these conditions, or even on the
strength of the stimulus itself.
As has been already shown, the respiratory centre
normally responds with rhythmic inspiratory and ex-
piratory responses to the stimulus of a very minute
REGULATION OF ENVIRONMENT 87
diminution in the alkalinity of the blood. But the
duration of the responses is modified by stimuli de-
pendent on inflation or deflation of the lungs, while
the extent of inflation or deflation which is effective
in this direction depends on the strength of the
primary chemical stimulus. The effect of this primary
stimulus is also dependent on the supply of oxygen to
the centre, and is increased if the oxygen supply is
defective. If we prefer to put the matter in another
way, deficiency of oxygen is itself a stimulus to the
centre, but is dependent for its effect on the reaction
of the blood, and is quite ineffective if the alkalinity
increases slightly. Other substances, such as morphia,
chloral, or chloroform, diminish the responses of the
centre to a given diminution in blood alkalinity; and
from the analogy of other tissues we may be quite
sure that slight changes in the concentration of the
salts and other substances in the blood, or changes
in its temperature, must similarly affect the response
of the centre in one direction or another. We can even
imagine the respiratory centre responding, not, as
normally, to changes in alkalinity, but to changes in the
concentration of, say, calcium salts.
When we seek for the "cause" of a physiological
reaction we are thus landed in a maze of contributory
causes. We can wander in this maze for as long as we
like, but there is no end to it. So far as it is possible
to judge, those who seek in physiological phenomena
for the same kind of causal explanations as can
usually be assigned in connection with inorganic phe-
88 ORGANISM AND ENVIRONMENT
nomena have no prospect but to remain seeking indefi-
nitely, unless they cut the knot by relapsing into vital-
ism.
But is there no scientific clue through this apparent
maze? Does not the element of regulation which, as
we have seen throughout, is the outstanding feature
of biological phenomena, furnish the clue? In the
next lecture this question will be discussed.
IV
ORGANIC REGULATION AS THE ESSENCE
OF LIFE. INADEQUACY OF MECHAN-
ISTIC AND VITALISTIC
CONCEPTIONS
In the previous lecture we saw that the internal
environment is kept constant as the result of a con-
tinuous and extraordinarily delicate regulation of the
balance between opposing activities. What general
conception can we form of this balancing process?
An obvious possible interpretation is that each of
the various organs concerned in the balancing process
has such a physical and chemical structure that it
reacts to a given small deviation in the internal en-
vironment so as to prevent further deviation in this
direction. As the combined result of the reactions of
all the organs the internal environment as a whole
remains constant. It is evident, for instance, that the
respiratory centre reacts to very small differences in
the hydrogen ion concentration in the blood, in such a
way as to prevent larger differences from occurring.
The temperature-regulating centre reacts to small dif-
ferences in the blood-temperature. The kidneys react
in a similar way to very small differences in the con-
centrations of water, urea, and numerous other inor-
90 ORGANISM AND ENVIRONMENT
ganic or organic substances. The organs, such as the
liver, or fat-containing tissues, in which material is
stored, appear to behave similarly; and we have now
every reason to believe that we should find the same
regulating activity in every organ or part of the body
if our methods of investigation were sufficiently deli-
cate, and we knew the small differences to be detected.
In every direction the progress of physiology and
pathology is revealing the astounding delicacy and
complication of the regulating processes.
Up to a certain point we can rest satisfied in the
idea that the regulation of the internal medium de-
pends upon the specific structures and corresponding
reactions of the organs which bring about the regula-
tion. But the more we learn about the delicacy and
complexity of the regulating processes, the more defi-
nitely does a difficulty appear. It is not for nothing
that the body regulates its internal environment so
exactly. The investigations which reveal the exacti-
tude of the regulation reveal equally its fundamental
importance to the nutrition and normal working of
every part of the body. The organs and tissues which
regulate the internal environment are themselves
centres of nutritional activity, dependent from moment
to moment on their environment. They are constantly
taking up and giving off material of many sorts, and
their "structure" is nothing but the appearance taken
by this flow of material through them. The fact has
already been referred to that when the supply of
oxygen to the tissues is seriously restricted the result
is not merely a slowing down of activity, but actual
ORGANIC REGULATION 91
structural change. Similar structural change is known
to result from many other slight alterations in the
composition of the blood; and so far as the evidence
goes, it points to the conclusion that the specific struc-
ture of every part of the body depends upon the spe-
cific composition of the blood, as well as on the influ-
ence of the adjacent tissues or external environment.
The regulation by the tissues and organs of the inter-
nal environment is thus only their regulation of their
own structure and activity.
A living organism has, in truth, but little resemblance
to an ordinary machine. The individual parts of the
latter are stable, within very wide limits of immediate
environment, and in no way dependent on whether
the machine is in action or at rest. This stability does
not exist in the living organism. We find, it is true,
that the living organism may react in a constant man-
ner to a given change, just as a machine might do ; but
on investigation this turns out to be because the inter-
nal environment is at the time constant or "normal."
Were it otherwise not even the superficial resemblance
would hold. As we have seen, for example, in the
case of the respiratory centre, this reasoning applies
to nervous reactions just as much as to other physi-
ological reactions.
It seems clear, therefore, that we cannot base our
explanation of the constancy of the internal environ-
ment on the structure of the organs which regulate
it, since closer examination shows that the "structure"
of these organs is itself dependent on the constancy
of the internal environment. We are only reasoning
92 ORGANISM AND ENVIRONMENT
in a circle when we attempt to explain the constancy
of the internal environment by the specific characters
of bodily structure. The fact is that both the internal
environment and the "structure" of the body remain
approximately constant; but of this fact no explana-
tion has been reached.
The explanation cannot lie in the external environ-
ment, since this is far less constant than the internal
environment, which it constantly tends to disturb.
It is nevertheless the case that the external environ-
ment, in so far as it is in relation with the organism,
exhibits constancy. The composition and amount of
the food and drink in the alimentary canal approxi-
mate to a certain average; the partial pressures of
oxygen and carbon dioxide in the air which is in
contact with the body, in the lungs, remain also nearly
constant under most conditions ; the impressions trans-
mitted inwards from without are similarly more or
less constant on an average; and excesses of heat or
cold are generally avoided. Just as the internal en-
vironment seems, at first sight, to be regulated by the
organism, so also does the external environment, but
to a far less intimate extent. /In both external and
internal environment, the regulation is the expression
\l of a balancing of opposing processes of loss or gain
of material or energy ; and the processes involving loss
are no less persistent on the whole than those involving
gain.
It is mainly through the nervous system that the
body is, in the higher organisms, in relation with the
external environment. When we look broadly at the
ORGANIC REGULATION 93
activities of the nervous system, they are evidently
of such a character that the external environment,
is regulated just as is the internal environment. It is
in virtue of these nervous activities that the stream
of material and energy which is constantly entering
and leaving the body is kept so nearly constant.
Appetite and satiety, muscular activity and fatigue,
external temperature and heat loss, external light or
sound or other sensory stimuli and the responses to
them, are balanced against one another through the
nervous system. We cannot draw any complete line
of separation between the regulation of the internal
and that of the external environment; for evidently
the one is complementary to, and indispensable to,
the other. Regulation of the external environment
is in fact only the outward extension of regulation
of the internal environment, and the ultimate de-
pendence on the external environment of the organs
which regulate it is as evident as their more immediate
dependence on the internal environment. Deficiency
or excess in normal stimuli, normal nutrition, normal
temperature and respiratory exchange, are as impor-
tant to the nervous system as to other organs. The
environment determines the nervous reactions, and the
nervous reactions the environment, but the constancy
or regulation which emerges is still unexplained. The
conception of an organism as a mere labile structure
which determines, and is at the same time determined
by, its environment is unsatisfactory, for the reason
that the specific persistence of life is left unaccounted
for. The facts must be examined more closely.
94 ORGANISM AND ENVIRONMENT
We have seen that it is characteristic of an organ-
ism to react towards disturbing influences in such a
way as to maintain approximate constancy in its struc-
ture, internal environment, and even external environ-
ment. If the disturbance is merely slight, temporary,
and of normal occurrence, a simple and normal com-
pensating reaction occurs, and everything seems after-
wards to return again to its former state. But if the
disturbance is abnormal, or continued, a significant
fact emerges more and more clearly: for new and
apparently original compensatory reactions arise, or
an ordinary compensatory reaction is greatly strength-
ened, or supplemented. The new reaction is accom-
panied by corresponding structural change, which re-
mains to a greater or less extent after the cause of
distuibance has disappeared.
We are now in contact with facts of a sort which
tend to lie in the background in connection with the
customary laboratory physiology of the present time,
but which spring into such prominence in common
everyday observation, and particularly in connection
with clinical medicine and surgery, as to make the
physiology of ordinary text-books appear somewhat
unreal. In the course of these lectures various facts
of the class here referred to have been described.
The Anglo-American expedition to Pike's Peak was
undertaken with the express object of ascertaining to
what extent, and in what manner, the body adapts
itself to a continued diminished concentration of oxy-
gen in the air breathed. The results showed that new
adaptations, apart from those demonstrable during
ORGANIC REGULATION
95
short exposures, come into play during prolonged ex-
posure to a diminished oxygen concentration. Another
striking instance of the same class of fact is in con-
nection with the effects, referred to in the previous
lecture, of repeated bleeding or transfusion of blood,
as observed by Boycott and Douglas. After repeated
bleedings the animal replaces the lost blood with
increasing rapidity. After repeated transfusions it
gets rid of the excess with corresponding readiness.
Presumably in the one case there is an increase in
the amount or activity of the blood-forming tissues,
and in the other an increase of the blood-destroying
tissues.
We have only to look round, outside the limits of
the present conventional physiology, in order to find
innumerable instances of similar facts. Striking ex-
amples are afforded by the phenomena of immunity
to attacks by micro-organisms, and to the action of
poisons. Still more remarkable instances are those
connected with the recovery of function or reproduc-
tion of tissue after injury or disease, or even complete
loss of parts of the body. In the higher organisms
reproduction of lost parts is a less prominent feature
than in lower organisms, but indirect restoration of
function is a fact of common observation, and is in
some ways more significant and remarkable.
It thus appears that with disturbance of external or
internal environment, or living structure, the reactions
which occur are, whether immediate or gradual, of such
a character that the organism adapts itself so as to
maintain, not merely its existence as a structure, but
96 ORGANISM AND ENVIRONMENT
also its characteristic activities and relations to exter-
nal environment. The life of the organism may be
modified, it is true ; but in the modification it retains all
its essential characteristics, so that its identity is un-
mistakable. It persists actively, and not merely pas-
sively. Without active adaptation everything would
tend to go from bad to worse, as in the case of an
untended machine.
If the internal environment is interfered with, as by
loss of material or the introduction of foreign or super-
fluous material, the occurrence of adaptive changes
is evident. If the structural elements of the body are
interfered with, as in local injuries or infective attacks,
processes of repair soon manifest themselves at the
damaged point : the leaky and paralysed blood-vessels
become functionally competent again : exuded material
is absorbed ; and the altered and functionally abnormal
tissue elements and nerve-endings return to a normal
condition. We are gradually coming to realise how
intensely delicate is the adjustment of immediate
internal environment and organised structure involved
in the existence of normal conditions, and the more we
realise this the more significant appears the process of
recovery or adaptation. Another point with regard to
this process is that if injury has not gone too far the
restored tissues have become more resistant. It is, for
instance, a well-known fact that the blisters and other
signs of local injury produced by unaccustomed hard
use of the hands or feet are no longer produced after
"hardening" by practice. The tissues have become
adapted to the new conditions, and the adaptation is
ORGANIC REGULATION
no mere "functional" change, but is also "structural,"
as shown, for instance, by thickening of the epithelium.
When structural elements are destroyed or actually
removed, the process of reproduction is limited in the
higher organisms. We then observe the phenomenon
of other parts with similar function taking on the
special functions of the lost part. Gradual recovery
owing to other parts performing missing functions is a
matter of everyday experience in Medicine and Sur-
gery ; and though the evidence is to a large extent still
indirect, we cannot doubt that in all such cases struc-
tural changes are associated with the functional adap-
tation. The phenomena of vicarious function are also
quite clearly adaptive changes, i.e., changes of such a
nature that the life of the organism maintains as a
whole its identity.
When one regards the facts of memory from the
purely physiological standpoint it is evident that
memory is a phenomenon of the same nature as adap-
tation. An experience or effort which has been gone
through leaves its mark in the body as increased power
of reaction to a similar experience or performance of a
similar effort, just as an attack of an infectious disease,
or vaccination, leaves its mark in a power of quickly
repelling a similar infection. Were it not so memory
would be a useless incumbrance.
In this connection we may recall the facts relating
to the effects of practice in the carrying out of any
operation, such as writing, riding a bicycle, or playing
a musical instrument. Here frequent repetition of
what was at first a difficult and very imperfectly per-
98 ORGANISM AND ENVIRONMENT
formed operation leads to its being performed with
ease and certainty, without there being- any conscious-
ness of the innumerable details of nervous and muscu-
lar adjustment which are involved.
Of all other analogous facts the most remarkable,
in the higher organisms, are those relating to reproduc-
tion of the whole organism. None of the innumerable
structures special to the adult organism are present in
the developing ovum ; but as if guided by stimuli which
awaken memories of its parents and ancestors, it
builds up the adult structures and activities by degrees,
often reproducing even the finest nuances in the
character of either parent. In a living organism the
past lives on in the present, and the stored adaptations
of the race live on from generation to generation, wak-
ing up into response when the appropriate stimulus
comes, just as conscious memory is awakened.
Looking at all these facts we are inevitably forced
to the conclusion that the life of an organism, includ-
ing its relations to internal and external environment,
is something of prime reality, since it persists actively
and as a whole, and moreover tends to do so in more
and more detail with enlarging experience, so that life
is a true development. What persists is neither a mere
definitely bounded physical structure nor the activity
of such a structure. There is no sharp line of demar-
cation between a living organism and its environment.
The persistence of the internal environment and its
activities is, in fact, as evident as that of the more
central parts of an organism ; and a similar persistence,
becoming less and less detailed, extends outwards into
ORGANIC REGULATION 99
the external environment. An organism and its en-
vironment are one, just as the parts and activities of
the organism are one, in the sense that though we can
distinguish them we cannot separate them unaltered,
and consequently cannot understand or investigate one
apart from the rest. It is literally true of life, and no
mere metaphor, that the whole is in each of the parts,
and each moment of the past in each moment of the
present. Organic wholeness covers both space and
time, and in the light of biological fact absolute space
and time, and self-existent matter and energy, are but
abstractions from, or partial aspects of, reality.
We are thus brought face to face with a conclusion
which to the biologist is just as significant and funda-
mental, and just as true to the facts observed, as the
conclusion that mass persists is to the physicist.
We saw previously that the structure of a living
organism has no real resemblance in its behaviour to
that of a machine, since the parts of a machine can be
separated without alteration of their properties. All
of these properties are also independent of whether the
machine is in action or at rest. In the living organism,
on the other hand, no such separation can be made, and
the "structure" is only the appearance given by what
seems at first to be a constant flow of specific material,
beginning and ending in the environment. We have
now seen that the apparent flow has a persistence and
power of development of its own, which we cannot
account for by mere constancy in the physical and
chemical environment. What persists is not mere
matter or energy: for the matter and energy which
100 ORGANISM AND ENVIRONMENT
seem to pass through an organism are constantly being
replaced. Nor is it mere form : for the flowing mate-
rial is intensely specific. Structure, composition and
activity are inseparably blended together in life, and
no phenomenon in the inorganic world seems to us to
be similar to the phenomenon of life. The funda-
mental facts with regard to life do not fit into the
conceptions by means of which we at present interpret
inorganic phenomena. Life is something which .the
biologist as such must treat as a primary reality, and
no mere artifact. It is with life, and not merely with
physics or chemistry, or bio-physics or bio-chemistry,
that these lectures have dealt. From the outset of my
own scientific work I have been guided by the concep-
tion that it is with life, and not with what physics and
chemistry are at present capable of interpreting, that
physiology deals; and this conception has grown
clearer in my mind as a scientific working hypothesis
with advancing experience as a physiological worker.
What aims does this conception carry with it for
physiological investigation? The ground hypothesis
or conception is that each detail of organic structure,
composition, and activity is a manifestation or expres-
sion of the life of the organism regarded as a separate
and persistent whole. We have therefore to make
use of this hypothesis as a tool for investigation, just
as the physicist uses the conceptions of mass and
energy, or the chemist the atomic theory. We assume,
therefore, that it will be found on sufficient investiga-
tion that the scattered observations of living organisms
with which preliminary sensory observations supply
ORGANIC REGULATION 101
us are capable of unification under our guiding
hypothesis ; and we proceed to investigate them further
with this faith present to us. We notice, for instance,
that animals breathe. The breathing is a manifesta-
tion of the animal's life, for any hindrance to breath-
ing is violently resisted with the animal's whole
available power. Further investigation shows us more
definitely what' breathing is, the essential element in
breathing being the due supply of oxygen to the body,
and removal of carbon dioxide. By more detailed
investigations, such as I have endeavoured to describe
in these lectures, we reach a further knowledge of how
the phenomena of breathing are integral manifesta-
tions of the whole life of the organism, including its
past history ; and the aim remains before us of reach-
ing similar knowledge of how the development, main-
tenance and functional efficiency of each structural
element are regulated.
One of the earliest steps in this voyage of discovery
is to find any detail of structure or activity that can
be regarded as a "normal." We look for normal
structure, normal chemical composition, and normal
standards of activity. And we do so because we know
that life maintains itself: that this maintenance ex-
presses itself in normals for everything connected with
life. In the inorganic world there appear to be no
normals in this sense; and chance, not order, seems,
to the present very limited vision of physical science,
to reign supreme.
When we have found what appears to be a normal,
such, for instance, as a normal concentration of carbon
102 ORGANISM AND ENVIRONMENT
dioxide in the alveolar air, we first test it under vary-
ing conditions so as to make sure of its relative
stability, and then proceed to investigate its connection
with and subordination to other normals. Thus we
find that the normal concentration of carbon dioxide
in the alveolar air is connected with or subordinate to
the normal composition of the blood, the normal
activity of the respiratory centre, heart, kidneys, and
other organs, the normal composition and amount of
the food and the normal concentration of oxygen in
the air. Our general working hypothesis would have
told in a general way that connections of this kind
must exist; but special investigation could alone tell
us how they exist and how one is directly subordinate
to another. It is this kind of investigation that is
experimental physiology. The normals of anatomy
are not mere physical structure, nor are the normals of
physiology mere averages : they are manifestations of
the life of an organism regarded as a whole. We
have seen, for instance, in the case of the alveolar
carbon dioxide pressure, in the percentage of haemo-
globin in the blood, in the structure of bone-marrow,
how a subordinate normal alters as the organism
adapts itself so as to preserve its more fundamental
normals under new conditions. In pathological condi-
tions we find remarkable alterations in subordinate
normals, and these alterations are undoubtedly the
expression, to a large extent, of adaptations to the
altered conditions. Pathological phenomena are not
mere chance effects of the environment on the organ-
ORGANIC REGULATION 103
ism. Pathology is a real science, and part of the
science of biology.
Anatomy and physiology, but more particularly
anatomy, have become hide-bound in the conception
that living structure is simply physical structure; and
in consequence of this anatomy has for the present
the aspect of almost a dead science, in spite of the new
life impulse from experimental embryology. The time
has come for biology to liberate herself and step forth
as a free and living experimental science, with a world
before her to conquer by the help of clearer ideas of
what life is, and how it can be investigated.
Biology is no inexact science, contented with rough
pictorial approximations. The bane of physiology in
the past has been inexact measurement and imperfect
observation. The new physiology will be different.
Its* measurements and observations will be more exact,
and, as has been shown in the previous lectures from
actual instances, of a delicacy often far exceeding that
of existing physical and chemical methods. But the
observations and measurements will not be of phe-
nomena which if isolated are mere illusions. The new
physiology will not be content with causes, but will
seek out the organisation of which "causes" are only
the outward appearance.
For the reasons already given, organism and en-
vironment cannot be separated in considering life.
But we seem to be able to reach a satisfactory inter-
pretation of the physics and chemistry of the external,
and even of the internal environment, when these
states are looked at apart from their relations to
104 ORGANISM AND ENVIRONMENT
organic activity. The oxygen which passes into the
lungs is just ordinary oxygen, driven inwards to the
alveoli by an ordinary atmospheric pressure difference.
The process is organically regulated, but the regulation
appears to be something external to the oxygen, which
still retains its usual properties. We can then trace
its diffusion into the blood, its combination with haemo-
globin, its carriage onwards by the pumping action
of the heart, and its dissociation from the haemoglobin
in the systemic capillaries. It has come under more
intimate organic control in the blood, but we can still
trace it as molecules of ordinary oxygen. When it
reaches and is absorbed by the tissues in cell metabol-
ism the organic control becomes far more intimate.
It is caught up in a whirl in which its behaviour is
from the physical and chemical standpoint utterly mys-
terious. We can imagine no form of chemical com-
bination which will now explain the behaviour of the
oxygen. The mental picture of oxygen atoms or mole-
cules seems to fade away, and to be replaced by an-
other picture in which organisation is not something
external to organised material, but is absolutely iden-
tical with the material, so that both the material
and its movements are nothing but manifestations of
the organisation. It is life and not matter which we
have before us.
We can endeavour to hold on to the physical and
chemical picture, and to seek for substances in the
living structure which combine with, or enter into
other physical or chemical relations with the oxygen.
But a little consideration shows that even if we find
ORGANIC REGULATION 105
such instances, their presence and formation is organic-
ally determined by something beyond; and of this
something we can form no physical or chemical pic-
ture. We also realise more clearly that in following
the physical and chemical picture of the oxygen from
the outset we have only done so by ignoring the organic
control which, though present, seems less intimate.
We have ignored, or put aside for the time, the regu-
lated maintenance of breathing, the maintenance of
the delicate normal structure of the lungs and of other
parts connected with breathing, the regulation of the
circulation and of the composition of the blood, and
the maintenance of endless other things in which
organic regulation manifests itself. But when we
reach the living tissues we can ignore the organic regu-
lation no longer : for we can see nothing clearly except
an evident manifestation of the most intimate organic
regulation. The physical and chemical picture is
entirely obliterated by the picture of organism.
We may reflect that although we cannot at present
trace the combinations into which oxygen enters in the
living tissues, yet the oxygen atoms are there in some
form. We can demonstrate their presence by ele-
mentary analysis, and we can separate chemical com-
pounds, such as proteins, which contain oxygen. It
can therefore be only a matter of further investigation
to discover how the oxygen and other atoms combine
in the living tissues and how these compounds react
with one another to bring about the phenomena of life.
This reflection brings us very close to a fundamental
question. Physics and chemistry have brought us not
106 ORGANISM AND ENVIRONMENT
one step nearer to a physico-chemical conception of the
characteristic phenomena of life, though they have
been indispensable in elucidating these phenomena —
in enabling us to formulate with increasing sharpness
and detail the preponderant and omnipresent role of
organisation in connection with biological phenomena.
The more clearly we consider the matter the more
clearly does it appear that this failure is not merely
due to lack of ordinary physical and chemical data of
the kind already familiar to us. No such data that
we can remotely conceive would help us : no advance,
for instance, in our knowledge of the chemical consti-
tution and physical properties of protein compounds.
We can reach no other conclusion than that it is the
very conceptions of matter and energy, of physical
and chemical structure and its changes, that are at
fault, and that we are in the presence of phenomena
where these conceptions, so successfully applied in our
interpretation of the inorganic world, fail us.
What reasons have we for assuming, as we are apt
to assume, that our physical and chemical conceptions
or mental pictures of the surrounding universe corre-
spond with reality ? The reason is that they do actually
enable us to predict much of our experience of the
inorganic world, and up to a certain point have proved
eminently reliable. Nevertheless they leave an enor-
mous blank in our knowledge : for they assume a world
of various kinds of matter and various forms of
energy, variously distributed ; but as to why this vari-
ety and distribution exist they leave us in ignorance.
From the very nature of the ordinary conceptions of
ORGANIC REGULATION 107
matter and energy as independent entities this igno-
rance is unavoidable. Clear enough indications exist,
however, that the progress of pure physical and chemi-
cal investigation is pointing towards truer and more
adequate conceptions. The discoveries of the periodic
law and of the transmutations of chemical elements
in connection with radio-activity indicate an underlying
connection between different forms of matter. With
Faraday's discovery that in electrolytic dissociation
the ions have each a definite electrical charge, and the
more recent discoveries of the energy locked up in
atoms, and liberated as radio-activity in their decompo-
sition, an underlying connection between matter and
the energy associated with it has become no less ap-
parent. Thus even if we look only at the evidence
afforded by the investigation of the inorganic world it
seems clear enough that our present conceptions are
only working hypotheses: — the pictures which our
own generation has formed of it; but only imperfect
pictures not adequately representing reality.
In the organic world we meet with something in
the face of which these working hypotheses are far
more definitely inadequate; and the very existence of
biology is a direct challenge to them. We can never-
theless see how they can, up to a certain point, be used
successfully in interpreting biological phenomena. For
we can take the structure of the living body, not as
living structure, but as something given and independ-
ent of its environment; and having once made this
fundamentally false assumption we can proceed with
the investigation of the supposed physical structure
108 ORGANISM AND ENVIRONMENT
in the same way as the physicist or chemist would pro-
ceed. This method yields much provisional informa-
tion for further investigation and more correct inter-
pretation, through which real physiology advances;
and the mere possession of the provisional informa-
tion is itself of great value. By showing that the living
body could in certain respects be regarded as a heat-
producing machine Lavoisier made a great step for-
wards, though he did not realise that the heat-produc-
tion is organically regulated. For an animal in normal
environment the hypothesis that there is a constant
relation between intake of energy in the form of free
oxygen and food-material, and output of energy as
heat and in other forms, has stood the test of the most
rigorous experiments. The fundamental observations
of Regnault and Reiset, Pfluger, Rubner, and others
have, however, shown that both intake and output of
energy are strictly regulated, like other physiological
activities ; and what is implied in this organic regula-
tion has already been discussed. The preliminary
comparison of the organism to an energy-transforming
machine has been of great value in certain directions,
but has misled, and still continues to mislead, physiolo-
gists in others. The real source of the misunder-
standing has been the assumption that physical and
chemical working hypotheses are more than working
hypotheses of limited profitable application, and accu-
rately correspond to reality itself.
This assumption has given rise to the mechanistic
theory of life as a necessary corollary, as well as to
all that is vaguely designated as "materialism." But
)RGANIC REGULATION 109
though the assumption is false it must be borne in mind
that working hypotheses applicable to the available
sense data are indispensable to the advance of knowl-
edge and practice. With limited data crude and simple
working hypotheses, sufficient to cover the data with-
out further complication, are alone of practical use;
and both knowledge and practice, in dealing with iso-
lated and imperfect data, naturally proceed on crude
hypotheses. Where we can as yet see no organic
determination in isolated observations relating to life
the best available description of them is in mechanis-
tic terms such as we apply to the inorganic world.
Such descriptions supply an indispensable basis for
more adequate description and interpretation; but to
give a general application to the crude working hypothe-
ses on which these descriptions are based implies a
disregard of the wider biological observations which
indicate that further investigation would reveal organic
determination. This disregard is a very marked fea-
ture in current text-books of physiology. Each part
of physiology, and even each subdivision of a part,
is apt to be treated in isolation from the rest, with the
necessary consequence that not only is no place left
for the facts relating to organic determination, but
the isolated details are very imperfectly described, as
has been illustrated again and again in the course of
these lectures.
The real reason of this defect is that physiologists
have been endeavouring to fit their descriptions to the
imperfect current working hypotheses of physics and
110 ORGANISM AND ENVIRONMENT
chemistry — an attempt which, in view of the facts of
physiology can only end in certain failure. They
assume as self-evident, for instance, that what they
are dealing with is "living matter." In reality these
two words contradict one another. What we interpret
as being in the sense ordinarily current, "matter,"
cannot be also interpreted as living.
Why has physiology failed to free herself from this
misunderstanding? The fact of organic regulation
has been evident enough from early times, and, except
in more or less recent text-books, has received promi-
nent attention from physiological writers. Various
causes have, I think, contributed, and I should like now
to refer to one which is specially prominent.
The physiologists who laid most stress on organic
regulation adopted the theory known as Vitalism —
a theory which, though unorthodox, is still very much
alive, and of which the eminent experimental embryol-
ogist, Hans Driesch, is probably the best-known living
representative. The vitalistic theory is that although
matter and energy are, whether outside or inside of the
body, just what current physical and chemical con-
ceptions describe them as, yet in the living body they
are guided by what older physiologists called the "vital
spirit," "vital force," or "vital principle," and what
Driesch1 calls "entelechy." As is well known, Driesch
discovered the fact that if the constituent cells of an
embryo in its earliest stages of development are dis-
clearest and shortest exposition of Driesch's argu-
ment is, I think, contained in his recent book, The Problem
of Individuality, London, 1914.
ORGANIC REGULATION 111
arranged, or separated entirely from one another, a
complete embryo may still develop, even from a single
cell. He argues from this and other facts of analogous
character, (1) that any mechanistic explanation of life
is unthinkable, and (2) that we must assume the inter-
ference of a guiding influence, "entelechy," which
directs the material present, so that it develops in the
right way.
Driesch's destructive criticism of the mechanistic
theory is particularly searching and cogent, and it
seems to me that both he and the older vitalists have
been justified up to the hilt in refusing to accept this
theory. In the previous part of this lecture I have
endeavoured to express the vitalistic criticism in a
still more general form than it has assumed in the
writings of the vitalists. To me the mechanistic theory
of life appears impossible, not merely in connection
with the facts of heredity and embryology, but at
every point in biology.
To the vitalistic theory itself, however, there are
insuperable objections. Experience shows us that
where an organism reacts in any way it is always in
response to some stimulus, whether this stimulus origi-
nates from without or within. The stimulus of fertili-
sation normally initiates the segmentation of an ovum,
and from all analogy we must conclude that the differ-
ential stimuli arising from neighbouring cells or other
parts determine the subsequent differential behaviour
of each cell in the segmented ovum. On separating the
cells these differential stimuli are removed, and each
cell naturally starts again from the beginning.
ORGANISM AND ENVIRONMENT
Perhaps the case of the respiratory centre or of
the kidney illustrates as well as anything else the ob-
jections to vitalism. We have seen with what marvel-
lous exactitude the respiratory centre regulates the
hydrogen ion concentration of the blood, but also that
the response of the centre is nevertheless dependent on,
and proportional to, an increase, however small, in the
hydrogen ion concentration of the blood. If our
methods of measurement had been less exact, if, for
instance, we had employed rougher methods of gas
analysis in investigating the alveolar air, or if we had
been compelled to rely simply on the methods, delicate
as they seem to a chemist, which are at present avail-
able for measuring hydrogen ion concentration, it
might have seemed as if the respiratory centre acted
without a stimulus, guided by an outside agency, just
as a locomotive is guided by the driver, who shuts off
or turns on steam according to requirements, and thus
keeps his train up to time in spite of various accidental
hindrances. Vitalism is a theory of this kind: it
ignores the participation of the environment in the
regulation, and consequently does not correspond to
the observed facts, and is thus of little use as a work-
ing hypothesis in actual investigation. Its only real
merit is that it serves as a means of expressing facts
relating to organic regulation, and the defects of
mechanistic theories. These facts are registered by
referring them to the vital principle or entelechy.
The further physiology seems to advance in the
direction of mechanistic explanations the more ob-
viously it is driven into vitalism. For advance in
ORGANIC REGULATION 113
mechanistic explanation implies the assumption of
more and more definite and complex physical and
chemical structure in the body, and the development
and maintenance of this structure has then to be
accounted for, with a resulting relapse into vitalism,
whether acknowledged or only implied. The help-
less struggling in this direction of the mechanistic
school which still represents modern orthodox physiol-
ogy will be a marvel to future generations. It is in
vain that the mechanistic theorists endeavour to exor-
cise what du Bois-Reymond called the "spectre of
vitalism." This spectre is nothing but the shadow
cast by the mechanistic theory itself — a shadow which
has only become, and could only become, deeper the
longer the mechanistic theory has lasted.
Both the mechanistic and the vitalistic schools have
survived up to the present day, but we can under-
stand that actual investigators have preferred to avoid
vitalism so far as they could, as the vitalistic hypothe-
sis seemed to set a limit to experimental investigation,
and they rightly and instinctively felt that there is no
such limit. So long as vitalism seemed the only alter-
native to mechanistic interpretations, they were driven
towards the latter. In the din of controversy between
vitalists and mechanists there was, however, a com-
plete failure to go to the root of the matter, and en-
quire into the validity of the assumptions as to physi-
cal reality which were accepted by both sides.
In considering the facts of physiology we have
hitherto looked at them from the standpoint of the
individual organism only. But we know that in all
114 ORGANISM AND ENVIRONMENT
but the lower forms of animal and vegetable life the
body is made up of cells and cell-territories, and that
each cell is a centre of life. The life of the body as
a whole is maintained by co-operation amongst the
constituent cells. In the course of the common life
the individual cells are constantly perishing and being
reproduced, but the continuity or persistence of the
common life is as evident throughout these changes as
throughout the nutritive processes in which the chemi-
cal molecules passing through the body are constantly
being replaced.
Not only do the constituent cells reproduce them-
selves and perish, but so does the whole organism it-
self ; and its death is evidently just as much a normal
phenomenon as is the death of any of its constituent
cells. Death has sometimes been compared to the
wearing out of a machine, but such a comparison
throws no light on death, since the body is not a
machine. Besides death and reproduction, there are
many other biological phenomena which show us that
life is not merely the life of individual organisms, but
the life of a society of organisms. It is the life of a
family, and beyond 'that the life of a species ; or if we
endeavour to push the biological analysis still further,
the life of the universe itself, though such a life must
remain outside the limits of clear mental vision until
we can connect biological with physical and chemical
conceptions.
The distinctively biological conception which I have
endeavoured to formulate more definitely in these lec-
tures enables us to interpret what are ordinarily re-
ORGANIC REGULATION 115
garded as biological phenomena. But the higher
organisms, at any rate, are also centres of knowledge
and volition. It is unmeaning to treat consciousness
as a mere accompaniment of life, or to ignore the
differences between blind organic activity, and rational
behaviour. Conscious personality is far more than
mere organism, and the conception of life is just as
inadequate in connection with personality as the con-
ceptions of matter and energy in connection with life.
It is not the time and place to recapitulate the rea-
soning which leads to this conclusion ; but we may, per-
haps, ask why, if the reasoning is correct, there is still
a place for human physiology as distinguished from
psychology. The practical reason is that although a
man is a person and not a mere organism, we cannot
trace personality throughout all, or nearly all, of what
we observe in a man. To interpret the details as best
we can, we have to fall back on the conception of life
in the biological sense, just as in details of what we
observe in connection with living organisms we have
to fall back on ordinary physical and chemical inter-
pretations. Though we know that these interpreta-
tions on a lower plane of knowledge can only be pro-
visional, yet we should be very helpless in practical
life without them. Their practical value is unmis-
takable, and we cannot dispense with them. On this
view the conflicts between materialism and spiritual-
ism, realism and idealism, science and philosophy, are
only apparent.
In establishing the Silliman Lectures, the Founders,
although they left complete freedom to lecturers to
116 ORGANISM AND ENVIRONMENT
treat their subjects as they thought fit, expressed the
wish that the courses should have reference to "the
presence of God in the natural and moral world." It
is with hesitation that I venture to refer to this wish:
for I know that in some ways my own conclusions are
probably different from those of many who have
thought very deeply on this subject.
In the preceding lectures I have endeavoured to
describe the results of investigations on the physiology
of breathing, and at the same time to show that these
and other investigations lead to a biological concep-
tion of life which cannot be reconciled with the
mechanistic conceptions handed down to us from the
latter half of the last century. I have also argued that
in virtue of this biological conception we must claim
for biology an independent position as a science deal-
ing with the manifestations of an order immanent in
the natural world. This order is of a far more inti-
mate character than the order hitherto disclosed by
study of what we at present call the inorganic world.
To some men it has seemed that the facts of organic
life furnish evidence of the existence of an external
creator. The writings of Paley, for example, have
popularised this view. If, as Paley tacitly assumed,
organisms were machines there would be some basis
for this argument: for the formation of the body
cannot be explained as a physical and chemical pro-
cess. The hypothesis that the body is formed in each
individual by an act of miraculous creation would at
any rate serve to stop a gap in our knowledge, though
a God who did nothing but create machines would be
ORGANIC REGULATION 117
a mere Juggernaut. We have seen, however, that
organisms are not machines, and with the machine
theory the argument, such as it was, for special crea-
tion disappears. Biology leads us to the conception, not
of an external Creator, but of an order immanent in
the natural world. This order is, however, conceived
as blind and unconscious, and cannot, so conceived,
be identified with what we have learnt to understand
as God.
It is not from the data of biology, and still more
clearly not from those of the physical sciences, that
we derive our conception of God, but from the facts
of knowing and consciously doing which we observe
in ourselves and our fellow men as conscious person-
alities. In knowledge the mind extends itself over
our whole universe, so that what exists for us exists
as known, however imperfectly, and as a sphere of
our activities, however imperfect these activities may
be. But we find that neither knowledge nor conscious
activity in general is the mere knowledge or activity of
individual men. Just as the behaviour of the cells in
a compound organism is unintelligible if they are con-
sidered one by one, apart from their relations to the
whole organism, so the acquisition of knowledge and
conscious activity in general, are unintelligible from
the point of view of the individual man. We can
endeavour to picture to ourselves a man who would
be entirely self-centred — who would be a God to him-
self ; but the attempt ends in failure. It is the percep-
tion that in us as conscious personalities a Reality
118 ORGANISM AND ENVIRONMENT
manifests itself which entirely transcends our individ-
ual personalities, that constitutes our knowledge of
God. In the world of duty and knowledge, not in the
natural world as such, we find the God whom our
fathers have worshipped, and in whose strength they
have been of good courage, and faced trouble, danger
and death. God is near to us, and not far away.
The facts of biology lead to the conclusion that the
physical and chemical interpretation of the world is
fundamentally imperfect, however useful it may be.
The biological interpretation is itself similarly imper-
fect in view of the facts relating to conscious person-
ality. But when we regard the natural world, as it
seems to me we ought and must, not as something com-
pletely interpreted in the light of existing theory, but
as an imperfect interpretation which is the expres-
sion of countless centuries of human effort, the natural
world becomes part of the world of duty and knowl-
edge. Natural science and its applications are the
rough-hewing in the spiritual world, and the funda-
mental conceptions of each of the natural sciences are
the tools, fashioned by human endeavour, with which
this rough-hewing is done. Scientific results are in
themselves only incomplete and abstract presentations
of reality, just as the stones are not part of the build-
ing till they are dressed and fitted into place. Other
workers do their part in the building, but without the
rough-hewing their efforts would be in vain. Biology,
for instance, is absolutely dependent on the preliminary
work of the physical sciences, just as other more con-
crete sciences are dependent on biology. The claim
ORGANIC REGULATION 119
is often made, either explicitly or implicitly, and in
our own times particularly on behalf of the mathema-
tical and physical sciences, that scientific results repre-
sent complete and "objective" reality. This claim can-
not be justified.
We learn to know God, not by any process of ab-
stract reasoning or external revelation, but by practic-
ally realising in our own everyday lives, and those of
our fellow men, that we are not mere individuals but
one with a higher Reality. In losing our individual
lives we find our true life, and in no part of human
activity is this losing of the individual self more clearly
realised than in scientific work. When, but only
when, we see that the natural world appears to us
as it does through the devoted scientific work which
has fashioned its present appearance, we have found
God in the natural world. The life of such a man as
Charles Darwin is in truth a standing proof of the
existence of God.
I think the Founders of the Silliman Lectures must
have felt this when they left complete liberty to each
lecturer to treat his subject just as seemed best for his
immediate purpose, and without reference to theology.
INDEX
INDEX
Abruzzi, Duke of the, 58
Absorption curve of carbon
dioxide, constancy of, 34
effect of dissociation of
haemoglobin on, 33
in blood, 32, 33, 34
Accelerator nerve, 73
effect of rise in venous
pressure on, 73
Acclimatisation, at high alti-
tudes, 48, 56, 58, 59
at high altitudes, effect on
haemoglobin percentage,
51, 52, 56, 57
at high altitudes, factors in,
59
to oxygen want, 47, 48, 49,
55, 58, 59
to repeated balloon ascents,
59
Acid poisoning, ammonia
formation in, 39
Acidosis, ammonia formation
in, 39
effect on alveolar CO2, 27
Acids, effect on alveolar CC>2,
35
effect on breathing, 35
effect on dissociation of
oxy-haemoglobin curve,
31
effect on respiratory cen-
tre, 36
Activity, "normal," 1
Adaptation, alteration of the
normal in, 102
in memory, 97
in reproduction, 98
of epithelium to injury, 96
structural changes in, 94
to changes in environment,
93, 94, 95, 96
to disease, 95, 96
to injury, 95, 96, 97
to oxygen want, 94
to repeated bleeding, 95
to repeated blood transfu-
sion, 95
Adrenal, glands in regulation
of vaso-constriction, 75,
80
Adrenalin, in regulation of
vaso-constriction, 75
Aerotonometer, 53
Aggregation of haemoglobin
by inorganic salts, 31
Air, supply, to divers, 20
regulation of, 4
vitiated, 18
Albuminous substances in
blood, as weak acids, 32
124
INDEX
Alkali, effect on alveolar
CO2, 35
effect on dissociation curve
of oxyhaemoglobin, 31
Alps, 50
Altitudes, acclimatisation at,
48, 56, 58, 59
alveolar CC>2 at, 47
alveolar oxygen pressure
at, 61
arterial oxygen pressure at,
58, 61
blood reaction at, 50, 51
circulation rate at, 57
dissociation of oxy-haemo-
globin at, 50
effect of muscular exertion
at, 56
effect on blood volume, 52
effect on breathing, 47, 48
effect of oxygen deficiency
at, 47, 49
increase of red blood cor-
puscles at, 51
oxygen consumption at, 57
oxygen pressure in blood
at, 56, 57, 61
oxygen secretion at, 56
percentage of haemoglobin
at, 51, 52, 56, 57
secretion of oxygen by
lungs at, 53, 54, 56, 57
Alveolar air, CO2 percentage
in, 8, 9, 10, 11, 12, 13, 14,
15
oxygen pressure in, 30
sampling of, 8
Alveolar carbon dioxide
and Hering-Breuer in-
hibition, 25
at high altitudes, 47
calculated for dry air, 14
constancy of, 8, 10
during severe exertion, 27,
41
effect of acids on, 35
effect of alkalis on, 35
effect of diabetes on, 35
effect of diet, 35
effect of increased oxygen
pressure on, 49
effect of oxygen deficiency
on, 27
effect of partially ob-
structed breathing on, 13
effect on breathing, 8, 9,
10, 11, 12, 13, 14, 15
in acidosis, 27
regulation of breathing by,
7, 9, 11, 14
relation to barometric pres-
sure, 14
Alveolar carbon dioxide
pressure, and percentage,
relation to barometric
pressure, 14
during rest, 27
relation to alveolar oxygen
pressure, 49
Alveolar oxygen, constancy
of, 10
effect on breathing, 8
regulation of, 10
INDEX
125
Alveolar oxygen pressure, at
high altitudes, 61
Alveoli, aqueous vapour in,
13, 14
CO2 percentage in, 8, 9, 13
Ammonia, formation in aci-
dosis, 39
formation in intestines, 39
in regulation of blood al-
kalinity, 38, 39
Anglo-American expedition,
47, 49, 51, 55, 56, 94
Apnoea, 6, 9, 22
after forced breathing, 9,
46, 47
artificial respiration dur-
ing, 25
chemical, 22
CC>2 in alveoli and arterial
blood in, 22, 9
"vagus," 22
Aqueous vapour, in alveoli,
13, 14
Arterial gas pressure, 71, 72
regulation of, 72
Arterial pressure, regulation
of, 73
Artificial respiration, 25
during apnoea, 25
and Hering-Breuer inhibi-
tion, 25
Bainbridge, 73
Balloon ascensions, acclima-
tisation in, 59
effect of oxygen want in,
43, 44
Barcroft, 31, 34, 50, 69, 71
Barometric pressure, rela-
tion to partial pressure
of CO2, 13
relation of pressure and
percentage of alveolar
CO2 to, 14
Bernard, C, 3, 45, 68, 70, 76,
77,81
Bert, P., 13, 44, 49
Bichat, 3
Biological phenomena, inter-
pretation of, 107
Biology, 103, 116, 118
Biot, 62
Black, 3
Bleeding, effect on blood vol-
ume and regeneration of
red blood cells, 80, 81
effect of repeated, 81, 95
Blood, absorption curve of
carbon dioxide in, 32, 33,
34
arterial gas pressure of, 71,
72
as the internal environ-
ment, 76
behaviour of albuminous
substances in, 32
capacity for taking up CC>2,
41
carbon dioxide in, 27, 32
changes in lungs, 33
colour of, 6, 7
dissociation curve as reac-
tion index of, 31
126
INDEX
temperature regulation, 80
function of, 68
percentage of oxygen in, 28
saturation with mixture of
CO and oxygen, 53, 54
sugar contents of, 76, 77
Blood, concentration after
sweating, 79
venous gas pressure of, 71,
72
Blood composition, and spe-
cific "structure," 90, 91
effect of sweating on, 79
Blood flow, in organs, 69, 70,
71
effect of metabolism on, 70
relation to blood composi-
tion, 76
subordinate centres regu-
lating, 70
Blood alkalinity, 36, 38
at high altitudes, 50, 51
at low barometric pressure,
51
dissociation curve as index
of, 31
effect of diet on, 37
in regulation of breathing,
by, 42
nitrogen of urine as index
of, 39
regulation by ammonia, 38,
39
by "buffer" substances,
36
by kidneys, 39, 40, 51
by liver, 39, 40, 51
Blood pressure and oxygen
deficiency, 75
Blood reaction (see blood
alkalinity)
Blood transfusion, effect on
blood volume and red
blood corpuscles, 80, 81
effect of repeated, 81, 95
Blood volume at high alti-
tudes, 52
effect of bleeding on, 80
effect of transfusion, 80,
81, 95
Bohr, 30, 53, 63
Bone marrow, formation of
red blood corpuscles in,
81
Boothby, 71
Boycott, 50, 80, 95
Breathing, 3, 100, 101
after excessive ventilation,
46, 47
apnoea after excessive, 9,
46, 47
at altitudes, 47, 48
CO2 in regulation of, 7, 9,
11, 14
CO2 pressure in regulation
of, 34
during exercise, 10
effect of acids on, 35
effect of alkalis on, 35
effect of alveolar CC>2 on,
8, 9, 12
effect of alveolar oxygen
on, 8
INDEX
127
effect of CO2 pressure on,
34
effect of cutting vagus
nerves on, 21, 25, 26
effect of oxygen deficiency
on, 42, 43
effect of partial obstruc-
tion on alveolar CO2, 13
essential factors in, 3
extent of voluntary con-
trol, 11
frequency relation to alve-
olar CO2, 12
in diabetes, 35
in regulation of alveolar
CO2, 7, 9, 11, 14
influence of vagus nerve
on, 21, 22, 23, 24, 26
influence of vagus nerve in
man on, 23, 24
"mechanism" in regulation
of, 16
regulation of, 7, 9, 11, 14,
26, 27, 38, 40, 42, 43, 46,
47
regulation of, in oxygen
deficiency, 43
vagus nerve in regulation
of, 21, 22, 23, 24
"vitalism" in regulation of,
17
Breuer, 21, 23
"Buffer substances" in blood,
36
in urine, 40
Canaries, in detection of
small percentages of car-
bon monoxide, 46
Capillaries, activity of walls
after bleeding and trans-
fusion, 80
passive congestion in regu-
lation of venous pres-
sure, 74, 75
Carbon dioxide, 3, 4
absorption curve in blood,
32, 33, 34
absorption in blood, 41
absorption in blood during
violent exercise, 41
effect on divers, 19, 20
effects on circulation, 15
in arterial blood, 27, 32
in chemical combination in
blood and plasma, 31
in inspired air, effect of
high percentage of, 9
in regulation of gaseous
contents of blood, 72
"mass influence" of, 32
regulation of circulation
rate by, 76
relation of barometric
pressure to partial pres-
sure of, 13
removal in a vacuum, 32
secretion by lungs, 67
Carbon dioxide in alveoli,
and frequency of breath-
ing, 12
at high altitudes, 47
128
INDEX
calculated for dry air, 14
constancy of, 8, 10
during apnoea, 9, 22
during rest, 27
during severe exertion, 27,
41
effect of acids on, 35
effect of alkalis on, 35
effect of diabetes on, 35
effect of diet on, 35
effect of hyperpnoea on, 42
effect of partially ob-
structed breathing on, 13
effect on breathing, 8, 9
in oxygen deficiency, 27
percentage, 8, 9, 13
pressure and percentage at
various barometric pres-
sures, 14
regulation during exercise,
10
regulation of breathing, 7,
9, 11, 14
relation of oxygen alveolar
pressure to, 49
relation to barometric pres-
sure, 14
Carbon dioxide in blood, and
hydrogen ion concentra-
tion, 37
dissociation of, 31
during apnoea, 9, 22
indirect regulation by en-
dothelial cells, 41, 42
regulation of breathing by,
27, 42
regulation of venous con-
striction by, 74
regulation of venous pres-
sure by, 74, 75
Carbon dioxide deficiency, in
"shock," 15
symptoms of, 16
Carbon dioxide excess, effect
on breathing during ex-
ertion, 19
symptoms of, 16
Carbon dioxide percentage,
in alveoli, 8, 9, 13
Carbon dioxide pressure, and
hydrogen-ion concentra-
tion of blood, 37
at different altitudes, 49
effect of increased oxygen
pressure on, 49
effect on dissociation curve
of oxy-haemoglobin, 30,
31
regulation of breathing, 34
relation to alveolar oxygen
pressure, 49
Carbon monoxide, combina-
tion with haemoglobin,
45
method of determining
oxygen pressure in blood
leaving lungs with, 54
Carbon monoxide, saturation
of blood with mixture of
oxygen and, 53, 54
test for presence of, 46
Carbon monoxide poisoning,
cause of, 45
INDEX
129
compressed oxygen in
treatment of, 45
in mines, 18, 45
oxygen deficiency in, 44, 45
remote effects of, 46
symptoms of, 46
Causation, physiological, 86,
87, 103
Cell metabolism, 85
Chemical apnoea, 22
Chemistry and physics in life
phenomena, 105, 106
Christiansen, 32
Circulation, 4
effect of CO2 on, 15
function of, 68
in small animals, 46
regulation of, 68, 69, 73, 75
Circulation rate, and oxygen
consumption, 71, 76
at high altitudes, 57
local regulation by vaso-
constrictors, 72
method of determining, 71
of body as a whole, 71
regulation by CO2 elimina-
tion, 76
regulation by heart, 72, 73
regulation by oxygen con-
sumption, 76
Clinical medicine and physi-
ology, 94
Coal mines, gases in, 7
Co-ordination in physiologi-
cal activities, 1, 2, 26
Coxwell, 44
Croce-Spinelli, 44
Darwin, Charles, 119
Death, 114
Delage, G., 3
Diabetes, alveolar CO2 in, 35
respiration in, 35
Diet, effect on alveolar CC>2,
35, 37
effect on H-ion concentra-
tion of blood, 37
Disease, adaptation to, 95,
96
Dissociation curve, constancy
of, 34
Dissociation of oxy-haemo-
globin, 29
at high altitudes, 50
Dissociation of oxy-haemo-
globin curve, 29, 30, 31,
34
and inorganic salts in red
blood cells, 31
as index of reaction of
blood, 31
effect of acids on, 31
effect of alkali on, 31
effect of CC>2 of blood on,
30, 31
effect on absorption curve
of carbon dioxide, 33
Divers, air supply to, 20
Diving, effect of CO2 in, 19,
20
Douglas, 32, 41, 54, 55, 58, 80,
95
Dreser, 63
Driesh, Hans, 110, 111
130
INDEX
Electric conductivity of se-
rum after drinking dilute
sodium chloride solution,
79
after excessive water in-
take, 78, 79
Electrolytic dissociation, 107
Embryo, development of, 110,
111
Embryology, experimental,
103
Emphysema, in mine work-
ers, 19
Endothelial cells, indirect
regulation of CO2 in
blood by, 41, 42
Energy, and food supply, 84
intake and expenditure of,
108
"Entelechy," 110, 111, 112
Environment, adaptation to
changes in, 93, 94, 95, 96
and organism, 2, 98, 99,
103
external, 92, 93
external, regulation of, 92,
93
internal, blood as the, 76
in relation to function,
82, 83, 84, 93
influence on response to
stimulus, 86
maintenance by cell me-
tabolism, 85, 86
regulation of, 89, 90, 91
relation of nervous system
to, 92, 93
Epithelial cells of lungs, gas-
eous exchange by, 52, 53
function of, 61
secretion of oxygen by, 53,
54, 56, 57
selective secretion, 62
Epithelium, adaptation to in-
jury of, 96
Erythrocytes (see red blood
corpuscles)
Excretion of urea, 39, 83
of water, 77
Exercise, effect on breathing,
10
Expiration, cause of, 22
Faraday, 107
Fertilisation, stimulus of, 111
Filippi, 58
Fitzgerald, 49, 52, 55
Forced breathing and apnoea,
9
Fredericq, 6, 53
Fredericq's experiment, 6
Gas pressure in arterial
blood, 71, 72
in venous blood, 71, 72
Gases, in coal mines, 7
solution in liquids, 27
Gaseous exchange by lung
epithelium, 52, 53
Glaisher, 43, 59
God, conception of, 117, 119
Growth, secretion and, 66
INDEX
131
Haemoglobin, 6, 28
aggregation of molecules
by inorganic salts, 31
behaviour as a weak acid,
32
colorimetric estimation of,
52
combination of carbon
monoxide with, 45
function of, 7
percentage, after excessive
water drinking, 78
at high altitudes, 51, 52,
56, 57
effect of increased oxy-
gen pressure on, 52
Hasselbalch, 36, 49, 51
Heart, function of, 72
nerve supply, 73
regulation of circulation
rate by, 72, 73
regulation of discharge, 74
sympathetic control, 73
vagus control, 73
Hemorrhage, effect of (see
bleeding)
Henderson, L. J., 40
Henderson, Yandell, 15, 25,
46, 55, 74
Henry, law of, 28
Hering, 21, 23
Hering-Breuer inhibition and
alveolar CO2, 25
and artificial respiration, 25
Himalayas, 58
Hook, 6
Hydrogen ion concentration,
36
and CO2 pressure in blood,
37
effect of diet on, 37
effect on respiratory cen-
ter, 37, 89, 111, 112
under low atmospheric
pressure, 51
Hyperpnoea, 6
effect on alveolar CC^, 42
Immunity to micro-organ-
isms, 95
to poisons, 95
Inspiration, cause of, 22
Intestines, formation of am-
monia in, 39
passage of salts into, after
excessive water drinking,
78, 79
Kidneys, excretion of water,
77
in regulation of blood re-
action, 39, 40, 51
Kidney secretion, 64, 65
effects of drugs on, 65
effects of excessive water
drinking on, 79
effects of oxygen want on,
65
effects of sweating on, 79
regulation of, 89
Krogh, 53, 57, 67
132
INDEX
Lactic acid, formation during
muscular exertion, 35,
41, 50
formation in oxygen defi-
ciency, 35, 50
in urine after violent mus-
cular exertion, 41
Lavoisier, 3, 108
Law, periodic, 106, 107
Liebig, 82, 83
Life, conceptions related to,
100
Life, mechanistic theory of,
108, 109, 110, 111, 112,
113, 116
Liljestrand, 25
Lindhard, 49, 51, 57
Liquids, solution of gases in,
27
Liver, destruction of red
blood cells by, 81
regulation of alkalinity of
blood by, 39, 40, 51
regulation of blood sugar
contents by, 77
Living matter, 109, 110
Living structures, character-
istics of, 66
molecular activity in, 66, 67
Ludwig, 34, 53, 63
Lundsgaard, 36
Lung epithelium, gaseous ex-
change by, 52, 53
function of, 61
oxygen secretion in rela-
tion to CO2 pressure, 62,
63,64
secretion of oxygen at high
altitudes, 53, 54, 56, 57
selective secretion by, 62
Lungs, 4
blood changes in, 33
"Materialism," 108
Matter, relationship of, 107
Mavrogorato, 23
Mayow, 3
Mechanism, 2, 99
and regulation of breath-
ing, 16
Mechanistic theory of life,
108, 109, 110, 111, 112,
113, 116
of regulation, 5
Medulla oblongata, 5, 21, 70
Memory, adaptation in, 97
Metabolism, effect on vaso-
motor nerves, 70
in regulation of circula-
tion, 75
nitrogen, 83, 84
of cell, 85
on local blood flow, 70
Micro-organisms, immunity
to, 95
Miners, effect of oxygen de-
ficiency in, 43
emphysema in, 19
Mines, CO poisoning in, 45
CO2 in air of, 18
gases in, 7, 18, 45
ventilation in, 19
Moreau, 62, 63
Mountain sickness, 55
INDEX
133
Miiller, Johannes, 66
Muscular exertion, at high
altitudes, 56
lactic acid formation dur-
ing, 35, 41, 50
Nerve, vagus, 21, 22, 23, 24,
25, 26, 73
Nerves, vaso-motor, 70
Nilsson, 25
Nitrogen metabolism, 83, 84
relation to urea, 83
Nitrogen of urine, as index
of blood alkalinity, 39
Normals of anatomy, 102
Nutrition, coordination in, 81
Organic regulation, 108, 110
Organic regulation in tissues,
104, 105
"Organicism," 3
Organisation, manifestations
of, 104
Organism, and mechanism,
99
as a machine, 91
"structure of," 99
Organism and environment,
2, 98, 103
unity of, 98, 99
Oxidation, and oxygen sup-
ply, 4
in starvation, 84
regulation of, 4
site of, 3, 4
Oxygen, 3, 4, 7
alveolar, 8, 10
regulation of supply, 42
under compression in CO
poisoning, 45
Oxygen consumption, and
rate of circulation, 71, 76
at high altitudes, 57
in starvation, 4, 83
Oxygen deficiency, acclimati-
sation to, 47, 48, 49, 55,
58, 59
adaptation to, 94
and blood pressure, 75
at high altitudes, 47, 49
effect of, long continued,
47
effect on alveolar CO2, 27
effect on breathing, 7, 42,
43
effect on kidney secretion,
65
effect on physiological ac-
tivity, 90
effect on respiratory cen-
tre, 47
formation of lactic acid in,
35, 50
in balloon ascensions, 43,,
44
in CO poisoning, 44, 45
in mines, 43
regulation of breathing
during, 42, 43
symptoms of, 42, 43
Oxygen percentage, in alve-
oli, regulation of, 10
in blood, 28
Oxygen pressure, effect on
alveolar CO2, 49
134
INDEX
effect on haemoglobin, 52
in alveolar air, 30
in arterial blood at high
altitudes, 56, 61
in blood leaving lungs, by
CO method, 54
in capillaries at high alti-
tudes, 57
in sea water, 62
Oxygen secretion, at high
altitudes, 56, 57
by lung epithelium, 53, 54,
56, 57, 63
in swim bladder of fishes,
62, 63, 64
relation to oxygen pressure
in lungs, 63, 64
Oxy-haemoglobin, dissocia-
tion of, 29
effect on absorption curve
of CO2 in blood, 33
properties of, 28
regulation of blood gases
by, 72
Oxy-haemoglobin dissocia-
tion curve, 29, 30
and CO2 pressure in blood,
30, 31
and inorganic salts in red
blood cells, 31
as index of reaction in
blood, 31
at high altitudes, 50
constancy of, 34
effects of acid on, 31
effects of alkali on, 31
Paley, 116
Partial pressure CO2, rela-
tion to barometric pres-
sure, 13
Pathological phenomena, 102
Pathology, 102
Peak of Teneriffe, 50
Pfliiger, 53, 108
Physics and chemistry in life
phenomena, 105, 106
Physiological activities, co-
ordination of, 1, 2, 26
Physiology, and clinical med-
icine, 94
and structure, 102
and surgery, 94
definition, 1
the "new," 103
Pike's Peak expedition, 47,
49, 51, 55, 56, 94
Pituitary gland in physiologi-
cal regulation, 80
Poisons, immunity to, 95
Priestley, 3, 8, 77, 78
Psychology, 115
Radioactivity, 107
Reaction of blood (see
blood alkalinity)
Reaction of urine, 40
Reality, "objective," 118
Red blood corpuscles, 28
at high altitudes, 50, 51
destruction, 81
effect of bleeding on regen-
eration of, 80, 81
INDEX
135
effect of transfusion on, 80,
81, 95
formation, 81
relation of dissociation
curve to salts in, 31
Regnault, 108
Regulation, in respiratory
disturbances, 35
mechanistic theory of, 5
of air supply, 4
of alveolar CC>2 during
exercise, 10
of alveolar CC>2 in breath-
ing, 14
of arterial gas pressure, 72
of arterial pressure, 73
of blood alkalinity, 36, 38,
39, 40, 86
of blood alkalinity, by am-
monia, 38, 39
of breathing by blood re-
action, 38, 39, 40, 42
by CO2, 7, 9, 11, 14, 26
by vagus, 21, 22
during excessive ventila-
tion, 9, 46, 47
in oxygen deficiency, 43
of circulation, 68, 69, 73,
75
of environment, 89, 90, 91,
92, 93
of kidney secretion, 89
of local blood flow, 69, 70,
71
of oxidation, 4
of oxygen percentage in
alveolar air, 10
of temperature, 80, 89
of temperature in dog, 13
of vaso-constriction by ad-
renals, 75
of water contents of blood,
77, 78, 79
organic, 104, 105, 108, 110
vitalistic theory of, 4, 17
Reiset, 108
Reproduction, 98, 114
Respiration (see breathing)
Respiration, artificial, 25
artificial, and Hering-
Breuer inhibition, 25
artificial, in apnoea, 25
effect of CC>2 pressure on,
13
Respiration rate, and alveo-
lar C02, 12
Respiratory center, 5, 17, 24,
26, 37, 86, 91, 111, 112
and hydrogen-ion concen-
tration, 37, 89, 111, 112
as index of blood alkalin-
ity, 38
blood constancy to, 38
delicacy of response, 14, 15
effect of acids on, 36
effect of alveolar CC>2 on,
11
effect of drugs on, 86
effect of excessive ventila-
tion, 47
effect of oxygen deficiency
on, 47
factors affecting, 87
136
INDEX
influence of pulmonary in-
flation and deflation on,
86, 87
latency of response, 11
Respiratory exchange, in
small animals, 46
Reymond, du Bois, 113
Ringer, Sidney, 66
Rosenthal, 6
Rubner, 83, 108
Ryffel, 41, 50
Salivary secretion, 68, 69
Salts, aggregation of haemo-
globin by, 31
passage into intestines af-
ter water drinking, 78, 79
Sampling, alveolar air, 8
Schafer, Sir Edward, 17
method applied during ap-
noea, 25
Schmiedeberg, 38
Schneider, 55
Scott, 25
Sea water, CC>2 pressure in,
62
Secretion, and growth, 66
kidney, 64, 65, 79, 89
of CO2 by lungs, 57
salivary, 68, 69
selective, by lungs, 62
Secretion of oxygen, at high
altitudes, 56
by lung epithelium, 53, 54,
57
by lungs, 53, 54
in swim bladder of fishes,
62, 63, 64
Secreting cells, synthesis by,
65
"Shock," CC>2 deficiency in,
15, 42, 43
Sivel, 44
Smith, Lorrain, 52, 53, 57
Sodium chloride in urine,
after large intake of
water, 78
Specific "structure" and com-
position of blood, 90, 91
Starvation, oxidation in, 84
Starvation, oxygen consump-
tion in, 4, 83
Steel chamber experiments,
49, 50
Structure, "normal," 101
Sugar contents of blood, 76,
77
Suprarenal glands, and vaso-
constriction, 75
in physiological regulation,
80
Surgery and physiology, 94
Sweating, effects on blood
concentration, 79
effects on blood constitu-
ents, 79
effects on urine secretion,
79
Swim bladder of fishes, ef-
fects of drugs on oxygen
secretion of, 63
function of, 62, 63
INDEX
137
nervous control of oxygen
secretion in, 63
reversal of direction of
oxygen secretion in, 64
structure, 63
Sympathetic nerves, to heart,
73
Symptoms of CO poisoning,
48
oxygen deficiency, 42, 43
Temperature regulation, 80,
89
in dog, by respiration, 13
Teneriffe, Peak of, 50
Test for presence of CO in
air, 46
Thyroid in physiological reg-
ulation, 80
Tissandier, 44
Unconscious activities, 1
Urea, 39
Urea excretion, 83
in starvation, 83
Urine, "buffer substances" in
40
lactic acid in, 41
nitrogen of, as index of
blood alkalinity, 39
reaction of, 40
secretion, effect of sweat-
ing on, 79
sodium chloride of, after
large intake of water, 78
Vagus apnoea, 22
Vagus nerves, effect of cut-
ting on breathing, 21, 25,
26
influence on breathing, 21,
22, 23, 24, 26
to heart, 73
Vapour pressure, in alveoli,
13, 14
Vaso-constriction, chemical,
70
nervous, 70
regulation by adrenal
glands, 75
regulation of circulation
rate by, 72
Vaso-motor center, 70
control of local blood sup-
ply by subordinate, 70
Vaso-motor nerves, 70
Veins, regulation of venous
pressure by contraction
of peripheral, 74
Venous constriction, in rela-
tion to CO2 contents of
blood, 74, 75
Venous gas pressure, 71, 72
regulation of, 72
Venous pressure, effect on
accelerator nerve, 73, 74
in regulation of output
from heart, 74
regulation by CO2 contents
of blood, 74, 75
regulation by passive con-
gestion of capillaries, 75
138
INDEX
regulation by peripheral
constriction of peripheral
veins, 74
Ventilation in mines, 19
Vicarious function, 97
"Vital force," 110
"Vital mechanisms," 77
"Vital principle," 2, 4, 82,
110, 112
"Vital spirit," 110
Vitalism, 2, 4, 82, 87, 110, 112,
113
and regulation of breath-
ing, 17
Vitalistic theory, 111
of regulation, 4
Vitiated air, 18
Voluntary control of respira-
tion, 11
Von Baer, 3
Von Bezold, 73
Water excretion, 77
Water intake, effect on
haemoglobin percentage,
78
effect on kidney secretion,
79
effect on sodium chloride
of urine, 78
Water regulation in blood,
77, 78, 79
Weber brothers, 73
Wollin, 25
l-NIVKRSITY OF CALIFORNIA MEDICAL SCHOOL LIBRARY
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