J Physiol 594.

5 (2016) pp 1113–1125 1113

TO P I C A L R E V I E W

Sir Joseph Barcroft: one victorian physiologist’s

contributions to a half century of discovery
Lawrence D. Longo†
Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA

Abstract During the first half of the 20th Century, Joseph Barcroft, KBE, FRS of Cambridge
University became a world leader in respiratory physiology. He determined the role of neural
stimulation in the oxygen consumption of several organs, established many of the factors
that regulate the binding of oxygen to haemoglobin, explored the determinants of a human’s
acclimatization to high altitude and developed the field of fetal cardiovascular physiology. Chair
The Journal of Physiology

of the Cambridge Department of Physiology from 1925 to 1937, he served as a consultant and
member of many UK governmental committees. During World War I, he led a British research
unit exploring the effects of poisonous gases on pulmonary function and related problems. In
addition to his almost 300 publications, several of his monographs are considered as classics.
(Received 27 March 2015; accepted after revision 26 April 2015; first published online 1 May 2015)
Corresponding author L. D. Longo: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma
Linda, CA 92354, USA. Email: llongo@llu.edu † Dr. Lawrence D. Longo passed away in January 2016.

Introduction Barcroft’s scientific career may be divided into four

major phases of inquiry: that of oxygen (O2 ) consumption
Among those who changed and vitalized the course of
in tissues; the definition of the oxyhaemoglobin saturation
physiological research in the first half of the 20th Century
[HbO2 ] curve; establishing the limits of human tolerance
was the seminal investigator Joseph Barcroft (1872–1947;
to high altitude; and pioneering the exploration of various
later Sir Joseph; ‘JB’ or ‘Jo’ as he was known to his friends)
aspects of oxygenation of the fetus in utero (some suggest
of Cambridge University (Fig. 1). Of Quaker heritage,
a fifth area: the role of the spleen on the storage of
Barcroft grew up in Ulster, Northern Ireland. In 1888,
erythrocytes; West, 2013). In each of these topics, his
at the age of 16 years, with a keen interest in science, he
contributions were vital in opening new fields of thought
was sent to Leys School, Cambridge. In 1896, he graduated
and investigation. A number of writers have presented
from King’s College. At Cambridge, he served as president
various aspects of Barcroft’s life and work (Anonymous,
of the University Natural Science Club, the membership of
1947; Barron, 1973; Breathnach, 1974; Dale, 1949; Dunn,
which during its first 100 years included 10 future Nobel
2000; Franklin, 1953; Holmes, 1970; West, 2013; 2015;
Laureates. After graduation, he joined the Physiological
Young, 1992).
Laboratory founded and directed by Michael Foster (later
Sir Michael; 1836–1907). During these years and the next
few decades, Cambridge was a virtual hotbed of scientific
Salivary gland metabolism
talent. The question arises: what we can learn from the life
and work of one born almost a century and a half ago and After his graduation from Cambridge University, and as a
who died seven decades ago? member of the Physiological Laboratory, Barcroft’s earliest

Lawrence D. Longo (Loma Linda University, Loma Linda, CA, USA) completed a residency in obstetrics and gynaecology at the
University of Southern California, Los Angeles County Hospital. Following fellowship, he served on the faculty of the University of
California Los Angeles and the University of Pennsylvania. He has authored more than 250 scientific publications and more than
120 review articles/book chapters. His most recent books are The Rise of Fetal and Neonatal Physiology: Basic Science to Clinical Care
(2013) and, as co-author with Lawrence P. Reynolds, Wombs with a View: Illustrations of the Gravid Uterus from the Fifteenth through
the Nineteenth Century (2015). Both volumes are published by Springer.


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1114 L. D. Longo
studies were suggested to him by the departmental chair
John Newport Langley (1852–1925). A controversy at
this time was the role of neural input into the secretory
activity of salivary glands. By use of the submaxillary gland
in the anaesthetized dog, Barcroft explored the gland’s
respiratory gas metabolism and its changes during several
active states: that of the relationship between the quantity
of O2 utilized by the organ under basal conditions and
that when secreting saliva. He determined the oxygen
consumption of the salivary gland and the manner in
which this increased in response to neuronal stimulation.
To accomplish this, however, he had to surmount
the problems associated with quantifying oxygen (O2 )
and carbon dioxide (CO2 ) in extremely small blood
samples (Barcroft, 1899; 1900a). Barcroft demonstrated
that oxygen consumption increased significantly during
stimulation and continued even after the flow of saliva
stopped (Barcroft, 1900b; 1900c; 1901). These studies
demonstrated for the first time several quantitative aspects
of organ metabolism under various circumstances, and led
to the concept of oxygen ‘debt’ in muscle and other tissues.
In collaboration with other specialists, he also quantified
tissue O2 consumption in the kidney (Barcroft & Brodie,
1904a; 1904b; 1905), pancreas (Barcroft & Starling, 1904),
liver (Barcroft & Shore, 1912; Gotch et al. 1908) and heart
(Barcroft & Dixon, 1907). Barcroft’s joining of circulatory
and respiratory investigation served as a prelude to his
life’s work.
Figure 1. Sir Joseph Barcroft.
J Physiol 594.5
Blood gas analysis and haemoglobin
During the course of his studies, in an attempt to
measure blood gases in ever smaller samples, Barcroft
developed the differential blood gas manometer and
also the tonometer for equilibrating blood with gas
mixtures. He then employed these tools to characterize
the properties of haemoglobin, exploring its affinity
and reversible equilibrium with O2 , thus defining the
oxyhaemoglobin saturation [HbO2 ] curve, and its shift
in response to changes in temperature, electrolytes, CO2
and other factors (Barcroft, 1908; Barcroft & Camis, 1909;
Barcroft & Haldane, 1902; Barcroft & Nagahashi, 1921;
Barcroft & Roberts, 1910), as well as the changes at high
altitude (Barcroft, 1911; Barcroft et al. 1923). In his 1914
publication, The Respiratory Function of the Blood, Barcroft
summarized this area of research over the previous decade
and a half (Barcroft, 1914).
Studies at high altitude
Another problem at this time was the extent to which, if
any, the pulmonary alveolar epithelium secretes O2 into
the capillary blood, particularly under hypoxic conditions
such as those experienced at high altitude (Barcroft et al.
1920). A related question regarded the extent to which
blood oxygen affinity changed with hypoxia. In an attempt
to determine the mechanism of O2 transfer across the
alveolar capillary membrane, Barcroft participated in
three expeditions to high altitude. The first, in 1910,
was to El Teide, a massive volcano (3718 m, 12198 feet)
on Tenerife (also Teneriffe), the largest of the Canary
Islands a Spanish archipelago southwest of the coast of
Morocco. The Alta Vista hut (Fig. 2) was at 3353 m
(11000 ft). This expedition was led by the German physio-
logist Nathan Zuntz (1847–1920) (Barcroft, 1911; Durig
Figure 2. Alta Vista Hut, Teneriffe, 1910 (Franklin, 1953).

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J Physiol 594.5 Joseph barcroft in an age of enlightenment
& Zuntz, 1912; Gunga, 2009; Starling et al. 1912). The
following year (1911), Barcroft also spent some time on
Monte Rosa in the Swiss-Italian Alps (4554 m, 14941 feet)
at the Capanna Regina Margherita or Margherita Hut
(Fig. 3) on the Signalkuppe [summit signal]. His third
and most productive high altitude expedition was to
Cerro de Pasco (4300 m, 14108 feet), Peru, for 1 month
in December 1921/January 1922 (Barcroft, 1922; West,
2013). Their mobile laboratory in a railway car is shown in
Fig. 4.
As noted, a question at this time was the extent
to which, if any, under various hypoxic conditions,
the pulmonary alveolar membrane secretes O2 into the
capillary blood. The studies of several European physio-
logists had suggested this to be an important mechanism
(Breathnach, 1974; West, 2013). In addition, in other
Figure 3. Capanna Regina Margherita, Monte Rosa, 1911 (Franklin,
1953).
Figure 4. Interior of mobile laboratory, Cerro de
Pasco, 1921–1922 (Franklin, 1953)

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studies, including the 1911 ascent of Pike’s Peak (4302 m,
14115 feet), Colorado, with several other physiologists,
John Scott Haldane (1860–1936) obtained data to suggest
that, at high altitude, the lung secreted O2 into the
arterialized blood so that the O2 partial pressure in
arterialized blood exceeded that of the pulmonary alveolar
gas by 7–32 Torr (Douglas et al. 1913; West, 2012).
Appreciating that this idea was probably untenable and
that some of the assumptions made in the calculations
may not have been valid, in February 1920, Barcroft
performed an experiment on himself, spending 6 days
in a plate glass chamber at Cambridge (Fig. 5). In
that study, over several days, the ambient O2 level was
decreased to approximately one-half atmosphere (84 Torr,
equivalent to 5486 m, 18000 feet). At both rest and
during exercise on a bicycle ergometer in which his O2
consumption was doubled, arterial blood was obtained
from his surgically exposed and severed left radial artery
(Barcroft et al. 1920). The period of almost 1 week of
hypobaric exposure was chosen because Haldane and his
co-investigators maintained that the ability of the alveolar
membrane to secrete O2 into the blood increased with
the time under hypoxic conditions. In Barcroft’s rather
heroic studies, under no circumstances, including during
exercise, could pulmonary O2 secretion be demonstrated
(Barcroft et al. 1920; West, 2013). As an aside, again, as
he had experienced earlier at Tenerife, Barcroft suffered
the effects of diminished O2 partial pressure on his
nervous system, including distressing headaches and
visual impairment (Barcroft et al. 1923; Barron, 1973).
Barcroft summarized these studies from the high altitude
excursions and the glass chamber experiments in his
publication, Respiratory Function of the Blood. Part I,
Lessons from High Altitude (Barcroft, 1925).
1116 L. D. Longo
During World War I, rather than joining one of the
Royal Combat Services, compatible with his Society of
Friends heritage, Barcroft interrupted his research at
Cambridge to serve as a civilian Chief Physiologist at
the British research facility, Royal Engineers Experimental
Station, Porton Down, near Salisbury, Wiltshire. There,
he studied the medical aspects of gas poisoning, which,
in 1915, the Germans had introduced into warfare
(Franklin, 1953; Roughton, 1948). The chemical weapons
tested included chlorine gas, phosgene and mustard gas.
In 1917, following a series of studies of the toxicity
curves in several avian (canary, chicken, pigeon) and
mammalian (cat, dog, goat, rabbit, rat, others) species, and
in another classic case of self-experimentation, Barcroft
exposed himself and a large dog (weighing 12 kg) to
one part in 2000 of hydrogen cyanide within a glass
chamber. Although Barcroft experienced only moderate
respiratory distress, the dog was in extremis within 1.5 min;
however, by the next day, it had recovered (Barcroft, 1931;
Roughton, 1948). (Another biographer stated incorrectly
that the dog died; Anonymous, 1947). One valuable
consequence of this experiment was a demonstration of
the large species differences in response to toxin exposure,
although the biological basis for these differences remains
unknown.
During his month at Cerro de Pasco, a mining town
in the Peruvian Andes, at an altitude approximately
matching that of Pike’s Peak, and after recovering for a
few days from soroche, a mild form of acute mountain
sickness, in addition to the respiratory studies, the
Barcroft group conducted a number of neuropsychiatric
measurements (memorization, multiplication and other
J Physiol 594.5
tasks) on three groups of individuals: the expedition
physiologists, mining engineers originally from sea level
but who were acclimatized to high altitude for months or
years, and the indigenous high altitude people (Barcroft,
1925; Barcroft et al. 1923). Barcroft noted that his own
mental concentration was more difficult and that ‘Time
was wasted in trivialities and bungling’ [not being able to
organize or perform tasks efficiently] that would not take
place at sea level (Barcroft et al. 1923, p. 453). Among his
observations, Barcroft concluded that, ‘The acclimatized
man is not the man who has attained to bodily and mental
powers as great in Cerro de Pasco as he would have in
Cambridge . . . Such a man does not exist. All dwellers at
high altitude are persons of impaired physical and mental
powers’ (Barcroft, 1925, p. 176). As may be imagined,
this statement incited considerable controversy. The
Peruvian physician–physiologist Carlos Monge Medrano
(1884–1970) took great exception to this view, stating
that ‘ . . . Professor Barcroft was himself suffering from
a subacute case of mountain sickness without realizing it’
(Monge, 1948; West, 2013; 2015). In a paper published
after his death, Barcroft observed, ‘I have seen quite
amicable people, when living at a height of 15000 feet or
so, become troublesome, garrulous or morose. This may
be the result of oxygen deficiency . . . ’ (Barcroft, 1951,
p. 1177).
Following the Great War, Barcroft extended his studies
of high altitude physiology and the mechanisms by which
the body acclimatizes to long-term hypoxia, participating
in another chamber experiment (Barcroft et al. 1931; West,
2013; West & Sidebottom, 2006). With his great interest
in hypoxia, he commenced studies of blood storage in the
Figure 5. ‘Glass Chamber’ at Cambridge
University, 1920 (Franklin, 1953).

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J Physiol 594.5 Joseph barcroft in an age of enlightenment
spleen and its relationship with blood volume (Barcroft,
1926a; 1926b). Based on his 1929 Edward Kellogg
Dunham (1860–1922) lectures at Harvard University, in
1934, Barcroft published his monumental Features in the
Architecture of Physiological Function (Barcroft, 1934a). Of
this work, the Nobel laureate Schack August Steenberg
Krogh (1874–1949) stated it to be a volume ‘ . . . which
gives an integration of physiology of such a kind that it
ought be read by everyone who is going into experimental
work in physiology. It gives the general ideas which cannot
be obtained from any other book in existence’ (Franklin,
1953, p. 213).
Studies in fetal development
As noted, during the latter 1920s, Barcroft became inter-
ested in blood volume, its stores and the role of the
spleen as a reservoir of erythrocytes. For the most part,
he studied this in dogs in which the spleen had been
exteriorized, developing several methods for observing its
change in size. Somewhat serendipitously, he observed
that the spleen of one of his dogs at rest was contracted
to an unusual degree. At autopsy, the animal proved to
be pregnant with widely dilated uterine veins (Barcroft
& Stephens, 1928). This raised in his mind the question
of the quantity of blood required by the uterus during
pregnancy. He then measured the amount, finding it to be
unusually large, even during the early stages of pregnancy
(Barcroft, 1932; Barcroft & Rothschild, 1932). Shortly
thereafter, Louis Barkhouse Flexner (1902–1996), then
of the Department of Anatomy at the Johns Hopkins
University, spent 2 years as a fellow with Barcroft.
With Flexner, Barcroft performed his initial study in
developmental physiology measuring cardiac output in
the fetal goat (Barcroft et al. 1934a) and fetal oxygenation
in the rabbit (Barcroft et al. 1934b). Following other studies
conducted together (Barcroft et al. 1936), Flexner went on
to become a leader in both neuroscience and placental
exchange mechanisms.
Prior to the fourth decade of the 20th Century, there was
little interest in the physiology of the fetus or newborn
infant. Hitherto, the subject comprised a miscellany
of studies: anatomic morphological and comparative
anatomy, histology, embryology and the occasional bit of
biochemistry. In an historical perspective, Donald Henry
Barron (1905–1993), who worked with Barcroft from 1935
to 1940, noted that his interest in the course of blood flow
through the fetal heart and the timing of the closure of
the ductus arteriosus arose from his studies on the oxygen
environment of the fetal brain, as well as the dramatic
changes at the time of birth with expansion of the newborn
lungs and arterialization of blood (Barcroft, 1938; Barron,
1979). Barcroft concluded that the crossing of the superior
and inferior vena caval streams in the heart was essentially
complete, and that the quantity of blood ejected from the

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1117
right ventricle via the ductus arteriosus equalled the volume
in the left ventricle that had flowed through the foramen
ovale (Barcroft, 1935a).
An example of the manner in which Barcroft could
synthesize data, incorporating and expanding upon the
work of others, is illustrated by his determination of the
fetal and maternal oxyhaemoglobin saturation curves.
A master in analysing blood and its oxygen affinity,
Barcroft stressed the essential nature of haemoglobin and
its physical and chemical environment in determining
blood O2 binding characteristics. The St Thomas’
Hospital physiologist Arthur St George Joseph Huggett
(1897–1968) had reported the fetal blood oxygen affinity
to be significantly different from that of the adult
(although reporting it to be less rather than greater, e.g.
P50 40 Torr) (Huggett, 1927). With his great interest in
this topic, using blood at constant conditions (38°C, P CO2
50 Torr), Barcroft and colleagues reported the correct
curves for the newborn goat and its mother (P50 = 30 and
37 Torr, respectively) and also compared these at several
times during the course of gestation (Barcroft, 1933; 1934c;
Barcroft et al. 1934a; Windle, 1940). In a subsequent study,
Barcroft and colleagues compared [HbO2 ] and O2 capacity
in fetal sheep blood from 63 days to term at 145 days
after conception, reporting on apparent peak in [HbO2 ]
of 70% at 100 days, decreasing from that value until term
(Barcroft, 1935a; Barcroft et al. 1940a; 1940b).
Barcroft also recorded that, during pregnancy, uterine
venous [HbO2 ] declined, reaching such low levels that
it appeared impossible to maintain a normal state of
fetal oxygenation (Barcroft, 1935a; 1935b; 1935c; 1935d;
Barcroft et al. 1940b). These findings, along with other
studies (Barcroft, 1941; 1942; 1943), contributed to his
concept that the ‘newborn’s first breath was the fetus’
dying gasp’. Thus, arose the dictum of the fetus being
at ‘Mt Everest in utero’ (Barcroft, 1933).
David J. Mellor has recalled an incident in the early years
of these studies:
Prof Huggett said that he had shown Sir Joseph Barcroft
how to do his first Caesarian section in sheep. He claimed,
and I want to emphasize the words ‘he claimed’, that
he anaesthetized a pregnant ewe, did a ventro-lateral
abdominal incision, and just as he was moving viscera
aside in order to draw out the uterus, Barcroft . . . elbowed
him to one side with words to the effect, ‘I can take it
from here Huggett!’, whereupon he promptly incised the
rumen!
(Longo, 2013, p. 23)
Fortuitously, in the summer of 1934, Barcroft met
Donald Barron, a Fellow of the National Research
Council, USA, working at Cambridge on spinal cord
action potentials (Barron & Matthews, 1935). At that
time, Barcroft headed one of the most spacious and
well-equipped physiology departments in the UK. In
1118 L. D. Longo
a chance conversation at afternoon tea, upon learning
that Barcroft had purchased 50 ewes for his studies,
Barron inquired as to whether he proposed to study
the functional development of the mammalian nervous
system. Admitting that he knew nothing about this topic,
Barcroft asked Barron to edify him on the subject. After
learning of the little that was known, and questions
regarding the controversy as to the applicability of findings
in the nervous system of a salamander to that of mammals,
Barcroft invited Barron to join him in studying some
aspects of its functional development (Longo, 2013).
By use of the technique developed by Huggett, of
performing a Caesarean section in a warm saline bath
to maintain the placental circulation, in November 1934,
Barcroft and Barron commenced their studies on a sheep
fetus at 46 days of gestation. Fortunately, for the future
of the project and the field of developmental physio-
logy, the fetus showed considerable activity, ‘respiring’
spontaneously with rhythmic diaphragmatic movements
(Barcroft et al. 1936). In the spring of 1935, shortly before
he was made Knight Commander of the British Empire,
Barcroft invited American investigators from opposing
schools of thought regarding neural development to
collaborate with him on this line of investigation. One
of these, William Frederick Windle (1898–1985) from
New York University, accepted the invitation. In the winter
of 1935–1936, Barcroft, Barron and Windle attempted to
determine the extent to which the first movements by the
fetus represented a response to local reflexes, as opposed
to mass movements. Although the group could not agree
on the interpretation of their findings, they demonstrated
that these movements appeared before the central nervous
system was fully functional (Barcroft et al. 1936; Barcroft
& Barron, 1936; 1937; 1939). In conjunction with these
studies, they performed some of the earliest studies on
development of fetal breathing movements (Barcroft &
Barron, 1936).
Barcroft’s and Barron’s further studies, demonstrating
the importance of the ductus arteriosus being patent
in the fetus but closing during the newborn period,
raised the question of when and by what mechanism
this occurs. A serendipitous and fateful event at the
March 1937 London meeting of the Physiological Society
significantly influenced the course of fetal physiology.
A film made by Barcroft and Barron, ‘Experimental
“chronic” lesions in the central nervous system of the sheep
foetus’ (Barcroft & Barron, 1937), was shown immediately
before one made by Kenneth James Franklin (1897–1966)
a fellow of Oriel College, Oxford, and a colleague, ‘X-ray
cinematographic film of a dogs heart’. As recorded by
Alfred Ernest Barclay (1876–1949) and colleagues, ‘This
accidental juxtaposition of the two films suggested to
Barron the new line of attack’ (Barclay et al. 1944, p. v).
Barron has recorded, ‘The clarity of his pictures was
impressive’ (Barron, 1979, p. 2). Following this meeting,
J Physiol 594.5
on the train returning to Cambridge, Barron suggested to
Barcroft the potential value of cineradiology in the study of
the long-standing problem of the course of the fetal central
circulation and the timing of ductus closure. Barcroft with
Barron then developed a collaboration with Franklin and
Barclay that lasted from 1937 to 1940 (Barclay et al. 1944,
p. vi; Dawes, 1994). Barron has recorded some of the
vicissitudes of these studies (Barron, 1979). Particularly
annoying was the fact that, without consultation with
either Barcroft or Barron, Barclay and Franklin published
a detailed account of these studies, in which they claimed
that the ductus closed prior to clamping of the umbilical
cord or visualization of air in the trachea (Barclay et al.
1938). On later analysis, this erroneous interpretation
was shown to have resulted from the obscuring of the
ductus by pulmonary vessels (Barron, 1979). Subsequent
cineradiographs of the pattern of circulation in the fetal
heart and great vessels demonstrated closure of the ductus
arteriosus some minutes following birth. In these studies,
they also compared the central circulation in the fetus with
that of the adult (Barclay et al. 1939). In relation to this
fiasco, Barron noted that ‘The celebrated German physio-
logist Carl Ludwig [(1816–1895)] is said to have remarked,
“In science, method is everything.” In this study it was!’
(Barron, 1979, p.3).
Following the outbreak of World War II, in 1940 Barron
returned to the USA and, in 1943, joined the Department
of Physiology at Yale University, where he continued his
studies on the fetal circulation and the placental exchange
of respiratory gases (Barron, 1946; 1952). In a critical
review of the changes in the central circulation from fetus
to newborn at the time of birth, Barron placed the entire
field into perspective (Barron, 1944).
During the decade following his initial studies, Barcroft
published a number of contributions on fetal respiration,
blood volume and circulation (Barcroft et al. 1933; 1939a;
1939b; 1940a; 1940b; Barcroft & Kennedy, 1939). The onset
of World War II, however, terminated these productive
collaborations. During the war, Barcroft chaired the UK
Food Investigation Board and founded Britain’s Nutrition
Society (Franklin, 1953). In the early 1940s, Maureen
Young, later of St Thomas Hospital Medical School,
worked with Sir Joseph. She has written:
I assisted ‘Jo’ . . . in a study at Cambridge towards the
end of WWII. I had been at the South West London
Blood Transfusion Unit for two exciting years when Nora
Edkins and Margaret Murray persuaded me to join them
in the Department of Physiology at Bedford College,
Bedford, as a Demonstrator, to ‘keep the lamp of learning
burning’. They had been evacuated to Cambridge where
our teaching took place in the theatres and lab when free
of their own students. Jo, already in his early 80s, was still
working. We all were invited to ‘assist’ at his experiments
on foetal sheep, which at this time was delivered into
a huge saline bath! At the end of the day, we all were

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J Physiol 594.5 Joseph barcroft in an age of enlightenment
rewarded with a most welcome lamb joint to take home
for Sunday lunch.
One day Jo stopped me in the corridor and said that he had
asked Dr Edkins if I might give him a little of my time to
help him with a small study. He said, ‘my fingers and eyes
are no longer organs of precision!’ The fetuses of pregnant
rabbits treated with progesterone became post mature and
died ‘in utero’. Jo wanted to know if they had outstripped
their placental oxygen supply and needed blood samples
from them . . . He found an animal table on which he
could work in his small office and asked Adaire – another
delightful ‘retired’ gentleman in the lab – to teach me
how to use the original van Slyke apparatus to measure
the blood oxygen content. It was a splendid experience.
Taking blood from the carotid artery of the rabbit foetus
did not prove a problem, and gave me courage to use the
perfused placental preparation later on in my career. The
fetuses also provided another small observation, namely
that the umbilical cord had a little sphincter only at its
junction with the abdomen. Jo found me cutting sections
of this one day and said that it should be published in
Nature (Young, 1953), and there it is!
With great charm and marvelous curiosity to the end of
his life, Jo joins Widdowson and McCance for creating
the stimulus for our interest in and the great progress
which has been made in the subject of Perinatal Physiology
worldwide during the last eighty years.
(Longo, 2013, p. 28–29)
During and following his studies on the fetus, Barcroft
summarized his work in several lectures and reviews
(Barcroft, 1933; 1935; 1936; 1943). Each of these
was notable for the manner in which Barcroft posed
provocative questions to explore. Some of his many awards
and honors are given in Table 1.
His reviews laid the groundwork for Barcroft’s collation
of these and other studies, into his last monograph,
Researches in Pre-natal Life, Part I (Barcroft, 1946). In
this volume, Barcroft reviewed in extenso the discoveries
to that time, and the many factors to consider with respect
to oxyhaemoglobin relationships in the fetus and mother
of humans, as well as that of other species (Barcroft, 1946).
In the preface of this work, which he dedicated to Donald
H. Barron ‘ . . . to whom the work . . . owes so much’,
Barcroft stated:
This work partakes very much of the nature of a will – I
hope not my last. In the days of bombs it seemed
to me only the due of the many who had given me
encouragement and support, not least the Rockefeller
Foundation, that I should set down in some connected
form such information as I had accumulated concerning
pre-natal life; then, if the bomb came my way, the
information, for what it was worth, would remain. I say
‘in some connected form’ because not the least interesting
part of the work has been the fitting together of individual
items, dealt with in individual papers, into a picture

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from which a likeness of the organism is commencing
to emerge . . .
As regards the scope of the book, it purports to deal
primarily with researches in which I have had a hand
myself, and with observations by others germane to such,
but it goes a little further and includes work by colleagues
which I have been privileged to see . . . The general aim,
then of this book is to trace the development of function in
the mammalian foetus, never losing sight of the fact that
one day the call will come and the foetus will be born. Not
only has the foetus to develop a fundamental life which
will suffice for intra-uterine conditions, but at the same
time it has to develop an economy which will withstand
the shock of birth, and will suffice, nay more than suffice,
for its new environment.
(Barcroft, 1946, p. ix)
Sir Joseph ‘ . . . was “nettled” by people who volunteered
facile explanations for fetal circulatory responses, based on
their knowledge of adult physiology only’ (Young, 1992,
p. 608). In twenty-two chapters, in each of which he clearly
stated a specific question to be explored, Barcroft reviewed
what was known regarding the topic. Early chapters
consider aspects of the maternal and fetal placental
vasculature and nutrient exchange, determinants of fetal
growth, fetal blood volume and oxygen consumption.
In Chapter V, ‘The relative claims of the foetus and
mother to available nutritive material’, Barcroft stressed
the symbiotic relationship of fetus to mother, at a time
in which the fetus was considered a ‘parasite’. Applying
the principle that nutrient partition among organs was
determined by their metabolic rate, he argued that, with its
relatively high rate of metabolism, the fetus could compete
with maternal tissues. The latter two-thirds of Researches
on Pre-natal Life summarize much of Barcroft’s and
Barron’s work that considered blood pressure and vascular
reflexes, fetal blood oxygen capacity and oxyhaemoglobin
saturation curves, the central circulation with roles of
the ductus venosus and ductus arteriosus, and the onset of
respiration at birth. Seven appendices included variations
in respiratory activity at birth, measurements of blood
sugar, lipids and the molecular weight of sheep fetal
haemoglobin. Also included were recently derived blood
gas values obtained by Barron, ‘ . . . from the small
arteries and veins going to and leaving a cotyledon,
and . . . therefore more fully representative of placental
conditions’, which again suggested a significant decrease
near-term (Barcroft, 1946, p. 285). In several asides
in the volume, Barcroft considered the difficulties in
acute studies of obtaining reliable samples of fetal blood
(umbilical vessels, p. 187, and carotid artery, p. 197),
that truly were representative of its physiological state.
He noted that:
. . . such results are frankly worthless – some guarantee
must be given that the blood in these vessels, so sensitive
1120 L. D. Longo J Physiol 594.5

Table 1. Honors and awards

1910 Election, Fellow of the Royal Society

1918 Commander British Empire
1922 Awarded Royal Medal of the Royal Society
1935 Knight Commander of the British Empire
1938 Elected Foreign Honorary Member, American Academy of Arts and Sciences
1943 Awarded Copley Medal of the Royal Society
1944 Fellow ad eundem Royal Society of Obstetricians and Gynaecologists

to any kind of manipulation, is coursing at the normal
rate; some guarantee must be given that the foetus is in
a normal state; some guarantee must be given, and this
is often overlooked, that the circulation in the mother is
also normal: and lastly when the worker has satisfied his
readers and, what is probably more difficult, himself, that
the data are as nearly correct as may be, there remains the
question – to what stage of pregnancy do they refer?
(Barcroft, 1946, p. 187)
It would be two decades later that Meschia, Barron
and coworkers first reported on the use of chronically
indwelling catheters for in vivo measurement of
respiratory gas values in fetal blood that made such
measurements of physiological relevance (Meschia et al.
1965). This technique of chronic catheterization placed
the study of the fetus in utero on a firm physiological basis.
Barcroft had intended to prepare a second volume, Part
II, that would deal with both the nervous system and
metabolism. With his demise shortly following the 1946
publication, this was not to be. It must be recalled that
Barcroft was in his early sixties when he embarked upon
his studies of fetal physiology, and upon which he worked
for the next decade and a half.
Publication of Barcroft’s Researches on Pre-natal Life,
immediately following the end of World War II, appeared
at the beginning of what some call the ‘golden age’ of
medical research. Governmental support for biomedical
studies increased greatly, as did increasing interest
in biology, from cellular and subcellular mechanisms
to organ and systems function, as well as clinical
care, including that for the mother and newborn
infant. With concomitant technological advances that
allowed ever more detailed determinations and studies,
Barcroft’s volume had considerable impact with respect
to promoting basic research and also that of translational
and clinical medicine (Anonymous, 1947; Dawes, 1968;
1994; Holmes, 1970; Longo, 2013; Young, 1992).
Barcroft’s research style
One might ask, what was it about Barcroft’s research that
helped to keep him on the forefront with fresh ideas?
Although Barcroft wrote essentially nothing in this regard,
in the preface to his 1914 volume on the respiratory
function of the blood, he observed:
At one time, which seems too long ago, most of my leisure
was spent in boats. In them I learned what little I know
of research, not of technique or of physiology, but of the
qualities essential to those who would venture beyond the
visible horizon.
The story of my physiological ‘ventures’ will be found
in the following pages. Sometimes I have sailed single
handed, sometimes I have been one of a crew, sometimes
I have sent the ship’s boat on some expedition without
me. Any merit which attaches to my narrative lies in the
fact that it is in some sense at first hand . . . I should like
to have called the book, what it frankly is – a log; did not
such a title involve an air of flippancy quite out of place in
the description of the serious work of a man’s life. I have
therefore chosen a less exact, though more comprehensive
title . . . .
After all, the pleasantest memories of a cruise are those
of the men with whom one has sailed. The debt which
I owe to my colleagues, whether older or younger than
myself, will be evident enough to any reader of the book.
It leaves me well-nigh bankrupt – a condition well known
to most sailors. But I owe another large debt of gratitude
to those who, as teachers, showed me the fascination of
physiology . . .
(Barcroft, 1914, p. vii)
Of note, he repeated this account in both his volumes on
high altitude (Barcroft, 1925, p. vii) and on the respiratory
function of the blood, part II haemoglobin (Barcroft, 1928,
p. v).
Several of Barcroft’s colleagues also have addressed
the issue of his approach to investigation (Barron, 1973;
Breathnach, 1974; Dale, 1949; Franklin, 1953) (Fig. 6). For
example:
. . . he never really grew old and he never lost the knack of
reducing a problem to its simple elements and then finding
an answer by the most direct method. One of his most
fruitful methods was to look for help in all directions, to
bring in new recruits and to get as a catalyst in translating
their ideas into practical outcome. Many worked with him
and experienced his remarkable power of forging ahead
all the time
(Adrian, 1949, p. 3–4)


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J Physiol 594.5 Joseph barcroft in an age of enlightenment
. . . he never lost that air of youthful enthusiasm, the
attitude which regarded research as an amusing adventure.
In many ways he seemed to have the ideal research
temperament, not over-elated by success or cast down
by lack of it, or put out of countenance by the unexpected.
He never lost his eagerness, but always tempered it with a
humorous equanimity
(Dale, 1949, p. 10)
The direction of Barcroft’s research was not, as a super-
ficial survey might suggest, that of a craft carried by
the winds and currents on a random course, but one
determined by a sure hand on a tiller that took advantage
of both on a voyage of discovery . . . Barcroft saw in
the familiar . . . questions which opened the way to the
disclosures of new mechanisms and a broader under-
standing of their role in the economy of the whole animal.
His interests were in architecture and only secondary in
the building material
(Barron, 1973, p. xxi)
Figure 6. Joseph Barcroft measuring blood gases, 1928 (Franklin,
1953).

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1121
Barcroft’s lectureship style
Although even as Departmental chair not having to carry a
heavy teaching load, Barcroft was noted to be an engaging
lecturer (Fig. 7), commencing with a joke, and recounting
anecdotes to maintain his audience’s interest. He lectured
without notes, telling his brother-in-law, ‘I look things up
before the lecture. If the student is expected to remember
what he hears for all time, we who tries to teach him
ought to be able to retain in his own head, for a few
hours, that which he intends to say’ (Breathnach, 1974,
p. 234–235). His engagement as a lecturer was said to be
accomplished, in part, by use of analogy and anecdote to
join the experience of his audience with the material he
was presenting.
Personal life and philosophy
Not a great deal has been written of Barcroft’s personal
life. Probably of Norman origin, the early years of the
Barcroft family, from the de Berecrofte (or ‘barley-crafters’;
Breathnach, 1974) of the 13th Century to the late
Figure 7. Joseph Barcroft lecturing, 1935 (Franklin, 1953).
1122 L. D. Longo
18th Century have been traced in the historical survey
Barcroft of Barcroft (Barcroft, 1960). In 1903, he married
Mary Agnetta (Minnie) Ball (1875–1961), daughter of
Sir Robert Stawell Ball (1840–1913), the Astronomer Royal
of Ireland and later Lowndean professor of astronomy
and geometry at Cambridge University. Lady Barcroft
‘ . . . inherited her father’s sense of fun, and the laughter
which, like a nosegay, decorated their joint lives made
them the most perfect partners and the most perfect
hosts’ (Anonymous, 1947, p. 431). Barcroft’s first son,
Henry Barcroft (1904-1998) MBBS, MD, FRS, also devoted
his life to physiology, contributing to an understanding
of the regulation of the systemic circulation and limb
blood flow, and chairing the Departments of Physio-
logy at both Queen’s University, Belfast, Ireland and the
Sherrington School of Physiology, St Thomas’ Hospital
Medical School, London (Greenfield & Roddie, 2000).
In reference to his consummate Victorianism mentor
Sir Joseph, Donald H. Barron recorded, ‘ . . . he appears
to have inherited that emotional balance for which so
many strive but so few achieve. It never deserted him.
Equanimity and self-mastery came early to him . . . His
heritage . . . included . . . a belief that the only guide to
a man’s conduct must be his own “inner light”, that truth
is to be sought, that life is to be lived . . . ’ (Barron, 1973,
p. xiv-xv).
In terms of philosophy of life ‘ . . . he often remarked,
in substance, that there are two categories of things
about which one should never worry; those that you can
do nothing about, and those about which you can do
something’ (Barron, 1973, p. xix). In a paper discovered
following his death, an address to the student Christian
movement, Newnham College, Barcroft addressed the
issue of Christianity as a ‘ . . . working hypothesis’
(Barcroft, 1951, p. 1177). In his usual manner, he
commenced with a question, ‘ . . . what is it that needs
reconciling?’ He then explored the relation of the mind
to the brain and body and the pursuit of morality and
truth, whether in science or religion (Barcroft, 1951).
This ‘hard problem’, the existence of the mind and
consciousness in the cerebrum, had long been an issue in
the history of ideas during this time, and was the subject
of considerable discussion by philosophers, psychologists
and others (Pratt, 1920; Strawson, 2015).
Eulogies
Following his death, Huggett wrote a tribute to Barcroft
in which he cited Researches on Pre-natal Life as ‘ . . . a
landmark in experimental physiology, a fitting successor
to [Wilhelm Thierry] Preyer’s (1841–1897) volume [1885]
on the physiology of the embryo in the last century’
(Huggett, 1947/1948, p. 231). He continued:
Barcroft’s death marks the end of an era in the
physiology of the foetus . . . era . . . of observational
J Physiol 594.5
physiology . . . After the introduction of the saline-bath
technique in the twenties of this century, physiological
facts have accumulated rapidly – largely under the
influence of Barcroft’s drive, personality, and ability
to see the essentials of a problem, to dissect it into its
component parts, and to inspire workers . . . to tackle
the several aspects so exposed . . . we must look forward
to a synthesis of all these lines of approach directed
to the study of the peculiarly foetal problems of how
function is initiated in the embryo and how it can be
controlled . . . The modern applications of biophysics
must come into the field of experiment, to explain how
the gene, the hormone, the vitamin, and the nutrient
react with the mother to produce the newborn.
(Huggett, /1947/1948, p. 232)
In his obituary notice of Fellows of the Royal Society, the
Cambridge biochemist–physiologist Francis John Worsley
Roughton (1899-1972) recalled:
. . . [he] retained his youthful freshness of mind and sense
of wonder right through till the end of his days . . . He
would be apt to choose a field which was not at the
moment in the forefront of the battle, . . . however slight
his knowledge at the start . . . he would soon be asking
shrewd questions and talking in telling fashion about the
existing ideas and conceptions of the subject. Then, by
some process of intuition, which rarely seemed to fail
him, he would succeed in picking out new and salient
points of attack which, for one reason or another, had
eluded his predecessors. Next he would gather round him
one or more younger colleagues and infect them with his
own enthusiasm for the new venture. In their company
he would buckle to and, if need be, devise methods
which were often simple . . . , but would almost always be
singularly effective in guiding him quickly to significant
results . . . The results, once established to his satisfaction,
would then be prepared for final publication with an ease
and a gusto which many scientists, who find ‘writing up’
so irksome, might well envy.
(Roughton, 1948, pp. 329–330)
A 1949 symposium in Sir Joseph’s honor devoted
to the chemistry and physiology of haemoglobin,
includes tributes to him (Roughton & Kendrew, 1949).
Acknowledging the inspiration he received from, and
debt to, Barcroft, Barron recalled a number of aspects
of Barcroft’s contributions to life (Barron, 1973). In an
earlier essay, he had noted:
I loved Sir Joseph above all men. I loved him for his
passionate devotion to the truth; for his charity towards
his fellow man in all walks of life; for his devotion to young
men and a host of other intangible qualities. To emulate
him was and will remain my life’s purpose; I can conceive
no higher purpose . . . No one has contributed more
generously to the physiological thought of this country
than he. The host of students who went through his
laboratory, learned his methods and acquired new vistas
are spread throughout this country, and they recall with
advantage the days and weeks they enjoyed as members of

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J Physiol 594.5 Joseph barcroft in an age of enlightenment
his School. And there are those yet unborn who will catch
the spark of his wisdom through the thoughts he put to
pen. Few have given so much; fewer there are who had so
much to give.
(Barron in Franklin, 1953, pp. 339–340)
Perspective
As noted in the Introduction, the question arises
of what can we learn from the contributions of a
physiologist–biochemist who lived a century ago? What
do we gain in pondering the impact of an individual
scientist on the growth of science? In contemplating the
life of Sir Joseph Barcroft, a virtual plethora of terms
come to mind: dedication to excellence, creative, integrity,
perseverance and willingness to support others. Barcroft
had a clear gift for innovation and solving problems,
well ingrained self-control and a dedication to long-term
goals with a vision for the future. In pursuing critically
important scientific questions, our own need is to address
the challenges of the complex and difficult task ahead.
Joseph Barcroft was a role model of intellectual talent,
true to his discipline, who demonstrated ingenuity and
productivity in his many contributions to an increased
understanding of biomedical science. Can we have as our
goal to do any less?
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