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Hypoxia, Fetal & Neonatal Physiology:
100 years on from Sir Joseph Barcroft
1D A Giussani, 2L Bennet, 1A N Sferruzzi-Perri, 1O R Vaughan & 1AL Fowden
1Department of Physiology, Development & Neuroscience, University of Cambridge,
Cambridge, CB2 3EG, UK
2The Department of Physiology, University of Auckland, Auckland, New Zealand
Journal: Journal of Physiology
Submission: Editorial
Correspondence: Professor Dino A Giussani, Ph.D.
Department of Physiology Development & Neuroscience
Downing Street
University of Cambridge
Cambridge
CB2 3EG
UK
Tel: +44 1223 333894
E-mail: [email protected]
1 1 During the history of the Earth there have been dramatic changes in its oxygen
2 (O2) availability (Graham et al. 1995). Geochemical models suggest that in the
3 mid-to-late Devonian era (ca. 380 million years ago, mya), O2 levels in the Earth’s
4 atmosphere increased from ~18 to 20%. By the late Carboniferous period (286
5 mya), the Earth’s oxygenation had risen sharply to ~35%, which palaeontologists
6 refer to as ‘the oxygen pulse’. Through the following Permian and Palaeozoic eras,
7 approximately 250 mya ago, O2 concentrations fell to ~11%. Thereafter, in the last
8 200 million years, O2 levels steadily increased again, settling at the present day
9 level of ~21%.
10
11 These fluctuations in O2 availability have shaped the evolution of animal life on
12 Earth and are one of the earliest challenges in physiological history. When O2
13 availability increased animals harnessed this new fuel and grew larger irrespective
14 of their phyla. Falkowski and colleagues (2005) suggest that the doubling in O2
15 over the last 200 million years coincided with the evolution of physiological traits
16 that allowed mammals to thrive. These traits include endothermy and the
17 appearance of placentation (80-60 mya), which channelled O2 to the growing
18 conceptus, thereby allowing mammalian diversification. Since the Earth became
19 better oxygenated, the greatest challenge to aerobic animals became hypoxia.
20 Therefore, animals evolved compensatory mechanisms to withstand episodes of O2
21 deprivation. How organisms consumed, distributed and utilised O2 under normoxic
22 and hypoxic conditions became a key focus of Sir Joseph Barcroft’s research.
23 Generations of physiologists have since delineated the mechanisms which allow
24 fetal and adult animals to compensate for a low PaO2. These concepts resonate
25 through many of the papers presented in this issue of The Journal of Physiology,
26 which is devoted to celebrating the centenary of Barcroft’s research and is
27 appropriately entitled: Hypoxia, Fetal and Neonatal Physiology: 100 years on from
2 1 Sir Joseph Barcroft. The initial motivation for this volume was the centenary
2 celebration of the 1914 opening of the Physiological Laboratory, a purpose built
3 research building for the Department of Physiology on the Downing site of the
4 University of Cambridge, where Joseph Barcroft worked for most of his career.
5
6 Barcroft’s childhood and undergraduate studies
7 Joseph Barcroft, born July 26th 1872, was the second of five children of the linen
8 merchant Henry and his wife Anna. As a child in Northern Ireland, Joseph enjoyed
9 the outdoors, sports and painting, but had no formal lessons in reading, writing or
10 arithmetic until the age of seven (Plate 1). He came to Cambridge for his schooling
11 as a teenager and, whilst still at the Leys school, achieved the impressive feat of
12 obtaining a Bachelor of Science degree from the University of London (Plate 1).
13 Joseph went on to study Natural Sciences at the University of Cambridge, being
14 admitted to King’s College, where he remained as a Fellow for the rest of his life.
15 As an undergraduate, Barcroft was keenly interested in all branches of the
16 sciences; he even made one of the first British demonstrations of an X-ray
17 photograph to the Natural Sciences club. In his third undergraduate year, he
18 specialized in Physiology, when again he excelled, obtaining a first class degree in
19 1897. Although, reports suggest that he was self-deprecating about his successes,
20 claiming that he had obtained his high marks only by playing off the internal
21 against the external examiner! (Roughton, 1949a; Roughton, 1949b; Franklin,
22 1953).
23
24 Barcroft’s research and 100 years on
25 Joseph Barcroft began experimental research as soon as he graduated from
26 Cambridge in 1897 and continued until the day of his death aged 74 (Frankin,
27 1953). He had no formal mentor or supervisor but his first project was suggested
3 1 by Langley, who was then The Professor of Physiology at Cambridge. Barcroft was
2 to investigate the role of nerves in regulating the production of saliva. This
3 involved measuring the rates of O2 uptake and carbon dioxide output as well as
4 saliva production by a small secretory gland found in the lower jaw of most
5 mammals. This research showed for the first time that nerves were important in
6 stimulating saliva production, in part, by increasing O2 consumption (Barcroft,
7 1900). It also initiated Barcroft’s life-long interest in the respiratory gases and, in
8 particular, in O2 and its association with haemoglobin in the blood.
9
10 Barcroft’s research has interested scientists for decades and many accounts of his
11 works are available today. In this issue of The Journal of Physiology, there are
12 additional biographical articles. Lawrence Longo describes this Victorian
13 Physiologist's Contributions to a Half Century of Discovery with traditional authority
14 not only in the understanding of physiology but also with command as a medical
15 historian (Longo, 2015). John West (2015) writes a controversial piece highlighting
16 Barcroft's bold assertion that all dwellers at high altitudes are persons of impaired
17 physical and mental powers (Barcroft, 1925), a statement that understandably
18 continues to trigger much ongoing discussion today! Finally, Peter Nathanielsz
19 (2015) adds a personal touch, reporting on the 1972 symposium on Fetal and
20 Neonatal Physiology that he helped organise for the Physiological Society to
21 celebrate the centenary of Joseph Bancroft’s birth. Many of these biographical
22 accounts state that from about 1900, Barcroft began working on the handling of
23 gases in the blood more directly. He was interested in how tissues of the body
24 received and used O2, especially at high altitude where O2 is limited in availability.
25 In 1910 and 1911, he led mountain expeditions to Tenerife and Italy to study
26 oxygenation and haemoglobin function at lower than normal partial pressures of
27 O2. This period of research culminated in the publication of his first book, The
4 1 Respiratory Functions of Blood in 1914. His expertise in this area, and his success
2 as a scientist generally, were based on two main attributes; first, his technical
3 ability in making new equipment to measure, for instance, the volume and partial
4 pressures of gases in small amounts of blood and, secondly, his intellectual ability
5 in designing and performing experiments that others thought impossible, often
6 carrying them out on himself (Plate 2). An early film on the study of the blood-
7 oxygen equilibrium, originally made by Joseph Barcroft and found by chance in
8 some obscure corner of Cambridge beautifully, and somewhat amusingly,
9 demonstrate these attributes (https://archive.org/details/Bloodandrespiration-
10 wellcome, Wellcome Trust).
11
12 As a Quaker, Barcroft was seconded to government research at Porton Down during
13 the First World War as the Chief Physiologist. Given his interest in respiration, his
14 instructions were to investigate the causes, consequences and possible treatments
15 of gas poisoning, a common weapon in trench warfare on the Western front. Again,
16 his investigations were frequently ‘self-experiments’, pushing himself to the limits
17 of his own physiological compensation on several occasions (Roughton, 1949a;
18 Roughton, 1949b; Franklin, 1953). After the war, Barcroft returned to Cambridge
19 and undertook more basic research on the distribution of blood to different organs
20 and on the question of whether O2 was secreted actively into blood from the lungs
21 when its atmospheric concentration was low. To answer this question, Barcroft
22 took two different approaches. First, he led another, longer expedition to Cerro de
23 Pasco in Peru from 1920-1921 to study pulmonary gas exchange and blood
24 chemistry at high altitude. This expedition was funded by the Royal Society and
25 was better equipped and manned than his previous expeditions. It involved taking
26 a train with a mobile laboratory car to an altitude of 4,328 m (Plate 3) and
27 analysing the O2 content of blood by direct arterial puncture of expedition
5 1 volunteers and of members of non-native and native communities who had been
2 living at this altitude for months or several generations, respectively. An account of
3 this expedition can be read in the transcripts of letters from Barcroft sent home to
4 his family that are housed in the archives of The Royal Society in London and in the
5 library of the Department of Physiology, Development and Neuroscience at
6 Cambridge. Secondly, he built himself an air-tight glass chamber at the
7 Physiological Laboratory, where he could live and exercise at O2 levels equivalent to
8 4,877 m (Plate 3; Barcroft, 1920). In this latter paper, Barcroft adds some
9 colourful description of his self experimentation, including radial artery
10 catheterisation, and recovery following fainting with tea and brandy! Barcroft was
11 so enthusiastic about these experiments that he had to be extracted by his
12 colleagues from his hypoxic ‘room’ after close to 6 days in situ (Franklin, 1953).
13 Together, these experiments proved that O2 was not secreted from the lungs but
14 moved into the blood by diffusion, although there were changes in the O2
15 dissociation curve of blood with acclimatisation to low O2 levels. He, therefore,
16 updated his book, The Respiratory Functions of Blood and divided it into two parts,
17 one dealing with the lessons from high altitude (1925) and the other with the
18 contribution of haemoglobin to tissue O2 delivery (1928).
19
20 Fascination with the physiological effects of high altitude persists to this day. In
21 this issue of The Journal of Physiology, Murray & Horcroft (2015) and Jacobs and
22 colleagues (2015) expand on the effects of high altitude on mitochondrial function
23 and density in muscle, recapitulating Barcroft’s self-experimentation and reporting
24 on investigations performed on biopsies of their own vastus lateralis! Similarly,
25 Veith et al. (2015) and Hodson et al. (2015) bring us up-to-date with the molecular
26 mechanisms underlying HIF-induced pulmonary hypertension and the importance of
27 the principal HIF prolyl hydroxylase PHD2/HIF-2α enzyme-substrate couple in
6 1 modulating ventilatory sensitivity to hypoxia. Finally, Fatemian et al. (2015)
2 report that the peripheral chemoreflex sensitivity to CO2 can serve as a predictor of
3 human acclimatization to high altitude hypoxia.
4
5 The final phase of Barcroft’s research for which he is best remembered now did not
6 begin until 1932, when he was 60 and, upon the death of John Newport Langley, he
7 was appointed to be The Professor of Physiology at Cambridge. Barcroft became
8 intrigued in how the fetus, developing within its mother, received enough O2 to
9 grow so rapidly. This was one area in which he could not experiment on himself so
10 he used pregnant animal models to determine how fetuses respire. He thought that
11 the fetus had a lower basal arterial O2 level than its mother and might be like the
12 acclimatised mountaineer at high altitude. So he set about studying how fetuses
13 survived and thrived on ‘Everest in utero’, a phrase he coined which has been used
14 extensively since to describe the conditions in which the fetus normally develops
15 (Barcroft, 1935). Using pregnant sheep, under the influence of anaesthesia, in
16 acute preparations developed by Huggett (1927) where fetuses were delivered into
17 a warm water bath, Barcroft measured placental function, fetal growth rate, fetal
18 haemoglobin and O2 carrying capacity, fetal respiratory movements, fetal and
19 placental blood flow and the changes that occur in the fetal circulation and lungs at
20 the time of birth. These studies resulted in the publication of his final book,
21 Researches on Pre-natal Life, in 1946, the year before he died.
22
23 Without question, this publication laid the foundation for Fetal and Neonatal
24 Physiology as a separate branch of Physiology and opened up a new era of basic
25 and clinical research into fetal growth and development during healthy and
26 compromised pregnancies. Although the sheep remains the animal model of choice
27 for studying pregnancy and fetal development, Barcroft’s initial acute preparation
7 1 has been refined to allow studies in the conscious state, through the efforts of
2 Donald Barron, one of Barcroft’s most influential post-doctoral fellows, and of
3 Barron’s post-doctoral researchers, Giacomo Meschia and Frederick Battaglia. They
4 developed the chronically catheterised fetal sheep preparation, now used
5 worldwide, which allows the study of the physiology of the mother and fetus after
6 full recovery from surgery without the confounding effects of pre-operative fasting,
7 anaesthesia and surgical stress (Meschia et al. 1965).
8
9 In this issue of the Journal of Physiology, seven papers from laboratories in North
10 and South America, Europe, Australia and New Zealand, report on findings using
11 this type of chronically-instrumented ovine preparation (Allison et al. 2015; Chang
12 et al. 2015; Clifton et al. 2015; Galinsky et al. 2015; Giussani, 2015; Herrera et al.
13 2015; Lear et al. 2015). Giussani (2015) reviews the fetal cardiovascular defence
14 to acute hypoxia, highlighting neural, endocrine and vascular redox mechanisms,
15 and introducing the concept of the fetal brain sparing index. Herrera et al. (2015)
16 report on cardiovascular function in term fetal sheep conceived, gestated and
17 studied under the influence of chronic hypoxia by exploiting the natural laboratory
18 of the high altitude of the Andean altiplano. Almost ‘keeping it in the family’, again
19 recapitulating many of Barcroft’s preoccupations, Allison et al. (2015) bring the
20 Andean mountains back to Cambridge. Combining bespoke isobaric hypoxic
21 chambers and a wireless data acquisition system, they introduce a new technique
22 that is able to maintain chronically instrumented pregnant ewes and their fetuses
23 under isobaric chronic hypoxia for most of gestation at lower levels than can be
24 achieved by habitable high altitude and of direct relevance to the degree of hypoxia
25 seen in human infants with significant intrauterine growth restriction. The
26 technology also permits, for the first time, longitudinal wireless recording of
27 maternal and fetal cardiovascular function in free-moving animals, including beat-
8 1 to-beat alterations in arterial blood pressure and blood flow signals in regional
2 circulations. Lear and colleagues (2015) challenge the long held assumption that
3 the sympathetic nervous system mediates fetal heart rate (FHR) variability in
4 labour. The clinical significance of this report is important and is reviewed by Shaw
5 et al. (2015), as this finding directly contradicts the established clinical
6 interpretation that preserved FHR variability implies adequate fetal physiological
7 compensation. Galinsky et al. (2015) caution on the clinical use of magnesium
8 sulphate for the treatment for pre-eclampsia and perinatal neuroprotection, as it
9 alters the perfusion of several vascular beds during acute asphyxia; effects which
10 may place the preterm fetus at greater risk of intestinal and renal compromise.
11 Chang et al. (2015) use a transcriptomics approach to predict that hypoxia
12 activates inflammatory pathways and reduces metabolism in the fetal kidney
13 cortex, and show that ketamine ameliorates this response. Thus, their data suggest
14 that ketamine may have therapeutic potential for protection from ischaemic renal
15 damage. Clifton et al. (2015) introduce an ovine experimental model to investigate
16 the effects on the fetus of maternal asthma in pregnancy, permitting evaluation of
17 current as well as novel clinical interventions.
18
19 This issue of the Journal of Physiology also focuses on continuing studies on the
20 placenta, the interface between mother and the fetus. In placentae obtained from
21 normotensive and pre-eclamptic women at sea level and at high altitude, Kurlak et
22 al. (2015) report that the placental renin-angiotensin-system is responsive to
23 changes in tissue oxygenation. They introduce the concept that this could be
24 important in the interplay between reactive oxygen species as cell-signalling
25 molecules for angiogenesis and, hence, placental development and function. Three
26 studies that model hypoxic pregnancy in mice highlight placental adaptations to
27 decreased oxygenation at functional, cellular and molecular levels. Higgins et al.
9 1 (2015) report that hypoxia modifies the placental transport phenotype and resource
2 allocation to fetal growth. The study highlights that there appears to be a threshold
3 between 13% and 10% of maternal inspired O2, corresponding to altitudes between
4 ca. 3700m and 5800m, at which the mouse placenta can no longer adapt to
5 support fetal resource allocation with implications for human pregnancies at higher
6 altitudes. Using the same mouse model of hypoxic pregnancy, Skeffington and
7 colleagues report that adenosine monophosphate-activated protein kinase (AMPK)
8 is a uterine artery vasodilator and may provide a key molecular link between
9 maternal uterine vascular responses, placental function and fetal growth in normal
10 and complicated pregnancy. They show that manipulation of AMPK may be a novel
11 mechanism for developing new therapies in pregnancies complicated by chronic
12 hypoxia. Finally, Matheson et al. (2015) report further placental adaptations to
13 chronic hypoxia at the molecular level, showing activation of endoplasmic reticulum
14 stress, a conserved homeostatic response that mediates translational arrest
15 through phosphorylation of the eukaryotic initiation factor 2 subunit alpha (eIF2α),
16 which may underlie fetal growth restriction. They also report sexually dimorphic
17 morphological and molecular changes in the murine placenta exposed to
18 normobaric hypoxia throughout pregnancy.
19
20 Further reports in this issue of the Journal of Physiology focus on the transition to
21 postnatal life and potential therapy to ameliorate the problems that face the
22 vulnerable infant. In a beautiful imaging study using simultaneous phase-contrast
23 X-ray and angiography in rabbits, Lang et al. (2015) discuss previously unknown
24 mechanisms responsible for mediating the increase in pulmonary blood flow at
25 birth. They conclude that mechanisms unrelated to oxygenation or to the spatial
26 relationships that match ventilation to perfusion, initiate the large increase in
27 pulmonary blood flow at birth. McGillick et al. (2015) provide evidence for
10 1 stimulatory effects of vascular endothelial growth factor (VEGF) administration on
2 structural maturation in the lung of both the normally grown and placentally-
3 restricted IUGR sheep fetus, raising VEGF as an interesting potential candidate for
4 therapy against respiratory distress syndrome of the preterm infant. Additional
5 candidate protective therapy for newborn life is provided by Aridas and colleagues
6 (2015), who report that umbilical cord blood stem cells administered after perinatal
7 asphyxia can convey neuro-protection in newborn lambs, with translational
8 potential for the treatment of human infants following hypoxic ischaemic
9 encephalopathy. In contrast, Barton et al. (2015) caution on the potential adverse
10 side effects of erythropoietin administration as a neuroprotective therapy. They
11 report that erythropoietin administration within minutes of the onset of injurious
12 ventilation in newborn lambs can amplify pro-inflammatory cytokine gene
13 expression in both the periventricular and subcortical white matter.
14
15 In 1946, Barcroft wrote: “never losing sight of the fact that one day the call will
16 come and the fetus will be born. Not only has the fetus to develop a fundamental
17 life which will suffice for intrauterine conditions, but at the same time it has to
18 develop an economy which will understand the shock of birth, and will suffice, nay
19 more than suffice, for its new environment.” This statement hints that Barcroft
20 begun to think like many developmental physiologists do today, agreeing that
21 sometimes compensation carries a price. Now we know that compensatory or
22 adaptive responses to adverse intrauterine conditions, while beneficial in terms of
23 survival in utero, may sometimes trigger unwanted adverse side effects in the
24 offspring, increasing the risk of pathology in later life (Barker, 1998; Fowden et al.
25 2006; Gluckman et al. 2008). In fact, programmed cardiovascular and metabolic
26 disease in later life specifically linked to chronic fetal hypoxia has been recently
27 reviewed by Giussani & Davidge (2013). While chronic fetal hypoxia is known to
11 1 increase the risk of cardiac and endothelial dysfunction in later life (Giussani et al.
2 2012), recent focus has been on the effects of combined pre-and post-natal
3 challenges. In this issue of the Journal of Physiology, Walton et al. (2015) show
4 that late gestational hypoxia combined with a postnatal high-salt diet exacerbates
5 the programming of endothelial dysfunction and arterial stiffness in adult mouse
6 offspring. Shah and colleagues (2015) report that resveratrol, a natural polyphenol
7 found in grape skin, improves cardiovascular and metabolic health in adult rat
8 offspring exposed to prenatal hypoxia and a postnatal high-fat diet, and that this
9 protective effect is independent of the sex of the offspring. Vega at al. (2015)
10 conclude that resveratrol also partially prevents increased indices of oxidative
11 stress in the mother, placenta and offspring in pregnancy complicated by maternal
12 under-nutrition and that some of these effects protect the mother and offspring
13 against metabolic dysfunction.
14 Barcroft: the person, his final days and his legacy
15 Joseph Barcroft became much loved for his enthusiasm, kindness and attention to
16 detail as a mentor and teacher as well as being a great communicator, often
17 lecturing without notes (Plate 4). In the decade preceding World War I, he had
18 supervised almost every Cambridge physiologist, many of whom became successful
19 scientists themselves. According to his biographer, Francis Roughton (1949a): “one
20 of his most charming characteristics was that he always took particular trouble to
21 get to know and to help those working on all rungs of the ladder, from top to
22 bottom, of any institution or concern with which he was connected”. During his
23 career, Barcroft published >300 papers, books and research reports, and travelled
24 widely within the UK and abroad to scientific and other educational meetings. He
25 talked “in that simple, always exciting and slightly breathless way he had, making
26 all he had discovered seem so self-evident, poking fun at himself and paying
12 1 generous tribute to his collaborators” (Roughton, 1949a, Roughton, 1949b).
2 Barcroft also had an ability to attract bright young people to work with him, many
3 of whom continued with research into hypoxia, and fetal and neonatal physiology
4 after his death. It was common knowledge that Barcroft attributed his success to
5 only one thing - a daily afternoon nap! Although Joseph Barcroft retired as
6 Professor in 1937, he remained scientifically active until his sudden death of a heart
7 attack ten years later. According to his colleague Roughton, that morning, Barcroft
8 had been his usual energetic, shrewd and good-humoured self, departing to catch a
9 bus with a quip and a smile. When they later heard the news of his death, his
10 colleagues remarked that Joseph Barcroft had gone on doing first class work right
11 up to the last moment of his life, and for him ‘physiology was the greatest sport in
12 the world’! (Plate 5). This special issue of The Journal of Physiology is a testament
13 to Barcroft’s continuing legacy and to the fascination many of us still find in the
14 unanswered physiological questions that drove his research more than 100 years
15 ago.
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17 LEGENDS
Plate 1. Joseph Barcroft, a month before his third birthday (left) and as Bachelor of
Science of the University of London (19 years of age, right).
Plate 2. Joseph Barcroft’s apparatus for blood gas extraction (1900). Franklin
1953.
Plate 3. Joseph Barcroft inside the ‘Glass chamber’ during his experiment in 1920.
Franklin 1953.
Plate 4. Joseph Barcroft lecturing in Lecture Theatre 1 at the Physiological
Laboratory, University of Cambridge in 1935 (left) and discussing science with
August Krogh in 1929 (right).
Plate 5. Joseph Barcroft driving off (1929, left) and in the preface to his book “The
Respiratory Function of the Blood”, 1914, right in which he stated: ‘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.‘
18 ACKNOWLEDEGEMENTS
Dino Giussani is supported by the British Heart Foundation, The Biotechnology and
Biological Sciences Research Council, The Royal Society, The Wellcome Trust,
Action Medical Research and the Isaac Newton Trust.
CONFLICTS OF INTEREST DISCLOSURES
The authors declare no conflicts of interest.
19 Plate 1. Joseph Barcroft, a month before his third birthday (left) and as Bachelor of Science of the University of London (19 years of age, right). Franklin 1953.
Plate 2. Joseph Barcroft’s apparatus for blood gas extraction (1900). Franklin 1953. Plate 3. Joseph Barcroft inside the ‘Glass chamber’ during his experiment in 1920. Franklin 1953. Plate 4. Joseph Barcroft lecturing wearing a gown in Lecture Theatre 1 at the Physiological Laboratory, University of Cambridge in 1935 (left) and discussing science with August Krogh in 1929 (right). Franklin 1953. Plate 5. Joseph Barcroft driving off (1929, left) and in the preface to his book “The Respiratory Function of the Blood”, 1914 (right) in which he stated: ‘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.‘ Franklin 1953.