Sir Joseph Barcroft: one victorian physiologist's contributions to a half century of discovery

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 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.

Introduction

Among those who changed and vitalized the course of physiological research in the first half of the 20th Century was the seminal investigator Joseph Barcroft (1872–1947; later Sir Joseph; ‘JB’ or ‘Jo’ as he was known to his friends) of Cambridge University (Fig. 1). Of Quaker heritage, Barcroft grew up in Ulster, Northern Ireland. In 1888, at the age of 16 years, with a keen interest in science, he was sent to Leys School, Cambridge. In 1896, he graduated from King's College. At Cambridge, he served as president of the University Natural Science Club, the membership of which during its first 100 years included 10 future Nobel Laureates. After graduation, he joined the Physiological 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 talent. The question arises: what we can learn from the life and work of one born almost a century and a half ago and who died seven decades ago?

Figure 1.

Sir Joseph Barcroft.

Barcroft's scientific career may be divided into four major phases of inquiry: that of oxygen (O₂) consumption in tissues; the definition of the oxyhaemoglobin saturation [HbO₂] curve; establishing the limits of human tolerance to high altitude; and pioneering the exploration of various aspects of oxygenation of the fetus in utero (some suggest a fifth area: the role of the spleen on the storage of erythrocytes; West, 2013). In each of these topics, his contributions were vital in opening new fields of thought and investigation. A number of writers have presented various aspects of Barcroft's life and work (Anonymous, 1947; Barron, 1973; Breathnach, 1974; Dale, 1949; Dunn, 2000; Franklin, 1953; Holmes, 1970; West, 2013; 2016; Young, 1992).

Salivary gland metabolism

After his graduation from Cambridge University, and as a member of the Physiological Laboratory, Barcroft's earliest 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; 1900 a). Barcroft demonstrated that oxygen consumption increased significantly during stimulation and continued even after the flow of saliva stopped (Barcroft, 1900 b; 1900 c; 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, 1904 a; 1904 b; 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.

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 physiologist Nathan Zuntz (1847–1920) (Barcroft, 1911; Durig & 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.

Figure 2.

Alta Vista Hut, Teneriffe, 1910 (Franklin, 1953).

Figure 3.

Capanna Regina Margherita, Monte Rosa, 1911 (Franklin, 1953).

Figure 4.

Interior of mobile laboratory, Cerro de Pasco, 1921–1922 (Franklin, 1953)

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 physiologists had suggested this to be an important mechanism (Breathnach, 1974; West, 2013). In addition, in other 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).

Figure 5.

‘Glass Chamber’ at Cambridge University, 1920 (Franklin, 1953).

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 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; 2016). 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 spleen and its relationship with blood volume (Barcroft, 1926 a; 1926 b). 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, 1934 a). 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 interested 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. 1934 a) and fetal oxygenation in the rabbit (Barcroft et al. 1934 b). 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 right ventricle via the ductus arteriosus equalled the volume in the left ventricle that had flowed through the foramen ovale (Barcroft, 1935 a).

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. P ₅₀ ∼40 Torr) (Huggett, 1927). With his great interest in this topic, using blood at constant conditions (38°C, $P_{\mathrm{C}{\mathrm{O}}_2}$ ∼50 Torr), Barcroft and colleagues reported the correct curves for the newborn goat and its mother (P ₅₀ = 30 and 37 Torr, respectively) and also compared these at several times during the course of gestation (Barcroft, 1933; 1934 c; Barcroft et al. 1934 a; 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, 1935 a; Barcroft et al. 1940 a; 1940 b).

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, 1935 a; 1935 b; 1935 c; 1935 d; Barcroft et al. 1940 b). 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 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 physiology, 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, 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 physiologist 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; 1939 a; 1939 b; 1940 a; 1940 b; 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 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.

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

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 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 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:

Figure 6.

Joseph Barcroft measuring blood gases, 1928 (Franklin, 1953).

… 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) … 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 superficial 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 understanding 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)

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.

Figure 7.

Joseph Barcroft lecturing, 1935 (Franklin, 1953).

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 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 Physiology 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 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 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?

Biography

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.