Phcmtu
(1992), 13,607-612
Classics Revisited: Researches Life by Sir Joseph Barcroft
on Pre-natal
MAUREEN YOUNG 4 Preston Close, Toji, Cambridge CB.? 7R.C’
Sir Joseph, or J.B. as he was called during a long and very active life in experimental physiology, wrote ‘Researches on Prenatal Life’ during World War II. The preface starts ‘This work partakes very much of the nature of a will . . .. In the days ofbombs 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. . . . because not the least interesting part of the work has been the fitting together of individual items, . . . into a picture from which a likeness of the organism is beginning to emerge. . . . I have put down all that is supported by experiment. . . . Not only has the fetus 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’. With characteristic generosity, it is dedicated to D. H. Barron, ‘to whom the work, ofwhich this book treats, owes so much’.
BARCROFT The embryo, and the placenta and fetus, had long interested anatomists and physiologists, but Barcroft’s experimental approach gave the study of intrauterine life, and the preparation of the conceptus and reproductive organs for birth, a great impetus. His work on this subject started when he was 60 years old and took place between 1932 and 1947. That Joe, as he was called by this time, should have provided the stimulus for a new chapter in physiology is no surprise. Those members of today’s physiology community who have not already read F. J. W. Roughton’s obituary of Sir Joseph (1948) will find a tribute to an investigator whose ‘science and research were not only his life’s work, but also his life-play’; a family man, fond of good company, courageous and humorous and, above all, with a great capacity for work and the encouragement of colleagues. The memoir recounts his early experimental work on the oxygen consumption of the salivary gland, how this was increased by nerve stimulation and how- the increase continued after the flow of saliva had stopped-foreshadowing the concept of oxygen dept in muscle. This led on to a consideration of the oxygen supply to many other tissues, the importance of blood oxygen tension and studies of the haemoglobin oxygen dissociation curve. He developed the differential blood gas manometer and the tonometer, a simpler method than previously used, for equilibrating blood with gas mixtures; with these he characterized 0143-4004/92/060607
+ 06 $0%00/O
0
1992 Baillikre Tindall L.td
608
Placenta(lW2), Vol. 13
the properties of haemoglobin in blood which we know so well from our textbooks today. Classic, too, are his interests in hypoxia and his contributions to the physiology of high altitude. In turn, these observations led to his work on blood storage organs, particularly the spleen and the influence of stress on blood volume. These highlights serve to show why his influence spread and so many visitors from laboratories in the UK and the USA gathered in his department in Cambridge, to assist in the last chapter of his work. It was very characteristic of Barcroft to involve many people in his work and to choose studies of physiological problems which had previously received little attention; the physiology of prenatal life was fortunate to have attracted the interest of an investigator with such wide vision, experimental experience, dedication and enthusiasm.
THE BOOK ‘Researches in Pre-natal Life’ is mainly concerned with descriptions of observations made on the fetal lamb, using a technique introduced in the mid-1920s by A. St G. Huggett; the ewe, under spinal anaesthesia, lay with her abdomen immersed in a saline bath at 37X, so that the fetus could be delivered with an intact umbilical circulation into a warm environment at caesarean section. Goats, rabbits and guinea-pigs were also studied and Barcroft stressed the differences between the species in the extent of development of function during intrauterine life. He records that he was ‘nettled’ by people who volunteered facile explanations for fetal circulatory responses, based on their knowledge of adult physiology only! Sir Joseph also had the application of his work to the welfare ofwomen and infants clearly in view, for he had once wanted to be a doctor and had strong affinity with the profession. He discussed his results with medical colleagues, sought their advice and correlated his observations with theirs in the clinic. Each chapter of the book sets out to answer specific questions which are always clearly stated. Barcroft had the advantage that no great volume of literature existed before he started his fetal studies and when reference was made to previous work it was always analytical but courteous. But intrauterine experiments are very challenging: the fetus itself is relatively frail and the umbilical vessels particularly reactive; moreover, the apparatus available for his measurements was still very clumsy and there was no means of measuring blood flow or oxygen tension directly. He gave great consideration to the potential shortcomings of all his observations (calling some values ‘rugged’!) and to their interpretation. The placenta and fetal development The first third of Barcroft’s book tells of observations on the placenta and fetal growth. The data is not so open to experimental error as those on the circulation and, though not so well known, the concepts are far reaching and have been of great value to the clinician. Studies on the physiology of the placenta, ‘the disposition of the vessels’and its histological structure are described; the osmotic pressure differences between the maternal and fetal bloods together with ‘crossing the placental barrier’, giving ‘pride of place’ to water as having the greatest net transfer, are given careful consideration. Data on fetal growth follows, with a description of the critical growth periods of the various organs and with evidence that variation in the average whole body growth rate occurs only in the last 30 days of the 160 days gestation period in the ewe. The small difference in fetal size in twin pregnancies, despite the smaller cotyledon number and weight, indicated the plasticity of the system. The possible interaction of a nutritional as well as a genetic framework for growth is
1 bung: Uussics Rmisited
609
introduced in a chapter on the ‘relative claims of the fetus and mother to available nutritive material’: Barcroft stressed the symbiosis of the relationship at a time when the fetus was still regarded as a parasite. Applying Child’s general hypothesis (1920) that the partition of nutrients between different organs was determined by their metabolic rates, Barcroft and Hammond argued that the fetus with a high metabolic rate would compete with the maternal tissues-but only in so far as these were able to continue the supply. ‘Metabolic rate’ was represented by oxygen consumption measured in tissue slices; such measurements had been an integral part of Barcroft’s early work and Carlyle (1948) was introduced to the complexities which this subject presents when the fetus is studied. In order to measure oxygen consumption of the whole fetus during intrauterine life the increasing amount of active metabolic structure in each organ must be known, besides the changing proportions of their weights contributing to the whole body weight during development. It was found that oxygen consumption by fetal tissues (with the exception of the brain) was higher than those of the mother, decreasing towards her levels near term. The oxygen uptake of the whole fetus could be calculated, in ml/Kg/min, and the figures showed that oxygen consumption declined to levels comparable with those of the mother at the end of gestation due, principally, to the declining weight of the liver and the increasing weight of the skin. In evaluating the influence of nutrition on fetal growth Barcroft drew on the work of W’allace (1948) and others. Fetal growth had been shown to be retarded by low planes of nutrition in the pregnant ewe; growth of the brain and skeletal muscle were the least affected while that of the liver, with the highest metabolic rate, was reduced the most. However, newborn weight was not improved in the first dietary supplement study in a disadvantaged group of women in Toronto in 1942, showing that Wallace’s results in the ewe could not be readily transferred across the species. Barcroft was also interested in the first epidemiological study of the influence of low income on maternal stature and weight and their effects on pregnancy outcome, carried out by Baird (1945) in Aberdeen. His particular interest in these well-known observations lay in the incidence of prematurity which was usually assessed on a weight basis, 5.51bs and less, rather than gestation length; analysing the figures he concluded that about one-third of the cases of unexplained low birthweight infants might have been due to premature onset of labour. IIearing of Smith’s (1947) observations on Dutch women undernourished in Holland during the winter of 1944-1945, at the end of World War II, Barcroft obtained a prepublication abstract of the results to publish in his book. Smith separated the weights of offspring of undernourished mothers born at full term from those born prematurely; in both groups the slopes of the birth weights declined in parallel during the 6-month period of general undernutrition, showing that the lighter weight of the premature was not due to a decrease in gestation length. Further, the slope of the reduction in birth weight was steeper in babies born during the first 3 months of the malnutrition period, indicating that maternal nutrition was most important in the last trimester of pregnancy. The fetal circulation and the changes at birth. The onset of respiration Rarcroft’s work on the fetal circulation and respiration, was undertaken with Barron and many colleagues; it forms two-thirds of the book and is the best known. The results of their experiments provided the first physiological foundation for our understanding of the development of the supply of nutrients to the fetal tissues and how this is changed at birth. Much of the evidence for the pathways of the fetal circulation came from anatomical studies and obsemations following the injection of radiopaque material; but evidence from the
610
Placenta (1 !WZ), V01. 13
oxygen content of blood was the most definitive, showing the differences in the environment of the various fetal tissues and how this was altered at birth. But, to quote, ‘oxygen-is-but one of the proximate principles of nourishment’ (p. 126) and metabolism would have been one of the subjects of volume II -never published. Investigations were made into the way this oxygen was carried by the blood and the characteristics of the fetal haemoglobin: how oxygen was unloaded from the mother to the fetus and the influence of carbon dioxide are described: investigations, too, of the pressures in the vessels supplying the placenta and fetus: of cardiac output, the heart rate, its changes during gestation, development of the innervation and the effect of asphyxia. The influence of uterine contractions on the circulation, changes in the blood volume distribution between the fetus and placenta during gestation and transfer of blood from the placenta to the newborn at delivery, all attracted their attention. The values provided by their observations were all very carefully scrutinized and appraised in relation to the needs and responses of the fetus. Their last researches were concerned with characterizing the development of fetal movement with special reference to that of the chest. The anatomical foundations were established by sectioning the medulla and pons at various stages of development, in the first chronic intrauterine fetal preparations in the lamb. Finally, their thoughts were turned to the mechanism of the first breath. To quote again, ‘so much for the instrument, a few words in conclusion about the hand which strikes it’. (p. 269). ‘Researches on Pre-natal Life’ was published at a time of great expansion in investigative medicine, at the end ofWorld War II. In this atmosphere the fundamental knowledge that the book provided helped to widen interest in the care of the mother, the fetus and the newborn and to stimulate research in paediatrics and obstetrics. It came at a time when open chest surgery had started, providing the possibility for correcting congenital heart defects in newborn infants: at a time, too, when intensive care units were being created with the need for information on the homeostatic responses of the developing circulation and respiratory systems, particularly: at this time, too, treatment of small patients was greatly helped by the improvement of instrumentation which was giving us micromethods for analyses on small samples of body fluids, together with that boon, the fine plastic catheter. Further, the prospect of malnutrition occurring widely in the developing countries, saw the beginning of studies on the influence of maternal malnutrition on fetal weight and welfare in human pregnancy, guided by experimental work in animals. The worldwide establishment of experimental perinatal and developmental physiology departments, together with the large number of societies, books and journals for mutual discourse between laboratory-based investigators and the expanded paediatric and obstetric departments, all bear witness to the great interest engendered by the studies of ‘which this book treats’ and its value to the mother and her child. The book was also a great stimulus to physiologists to improve the experimental procedures for studying the fetus and the placenta. No conclusion of Barcroft’s was ‘ex cathedra’ and his uncertainty over the correct values for the oxygen environment of the fetus,* in particular, was a great stimulus for this improvement. Thus Barron, who had already kept fetal lambs alive ‘in utero’ following CNS section for the respiratory studies, developed with Meschia and Battaglia, the chronic preparation with indwelling catheters in the umbilical vessels of the fetal lamb and, later, in branches of the uterine artery and vein of
* At the bottom of pages 187 and 197, the reader will find pragmatic and amusing accounts of the hazards in obtaining meaningful samples of blood from the umbilical vessels and carotid artery, in Barcroft’s time; they are too long to quote here in full.
kbrtn~: Classics Rtvisitd
611
the mother; it was a happy coincidence that the ewe’s uterus should be so unresponsive to surgery. The paper establishing values for the blood gases in the umbilical vessels of the unanaesthetised fetus in the uterus of a mother standing in her normal posture, days after recovery from the operative procedure, was published in 1965. The low oxygen content and tension which Barcroft had found in the umbilical vein blood was now firmly established and the fetal blood gas environment shown to be constant during the last quarter of gestation; the haemoglobin content of the blood during this period was also constant and showed no evidence of an hy-poxic response of the fetal haemopoeitic system. This chronic preparation is unique in physiology and has had a widespread influence in furthering an understanding of the circulatory, respiratory and metabolic mechanisms in the intact unit of fetus and placenta. The need to understand the separate placental mechanisms in fetal nutrition stimulated, in its turn, the development of perfusion techniques; the smaller animals used were easier to handle, and more appropriate to the human situation by virtue of the structure of their placental membranes. The isolated human placental cotyledon is, now, not only perfused but the whole tissue used extensively for a host of micro-cellular and molecular studies.
EPILOGUE ‘Researches on Pre-natal Life’ will always be beloved by those of us who read the book when it was first published and it continues to delight many more. It was written by a man who would have thoroughly appreciated all the work which the book has inspired; the more rigorous experimental proof of his ideas afforded by modern technology and the use of this technology to study those fragile subjects, the fetus and newborn, with minimal disturbance. Investigators in cellular and molecular biology would have found him very good company. Most of all he would have been proud to know that his work had contributed to the increased care of the mother and child, and the decrease in perinatal mortality, which has taken place during the last half century. Sir Joseph Barcroft’s work was recognized by the Royal Society and by the National Academy of Sciences in the USA and many other institutions; when he was made an honorary FRCOG in 1944, Sir Charles Sherrington wrote in his letter of congratulation, ‘-an outstanding compliment. You have founded a new line of enquiry and they recognize that-’ (see Franklin, 1953). He was still full of interest and fun until within minutes of his sudden death from a heart attack: Roughton (1949) recalls meeting him in the lab on that last morning, ‘Now let’s hear what you’ve been doing with my ewe blood, -‘.
REFERENCES Baird, D. (1945) Influence of social and economic factors on stillbirths and neonatal deaths.Jobunal of Obstetrics and ~ynaecology, 52, 217-234. Barron, D. H., Meschia, G., Cotter, J. R. & Breathnach, C. S. (1965) The haemoglobin, oxygen, carbon dioxide and hydrogen ion concentrations in the umbilical bloods of sheep and goats as sampled via indwelling plastic catheters. @ar&~3oumal ofExperimental Physiology, 50, 185-195. Carlyle, A. (1948) An integration of the total oxygen consumption of the sheep fetus from that of the tissues.3ofounul ofPhysiology, 107,355-364. Franklin, K. J. (1953) Joseph Barcroft, 1872-1947. p. 305. Oxford: Blackwell’s Scientific Publications. Huggett, A. St G. (1927) Fetal blood gas tensions and gas transfusion through the placenta of the goat.3oumal oj Physioloo, 62,363-384. Roughton, F. J. W. (1948) Joseph Barcroft, 1872-1947. R/!~dSocie
(1992), 13,607-612
Classics Revisited: Researches Life by Sir Joseph Barcroft
on Pre-natal
MAUREEN YOUNG 4 Preston Close, Toji, Cambridge CB.? 7R.C’
Sir Joseph, or J.B. as he was called during a long and very active life in experimental physiology, wrote ‘Researches on Prenatal Life’ during World War II. The preface starts ‘This work partakes very much of the nature of a will . . .. In the days ofbombs 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. . . . because not the least interesting part of the work has been the fitting together of individual items, . . . into a picture from which a likeness of the organism is beginning to emerge. . . . I have put down all that is supported by experiment. . . . Not only has the fetus 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’. With characteristic generosity, it is dedicated to D. H. Barron, ‘to whom the work, ofwhich this book treats, owes so much’.
BARCROFT The embryo, and the placenta and fetus, had long interested anatomists and physiologists, but Barcroft’s experimental approach gave the study of intrauterine life, and the preparation of the conceptus and reproductive organs for birth, a great impetus. His work on this subject started when he was 60 years old and took place between 1932 and 1947. That Joe, as he was called by this time, should have provided the stimulus for a new chapter in physiology is no surprise. Those members of today’s physiology community who have not already read F. J. W. Roughton’s obituary of Sir Joseph (1948) will find a tribute to an investigator whose ‘science and research were not only his life’s work, but also his life-play’; a family man, fond of good company, courageous and humorous and, above all, with a great capacity for work and the encouragement of colleagues. The memoir recounts his early experimental work on the oxygen consumption of the salivary gland, how this was increased by nerve stimulation and how- the increase continued after the flow of saliva had stopped-foreshadowing the concept of oxygen dept in muscle. This led on to a consideration of the oxygen supply to many other tissues, the importance of blood oxygen tension and studies of the haemoglobin oxygen dissociation curve. He developed the differential blood gas manometer and the tonometer, a simpler method than previously used, for equilibrating blood with gas mixtures; with these he characterized 0143-4004/92/060607
+ 06 $0%00/O
0
1992 Baillikre Tindall L.td
608
Placenta(lW2), Vol. 13
the properties of haemoglobin in blood which we know so well from our textbooks today. Classic, too, are his interests in hypoxia and his contributions to the physiology of high altitude. In turn, these observations led to his work on blood storage organs, particularly the spleen and the influence of stress on blood volume. These highlights serve to show why his influence spread and so many visitors from laboratories in the UK and the USA gathered in his department in Cambridge, to assist in the last chapter of his work. It was very characteristic of Barcroft to involve many people in his work and to choose studies of physiological problems which had previously received little attention; the physiology of prenatal life was fortunate to have attracted the interest of an investigator with such wide vision, experimental experience, dedication and enthusiasm.
THE BOOK ‘Researches in Pre-natal Life’ is mainly concerned with descriptions of observations made on the fetal lamb, using a technique introduced in the mid-1920s by A. St G. Huggett; the ewe, under spinal anaesthesia, lay with her abdomen immersed in a saline bath at 37X, so that the fetus could be delivered with an intact umbilical circulation into a warm environment at caesarean section. Goats, rabbits and guinea-pigs were also studied and Barcroft stressed the differences between the species in the extent of development of function during intrauterine life. He records that he was ‘nettled’ by people who volunteered facile explanations for fetal circulatory responses, based on their knowledge of adult physiology only! Sir Joseph also had the application of his work to the welfare ofwomen and infants clearly in view, for he had once wanted to be a doctor and had strong affinity with the profession. He discussed his results with medical colleagues, sought their advice and correlated his observations with theirs in the clinic. Each chapter of the book sets out to answer specific questions which are always clearly stated. Barcroft had the advantage that no great volume of literature existed before he started his fetal studies and when reference was made to previous work it was always analytical but courteous. But intrauterine experiments are very challenging: the fetus itself is relatively frail and the umbilical vessels particularly reactive; moreover, the apparatus available for his measurements was still very clumsy and there was no means of measuring blood flow or oxygen tension directly. He gave great consideration to the potential shortcomings of all his observations (calling some values ‘rugged’!) and to their interpretation. The placenta and fetal development The first third of Barcroft’s book tells of observations on the placenta and fetal growth. The data is not so open to experimental error as those on the circulation and, though not so well known, the concepts are far reaching and have been of great value to the clinician. Studies on the physiology of the placenta, ‘the disposition of the vessels’and its histological structure are described; the osmotic pressure differences between the maternal and fetal bloods together with ‘crossing the placental barrier’, giving ‘pride of place’ to water as having the greatest net transfer, are given careful consideration. Data on fetal growth follows, with a description of the critical growth periods of the various organs and with evidence that variation in the average whole body growth rate occurs only in the last 30 days of the 160 days gestation period in the ewe. The small difference in fetal size in twin pregnancies, despite the smaller cotyledon number and weight, indicated the plasticity of the system. The possible interaction of a nutritional as well as a genetic framework for growth is
1 bung: Uussics Rmisited
609
introduced in a chapter on the ‘relative claims of the fetus and mother to available nutritive material’: Barcroft stressed the symbiosis of the relationship at a time when the fetus was still regarded as a parasite. Applying Child’s general hypothesis (1920) that the partition of nutrients between different organs was determined by their metabolic rates, Barcroft and Hammond argued that the fetus with a high metabolic rate would compete with the maternal tissues-but only in so far as these were able to continue the supply. ‘Metabolic rate’ was represented by oxygen consumption measured in tissue slices; such measurements had been an integral part of Barcroft’s early work and Carlyle (1948) was introduced to the complexities which this subject presents when the fetus is studied. In order to measure oxygen consumption of the whole fetus during intrauterine life the increasing amount of active metabolic structure in each organ must be known, besides the changing proportions of their weights contributing to the whole body weight during development. It was found that oxygen consumption by fetal tissues (with the exception of the brain) was higher than those of the mother, decreasing towards her levels near term. The oxygen uptake of the whole fetus could be calculated, in ml/Kg/min, and the figures showed that oxygen consumption declined to levels comparable with those of the mother at the end of gestation due, principally, to the declining weight of the liver and the increasing weight of the skin. In evaluating the influence of nutrition on fetal growth Barcroft drew on the work of W’allace (1948) and others. Fetal growth had been shown to be retarded by low planes of nutrition in the pregnant ewe; growth of the brain and skeletal muscle were the least affected while that of the liver, with the highest metabolic rate, was reduced the most. However, newborn weight was not improved in the first dietary supplement study in a disadvantaged group of women in Toronto in 1942, showing that Wallace’s results in the ewe could not be readily transferred across the species. Barcroft was also interested in the first epidemiological study of the influence of low income on maternal stature and weight and their effects on pregnancy outcome, carried out by Baird (1945) in Aberdeen. His particular interest in these well-known observations lay in the incidence of prematurity which was usually assessed on a weight basis, 5.51bs and less, rather than gestation length; analysing the figures he concluded that about one-third of the cases of unexplained low birthweight infants might have been due to premature onset of labour. IIearing of Smith’s (1947) observations on Dutch women undernourished in Holland during the winter of 1944-1945, at the end of World War II, Barcroft obtained a prepublication abstract of the results to publish in his book. Smith separated the weights of offspring of undernourished mothers born at full term from those born prematurely; in both groups the slopes of the birth weights declined in parallel during the 6-month period of general undernutrition, showing that the lighter weight of the premature was not due to a decrease in gestation length. Further, the slope of the reduction in birth weight was steeper in babies born during the first 3 months of the malnutrition period, indicating that maternal nutrition was most important in the last trimester of pregnancy. The fetal circulation and the changes at birth. The onset of respiration Rarcroft’s work on the fetal circulation and respiration, was undertaken with Barron and many colleagues; it forms two-thirds of the book and is the best known. The results of their experiments provided the first physiological foundation for our understanding of the development of the supply of nutrients to the fetal tissues and how this is changed at birth. Much of the evidence for the pathways of the fetal circulation came from anatomical studies and obsemations following the injection of radiopaque material; but evidence from the
610
Placenta (1 !WZ), V01. 13
oxygen content of blood was the most definitive, showing the differences in the environment of the various fetal tissues and how this was altered at birth. But, to quote, ‘oxygen-is-but one of the proximate principles of nourishment’ (p. 126) and metabolism would have been one of the subjects of volume II -never published. Investigations were made into the way this oxygen was carried by the blood and the characteristics of the fetal haemoglobin: how oxygen was unloaded from the mother to the fetus and the influence of carbon dioxide are described: investigations, too, of the pressures in the vessels supplying the placenta and fetus: of cardiac output, the heart rate, its changes during gestation, development of the innervation and the effect of asphyxia. The influence of uterine contractions on the circulation, changes in the blood volume distribution between the fetus and placenta during gestation and transfer of blood from the placenta to the newborn at delivery, all attracted their attention. The values provided by their observations were all very carefully scrutinized and appraised in relation to the needs and responses of the fetus. Their last researches were concerned with characterizing the development of fetal movement with special reference to that of the chest. The anatomical foundations were established by sectioning the medulla and pons at various stages of development, in the first chronic intrauterine fetal preparations in the lamb. Finally, their thoughts were turned to the mechanism of the first breath. To quote again, ‘so much for the instrument, a few words in conclusion about the hand which strikes it’. (p. 269). ‘Researches on Pre-natal Life’ was published at a time of great expansion in investigative medicine, at the end ofWorld War II. In this atmosphere the fundamental knowledge that the book provided helped to widen interest in the care of the mother, the fetus and the newborn and to stimulate research in paediatrics and obstetrics. It came at a time when open chest surgery had started, providing the possibility for correcting congenital heart defects in newborn infants: at a time, too, when intensive care units were being created with the need for information on the homeostatic responses of the developing circulation and respiratory systems, particularly: at this time, too, treatment of small patients was greatly helped by the improvement of instrumentation which was giving us micromethods for analyses on small samples of body fluids, together with that boon, the fine plastic catheter. Further, the prospect of malnutrition occurring widely in the developing countries, saw the beginning of studies on the influence of maternal malnutrition on fetal weight and welfare in human pregnancy, guided by experimental work in animals. The worldwide establishment of experimental perinatal and developmental physiology departments, together with the large number of societies, books and journals for mutual discourse between laboratory-based investigators and the expanded paediatric and obstetric departments, all bear witness to the great interest engendered by the studies of ‘which this book treats’ and its value to the mother and her child. The book was also a great stimulus to physiologists to improve the experimental procedures for studying the fetus and the placenta. No conclusion of Barcroft’s was ‘ex cathedra’ and his uncertainty over the correct values for the oxygen environment of the fetus,* in particular, was a great stimulus for this improvement. Thus Barron, who had already kept fetal lambs alive ‘in utero’ following CNS section for the respiratory studies, developed with Meschia and Battaglia, the chronic preparation with indwelling catheters in the umbilical vessels of the fetal lamb and, later, in branches of the uterine artery and vein of
* At the bottom of pages 187 and 197, the reader will find pragmatic and amusing accounts of the hazards in obtaining meaningful samples of blood from the umbilical vessels and carotid artery, in Barcroft’s time; they are too long to quote here in full.
kbrtn~: Classics Rtvisitd
611
the mother; it was a happy coincidence that the ewe’s uterus should be so unresponsive to surgery. The paper establishing values for the blood gases in the umbilical vessels of the unanaesthetised fetus in the uterus of a mother standing in her normal posture, days after recovery from the operative procedure, was published in 1965. The low oxygen content and tension which Barcroft had found in the umbilical vein blood was now firmly established and the fetal blood gas environment shown to be constant during the last quarter of gestation; the haemoglobin content of the blood during this period was also constant and showed no evidence of an hy-poxic response of the fetal haemopoeitic system. This chronic preparation is unique in physiology and has had a widespread influence in furthering an understanding of the circulatory, respiratory and metabolic mechanisms in the intact unit of fetus and placenta. The need to understand the separate placental mechanisms in fetal nutrition stimulated, in its turn, the development of perfusion techniques; the smaller animals used were easier to handle, and more appropriate to the human situation by virtue of the structure of their placental membranes. The isolated human placental cotyledon is, now, not only perfused but the whole tissue used extensively for a host of micro-cellular and molecular studies.
EPILOGUE ‘Researches on Pre-natal Life’ will always be beloved by those of us who read the book when it was first published and it continues to delight many more. It was written by a man who would have thoroughly appreciated all the work which the book has inspired; the more rigorous experimental proof of his ideas afforded by modern technology and the use of this technology to study those fragile subjects, the fetus and newborn, with minimal disturbance. Investigators in cellular and molecular biology would have found him very good company. Most of all he would have been proud to know that his work had contributed to the increased care of the mother and child, and the decrease in perinatal mortality, which has taken place during the last half century. Sir Joseph Barcroft’s work was recognized by the Royal Society and by the National Academy of Sciences in the USA and many other institutions; when he was made an honorary FRCOG in 1944, Sir Charles Sherrington wrote in his letter of congratulation, ‘-an outstanding compliment. You have founded a new line of enquiry and they recognize that-’ (see Franklin, 1953). He was still full of interest and fun until within minutes of his sudden death from a heart attack: Roughton (1949) recalls meeting him in the lab on that last morning, ‘Now let’s hear what you’ve been doing with my ewe blood, -‘.
REFERENCES Baird, D. (1945) Influence of social and economic factors on stillbirths and neonatal deaths.Jobunal of Obstetrics and ~ynaecology, 52, 217-234. Barron, D. H., Meschia, G., Cotter, J. R. & Breathnach, C. S. (1965) The haemoglobin, oxygen, carbon dioxide and hydrogen ion concentrations in the umbilical bloods of sheep and goats as sampled via indwelling plastic catheters. @ar&~3oumal ofExperimental Physiology, 50, 185-195. Carlyle, A. (1948) An integration of the total oxygen consumption of the sheep fetus from that of the tissues.3ofounul ofPhysiology, 107,355-364. Franklin, K. J. (1953) Joseph Barcroft, 1872-1947. p. 305. Oxford: Blackwell’s Scientific Publications. Huggett, A. St G. (1927) Fetal blood gas tensions and gas transfusion through the placenta of the goat.3oumal oj Physioloo, 62,363-384. Roughton, F. J. W. (1948) Joseph Barcroft, 1872-1947. R/!~dSocie
