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J Physiol 594.5 (2016) pp 1135–1136

EDITORIAL

The legacy of the Barcroft Symposium 1972 Peter Nathanielsz University of Wyoming, Department of Animal Science, College of Agriculture and Natural Resources, 1000 E. University Avenue, Laramie, WY 82071, USA Email: [email protected]

The Journal of Physiology

‘None knew thee but to love thee, nor named thee but to praise.’ - Donald Barron’s tribute to Sir Joseph Barcroft in Foetal and Neonatal Physiology, Proceedings of the Sir Joseph Barcroft Centenary Symposium. In 1969 The Physiological Society decided to organize a centenary symposium on Fetal and Neonatal Physiology to celebrate Sir Joseph Barcroft’s birth, 26 July 1872. The obvious location was his old laboratory, the Physiological Laboratory, on the Cambridge University Downing Site. The organizing committee decided not to issue speaker invitations. Everyone wishing to speak had to submit an abstract for consideration. Presentations were encouraged across developmental physiology, with the exception of immune system development and maternal–fetal immune interactions, areas still poorly understood. Attendance could only be 250 since the meeting was in the Physiology Department Lecture Theatre, Sir Joseph’s portrait presiding over the entrance. Funding was acquired more swiftly than it is today. We wrote simple request letters to funders. Planning was made possible with the Wellcome Trust’s generous guarantee of half the cost. Advances against registration fees were provided by the National Institutes of Health in the USA, the Royal Society, International Union of Physiological Sciences, Neonatal Society, Blair Bell Society, Glaxo and ICI. An anonymous benefactor, probably Donald Barron, gave repeated donations to support young investigators. In the symposium proceedings, Donald Barron wrote a tribute celebrating Barcroft’s many friendships and enormous contribution to physiology in general and developmental physiology in particular, in the first half of the 20th Century. Barron was Barcroft’s most influential post-doctoral student. When he left Cambridge for

America, Barron took with him Barcroft’s approaches to fetal sheep studies. At Yale he recruited two Italian post-doctoral fellows Giacamo Meschia and Fredrick Battaglia. They developed techniques for implantation and maintenance of sheep umbilical vascular catheters (Meschia et al. 1965). Prior sheep studies were acute experiments limited by anaesthetic confounds. Meschia and Battaglia moved to Denver to establish a major Barcroft legacy, the Denver metabolic studies group. The Symposium was divided into six sessions – Central Nervous System, Circulation and Breathing, Placental Function, Metabolism, Endocrinology, and a Colloquium on Surfactant. Reading these papers after 43 years shows the advances in knowledge of cellular and molecular physiology since the Symposium. The papers in the central nervous system session clearly showed the current emphasis on electrophysiology, limiting studies to live tissues. Today’s standard techniques on fixed and frozen tissues identify and quantify DNA, RNA, protein product and microscopic analysis of organ composition providing powerful tools for investigators. Sir Joseph Barcroft described the fetus as ‘living on Mount Everest’ because of its low vascular P O2 . His main interests, the fetal circulation, breathing and oxygenation were well represented in the Symposium. Papers by Geoffrey Dawes and colleagues from Oxford and Abe Rudolph and colleagues from San Francisco reported studies laying the groundwork for our understanding of fetal behavioural and cardiovascular states. They started the process of unravelling how these critical systems respond to challenges that occur in hypoxia (Cohn et al. 1974; Dawes, 1974). Related studies extending Barcroft’s approaches in sheep and other species continue in the Barcroft Laboratory, Cambridge guided by Professors Giussani and Fowden – a direct and local Barcroft legacy (Gardner et al. 2002). We need to be reminded that sheep studies underpin knowledge of the fetal biophysical profile, important clinically in determining fetal well-being (Dawes et al. 1972). Much work presented was based on integrative techniques such as in vivo blood flow measurements, rarely used today, that are very powerful in determining adaptive

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changes fundamental to understanding developmental programming mechanisms (Giussani, 2016). In vitro approaches to cellular and organ function, common today, were hardly discussed. An exception was the study by Kern Wildenthal on developing hearts in vitro (Wildenthal, 1972), a new departure and forerunner of dispersed cell methods. This was one of the first papers to discuss insulin’s action as a developmental growth factor directly on the developing heart, an observation made possible by isolating the heart. There was much interest in the story of how the fetus initiates parturition through its own adrenal axis in papers by Robert Comline’s group at Cambridge (Nathanielsz et al. 1972), ‘Mont’ Liggins in New Zealand (Liggins & Howie, 1972) and Geoffrey Thorburn in Australia (Bassett & Thorburn, 1969). The related finding by Liggins that fetal glucocorticoids also control fetal lung maturation was the basis of the symposium on surfactant. This observation paved the way for clinical management in pregnant women threatening preterm labour by treating them with synthetic steroids to prevent neonatal respiratory distress (Liggins & Howie, 1972). This treatment has saved the lives of thousands of premature infants over the intervening 40 years. The meeting ended on 27 July 1972 and the Symposium Proceedings went to Cambridge University Press on 11 August following a week of all-day editorial sessions. There were no computers and word processing packages. The book entitled Foetal (spelled thus because of the view, now considered erroneous, that ‘fetal’ has a Greek not Latin origin) and Neonatal Physiology is a historical record of contemporary understanding of pregnancy and developmental physiology. How did the Barcroft Symposium influence research in fetal and neonatal development? First it brought together key leaders from around the world making them available for discussion with those like myself just entering the field. The symposium marked an extremely productive period of whole-animal physiology before the genome revolution gathered force. The various maternal, placental, fetal and neonatal systems were discussed with little reference to gene mechanisms. It was

DOI: 10.1113/JP271878

1136 19 years since Crick and Watson’s Nature paper but incorporation of molecular biology techniques was still unharnessed in this area of physiology. There was no consideration of gene–environment interaction and epigenetics, the basis of developmental programming. Yet, rereading these chapters one is constantly reminded of our goal as physiologists to define phenotype and whole organism function. Understanding of phenotype must be based on gene, protein, and cellular reductionist approaches and synthesis of whole animal systems physiology. Compensation and adaptive mechanisms demonstrate that the whole is more than the sum of the parts. The integrative studies in this unique volume can bring us back to the fundamental truth that understanding phenotype is necessary to improve health. If Sir Joseph Barcroft were with us today he would be proud of his legacy of research and the excitement shown by investigators world-wide at all stages of their careers. The Symposium helped build the platform from which the current emphasis on the fundamental importance of fetal and neonatal life for the quality of

Editorial lifecourse health from womb to tomb. A suitable metaphor might be that the studies presented showed that if we do not construct the automobile that will carry us through life to as near as possible its original blueprint, it will not run as well, as far, or for as long as it is capable. Sir Joseph was one of the original proponents of the importance of understanding developmentof the mammalian organism, including our own human physiology. References Bassett JM & Thorburn GD (1969). Foetal plasma corticosteroids and the initiation of parturition in sheep. J Endocrinol 44, 285–286. Cohn HE, Sacks EJ, Heymann MA & Rudolph AM (1974). Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol 120, 817–824. Dawes GS (1974). Breathing before birth in animals and man. An essay in developmental medicine. N Engl J Med 290, 557–559. Dawes GS, Fox HE, Leduc BM, Liggins GC & Richards RT (1972). Respiratory movements and rapid eye movement sleep in the foetal lamb. J Physiol 220, 119–143.

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Gardner DS, Fowden AL & Giussani DA (2002). Adverse intrauterine conditions diminish the fetal defense against acute hypoxia by increasing nitric oxide activity. Circulation 106, 2278–2283. Giussani DA (2016). The fetal brain sparing response to hypoxia: physiological mechanisms. J Physiol 594, 1215–1230. Liggins GC & Howie RN (1972). A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50, 515–525. Meschia G, Cotter JR, Breathnach CS & Barron DH (1965). The diffusibility of oxygen across the sheep placenta. Q J Exp Physiol Cogn Med Sci 50, 466–480. Nathanielsz PW, Comline RS, Silver M & Paisey RB (1972). Cortisol metabolism in the fetal and neonatal sheep. J Reprod Fertil Suppl 16(Suppl 16), 39–59. Wildenthal K (1972). Studies of isolated fetal mouse hearts in organ culture. Evidence for a direct effect of triiodothyronine in enhancing cardiac responsiveness to norepinephrine. J Clin Invest 51, 2702–2709. Additional information Competing interests

No competing interests declared.

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The legacy of the Barcroft Symposium 1972.

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