Plenary Lectures Plenary Lectures
Plenary Lectures Sun YH, Chen SP, Wang YP, Hu W & Zhu ZY. (2005). Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish (Carassius auratus) Enucle-
PL-01 What can physiology learn from systems biology and evolutionary biology?
ated Eggs Biology of Reproduction 72, 510-515.
*D. Noble Department of Physiology, Anatomy and Genetics, Oxford, UK
PL-02 Calcium phosphate metabolism – Walking the tightrope
For much of the twentieth century physiology was sidelined from the centre stage of biology because, according to the Modern Synthesis, functional characteristics of the phenotype were not thought to be a source of genetic variation on which natural selection could act. Variations were assumed to be entirely random with respect to function and an organism could, in principle, be defined entirely in terms of its genome. That viewpoint was popularised by The Selfish Gene, and it reached its culmination in the idea that the genome is ‘the book of life’. We now know that (1) genome change is not functionally random; (2) mobile genetic elements include DNA transfer between totally unrelated species, for example between bacteria and insects; (3) organisms are strongly buffered against many genomic changes; (4) cross-species clones reveal cytoplasmic effects; (5) acquired characteristics can be robustly inherited. All the major assumptions of the Modern Synthesis have now been shown to be broken and the ‘selfish gene’ idea is not even falsifiable in physiology. Physiology therefore moves back onto centre stage as a systems biology approach to evolution is required.
Acuña R, Padilla B, Flórez-Ramosa CP, Rubio JD, Herrera JC, Benavides P, Lee S-J, Yeats TH, Egan AN, Doyle JJ & Rose JKC. (2012). Adaptive horizontal transfer of a bacterial gene to an invasive insect pest of coffee Proceedings of the National Academy of Sciences 109, 4197-4202. Dawkins R. (1976, 2006). The Selfish Gene. OUP, Oxford. Gissis SB & Jablonka E, ed. (2011). Transformations of Lamarckism. From Subtle Fluids to Molecular Biology. MIT Press, Cambridge, Mass. Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, Lee W, Proctor M, St Onge RP, Tyers M, Koller D, Altman RB, Davis RW, Nislow C & Giaever G. (2008). The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science 320, 362-365. Huxley JS. (1942). Evolution: the modern synthesis. Allen & Unwin, London. Nelson VR, Heaney JD, Tesar PJ, Davidson NO & Nadeau JH. (2012). Transgenerational epigenetic effects of Apobec1 deficiency on testicular germ cell tumor susceptibility and embryonic viability. Proceedings of the National Academy of Sciences 109, E2766–E2773. Noble D. (2006). The Music of Life OUP, Oxford. Noble D. (2011). Neo-Darwinism, the Modern Synthesis, and Selfish Genes: are they of use in physiology? Journal of Physiology 589, 10071015. Noble D. (2013). Physiology is rocking the foundations of evolutionary biology Experimental Physiology 98, 1235-1243. Shapiro JA. (2011). Evolution: a view from the 21st century. Pearson Education Inc, Upper Saddle River, NJ.
Department of Physiology, University of Tübingen, Germany
Phosphate and calcium crystalize at concentrations exceeding solubility and are thus crucial bone components. Both serve a wide variety of additional fundamental cellular functions. Regulation of calcium phosphate metabolism must accomplish constancy of plasma calcium and phosphate concentrations, adequate mineralisation of bone and by the same token avoidance of calcium phosphate precipitations in other tissues. The attempt to exclusively precipitate calcium phosphate in bone means walking the tightrope and fighting an eventually loosing battle. Calcium phosphate precipitation is inhibited by pyrophosphate and by binding of calcium to plasma proteins such as fetuin-A. The enzyme alkaline phosphatase degrades pyrophosphate and thus stimulates calcium phosphate precipitations. Increases of phosphate concentrations stimulate osteogenic signaling eventually leading to enhanced alkaline phosphatase activity. Acutely, constancy of plasma calcium concentration has highest priority in the regulation of calcium phosphate metabolism, as multiple calcium dependent physiological functions critically depend on extracellular calcium concentration. Regulation of extracellular calcium concentration is the prime function of parathyroid hormone (PTH). Release of PTH is stimulated by hypocalcemia. PTH rapidly restores plasma calcium concentration by mobilisation of bone minerals, such as calcium phosphate and calcium carbonate, stimulation of renal calcium reabsorption and inhibition of renal phosphate and bicarbonate reabsorption. Renal loss of phosphate and carbonate prevents precipitation of calcium phosphate or calcium carbonate following increases of calcium concentration. PTH accomplishes normalisation of plasma calcium concentration at the expense of bone minerals. In order to prevent demineralisation of bone, PTH stimulates the renal formation of 1,25(OH)2D3, the active form of vitamin D. Vitamin D (cholecalciferol) comes from dietary intake or from UV-radiation dependent formation from 7-dehydrocholesterin. Vitamin D is converted to 25(OH)D3 in liver and to 1,25(OH)2D3 in various organs including the kidney. 1,25(OH)2D3 stimulates the intestinal absorption and renal reabsorption of calcium and phosphate and thus sets the stage for remineralisation of bone. 1,25(OH)2D3 further modifies calcium transport in a wide variety of nonepithelial cell types and influences multiple functions including metabolism, platelet activation, mast cell activity, immune response and mood. If osteoblasts are sufficiently provided with phosphate, they produce „fibroblast growth factor“ FGF23, which inhibits renal formation of 1,25(OH)2D3, an effect requiring the renal protein klotho. Thus, intestinal uptake of calcium phos-
phate is adjusted to the requirement of bone. Hypercalcemia stimulates the release of calcitonin from thyroid glands, which inhibits renal phosphate resorption, stimulates bone mineralisation and fosters renal formation of 1,25(OH)2D3. Unlike PTH, 1,25(OH)2D3, FGF23 and klotho, calcitonin is a dispensible hormone and does not require replenishment e.g. after thyroidectomy. Formation of 1,25(OH)2D3 is further stimulated by growth hormone, which fosters bone formation. Adequate bone mineralisation further requires estrogens (e.g. estradiol), which inhibit apoptosis of bone forming osteoblasts and stimulate apoptosis of bone reabsorbing osteoclasts. Several clinical disorders affect mineral metabolism. For instance, enhanced PTH release (hyperparathyroidism) lead to hypercalcemia, hypercalciuria and kidney stones, hypoparathyroidism to hypocalcemia and tetany. Consequences of 1,25(OH)2D3 deficiency include rickets & osteomalacia, cardiovascular disease, allergy, depression and cognition impairment. Deficiency of FGF23 and klotho is followed by excessive 1,25(OH)2D3 formation with multiple age related disorders including osteopenia & decrease of bone density, severe vascular calcification, cardiac hypertrophy, emphysema, hypogonadism & infertility, thymus, fat & skeletal muscle atrophy, hearing loss and cognition impairment. The most common severe disorder of calcium phosphate metabolism is renal insufficiency with impaired renal phosphate elimination leading to hyperphosphatemia, severe tissue calcification and rapid ageing. In conclusion, mineral metabolism impacts on a wide variety of physiological functions beyond kidney and bone.
and adult animals showed that GRN led to an improved long-term outcome and to an increased seizure threshold in the pentylenetetrazol-injection assay. Conclusions: (i) the post-asphyxia seizures are attributable to enhanced extrusion of acid by BBB-located Na/H exchange, which leads to a brain-confined alkalosis and enhanced neuronal excitability; (ii) fast resuscitation of asphyxic newborns in the clinic may trigger seizures; (iii) GRN is likely to be an effective therapy for the prevention of birth-asphyxia seizures; and (iv) pharmacological inhibition of the BBB-located Na/H exchange may also turn out as an effective therapeutic strategy.
PL-03 Why is it risky to be born? Mechanism of birth asphyxia seizures *K. Kaila University of Helsinki, Department of Biosciences, Helsinki, Finland
The mechanisms underlying birth-asphyxia seizures are not known, and current therapies are largely inefficient. We have used a rodent model that mimics the pathophysiological alterations in systemic CO2 and O2 levels. 6-day old rats were exposed for 1 hour to combined ambient hypercapnia (20% CO2) and hypoxia (9% or 4% O2). Recovery from experimental asphyxia was immediately followed by a large seizure burden, which was tightly paralleled by a rise in both extracellular and intracellular brain pH as measured using pH microelectrodes and two-photon imaging of BCECF fluorescence. Strikingly, graded restoration of normocapnia (GRN; reducing the post-asphyxia CO2 level gradually from 20% to 10, 5 and 0%) resulted in a marked suppression of the brain alkalosis and seizures. Simultaneous electrode recordings of pH in the brain and trunk demonstrated a net efflux of acid equivalents across the BBB, which was abolished by the Na/H exchange inhibitor, amiloride. Notably, amiloride also suppressed the seizures. Neuronal damage caused by asphyxia was reduced by the GRN treatment. Behavioural tests in juvenile