ISSN 2397-9917 Issue 3 Winter 2016-2017 Exploring Human Heredity The Galton Review www.galtoninstitute.org.uk CONTENTS Editorial 3 Galton Institute Conference 2016 Environmental factors in gene regulation 4 The Artemis Trust 10 The Alzheimer’s Association International Conference 2016 11 Gordon Research Conference 2016 13 16th World Congress on Pain 16 The African Society for Human Genetics Conference 2016 17 Galton Institute Postdoctoral travel grant 19 Galton Institute conferences 2017 20 Front Cover Image: Depositphotos.com Published by: The Galton Institute, 19 Northfields Prospect, London, SW18 1PE Tel: 020 8874 7257 www.galtoninstitute.org.uk General Secretary: Mrs Betty Nixon [email protected] Review Editor: Mr Robert Johnston 2 EDITORIAL The highlight of the Institute’s year is always the Annual Conference and this year’s event proved to be extremely popular with over 250 delegates in attend- ance. A full report of the proceedings can be found on page 4. The Galton Lecture is, in turn, the highlight of the Conference and the 2016 edi- tion was especially noteworthy as it was the 100th in the series. It was first given in 1914, and there has since been an almost unbroken run, with only three omis- sions in all that time. The list of speakers reads like a veritable ‘who’s who’ of eminent social and biological scientists who have been associated with the Gal- ton Institute. Many were experts of world renown, including three Nobel laure- ates, and all considered themes which were of great significance at the time. In 1943 Sir William Beveridge delivered his Galton Lecture on the very day the ‘Beveridge Report’ was being debated in the House of Commons. There was William Bateson, the man who coined the word ‘genetics’, who spoke in 1921. Julian Huxley had two Galton lectures to his name; 1936 and 1962. John Maynard Keynes, the most influential economist of the 20th century gave per- haps the most famous Galton Lecture of all in 1937, the year after his magnum opus, The General Theory of Employment, Interest and Money, was published. His lecture was entitled ‘Some economic consequences of a declining popula- tion’. To this esteemed list can be added this year’s lecture on ‘Nutrition and Lifespan’ by the premier expert on biogerontology, Dame Linda Partridge. A video of her inspirational lecture can be viewed on our website. Finally, I should also like to draw your attention to the latest Genetics in Medi- cine booklet on precision medicine produced by our ‘Manchester Team’ of Helen Middleton-Price, Andrew Read and Dian Donnai. It can be seen on our website or is available as a hard copy from Betty Nixon. Robert Johnston 3 The Galton Institute Annual Conference Environmental Factors in Gene Regulation 16 November 2016 at the Royal Society This year’s conference attracted over 250 delegates to listen to experts in the field of ‘gene regulation’. The full programme is available on our website. It was organised by the President, Professor Veronica van Heyningen, FRS and Dr Branwen Hennig. The President started proceedings with a brief account of the aims and activities of the Galton Institute. She described the various activities we undertake including publications, conferences, prizes and grants. (For details please see www.galtoninstitute.org). Dr Hennig chaired the first session in which Professor Sir Peter Ratcliffe from the University of Oxford and the Francis Crick Institute in London discussed ‘Oxygen sensing and hypoxia signalling’. He is particularly interested in the role of oxygen in tumour growth. The transcription factor Hypoxia-inducible factor (HIF) plays an important role in cellular response to systemic oxygen levels in mammals and many pro- cesses are associated with regulation of HIF. HIF is overexpressed in many human cancers and this overexpression is heavily implicated in promot- ing tumour growth and metastasis through its role in initiating angiogenesis and regulating cellular me- tabolism to overcome hypoxia. Professor Ratcliffe questioned whether HIF activation causes cancer and he described various experiments to test this. HIF rarely mutates but it seems that genetic pre- Professor Sir Peter Ratcliffe, FRS disposition may shift the HIF pathway to become ‘more oncogenic’. The HIF pathway is under strong selection once activated by the VHL switch. He finished by suggesting that cancer cells should be easier to kill as they’re ‘living on the edge’ but there may be many other pathways affected. These discoveries pave the way for translational research and development of targeted therapies. 4 The second session was chaired by Professor David Burt and the first speaker was Professor Akhilesh Reddy from the University of Cambridge and the Fran- cis Crick Institute in London. He spoke on ‘Regulation of circadian clocks by redox homeostasis’. Circadian rhythms are not driv- en by the environment but are endogenous, be- ing re-set by the environment when appropriate. They allow organisms to anticipate regular changes in light, temperature etc. He noted that the mechanisms involved vary dramatically be- tween plants and animals suggesting that they evolved independently but he wondered whether this is true. It is now known that these ‘internal clocks’ are in every Professor Akhilesh Reddy cell and are not simply located in places such as the suprachiasmatic nucleus in the hypothalamus of the brain in humans. Indeed isolated cells of many types in the laboratory can be shown to ‘keep time’. These clocks have a profound effect on many aspects of metabolism in all animals. The classic explanation is the negative feedback oscillator system but Professor Reddy questioned whether this actually drives the rhythm. He showed that in fact redox circadian oscilla- tions are pervasive across life, from bacteria to humans, and described how peroxiredoxin proteins are the drivers of such rhythms. This may have important implications for human health as it has been shown that people subjected to fre- quent jet-lag or disrupted shift patterns are at a greater risk of developing some cancers. The second talk of this session was on ‘Circadian regulation of innate immun- ity and inflammation’ by Dr Julie Gibbs from the University of Manchester. She described how all immune cells have intrinsic clocks including ‘resident’ im- mune cells. Healthy clocks are needed for healthy immunity. She described vari- ous experiments using LPS as a test substance and found that microphage re- sponse is gated by internal cellular clocks. She found that club cells in lungs show rhythm of cytokine production at different times of the day and that they are affected by glucocorticoid signalling but only when the clock is functioning. She went on to consider whether such clocks affect long-term inflammation in 5 conditions such as rheumatoid arthritis. Studying similar conditions in mice, it has been found that symptoms are worse during daylight hours even when the mice are subjected to constant light, ie a circadian rhythm is acting. She also observed an increase in the number of circulating T-cells, microphag- es, neutrophils and fibroblast-like synoviocytes during daylight hours, which may explain how symptoms may fluctuate during the day. Adaptive immunity is a growing field and it has been found that it is subject to circadian rhythms with levels of B and T cells fluctuating. This work should eventually lead to a search for more effec- tive therapeutic targets and a better understanding Dr Julie Gibbs of how time of day may influence the effectiveness of vaccine and drug delivery. The session after lunch was chaired by Professor Dian Donnai. Dr Amanda Drake from the University of Edinburgh spoke first on ‘Early environmental reg- ulation of glucocorticoid receptor gene expression’. Her talk focussed on how pre- and post-natal environments influence disease risk in later life. It has been known for some time that a high birth weight leads to an increased risk of hyper- tension, type 2 diabetes, hypothalamic–pituitary–adrenal axis activation and neu- rodevelopmental disorders. Genes, maternal size, maternal nutrition and gluco- corticoids given antenatally all influence this. More recent work with rats has shown that a rise in corti- sone results in reduced birth weight probably by causing epigenetic dysregulation by increased methylation of DNA or histone modification. Dr Drake went on to consider how such knowledge can help us to address the major problem of ‘pre- term babies’ which also leads to health issues in later life including hypertension, glucose intolerance Dr Amanda Drake and various neurodevelopmental conditions. She 6 concluded with the concern that there may be intergenerational effects with such epigenetic conditions passed on to children and grandchildren. The second talk of the session was by Professor Michèle Ramsay from the Uni- versity of Witwatersrand in Johannesburg and concerned how ‘Foetal exposure leads to altered gene expression’. She began with the prediction that over the next 30 years, there is expected to be a huge rise in the number of women of childbearing age across Africa. The major medical concerns for many women in South Africa are exposure to alcohol and maternal obesity. Foetal alcohol syn- drome has become worryingly common in South Africa and can lead to changes in foetal facial morphology, reduced birth weight and neurological disorders. It is a complex trait which is af- fected by a number of environmental factors but is also influenced by genetic predisposition. Work in mice has revealed that epigenetic mechanisms are involved but also that effects may be due to damage of placental DNA rather than DNA in the embryo itself. Maternal obesity is becoming increasingly widespread in South Africa and has in turn caused a steep in- Professor Michèle Ramsay crease in gestational diabetes. The increase in mater- nal blood glucose causes epigenetic changes, largely de-methylation, in a signifi- cant number of genes in both mother and infant and these may turn out to be criti- cal to the future of the child.