PHYSIOLOGY NEWS

winter 2010 | number 81

Snapshots from A. V. Hill’s photo album Cystic fibrosis – a micromolecular sticky problem Inspiring women – The Society mentoring scheme Parkour – not just a 007 stunt Keep students learning in and out of the lab

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UK physiology ad - general.indd 1 29/10/10 1:25 PM PHYSIOLOGY NEWS Editorial Austin Elliott 3 The Society’s dog. ‘Rudolf Magnus Meetings gave me to Charles Sherrington, who Cellular and Integrative Neuroscience Themed Meeting gave me to Henry Dale, who gave Jon Robbins, Pat Doherty, Jeremy Ward 4 me to The Physiological Society in Cardiac & Respiratory Physiology Themed Meeting October 1942’ Fahima Syeda, Melissa Brereton 5 Festschrift in honour of Bernd Nilius Thomas Voets 7 Published quarterly by The Physiological Society The biomedical basis of elite performance Paul Greenhaff 8 Contributions and queries Gordon Research Conferences Angus Brown 10 Senior Production Editor 2010 Nobel Prize Jill Berriman Awarded to Professor Robert Edwards 12 Editorial Administrator Interview Maev Fitzpatrick What makes ion channels exciting – a penetrating interview The Physiological Society Publications Office with Bertil Hille Angus Brown 13 PO Box 502, Cambridge CB1 0AL, UK History Tel: +44 (0)1223 400180 Fax: +44 (0)1223 246858 A. V. Hill’s photograph album William Van der Kloot 17 Email: [email protected] Opinion Website: www.physoc.org ‘...and nothing but the truth’. Simon Singh discusses the Magazine Editorial Board peculiar nature of British libel law Simon Singh 22 Book review 23 Editor Austin Elliott Women in Science University of Manchester, Manchester, UK Inspiring women – The Society mentoring scheme Deputy Editor Valerie Gladwell, Louise Robson 24 Patricia de Winter Science News and Views University College London, London, UK Exercise can help rewire the brain: neuroplasticity and motor Members cortex function in physically active individuals Angus Brown John Semmler, John Cirillo 26 University of Nottingham, Nottingham, UK The physiology of Casino Royale: proteins to parkour Sarah Hall Martin McDonagh 29 Cardiff University, Cardiff, UK Vagal baroreflexes in astronauts during spaceflight Munir Hussain Dwain Eckberg 32 University of Bradford, Bradford, UK Phantom hands: a window into how we perceive limb position John Lee and movement Lee Walsh, Simon Gandevia, Janet Taylor 34 Rotherham General Hospital, Rotherham, UK Cystic fibrosis: a lesson in chemistry Thelma Lovick Ruth Muchekehu, Paul Quinton 37 University of Birmingham, Birmingham, UK Sympathetic nervous system and volume regulatory hormones: Samantha Passey interactions during dehydration JA Rabbitts, N Charkoudian 39 Bristol Heart Institute, Bristol, UK Heart rate regulation during exercise James Fisher, Niels Secher, Foreign Correspondents Paul Fadel 41 John Hanrahan The KATP channel is a molecular sensor of atrophy in skeletal McGill University, Montreal, Canada muscle Domenico Tricarico 44 John Morley Noticeboard 43 University of Western Sydney, NSW, Australia Techniques © 2010 The Physiological Society The ‘why’s’ of Western blotting. Part I Patricia Leoni 46 ISSN 1476-7996 (Print) Reports ISSN 2041-6512 (Online) Struggling for breath: latest advances in medical research for asthma patients and their families Steven Forrest 49 The Physiological Society is registered in England as a company limited by guarantee: No 323575. Cystic fibrosis event in Glasgow 50 Registered office: Peer House, Verulam Street, London Science is Vital Rally Liz Bell 50 WC1X 8LZ. From the archives Austin Elliott 51 Registered Charity: No 211585. Unbelievable! 52 Printed by The Lavenham Press Ltd Society Mobile Teaching Unit sponsorship 53 Outreach activity at The Physiological Society Jonathon Holland, Caroline Sunderland, Michelle Sleeth, Andrew Murton 54 Young Physiologists’ Symposium – Neuromodulation Catherine Dunford 57 New Chief Executive Philip Wright 58 Ask a physiologist! 59 The Society’s journals The Journal of Physiology - New Editors 61 Cover image: Mucus retention in uterine Advancing the science of life – glands +/– HCO3 , p.37. PHYSIOLOGY NEWS Action points Guidelines for contributors In this issue Grants These guidelines are intended to assist Welcome to the final Physiology News The Society offers funding authors in writing their contributions of 2010. and to reduce the subsequent editing through the following grant process. The Editorial Board of Summer conference season seems schemes: Travel Grants, Non- Physiology News tries to ensure that all to get ever longer, and now lasts Society Symposia Grants, articles are written in a journalistic style well into September. We have Outreach Grants, International so that they will have an immediate another crop of conference reports Teaching and Research Grants interest value for a wide readership and this time (pp. 4–12), including one and the Vacation Studentship and will be readable and comprehensible to on the Festschrift for former J Physiol non-experts. Scientific articles should Reviewing Editor Bernd Nilius. Departmental Seminar Schemes. give a good overview of a field rather For full information, please visit: than focus entirely on the authors’ own History – of which conferences form www.physoc.org/grants research. a part, certainly in science – can Format of articles sometimes be brought alive by Membership applications The main message or question posed a photographic image. On p. 17 Applications for membership should be introduced in the first Bill Van der Kloot takes us for a to The Physiological Society are paragraph. The background for the fascinating rummage through A.V. considered on a rolling basis, topic should then be established, Hill’s photo album. We also have an and a decision is normally made leading up to the final conclusion. in-depth interview with ion channel pioneer Bertil Hille (p. 13), including within 15 working days. For full Length of articles some reminiscences of the greats of information, please visit: This will be determined by the subject early post-war electrophysiology. www.physoc.org/membership matter and agreed with the Senior Production Editor. Given what some people see as the Is your membership information Submission of articles ever-growing dominance in science correct? Authors should submit articles as a of molecular biology, it is pleasing Word document attached to an email. to see that several of the scientific Please check and update your features in this issue have a human details at www.physoc.org, under Illustrations should be sent as separate attachments (see below) and not physiology theme. There cannot ‘My Physoc Profile’. embedded in the text. be many physiology magazines that can boast the science of James Illustrations and authors’ photographs Bond (p. 29), spaceflight (p. 32) and Authors are encouraged to submit phantom limbs (p. 34) in the same Physiology News diagrams, drawings, photographs or issue! We also continue our popular Deadlines other artwork with their articles and a Methods series with an article I am photograph of the author(s) should tempted to sub-title ‘Everything Letters and articles and all other accompany submissions. Illustrations you always wanted to know about contributions for inclusion in the and photographs may be colour or black Western blotting (Part 1)’ (p. 46). Spring 2011 issue, No. 82, and white, and preferably TIFF, JPEG, PNG, PDF or AI files with a minimum In the present economic climate, should reach the Publications resolution of 300 dpi. Office ([email protected]) engagement by scientists with the References wider world is assuming ever greater by 13 January 2011. Short news Authors are requested to keep the importance. We have an extended items and letters are encouraged, number of references to a minimum – section this issue detailing some of and can usually be included as late preferably no more than two or three. the outreach work carried out by copy if space permits. Please cite all references in the style of Society members (pp. 53–57). And The Journal of Physiology (see engagement goes beyond simply Suggestions for articles Information and Guidance for Authors at talking about science – see the Suggestions for future articles are http://jp.physoc.org). Science is Vital rally report on p 50, welcome. Please contact either or Simon Singh’s discussion of the the Editorial Administrator or a The Physiological Society permits the scientific debate-chilling effect of single copying of individual articles for England’s libel laws on p. 22. member of the Editorial Board private study or research. For permission of Physiology News (see contents to copy or reproduce for any other Last but not least, it is a special page for details). purpose contact [email protected]. pleasure to applaud the award of the 2010 Nobel Prize for Physiology or Opinions expressed in articles and letters Medicine to Professor Bob Edwards, Physiology News online submitted by, or commissioned from, long-time member of the Cambridge Physiology News online: Members, Affiliates or outside bodies are not necessarily those of The Physiological Physiological Laboratory. His www.physoc.org Society. pioneering of IVF exemplifies how basic science can change the world – politicians please note (p. 12). Austin Elliott Editor EDITORIAL PN 3

Smoke signals... or just abolition of the Regional Development It was also less than the 0.63 per cent Agencies. recorded for the UK in 1995.” smoke? These remain uncertain times for UK The detailed share-out of funds between This is not a cheering picture and raises physiologists. The results of the UK the different research councils also two issues. The first is whether there Government’s Comprehensive Spending remains unknown. Overall though, will be a ‘brain drain’ of scientists out Review (CSR) were announced last it seems absolutely inescapable that of the UK to other countries where month. So now that the dust has settled grant funding rates, already well the funding situation is less grim – for – if it has – is the picture any clearer? below 20%, will fall further, with even instance, Germany is actually set to more high-alpha rated grants going increase science funding. The second I should note first that, between the unfunded. Many commentators predict issue is whether there is any prospect summer and the CSR, we saw perhaps the research councils will respond for increasing funding in the UK if the the most concerted campaign of recent by focussing more overtly than ever economy picks up. Many science policy times by the UK science community on ‘priority areas’, or by setting commentators have noted rather to seek to mitigate the likely scale of up mechanisms to prevent serially pointedly that the Treasury, the most the cuts. The learned societies, UK unsuccessful applicants from applying powerful UK Ministry and ‘gatekeeper’ industry, university heads, leading for funding for some subsequent period to funding, is the only ministry not to scientists, political figures and science of time. have a Chief Scientific Adviser. Some journalists all lobbied hard to get across see this as symptomatic of a failure by to the Government that science is a key The other looming iceberg for university the Treasury to appreciate the key role engine of progress and prosperity. A science in the UK is the major changes science plays in the economy. Ward special mention has to go the Science set to be imposed on the funding for notes: is Vital campaign, masterminded by a university teaching. Large cuts to the “[UK Science minister David] Willetts small group of working scientists [1]. university teaching budget are to be will need a lot of help over the next They managed in only a few weeks to coupled with legislation to raise the four years to convince the treasury that conjure up both a petition with over cap on tuition fees to £6–9K pa, in more should be invested in science and 35,000 signatures, and a rally of 2000 line with the recommendations of research. The research community must people in London outside the Treasury the recent Browne Review on funding assist him by demonstrating clearly tuition. Though some direct funding for which gained considerable media that such an investment will improve undergraduate teaching in ‘strategically coverage (see p. 50). There seems our international competitiveness, important’ subjects like science will little doubt that this campaign, and and increase the nation’s long-term remain, student fees will become the the other representations made to the prosperity and well-being.” Government, allowed Science Minister major source of teaching income. David Willetts to argue for science to be So how can scientists help with this? The at least partially spared. Although the research and teaching success of the Science is Vital campaign funding streams are notionally separate, suggests that science does have political However, despite that, the result is still the separation is artificial, given that pull, if it can organize itself to use it. So cuts. They are far less bad than had been most university academic staff do maybe it is incumbent on us to keep feared, but the ‘cash freeze’ on the UK both. Falls in academic staff numbers showing the politicians all the ways in science budget announced in the CSR are widely predicted as universities which science is important. amounts to a progressive annual cut of struggle to make savings. Staff will thus somewhere around 2–3%, year on year, be under pressure to deliver ‘more for This is not, note, a call to write more over the next four years. This is better less’ in teaching, just as in research. And hyperbolic and inaccurate press releases than the 15–20% cuts (over four years) meanwhile, the universities in which about the future implications of that had been widely trailed, but it still scientists work will be undergoing research, still less overblown ‘projected means less grants funded, less postdocs changes on a scale not seen in many impact statements’ of the kind that and less PhD students. decades. None of this is comforting annoy people on grant application news. forms. It is, though, a call to all It is also necessary to say that we still academics to think about how research do not know many of the details. Evan How does what the UK is doing compare – their own and others’ – in the field Harris, the former MP and science with its competitors? Here again, things they work in has impacted on the world. advocate, published a useful checklist are less than rosy. UK R&D (research and Concrete examples play far better with on his Guardian blog as ‘Don’t Be Spun development) spending before the cuts politicians than sweeping statements on Science Funding’[2]. So far it seems was already less than in many developed – and these concrete examples are the clear there will be large cuts to capital countries. As science policy specialist tools that science ministers need to spending, so most infrastructure Bob Ward explains on the New Scientist’s convince the Treasury. projects – e.g. new university ‘S Word’ blog [3]: laboratories – will be on hold for several I imagine quite a few UK-based readers years. The new UK Medical Research “According to the OECD’s [Organisation wrote to their MPs about Science is Vital. Centre at St Pancras will go ahead, of Economic Cooperation and That was a good thing. Perhaps now is but other national-level projects are Development’s] latest figures, the time to write them the next letter. likely to be cut. Research spending by government-financed gross domestic other ministries is also likely to be cut, expenditure on R&D by the UK was 0.54 Austin Elliott though this is perhaps less worrying to per cent of Gross Domestic Product 1http://scienceisvital.org.uk/ biological science than to engineering in 2008. This was less than the OECD 2http://www.guardian.co.uk/science/political- and technology. English universities average of 0.64 per cent, and markedly science/2010/oct/20/1 outside the South East are also likely lower than the corresponding figures for 3http://www.newscientist.com/blogs/ to take a science funding hit from the Canada, France, Germany and the US. thesword/2010/10/

Physiology News | No. 81 | Winter 2010 | www.physoc.org 4 PN MEETINGS

Cellular and Integrative Neuroscience Themed Meeting, London, 6–8 April 2011 From neurones to networks: birth, death, disease and repair of the nervous system Where will you be able to watch the construction of the tallest building in the European Union? Have a pint in London’s only surviving galleried coaching inn? Grab your lunch in the best food market in London? Get locked up in jail as well as participate is a world-class neuroscience meeting? The Guy’s Campus, King’s College London, that’s where.

Neuroscience is a broad subject that requires a significant depth of understanding and added to this, it is at present a very fast moving field. The symposium will provide three days of symposia covering some major areas of neuroscience in depth. These will be accompanied by oral communications and poster sessions. The evening before the meeting starts there will be the Hodgkin–Huxley–Katz Prize Lecture given by Roger Nicoll to appropriately kick things off. The lively poster sessions on days 1 London. The location is served by first day of the meeting will cover and 2. So, as you can see, there one mainline rail station (London ‘Development of the nervous Bridge) three tube stations (London system’ in a symposium organised is something for everyone and a Bridge, Borough and Monument) by Andrew Lumsden; following lot for many. Topics that will be and 24 bus routes. If you register on this ‘Circuits to synapses’ which covered include neurogenesis, line you can use a Boris Bike (first will be overseen by Ian Thompson neuronal stem cells, signalling 30 minutes is free!). The new South and Juan Burrone. On day two pathways, depression, schizophrenia, Bank has a plethora of restaurants, we move on to ‘Degeneration of neurodegerative disease and pubs, hotels, art and entertainment, the nervous system’ organised psychiatric disorders, to name a few. so the evenings will be as busy as the by Jean Marc Gallo and sensibly The special interest groups that are days. following this Pat Doherty has a particularly relevant to this meeting are Blood–Brain Barrier, Cellular session on ‘Regeneration of the So clear your diary, submit your Neurophysiology, Cellular Signalling, nervous system’. Day three and abstract(s), book your train tickets Development and Plasticity, Ion Jack Prince with Carmine Pariante and get you accommodation Channels, Neuroendocriology, are running ‘Cellular modelling of arranged so that you can see all Sensorimotor Control, Sensory neural development and disease’ 310 metres (over 1000 feet in Functions and Somatosensory which is followed by ‘Transcriptional imperial units) of the Shard being Physiology. However, we think and epigenetic regulation in built, have a pint (or two) in the neurological, neurodegenerative and all physiologists will find much George Inn, grab a snack in Borough psychiatric disorders’ organised by of interest – after all the nervous Market, escape from the Clink Noel Buckley and Jonathan Mill. system controls all that we do. and get an update on the state of Neuroscience in 2011. Key note presentations will The venue is the Guy’s Hospital be interspersed with oral Campus, now located in the ‘London Jon Robbins, Pat Doherty and communications and we predict Bridge Quarter’, King’s College Jeremy Ward

Physiology News | No. 81 | Winter 2010 | www.physoc.org MEETINGS PN 5

Cardiac & Respiratory Physiology Themed Meeting, Birmingham 1–3 September 2010

A 3-day Themed Meeting on Cardiac and Uzo Sampson (Manchester) & Respiratory Physiology was showed that although the causes held in Birmingham in September of HPV and FGR may be similar, the 2010, with a focused symposium mechanisms, especially with regards on hypoxaemia – ‘Coping with to KV channels, are not. hypoxaemia: strategies and The comparative physiology session solutions’. The meeting was divided on the second day began with into five sessions (O sensing 2 a fascinating talk by Bill Milsom mechanisms, blood flow regulation, (British Columbia) on adaptations lessons from comparative studies, Lord Mayor of Birmingham, Len Gregory to hypoxia in a bird that migrates at intermittent hypoxia and chronic (left) and Stuart Egginton, scientific high altitude, the bar-headed goose. hypoxia) that gave an insight into organiser of the meeting. These adaptations include their more research on the strategies for coping effective ventilation which involves with hypoxia in a wide range of slow and deep breathing, producing animals, through the mechanisms less dead space in the lungs. In of hypoxia sensing, to hypoxaemia- these geese, oxygen availability associated diseases. Some personal and utility is enhanced by their highlights are given here. high-affinity haemoglobin, greater The first day focused on cellular muscle capillarity and increased responses associated with exposure mitochondria compared with other to hypoxia, predominantly hypoxic species. Tobias Wang (Aarhus) pulmonary vasoconstriction (HPV) followed with his talk on how and oxygen sensing by the carotid Left, Luc Teppema, Leiden University reptiles cope with hypoxia by mixing Medical Center, The Netherlands and body. The different hypotheses for oxygenated and deoxygenated blood oxygen sensing were presented: (right) George Balanos, University of Birmingham, UK, scientific organiser. in two-chamber hearts, a real feat of whether the primary mechanism of flow control by variable resistances. carotid body activation was through Stephen Archer (Chicago), and Göran Nilsson (Oslo) described + oxygen-sensitive voltage-gated K Jeremy Ward on whether the ‘redox the mechanisms of survival under channels (e.g. the KV4.3 subtype) hypothesis’ or the ‘mitochondrial anoxia by crucian carp, which (T. Perez Garca, Universidad de hypothesis’ was correct. It was initially change their gill structure in Valladolid, Spain), mitochondrial agreed, however, that more response to hypoxia to increase the metabolism (Jeremy Ward and surface area for oxygen diffusion. consistency between the PO2 levels Keith Buckler, KCL and Oxford) or used in experiments was needed High glycogen stores in muscle, and AMP kinase activation (Mark Evans, to explain some of the differences the ability to convert excess lactate Edinburgh) were discussed in detail. seen between labs, and the produced by anaerobic respiration This debate continued through to physiological relevance of oxygen into ethanol, which is released into the Early Career Scientists’ Session tensions used to mimic chronic the environment, then supports on the last day of the meeting hypoxia was questioned. The roles long-term survival in anoxia. Carp although no firm conclusion was of these mechanisms in fetal growth also increase the production of the reached, even after the stimulating restriction (FGR), which is also endogenous tranquiliser, GABA, (and often heated) discussion by caused by hypoxia, were discussed which reduces their activity and

Physiology News | No. 81 | Winter 2010 | www.physoc.org 6 PN MEETINGS preserves energy. These clever and steroids, as an alternative to my PhD research investigates the mechanisms of survival in hypoxic steroid-only treatment in steroid- regulation of blood flow across conditions have hopefully inspired resistant diseases such as chronic the human placenta by oxygen- biomedical scientists to try and obstructive pulmonary disease sensitive potassium channels. As our transfer these mechanisms for (COPD) and in asthmatic smokers, understanding of these processes manipulation in humans at high where oxidative stress caused by in the placental vasculature is at altitude, although survival on a cigarette smoke promotes excessive an early stage, using the existing similar regime of ‘drugs and alcohol’ inflammatory protein synthesis. knowledge of other vascular beds may be questionable! Nanduri Prabhakar discussed is crucial in advancing this field. To possible carotid body-mediated gain expertise and advice from these The afternoon’s talks were varied, mechanisms whereby the internationally renowned scientists from students’ talks on hypoxia- intermittent hypoxia that occurs whose research I have admired and induced reduced glucose sensitivity in sleep apnoeic patients might am inspired to replicate, was an in the isolated whole carotid body, give rise to a plastic change in opportunity not to be missed! to the mechanisms of intermittent chemoreceptor function leading to Embarking upon a research career as hypoxia-induced sleep apnoea, elevated blood pressure. and the ability of hypoxia to cause a young scientist in a research field respiratory muscle weakness The talks were interspersed with filled with many controversies can be as a result of increased muscle poster sessions and coffee breaks a daunting prospect. One highlight plasticity. The day ended with a talk that allowed one-on-one discussions for me was the Point–Counterpoint by Janice Marshall (Birmingham) between early-career and established early career scientists’ session on local mediators of acute and scientists. Particularly useful was which helped alleviate these fears chronic hypoxia in muscle, with the Point–Counterpoint session held somewhat and emphasise that particular reference to adenosine at the end of the meeting, which these controversies are real. They metabolism and its contribution to demonstrated the need to challenge do not result from inexperience endothelium dysfunction, leading one another’s ideas to further our or a lack of understanding of the to cardiovascular disease in adult knowledge and understanding. subject area. One of the steepest life. High altitude was the subject of Well-deserved poster prizes were learning curves we have to try and the day, and at the Society Dinner awarded to Melissa Brereton overcome during the transition from that evening held at the National (Manchester; see below) and Andrew an undergraduate student to an Sea Life Centre in Birmingham, Chris Holmes (Birmingham). All in all, a independent scientist is accepting Imray (Coventry) gave an excellent thoroughly enjoyable meeting, in a that research is not black or white. after-dinner presentation on his fantastic canal-side venue in central There is a multitude of ways to experiences carrying out hypoxia Birmingham – with good catering interpret a biological mechanism research on Mount Everest. He too! or phenomenon. The real skill described the extremely difficult, Fahima Syeda young scientists have to learn is to emotional but ultimately successful formulate an opinion based on the Birmingham University experiences his team encountered available evidence, question and generate exciting new research on their journey. If only they were More from an early-career bar-headed geese... questions. Although this skill is not scientist as easy as learning a new technique The final session of the meeting The second Cardiac and Respiratory in the lab, I think more meetings began with a talk by Andy Cossins Physiology Themed Meeting, ‘Coping such as this one that include debate (Liverpool) challenging current with hypoxaemia: strategies and sessions and encourage active ideas on myoglobin as an exclusively solutions’, with an impressive array exchange of ideas would motivate muscle protein, as it also exists of keynote speakers and sessions and inspire the next generation of in brain and in the vasculature of dedicated to early career scientists, scientists. fishes. Asif Ahmed (Edinburgh) was the ideal forum to present my described the protective effects of research to leading experts away I thank The Physiological Society for haemoxygenase in pre-eclampsia from the intimidating arena of some allowing me to present my research (another disease associated with low larger meetings. at this meeting and awarding me oxygen content), and the possibility the prestigious Physiological Society of a novel use for the anti-cholesterol Many of the keynote speakers at Poster Competition Prize. I highly drug simvastatin in clinical therapy this meeting performed the early recommend young scientists to for hypoxaemic diseases. pioneering work elucidating the attend meetings such as this in mechanisms of oxygen sensing the future as it was a thoroughly There were two plenary lectures. and blood flow regulation in enjoyable and beneficial experience. Peter Barnes (Imperial) presented the systemic and pulmonary non-antibiotic macrolides or vasculature. Although not strictly Melissa Brereton combination therapy of theophylline cardiac or respiratory physiology, University of Manchester

Physiology News | No. 81 | Winter 2010 | www.physoc.org MEETINGS PN 7

Festschrift in honour of Bernd Nilius From 22 to 24 September, researchers from 20 countries gathered in Leuven (Belgium) for ‘TRP 2010: TRP channels, from structure to disease’. This meeting was organized on the special occasion of the 65th birthday of Bernd Nilius, founder of the Laboratory of Ion Channel TRP 2010 participants in front of the Leuven town hall. Research at the University of Leuven, former Reviewing Editor of The Journal and extremely funny foreword on through TRPC3 for induction of NFAT of Physiology, and one of the leading the connections between Bernd signalling in cardiac myocytes was figures in the ever-expanding field of Nilius, Leuven, Father Damian, awarded the poster prize. TRP channel research. Molokai and the selectivity filter of TRP channels. Somewhat unruly, The last afternoon started with After a good night’s sleep following Ardem Patapoutian (The Scripps Sven-Eric Jordt (Yale University) the well-appreciated get-together Research Institute, La Jolla) presented describing the role of TRPA1 as a party with Belgium’s premium a completely TRP-free lecture about detector of environmental chemicals products (Trappist beers and cheese), the recent discovery of Piezo1 and by the respiratory system, and its the 145 participants met at the Piezo2, which probably form (part contribution to the development medieval Grand Béguinage for two of) the long-sought mechanically of asthma. Using the fruit fly as a exciting days filled with accounts activated cation channel. model, Craig Montell (Johns Hopkins of today’s TRP channel research in Institute, Baltimore) drew molecular all its facets (featuring 15 invited parallels between the visual system speakers), vivid and open discussions and regulation of thermosensitivity. and amusing anecdotes about Bernd Bernd Nilius Dan Cohn (Cedars-Sinai Medical Nilius’ career and personality. answering Center) gave a clinical view on the questions variety of TRPV4 gene mutations that Day 1 started with molecular detail after his ‘final’ cause bone deformation diseases, of TRP channel function, with lecture. thereby illustrating the high medical Rachelle Gaudet (Harvard University) relevance of basic TRP channel presenting data on the crystal research. Finally, the celebrant structures of intracellular domains Day 2 started with Lutz Birnbaumer himself spoke about the ‘irritating of TRPV channels and their role in (NIEHS at Research Triangle Park), nature’ of TRP channels, referring not channel regulation, and Giovanni who presented data to support his only to the role of these channels as Appendino (Università del Piemonte controversial view on the role of sensors of irritating chemicals, but Orientale A. Avogadro) providing a TRPC channels and Orai proteins also to their complex, mind-boggling chemist’s view on natural products in store-operated Ca2+ entry. Next, and poorly understood biophysical as potent TRP channel ligands. Stuart Gary Lewin (Max Delbrück Center for properties. At the end of his inspiring Bevan (King’s College London) then Molecular Medicine, Berlin) revealed lecture, Bernd Nilius even performed presented a new animal behavioural his unpublished work on the role of an hilarious live experiment – a assay to pin down the contribution of TRPV4 as a peripheral osmosensor, modern version of EH Weber’s silber TRP channels to cold sensing, thereby and Thomas Gudermann (Ludwig- Thaler illusion – to directly ‘prove’ the settling some long-standing disputes Maximilians-Universität München) mechanosensitivity of TRP channels. in the field. showed the dramatic effects of No better way to demonstrate that loss of TRPM6 function in mice. good science and great fun can go The physiological roles of the David Clapham (Children’s Hospital, hand in hand. 2+ Ca -activated TRP channels TRPM4 Boston) not only discussed the role of and TRPM5, in particular in the TRPC5 in fear-related behaviour, but The organizers would like to thank cardiovascular system and the also pinpointed some important open The Journal of Physiology and The pancreas, formed the topic of the questions in the TRP channel field, Physiological Society for their lecture of Rudi Vennekens (University including Bernd Nilius’ further career generous financial support of TRP of Leuven). René Bindels (Radboud planning. 2010. Look forward to the Bernd University Nijmegen) provided a Nilius festschrift in The Journal of nice overview of the function and In addition to the invited lectures, Physiology, to be published early in regulation of the epithelial Ca2+ and there were also two vivid poster 2011, presenting symposium reviews Mg2+ entry channels TRPV5/6 and sessions, with a total of 36 posters. by five of the invited speakers. TRPM6. Reinhold Penner (University The poster presented by Michael of Hawaii) started his lecture on Poteser (University of Graz) on the Thomas Voets TRPM2 with a brilliant, touching importance of calcium permeation University of Leuven

Physiology News | No. 81 | Winter 2010 | www.physoc.org 8 PN MEETINGS

The biomedical basis of elite performance

All eyes will be on Britain in 2012, as London plays host to the Olympics. To celebrate the achievements of these elite athletes, and to showcase world-leading sport and exercise-related medicine, physiology and pharmacology research, The Physiological Society and the British Pharmacological Society will host a three-day sports science and medicine meeting at The Queen Elizabeth II Conference Centre, London from 19 to 21 March 2012. This meeting will be supported by The Journal of Physiology, Experimental Physiology, the British Journal of Pharmacology and the Scandinavian Journal of Medicine and Science in Sports. All four participating journals are published by Wiley-Blackwell.

The meeting will comprise symposia, oral communications, posters and plenary lectures, all of which will focus on basic and applied scientific and medical issues of direct relevance to athletic performance. Furthermore, to increase the impact, all invited speakers have agreed to contribute a manuscript to be published prior to the meeting across the participating journals.

More specific details about the meeting will follow in due course. However, to kick start this exciting venture we will be publishing a series of Olympics-themed articles. As Chair of the Scientific Programme Committee for the 2012 Games meeting I have agreed to contribute the first of these articles. Paul Greenhaff Chair, Scientific Programme Committee, School of Biomedical Sciences, University of Nottingham

Professional athletes are aim of minimising pain and injury and performance. However, there is a commonly taking non-steroidal thereby enabling training loads and body of evidence documenting clear anti-inflammatory drugs during adaptation to be maximised. adverse effects of NSAID ingestion on periods of intense training. But just cardiovascular, gastrointestinal and because these drugs aren’t banned by NSAID use is on the increase in top musculo-skeletal systems, particularly the World Anti-Doping Agency, does level sport (2), perhaps because with prolonged use. Moreover, in that mean they’re worth taking? the performance-related stakes are the context of maximising muscle getting higher. This latter point is training adaptation, it has been Non-steroidal anti-inflammatory emphasised by the recent publication known for some time that the drugs (NSAIDs) are a class of of Garnham (4), which reported increase in muscle protein synthesis non-prescription drugs (i.e. freely that about 50% of a sample of elite normally seen following eccentric available over the counter) that (world class) athletes confirmed they exercise is blunted following NSAID exert anti-inflammatory and would take an undetectable illegal ingestion (5). analgesic effects by inhibiting substance if it guaranteed them an cyclo-oxygenase (COX) isozymes, the Olympic gold medal, even if they Ironically, inflammation as the rate-limiting step in the formation were aware that it would kill them result of intense athletic training of prostaglandin, and by doing so within five years! Interestingly, no may actually work to an athlete’s reduce musculoskeletal pain. These data appear to be available that show advantage. A role is emerging for drugs are not included in the World NSAID use by elite or recreational exercise-induced inflammation Anti-Doping Agency’s list of banned athletes reduces injury prevalence stimulating positive adaptive substances and therefore can be used or improves muscle and exercise responses in skeletal muscle. It by athletes, perhaps most frequently is known from gene transcript during intensive periods of training profiling that a single bout of when injury, inflammation and pain resistance exercise (particularly are most common. eccentric exercise, i.e. lengthening contractions) induces inflammatory As one might expect, athletes gene responses in human are frequent users of NSAIDs. quadriceps muscle (6), and that Approximately 25% of those these inflammatory responses are competing at the Sydney 2000 maintained when a second bout of Olympics reported NSAID use in eccentric exercise is performed (7). the three days before random drug testing (1). While large scale use of Animal studies have shown increased NSAIDs might reflect the physical expression of the pro-inflammatory cost of elite athletic training, cytokine IL-6 (8), and the myogenic additional data point to athletes’ transcription factors Myf-5 and MyoD potential misuse of open access to (9), in muscle following lengthening these substances (2,3). Specifically contractions. Given that IL-6 has of concern is the prophylactic use of been shown to promote satellite NSAIDs for extended periods with the cell-mediated hypertrophy in isolated

Physiology News | No. 81 | Winter 2010 | www.physoc.org MEETINGS PN 9 muscle cells (10), these fi ndings prophylactic use of NSAIDs may 5. Trappe RA et al. (2002). Effect of ibuprofen collectively point to augmented actually impair muscle adaptive and acetaminophen on postexercise muscle myogenic growth factor expression protein synthesis. Am J Physiol Endocrinol Metab responses to resistance training 282, E551–E556. and satellite cell proliferation – and blunt athlete performance occurring secondary to muscle 6. Chen YW et al. (2003). Molecular responses development, which brings into of human muscle to eccentric exercise. J Appl infl ammation – as mechanisms by question the merits of prophylactic Physiol 95, 2485–2494. which resistance training might use of NSAIDs for extended periods 7. Hubal et al. (2008). Infl ammatory gene induce augmented muscle mass and of time. Clearly this warrants further changes associated with the repeated-bout strength gains over time. investigation and has signifi cant effect. Am J Physiol Regul Integr Comp Physiol 294, implication for issues beyond athletic R1628–R1637. It has recently been demonstrated adaptation, such as the loss of 8. Tomiya A et al. (2004). Myofi bers express IL-6 that the anti-infl ammatory effect skeletal muscle with ageing. after eccentric exercise. Am J Sports Med 32, of prostaglandin blockade inhibits 503–508. muscle satellite cell proliferation References 9. Armand AS et al. (2003). Effects of following acute eccentric exercise eccentric treadmill running on mouse soleus: in humans (11). In keeping with 1. Corrigan B & Kazlauskas R (2003). Medication use in athletes selected for doping control at degeneration/regeneration studied with Myf-5 this, McKay et al. (12) recently the Sydney Olympics (2000). Clin J Sport Med 13, and MyoD probes. Acta Physiol Scand 179, demonstrated a clear association 33–40. 75–84. between increased muscle IL-6 2. Tscholl P et al. (2008). The use of medication 10. Serrano AL et al. (2008). Interleukin-6 is an levels and satellite cell proliferation and nutritional supplements during FIFA essential regulator of satellite cell-mediated in humans after a single bout of World Cups 2002 and 2006. Br J Sports Med 42, skeletal muscle hypertrophy. Cell Metab 7, 33–44. eccentric exercise. What is not yet 725–730. clear is whether these responses 3. Warner DC et al. (2002). Prevalence, attitudes, 11. Mikkelsen UR et al. (2009). Local NSAID infusion inhibits satellite cell proliferation in persist with training, thereby and behaviors related to the use of nonsteroidal anti-infl ammatory drugs (NSAIDs) in student human skeletal muscle after eccentric exercise. J potentially underpinning augmented athletes. J Adolesc Health 30, 150–153. Appl Physiol 107, 1600–1611. muscle adaptation. 4. Garnham AP (2009). Predicting recovery 12. McKay BR et al. (2009). Association of interleukin-6 signalling with the muscle stem It seems there is a distinct possibility from muscle strains, a new take on “infl ammation” and the Goldman Dilemma.Br J cell response following muscle-lengthening that, contrary to popular opinion, Sports Med 43, 805–806. contractions in humans. PLoS One 4:e6027. The Biomedical Basis of Elite Performance London 19–21 March 2012

• Cardiac, respiratory and vascular aspects of performance • Neuromuscular function, muscle phenotype and mass regulation • Drugs in sport • Exercise metabolism • Thermoregulation • Sport and exercise medicine • Genomics and exercise

For more information, email: [email protected] or

Joint Meeting of The Physiological Society and the British Pharmacological Society Society Pharmacological and the British of The Physiological Joint Meeting and Journal of Pharmacology , the British Physiology , Experimental Supported Journal of Physiology The by in Sports Wiley-Blackwell) Journal of Medicine & Science (published by the Scandinavian [email protected]

flyer vA5.indd 1 10/11/2010 11:43:55 AM Physiology News | No. 81 | Winter 2010 | www.physoc.org 10 PN MEETINGS

Gordon Research Conferences An invitation to speak at a Gordon with the number of conferences Research Conference (GRC) affords and attendees doubling under his a unique opportunity that is not leadership. The meetings remained available at more conventional on the East Coast until 1963, when conferences such as Society they expanded to Santa Barbara, for Neuroscience or Physiology CA on the Pacific Coast. In 1980 the Society meetings thus, when I was West Coast venue moved to Ventura, invited to attend the Glial Biology: CA, about one and half hours north Functional Interactions among Glia of Los Angeles, and in 1990 the first and Neurons conference which was conferences were held outside of the held in Ventura, CA last year, I had USA. Cruickshank was instrumental no hesitation in accepting. Although in encouraging conference chairs GRCs offer an air of exclusivity since to apply for external funding and the opportunity to present at a GRC federal grants for the purpose of is by invitation only, there are a subsidizing speakers and keeping limited number of places available costs down for attendees. On for graduate students and post-docs. Cruickshank’s retirement in 1993 Before describing the highlights of he had devoted 47 years to the this conference, a brief history of The three living Directors (left to right): Alex Cruickshank, Nancy Ryan Gray and GRC, 25 as director. Carlyle B. these unique conferences may be Carlyle B. Storm. Storm succeeded Cruickshank, and enlightening. the expansion of GRC continued Chesapeake Bay region of Maryland, with conferences held in Tuscany, History but moved to Gibson Island in the Oxford, Japan and Hong Kong. In The first official Gordon Research mid 1930s. Although Gordon moved 2002 GRC moved its headquarters to Central College, Missouri, the Conference took place in 1931, to West Kingston, Rhode Island conferences continued to be run but the idea of an annual series of and on Storm’s retirement in 2003 from Johns Hopkins. Fortuitously, conferences had been germinating directorship was taken over by Gordon had become secretary of for a couple of years in the mind Nancy Ryan Gray, who remains the the American Association for the of Dr Neil E. Gordon, a chemistry current director. That there have Advancement of Science (AAAS), professor at Johns Hopkins been only five directors in the GRC and thus the AAAS took over University. At around this time Johns history goes a long way to explain management of the conferences Hopkins University was pioneering not only the success, but also the and Gordon became the official research-based chemistry education, stable format of the conferences. and the Chemistry department was director of the conferences in 1939. at the cutting edge of translating Untouched by the escalating war Format theoretical chemistry into applied in Europe, in 1941 eight separate research. This led to seminars being conferences were held, at which A key aspect of the conferences held in the summer to present new point larger premises on the island that has remained unchanged since findings in the field of chemistry, were purchased. In 1942 Gordon their inception is that they last which visiting scientists as well as moved to become chair at Wayne five days. The initial conferences graduate students could attend. University Chemistry department were billed as summer courses, Although a series of informal and he relinquished directorship in which ran from Monday to Friday chemistry meetings had been held 1945. In 1947 the AAAS appointed with the conference season lasting in the summer at Johns Hopkins W. George Parks as director and five weeks, and each conference University, Gordon instituted a moved the conferences to Colby focusing on a specific topic. Current more formal conference format. Junior College in New Hampshire. conferences now run from Sunday It was Gordon’s intention that Under Park’s directorship the night until Friday morning with these seminars would focus on an conferences continued to expand the daily schedule encompassing individual topic per conference and and by their 25th anniversary communal breakfast, presentations provide an opportunity for small four thousand scientists attended in the morning, afternoon free, groups of scientists working at thirty-six conferences. In 1956 communal dinner, followed the frontiers of a particular aspect GRC became an independent by evening presentations. The of research to come together and non-profit organisation devoted to afternoons usually contain informal discuss in-depth aspects of the scientific and educational purposes. discussion groups organised most recent advances in the field, Parks resigned in 1968 and his at the conference, for in-depth and to stimulate new directions deputy Alexander Cruickshank discussion of specific topics. In for research. From 1931 to 1947 took over. This was a period of order to avoid the distractions the conferences were held in the enormous expansion of the GRC that are an unavoidable hazard of

Physiology News | No. 81 | Winter 2010 | www.physoc.org MEETINGS PN 11

Glial Biology: Functional Interactions among Glia and Neurons This conference was chaired by Professor Bruce Ransom, University of Washington, with Professor Philip Haydon, Tufts University, acting as vice chair. This is the 4th such conference, the initial one being chaired by Gerry Dienel in 2003. It is an indicator of the momentum of glial research that such a conference is not only viable, but that it encompassed a very broad range of topics. The sessions were: Form and functions of synaptic-glial The harbour at the site in Ventura at the Four Points Sheraton. interactions conventional conferences held in Alex Cruickshank who encouraged Lessons learned from flies and urban areas, GRCs are intentionally a more decentralised financial worms held in remote locations. There is approach to the conferences, which Glial regulation of neurogenesis, an emphasis on the presentation of allowed the chairs of conferences neural migration and neural unpublished data, which hopefully to apply for external funding, which plasticity will engender helpful discussions in turn allowed greater subsidy for about the progress and direction of speakers and graduate students. Glia and ischemic brain injury future studies. Unlike many other The contribution of students and Glial control of CNS vasculature and conferences, abstracts or conference post-docs is a key aspect of the the brain–blood interface proceedings are not published. conferences. While the GRCs try to Glia and information processing maintain the number of participants Growth of conferences and as small enough to promote full Microglia and CNS pathology attendees participation and discussion, they Metabolic interaction among Since their inception over 600,000 must also be large enough to neurons and glia scientists at over 5,500 conferences support the diversity of participants from professors to students. Molecular pathophysiology of have attended GRCs, and currently, gliomas and dysplastic glia. over 25,000 scientists attend the The GRCs are keen to encourage 200 or so annual conferences (the Given the remit of GRCs not to attendance of post-graduate average number of attendees is 140 report on unpublished or preliminary students and post-docs, and at some with attendance ranging from 110 to data, I will limit my discussion to GRCs a pre-meeting symposium 200 maximum). published data and highlight a few is arranged, which takes place on notable presentations. Although the original conferences the Saturday and Sunday before were focused on the topic of the meeting, with attendance In the 2nd session David the initiator, chemistry (in the limited to graduate students and Featherstone, University of Chicago, initial years the conferences post-docs. These new Gordon presented an astonishing talk based focused on topics such as x-ray Research Seminars (GRS) are on studies in Drosophila in which crystallography, organic chemistry designed to provide a stimulating mutation of a glutamate cystine and colloidal chemistry), the scope and non-intimidating environment transporter altered the mating of the conferences has expanded, for graduate students and post-docs behaviour of male flies. Normal encompassing not only the life to present their research in talks and male flies will mate only with female sciences, but also the physical poster sessions. There were 19 of flies, but male flies with a reduced sciences. It is a sign of the times these in 2009, 28 in 2010 and there expression of the transporter, named that conference topics now include will be 52 in 2011, with the numbers genderblind, will attempt to court renewable energy. expected to increase. GRCs offer male flies as well as female flies, students an opportunity to not only thus exhibiting bisexual behaviour. The number of conferences and hear experts in their field present, In the recently published article attendees continues to grow from but also to interact with them on Dr Featherstone hypothesised the initial few conferences per year at a relatively informal basis. Such that glutamatergic synapse East Coast locations. This was most opportunities are strictly limited at strength mediated the genderblind noticeable under the stewardship of other conferences. phenotype, based on experiments

Physiology News | No. 81 | Winter 2010 | www.physoc.org 12 PN MEETINGS/NOBEL PRIZE in which the glutamate antagonist experiments that showed how DGG eliminated bisexuality in the blocking Cl– channels inhibited 2010 Nobel Prize genderblind mutants, and conA, brain tumour development. The The much-deserved Nobel Prize a glutamate receptor agonist that theory behind this work is that awarded to Professor Bob Edwards inhibits desensitization, induced in order for tumours (which are [1] marks the culmination of one bisexual behaviour in the wild nearly all of glial origin in the brain) of the great stories of late 20th type male flies. Imagine a similar to invade neighbouring tissue in century physiology and medicine; situation in humans! In a personal the brain, which is composed of the years of painstaking work that communication Dr Featherstone densely compacted cells, the tumour related how he had been inundated cells co-localise a Ca2+-activated culminated in the birth of the first by calls from worried parents K+ channel and a CIC-3 Cl– channel ‘test tube baby’, Louise Brown, in seeking advice on how to ‘fix’ their in the invading processes. The 1978. It is a pleasure to welcome his homosexual children. activated channels release K+ and honouring by the Nobel Committee. Cl– and water follows, resulting in cell The award of the Nobel Prize I was initially disappointed that shrinkage, which facilitates tumour Maiken Nedergaard, Univerity of for the discovery of IVF (in vitro invasion via the narrow extracellular Rochester, chose to change her fertilisation) by Edwards and his space. Blocking the Cl– channels talk from astrocytic buffering of clinical collaborator, Patrick Steptoe, with chlorotoxin reduces cell volume potassium as I was hoping to pick perhaps throws into sharp relief decrease, which hampers tumour up some novel information for some of the recent debates about cell invasion. Chlorotoxin is now in undergraduate lectures. However, Phase III clinical trials and shows ‘blue skies’ research – and the need her replacement lecture was great selectivity for gliomas. for research to be perceived as fascinating – a comparison of the cutting edge, or to have ‘economic morphology of astrocytes from The next Glial Biology conference impact’. Edwards was a basic humans and rodents. Maiken’s is scheduled to take place from 6 researcher in a university Physiology talk, based on a recent publication, to 11th March 2011 in Ventura, department, and the IVF work was illustrated, not surprisingly, that CA. I strongly encourage any PhD preceded by many years of lab work human astrocytes exhibited a far students or post-docs working in on animal, as well as human, oocyte more complex morphology than the field of glial research to consider physiology and fertility. The IVF rodent astrocytes, but additionally applying for attendance at the work was not ‘fashionable’ at the demonstrated that human astrocytes conference. The GRC website (www. time; the focus in fertility research display overlapping regions, not grc.org) contains information on in the 1960s and 70s was on seen in rodents, and conduct Ca2+ up-coming conferences, application reducing fertility, and Edwards and waves faster than the rodent. In and registration procedures, and addition, human astrocytes were Steptoe had to scrabble for funding. information for students and Notably the MRC, then the major shown to have similar morphologies post-docs. A separate website (www. British funder of medical research, to primate (macaque monkey frontiersofscience.org) is dedicated declined to support Edwards and and chimpanzee) astrocytes. It to the first 75 years of the GRCs Steptoe’s work in 1971 on ethical is interesting to note that on a and contains a treasure trove of grounds, though a fascinating morphological basis there is very information, including memories recent historical paper reveals the little that distinguishes human of distinguished GRC participants. reasons behind the decision were layer 5 pyramidal cells from an A related publication ‘Reflections equivalent rodent cortical neurone, from the Frontiers’ is available from far more complex [2]. Following suggesting that the enormous Amazon.com. the MRC’s decision, Edwards and complexity of the human brain Steptoe’s work continued with function compared with the rodent Angus Brown private money, notably from the may at least in part be due to the USA, until Louise Brown’s birth References complexity of astrocytes. After triumphantly vindicated them. all, Einstein had a higher density Grosjean Y, Grillet M, Augustin H, Ferveur The 4 million plus children born by JF & Featherstone DE (2008). A glial amino- of cortical astrocytes than mere IVF since Louise Brown, and now mortals. acid transporter controls synapse strength and courtship in Drosophila. Nat Neurosci 11, the children of those children, are 54–61. In the final session, at least from a eloquent testimony to Edwards’ clinical point of view, was perhaps Oberheim NA, Takano T, Han X, He W, Lin JH, vision and perseverance. the more interesting talk. Harald Wang F, Xu Q, Wyatt JD, Pilcher W, Ojemann JG, Ransom BR, Goldman SA & Nedergaard M References Sontheimer, University of Alabama, (2009). Uniquely hominid features of adult 1 described his experiments based human astrocytes. J Neurosci 29, 3276–3287. http://nobelprize.org/nobel_prizes/ medicine/laureates/2010/press.html on a recent publication, on the role Sontheimer H (2008). An unexpected role for of ion channels in brain tumour 2Johnson MH et al. (2010). Hum Reprod 25, ion channels in brain tumor metastasis. Exp 2157–2174. metastases. Harry described Biol Med 233, 779–791.

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What makes ion channels exciting – a penetrating interview with Bertil Hille On a recent trip to Seattle Angus Brown took the opportunity to catch up with Professor Bertil Hille in the Department of Physiology and Biophysics at University of Washington. Bertil is one of the founding fathers of modern membrane biophysics. Angus Brown (AB): Could you tell us AB: So there are no hard feelings where you did your undergraduate obviously but it’s not the best way to and PhD degrees? set out on your career is it? Bertil Hille (BH): I was an BH: I learned that that was not a way undergraduate at Yale University I would like to work with post-docs studying Zoology, but I also took and it helped me to be a better and a whole series of courses called more sympathetic post-doctoral Biophysics, so I could have had a advisor [in Bertil’s 42 years at the degree in Biophysics as well. Then University of Washington he has I went to Rockefeller University in supervised 46 postdocs and 18 New York City where the degree was graduate students]. called Life Sciences and graduated As an aside Bertil showed me a letter in 1967 after 5 years. It was a very sent to him by Marni, Hodgkin’s wife, advanced and modern environment after Hodgkin’s death. She wrote: “But where there were many professors Bertil Hille he (Hodgkin) followed your career with and a few students, so we could great interest and latterly with a faintly make up our own programme. the squid, and Hodgkin was a person disapproving feeling that you were whose focus was so total that he writing too much and experimenting AB: Your father was a famous couldn’t think about another thing at too little, but then experimental mathematician at Yale, who wrote the same time. I was basically put in scientists always do feel like that.” numerous textbooks. What influence another room and didn’t have much did he have on you? exposure to Alan during that time. AB: One aspect of ion channel history BH: My father was a role model for Richard Keynes realised that I knew has always puzzled me and I may a quiet academic. He was totally about electricity and I could measure be wrong in this, but if we think involved with his mathematics and electrical things, so by the time I had of the first generation of modern other intellectual things. What I got been a post-doc with Alan Hodgkin researchers in the field of neuronal from him included how to think hard for maybe a month and a half, really excitability, Cole excluded, they were and steadily and not having to have being told to work by myself, Richard predominantly British: Hodgkin, entertainment while thinking about Keynes had acquired me so I spent Huxley, Katz (German working in science. He also was a role model the rest of the year in Richard Keynes’ Britain) and Lord Adrian, but the next with respect to having written 14 lab working with Larry Cohen. In generation were almost exclusively books in his lifetime, and so that fact, after the squid season was over, American: you, Clay Armstrong, made it very natural for me to write Alan Hodgkin said there was no place Bill Catterall, Richard Aldridge and a book and feel, half-way through my in his lab for me, I had better do a numerous others. Why do you think career, that that was the appropriate theoretical problem. Since I had no the British influence so dramatically thing to do. theoretical problem in mind, when dissipated? BH: I think you’re quite right and this AB: You worked with Alan Hodgkin Richard Keynes said, “Why don’t you is a very interesting sort of science/ for a year as a post-doc, in 1967–8. come to our lab in Babraham”, that sociology issue. There are quite a What was that experience like? seemed like a much better prospect. number of factors I could identify BH: Alan wrote to me a few months AB: And you weren’t given any squid which I think weigh equally. One was before I went that his laboratory was – you were neglected? that Hodgkin, Huxley and Katz had full and he was fully preoccupied, BH: It was hard to get the squid. It all felt that the excitability problem so it would be best if I came a year seemed like Hodgkin and Blaustein had been solved and finished. So later. Well, it wasn’t really in my should have the squid, and they were when the papers were published plans to come a year later so I went the ones who gave out the squid. in 1952, they thought that there anyway, and he was actually fully I got some, but it was hard for me was nothing more to do and they preoccupied. At the time Hodgkin, to even learn how to open a squid. projected that to anybody who Mordy Blaustein, Peter Baker and Trevor Shaw came from London talked to them. They got rid of their Rick Steinhardt were discovering the and he was very nice and helpful. amplifiers and they each turned, sodium–calcium exchanger in squid He showed me the dissection and very productively, to other fields. giant axon. Mordy Blaustein was to helped me get some apparatus while It meant that they felt they had work with Hodgkin in Plymouth on I was there in Plymouth. finished – the Hodgkin and Huxley

Physiology News | No. 81 | Winter 2010 | www.physoc.org 14 PN INTERVIEW papers were so alarmingly new and important do you think modelling is and memorised all the enzymes different and hard to accept that in the field of ion channel biophysics? and intermediates of intermediary people outside had no idea what to BH: I continue to model all the time metabolism. We knew that there do next either. So it was a surprising so to me it’s very easy. I still am were hundreds of enzymes and time in science when papers had a conscious of the feeling of many hundreds of genes. I was impressed giant impact and nobody had any biologists that it’s too easy to model: that all of biology used proteins; for idea what we could do further. Then if you have several parameters, you each job there was a different protein another factor would be, I’ll speak can make an elephant wag its tail. At each with its own specificity. The about Hodgkin particularly, that Alan the same time I find it very satisfying enzymologists were purifying these Hodgkin had almost no research to make models. I think the models proteins and could study them in the students. Richard Keynes was one, are like a physical explanation of test tube one at a time, and show and he continued the excitability things using whatever concepts as far that they had different amino acid question in Britain. His agenda as they can go – often just kinetics, sequences and different properties was to study everything except so you don’t quite know what the and different active sites. That was electricity about excitability, so he molecules are, or if you do know the background that I came to the studied light, heat and isotopes. the molecules, it is still at some excitability problem with, thinking The only other student that I know simplified view of them as charges that for every biological function of Alan Hodgkin’s is Peter Stanfield. and as dipoles. But in the end you there would be some series of Thus, there is this big hiatus where can show that a certain class of proteins, each one specialised for an Hodgkin, Huxley and Katz produced thinking does work to explain your individual job. I just thought, without almost no research students meaning phenomenon. Hodgkin was very even knowing any experiments, that there were no new PhDs developing clever about it in many of his papers. there would be sodium channels their ideas in Britain. As an anecdote For example, when Hodgkin and and potassium channels and calcium I can tell you that while we were Keynes measured isotope fluxes in channels that would serve those not able to get squid in Plymouth, potassium channels and people now functions and they would be different Alan Hodgkin told me that he was say that they showed it was a long molecules and one could study them annoyed at training Americans who pore, Hodgkin would write instead just as the biochemists studied the then all went back to America with that “the system behaves like one in enzymes. I also thought they should his good ideas and continued to which there was a long pore through be pores. work on them. Now what he really which particles were moving.” That’s AB: So it was just intuitively obvious meant was that Great Britain had no quite different from the strident to you that there would be selective system for post-doctoral support. So words, ‘strongly proves that such and proteins for each ion? in the laboratories of Huxley, Katz such’, which people think is a good BH: I think it was just a frame and Hodgkin there were post-docs way to express their belief in some of mind. It wasn’t probably very from the United States mostly, scientific conclusions. and a few from Germany, but not thoughtful. It was just that I came to AB: You were the first to coin the biology at that point from the point from Great Britain. This meant that phrase ‘ion channel’. How did you they produced no progeny. It was a of view that it’s going to be protein come to your views on channels pores that are specific. Now Clay mistake in respect to advancement selective for sodium and potassium? of science that in Britain there was no Armstrong who is 6 years older than BH: We can go back to Hodgkin I am, was already, just a year before post-doctoral support system. That first. He was making models in the kind of programme did not exist, I started, working with squid giant sense that there is no discussion of axons in Cole’s lab in Woods Hole and it existed quite completely in molecules, except for water, and the United States even for people to and he was very clearly beginning to sodium, potassium and calcium, write in the same framework, so Clay leave the United States with money and ATP. He wasn’t a chemist who to do their work in other countries. and I were I think fully parallel and thought about what a molecule looks in full agreement even though we But we shouldn’t forget though that like or what its chemical properties there was also Otto Hutter in London didn’t spend a lot of time together are. He said to me that he and talking about it. who Denis Noble worked with, so Andrew Huxley were disappointed in AB: You were working independently. Denis Noble carried the banner for the results of their papers because the cardiac side of excitability, and they had thought they would be able BH: We were independent. But we Denis Hayden was in Cambridge to describe the mechanism. In the had exactly the same point of view. and was studying the gramicidin end they felt that their model was And I think we, cynically, had exactly channel. I think Hodgkin and Huxley just a model and didn’t prove that the same negative feelings about are so unusual that you don’t expect the mechanism was correct, which the other people who had a different to have them repeated ever again, they state in the last paper, “there’s point of view. neither in Britain nor in America nor nothing about our equations that AB: When you came to Seattle in anywhere else [laughs]! says this is the right thing”. Now for the late 1960s a colleague tried AB: Your early work had a significant me, I was a student at Rockefeller to dissuade you by calling it an modelling component. How University and we had studied ‘intellectual desert’. It’s very hard

Physiology News | No. 81 | Winter 2010 | www.physoc.org INTERVIEW PN 15 to believe nowadays, 40 years later. the dial and the computer recorded you can grow so much material and What was the department like when whatever happened. Only later because the molecules of bacteria you joined it? was it possible to actually have the are not glycosylated. If you have BH: It was the Department of computer generate the voltages. glycosylation, which is like cotton, Physiology and Biophysics; it was AB: You’ve mastered a variety of it’s hard to pack proteins together in extremely strong as one of the techniques including the ability a regular structure. Instead there’s best in the country. It took 14 or to build your own amplifiers some springiness and you get an 15 students each year, which is a and oscilloscopes, computer irregular crystal but it’s not good fantastically large number, so it had programming, knowledge of enough to get a structure. So neither 45 students at any moment and if enzyme kinetics, chemical radii, the sodium channel nor the calcium you look at the list of students you’ll electrophysiological recordings from channel has been crystallised. see that each year, 4 or 5 people who nodes and various other techniques. AB: Your research changed tack in we know well came in who are now Moving on to the 21st century, what the mid 1980s when you started to chairs and professors who have to skills do you think are essential for focus on signalling via G-protein- do with ion channels and electrical students entering neuroscience? coupled receptors in both excitable excitability. There was a very BH: Well now if neuroscience means and non-excitable cells so what significant interest in excitability. things that I’m interested in, that prompted this change in direction? AB: Could you tell us a bit about is cellular electrophysiology of BH: It was very consciously taken. I the computer aspect as one of the neurons and of ion channels, then I had written my book, published in attractions? would say that everything modern 1984, and that allowed me to review BH: I made a tour of a few schools has to be done. It’s patch clamp all of my life because most of the on the East Coast and mostly schools now. Although you don’t have to chapters in my book were something on the West Coast looking for a job, know how to build the amplifier I had done sometime or other. The and since I had used a voltage clamp anymore, you have to learn about book was written because I felt that with a computer in my graduate Ohm’s Law and capacitors and you biophysicists were moving too far studies I felt that it was necessary have to be able to think about what away from biology and were writing to have a computer online to make the amplifier is doing. When I first papers that were incomprehensible the use of voltage clamp reasonable. saw that Erwin Neher was able to do to other fields like structural, Almost every school had no idea patch clamp, before they published chemical, developmental and cell what an online computer would be. their famous paper, I came back biology. We needed the input from So this was far and away the only and and built five and I gave one to all those people to help us realise the most knowledgeable department Peter Detwiler just to get people significance and mechanisms of ion with respect to online computing. interested in it. I think microscopy channels. Looking at the book, I felt They said, yes, I could use their and imaging have become our ‘new too that I needed to turn my work computer on Saturdays. So I did all and essential.’ Confocal microscopy towards more biological questions. is already fairly old but it’s essential. So instead of asking how many my experiments for the next 10 or Newer forms: FRET (fluorescence tenths of an Angstrom the hole in 15 years on Saturdays. resonance energy transfer), TIRF the sodium channel was, I would AB: You were the first researcher (total internal reflection microscopy), try to get what I perceived to be to record electrophysiological data and continually new forms of how hormones acted on cells. That using a computer: how important microscopy are things that you’ll was G-protein-coupled receptors, was this as an advance in routine lab need to bring in. Next is molecular basically things that affected mood studies? biology, the ability to stitch together and all the outputs of the whole BH: Instead of having to take a week alterations of genes and to express autonomic nervous system. So it was to analyse the data you could do it them in cells, typically in cell lines. a real change for me, I felt somewhat in minutes. I’d say anybody who was But if a neurobiologist really does naked and delicately exposed while I patch clamping today and not given neurobiology, you have to express didn’t know much about those fields. a computer would be alarmed. You them in real neurons, either knocking AB: A lot of your studies were in would never want to photograph down expression or expressing non-excitable cells. a million single channel openings mutants. Very successful in the last BH: As an undergraduate zoologist and try to analyse them from 10 years is to knock out a gene in a I was interested in all kinds of measurements on a film. mouse and then to study the cells biology, which could be in kidneys AB: So you effectively wrote the in which you have re-expressed a or muscle, so it seemed to me that prototype for Axon pCLAMP? mutant form of the same gene to ask the significance of ion channels, and BH: Yes, except in the beginning I what part of the molecule’s doing the significance of G-protein-coupled had an analog way of making the what thing and what it’s for. receptors, was as great in all other pulses, so I personally would turn a AB: Why do you think the sodium cells as it was in neurons. There dial, which I arranged to click in steps channel hasn’t been crystallised yet? was no need to focus on neurons. I so that you got particular voltages. I BH: Most of the ion channel crystals never have truly regarded myself as controlled the experiment by turning are bacterial proteins partly because a neurobiologist, you know. I have

Physiology News | No. 81 | Winter 2010 | www.physoc.org 16 PN INTERVIEW studied ion channels and cells and day they would feel like they should it enough that I think I learned a lot how the cell membrane negotiates try another chapter, and in that way from each of the teachers on how passing ions through it, but I’ve never they got deeper and deeper into the to do that. Right from the seventh used more than one cell at a time difficulties that we all know about ion grade I’d say I learned a lot. I also in a dish. I’ve never had a two-cell channels. studied. If you read authors who you preparation, which means that you AB: And how did the book evolve think write in a way that’s accessible, can’t do too much neurobiology! over the subsequent editions? those are good models for how to AB: Could you tell us how you came BH: Well, it got longer. The first write. So if you read William Faulkner to write your book ‘Ionic Channels time I wrote the book there were and you find it difficult to read, I of Excitable Membranes’, and how 7,000 papers about ion channels, the wouldn’t write science like that. If it evolved over the subsequent second time there were 30,000, and you read Winston Churchill, about editions? I have a personal interest the third time there were 100,000 the Second World War, it’s very in this in that the 1st edition of papers out there in the literature. For accessible and so maybe that’s a your book came out in 1984, and that reason I’m not ever going to do good way to write. You can look at as an undergraduate in Dundee in that again (laughs)! The third edition, different authors, completely out 1985 I was given that book as part I feel retrospectively was much too of science now, and decide and just of our course by Jim Elliott. In fact, long, it should have been briefer like say, “Now I’m going to look at the your book was a major influence in the original edition, which had the page to see how long the paragraphs steering me towards a career as an real advantage that you could almost are and what they said in the first electrophysiologist, which 25 years have it as bedtime reading instead of paragraph and how they developed later I still am. having to labour over it. the paragraph.” I don’t want to know about this battle in the Second World BH: I had come to the point of feeling AB: Your style of writing has always War, but I want to see how the words that the biophysicists were not struck me as a sort of perfect balance were put together in a way that talking in a vocabulary that was good of amenable prose combined with seemed to work. for talking to other biologists. Yet scientific insight. Are you a naturally I knew that we had lots of exciting gifted writer or did you actively study Readers interested in Bertil Hille’s discoveries, starting with Hodgkin how to write accessible scientific career are directed to an extensive and Huxley, and that papers as prose? brilliant as Hodgkin and Huxley’s interview conducted by Eric Kandel BH: I think scientists are bred to be were almost unreadable to most of on the occasion of the Lasker modest, most of them, so (laughs) the people who I wanted to know Foundation Basic Medical Research it’s not appropriate to say that I’m a about this exciting research. I wanted Award to Bertil in 19991. In addition, naturally gifted writer! to find a way to tell people about Bertil has contributed a chapter the basic discoveries and what was AB: Did you study creative writing at to The History of Neuroscience in known without having to envelop it university? Autobiography series published by with excess physical and theoretical BH: Well, yes, in a way. In all the the Society for Neuroscience, which baggage. I was inspired by my schools that I went to I took courses, will be included in Volume 7 to be father’s having written textbooks which in American education are published in 2011. before. So I wrote a book in which typically required, on writing essays 1http://www.laskerfoundation.org/ the first chapter was easier, and the and writing compositions. I enjoyed awards/1999_b_interview_hille.htm second chapter was a little less easy, and the third chapter was a little less easy, instead of starting like an encyclopaedia, where it’s of uniform Exceptional Products Enhancing difficulty and assumes that you know some other stuff. 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Physiology News | No. 81 | Winter 2010 | www.physoc.org HISTORY PN 17

A. V. Hill’s photograph album

Hill’s papers in the Archives at Churchill College Cambridge are filed in dozens of manila envelopes. Among them is an album of photographs from the 1920s, mostly of fellow scientists. His grandchildren recall that he was a keen photographer with a home darkroom. Some of his photographs are eye-catching. (He was also good at drawing.)

Obviously he did not take Fig. 1, but it may have been taken with his camera. It shows Hill and Otto Meyerhof. They shared the Nobel Prize in 1922 for their discoveries on muscle (Katz, 1978). Hill used thermocouples to measure the heat released during contraction and recovery. Meyerhof measured the rise in lactic acid during tetanus and its fall during recovery, when part was oxidized and the rest rebuilt into carbohydrates. They are at the German border on their way to Stockholm for the Physiological Congress of 1926. Their costumes suggest that they may have been travelling in an open automobile. Hill was keen on cars, motorcycles and power boats.

For the first 16 months of World War I Hill served as an infantry Figure 1. A. V. Hill (1886–1977) is on the left; Otto Meyerhof (1884–1951) is on officer. Then he was transferred to the right. (All photographs are from the Churchill Archives Centre, A.V. Hill Papers, the Ministry of Munitions to work AVHL II 5/119.) on anti-aircraft gunnery, because, as he put it, he “had shown signs of the unpleasant habit of inventing things” (Hill 1918). He devised a method for measuring the position of flying objects with two widely separated mirrors. Conscription forced him to recruit over- or under-age, mathematically talented collaborators. Eventually there were more than 100; they were dubbed “Hill’s Brigands”. With the mirrors they located shell bursts from test firings. First trained in maths, Hill became known in physiology by fitting equations to data on the contraction of the frog rectus abdominis in response to different Figure 2. William Hartree (1870–1943) dissecting a frog muscle in the Cambridge concentrations of nicotine, based Physiological Laboratory. Note his cylindrical slide rule for high-precision calculations. on nicotine binding to a receptor Some of his maths was to correct their thermocouple measurements for the delays in substance in the muscle, and to their recording apparatus.

Physiology News | No. 81 | Winter 2010 | www.physoc.org 18 PN HISTORY

HCl into the duodenum stimulated secretion, even when the vagus was cut. Their hypothesis was that the reflex operated through an abdominal nerve network. Therefore they tied off a segment of duodenum and painstakingly severed every nerve running to it. Dilute HCl injected into intact duodenum elicited secretion. So did injection into the isolated, denervated segment. Quick as a flash, Starling announced that there must be a chemical messenger. He snipped out a piece of the isolated segment and ground it in a mortar Figure 3. Ernest Starling (1866–1927) in his laboratory at UCL with two assistants. His gaunt, cachectic appearance shows that his health was failing; in 1920 he had been operated on for a colon cancer. data on the dissociation of O2 from the war he stayed on as a volunteer. haemoglobin, introducing the idea Together they published 36 papers that it has several binding sites. on muscle. The Brigands pulled off the greater challenge of fitting the positions After the war, Hill became professor of shell bursts with equations at Manchester, where he studied that accurately describe the path human exercise, coining the term of projectiles hurtling skywards, ‘oxygen debt’. He was a keen runner. including the effects of wind, Then he was brought to UCL to temperature and shell velocity. They replace Ernest Starling (Fig. 3), who also developed apparatus to locate became a Foulerton Royal Society aircraft by sound. The Brigands took research professor (Henderson, their science into the field – they 2005). Every physiologist can list pioneered operations research. Starling’s great ideas that emerged from brilliant experiments. On a Hill led the group intellectually and memorable day in 1902 he and his also made science glorious fun. One collaborator and brother-in-law, of his recruits was William Hartree William Bayliss (1860–1924) were (Fig. 2), a retired engineer, who so working on pancreatic secretion. enjoyed working with Hill that after It was known that injecting dilute Figure 4. Ivan Pavlov (1849–1936).

with sand and some of the HCl. Injecting the filtered solution into the jugular evoked secretion; HCl alone did not. A few weeks later they proposed that such chemical messengers should be called hormones.

The doyen of gastrointestinal physiology was Ivan Pavlov (Fig. 4). He measured the volume and composition of digestive secretions by diverting output to an opening on the dog’s body surface; he would study these animals for years. He concluded that these secretions were Figure 5. Gleb Anrep (1891–1955) on the right, working at UCL during the 1920s. regulated by nerve reflexes.

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In his Nobel Lecture in 1904 he did not mention hormones. He had tried to repeat the UCL experiment, but his intestinal extracts did not evoke secretion. On the other hand, he had reported that stimulating the vagus elicits copious secretion from the pancreas; at UCL vagal stimulation elicited scanty secretion at best.

Pavlov came to England in 1912 for the celebration of the 250th anniversary of the Royal Society, and also received an honorary degree from Cambridge. Instigated by Hill, when Pavlov sat after receiving his diploma the students lowered from the ceiling into his lap a toy dog kitted out with glass and rubber tubing. Pavlov prized this salute from the younger generation and it is now displayed in a St Petersburg museum (Henderson, 2005).

The conflicts in results were resolved in 1912 when Pavlov sent a medical student, Gleb Anrep (Fig. 5), to UCL during the long vacation (Gaddum, 1956). They showed him how to prepare the hormone. They also showed him that Pavlov’s Figure 6. August Krogh (1874–1949). protocol destroyed the secretin by over-neutralizing the extract. In his Moslem women would not be J. S. Haldane, at Oxford, and J. turn, Anrep tried to show them that treated by males. This may have Barcroft, at Cambridge, had argued vagal stimulation elicited pancreatic influenced his son’s undertaking a that oxygen must be transported secretion. His first two tries failed. professorship at the University of actively. At the end of his life Krogh He discovered that UCL dogs were Cairo in 1931, where he strove to was investigating active transport of given morphine before anaesthesia. build a department like Pavlov’s and ions into marine organisms. He was It was not used in Russia. Without Starling’s. He worked on histamine curious about everything. He worked morphine, vagal stimulation worked and set up the first human heart– on topics as diverse as the diet of splendidly. Anrep visited thrice in the lung preparations. He was sacked Eskimos, the physiology of the blue next years, publishing his first paper following the nationalist revolution whale, and how insects prepare for in The Journal of Physiology. His last in 1952. flight. visit was cut short by the outbreak of war in 1914. He returned to finish August Krogh (Fig. 6) shared Hill’s In 1926 Hill also became a Foulerton medical school and then served in interest in exercise physiology professor, which freed time for the Russian Army and the White (Henriksen, 2000). He was research, but he was not permitted Army. When the counterrevolution awarded the Nobel Prize in 1920 to opt out from UCL committees, was defeated he emigrated to for proving that capillaries open where he did such good service. Britain, working at UCL and up when muscles contract, which (Starling had been allowed to Cambridge. He translated Pavlov’s he showed by injecting India escape, and was missed.) The wise lectures on conditioned reflexes, ink into the circulation and then hand steering the biological side published in 1927, for which the fixing and sectioning resting and of the Royal Society at that time Royal Society paid him £100. contracting muscles. The University was William Bate Hardy (Fig. 7). of Copenhagen established a He started as a zoologist, taught Anrep’s father was a pharmacologist Department of Zoophysiology for histology to the Cambridge who, at the Tsar’s command, Krogh and his wife Marie, also a physiology students, studied the established the first medical school talented experimenter. They showed effects of radiation on cells (burning for women in Russia. Female that oxygen diffuses from the himself with radium carried in his physicians were needed because alveolus into the blood. Previously, vest pocket), and then moved on

Physiology News | No. 81 | Winter 2010 | www.physoc.org 20 PN HISTORY

frogs, some of whom have a low of blood. Like Hill he was a champion titre of the esterase. Those who of biophysics. He was celebrated tried unsuccessfully to replicate his for his writings on how the earth’s experiment were naturally dubious. chemistry favoured life. He also After he identified the transmitter strongly supported and taught an he solved the problem by inhibiting esoteric theory of sociology. the enzyme with neostigmine, but naturally was apprehensive – we all The Nazis threw out hundreds know that demonstrations are dicey. of intellectuals in the 1930s – an In Stockholm he was successful 18 astonishingly generous donation times with the same two frog hearts. to their opponents. Hill was active (Loewi, 1960) in finding places for scientific castaways; for example, bringing The photograph in Fig. 9 of L. J. Bernard Katz to UCL. Meyerhof Henderson must have been Hill’s ended his career at the University favourite: there are two different of Pennsylvania and Loewi at NYU. prints in the album. A Harvard In 1951 they had an embarrassing professor, it was taken at his camp encounter on a train going from at Morgan Center Vermont. Every New York City to New Haven, physiologist knows the Henderson– Connecticut. Both were on their Hasselbalch equation, a product of way to Yale to receive honorary Figure 7. William Bate Hardy (1864– 1933). Labelled in the album as ‘W. his work on the physical chemistry degrees, but were pledged to B. Hardy photographed by A. V. H. at University College.’ to colloids, lubricants, and finally marine biology. If one follows the steps it was a logical progression. As a scientific statesman he was a model for Hill, who in turn became deeply involved in public issues, even serving a term as an MP. Both had to cope with the irrationality of politics. For example, in 1917 Hardy had to cope with a government food controller who instructed the public not to eat bread and meat at the same sitting because it doubled the work of digestion.

Otto Loewi (Fig. 8), professor of Pharmacology in Graz, Austria, took a prominent role in the 1926 Physiology Congress, where he was invited to demonstrate his great experiment – famously its protocol came to him in a dream. He stimulated the frog vagus for a few minutes until the isolated heart slowed and contracted with less force. Then he transferred the Ringer solution from this heart to a second, which also slowed and beat less strongly, showing that the vagus released a chemical. This experiment is tricky to replicate. Usually released acetylcholine is swiftly hydrolyzed by acetylcholine­ Figure 8. Otto Loewi. He shared the Nobel Prize for 1936 with his friend Sir Henry esterase. He was lucky. His first tries Dale for their work on chemical transmission. They first met in Starling’s lab at UCL in worked because he used winter 1902.

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secrecy, so during the journey they meticulously, but with obvious difficulty, evaded discussion of why they were on the train. William Van der Kloot SUNY at Stony Brook

References Gaddum JH (1956). Gleb Anrep 1891–1955. Biogr Mem Fellows R Soc 2, 19–34. Hill AV (1918). Antiaircraft Experimental Section of the MID (1916–1918). Archives of Churchill College, AVHL 1/37, 1918. Henderson J (2005). A Life of Ernest Starling. Oxford University Press, Oxford. Henriksen JH (2000). Ernest Henry Starling. Laegeforenings Forlag, Copenhagen. Katz B (1978). Archibald Vivian Hill. Biogr Mem Fellows R Soc 24, 71–149. Loewi O (1960). An Autobiographical Sketch. Perspect Biol Med 4, 3–25. Acknowledgements I am grateful to the staff of the Churchill Figure 9. Lawrence J. Henderson (1878–1942). Under the second print of this Archives Centre, Cambridge, to Susannah photograph in his album Hill wrote, ‘And the spirit of God moved up the face of the Bramley, the representative of the Hill family, and to John Henderson for discussion. waters.’

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Physiology News | No. 81 | Winter 2010 | www.physoc.org 22 PN OPINION

‘...and nothing but the truth’. Simon Singh discusses the peculiar nature of British libel law I wrote an article in the Guardian University, who criticised a supposed in April 2008, which criticised lie detection device in an academic spinal manipulation as a treatment journal. The Israeli technology for children with asthma, ear company behind the device sued for infections or colic. The British the libel and the journal could not Chiropractic Association (BCA) was afford to defend itself, so Lacerda’s somewhat upset by my analysis article was withdrawn. The UK of the evidence, but instead of government has spent £2m on the discussing the evidence, the BCA device, but we can no longer read threatened legal action against me Professor Lacerda’s critique. personally. The Guardian tried to find a compromise, but the BCA refused Another case involved the Danish the offer of a clarification and radiologist Henrik Thomsen, who rejected a right of reply. So, before was sued in London by America’s the summer was over, I was being GE Healthcare Corporation for slides sued for a libel. presented at an academic seminar in Oxford. For over two years he The case lasted two years until the came under intense legal pressure BCA eventually dropped its action Simon Singh to apologise for raising concerns against me, thereby allowing my about Omniscan, a contrast agent article to go back online and my Britain has a growing reputation used in patients undergoing MRI concerns to be aired once again. for libel tourism. In other words, scans. Eventually, public outcry and As the case progressed, I received Russian oligarchs, Saudi billionaires the lack of any real case caused GE a great deal of support from and overseas global corporations Healthcare to drop the case. researchers, doctors, journal editors sue overseas journalists at the Royal The eminent English cardiologist and, in particular, The Physiological Courts of Justice. Peter Wilmshurst is currently being Society, who were all outraged that sued in London by an American a medical debate was being crushed The problem is so serious that company after comments made in by a legal threat. Americans, who truly value free speech, have made no secret of America at an American conference Many words have been written the fact that they have nothing to an American online magazine. about the reasons why English libel but contempt for English libel law. After almost three years of refusing law is so terrible, so I will not bother Indeed, this year President Obama to back down on a matter of public going through the problems again. signed legislation that effectively interest, Dr Wilmshurst risks However, if you have not followed blocks the impact of English libel law bankruptcy if the judge ultimately libel debate, then I would encourage on US citizens. rules against him. you to read the archive of the Despite the growing campaign for Most bizarrely of all, the journal legal blogger Jack of Kent (http:// libel reform, there are some people Nature is in the middle of a libel jackofkent.blogspot.com), who has who ask if libel is really such a big battle after being sued by a covered my case and the campaign problem. They may have read about cosmologist. for libel reform with clarity and my particular legal battle, but they expertise. In the meantime, I will wonder if one libel case is enough to These cases are merely the tip of point out that it is easy to see that justify changing the entire law. the iceberg. Many other libel actions there must be something wrong are settled at an early stage, when with our libel law by looking at Unfortunately, my case is not the authors and publishers who cannot how the rest of the world views our only one. During the course of afford the risk of losing will back approach to free speech. my case, Ben Goldacre and the down and apologise even if they Guardian newspaper were sued believe their criticisms are valid. For example, overseas claimants for libel for criticising Matthias who try to quash criticism about Rath, who promoted vitamins in And there are countless authors themselves will try and bring a South Africa to treat AIDS patients. who self-censor articles, books and libel case to London, the world’s Rath eventually backed down, papers because of the co-called libel capital, if at all possible. This but the Guardian lost £175,000 in chilling effect of libel. We rarely is not because our libel law is so unrecovered legal costs. appreciate the extent of this great, but rather because it is so problem, because the damage is anti-free speech. We now have the And there is the case of Professor done prior to publication, but I embarrassing situation whereby Francisco Lacerda of Stockholm was made very aware of it when

Physiology News | No. 81 | Winter 2010 | www.physoc.org OPINION/BOOK REVIEW PN 23

Nick Miller, health correspondent The other brain: from characters behind the major advances at the Australian Age newspaper, dementia to schizophrenia, in the study of glia where the interviewed me about homeopathy. narrative really shines. Palpable glee He wrote up the interview, but his how new discoveries and insights into vivid imaginations in-house lawyer refused to allow about the brain are make these additions a real joy. Fields explores the contributions him to quote my harshest criticisms revolutionizing medicine in case the newspaper was sued in of a number of scientists: from the London. Instead, he wrote a blog and science foundations of modern neuroscience with Ramon Y Cajal, Golgi and his about how tough it was to be a By R. Douglas Fields student, the Arctic explorer and health journalist in Melbourne when Simon & Schuster £17, 384 pages, hardback part-time neuroscientist Fridtjof there was the threat of ending up Nansen, who touted glia as a possible in an English court on the other ISBN-10: 0743291417 ‘seat of intelligence’, through to side of the planet. (For the record, I ISBN-13: 9780743291415 Rudolf Virchow’s notorious coining of know that all my comments about For too long neuroscientists have the phrase that translates to ‘neuro homeopathy were justified.) neglected glia in favour of their glue’, to the bolshie and determined more electrically excitable cousins, American physician Gajdusek who In short, English libel law is the neurones. Only with the advent muscled less able and resolute relentlessly hostile to writers and of calcium imaging and a variety of researchers out of the way to elucidate scientists, while it seems to be other modern techniques, have glia the secrets of the devastating disease deeply supportive of anyone or revealed their secrets, which long Kuru. The sad fate that befell Schwann any corporation that receives the remained hidden in times when at the hands of his fellow academics slightest criticism. The result is that electrophysiological recordings were is a sanguine warning of the scientific debate is hindered and the dominant tools of neuroscience. consequences of unjustified criticism. robust criticism is gagged. Inspired by his own research into the subject R. Douglas Fields dedicates Fields is clearly baffled at how these The good news is that Parliament the majority of just over 300 pages to cells could have been overlooked and seems to be enthusiastic about libel carefully explaining why glial cells, ‘the neglected for centuries. He concludes reform. Indeed, both the previous other brain’, demand our collective that research in this ‘other brain’ is Labour Government and the new attention. over a hundred years behind that of Coalition Government is committed the neuronal brain and believes that this is why much of the functioning to a Defamation Bill that will be The book is aimed at a general of the brain eludes our grasp of developed over the next year. audience, and Fields does an excellent job of explaining introductory understanding. Overall the narrative The Physiological Society and the concepts for glia novices. The is engaging and accessible and it scientific community in general can structure of the book is thoughtful fills a noticeable gap as a highly take great pride for having helped and fluid. In three acts we are included recommended complementary text to politicians realise that English libel in Fields’ exploration of the annals undergraduate studies. law is a disgrace that crushes free of the history of glia. He starts with speech globally. Marion Diamond and her endeavour Angus Brown and Julia to unlock the mysteries of Einstein’s Barber However, it is still crucial that we brain and the key to his genius (the continue to speak out on behalf of answer is astrocyte density), then an science and free speech, otherwise intermission to cover neuroscience Life Science Careers vested interests will pressurise essentials. The main text of the Conference 2010 politicians into creating a watered book is then taken up with Fields’ The next conference, for under­ down and ineffective libel reform exploration of the involvement of glia graduates and postgraduates bill. If you have not yet signed the in health and disease starting with the working in the life sciences, will be petition for libel reform, then please long-established roles in brain cancer, held at King’s College London on 24 visit www.libelreform.org – and infection and injury to more nebulous November 2010. Registration is now failures of the brain such as psychiatric if you have already signed, then open. please encourage friends, family and illness, neurodegenerative disease, The conferences cover a wide colleagues to back the campaign for pain and ageing with a final section on glia in thought and memory and the range of science-related career libel reform. unconscious mind. Individual chapters opportunities, a CV workshop Simon Singh are devoted to each topic and can be providing tips on how to ensure you read as self-contained treatises. It is secure an interview, and a chance within these chapters that the true Simon Singh is a science writer and to mingle with experts and ask contribution of glia to brain function the author of Fermat’s Last Theorem, informal questions. and dysfunction is revealed. Big Bang and Trick or Treatment? Registration is £10 and includes Alternative Medicine on Trial (with It is the encounters with great minds, entry to the exhibition hall, lectures, Professor Edzard Ernst). the brilliant and sometimes vivacious a buffet lunch and refreshments.

Physiology News | No. 81 | Winter 2010 | www.physoc.org 24 PN WOMEN IN SCIENCE

Inspiring women – The Society mentoring scheme The Physiological Society’s mentoring do Pharmacology and Biochemistry scheme for women is entering its in my first year). When I completed second year with over 50 participants two lab projects during my degree already. In 2009, 10 mentees were (a summer vacation one, funded if I matched with 9 mentors, and this remember correctly by The Society year the numbers have increased and a final year project) I knew that with 16 mentees matched with 15 a PhD and research was for me. mentors. This scheme is aimed at I really enjoyed the challenge of helping women progress and stay in learning new techniques, getting to science by allocating women a mentor grips with designing experiments to to discuss issues and problems that Louise Robson and her children. address research questions and then may arise. Despite improvements presenting my findings in the context Valerie Gladwell (VG): Who are you? in government policy and even of the literature. Funnily enough I Tell us a bit about you and your family. support by the Prime Minister to try also ended up doing some teaching and improve the gender balance in Louise Robson (LR): I am married during my PhD, and from then on I science, engineering and technology to Richard (just celebrated our 20th was hooked on getting an academic (www.theukrc.org/news/2010/07/ wedding anniversary) and have two position. ukrc-addresses-pm-on-his-policies-for- kids – Jacqueline (15) and Oswald supporting-women), there are still (10). I have been in academia for VG: Is there any moment you can fewer women continuing a science 21 years (from the start of my PhD). remember that stands out which career. changed your career path? VG: Where do you work? LR: The biggest moment was winning In the next few issues of Physiology LR: I work at Sheffield in the News we are hoping to help to inspire my scholarship, as without this I Department of Biomedical Science, would not have been able to do my young scientists by interviewing and have been here for 14 years. This women that have been very successful PhD and I probably wouldn’t be doing was my first academic position, and my job (which I love). in their careers. I started as a junior lecturer, before VG: Who inspired you? This first article looks at balancing promotion to senior lecturer a few a family and other parts of your life years ago. LR: It has to be my PhD supervisor, with a science career. In a recent VG: When did you start your career in Malcolm Hunter, who has just retired report married mothers are 35% less science and can you tell us about your from Leeds. He was amazing! He likely to enter tenured posts than key milestones? instilled in me a passion for both married fathers (Nature 462, 375, research and teaching, something LR: I started ‘work’ in science at 18 November 2009). Furthermore, that I still have today. The dedication the start of my PhD in 1989. Key mothers who do try and continue he showed to both these areas made milestones for me would be: (1) science careers tend to devote most of a massive impact on my own work Doing a summer vacation project as their non-childcare time to their career ethic. this was the reason I decided to do a (Nature 466, 279, 7 July 2010). PhD. (2) Winning the scholarship that VG: What is your current role at work? I am a mother with three young allowed me to do my PhD. (3) Getting LR: I am a senior lecturer and also children who strives to get the life– my academic position at Sheffield. chief UCAS selector. work balance and I try to ensure that (4) Winning the first ever Biller prize. VG: Briefly what does this involve? I devote enough time to the family (5) Publishing my first independent as well as progressing through on paper. (6) Taking over as chair of the LR: You name it I do it! I have a my career (I am currently an ESRC Education Committee at The Society. research lab, with a postdoctoral Research Fellow but have a permanent (7) Winning a Senate Award for researcher, technician and two PhD position as a Senior Lecturer at the sustained excellence in learning and students. I have a heavy teaching University of Essex). I am always teaching at Sheffield. load as I teach across all levels, inspired by women who are managing particularly final year students. I run VG: Why a career in science? to keep not just their careers going undergraduate admissions for the but also manage a hectic family life LR: I always enjoyed science at school department. I also run our summer too. One such inspiring person, whom and for me I knew I wanted a career vacation studentship scheme (to try I met on my time on The Physiological involving bioscience. I actually had a and get the current students into Society Council, is the Head of the place to study medicine, but dropped research and academia). I am also Education Committee Louise Robson. a grade in my physics A level and chair of the Education Committee at Recently I met up with Louise and ended up doing Physiology at Leeds The Society, and Member of Council (got in through clearing). This was posed her a few questions to find out and Exec. what drives her, who inspires her, actually the best thing that happened what she does in her spare time (if she as I quickly realised I loved the basic VG: What is your current research has any) and what her personal goals science side of human biology, area? How much time do you get to are. particularly physiology (I also had to devote to this?

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LR: I am interested in ion channels maternity leave, but I know that not in epithelial cells, particularly in the all women get the same treatment. So kidney and the airway. I am currently one thing that needs to change is the working on K+ (renal) and Cl– (airway) attitude to women taking time off to channels. I spend about half my time have a family. How to achieve this is on research, although I don’t get to another question, and one that I am spend as much time actually doing the not sure I can answer. One thing we research as I would like. can do is let young female researchers know that success can be theirs. The VG: Can you give us one of your key papers? Society is doing this in a number of different ways. For example, we LR: One of the first papers I published are running a mentoring scheme, + as a principal investigator: Na –alanine pairing junior female researchers – uptake activates a Cl conductance with experienced female academics. in frog renal proximal tubule cells The Society has also recently become via nonconventional PKC (2001). ID involved with the Daphne Jackson Millar and L Robson. Am J Physiol Renal Trust, part sponsoring a scholarship Physiol 280, 758–767. for a female physiologist to go back The first paper from an ongoing into research after taking a career collaboration: break. Valerie Gladwell with her family. The formation of the cAMP/protein VG: Is there any aspect of life you kinase A-dependent annexin 2– would like to improve on? to keep in touch. Coming back and S100A10 complex with cystic fibrosis juggling family life and work demands LR: I would like to spend less time conductance regulator protein (CFTR) was difficult. So perhaps the best at my desk pushing pieces of paper regulates CFTR channel function piece of advice I would give would around and have some time to get (2007). LA Borthwick, J Mcgaw, G be to make sure you are completely into the lab. Conner, CJ Taylor, V Gerke, A Mehta, L organised in all aspects of your life – it Robson and R Muimo. Mol Biol Cell 18, VG: How would you like to be makes it much easier to achieve in all 3388–3397. remembered? areas. VG: What are your career goals? LR: As someone who always put 100% VG: You are part of The Physoc (Where would you like to see yourself into everything they did. Council; how did you get involved? in 10 years?) What is your role? VG: Spare time! Do you have any? LR: I absolutely love my job, and LR: I joined Council when I was asked What do you do? wouldn’t want to do anything else, to take over as chair of the Education LR: I like to think I have a good work/ although I am looking towards Committee. This role involves life balance. Both of my children promotion to professor. I know that overseeing all of the educational are competitive swimmers, so my some senior academics take a large activities of The Society. It is quite a husband and I spend quite a lot of management role as they progress big job, but helped out by the great time at swimming pools so they can through their careers, but I am not staff we have in The Society office train or race. The club they belong sure that is for me. I enjoy my research and Members of the Committee as to (like most kids sports clubs) is run and teaching too much! well. Given that our activities cover on a voluntary basis, and we help VG: What have been your barriers/ the full spectrum from schools to out as much as possible. I sort out hurdles to overcome to get where you postgraduate/postdoctoral support, the gala entries, run the web page are now? the committee has a huge variety and actually teach little ones to swim LR: My biggest barrier was not being of schemes to run and evaluate. Of as well. I recently passed my level 1 eased into teaching when I started at course, we are always looking for swimming teacher qualification and Sheffield. As I was recruited to start new ways to improve our educational have also recently passed level 2 (it teaching straight away, I took on a full impact as well. As chair I also sit was somewhat scary doing exams teaching load from the word go. This on the Executive Committee and again after so long). This means I am meant that I had less time for research therefore play an important role in really busy, but I find the different in the first few years compared to taking suggestions and ideas to the activities I do at the club really keep others, and I know this has impacted other trustees to ensure that The me motivated at work. on the development of my research Society is doing the very best for its lab. As a female I cannot say any of Members. VG: You sound like you are a super the typical perceived barriers have hero but if you could be any superhero impacted negatively. I have a family, VG: What do you think could be what would you be? and had my first child when a postdoc done to improve retaining women in LR: Supergirl, so that I could fly to and then my second as a lecturer. For science? work and not have to use public both I took 7 months ‘off’, although LR: I received great support from my transport to commute every day! This I did do some work during that time bosses when pregnant and then on would give me more time at work.

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Exercise can help rewire the brain: neuroplasticity and motor cortex function in physically active individuals Recent evidence with magnetic brain stimulation in human subjects shows that participation in regular physical activity influences brain function by enhancing neuroplasticity in motor cortex, which could improve motor skill learning and neurorehabilitation in physically active individuals.

Regular exercise is known to have 2009). TMS is a non-invasive an impact on most physiological technique that gives an indirect systems, and has been shown to assessment of motor cortex activity, improve cardiovascular health, and offers significant advantages bone mineral density, and provide in temporal resolution over other a decreased risk for cancer, stroke functional imaging techniques. and diabetes. More recently, TMS activates excitatory (and epidemiological evidence has inhibitory) interneurons in the accumulated to suggest that cortex, producing descending John Semmler (left) and John Cirillo. physical activity may provide health- volleys in corticospinal neurons with protective benefits for the nervous during attention-demanding tasks projections to spinal motoneurons. system, including improvements compared with untrained control This results in a short-latency in several neurological diseases. In subjects (Colcombe et al. 2004). contraction of contralateral muscles, addition to these neuroprotective These studies suggest that regular with the amplitude of the muscle- effects, exciting new evidence has exercise provides neuroplastic evoked potential (MEP) from the emerged indicating that regular benefits to the ageing brain, and electromyogram (Fig. 2A) reflecting physical activity and exercise can may even slow the neural ageing the excitability of the neurons increase brain plasticity (i.e. the process in humans. responsible for the movement capacity to reorganize connections of that particular muscle. At the in the brain), which is a process While the majority of these studies motor systems level, plasticity is believed to be instrumental in the have focused on plasticity associated examined by using TMS to measure formation of memories and learning. with neurocognitive function, it is the change in excitability of motor These neuroplastic benefits of unknown whether regular exercise cortex neurons before and after exercise are not only important for is beneficial for neuroplasticity an intervention. Any long-lasting cognitive function, but may also within the motor cortex, which is (<1 hour) increase in motor cortex extend to the neuromotor system to vital for learning new motor skills. excitability is interpreted as a facilitate motor skill learning. Recent advances in techniques of change in one or more mechanisms responsible for neuroplasticity, with In humans, robust effects of transcranial magnetic stimulation long-term potentiation (LTP) thought exercise have been most clearly (TMS) have allowed us to address to play a major role. demonstrated in ageing populations this question in humans (Cirillo et al. during tasks that specifically assess neurocognitive function (Colcombe & Kramer, 2003). These effects have been neatly summarized in a meta-analysis of 18 intervention studies examining the effect of long-term aerobic fitness training on various measures of cognitive performance (Fig. 1). The outcome of this analysis clearly shows that participation in regular physical activity and exercise improves cognitive function in sedentary older adults, with the greatest improvement observed in complex executive-control processes involving coordination, planning and working Figure 1. Effect sizes from 18 interventional studies published between 1966 and 2001. Executive tasks rely on complex cognitive function such as planning, inhibition memory. Furthermore, functional and scheduling of mental procedures. Controlled tasks involve effortful processing magnetic resonance imaging such as a choice reaction time task. Visuospatial tasks assess the participants’ ability revealed that highly fit subjects show to transform or remember visual and spatial information. Speed tasks involve simple greater task-dependent modulation reaction time or finger tapping. Error bars show standard error of the mean. Data of activity in various cortical regions were redrawn from Colcombe & Kramer, 2003.

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Several experimental protocols through LTP-like mechanisms in such as age, sex, handedness have been devised for inducing cortical circuits (Stefan et al. 2000). and cognitive state. Using TMS, cortical plasticity in humans (see Recent studies show that the effects we found that the input–output Ziemann et al. 2008 for review). of PAS and motor skill training curve for a small hand muscle was One commonly used protocol to interact, suggesting that they involve steeper in active subjects (Fig. 2B), artificially induce changes in the overlapping changes in functionally suggesting increased excitability in human motor cortex is paired relevant neuronal circuits. the corticospinal pathway to muscles associative stimulation (PAS), which not directly involved in the exercise. has been deliberately adapted from In a recent study, we used PAS to Furthermore, we found a 40% larger similar protocols in brain slices and examine the capacity for motor MEP in the active compared with neuronal cultures that demonstrate cortex plasticity in a group of 14 the sedentary subjects after PAS spike timing-dependent synaptic highly active and 14 sedentary (Fig. 2C), suggesting that regular plasticity. The conventional PAS young subjects (Cirillo et al. physical activity involving aerobic approach in humans combines 2009). Based on aerobic physical exercise contributes to increased low-frequency, percutaneous activity assessed via questionnaire, neuroplasticity after PAS. These electrical stimulation of the median individuals in the active group findings indicate that regular nerve at the wrist with TMS over performed moderate or vigorous- exercise may offer benefits to motor the contralateral motor cortex. The intensity exercise (involving running cortex function that extend beyond TMS is timed to coincide with the or cycling) an average of 9 times the neural boundaries for control arrival at the cortex of the afferent per week for at least 60 min in each of the exercising limb. Although volley evoked 25 ms earlier by the session. In contrast, individuals in many mechanisms are possible, the peripheral stimulus. This protocol the sedentary group performed beneficial effects of exercise on brain results in substantial increases in no more than three sessions of plasticity are likely to be mediated by the amplitude of hand muscle MEPs, walking each week for 20 min each increased vasculature, blood flow or which are long lasting (30–60 min), session. All other characteristics growth factors that provide a more and are thought largely to occur were well matched between groups, supportive cortical environment.

Figure 2. A, averaged MEPs (n = 10) in the abductor pollicis brevis (APB) muscle obtained before and after PAS. The numbers indicate the percentage increase in MEP amplitude after PAS. B, TMS input–output curve in 14 sedentary and 14 active subjects. C, mean (± S.E.M.) MEP values obtained in 14 sedentary and 14 active subjects before, 5 min after (After 5) and 30 min after PAS (After 30). RMT, resting motor threshold. Data were obtained from Cirillo et al. (2009).

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An important extension of this plasticity in two sedentary and active subjects, particularly in the work is determining whether these two active subjects that took part early stages of training (Fig. 3). differences in neuroplasticity are in our original investigation. The Furthermore, increased MEP functionally important for learning task was a brisk thumb movement amplitudes and TMS input–output new motor skills. As a first step in to maximise acceleration in the curves in physically active individuals addressing this question, we have abduction direction. These data accompanied this improved obtained preliminary data on motor show improved motor performance learning after training. These performance and motor cortex and faster learning in the physically preliminary data suggest that there is increased motor cortex plasticity in physically active individuals, and that this is accompanied by improved ability to learn new motor skills. However, we cannot yet exclude the possibility that the increased plasticity in physically active individuals is influenced by genetic or epigenetic factors, which makes these individuals more likely to participate in regular physical activity. Nonetheless, these findings offer promising new insights into the benefits of regular exercise on the motor system, which may improve motor skill learning and neurorehabilitation in physically active individuals. John G. Semmler and John Cirillo Discipline of Physiology, School of Medical Sciences, The University of Adelaide, Australia

References Cirillo J, Lavender AP, Ridding MC & Semmler JG (2009). Motor cortex plasticity induced by paired associative stimulation is enhanced in physically active individuals. J Physiol 587, 5831–5842. http://jp.physoc.org/content/587/24/5831.full Colcombe S & Kramer AF (2003). Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci 14, 125–130. Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, Webb A, Jerome GJ, Marquez DX & Elavsky S (2004). Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A 101, 3316– 3321. Stefan K, Kunesch E, Cohen LG, Benecke R & Classen J (2000). Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123, 572–584. Ziemann U, Paulus W, Nitsche MA, Pascual- Leone Pascual A, Byblow WD, Berardelli A, Siebner HR, Classen J, Cohen L & Rothwell JC (2008). Consensus: Motor cortex plasticity Figure 3. A, mean peak thumb acceleration with brisk thumb training in 2 active protocols. Brain Stimul 1, 164–182. and 2 sedentary subjects obtained at the start (1–10 movements), middle (141– 150 movements), and end (291–300 movements) of training. B, mean APB MEP Acknowledgements amplitudes obtained before, immediately after (Training 1) and ~25 min later The work from the authors was supported (Training 2). C, TMS input–output curve before and after training in sedentary and by the National Health and Medical Research active individuals. Council of Australia.

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The physiology of Casino Royale: proteins to parkour

In the film Casino Royale, James mechanisms of these properties at Bond chases terrorist Mollaka over the molecular level? a construction site in Madagascar. Mollaka leaps from crane to rooftop Muscle force increases with the and from rooftop to ground, landing velocity because stretch causes under control and able to resume high positive strain in muscle cross­ running immediately. These stunts bridges. This slows their power are not just filmic tricks – Mollaka stroke leaving more and more pre-stroke bridges attached, as Martin (Sébastien Foucan) is a top class McDonagh exponent of free running or velocity increases (Pinniger et al. parkour (see www.youtube.com/ 2006a). Force increases with stretch watch?v=Q0e7akuSgKI ). Despite amplitude because stretch increases Muscle fibres, although beautifully Foucan’s skill the shock to the legs the strain in the elastic crossbridges evolved to act as brakes, do not is still enormous – 17 body weights considerably above the values found act alone. The shock of landing is for a 1.8 metre fall (Yeadon et al. in an isometric contraction. The also absorbed by the tendons to 2010). How can he absorb this shock force rises in proportion to the strain which the muscles are attached. without injury? In engineering, shock until bridge detachment limits the Tendons have a complex structure absorbers prevent high-impact forces maximum force to around twice the but are mainly composed of the isometric value. Furthermore, recent by creating constant deceleration elastic protein collagen. They have work has also suggested that greater over a given distance or stroke 70 times the Young’s Modulus of stretch favours the attachment of length. Springs produce high fully activated muscle, but their the second myosin head found on decelerations towards the end of stiffness relative to muscle is reduced all muscle crossbridges ( Brunello the impact and dashpots produce because their cross-sectional area is et al. 2007) thus increasing the high decelerations at the start, thus often 30–100 times smaller than the available force. Elastic proteins many industrial shock absorbers use a attached muscle. With lower stiffness such as titin within the sarcomere combination of the two. the tendon can provide a greater and transverse elastic connections proportion of the total lengthening So where are the springs and between myofibrils may also increase of the muscle–tendon complex. dashpots of human shock absorbers force when stretched (Pinniger et al. Millimetres of the tendon lengthening and how do they work? To answer 2006b). will be particularly large when the this we need to integrate research findings all the way from the molecular mechanisms of muscle cells to the neural control of falling and landing.

On landing the impact causes ankle, knee and hip joints to rotate. This stretches the muscles opposing the movement which lengthen under control, reducing joint rotations and acting as a brake. When muscles are braking and lengthening the relationship between force and velocity is quite different from A.V. Hill’s classic shortening force–velocity curve. Firstly, force increases with velocity (dashpot effect); secondly, force increases with the amplitude of stretch (spring effect); and thirdly, the force can be up to twice that produced by an isometric contraction. Figure 1 shows the combined effects of amplitude and Figure 1. Force–velocity relationship of muscle during stretch. Note how force velocity for a human muscle. These increases both with velocity and amplitude of stretch. Shortening would show properties make stretching muscle opposite velocity effects and no amplitude dependence. The data are from the first a particularly effective brake; the dorsal interosseus muscle of the human hand and include tendon effects (see text). greater the shock the greater the Tendon effects reduce the imposed amplitude and velocity ‘seen’ by the muscle. force response. So what are the Group data from Cook & McDonagh (1995).

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extensor muscle brakes combined with the appropriate joint angle prior to impact (Yeadon, 2010)

Muscle–tendon complexes are more than just passive suspension systems, as their damping and the spring constants can be modulated by varying the activation of the muscle component. This is an active suspension system, exactly the type of suspension banned by Formula 1! With too little activation the joints over rotate and the subject collapses in a heap and cannot continue running. With too much activation muscles are stiff and the subject lands like a steel pin, joints under rotate, impact forces are high and bones may be broken. How does the brain get the activation right?

To tackle this question we varied the Figure 2. Effect of fall height on timing and amplitude of muscle activation. Fall impact force by asking subjects to heights increase from top to bottom. The dashed line marks take off and the arrow fall from different heights whilst we marks the start of the activation build-up (using an objective criterion). Note time recorded muscle activations from between dashed line and arrow (latency) increases with fall height but time between several flexor and extensor muscles of arrows to touch-down (duration) is relatively constant. Note greater amplitude and the leg (Santello et al. 2001). Figure steeper rise of EMG for greater heights. Single subject data for the ankle plantar 2 shows the results. The further the flexor m. soleus. In later experiments similar results were obtained from ankle plantar subjects fell the greater the activation flexor m. gastrocnemius and knee extensor m. rectus femoris. From Santello & of the muscles during the flight. Thus, McDonagh (1998). the central nervous system (CNS) tendon is long and thin and the because all the joints of the leg are predicts the required activation for muscle short and fat. For example, it involved. The sum of their rotation each height rather than setting one can be calculated from known values amplitudes (e.g. 33 deg ankle, activation level for all heights. The of Achilles tendon stiffness and peak 66 deg knee, 54 deg hip for a 1 m brain also needs to predict the timing impact forces that this tendon could fall) determines the distance the of the impact. A simple strategy stretch by 13 mm or 16% following a centre of gravity of the body moves would be to contract all the muscles fall from 0.8 m. Tendon stretch has following impact. This is equivalent at the same delay after take-off. Is the advantage of both increasing the to the stroke length of a mechanical this what happens? No, as Fig. 2 absorption of energy and preventing shock absorber. In simple terms shows, the longer the fall, the longer over-lengthening and damage to F = m g h/∆h, with gravitational the brain waits before triggering the muscle fibres (Cook & McDonagh, acceleration (g), the longer the contraction. However, the duration of 1995). stroke length (∆h), the smaller the the next time period, from the start average force (F) experienced over of muscle activation to floor contact, The energy of impact must be the stroke length by the centre of is relatively constant, irrespective of dissipated as well as absorbed, gravity of the subject’s mass (m) fall height. This period also shows otherwise on landing the subject will and the smoother the landing from how the motor programme increases be thrown upwards again by elastic height (h) ( Minetti et al. 1998). force. As greater fall heights are recoil. Energy is dissipated as heat Joint rotations and centre of gravity perceived, activation rises more by the muscle component which excursions increase with higher falls steeply so matching muscle force to acts as a damper as well as a spring. (Santello et al. 2001). In parkour the the expected impact. In summary, Damping occurs when impact forces impact force is further reduced by a the brain appears to predict both the cause actin and myosin filaments to roll on landing which increases the force and timing of impact and to slide apart, detaching crossbridges distance and surface area over which pre-programme the muscle activation as they go. In summary, the muscle– the shock is absorbed. Compression required to deal with it. The tendon complexes of the body shock to bones on impact is also mechanisms behind these predictions are a multi-mass, damped-spring minimized by landing with slightly require much further investigation suspension system. flexed joints which rapidly rotate. but probably involve a combination The absorption and dissipation of In addition, co-contraction of the of visual distance estimation, mental energy is sufficient to brake a fall flexors ensures correct stiffness of the clocks and sensorimotor memories.

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We can now answer, in a nutshell, the ‘Casino Royale’ question. Sébastien Foucan can absorb the shock of parkour because muscle–tendon complexes have evolved many ingenious shock-absorbing proteins, and mechanisms. The brain then tunes these shock absorbers using both pre-programmed control and adjustable reflexes to achieve injury-free landings over a wide range of impact conditions.

Martin McDonagh School of Sport and Exercise Sciences, University of Birmingham, UK

References Brunello E, Reconditi M, Elangovan R, Linari M, Sun Y, Narayanan T, Panine P, Piazzessi G, Irving M & Lombardi V (2007). Skeletal muscle resists stretch by rapid biding of the second motor domain of myosin to actin. Proc Natl Acad Sci U S A 114, 20115–20119. Figure 3. False floor separates pre-programmed and reflex responses. Fall of 0.7 m with false floor at 0.45 m. The three vertical dashed lines mark, from left to right: Cook CS & McDonagh MJN (1995). Force take off, false floor, and hard floor. Passage through the false floor is recorded by an responses to controlled stretches of infra-red sensor. Taking gastrocnemius as an example, note build-up of activation in electrically stimulated human muscle–tendon preparation for false floor, dying away of activity and then reflex at hard floor impact. complex. Exp Physiol 80, 477–490. Single subject data from McDonagh & Duncan (2002). Duncan A & McDonagh MJN (2000). Stretch reflex distinguished from pre-programmed However, prediction is not the whole as the subject descended below the muscle activations following landing impacts story. An examination of Fig. 2 shows false floor to impact on the hard floor. in man. J Physiol 526, 457–468. that EMG activity continues beyond On impact, joints rotated and a reflex McDonagh MJN & Duncan A (2002). impact. Is this a continuation of the response occurred at a mean latency Interaction of pre-programmed control and pre-programmed activation or a of 56 ms. Thus, the control of landing natural stretch reflexes in human landing reflex triggered by the impact? To depends on both pre-programmed movements. J Physiol 544, 985–994. settle this question we tricked the and stretch reflex responses. Minetti AE, Ardigo LP, Susta D & Cotelli F brain into expecting a landing after (1998). Using leg muscles as shock absorbers; Our data had one further surprise a short fall (0.45 m) but actually theoretical predictions and experimental in store. The amplitude of the reflex provided a lower landing surface at results of drop landing. performance. at hard floor impact in the ‘via false Ergonomics 41, 1771–1791. 0.7 m (Duncan & McDonagh, 2000). floor’ trials was double that for the Subjects expected to land on a false Pinniger G, Ranatunga KW & Offer G (2006a). direct fall (McDonagh & Duncan, What structures bear the tension and store floor which they saw 0.45 m below 2002). However, joint rotations energy in lengthening muscle? Physiology the take-off platform. This floor at impact were the same in each News 65, 1–2. easily gave way on contact with condition and there was no joint Pinniger G, Ranatunga KW & Offer G joint rotation and muscle stretch rotation at false floor level. Thus, (2006b). Crossbridge and non-crossbridge only occurring when the subject there was a larger response for the contributions to tension in lengthening rat hit the hard floor a further 0.25 m same stimulus i.e. an increase in muscle: force-induced reversal of power stroke. J Physiol 573, 627–643. below. Falls to visible hard floors at gain of the reflex loop. Eventually we 0.45 m and 0.7 m provided controls. concluded that this increase in gain Santello M & McDonagh MJN (1998). The The results were clear. The reflex was triggered by the non-occurrence control of timing and amplitude of EMG was only present if joints rotated. activity in landing movements in humans. Exp of expected joint rotation at the Physiol 83, 857–874. Figure 3 shows how the false floor predicted time of impact i.e. at trials separated the pre-programmed the false floor. In other words, the Santello M, McDonagh MJN & Challis JH from the reflex components. This (2001). Visual and non-visual control of absence of an expected event is as landing movements in humans. J Physiol 537, is particularly obvious for the much a signal for the CNS as the 313–327. gastrocnemius muscle. Muscle presence of an unexpected one. This Yeadon NR, King MA, Forrester SE, Caldwell activation whilst airborne was clearly idea is probably widely true in many GE & Pain MTG (2010). The need for muscle timed to the impact with the false other CNS control systems and co-contraction prior to landing. J Biomech 43, floor. This activation then died away deserves much further investigation. 364–369.

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Vagal baroreflexes in astronauts during spaceflight Astronauts returning to Earth from space commonly experience orthostatic symptoms, and rarely, frank syncope. Since a terrestrial analogue of space exposure, prolonged head-down bed rest, impairs both orthostatic tolerance and vagal baroreflex function, we studied the effects of spaceflight on astronauts’ vagal baroreflexes. We document significant vagal baroreflex impairment in space, which, considered with earlier studies, indicates that exposure to weightlessness diminishes vagal and augments sympathetic cardiovascular influences.

Before the manned space era, Fritsch, 1993), described originally scientists expressed trepidation by British Royal Air Force Flight regarding the potentially baleful Lieutenants, J Ernsting and DJ Parry consequences of human exposure (1957), to elicit entire sigmoidal to the totally unknown physiological baroreceptor stimulus–R–R interval influences of microgravity. On April response relations during one held 12, 1961, the Soviets launched the expiration. Pressure changes applied first human into space, Yuri Gargarin. non-invasively (and therefore, He returned to Earth after an 89 min safely) to the neck provoke parallel orbital spaceflight with no apparent linear changes of baroreceptive disability. However, the ninth man in carotid artery diameter (Kober & space, the American Wally Schirra, Arndt, 1970), which alter vagal returned after 9 h and 13 min in and sympathetic neural outflows space and experienced dizziness and trigger baroreflexes responses. upon standing up. Figure 1 shows American astronaut, Rhea Seddon performing baroreflex Orthostatic symptoms are common research on herself in space (left), a in astronauts returning from space; stylized neck pressure profile (A), an indeed, Buckey et al. (1996) reported Dwain Eckberg actual cardiac R–R interval response that 9 of 14 astronauts could not (B), and responses of a different stand quietly for 10 min, and two et al. 1990), it seemed reasonable to astronaut before and during of the others felt lightheaded at the test the hypothesis that microgravity spaceflight (C). end of 10 min. Since a terrestrial exposure impairs human baroreflex analogue of microgravity, prolonged responsiveness. We reported responses of 13 head-down bed rest, provokes both healthy astronauts studied before, orthostatic hypotension and vagal To study this possibility, we modified during and after two space shuttle baroreflex impairment (Convertino a neck chamber device (Eckberg & missions, in a recent issue of The

Neck pressure (mmHg) R-R interval (s) 1.10 40 C

0 1.00 -40 Earth A -80 R-R interval (s) 0.90 0.90 B 0.85 0.80 Space 0.80 D-2 Astronaut 3 0.75 0.70 0.0 2.5 5.0 7.5 10.0 70 110 150 190 Time (s) Carotid distending pressure (mmHg) Figure 1. Astronaut Rhea Seddon performing baroreflex research on herself in space, and baroreflex responses of other astronauts on Earth and in space. Figure 1 Physiology News | No. 81 | Winter 2010 | www.physoc.org SCIENCE NEWS AND VIEWS PN 33

MeanMean and and 95% 95% confidenceconfidence intervals intervals MeanMean and and 95% 95% confidence intervals intervals forfor baseline baseline measurementsmeasurements forfor baroreflex baroreflex R-R R–R intervalsintervals relations 130 A P = 0.064 120 1.0 (s) Systolic (mmHg) pressure P = 0.039 110 Minimum P = 0.015 across days 0.8 across days A

80 B P = 0.005 P = 0.051 0.2

70 (s) Range (mmHg) Diastolic pressure * 0.1 P = 0.051 B 60 P < 0.001 across days across days 60 ** C 9 P = 0.080 P = 0.037 50 8 R-R Pulse (mmHg) pressure P = 0.009 * 7 40 P < 0.001 across days (s) intervals across days C

P = 0.049 across days 1.2 P = 0.060 P = 0.020 1.1 D 1.1 1.0 (s) * (s) 1.0 * 0.9 P = 0.003 Maximum R-R interval R-R D 0.9 across days 0.8 2 4 6 8 1 4 7-10 2 4 6 8 1 4 7-10 Flight day Postflight day Inflight day Postflight day Landing Landing Preflight Preflight Figure 4 Figure 2 Figure 2. Mean haemodynamic measurements and 95% Figure 4. Baroreflex parameters of astronauts before, confidence intervals for all 128 subjects and all sessions. during and after spaceflight.

Journal of Physiology (Eckberg et al. higher on landing day than on all stimulus–sinus node response 2010). This research was remarkable other study days (Holm–Sidak test); relations for all astronauts before in the sense that the number of pulse pressure on landing day was and during spaceflight. With the subjects was larger than nearly all significant lower than on flight day 5, exception of flight day 4, all average studies conducted on astronauts in and pulse pressure on postflight relations were lower in space than space. Figure 2 shows mean (±95% day 4 was significantly higher than during preflight measurements. confidence intervals) haemodynamic preflight, landing day and postflight Ninety-five per cent confidence measurements, with data recorded day 1; and mean R–R intervals were intervals at higher carotid distending in space shown in red. Systolic, significantly lower on flight day 8 pressures did not overlap by flight diastolic and pulse pressures varied than preflight. day 8. Figure 4 shows changes significantly across days (repeated of individual parameters of measures analysis of variance). Figure 3 shows mean and 95% sigmoidal vagal baroreflex relations Diastolic pressure was significantly confidence intervals of baroreflex for all sessions. In general, all measurements declined steadily Mean andMean 95% and 95% confidence confidence intervals intervals before before as the space mission wore on, and andand during during spaceflight spaceflight returned towards preflight levels after astronauts returned to Earth. Preflight vs. Preflight vs. Preflight vs. Preflight vs. flightday 2 flightday 4 flightday 6 flightday 8 Our study fleshes out changes of baroreflex function in space and 1.2 A B C D extends earlier research (Cox et al. 2002), in which sympathetic and 1.1 vagal baroreflex responses were elicited during spaceflight with 1.0 Valsalva’s manoeuvre. These results, with those of another study of R–R intervals (s) 0.9

R-R intervalsR-R (s) astronauts (Ertl et al. 2002), suggest N = 13 N = 12 N = 11 N = 13 that although humans function very well, exposure to microgravity leads 70 130 190 70 130 190 70 130 190 70 130 190 to reduced vagal and augmented CarotidCarotid distending distending pressurepressure (mmHg) (mmHg) sympathetic influences in space. Figure 3. Sigmoidal baroreflex relations before and during spaceflight. Microgravity exposure reduces Figure 3

Physiology News | No. 81 | Winter 2010 | www.physoc.org 34 PN SCIENCE NEWS AND VIEWS blood volume, atrophies anti-gravity Phantom hands: a window into how we muscles and impairs vestibular function. Progressive impairment perceive limb position and movement of vagal baroreflex function may The senses of limb position and movement are critical to the represent neuroplastic changes occurring in response to major brain’s ability to control movement of the body. These senses changes of the autonomic milieu are derived from multiple signals and previously it was thought in space. As such, these results that all these signals came from the muscles, skin and joint. may provide a unique perspective Recent work using ‘phantom’ limbs in healthy subjects has on short-lived degradation and shown that signals originating in the brain itself also contribute subsequent restoration of clinically important human baroreflex to the senses of limb position and movement. function. Dwain L. Eckberg Departments of Medicine and Physiology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center and Medical College of Virginia at Virginia Commonwealth University, Richmond, VA, USA

References Buckey JC Jr, Lane LD, Levine BD, Watenpaugh DE, Wright SJ, Moore WE, Gaffney FA & Blomqvist CG (1996). Orthostatic intolerance after spaceflight. J Appl Physiol 81, 7–18. Convertino VA, Doerr DF, Eckberg DL, Fritsch JM & Vernikos-Danellis J (1990). Head-down bed rest impairs vagal baroreflex responses and provokes orthostatic hypotension. J Appl Physiol 68, 1458–1464. Cox JF, Tahvanainen KUO, Kuusela TA, Levine BD, Cooke WH, Iwase S, Saito M, Sugiyama Y, Ertl AC, Biaggioni I, Diedrich A, Robertson RM, Zuckerman JH, Lane LD, Ray CA, White RJ, Pawelczyk JA, Buckey JC Jr, Baisch FJ, Blomqvist CG, Robertson D & Eckberg DL (2002). Influence of microgravity on astronauts’ sympathetic and vagal responses to Valsalva’s manoeuvre. J Physiol 538, 309–320. Eckberg DL & Fritsch JM (1993). How should The authors and experimental equipment. From left to right: Simon Gandevia, Lee human baroreflexes be tested? News Physiol Walsh and Janet Taylor. Sci 8, 7–12. Eckberg DL, Halliwill JR, Beightol LA, Brown TE, Taylor JA & Goble R (2010). Human vagal A healthy person will always know increasing length of an adolescent’s baroreflex mechanisms in space. J Physiol 588, the position and posture of their legs during a growth spurt is very 1129–1138. http://jp.physoc.org/content/588/7/1129.long body in space. Even with our eyes slow compared to the changes that closed we know the position and our body schema has to follow when Ernsting J & Parry DJ (1957). Some observations on the effects of stimulating the size of our arms, legs, fingers, head, we move our limbs because limb stretch receptors in the carotid artery of man. etc. This is possible because the movements cover large distances in J Physiol 137, 45P–46P. brain maintains a ‘body schema’, a fractions of a second. The relatively Ertl AC, Diedrich A, Biaggioni I, Levine representation of our body and its slow changes to limb length and BD, Robertson RM, Cox JF, Zuckerman JH, position in space. This body schema size could easily be updated in the Pawelczyk JA, Ray CA, Buckey JC Jr, Lane LD, cannot simply be a fixed ‘map’ of our body schema over time by vision Shiavi R, Gaffney FA, Costa F, Holt C, Blomqvist CG, Eckberg DL, Baisch FJ & Robertson D body as our bodies are constantly and other senses and, because (2002). Human muscle sympathetic nerve changing position and size. Some such changes are small over long activity and plasma noradrenaline kinetics in of our body’s parameters change periods of time, it is not so critical space. J Physiol 538, 321–329. slowly. The length of our limbs, the for the body schema to track these Kober G & Arndt JO (1970). Die Druck- size of our muscles or circumference precisely. However, the large and Durchmesser-Beziehung der A. carotis of our waist changes as we grow, fast changes in joint angle that are communis des wachen Menschen. Pflugers Arch 314, 27–39. exercise and eat. However, even the associated with every voluntary

Physiology News | No. 81 | Winter 2010 | www.physoc.org SCIENCE NEWS AND VIEWS PN 35 movement must be tracked One way the brain can rapidly from the rate of change of length continuously and accurately so that update the body schema regarding of the muscles the velocity of joint we know at all times where our body movements is with information movements can be determined. and limbs are in space. This ability coming from the periphery. Interpretation of any muscle spindle is critical to the control of body Classically the peripheral receptors signal from a contracting muscle is movements. To perform the simple in the skin form the basis of our not simple because the size of the task of picking up a glass of water sense of touch. In addition to this signal is modified in complex ways by we must know the position of our role, some skin receptors also the fusimotor system. The signal also fingers, hand and arm, in addition signal how much the skin stretches diminishes if the muscle shortens to the location of the glass. It can be around a joint as it moves and thus too rapidly. Receptors located in the said that we know all these things provide useable information about joint capsule can also contribute because we can see our fingers, joint movement and position (e.g. information about joint movement. hand and arm as it picks up the Collins et al. 2005). Muscle spindle All these signals travel through large- glass. That is true, but if you know receptors can signal the length diameter nerves to the brain, which where the stationary glass is, you of muscles as well as their rate of means that the information gets can pick it up with your eyes closed. change of length. Muscle spindles there very fast, as is required to keep Furthermore, you can still do this if are sensitive to muscle vibration and the brain’s body schema updated there are unknown obstacles and with ongoing movements. These classic experiments by Goodwin et al. perturbations between your hand signals from the muscles, skin and (1972) showed that vibration of limb and the glass. This means that your joints provide critical information muscles induces illusory movements brain can track the position and about joint movement, and losing of the limbs. From the length of its movements of your arm, hand and this information results in serious surrounding muscles, the angle of fingers without the aid of vision. disability (Cole, 1991). However, the joint can be determined and How is this done? input from the peripheral receptors is not the only way the body schema is updated during movement.

Amputees often continue to perceive a limb or body part that has been removed. These sensations are referred to as ‘phantoms’ and can be explained by the body schema persisting in the brain, despite the limb having been amputated and no longer providing meaningful sensory information about itself. Another interesting thing about phantom limbs is that they can be ‘moved’. Often this is described as a phantom which itself is static but which moves along with the remaining part of the limb or a phantom that moves when partially amputated muscles, that were once involved in moving the missing limb, are activated (e.g. Reilly et al. 2006). However, some amputees are able to make movements of joints within a phantom that has none of its relevant musculature remaining. For example, an amputee whose arm Figure 1. A photograph of the experimental set-up used in Walsh et al. (2010). The is amputated at the shoulder may subject’s right arm rested on a table with the hand fixed into a manipulandum. In the make phantom finger movements. experiment a towel (not present in photograph) covered the subject’s right arm so they could not see their forearm, hand and wrist. The manipulandum could be locked It is possible to induce temporary into position and a load cell was used to train the subject to perform the efforts experimental phantoms in human before the cuff was inflated. The cuff was inflated to 250 mmHg around the upper subjects. A simple way of doing this right arm. The subject remained relaxed for 30–35 min, during which the ischaemic block developed. After the block was complete the subject performed voluntary for the wrist and hand is to inflate a efforts with their right arm and controlled the pointer with the left hand to indicate blood pressure cuff around the upper any perceived phantom movements. arm (Fig. 1). This cuts off the blood

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muscles are activated, how strongly they are activated, and for how long, is used to update the body schema. This information can give an accurate indication of the movement if there are no unexpected events. This mechanism is likely to be the one that allows amputees to move their phantom limbs.

It is not a new idea that information about motor commands could be used to tell us about the position and movements of our limbs. However, the idea was unpopular for most of the last century, despite the dominance of these signals in oculomotor theory (e.g. Donaldson, 2000). Over the last few years, Figure 2. Movements of a phantom hand during voluntary efforts. In our recent however, there has been increasing study (Walsh et al. 2010) subjects had their forearm, wrist and hand anaesthetised evidence that these signals which and paralysed by a cuff around the upper arm. When the block was complete subjects were asked to make voluntary efforts with their paralysed and anaesthetised originate in the brain combine with wrist and indicate with a pointer any movements that they perceived. The filled those sensory signals from the limbs hands (index and middle finger are shown) represent the actual position of the to give us our complete senses of subjects’ hand. The blue-outlined hands show the mean size of the phantom limb position and movement. The movements indicated by subjects during a voluntary effort that was 1 s long. The big question now is how do these red-outlined hand shows the mean size of the phantom movements reported by two classes of signals interact with subjects during a 5 s voluntary effort. The speeds of the movements produced by the each other to produce these critical four voluntary efforts shown are ranked by the terms slow, medium, fast and fastest. senses that we rely on every time we Subjects indicated that they perceived movements of their phantom which were bigger when they made stronger efforts or longer efforts and faster if they made make a movement. stronger efforts. Lee D. Walsh, Simon C. supply to the arm below the cuff. adopting a new position. If subjects After 30-40 min the arm will become made longer-duration efforts their Gandevia and Janet L. Taylor anaesthetised and paralysed. Motor phantom wrist moved further and if Neuroscience Research Australia and nerves cannot conduct commands they made stronger efforts it moved the University of New South Wales, to move the arm below the cuff further and faster (Fig. 2). Sydney, Australia and no sensory information is generated. Despite the lack of When we make movements the References brain generates central signals that sensory information, subjects Cole J (1991). Pride and a Daily Marathon. continue to experience the presence ultimately result in motoneurone Gerald Duckworth & Co., London. output to the appropriate muscles, of their anaesthetised and paralysed Collins DF, Refshauge KM, Todd G & Gandevia forearm, wrist and hand. That is, causing them to contract and SC (2005). Cutaneous receptors contribute they experience a phantom. We used move the limb. These signals are to kinesthesia at the index finger, elbow, and this method in a recent study (Walsh commonly referred to as ‘motor knee. J Neurophysiol 94, 1699–1706. et al. 2010) and once subjects were commands’ and our results Donaldson IM (2000). The functions of the paralysed and anaesthetised we suggest that information about proprioceptors of the eye muscles. Philos Trans asked them to make efforts to flex these commands is used to update R Soc Lond B Biol Sci 355, 1685–1754. or extend their wrist and to indicate the body schema regarding limb Goodwin GM, McCloskey DI & Matthews PBC what happened with a pointer. movements. There is no sensory (1972). The contribution of muscle afferents The subjects indicated that when information coming back to the to kinæsthesia shown by vibration induced they made voluntary efforts their brain from the anaesthetised wrist, illusion of movement and by the effects of paralysing joint afferents. Brain 95, 705–748. phantom wrists moved in the same but while the motor commands direction as their effort. If they made cannot get to the paralysed wrist Reilly KT, Mercier C, Schieber MH, Sirigu A (2006). Persistent hand motor commands in an effort into flexion with their wrist muscles to activate them, they the amputees’ brain. Brain 129, 2211–2223. they perceived their wrist to move are still generated by the brain into flexion, despite the muscles and presumably still undergo their Walsh LD, Gandevia SC & Taylor JL (2010). Illusory movements of a phantom hand grade being paralysed. This sensation normal processing. The idea is that with the duration and magnitude of motor was one of continuous movement when the brain generates a motor commands. J Physiol 588, 1269–1280. rather than of the phantom simply command, information about which http://jp.physoc.org/content/588/8/1269.long

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Cystic fibrosis: a lesson in chemistry Paul Quinton and Ruth Muchekehu examine a (micromolecular) sticky problem Physiology and medicine usually look afflicted by thick mucus in CF do not to the hard sciences for instruction. have this capacity to reabsorb fluids. However, the pathogenic mucus in The facts thus dictate that something the disease cystic fibrosis (CF) may be is still missing in our understanding Paul Quinton (left) and Ruth Muchekehu instructive for physics and chemistry of the physics and chemistry of – – in the forming of mucus gels. The mucus gel expansion. The disease function inhibits both Cl and HCO3 – – expansion of mucins into mucus gels pathophysiology implicates HCO3 . transport. Concurrent losses of HCO3 is largely understood in terms of the secretion occur in tissues affected exchange of monovalent for divalent Both mucus and bicarbonate equip by abnormal mucus in CF, and the the body with a protective gel – cations in anionic mucin networks loss of HCO3 transport seems to (Verdugo, 1991). Something may that coats the surfaces of hollow correlate with severity of the CF be missing though, since the cause organs, providing a physical barrier pathology (Choi et al. 2001). of thick, sticky mucus in CF patients and chemical buffer that guard the In the female reproductive tract, still perplexes physiologists and epithelial surface. Mucus production must be delicately balanced; too mucus viscosity and bicarbonate biochemists more than 60 years after little mucus leaves cells vulnerable change inversely during the the first descriptions of the disease. to solid and chemical irritants as well menstrual cycle. When HCO – is Some clues may come from the 3 as bacterial and viral pathogens, and at its maximum concentration abnormally thick mucus and defects too much mucus leads to stagnation, at ovulation, mucus viscosity is in bicarbonate secretion (HCO –) 3 inflammation and infections. As the minimal, and when HCO – is lowest at found in CF. 3 predominant extracellular buffer, the follicular phase, mucus viscosity – – Mucin molecules, the main bicarbonate (HCO3 ) must support is at its peak. HCO3 douching component of gel-forming mucus, gastroduodenal defence, suspend improves sperm penetration of are extremely long highly charged bile, stabilize digestive pro-enzymes, cervical mucus by reducing the anionic polymers that are stored in impede bacterial binding and serve viscosity of cervical mucus. This mucus cell granules at 1/1000 of as a critical adjuvant to antibacterial suggests the coordinated changes – their final volume after secretion. defensins. It is perhaps no marvel in mucus and HCO3 are not – To effect this tight, pre-secretory that mucus and HCO3 are allies, but coincidental, especially given that packing, the strong electrostatic are they more intimately involved? mucus thinning is absent in women repulsion of mucin negative charges with CF. All these observations imply CF provides clues that intrinsically – that HCO3 attends mucus viscosity. is neutralized by protons and high – 2+ link mucus and HCO3 . CF is a concentrations of divalent Ca . Until – hereditary disease caused by How, then, can HCO3 affect the now, the physical chemistry of mucin mutations in the gene that encodes physical properties of mucus? We polymer expansion during secretion the cystic fibrosis transmembrane surmise that, normally, secreted relied principally upon a Donnan -– conductance regulator (CFTR) HCO3 enables mucin expansion by effect thought to be due to simply Cl– channel protein, whose loss of sequestering the bound Ca2+ and exchanging these bound cations for mobile monovalent K+ and/or Na+ that almost instantly ‘hydrates’ the mucin molecules by about 1000-fold (Verdugo, 1991). However, the fluids that accompany mucus secretion in CF are replete with Na+ and K+, and yet the mucus afflicting the many glands in CF remains thick and adhesive.

Currently, the thick mucus in CF is generally assumed to be due to an Figure 1. The role of bicarbonate in mucus release. Highly condensed polyanionic abnormal hyperabsorption of fluid mucins are packaged within granules by virtue of high intragranular concentrations from secreted mucins. For example, of Ca2+ (shown) and H+ that shield negatively charged sites on mucins from 2+ + it is thought that water is excessively electrostatic repulsion. Sequestering Ca or buffering H from mucins immediately upon release from the cell allows the electrostatic repulsion of the fixed negative absorbed from mucus secreted charges to rapidly expand condensed mucins (right side). The presence of onto the airway surface in CF lungs – 2+ + extracellular HCO3 ensures unsheilding by sequestering the Ca and H of mucins. In making it difficult to remove. – the absence of HCO3 , excessive shielding remains, resulting in less expanded, more However, many of the organs viscous mucus.

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H+ from secreted mucins. This will expose negative charges, enabling electrostatic forces to vigorously and rapidly open the mucin molecule – (Fig. 1). That is, HCO3 changes the dynamics of mucin expansion by competing with the fixed anions of the mucin molecules for Ca2+ and H+ rather than Na+ and K+ competing with Ca2+ for the fixed anionic sites on mucins.

To test this notion, we used the female reproductive tract of wild type (WT) and CF ∆F508 mice mounted in a custom-fabricated Figure 2. Measurements of fluid secretion. One uterine horn is attached to a glass perfusion chamber. The lumens were capillary. The other uterine horn and the vaginal end are ligated to form a closed sac. Agonist-induced fluid secretion forces fluid into the capillary hydrostatically, and the perfused and bathed basolaterally – rate of secretion is measured by following the fluid meniscus in the capillary with a with either HCO3 -replete or – microscope micrometer. HCO3 -depleted Ringer solution and stimulated to acutely release mucus into the luminal perfusate. In wild type mice, mucus release was severely impaired in the absence – of extracellular HCO3 . In the CF ∆F508 homozygous reproductive tract, or when CFTR was inhibited pharmacologically in wild type tissues, mucus release was also significantly depressed (Muchekehu & Quinton, 2010).

Cyclic adenosine monophosphate (cAMP)-mediated fluid secretion is depressed in CF and may be important for mucus discharge. We tested the importance of fluid secreted from the reproductive tract by canulating one horn of the closed uterine sac with a glass capillary (Fig. 2). Fluid secretion was monitored by the displacement of the air–liquid meniscus in the capillary. In contrast to mucus release, stimulated fluid secretion – was not dependent on HCO3 or on CFTR function under these – conditions. Moreover, without HCO3 , mucus remained ‘trapped’ in the lumens of the uterine glands (Fig. 3) (Muchekehu & Quinton, 2010).

These findings present a new role – for HCO3 as a critical element in mucus release and in the regulation of mucus viscosity generally. Mucus Figure 3. Mucus is retained in the uterine glands in the absence of HCO –. Uterine 3 thinning at the ovulatory stage of the tissue was stimulated with PGE2 + carbachol for 20 min before fixing. In the presence – menstrual cycle allows the passage of serosal HCO3 minimal amounts of mucus remain in the glands. In the absence – of sperm through the reproductive of serosal HCO3 , MUC5B labelling demonstrates significant mucus retained in the lumen of the glands. MUC5B mucin staining (red) counterstained with DAPI (blue) to tract, but this role is not limited to visualize the nuclei. Scale bar, 25 μm. the reproductive tract as mucus

Physiology News | No. 81 | Winter 2010 | www.physoc.org SCIENCE NEWS AND VIEWS PN 39 release in the small intestine is also – Sympathetic nervous system and volume- HCO3 dependent (Garcia et al. 2009). Moreover, the principal gel-forming regulatory hormones: interactions during mucin of the gut (MUC 2) is not the same as in the uterus (MUC dehydration 5B); and the viscosity of the third Sympathetic nerve activity and volume-regulating hormones major gel-forming mucin (MUC 5AC) defend blood pressure and blood volume during dehydration. during stimulated secretion from Recent findings showing interactions between these systems cultured cells is markedly dependent – give us further insight into the complex adaptations to on extracellular HCO3 levels (Chen et al. 2010). Adding to this, the dehydration. common viscid mucus pathology The ability of the human body affecting different mucins secreted to adapt to and protect from by disparate organs in CF all strongly dehydration has fascinated imply that HCO -– is a common and 3 physiologists for centuries and yet necessary attendant to normal new insight continues to be gained mucus expansion. into the mechanisms involved. In a certain sense then, the Further understanding of these tables of the sciences may be interactions has broad implications turned as the physiology of the in healthy populations, from the female reproductive tract and the athlete to the elderly, as well as Nisha Charkoudian (left) and Jennifer pathophysiology of CF offer new patient populations, from the acutely Rabbitts. lessons for chemistry and physics on dehydrated surgical patient to the how mucin polymer gels expand. acutely or chronically ill medical of volume-regulating hormones, patient. including angiotensin, aldosterone Ruth W. Muchekehu1 and and vasopressin, which minimize Paul M. Quinton1, 2 Dehydration, along with the losses in plasma volume via associated changes in blood volume 1Department of Pediatrics-0830, antidiuretic effects on the kidney. and plasma osmolality, elicits a School of Medicine, University of range of physiological responses Recently, evidence has emerged California–San Diego, 9500 Gilman which must be integrated in order that there is an interaction between Drive, La Jolla, CA 92093-0831, USA to protect blood pressure and volume-regulating hormones and the 2Division of Biomedical Sciences, blood volume, thus maintaining sympathetic nervous system which is University of California–Riverside, perfusion pressure to vital organs not yet fully understood. Many of the Riverside, CA 92507-0121, USA such as the brain. In a dehydrated volume-regulating hormones have individual, the sympathetic been shown to alter sympathetic References nervous system is activated: neural control mechanisms in several Chen EY, Yang N, Quinton PM & Chin WC increases in cardiac sympathetic animal models (Fink, 1997; Hasser (2010). A new role for bicarbonate in mucus formation. Am J Physiol Lung Cell Mol Physiol activity cause increases in heart et al. 2000). For example, Cox and 299, L542–L549. rate and stroke volume, while Bishop found that angiotensin Choi JY, Muallem D, Kiselyov K, Lee MG, increases in vascular sympathetic administered exogenously to rabbits Thomas PJ & Muallem S (2001). Aberrant activity cause vasoconstriction affects sympathetic nerve activity – CFTR-dependent HCO3 transport in mutations and maintenance of arterial (Cox & Bishop, 1991). Furthermore, associated with cystic fibrosis. Nature 410, 94–97. pressure via increased peripheral Matsukawa et al. (1991) showed resistance. Simultaneously, the that exogenously administered Garcia MA, Yang N & Quinton PM (2009). Normal mouse intestinal mucus release renal volume-regulating system is angiotensin II has sympathetic neural requires cystic fibrosis transmembrane also activated, leading to release effects in humans. regulator-dependent bicarbonate secretion. J Clin Invest 119, 2613–2622. Muchekehu RW & Quinton PM (2010). A new role for bicarbonate secretion in cervico- uterine mucus release. J Physiol 588, 2329– 2342. http://jp.physoc.org/content/588/13/2329.long Verdugo P (1991). Mucin exocytosis. Am Rev Respir Dis 144, S33–S37. Acknowledgements This work was supported by grants from Cystic Fibrosis Research Inc., Nancy Olmsted Trust, Cystic Fibrosis Foundation, and NIH Figure 1. Dagrammatic representation of the placement of the microelectrode in the USPHS R01-HL084042. muscle sympathetic nerve fibres and the recording of sympathetic nerve activity.

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Figure 2. Muscle sympathetic nerve activity recordings from a single representative subject on two separate days, during euhydration (top recording) and dehydration (bottom recording).

We were interested in evaluating fibres. Figure 2 shows actual MSNA have implications in a spectrum of the influences of endogenous recordings in a subject. MSNA conditions associated with volume angiotensin in the context of human is quantified as burst frequency, depletion and is not yet fully dehydration. In our first study to burst incidence (which controls for understood. In terms of sympathetic address this goal we wanted to know difference in heart rates) or total neural effects, the roles of other whether the elevation in angiotensin activity (taking into account both endogenous hormones released during dehydration is causing neural burst number and size). during dehydration in humans, such changes during dehydration in as aldosterone and vasopressin, humans. Our hypothesis was that In order to test our hypothesis await future study. endogenous angiotensin II has a regarding the role of angiotensin in mediating changes in the mechanistic role in some of the J. A. Rabbitts and N. sympathetic neural changes that are sympathetic nervous system observed in dehydration in normal during dehydration, we measured Charkoudian humans. MSNA, heart rate and continuous Mayo Clinic Rochester, Rochester, blood pressure in 18 healthy young MN 55905, USA In the lab we are able to measure male and female subjects during the electrical activity in sympathetic euhydration and during dehydration References nerve fibres in humans, specifically induced by 24 hour fluid restriction postganglionic sympathetic fibres (Rabbitts et al. 2009). Figure 2 shows Cox BF & Bishop VS (1991). Neural and innervating the blood vessels humoral mechanisms of angiotensin- two tracings in the same individual dependent hypertension. Am J Physiol 261, in skeletal muscles (known as on two different study days, one H1284–H1291. muscle sympathetic nerve activity during euhydration and one during (MSNA)). Although this technique Fink GD (1997). Long-term sympatho- dehydration, illustrating that MSNA excitatory effect of angiotensin II: a is technically challenging, the data is increased during dehydration. mechanism of spontaneous and renovascular obtained can give unique insight With blockade of angiotensin II hypertension. Clin Exp Pharmacol Physiol 24, into the beat-to-beat function of receptors, this effect was reversed, 91–95. the sympathetic nervous system. confirming that in addition to its Hasser EM, Cunningham JT, Sullivan MJ, Curtis Figure 1 is a diagrammatic known volume-regulating effects, KS, Blaine EH & Hay M (2000). Area postrema and sympathetic nervous system effects representation of the placement angiotensin does mediate some of the microelectrode in the of vasopressin and angiotensin II. Clin Exp of the sympathetic effects of Pharmacol Physiol 27, 432–436. sympathetic nerve fibres and the dehydration. Thus, for the first recording of sympathetic nerve Matsukawa T, Gotoh E, Minamisawa K, Kihara time in humans we have shown M, Ueda S, Shionoiri H & Ishii M (1991). Effects activity. We commonly use the that endogenous angiotensin has of intravenous infusions of angiotensin II on peroneal nerve which is next to the sympathetic neural effects which muscle sympathetic nerve activity in humans. knee and innervates blood vessels of further protect blood pressure Am J Physiol 261, R690–R696. skeletal muscle of the lower leg and during dehydration. Rabbitts JA, Strom NA, Sawyer JR, Curry foot. Each one of the upward peaks TB, Dietz NM, Roberts SK, Kingsley-Berg in the MSNA recording is called a This interaction between the SM & Charkoudian N (2009). Influence burst of sympathetic nerve activity volume-regulating hormones and of endogenous angiotensin II on control of sympathetic nerve activity in human and represents a collection of action the sympathetic nervous system dehydration. J Physiol 587, 5441–5449. potentials in vasoconstrictor nerve to protect blood pressure could http://jp.physoc.org/content/587/22/5441.long

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Heart rate regulation during exercise Exercise-mediated increases in heart rate are elicited by a complex interaction of multiple neural control mechanisms. We have demonstrated that the activation of metabolically sensitive receptors in skeletal muscles (muscle metaboreflex) increases cardiac sympathetic nerve activity in humans, an effect that can be masked by elevations in parasympathetic tone. Thus, the muscle metaboreflex contributes importantly to the regulation of the heart during exercise. These findings have implications for disease conditions associated with low cardiac parasympathetic tone and exaggerated feedback from the exercising muscles, such as chronic heart failure. Profound alterations in cardio­ activating metabolically sensitive vascular regulation must occur in skeletal muscle afferents (muscle order to sustain exercise for more metaboreflex) involves the occlusion than a few moments. To meet of the circulation to the exercising the increased metabolic demand muscles just prior to the end of of the active muscles, local blood exercise and keeping it in place flow must increase. Consequently, for a period of exercise recovery. cardiac output increases and blood This ‘post-exercise ischaemia’ traps flow is redirected to the contracting the metabolites produced during muscles by vasoconstriction in exercise within the muscles after the regions such as renal and splanchnic contraction and effectively isolates vascular beds. Both the sympathetic From upper left and the muscle metaboreflex from the and parasympathetic branches of clockwise: James Fisher, exercise-induced activation of central Paul Fadel and Niels the autonomic nervous system command and mechanically sensitive Secher. are important in mediating this muscle afferents. The circulatory co-ordinated response and the particularly in human studies where occlusion can be performed simply elucidation of the underlying invasive methods are limited. by inflation of a cuff around the limb, regulatory mechanisms has engaged However, an array of ingenious proximal to the exercising muscles, researchers for a century. It is now experimental approaches (e.g. as first described by Alam & Smirk established that the cardiovascular neuro­muscular blockade, deep (1937). Alarmingly these pioneering responses to exercise result from brain stimulation, tendon vibration investigators also noted that ‘a the activation and interaction of and inflatable trousers) along with forearm may be devascularied and both central and peripheral neural deductive reasoning has brought the circulation arrested by plunging mechanisms. Feed-forward signals insight to this research area. it into a bath of mercury depth of from the brain (e.g. insular cortex), One approach that is commonly about 12 cm. above the elbow’, but known as central command, arise used in humans to investigate thankfully this approach has not in parallel with descending motor the cardiovascular effects of been adopted! drive to the exercising muscles and converge on the cardiovascular areas of the brain (e.g. nucleus tractus soltarii). Concomitant feedback from the active muscles via small group III and IV afferent nerves provides feedback to these cardiovascular areas in response to both mechanical and metabolic stimulation. As a consequence, the arterial baroreflex is reset to the prevailing heart rate and blood pressure established during exercise and this plays an important role in the neural regulation of the cardiovascular Figure 1. Schematic showing hypothetical integration of muscle metaboreflex and arterial baroreceptor feedback to the central nervous system during post-exercise system during physical activity. muscle ischaemia. Previous studies have clearly demonstrated that activation of The dissection of the discrete the muscle metaboreflex during post-exercise ischaemia causes an increase in sympathetic vasoconstrictor outflow to the peripheral vasculature (green arrow). contribution made by each of Our findings demonstrate for the first time in humans, that concomitant increases the neural control mechanisms in sympathetic outflow to the heart are dampened by cardiac parasympathetic implicated in the cardiovascular reactivation, probably due to arterial baroreceptor activation and/or the loss of response to exercise is challenging, central command and muscle mechanoreceptor input.

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25%25% MVCMVC 40%40% MVC MVC 160 Rest IHG PEI-M Recovery Rest IHG PEI-H Recovery

Control Beta-adrenergic blockade Parasympathetic blockade 120 ) -1

(b min (b 80 Heart Rate Rate Heart

40 0 0 60 60 120 180 240 300 360 420 480 540 600 660 720 120 180 240 300 360 420 480 540 600 660 720 Time (s) Time (s) Figure 2. Heart rate during isometric handgrip (IHG) and post-exercise ischaemia (PEI) under control, β-adrenergic blockade and parasympathetic blockade conditions. PEI-M, PEI following 25% IHG; PEI-H, PEI following 40% IHG; MVC, maximal voluntary contraction. Adapted with permission from Fisher et al. (2010).

Intriguingly, heart rate consistently mechanically sensitive skeletal sympathetic nerve activity would be falls to baseline values during muscle afferents on parasympathetic unmasked. post-exercise ischaemia while activity are lost in the transition exercise-induced increases in from exercise to post-exercise To investigate the potential blood pressure and vasoconstrictor ischaemia. Second, the elevation in influence of sympathetic nerve sympathetic nerve activity remain blood pressure during post-exercise activity on heart rate during elevated. This has led to the notion ischaemia could stimulate the post-exercise ischaemia we used that the muscle metaboreflex arterial baroreceptors and reflexively a pharmacological approach does not influence heart rate, increase parasympathetic tone. previously performed in exercising but raises blood pressure via As such, this parasympathetic dogs (O’Leary, 1993). The sympathetically mediated peripheral reactivation could obscure any cardiovascular responses to two vasoconstriction (Rowell & O’Leary, metaboreflex-mediated increase in intensities of muscle metaboreflex 1990). An alternative explanation cardiac sympathetic nerve activity activation were compared during is that an overwhelming effect of which would otherwise accelerate post-exercise ischaemia under parasympathetic reactivation slows heart rate (O’Leary, 1993). If this control conditions, and after the heart during post-exercise were the case, then the elimination parasympathetic and β-adrenergic ischaemia, and masks the influence of cardiac parasympathetic tone blockade (Fisher et al. 2010). As of sympathetic nerve activity on during post-exercise ischaemia expected, blood pressure was the heart (Fig. 1). This may occur should reveal an increase in heart increased from rest during moderate for two reasons. First, the inhibitory rate, as a muscle metaboreflex- metaboreflex activation and further effects of central command and mediated increase in cardiac elevated during high-intensity metaboreflex activation in all 25%25% MVCMVC 40%40% MVC conditions. We observed that *† during moderate-intensity 100 *† metaboreflex activation under control (no drug) conditions, heart *† *† *† rate was negligibly elevated from 50 *† *† *† rest (+3±2 beats min–1); however, when this was repeated following parasympathetic blockade (using the Heart Rate Heart (% End IHG) End (% 0 Drug P>0.001 Control muscarinic blocker glycopyrrolate) Phase P>0.001 Beta-adrenergic blockade an increase in heart rate was Trial P=0.156 * * Parasympathetic blockade -–1 Interaction P>0.01 * observed (+8±2 beats min ; Fig. 2). -50 Interestingly, when high-intensity metaboreflex activation was

End IHG PEI-M 15 PEI-M 30 PEI-M 45 PEI-M 60 End IHG PEI-H 15 PEI-H 30 PEI-H 45 PEI-H 60 performed an elevation in heart rate Figure 3. Heart rate during the first minute of post-exercise ischaemia expressed as a was noted, which was attenuated percentage of end isometric handgrip values (End IHG), under control, β-adrenergic with β-adrenergic blockade but was blockade and parasympathetic blockade conditions. PEI-M, PEI following 25% IHG; unchanged with parasympathetic PEI-H, PEI following 40% IHG. Time points represent 15 s averages. *P < 0.05 vs. blockade. Collectively, these control, †P < 0.05 vs. β-adrenergic blockade. Adapted with permission from Fisher et findings suggest that the muscle al. (2010). metaboreflex increases cardiac

Physiology News | No. 81 | Winter 2010 | www.physoc.org SCIENCE NEWS AND VIEWS PN 43 sympathetic nerve activity during 2Copenhagen Muscle Research Society Noticeboard post-exercise ischaemia in humans; Center, Department of Anaesthesia, however, it requires a robust muscle Rigshospitalet, University of Scientific Meetings – 2010 metaboreflex activation to offset the Copenhagen, Copenhagen, Denmark For a comprehensive overview visit the website influence of cardiac parasympathetic 3Department of Medical reactivation on heart rate. Pharmacology and Physiology, Cross Themed Meeting Durham University, UK, 15–17 December We also observed that the rate Dalton Cardiovascular Research Early bird deadline 22 November at which heart rate recovered Center, University of Missouri, from the end of exercise during Columbia, MO, USA Scientific Meetings – 2011 post-exercise ischaemia was slower References with parasympathetic blockade, Alam M & Smirk FH (1937). Observations Cellular & Integrative Neuroscience compared with the control or in man upon a blood pressure raising reflex Themed Meeting arising from the voluntary muscles. J Physiol King’s College London, UK, 6–8 April β-adrenergic blockade conditions 89, 372–383. (Fig. 3). We presume that this Cole CR, Blackstone EH, Pashkow FJ, Snader Physiology 2011 sluggish heart rate recovery is CE & Lauer MS (1999). Heart-rate recovery The Physiological Society Main Meeting due to gradual withdrawal of immediately after exercise as a predictor of University of Oxford, UK, 11–14 July cardiac sympathetic nerve activity mortality. N Engl J Med 341, 1351–1357. Fisher JP, Seifert T, Hartwich D, Young CN, Abstract submission and registration following the rapid loss of inputs Secher NH & Fadel PJ (2010). Autonomic open on 1 March from central command and muscle control of heart rate by metabolically sensitive mechanoreceptors during sustained skeletal muscle afferents in humans. J Physiol Epithelia & Membrane Transport Themed Meeting muscle metaboreflex activation. 588, 1117–1127. http://jp.physoc.org/content/588/7/1117.long University College London, UK These data are important because Imai K, Sato H, Hori M, Kusuoka H, Ozaki 1–3 September a delayed recovery in heart rate H, Yokoyama H et al. (1994). Vagally following exercise is a powerful mediated heart rate recovery after exercise is Vascular & Smooth Muscle Physiology independent predictor of mortality accelerated in athletes but blunted in patients Themed Meeting with chronic heart failure. J Am Coll Cardiol 24, Edinburgh, UK, December even in low risk patient populations 1529–1535. (Cole et al. 1999), an effect that O’Leary DS (1993). Autonomic mechanisms is linked to the reactivation of of muscle metaboreflex control of heart rate. J Scientific Meetings – 2012 Appl Physiol 74, 1748–1754. parasympathetic activity (Imai Human & Exercise Physiology Themed Rowell LB & O’Leary DS (1990). Reflex et al. 1994). Our findings broadly control of the circulation during exercise: Meeting, The biomedical basis of elite support this concept, and further chemoreflexes and mechanoreflexes. J Appl performance suggest that in the absence of Physiol 69, 407–418. The Queen Elizabeth II Conference parasympathetic reactivation, Centre, London, UK, 19–21 March Bebowlered Barcroft increased cardiac sympathetic Physiology 2012 nerve activity may also contribute In the Oxford Dictionary of Main Meeting, The Edinburgh to a delayed post-exercise recovery National Biography (2004), International Conference Centre, UK 3–6 of heart rate. These data may John West’s article on the July be clinically relevant for disease Cambridge physiologist Joseph conditions associated with altered Barcroft (1872–1947), includes The Journal of Physiology an anecdote recounted by CG skeletal muscle afferent sensitivity Symposia 2011 and low cardiac parasympathetic Douglas, another respiratory tone, such as chronic heart failure. physiologist. In the First World Physiology, pharmacology, and War Barcroft, being a Quaker, was pathology of tissue fluid exchange In summary, these findings suggest a non-combatant but he went to Satellite Symposium at the 31st that isolated muscle metaboreflex the French front in connection International Symposium on Intensive activation increases cardiac with his work on the effects of gas Care and Emergency Medicine sympathetic nerve activity during poisoning. Although he insisted on Brussels, Belgium, Tuesday 22 March post-exercise ischaemia in humans, standing in a prominent position Molecular mechanisms underlying but to have an effect on heart at a crossroads, no one fired at neurovascular protection in stroke rate, robust muscle metaboreflex him. It was suggested that his Experimental Biology 2011, activation is needed to offset cardiac bowler hat may have unsettled the Washington, DC, USA, Sunday 10 April parasympathetic reactivation. gunners. Human hand function: the limitations James P. Fisher1, Niels H. of brain and brawn Secher2 and Paul J. Fadel3 Physiology 2011 Wednesday 13 July 1School of Sport & Exercise Travel Grants Sciences, University of Birmingham, www.physoc.org/grants Edgbaston, Birmingham B15 2TT, UK Ann Silver www.physoc.org/international

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The KATP channel is a molecular sensor of atrophy in skeletal muscle

In a recent study in The Journal of slow-twitch muscle is associated

Physiology we demonstrated for the with an up-regulation of KATP channel first time that the metabolically subunits, while down-regulation of regulated ATP-sensitive K+ channel the Kir6.2/SUR1 subunits correlate

(KATP) can regulate the atrophic with a reduction of the fibre process in fast- and slow-twitch rat Domenico diameters leading to extensive skeletal muscle. The KATP channels Tricarico atrophy. The atrophy of fast- and are normally expressed in the slow-twitch rat skeletal muscle was sarcolemma and in mitochondrial also pharmacologically induced in membrane, sensing and coupling vitro by glibenclamide, a widely used anti-diabetic drug that blocks the intracellular nucleotide composition resistance and for a neuromuscular + Kir6.2/SUR1 channel subunits. The with K efflux and membrane disorder known as hypokalaemic effects of this drug were prevented potential. Channel opening occurs periodic paralysis. in response to a reduction in the by diazoxide, a well-known Kir6.2/ ATP/ADP ratio during metabolic We now provide evidence that SUR1 channel opener, supporting the involvement of this channel in stress, which is often associated the KATP channels play a role in with abnormal Ca2+ movements skeletal muscle plasticity, which is the observed phenomenon. All these across the cell membrane or inner the ability of the tissue to adapt findings corroborate the idea that mitochondrial membrane. to new conditions such as disuse KATP channels sense the changes in through changes in muscle fibre the muscle phenotype and in the The KATP macromolecule was phenotype composition, fibre fibre trophism (Tricarico et al. 2010). first discovered in 1983 in diameter and cellular metabolism. Similar effects of glibenclamide and cardiomyocytes and later found We made several observations: diazoxide were observed in other in pancreatic beta cells, vascular first, the molecular composition cell lines expressing Kir6.2/SUR1 myocytes and more recently subunits (Maedler et al. 2004, 2005). and properties of the KATP channels in neurons (Flagg et al. 2010). are muscle phenotype dependent The channel belongs to the ABC Atrophy is a condition affecting and muscle specific. This means both fast- and slow-twitch muscles, transporter superfamily: it is an that the channel properties are octameric complex formed by often showing different degrees of related to the speed of contraction damage depending on muscle type the inwardly rectifying K+ channel and strength, which are muscle and function. It is normally slowly subunits (Kir6.1 and Kir6.2) and the phenotype-dependent properties, reversible; for example, several regulatory sulfonylurea receptor but are also related to morphological months are needed to recover subunits (SUR1, SUR2A and SUR2B). characteristics of the muscles such muscle strength and morphology in The SUR subunits carry the binding as length and mass, and with their healthy individuals following partial site for drugs and nucleotides anatomical location. In this respect, arm or leg immobilization. Such as well as phosphorylation sites. we found higher expression/activity immobilization can, in severe cases, Our previous reports showed an of the Kir6.2/SUR2A or Kir6.2/SUR1 lead to an irreversible impairment intense KATP channel activity also in subunits in fast-twitch muscle as of muscle function. Atrophy is also mouse, rat and human fast-twitch compared with slow-twitch muscle observed following exposure to skeletal muscles in isolated phenotypes and differences in toxins, overdose of certain chemo- membrane patches in the absence the expression/activity of the KATP therapeutic drugs or corticosteroids of intracellular ATP (Tricarico et al. channel subunits have also been abuse. It is a common sympton 1999; Flagg et al. 2010). In resting observed within fast-twitch muscle of the cachexia associated with un-stimulated fibres, KATP channel types (Tricarico et al. 2006). High these and other pathophysiological activity contributes a few millivolts expression of the SUR1 subunit conditions. This process is generally (3–4 mV) to the resting potential; has been observed in the flexor considered to be caused by an however, large repolarizing KATP digitorum brevis muscle of the rat, imbalance between protein synthesis channel currents are observed which is a fast-twitch muscle with and degradation, in favour of the following insulin stimulation or elevated oxidative metabolism latter. Knowledge of the pathways high-frequency action potential devoted to the rapid movements responsible for atrophy is essential firing, thereby reducing fibre of the extremities, but also in a for prevention and appropriate excitability during muscle fatigue. slow-twitch soleus muscle, which therapy. Several intracellular factors

KATP channels therefore save the has postural function. Second, responsible for atrophy have been energy pool during metabolic stress in an accepted animal model of identified that lead to the activation and regulate glucose uptake into the muscle disuse, we demonstrated of proteolytic mechanisms and fibres. Secondary defects in channel that the characteristic slow-to-fast inhibition of protein synthesis subunits are responsible for insulin fibre transition occurring in the (Sandri, 2008).

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Our emerging idea is that K ATP IUPS Congresses channel activity also has a role in I doubt The Society has any regrets (yet) about the optimism that led to its the regulation or induction of the bid in 2005 for the XXXVII IUPS Congress to be held in Birmingham in 2013, atrophic process in skeletal muscle. twenty years after the XXXII Congress in Glasgow. None-the-less, a tale or Generally, KATP channel opening, if two from some past Congresses may concentrate the collective mind. No coupled to the energy demand of matter how exciting the science, recollections can be coloured for good or ill the cells, is considered protective by practical issues. Perhaps there are other physiologists with useful memories for the cells and mitochondria, to share. while irreversible channel closure Leiden is cytotoxic. Therefore, SUR1 inhibitors may induce atrophy or At the Leiden Congress in 1962 no one was around to prevent early arrivals contribute to the atrophic process from bagging other people’s Poster Board should they dislike their allocated site. I was displaced to a Board outside the Gents: this ensured a continuous, in skeletal muscle fibres expressing but not fully representative, audience. We had our lunch in two enormous this subunit. This is of relevance marquees. One night a tremendous gale damaged one of these so badly that considering the prescribed combined it was considered unsafe. This meant that everyone had to crowd into the anti-diabetic and chemo-therapeutic other, which had also been slightly torn. Most participants gobbled down drug therapy for the treatment of their food as fast as possible and made a rapid retreat. Not so the British, diabetic patients affected by cancer who phlegmatically took their time. John Phillis and family were camping or bacterial/virus infections. their way to Italy where they were to catch a boat home to Australia. He had to miss his session to get his bent tent repaired before nightfall. Domenico Tricarico Paris Department of Pharmacobiology, The 1977 Congress in Paris was memorable on several counts. On the Faculty of Pharmacy via Orabona first day, the thermoregulators couldn’t find the theatre specified for their No. 4, 70120 Bari, Italy opening lecture, so appropriated one they happened upon. Responding to the speaker’s request for a pointer, the projectionist produced a length of References plastic moulding that formed a U shape when raised. Just before the lecture Maedler K, Størling J, Sturis J, Zuellig RA, ended a man staggered in with an almost unliftable spar. When we left the Spinas GA, Arkhammar PO et al. (2004). Glucose- and interleukin-1β-induced β-cell theatre the same man was outside on his knees trying to saw a plank into apoptosis requires Ca2+ influx and extracellular more manageable lengths. Paris was also memorable for the reception signal-regulated kinase (ERK) 1/2 activation in the barely finished Pompidou Centre. The programme note saying it and is prevented by a sulfonylurea receptor 1/ was unsuitable for children under 12 was taken to mean a dearth of child- + inwardly rectifying K channel 6.2 (SUR/Kir6.2) friendly food, not that they risked being trampled under foot. And not just selective potassium channel opener in human islets. Diabetes 53, 1706–1713. the children – I was forced forwards towards the buffet by the press of the crowd, my hand ending up in some paté – and that was the sum total of my Maedler K, Carr RD, Bosco D, Zuellig RA, ‘refreshments’. Berney T & Donath MY (2005). Sulfonylurea induced β-cell apoptosis in cultured human Glasgow islets. J Clin Endocrinol Metab 90, 501–506. Many Members, whether or not wearing an organizers’ hat, will have varied Flagg TP, Enkvetchakul D, Koster JC & Nichols memories of the 1993 Congress in Glasgow. Cecil Kidd, who chaired the CG (2010). Muscle KATP channels: recent insights to energy sensing and myoprotection. Publications Committee, calculated that the Programme and Abstract Physiol Rev 90, 799–829. Books (a separate one for each of the 5 days) totalled over 7.5 million pages. Sandri M (2008). Signaling in muscle atrophy Not surprisingly, deadlines were alarmingly tight but Aberdeen University and hypertrophy. Physiology (Bethesda) 23, Press miraculously delivered everything on time to the Scottish Exhibition 160–170. and Conference Centre in Glasgow. Here a team was waiting to stuff the Tricarico D, Mele A, Camerino GM, Bottinelli Congress bags overnight ready for Registration next day on Sunday 1 R, Brocca L, Frigeri A, Svelto M, George AL Jr August. So far so good except there was no sign of the bags due to come & Conte Camerino D (2010). The K channel ATP from Cambridge University Press. Anxious calls to the Press (a Saturday is a molecular sensor of atrophy in skeletal muscle. J Physiol 588, 773–784. afternoon, mobiles still in their infancy) confirmed that the bags had indeed http://jp.physoc.org/content/588/5/773.long been dropped off at the SECC – there was a signed delivery note to prove it. The signatory was traced to the Catering Department where the bags were Tricarico D, Mele A, Lundquist AL, Desai RR, George AL Jr & Conte Camerino D (2006). rescued from the Nescafé cartons in which CUP had packed them. (As an Hybrid assemblies of ATP-sensitive K+ channels aside, the Congress literature and promotional handouts weighed about 4 kg determine their muscle-type dependent and the CUP bags had to be supplemented by strong plastic bags bearing the biophysical and pharmacological properties. Congress logo.) Proc Natl Acad Sci U S A 103, 1118–1123. Tricarico D, Servidei S, Tonali P, Jurkat-Rott And one small hiccup on the opening morning – the main area of the SECC K & Conte Camerino DC (1999). Impairment was partitioned off into a number of adjacent Lecture Theatres served by a of skeletal muscle adenosine triphosphate- common electricity supply. Several were plunged into darkness when David sensitive K+ channels in patients with Whitteridge caught his foot in a cable while introducing the first speaker. hypokalemic periodic paralysis. J Clin Invest 103, 675–682. Ann Silver

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The ‘why’s’ of Western blotting. Part I Electrophoresis of proteins and Western blot is a well-established biochemical technique that is now widely used in other disciplines, including physiology. Typically a lab will have its own established protcols, handed down from generation to generation. Scores of research students will have learnt the technique, diligently following their local step-by-step protocol. Although the ‘how to’ of Western blotting is disseminated in this manner, the ‘why’ is often regretfuly neglected. This short Techniques series will focus on the latter, and was commissioned in response to a request from a research student who found her ‘why’ questions unanswered. In this first article, Patricia Leoni, of Imperial College London, explains the principles of protein electrophoresis. Separation of proteins by The use of porous gel matrices electrophoresis such as starch, agarose and polyacrylamide minimizes these The electrophoretic properties of effects and adds the possibility of proteins have been used in research molecular sieving so that both size since the early 1930s (Tiselius, 1937). and charge are used to optimize The most useful developments in the separation. Other polymers such as field occurred in the sixties with the Duracryl have been developed for use description of discontinuous buffer Patricia Leoni as a matrix but are not widely used. systems, the use of polyacrylamide as support medium and the use depending on the content of these Electrophoresis on acrylamide gels of detergents. The separation of acidic and basic amino acids. The pH proteins by electrophoresis is one at which the positive and negative Polyacryamide gels are non-ionic of the most useful techniques for charges are in balance so that the net polymers of acrylamide (CH2=CH- biomedical research to separate charge of the protein is zero, is the CO-NH2) and a cross-linking and identify proteins in complex isoelectric point. co-monomer N,N-methylene mixtures. bis-acrylamide (CH2-CH-CO-NH- Positively and negatively charged CH2-NH-CO-CH=CH2). Acrylamide Five of the twenty amino acids which proteins, as all charged particles, is a potent neurotoxin and care determine the primary structure migrate in an electric field (Fig. 2). must be taken during the handling of proteins are highly ionized and of the monomer solution. Once therefore charged. Lysine, arginine The electrical properties of proteins polymerized it is no longer toxic. and histidine are positively charged, have been successfully used to glutamic acid and aspartic acid are separate complex mixtures of many The gels are transparent, chemically negatively charged (Fig. 1). proteins. It is possible to separate inert and stable over a wide range of proteins electrophoretically in pH, temperature and ionic strength. The degree of ionization, and free solution; however, this has The most important advantage of hence the charge, depends on the some disadvantages, in particular these gels is that the pore dimensions pH. At most pH values proteins convective and diffusion effects can be varied simply by increasing carry a positive or negative charge, which broaden the protein bands. the monomer and cross-linking agent concentration in order to optimize it for the separation of proteins of different sizes.

Two parameters are used to describe the gel composition:

Aspartic acid – Asp, D Glutamic acid – Glu, G %T = acrylamide monomer + cross- linking agent as % weight/volume

%C = percentage of cross-linking agent of the total monomer

The size of the pore can be adjusted by varying the amounts of acrylamide and bis. As %T increases the pore decreases; however, the increase of cross-linking agent over certain values can cause the three-dimensional structure of the gel to be disrupted and the gel can Arginine – Arg, R Lysine – Lys, K Histidine – His, H become opaque. Fortunately several Figure 1. Chemical structure of charged nucleic acids. commercial companies (e.g. National

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Electrophoresis of native proteins In situations where it is desirable to retain the biological activity of proteins, such as enzymatic activity and protein–protein interactions, the separation is carried out using a non-denaturing (native) gel of a suitable concentration and buffer with a pH dependent on the size and charge of the proteins of interest.

The charge of the proteins being separated depends on the pH of the Figure 2. Migration of proteins during electrophoresis. buffer used. At a pH close to their Diagnostics, Bio-Rad, Sigma, Fisher difficulties with reproducibility. It isoelectric point they are prone to Bioreagents, GE Healthcare, Roche) might be more practical, if possible, precipitate, at pH above 10 and provide ready-made, liquid or solid to purchase pre-cast gradient below 3 proteins are unstable due to mixtures optimized for protein gels. The most usual composition deamidation and hydrolysis, so these separation. The most commonly of these gels is 5%–20%T, 2.6%C; pH ranges should be avoided. used brands offer acrylamide: the molecular weight range of bis-acrylamide mixes in three proteins that can be separated is If biological activity needs to be different proportions: 10–200x103 kDa. Polymerisation assessed following electrophoresis, occurs in the presence of free the separation should be carried out Acrylamide: Bis-acrylamide 37.5:1, radicals provided by ammonium at a pH at which the protein is active. with 2,6% of cross-linking agent persulfate in a reaction catalysed In selecting the pH of the running suitable for the separation of high by tetramethylethylenediamine buffer it is important to remember molecular weight proteins. (TEMED). The advantage of using that acidic and basic proteins will Acrylamide: Bis-acrylamide 29:1, with ammonium persulfate rather than carry opposite charges and will 3.3% of cross-linking agent suitable other catalysts is that it migrates migrate in opposite directions. Basic for the separation of a wide range of in the same direction but faster proteins need to be separated under molecular weight proteins. than the molecules of interest. The acidic conditions and they need to presence of oxygen, which traps free be applied at the anodic end. Most Acrylamide: Bis-acrylamide 19:1, with radicals, inhibits polymerization. proteins will be negatively charged in 5% of cross-linking agent suitable In some cases it might be useful alkaline pH and will migrate towards for the separation of low molecular to remove most of the oxygen by the anode during electrophoresis. weight proteins. deaeration using a water vacuum The main disadvantage of using a Gradient gels pump or by bubbling nitrogen for a couple of minutes. single buffer in an electrophorectic The range of molecular weights that separation is that it is not suitable can be separated on a gel can be The amounts of ammonium for analysis of dilute samples when expanded by using gels containing persulfate and TEMED must be relatively large volumes are needed. a concentration gradient. These calculated to allow polymerization Samples must have a concentration gels have the added advantage of in approximately 2 hours or longer; greater that 1μg μl–1 in order to allow producing sharper protein bands; although many labs cut corners and the use of a very small volume of however, they are cumbersome use shorter times, these might lead sample; if samples are more diluted to prepare in the lab; they require to the formation of short polymer a discontinuous buffer system is additional equipment and there are chains and lack of elasticity. required.

Polyacrylamide gel electrophoresis using discontinous buffer systems This method is the one that is most commonly used. In this technique, discontinuities in the voltage and pH are introduced by using buffers of different composition and pH in different parts of the gel. A major advantage of a biphasic buffer system is its ability to concentrate proteins in dilute samples into a narrow stack. Time The system developed by Ornstein Figure 3. Pattern of protein migration in a discontinuous buffer system. (1964) and Davis (1964) uses a large

Physiology News | No. 81 | Winter 2010 | www.physoc.org 48 PN TECHNIQUES pore stacking gel with minimal and increase solubility: SDS (2%) the run. Excessive heat generation sieving effects, between the sample and NP-40 (0.05–1%) are the increases the rates of diffusion, well and the resolving gel (Fig. 3). most commonly used. To break which will make the bands diffuse. Both gels and the sample buffers the hydrogen bonds involved in High ionic buffer strength leads to contain chloride ions, while the aggregates, urea (7 M) is the most sharper bands but the conductivity electrode buffer contains glycinate common additive for unfolding is higher and so is the amount ions. The pH of the sample and proteins. Disulfide bonds between of heat generated; the choice of stacking gel buffer is 6.7 while the polypeptides can be disrupted buffer composition must represent pH of the resolving gel and electrode with reducing agents such as a compromise. In a discontinuous buffer is 8.9. 2-mercaptoethanol (100 mM) buffer system, the resistance of the or dithiothreitol (20 mM). Low system decreases during the run, Glycinate is not dissociated at pH 6.7, concentrations of a reducing agent given that the relations between the while chloride is highly dissociated. can be added to the buffer in the parameters are: In an electric field, chloride ions anode reservoir to maintain reducing H = V I/4.185 migrate rapidly, moving away from conditions during the run. To improve R = V/I the glycinate ions, leaving behind the efficiency of these denaturing where H is Joule heating (cal s–1), R is a solution with fewer ions and agents samples are boiled for up resistance (Ω), V is voltage (V) and I is hence low conductivity. The low to 5 minutes; however, urea can conductivity causes the field strength form cyanate ions which interact current (amperes). to increase and a steeper voltage with amino groups of proteins At a constant current, voltage gradient is established in this region. (carbamylation). This could result and heat will increase with time. Proteins have a lower mobilty than in anomalous separation profiles. At a constant voltage, current chloride ions, and will trail behind Cyanate formation increases with drops and heating is reduced. It them at pH 6.7. In the stronger fields, temperature so urea should be added is recommended therefore that proteins are accelerated and position to the samples after heating. the run is carried out at constant themselves immediately behind voltage to minimise diffusion. The the chloride ions. In the absence SDS-PAGE choice of voltage is a compromise of a sieving effect in this low pore Most proteins can bind up to 1.4 g between heat generated by the gel, proteins are concentrated into of sodium dodecyl sulfate (SDS; electrical energy and time required + a thin layer. When the migrating CH3-(CH2)11-O-SO3- Na ) per gram of for the run, as a long run time front reaches the separating gel, the protein. will result in increased diffusion. proteins in the sample encounter The running conditions must be a smaller pore size and a different The saturation of proteins with the adjusted according to the surface pH. At this pH, 8.9, glycinate is negatively charged compound masks and thickness of the gel. Standard dissociated and its mobility is similar the protein’s charge, so that the conditions are recommended by to that of chloride ions, and they net charge per unit mass becomes the equipment manufacturers. All both accelerate away from the constant and due only to the commercially available equipment proteins. Proteins will now separate negative charge of SDS. As a result includes some type of cooling according to their size and charge. of this, all proteins will move in the system. same direction in an electric field; Electrophoresis under denaturing the separation will depend entirely A practical description of the conditions on the relative molecular mass and complete procedure to run SDS-PAGE occurs solely as a result of sieving is beyond the scope of this article. For proteins in the sample that are through the pores of the gel. A very useful description of the poorly soluble or form multimeric methodology and equipment can aggregates, or for polypeptides that Conjugated proteins like lipo- and be found in technical manuals of are subunits of a larger structure, glyco-proteins cannot be saturated the companies that sell products for the electroseparation needs to effectively with SDS because the protein electrophoresis, such as GE be performed in the presence of carbohydrates and lipids in their Life Sciences. additives which increase solubility side chains do not react with it. This and disrupt aggregates. Protein causes bands to be less sharp and In the next article of this series, the aggregates are stabilized by could give erroneous results with preparation of samples for protein hydrophobic interactions and H respect to their molecular weight. electrophoresis wil be discussed. bonds. The structure of proteins SDS and disulfide bond-reducing formed by subunits is maintained agents used together dissociate Patricia Leoni through disulfide bonds. These most proteins into single polypeptide Imperial College London interactions need to be disrupted chains. References in order to obtain good quality Davis BJ (1964). Ann NY Acad Sci 121, separations. Detergents are used Running conditions 404–427. in order to break hydrophobic The ionic strength of the buffer and Ornstein L (1964). Ann NY Acad Sci 121, interactions involved in protein– the power applied determine the 321–329. protein and protein–lipid interactions amount of heat generated during Tiselius AJ (1937). Exp Med 65, 641–646.

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Struggling for breath: latest advances in medical research for asthma patients and their families The British Science Festival 2010, Dr Harrop explained that mucus Birmingham, 15 September production takes place in goblet cells Organised by The Physiological which make up part of the epithelial lining in our airways. When excessive Society, Society of Biology and mucus is produced (such as with Asthma UK asthma sufferers) mucus ‘plugs’ can The Festival saw a week-long form which restrict the airways and celebration of science through make it more difficult to breath. talks and practical demonstrations. These were coordinated by national Whilst mucus can form plugs which organisations on a variety of block our airways and restrict scientific topics but few quite as breathing, it is also exceptionally dramatic as Struggling For Breath, a useful when not over-produced. It talk organised by The Physiological forms our body’s first line of defence Society focusing on asthma. This against pathogens and noxious comprehensive talk gave me and gases. With this in mind, in treating other attendees a lucid insight into asthma we do not want to eliminate the prevalence of the condition mucus production in sufferers but with approximately four children instead return it to the levels seen in admitted as emergencies every non-sufferers. Below these mucus- hour. It also focused on the issues that 5.4 million people in the UK producing goblet cells there is the surrounding its diagnosis, in addition fibroblast cell layer which produces to current research into a promising suffer from asthma, with 1204 people in the UK dying from asthma lots of proteins which help impart new form of treatment. Elizabeth Bell structure to our airways. of The Physiological Society chaired in 2008 alone. That is more than three people dying every day of the the session. Research is being done into how the year. The statistics from Asthma UK goblet cells are connected to this show that roughly 75% of emergency Chris Corrigan (King’s College fibroblast cell layer as there could be admissions were from asthma and London) started with an overview of ‘cross-talk’ between the cells which nearly 90% of asthma deaths are the condition. He described asthma may regulate mucus production. as a variable blockage of our airways, preventable. Professor Corrigan or a hyper-responsiveness (abnormal added that asthma costs the NHS Using bronchoscopy, brushings ‘twitchiness’) of airways. £1 billion each year with one child and pinch biopsies Dr Harrop has entering emergency admissions been researching in this area. Both Sufferers experience asthma attacks every 17 minutes. procedures involve inserting tubes that can be triggered by smoke, through the patient’s mouth to take perfume, deodorant or even fog. Robin Gore (University of a ‘sample’ of the asthma sufferer’s Asthma attacks involve the sudden Manchester) was the next speaker airway. narrowing of the airways through at the event and presented a variety muscle contractions that crush the of case studies of people who The sample, consisting of extracted airways and reduce the volume of had been misdiagnosed as being epithelial cells, was then cultured asthma sufferers. He used audio air that can pass through them. The and found to produce biochemically clips from which you could hear the airways can also become inflamed identical mucus. This mucus layer different coughs before he went on and subject to an increase in mucus was then exposed to the fibroblast to analyse them. He made his point production which blocks them. layer and the mucus produced was clearly – there is no good bedside Both of these factors reduce the then analysed. It was found that test for asthma and it is very hard to volume of air that can pass through there was a decrease in mucus the airways and cause breathing diagnose the disease correctly. production over time which was the problems. With so many triggers, opposite of that found in asthmatics. asthma sufferers are constantly Post-doctoral researcher Ceri Harrop This suggested that the underlying living in panic with the prospect (University of Manchester) then fibroblast cells can regulate mucus of suffering an attack and needing talked about her research into production. The next step is to medical treatment. mucus, which we were informed is an important carbohydrate-rich find the natural regulator of mucus As a condition, asthma does not hydrated gel containing electrolytes, production and then reinsert this receive too much press coverage, proteins, lipids and different mucins into the deficient fibroblast cells which is surprising when you learn (different ‘sugar-coated ropes’). in asthma sufferers. This potential

Physiology News | No. 81 | Winter 2010 | www.physoc.org 50 PN REPORTS treatment would reduce the Science is Vital Rally on Saturday 9 October 2010 overproduction of mucus.

We then heard from an asthma sufferer, Sarah Matthews (linked to Asthma UK), who described how her life is affected by the disease. She described the treatment that she receives in terms of inhalers and nebulisers as well as how she deals with her hospital visits. This rounded off an impressive event which was well-attended and provided a better understanding of the disease and the biology behind it. Liz Bell with a new friend, Ben, an Steven Forrest economist who works for an investment Evan Harris. bank. Royal Holloway University of London We are all very concerned about the possible impact of the imminent Cystic fi brosis event in Comprehensive Spending Review on science funding. The Society has been working closely with the Campaign for Science and Engineering and the Society Glasgow, 4 September of Biology to respond to this, and there has been a very exciting development with the creation of the Science is Vital Campaign. The Society donated £1000 2010 to help them hold a rally outside the Treasury, led by our old friend the former MP Evan Harris. Thousands attended, including me, and the point was well made that scientists aren’t prepared to take cuts lying down. The pictures speak for themselves. If you haven’t yet got involved with the campaign you can fi nd more information at http://scienceisvital.org.uk/ Liz Bell

Telford Theatre, One Great George Street London, 14 December 2010 18:30-19:30

Bringing cannabis back into the medicine cabinet BPS President’s Public Lecture

Tickets are free and can be booked in advance: www.bps.ac.uk

As well as having a lot of fun at the asthma event at the BSA Science Festival in Birmingham, in September we also ventured north of the border to run an event on cystic fi brosis at the Glasgow Science Centre. Our speakers were: Doug Bovell, David Sheppard, Vicky Cowell, Chris Boyd and Jonathan Guest speaker McCormick, who covered a full Professor Les Iversen, FRS spread of views on CF issues from distinguished academic and the researcher, clinician and patient industrial scientist perspective. Most notable was author of the bestselling book the young mum of a CF baby who ‘The Science of Marijuana’ button-holed our speakers to discuss visiting professor of Pharmacology issues after the event. The event was at the University of Oxford email: [email protected] part of the Glasgow Science Centre’s visit: www.bps.ac.uk current Chair of the government’s Advisory Celebration of Science in Scotland call: 020 7239 0183 Council on the Misuse of Drugs programme.

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100 years ago studied science and then medicine at The action of atropine, the University of Aberdeen. Cushny had already decided to become a pilocarpine and physostigmine professional pharmacologist when he Arthur R. Cushny (1910) finished his medical degree in 1889; like J Physiol 1910 November 9; 41, many scientists of the era he travelled to the German-speaking laboratories to 233–245. learn the trade of research. He studied Arthur Robertson Cushny (1866–1926) in Berne and briefly in Würzburg before is remembered as the greatest of the settling for several years in Strasbourg early British pharmacologists. However, as assistant to Professor Oswald as there were no specialist journals of Schmiedeberg, often regarded as the pharmacology at the time, much of his resolution is now clear, namely the founder of modern pharmacology. published work appeared in The Journal gradual, but ultimately extensive, In 1893 Cushny became Professor of Physiology. The present paper comes remodelling of uterine tissue through of Pharmacology at the University from the middle phase of Cushny’s pregnancy. This includes the remodelling of Michigan in Ann Arbor, where he career, the thirteen years he spent as of physiological responses via changes did pioneering work on the action of the first Professor of Pharmacology at to both receptors and intracellular digitalis on the mammalian heart and University College London. It records the signalling pathways. wrote the first notable pharmacology contractile activity of both pregnant and textbook in English. Cushny’s Text-Book non-pregnant uterus in anaesthetised Cushny employs nerve stimulation in of Pharmacology and Therapeutics cats, and analyses responses to drug several experiments, with complex – subtitled ‘The action of drugs in injections into the animal. results; this will stimulate both health and disease’ – rapidly became a parasympathetic (cholinergic + nitrergic) global standard, going through many A theme that ran all through Cushny’s and sympathetic (noradrenergic) subsequent editions and remaining in career was his interest in the actions nerve supplies to the uterus, so it is print after his death. of natural products, particularly unsurprising the contractile effects are alkaloids. The 1910 paper employs unpredictable. In 1910 ideas on how In 1905 Cushny accepted the chair at several. The three in the title are a nerves stimulated actions like muscle UCL and returned to the UK, settiing up a muscarinic cholinergic antagonist contraction were still forming, with the department from scratch. The following (atropine, from deadly nightshade or concepts of chemical transmission in year he was elected FRS. Cushny’s Belladonna), the muscarinic agonist their infancy and a clear understanding research at UCL ranged over many pilocarpine from a tropical American of receptors many decades away. Given areas, including uterine contractility. shrub, and the cholinesterase inhibitor the complexity of the experimental It concentrated, however, on the two physostigmine (eserine) from the responses, it is a tribute to Cushny’s projects for which he is perhaps most calabar bean. Also used in the paper are analytical clear-sightedness that he remembered: the relationship between nicotine, ergotoxine (a preparation of is able to draw any firm conclusions. optical isomerism and pharmacological ergot alkaloids), and the non-alkaloid He correctly identifies atropine as action, and the mechanism of urine adrenaline. It is fascinating to note antagonizing the pilocarpine (muscarinic production by the kidney. that all six substances are still in use in cholinergic) response in the uterus: Throughout his career Cushny had medicine a full century later. “Pilocarpine differs from adrenaline sought practical applications for Cushny’s study could be labelled as any in being antagonised completely pharmacology in medicine, and in of ‘pharmacology’, ‘endocrinology’ or by atropine whether it contracts or 1918 he relocated from UCL to a ‘reproductive biology’, which serves inhibits the uterus, while the effects of Chair in Edinburgh, partly to seek once again to emphasise the central adrenaline or of [nerve] stimulation are closer collaborations with the clinical position of physiology. The study is also not changed in any way by atropine.” pharmacists. Here he remained active in notable in its suggestion of differences in research until his sudden death, from a And he comments on where the the physiological responses of uteri from stroke or heart attack, at the age of 60 actions probably occur, suggesting pregnant and non-pregnant animals to in 1926. In his obituary of Cushny, Henry that: “pilocarpine and atropine act some agents (pilocarpine) but not others Dale indicates that Cushny had been on receptive substances which are (physostigmine). Cushny also comments “aware of a danger threatening his life” associated with the nerve impulse path at various points on something that for some years since discovering, whilst to the uterus, but do not actually lie on has continued to tax researchers measuring his own blood pressure in a this path.” studying the uterus to the present practical class, that he had hypertension. Given the modern prominence of drug day – the variability of the contractile This prescient sentence implies treatments for high blood pressure, response to different agents. For pilocarpine and atropine are not actually and Cushny’s life’s work, there is a instance, adenaline causes contraction on the nerves, but are on the ‘pathway’ certain sad irony in the relative lack of in some of Cushny’s experiments, and from nerve to uterine contraction – they treatments then available. Dale adds relaxation in others. Nowadays we might act, as we now know, on muscarinic “When the end came it was sudden, as rationalise this in terms of variable receptors on the uterine muscle cells. [Cushny] would have wished, and free expression of α-adrenoceptors (raising ‘Receptive substances’ is the early 20th 2+ from the lingering disability which had [Ca ] and promoting contraction) and century concept, due to J.N. Langley, that been his only fear.” β-adrenoceptors (raising cAMP and led in turn to the idea of receptors. promoting relaxation) in the uterus. Though the problems of understanding Arthur Cushny, the fourth son of a Austin Elliott uterine contraction and regulation Scottish clergyman, was born near the Dale HH (1926). Arthur Robertson Cushny, remain, the overall outline of the cathedral city of Elgin in Moray and 1866–1926. Proc Roy Soc B 100, xix–xxvii.

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Professional paranoia professional life when you exceeded your initial expectations” there was in uncertain times one really totally discriminatory, superfluous and offensive question. As a neuroscientist and therefore “Can you please provide a list of being of sound mind and neural your scientific publications”. I then architecture, I do not under any tried to insert my twenty scientific circumstances suffer from anxiety or publications into a small box around paranoia. 2 centimetres high – at this point the But I have with increasing monotony electronic form removed 19 of them. closely observed my scientific honour, but the competition would After repeated attempts at this I colleagues and wondered: Which be really fierce as all my peers are phoned Human Resources and said one of you devious narcissists is really mediocre too. “I know I am not allowed to send plotting to ruin my career? And I you my CV but can I send you a copy I also think that the British have observed that English spiders of my publications as an appendix”. government is trying to drive me are increasing in size. I am convinced Human Resources were really insane and they are using a method that some of these spiders are helpful “We have made our position pioneered by the CIA in the 1970s. foreign and are therefore swarthy, clear – this is a form that we have They are trying to damage my untrustworthy and venomous. One designed to eliminate any possibility brain by asking me to fill out job day a foreign spider will bite my arm of discrimination or unfairness, we application forms that have been which will immediately wither, turn do not accept CVs or supplementary designed by extremely well-paid black and require amputation. material” they explained. “But consultant surrealists. One recent where do I put a list of my scientific I have wondered why I would application form for a lectureship publications?” I said. “That isn’t start to obsess about the size and post asked me to provide “evidence really a constructive attitude, is it?” I Machiavellian intent of potentially of visionary leadership”. What is was told. foreign spiders or the not so visionary leadership? How can common English scientist. I think you prove you are a visionary? I Why? Are employers interested in my the real reason is that I am about mentioned that I had a vision once! sex life? On one equal opportunities to be made redundant and when The doctor said something about form there was a request for me I look around my department I “schizoaffective disorder”. I didn’t to define my sexual orientation; realise that in the next three years think that would look very good after male heterosexual, male up to 25% of us are going to end on my CV so I decided to drop homosexual and male bisexual there up – well, anywhere but in science. the subject. Finally I thought the was another sinister box – ‘Other – I don’t know really who to blame – reference to “visions” might be Please specify’. This made me really our banks I suppose were crooked, an oblique suggestion that taking paranoid as in 1986 I did have a our ruling classes deranged, and I mescaline before a job interview brief drunken flirtation with a sheep suspect that the British government would provide me with the killer called Reg. Is there surviving CCTV minister responsible for science, competitive advantage, but the footage, does my potential employer Dr Vince Cable gets his profound only source of mescaline I have is really know? Will it affect my future insights into the construction of a small cactus I brought last year employment? Eventually in case my an effective British science policy (Lophophora williamsii, £2.35 in employers thought me odd I wrote for the 21st century by examining a British garden centre, the pink ‘Asexual’. the patterns produced by throwing flowers are really nice). Another But when I wrote this the spiders chicken entrails on the floor. Vince asked me to provide evidence that in the garden seemed to get much has told scientists that we “must I could work in a “dynamic and bigger. pay our way”, should abandon work rapidly shifting customer focused environment” (I won’t mention who that is “neither commercially useful Dr Keith Cormorant nor theoretically outstanding”, and produced this one). I had to fill out finally we also need to “screen out a special form that was designed Physiology News mediocrity”. to eliminate “discrimination”. Discrimination on the grounds of If you have enjoyed this issue of That last statement really caused suitability for the advertised post Physiology News please don’t throw it away. Put it in your coffee room so that me great offence. I am as mediocre I surmised later! I did have one others may see it too. as the next scientist! What’s wrong serious problem on this special and with mediocrity, it’s my human right no doubt expensively designed We are always looking for interesting to be mediocre, I dream of winning form. Immediately following the features, meeting reports, news the Nobel Prize for mediocrity. To be box posing the psychologically items and photographs. Contact us lauded as being the most mediocre probing question “explain how ([email protected]) with your scientist in my field would be an you felt at a critical phase in your suggestions.

Physiology News | No. 81 | Winter 2010 | www.physoc.org EDUCATION PN 53

Mobile Teaching Unit sponsorship For 2010, 2011 and 2012, The Physiological Society has committed sponsorship to the Mobile Teaching Unit (MTU), which is managed by the AIMS CETL (Applied and Integrated Medical Sciences Centre for Excellence in Teaching and Learning) within the University of Bristol. The MTU has proven to be a highly successful resource for raising the profile of physiology within schools and amongst the general public.

The MTU is a lorry that expands into an interactive learning centre, which delivers informal, hands-on physiology teaching sessions to students from the top primary class to A Level. Students have the opportunity to use a range The MTU visited Tiffin School on 22 June 2010. of clinical equipment to take physiological measurements (mainly School visits will occasionally be and students gained a great deal from in the cardiovascular, respiratory offered as a competition prize for the work they did with the team during and nervous systems) and talk our school/college contacts. We ran the day. The scheme is excellent... to physiologists about careers in three competitions offering the MTU and we will certainly encourage other physiology. Teaching materials as a prize in 2010: the first winner schools to take up the opportunity you on body structure and function, was Tiffin School in Surrey, who so generously gave to us.” including anatomical models and provided the following feedback: posters, are displayed and sessions Hilda Clark can be integrated with PowerPoint “On behalf of the school, I would like Headteacher, Tiffin School, Surrey presentations. Activities are to thank you very much for arranging designed to enrich current topics the [Mobile Teaching Unit] to come For more information about our based on human physiology in the to Tiffin on Tuesday 22 June. It was a school competitions, please visit curriculum and can be tailored to the tremendous success and both the staff www.physoc.org/competitions. audience.

A one-day visit can accommodate up to 150 students in groups of about 20 for 40–60 minutes each. Sessions are run by University of Bristol and AIMS CETL staff, and sometimes supported by local Physiological Society Members. For more information about the MTU, please visit the AIMS section of the University of Bristol’s website at www.bristol.ac.uk.

From 2010 to 2012, The Society will be arranging a number of visits of the MTU to schools and science festivals in Britain. At festivals, the MTU can be used as a drop-in facility with activity stations situated around the lorry. Earlier this year, The Society provided funding for the MTU to attend the Big Bang Fair in The lorry expands into a seminar room, which houses informal physiology teaching Manchester. sessions supported by presentations, posters and models.

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Outreach activity at The Physiological Society The Society encourages Members to organise outreach activities with Outreach Grants funding support from our Outreach The Outreach Grant scheme is open to all Ordinary Members, Affiliates Grant scheme. In 2010, we received and Associates of The Society who would like to communicate the a significant increase in applications excitement of physiology to young scientists and the wider community. and we would like to thank all those For more information, please visit our website at www.physoc.org/grants who have engaged in outreach or email [email protected]. on behalf of The Society; we look forward to building on this success in future years. The following section National Science and Engineering Weeks (NSEW) 2011 summarises some reports from the We are currently accepting Outreach Grant applications from Members outreach providers; full reports can who would like to organise an event during NSEW, 11–20 March 2011. be found on our website at The final deadline for applications is 31 January 2011. www.physoc.org/schools Cambridge Hands-On Science summer roadshow 2010 From 28 June to 25 July, Cambridge Hands-On Science (better known as CHaOS) toured Southern and Eastern England with a mission to make science more accessible to students and the general public. CHaOS is a non-profit voluntary group based at the University of Cambridge.

In the 2010 roadshow, the group delivered events to eleven schools (mostly for students aged 9 to 13) and eight public venues, reaching an estimated 4000 members of the public.

Some of the CHaOS team. Students meet ‘Boris’ to learn about radiographs.

Using fun, hands-on experiments, demonstrators guided small groups of students through a particular aspect of science, ranging from a large wooden model of the hand showing how antagonistic muscle groups work to genetics by means of extracting and precipitating DNA from kiwi fruit.

Many students appeared to gain a great deal of understanding from the interactive nature of our displays – as well as enjoy themselves too. The feedback we receive makes the effort to organise the roadshow all the more worthwhile – well illustrated by a quote from one student: “the best thing I’ve ever done in science!”

We are committed to educational outreach and thus keep entrance to our public events free. Although schools are asked for a small contribution to our costs, we rely upon sponsorship for the majority of funding. Careful budgeting and route planning ensures a cost of around £3 per visitor. CHaOS is very grateful for the Outreach Grant awarded to us by The Physiological Society as well as for assistance with the promotion of our events – no doubt many of the enthralled students will be submitting their ‘Ask a Physiologist!’ forms soon.

If you would like to learn more about CHaOS, please visit our website at www.chaosscience.org.uk, where a more detailed tour report can be found and contact details if you would be interested in having a visit from us as part of next year’s roadshow. Jonathon Holland

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Sport and Exercise Physiology Outreach at Nottingham Trent University

Eastwood Comprehensive School was welcomed to Nottingham Trent University (NTU) Sport Science Department to engage in a day of Sport and Exercise Physiology Master Classes. The first session involved the students measuring their own lung and respiratory function (including forced vital capacity and forced expiratory volume), and comparing this with normative data for the general population and athletes. The students discussed the implications of these measurements for both long-term health and sports performance.

The students then engaged in a submaximal exercise test that is used by health professionals to estimate maximal oxygen uptake. The students measured their heart rate response and oxygen uptake, and used this to estimate maximal oxygen uptake. The strengths and weaknesses of the estimation technique were evaluated, with the students providing very insightful comments.

Just prior to lunch, the students experienced the state-of-the-art British Olympic Association accredited environmental chamber, which can be used to manipulate altitude, temperature and humidity. A chilling experience was had by all.

Students use GPS units (situated between the shoulders) Students from Eastwood Comprehensive School with PhD to measure their speed and distance during a football student volunteers at the NTU Sport Science Department. match.

In the afternoon, global positioning satellite (GPS) was used to measure speeds, distances and forces whilst playing a football match. This technology has just been introduced by several elite clubs from different sports to precisely monitor training loads and match demands. This gave the students a real insight into their own performance and how it compares with elite football players.

Students were also given an insight into University life, and a tour of the facilities and campus.

The day introduced sport and exercise physiology, and provided the students with knowledge about the importance of physiology in both clinical and performance settings. The outreach event was enjoyed by the students (and teacher) from Eastwood Comprehensive, as well as increasing their interest in pursuing science at A2 Level and beyond. Of equal importance was our (staff and PhD students) enjoyment of the day and we have now made a link with the school; we are already arranging future outreach events. One student stated “Loved the day, hope to go again soon”; similarly, we can’t wait to welcome them back.

Caroline Sunderland

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‘An appetite for science?’ at Imperial College London In July 2010, the Section of Investigative Medicine at Imperial College London held an outreach event entitled ‘An Appetite for Science?’ Twenty-one 16–17-year-old students from across the UK took part in this fun and educational day, which was aimed at promoting accessibility to higher education, academia and science – and we believe there is nothing more accessible than the science of eating!

The day was run by a mix of scientists at different stages in their careers: academics, postdocs and PhD students with either basic science or medical backgrounds, providing the students with a range of perspectives about working in research. The use of informal lecture-style presentations, hands-on laboratory practicals, topical debates and group work allowed the students first-hand experience of what might await them at university.

A student gets to grips with a pipette whilst The students who attended ‘An Appetite for Science?’. performing an experiment to look for the hunger hormone ‘ghrelin’.

We started the day with an introductory lecture on the obesity epidemic before students were introduced to the science of appetite control. In small groups, students then learned about the benefits and pit-falls of the body mass index (BMI) by placing their favourite celebrities and sports stars in underweight, normal, overweight and obese categories. This prompted lots of discussion between the students as did the lively debate on the use of animals in scientific research that followed. After lunch, the students conducted a real laboratory experiment and quantified the levels of the ‘hunger hormone ghrelin’ in ‘plasma’ samples, which offered a fantastic opportunity for the students to bring together what they learnt from the lectures into practice in the lab.

Students also learnt about cutting-edge translational research – moving from lab-based in vivo studies through to studies in human volunteers. As part of this, the students undertook an activity to design a clinical trial for a hormone identified to have a role in appetite control. The day finished with a lecture from our resident bariatric surgeon. The students learned why the physiological changes in the gut following gastric by-pass surgery currently make it the most successful treatment option for obesity. The students particularly loved the accompanying gory videos of the surgery.

The feedback received from the students was excellent: a report by Sabrina, one of the students who attended the day, can also be found online:

www2.imperial.ac.uk/blog/reporter/2010/08/12/an-appetite-for-science/

We would like to thank The Physiological Society for their continued support of our outreach work, without whom we would be unable to hold this successful and rewarding day. Michelle Sleeth

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Metabolic Physiology Outreach at the University of Young Physiologists’ Nottingham Symposium – Neuromodulation On 9 July, the Metabolic Physiology group of the School of Biomedical Sciences at The University of Nottingham hosted an enthusiastic group 25–26 August 2010 of AS-level students keen to learn more about Human Physiology. We University of St Andrews opened our labs to students from The Beckett School and Eastwood This short symposium was held at the Comprehensive, allowing them a first-hand glimpse of what it is like to University of St Andrews, Scotland’s conduct research into Human Physiology in a university setting. oldest university and shortly to celebrate its 600th anniversary.

Almost a hundred years ago, the celebrated Scottish physiologist and mountaineer T. Graham Brown published his paper ‘The intrinsic factors in the act of progression in the mammal’. With the upcoming centenary of this seminal and defining work, and to celebrate the achievements of six centuries of research at St Andrews, young physiologists at the university identified the need to build a network of like-minded early-career researchers in a relevant physiological context.

The theme of Neuromodulation was chosen as it was felt that this best represented a specialism of St Andrews in the wider field of Students receiving guidance on how to measure blood pressure from Professor Cellular & Integrative Neuroscience. Ian Macdonald. Neurophysiology at the university is particularly focused on motor control The Metabolic Physiology group is home to a collection of scientists who and so in hosting this symposium we share a common interest in the regulation of metabolism during health wanted to attract delegates from both and disease in humans (www.nottingham.ac.uk/BioMedSci/world-leading- within our area of expertise and from research/metabolic-physiology.aspx). With help from postgraduate other areas of neuroscience. students along with postdoctoral and academic members of staff, we The symposium offered an informal arranged for the students to undertake several activities within our but professional setting and research, laboratory, exploring different aspects of cardiovascular, respiratory and both published and ongoing, muscle physiology. The overall aim of the day was to allow students to was presented by a good mix of see that it is possible to perform integrated physiological investigations postgraduate doctoral students, in humans. We also aimed to give them an appreciation that human postdoctoral researchers, and invited physiology can also be dovetailed with modern molecular biological speakers who included George approaches. Richerson (University of Iowa), Ole Kiehn (Karolinska Institutet), Jeremy As the day progressed, pre-conceived notions held by students of science being impenetrable, unfashionable or boring disappeared. The students also appreciated receiving hands-on experience of how to take common measurements such as blood pressure, as they were taken through the physiological principles underpinning these important techniques.

Overall, the day was a great success and we had as much fun engaging with the students as they did undertaking the activities. We are indebted to The Physiological Society for both the financial support and guidance that they provided in aid of the event. While the outreach event involved a lot of work, we would highly recommend engaging with local schools as we found the day immensely rewarding. Andrew Murton

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Lambert (University of Dundee) and Keith Sillar (University of St Andrews). New Chief Executive appointed by The Society

A wide breadth of posters were I am delighted to have been chosen displayed and talk highlights included: as the new Chief Executive of Retinoic acid synthesis in astrocytes, The Physiological Society by the Glycine and GABA receptor function President and Executive. Without in the higher centres of the CNS and doubt I have inherited a great team Modulation of short-term plasticity of staff from Mike Collis and with my of motor cortex via GABAergic feet newly under the desk, they are disinhibition by non-invasive sensory already helping me to settle in. depravation. I have known a number of the staff Sheena Tiong (University of Glasgow) won Overall Prize for Best Poster at The Society through a previous for ‘A combined anatomical and role at the Association of the electrophysiological study of lamina II British Pharmaceutical Industry interneurons in the rat spinal dorsal (ABPI) where we worked on key horn’ and Noboru Iwagaki (University policy issues affecting the life and of St Andrews) won the Best Talk for biomedical research base in the his presentation titled ‘Modulation UK, especially in relation to in vivo Philip Wright of spinal locomotor networks and sciences, education and research motoneuron activity by group I mGluR policy. During these encounters I this cannot mean that the voice of activation’. built a great respect for Mike and his physiology is not heard. team. The symposium dinner and ceilidh I believe that despite the tight fiscal ensured that there were more chances The next few months are going environment in which the UK finds to network as well as have a great to be a steep learning curve for itself, we have good reason to be time and a local record may have been me, set against a backdrop of a optimistic. The Society itself is in a set for the most physiologists in a serious threat to science funding strong position and we have a real room to ‘strip the willow’. and higher education – with the opportunity to significantly increase our external impact. Our themed The team behind the symposium was Coalition considering removing meeting on ‘The biomedical basis a small but dedicated and enthusiastic the upper limit on tuition fees and of elite performance’ in the run-up group of young researchers, and increasing the student loan interest although this was a steep learning rate significantly. This poses a to the Olympic games and the curve in terms of the organisation, real threat to resource-intensive hosting of the IUPS Congress in 2013 project management and external science education as well as the both provide opportunities for The liaison required (everything from the UK research base. It is critical that Society in the longer term. In the catering, the equipment and room The Physiological Society makes shorter term I will use the networks hire, to the travel arrangements, the views of its Members known to and contacts in Parliament and prizes and budgeting), this was an Government and works to sustain Government to ensure the voice of extremely worthwhile exercise in research and education funding. The Society is heard. team work, team building and forging lasting connections with other young Consequently, apart from getting to Over the next few months I want researchers. All of us involved in know the staff, Council and meeting to meet all the committees whose planning and running this event hope as many of the wider membership as members play a critical role by that we will continue to build on the I can, my key priorities for the year providing guidance and contributing networks we made as we progress are to: raise the profile of physiology their time and energy. I also hope through our future careers. in Government and Parliament; to meet as many of you as possible, by attending some of the scientific We would like to acknowledge the sustain investment in education from schools to Higher Education; meetings and other events The generous investment in our personal Society organises. However, I do development made by the GradSkills and sustain our research capability. hope that if you have any questions, team at the University of St Andrews, All these will have an impact on suggestions or ideas, you will not and we also thank our sponsors, the environment and long-term Digitimer. sustainability of physiology in the hesitate to get in touch. UK. In order to achieve these, it Above all, this symposium would is critical we work closely with Philip Wright not have been possible without the other like-minded learned societies Philip has over 16 years’ experience generous financial, directional and and organisations especially the of the pharmaceutical, biological and moral support of The Physiological Academy of Medical Science, the biomedical sectors, with a particular Society. British Pharmacological Society and focus on strategy, regulation and Catherine Dunford also the new Society of Biology, but external scientific affairs.

Physiology News | No. 81 | Winter 2010 | www.physoc.org ASK A PHYSIOLOGIST! PN 59

Ask a physiologist! hand, may eat more while searching Hiccups are extremely common, and for a fuller fl avour. In evolution, are rarely associated with severe Is it true that girls have more taste supertasters may have had some diseases. Most cases of hiccups buds than boys? If so, why? (Josh, advantage since many toxins are resolve inside a few minutes to an age 11) bitter in taste. This is particularly hour, and are known as common important for women since they hiccups. Persistent hiccups last for Professor Tim Jacob, University of are responsible for the diet of the up to 48 hours. If they last for more Cardiff, replies: baby in the womb and also after than 2 months they are classed birth while the baby is being breast as intractable or diabolic hiccups; Some people are ‘supertasters’ some fed. Interestingly, the sensitivity of these hiccups are usually due to are ‘regular tasters’ and others are women to bitterness commonly more serious illness or medication. ‘non-tasters’ based on their ability increases during the fi rst trimester Suffering long-term hiccups can to taste specifi c bitter substances of pregnancy when the fetus is most be a problem, since they can cause (the chemical name of one of them vulnerable to damage by many fatigue, loss of sleep and mental or is n-propyl thiouracil or n-PROP for toxins. For example, in some women physical exhaustion. short). Some people do not detect who typically love coffee a strong these substances at all, while others aversion to coffee’s bitterness occurs There are literally hundreds of fi nd them intensely bitter and as soon as they become pregnant. recommended ‘cures’ for hiccups: offensive. About a quarter of people drinking out of the back of a cup, a (25%) are supertasters, half (50%) Why do people hiccup? (Jamie, cold key down the shirt and being are regular tasters and a quarter are age 11) frightened are commonly used. non-tasters. Women are supertasters Usually the best cure is holding Dr Mary Morrell and Dr Alison or non-tasters more frequently, while your breath to gain control of your McMillan, Imperial College London, men tend to be regular tasters – this breathing muscles. Several more reply: applies to children as well. The physiological cures for chronic anatomical data also support the A hiccup occurs as a result of hiccups exist including stomach gender difference; women do indeed a sudden brief, often violent, distension, digital rectal massage, have more fungiform papillae (the involuntary contraction of pulling hard on your tongue. These little red dots on the front surface of the diaphragm, and the other work by stimulating the vagus nerve. your tongue) and more taste buds. muscles used when breathing in. The ability to taste or not taste these Physiologists have speculated that Hiccups have been around for bitter substances appears to be there could be a ‘hiccup-generating millions of years and the exact cause determined by genetics. Apparently, centre’ leading to stimulation of the remains a mystery. if you have a double copy of the phrenic nerve. But neither the centre gene that confers sensitivity to bitter nor the precise physiological trigger Get involved and write an taste, then you are a supertaster. If for the hiccup has been identifi ed so article for Physiology News far. The ‘hic’ noise comes when the you have one copy, you are a regular Have you done something in breath is cut off by the closure of the taster and if you have none, you your studies you would like to vocal cords snapping the windpipe are a non-taster. The tongues of recommend to other young shut. The stereotypical sequence of supertasters are physically different scientists, attended an amazing from non¬tasters. Supertasters have muscle contractions is complex and the hiccup shares some similarities training course or got an issue more taste buds on their tongue. with coughs, sneezes or yawns. you’d like to get off your chest? Consequently, there are more taste If you enjoy writing then why not buds to send bitter messages to There are many theories as to why contribute to Physiology News. We the brain. Our age plays a role in we hiccup although no one is really have an annual prize of £200 for the the number of taste buds on our sure. One idea is that hiccups evolved best published article written by an tongue. Children have the most when we walked on four legs, and Affi liate or young scientist. If that taste buds which may explain why that they helped us to swallow food isn’t enough incentive, contributing they are more sensitive and tend stuck in our throats. Now that we to the magazine is a great extra to be more fussy about what they walk upright, swallowing is aided by on your CV and a nice way to tell a eat. There is a decrease in taste gravity. The sharp breath in creates a broader audience about the things sensitivity with ageing in women. vacuum behind the food to help suck you do. We are always looking for Only about 7% of women 65 and the lump down. This might explain people to contribute to the Affi liate older were supertasters as compared why dogs eating food quickly are pages in the magazine and would with the expected 25% in younger prone to hiccups. Other suggestions love to hear from anyone who women. Supertasters tend to be thin are that hiccups result from our would like to get involved. and non-tasters tend to be heavier. evolution as sea creatures, when gills Possibly because of the intensity of were used to breath. Finally, they Email us for more information or to fl avours, supertasters tend to eat could be linked to how we learn to discuss ideas at less food. Non-tasters, on the other suck as babies. [email protected]

Physiology News | No. 81 | Winter 2010 | www.physoc.org 60 PN SOCIETY

5–7 January 2011 Robinson College, Cambridge, UK

DEADLINES: Abstract submission The Biochemical Society Annual Symposium 26 OCTOBER 2010 Earlybird registration Recent advances in 3 DECEMBER 2010 membrane biochemistry

Organizers: Frank Michelangeli Malcolm East

Overview: This symposium will focus on the latest developments and breakthroughs within the field of membrane protein structure and function. Membrane biology underpins a vast array of life Image kindly supplied by Frank MichelangeliImage of Birmingham, (University UK) kindly Frank supplied by processes such as bioenergetics, signalling and transport.

Topics: * Membrane protein expression and structural analysis * Recently elucidated membrane protein structures * Modelling of membrane protein structure, folding and dynamics * Lipid-protein interactions * Membrane proteins in pathology

Biochemical Society Transactions is the only publication to include this major international meeting. It is scheduled to appear in Issue 39(3) and as a stand-alone volume of the online Symposia series.

For a full programme please visit: www.biochemistry.org

Sponsored by:

Physiology News | No. 81 | Winter 2010 | www.physoc.org THE SOCIETY’S JOURNALS PN 61

circulation. His interest on the limits of human performance reflects his devotion to competitive endurance and middle distance running since New Editors 2010 Neuroscience in the Department of childhood. Cell Physiology and Pharmacology Ian D. Forsythe at Leicester in 2000, and in 2005 José is an international researcher. I moved to join Pierluigi Nicotera He completed his undergraduate in the MRC Toxicology Unit at studies in Physical Education in Leicester. Here I continued our basic Barcelona (Spain), his MA and studies of synaptic transmission PhD in Exercise Physiology at the and voltage-gated potassium University of Texas at Austin (USA) channels and allied this to applied and his post-doctoral training at the studies of neurodegeneration using August Krogh Institute, University of electrophysiological methods. Over Copenhagen. From 1999 to 2005, he Group Leader, Neurotoxicity at the the last 5 years we have focused worked as a senior researcher at the Synaptic Interface, MRC Toxicology on brainstem damage caused by Copenhagen Muscle Research Centre Unit, University of Leicester, Leicester hyperbilirubinaemia and auditory (CMRC), a world-renown centre of LE1 9HN, UK. insult, we have characterised the excellence in integrative human physiological mechanisms of nitric physiology directed by Professor I conducted my PhD on in vitro oxide signalling in the auditory Bengt Saltin. In 2006, José joined spinal cord neurophysiology at the brainstem, and are developing Brunel University’s School of Sport University of Southampton under methods to study neuronal and Education to create and direct the supervision of Gerald Kerkut and ion channel homeostasis and the Centre for Sports Medicine and Jeff Bagust. Maintaining an interest neurodegeneration. A key objective Human Performance. in primary afferent depolarization is to understand the different (PAD) and presynaptic inhibition, physiological roles of native delayed Paul Greenhaff I did my first postdoc at the John rectifiers (voltage-gated potassium Curtin School of Medical Research channels) in neuronal excitability. in Canberra, Australia under the I have recently joined the Editorial supervision of Steve Redman. In Board of The Journal of Physiology as 1985 I received a Fogarty Fellowship Senior Editor and Reviews Editor. to work with Phil Nelson and Gary Westbrook at NICHD, National José González-Alonso Institutes of Health, Bethesda, MD, where we first demonstrated slow time-course synaptic currents Paul Greenhaff is Professor of Muscle mediated by NMDA receptors at Metabolism at the University of glutamatergic synapses (this was Nottingham, where he has worked published in The Journal of Physiology for nearly 20 years (and which in 1988). Later in 1988 I returned to he believes have passed far too the UK to work with Peter Stanfield quickly)! Paul has specific research at the University of Leicester on interests in the area of skeletal voltage-gated potassium channels. I José González-Alonso, Professor muscle metabolism. Members of received a Wellcome Senior Research of Exercise and Cardiovascular his research group possess a range Fellowship to develop the auditory Physiology, Brunel University, West of expertise and skills necessary brainstem preparation from which in London. to perform integrated metabolic 1994 I first made direct patch clamp José González-Alonso is an investigations in healthy human recordings from the giant excitatory synaptic terminal called the calyx of integrative human physiologist with volunteers and patients, which are Held (also published in The Journal). particular interest in the regulation dovetailed with relevant animal and Our studies focused on exploring of skeletal muscle blood flow and molecular biological approaches the mechanisms of transmitter the cardiovascular determinants of facilitating a translational approach release, calcium channels, synaptic exercise performance. His research to research. Current research integration and brainstem auditory has contributed importantly to interests are focused on the control processing. I joined the Editorial advance our understanding of the and integration of muscle fuel Board of The Journal of Physiology circulatory limitations to exercise utilisation in health and disease, between 1995 and 2002 and I was and the role of erythrocytes and and the molecular regulation of a member of the Wellcome Trust coupled intravascular adenosine muscle mass under a variety of Neuroscience Panel from 2002 triphosphate (ATP) signalling in the conditions. Particular focus has been to 2005. I was awarded a Chair of control of the human skeletal muscle directed towards investigating the

Physiology News | No. 81 | Winter 2010 | www.physoc.org 62 PN THE SOCIETY’S JOURNALS impact that exercise, inactivity, and with an eye to determining what His laboratory studies the anatomical nutritional and pharmacological changes in neuronal function and and physiological properties of interventions have in modulating synaptic transmission underlie GABAergic interneurons and Cajal– muscle mass, metabolism and addiction. Retzius cells of the hippocampus, function. This is Paul’s second stint and their role in the regulation as a member of the Editorial Board Dr Lovinger received a BA in of physiological and epileptiform of The Journal of Physiology and he Psychology from the University network activity. is looking forward to the challenge. of Arizona in 1981 and in 1987 he received his doctorate in Psychology Over recent years he has also been Giovanni Mann from Northwestern University. At a member of The Society’s Council Northwestern, he worked with Dr and currently sits as a non-council Aryeh Routtenberg studying the member of The Society’s Finance roles of protein kinase C and its Committee. substrate, the GAP-43/F1 protein, in hippocampal long-term potentiation. David Lovinger His post-doctoral research at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health, focused on the effects of alcohol on ligand- gated ion channels. In 1991 Dr I obtained a BSc in Zoology (1973) Lovinger moved to the Vanderbilt from George Washington University, University School of Medicine Washington DC, USA and MSc as an Assistant Professor in the (1974) and PhD in Physiology (1978) Department of Molecular Physiology from University College London. I and Biophysics, where in 1998 he am currently Professor of Vascular David M. Lovinger is a neuroscientist rose to the rank of Professor. Dr Physiology in the Cardiovascular studying the neural basis of action Lovinger returned to NIAAA in 2002 Division, School of Medicine at control, habit formation and as a Senior Investigator and Chief King’s College London. In the addiction. Throughout his career he of the Laboratory for Integrative past I served as Chairman (and has examined neurophysiological Neuroscience. Deputy Chairman) of the Executive mechanisms that contribute to Committee of The Physiological brain information storage. Current Gianmaria Maccaferri Society, President of the European research in his laboratory is Pancreatic Society, and as a Council focused on molecules involved in Member of The Physiological modulation and plasticity of synaptic Society, Society for Free Radical transmission at corticostriatal Research-Europe, European synapses, with particular attention Society for Microcirculation, to long-lasting changes in synaptic Microcirculatory Society USA transmission (such as long-term International Liaison Committee and potentiation and long-term am currently President of the British depression of transmission) Microcirculation Society. thought to contribute to learning Dr Maccaferri received his MD and My research and editorial expertise PhD from the University of Milan, and memory. The laboratory is lies in the field of vascular biology Italy, where he worked with Dario also investigating how molecules and reactive oxygen species. I am DiFrancesco studying the role of the involved in striatal synaptic plasticity currently also an Associate Editor hyperpolarization-activated current participate in skill and instrumental for Free Radical Biology & Medicine in hippocampal pyramidal cells. He learning. Activity of neurons in and on the Editorial Boards of then trained as a post-doctoral fellow corticostriatal circuitry during Microcirculation and Free Radical with Chris McBain at the National action learning and performance Research and the International Institutes of Health, Bethesda, Peter is also a focus of Dr Lovinger’s Advisory Board for Acta Physiologica Somogyi, at the MRC, Oxford, and research. The corticostriatal Sinica. I currently chair the circuitry also participates in the Ray Dingledine at Emory University in Atlanta investigating the synaptic Translational Sciences Panel of development of addiction. In this Heart Research UK, and am on the context, the laboratory is examining properties of specific types of GABAergic interneurons. Board of External Referees for the neuropharmacological effects of BBSRC and College of Experts for addictive drugs on striatal synaptic In 2002, he joined the faculty at the MRC – Physiological Systems transmission. Effects of long-term Northwestern University where he & Clinical Sciences, and previously exposure to addictive drugs on this currently is Associate Professor at served on grant panels of the circuitry are also being investigated, the Department of Physiology. British Heart Foundation and Guy‘s

Physiology News | No. 81 | Winter 2010 | www.physoc.org THE SOCIETY’S JOURNALS PN 63

Charitable Foundation. At King‘s pay attention to diversities among I study sensory neurobiology and College London I am closely involved species. For two years after I moved specifically the chemical senses. My in postgraduate studies and as Head to Osaka University, it was necessary associates and I are interested in of Graduate Research in the School to live alone 120 miles away from the cellular and molecular events of Biomedical Sciences. Throughout my family, as is usual for many that occur in the peripheral sensory my career in the UK at UCL, Queen researchers in Japan. However, since organs of taste, and especially the Elizabeth College and King‘s College, spring of this year, I fortunately live synaptic interactions and signal I maintained a strong link with with my family in a town near Kobe processing that occur in taste buds physiology, supported The Journal city where I spent my high school during gustatory excitation. We both as an author and reviewer, and years. The town is close to both the use functional imaging to analyse hope to facilitate the submission of ocean and mountains. A historical how taste cells are activated vascular biology and redox signalling house that was designed by Frank by stimuli and to identify the papers to The Journal. Lloyd Wright is also close to our neurotransmitters released during house. We have fun walking along stimulation. Details are on my Yasushi Okamura the river and on the trails in the website: wood where we sometimes see wild www.biomed.miami.edu/sroper boar. Lin Chen Stephen Roper

I am currently the professor of the Department of Physiology, Professor at the Department of Graduate School of Medicine, Biological Science, Section of and Graduate School of Frontier Molecular and Computational Biosciences at Osaka University. My first opportunity to review for The Journal of Physiology was when Biology, University of Southern The physiology course has more I was a young American Fulbright California, Los Angeles, CA, USA. than 100 undergraduate students Scholar completing a PhD degree in every year. We decided to start Lin Chen (University of Southern Physiology at the ‘Godless Institution teaching individual students the California, USA) obtained his PhD of Gower Street’, University College two-electrode voltage clamp degree in the Chemistry department London, when AF Huxley was technique of Xenopus oocyte as at Harvard University in 1994. He department chairman. My thesis well as classical teachings such as did his postdoctoral training in advisor asked me to help him electromyograms. Our group has structural biology in the Department review a manuscript The Journal been studying ion channel molecules of Molecular and Cellular Biology had just sent him. I have held The and voltage-sensing phosphatase at Harvard University. His research Journal in high esteem ever since interests include: (i) mechanisms by integrating electrophysiology, and am delighted to join my expert of eukaryotic gene regulation, structural biology, enzyme chemistry colleagues on the review team. including the molecular basis of and mouse gentics. I started my After graduating from UCL, I trained signal transduction, transcription career working on developmental with Stephen Kuffler at Harvard and regulation and epigenetic control changes of membrane excitabilities subsequently joined the faculty at of chromosome structure; and (ii) during the ontogeny of tunicate, the University of Colorado Medical structure and function of nicotinic a marine invertebrate, under the School. From there I spent some acetylcholine receptors and other supervision of Professor Kunitaro time as chair of the newly named ligand-gated ion channels. Takahashi. I learned molecular Department of Anatomy and biology in the laboratory of Dr Neurobiology at Colorado State Flemming Dela Gail Mandel (who is a National University, then was recruited to Academy member, currently at the University of Miami School of Flemming Dela is 53 years old and Vollum Institute) as a postdoc. For Medicine where I am a professor has an MD from the University of many years from my earliest days in the Department of Physiology & Copenhagen (1989). He obtained in science, I have been lucky to Biophysics. When I’m not in the lab, his Doctor of Medical Sciences in work on my own project. Although I’m back in the Colorado mountains 1996. After basic clinical training, I am currently working on channel skiing or hiking with family and Flemming has been doing full-time molecules themselves and their friends, or sea kayaking in warm research with the focus on human functions in mammals, we always waters off the Florida coast. cardiovascular and metabolic

Physiology News | No. 81 | Winter 2010 | www.physoc.org 64 PN THE SOCIETY’S JOURNALS adaptation to exercise and physical period my work was focused on Conference 2010. Abano Terme, training in health and disease non-erythropoietic functions of a slow-paced spa resort close to (e.g. diabetes, insulin resistance, erythropoietin when injected in Padova and Venice, turned out to heart failure, atherosclerosis, humans. My current research group be an excellent location for the ischaemia). He is currently professor at the Zürich Center for Integrative symposium. The seven talks of the in Physiology at the University Human Physiology in Switzerland symposium were presented in the of Copenhagen in the Center for focuses on topics within human main lecture hall of the Congress Healthy Aging. physiology such as mitochondrial Center Pietro D’Abano and attracted function in health and disease, an audience of around 200 people. Carsten Lundby regulation of brain blood flow, The format of the symposium adaptations to altitude exposure, giving each speaker a relatively long regulation of cardiac output and time (about 30 min presentations blood volumes, and physiological followed by 10 min for questions) responses to exercise training and worked very well and inspiring bed-rest. Needless to say most of our discussions occurred after each lab meetings are held while jogging talk. Further discussions took place the Zürich hills. during the morning and afternoon coffee breaks and the lunch, which could be enjoyed outdoors in perfect In the mid 90s I was still in high The Journal of late-summer sunshine. A slightly school and trained running wearing Physiology symposium unexpected take home message a snorkel to induce hypoxia of the symposium was that muscle The Journal of Physiology symposium and thereby hoping to increase disuse, rather than increased muscle ‘Reactive oxygen and nitrogen performance – retrospectively this usage, is accompanied by problems species in skeletal muscle: acute may not have been very smart – but induced by reactive oxygen–nitrogen and long-term effects’ took place my interest for oxygen transport species. on Saturday 11 September in Abano always seems to have been there. Terme, Italy. It was organized My interest for integrative human by Roberto Bottinelli and Håkan The talks from the symposium physiology as a research topic was Westerblad as a satellite symposium will be published in The Journal of initiated when I participated as a preceding the European Muscle Physiology early in 2011. subject in a scientific high-altitude expedition to La Paz in Bolivia. During the ten-week-long study, new techniques and principles were Membership Subscriptions for 2011 introduced almost on a daily basis. The Society is pleased to announce that there will be no change to the The study was led by Professor membership subscriptions for 2011. Bengt Saltin from the Copenhagen Muscle Research Center in Denmark Membership Category Membership With Direct and included many international Fees 2011 Debit top researchers. I am not sure if my Ordinary member £90 £70 learning curve has been steeper since then! A few years later I Affiliate £20 £15 obtained my PhD from this institute, with Bengt Saltin as my supervisor. Associate £45 £35 Since the beginning of my research Undergraduate £15 career my main interest has been Associate oxygen transport and utilization, and how humans adapt to stimuli Join alone (single such as altitude, exercise and payment) pharmacological manipulations. After a postdoctoral period in Undergraduate £10 Switzerland, where I was introduced Associate to work done on transgenic animals Join as group of overexpressing erythropoietin, I members (single was appointed Assistant Professor payment) at the Department of Sport Science at the University of Aarhus, where The option for Ordinary Members to subscribe to hard copies of The Society’s journals has been removed. I was subsequently also appointed Associated Professor. During this For further information, please contact [email protected]

Physiology News | No. 81 | Winter 2010 | www.physoc.org www.iups2013.org

37th Congress of the International Union of Physiological Sciences

The International Convention Centre (ICC) Birmingham, UK

PN IBC 1010.indd 1 10/22/2010 1:43:07 PM Phantom hand movement (p. 34).

A publication of The Physiological Society www.physoc.org