PHYSIOLOGY NEWS

winter 2009 I number 77

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ADI_InstStudent_UK_PhysioNews.indd 1 15/5/09 2:32:20 PM PHYSIOLOGY NEWS Editorial 3 The Society’s dog. ‘Rudolf Magnus Meetings gave me to Charles Sherrington, who The hypothalamic paraventricular nucleus in health and disease gave me to Henry Dale, who gave Julian Paton 4 me to The Physiological Society in Epithelial form, function and environment Andi Werner, October 1942’ Mike Gray 6 Festschrift symposium in honour of Edward J Johns Published quarterly by The Physiological Society John Mackrill 7 Contributions and queries Lighthouses and lobsters in Woods Hole Rachel Ashworth 8 Senior Production Editor Translating ‘omics’ into functional and clinical applications Jill Berriman Thelma Lovick 9 Editorial Administrator Festschrift in honour of John Russell Mike Ludwig 10 Ed Sexton Physiology 2009 – Dublin James FX Jones 11 The Physiological Society Publications Offi ce PO Box 502, Cambridge CB1 0AL, UK IUPS Kyoto 2009 Douglas Bovell, Fiona Randall 12 Tel: +44 (0)1223 400180 A week in the life of... Fax: +44 (0)1223 246858 ... a neuroscientist comedian Dean Burnett 14 Email: [email protected] Interview Website: www.physoc.org Understanding ion channels and their role in brain disorders Magazine Editorial Board Bill Catterall, Angus Brown 15 Letter from Japan 3 Editor Embracing a new culture Fiona Randall 19 Austin Elliott Features University of Manchester, Manchester, UK Excitation-dependent Ca2+ infl ux in vertebrate skeletal muscle Members is in, again Bradley Launikonis, Oliver Friedrich, Angus Brown George Stephenson 20 University of Nottingham, Nottingham, UK Regulation of extracellular pH by purinergic signalling Patricia de Winter Jonathan Kaunitz, Yasutada Akiba 22 University College London, London, UK Fractals in human physiology revisited Can Ozan Tan, Sarah Hall Andrew Taylor 25 Cardiff University, Cardiff, UK Sheet-like tendons are stiffened by bulging muscles Munir Hussain Emanuel Azizi, Thomas Roberts 28 University of Bradford, Bradford, UK The placebo response: how words and rituals change brain John Lee circuitry Fabrizio Benedetti, Michele Lanotte, Leonardo Rotherham General Hospital, Rotherham, UK Lopiano 30 Thelma Lovick Neuromuscular interaction during human walking: how do University of Birmingham, Birmingham, UK changes in muscle–tendon mechanics affect the motor control of walking? Neil Cronin 32 Foreign Correspondents Techniques John Hanrahan Multiple tests correction, false discovery rate and q value McGill University, Montreal, Canada Fumiaki Katagiri 35 John Morley Reports University of Western Sydney, NSW, Australia The Hodgkin–Huxley–Katz Prize Lecture delivered by Eric Fiona Randall Kandel Otto Hutter 39 Okinawa Institute of Science and Technology, Okinawa, WHO does not recommend the use of homeopathy for HIV, Japan malaria, TB, infl uenza and infant diarrhoea Julia Wilson 40 © 2009 The Physiological Society From the archives Austin Elliott 41 ISSN 1476-7996 (Print) Society of Biology 42 ISSN 2041-6512 (Online) Unbelievable! 43 The Physiological Society is registered in England as a Musings from the Chief Executive’s Desk Mike Collis 44 company limited by guarantee: No 323575. The Society’s journals Registered offi ce: PO Box 11319, London WC1X The Journal of Physiology 45 8WQ. Membership Registered Charity: No 211585. Snakes and ladders David Green 47 Printed by The Lavenham Press Ltd XIth Little Brain Big Brain Meeting Christopher Keating 48 Noticeboard 48 Education Coming in from the cold: physiology at the Cheltenham Festival Sarah Hall 49 Young Physiologists’ Symposium, Dublin Karen Griffi n 50 The British Science Festival, Guildford 2009 Freya Hopper 50 New Council and Affi liate Members of Council 51 Obituaries Ron Cook Ann Silver, Peter Stanfi eld, Alan Cattell 54 Cover image: an ‘H-fractal’. From Tan & Jeff Potts Peter Raven, Jere Mitchell, Artin Shoukas, Julian Paton 55 Advancing the science of life Taylor, pp. 25 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 and to reduce the subsequent editing of 2009. through the following grant process. The Editorial Board of schemes: Travel Grants, Non- Physiology News tries to ensure that all This stage of the year usually Society Symposia Grants, articles are written in a journalistic style brings a round-up of the summer’s Outreach Grants, International so that they will have an immediate conferences, and this year is no Teaching and Research Grants interest value for a wide readership and exception – I think I counted nine and the Vacation Studentship and will be readable and comprehensible to reports – or it might have been ten non-experts. Scientific articles should or eleven! – including reports from Departmental Seminar Schemes. give a good overview of a field rather For full information, please visit: than focus entirely on the authors’ own three continents. www.physoc.org/grants research. An unusual ‘Week in the Life’ this Format of articles issue gives us – the neuroscientist- Membership applications The main message or question posed Applications for membership comedian. Neuroscientist-writers should be introduced in the first are perhaps not all that rare, but to The Physiological Society are paragraph. The background for the comedians are rather scarcer. considered on a rolling basis, topic should then be established, Though, as writer Dean Burnett and a decision is normally made leading up to the final conclusion. points out, there are ex-scientist, within 15 working days. For full Length of articles or ex-doctor, comedians – such as information, please visit: This will be determined by the subject the Irish Dara O’Briain (BSc Maths & www.physoc.org/membership matter and agreed with the Senior Production Editor. Theoretical Physics, UC Dublin) or British comic Harry Hill (MBBS St Submission of articles Is your membership information Georges Hospital Medical School). correct? Authors should submit articles as a Trying to juggle the comedy and the Word document attached to an email. Please check and update your science is even more of a challenge, details at www.physoc.org, under Illustrations should be sent as separate attachments (see below) and not as Dean describes in his diary (p. 14). ‘My Physoc Profile’. embedded in the text. Scientific content is served with six Illustrations and authors’ photographs News and Views articles, as well as Authors are encouraged to submit the latest in what is already proving Physiology News diagrams, drawings, photographs or to be a very popular Techniques Deadlines other artwork with their articles and a photograph of the author(s) should series. Something a bit unusual Letters and articles and all other accompany submissions. llustrations can be found on p. 30, where contributions for inclusion in the and photographs may be colour or black Fabrizio Benedetti et al. discuss the Spring 2010 issue, No. 78, and white, and preferably TIFF, JPEG, physiology, and brain circuitry, of the PNG, PDF or AI files with a minimum placebo response. Placebo therapies should reach the Publications resolution of 300 dpi. Office ([email protected]) also get a look-over in a somewhat References by 14 January 2010. Short news different context on p. 40. Authors are requested to keep the items and letters are encouraged, number of references to a minimum – This issue we are saying hello to a and can usually be included as late preferably no more than two or three. slate of new journal Editors, new copy if space permits. Please cite all references in the style of Society Council Members, and The Journal of Physiology (see new office staff, all of whom tell us Suggestions for articles Information and Guidance for Authors at Suggestions for future articles are http://jp.physoc.org). something about themselves (pp. 45 welcome. Please contact either and 51). The Physiological Society permits the the Editorial Administrator or a single copying of individual articles for Finally, as well as saying hello, the member of the Editorial Board private study or research. For permission issue also features some goodbyes. of Physiology News (see contents to copy or reproduce for any other Goodbyes can be celebrations of page for details). purpose contact [email protected]. the careers of colleagues who are Opinions expressed in articles and letters reaching well-deserved retirements Physiology News online submitted by, or commissioned from, (pp. 7 and 10) – though of course Physiology News online: Members, Affiliates or outside bodies are they may not really be retiring. not necessarily those of The Physiological Some goodbyes, like obituaries, www.physoc.org Society. mark sadder occasions (pp. 54 and 55). Even then, though, we can and should celebrate the life, and career, of scientists and friends. EDITORIAL PN 3

Targeted spending – is it scientists are paid, for the most part, by sigma scan reveals that according to public funds, and hence it is reasonable Foresight we’re not about to make an good value? that the public should know what it is impact. getting for its money. The good news So what, in the first 5 years of its life, The Department for Business, Innovation is that Lord Drayson has reiterated that did Foresight recommend be funded? and Skills (BIS) was created on 6th June the science budget is safe – funding Research into: integrative biology, of this year, expanding the politically earmarked for science cannot be neurodegenerative diseases, ageing, re-born Peter Mandelson’s empire redirected to meet shortfalls created genetic disease risk factors, new classes considerably, by the merger of the by the economic downturn. He has of therapeutics, recombinant technology, short-lived Department for Innovation, also stated his belief in the ‘Haldane diagnostic applications of molecular Universities and Skills (DIUS) and the principle’, that the distribution of biology, and immune manipulation. Department for Business, Enterprise science funding should be determined All, no doubt, logical enough bits of and Regulatory Reform (BERR). Lord by scientists. The worry, though, crystal ball gazing. So what, according to Mandelson heads a mega-department is the nature of the tune. What of them, has this focus actually achieved? of six ministers including fellow peer, basic science? Of physiology? Lord Somewhat surprisingly, the Foresight Paul Drayson, the new Minister for Drayson says that he understands website fails to comment on the above Science and Innovation. Lord Drayson’s the serendipity of science, and that areas but states that they have supported background is as a technologist; he without basic science, opportunities Green Technology (most laudable) and graduated in Production Engineering for its application are non-existent. inspired the Royal Society of Chemistry, from Aston University, from where The Office for Life Sciences Blueprint the Institute of Biology and the Institute he later obtained a PhD in Robotics. A has even acknowledged a skills gap in wealthy businessman – he describes of Physics to collaborate on a series of in vivo sciences, including physiology, workshops on future sources of energy. himself as a ‘high-tech entrepreneur’ and established an industry and HE – his recent speeches suggest that his forum that – by the time this article is The single thing prioritised by Foresight agenda for science is strongly influenced published – will have agreed actions to that has actually made rapid commercial by his background in enterprise. address the gap[3]. And yet in another strides is (largely non-biological) Basic scientists tend to be wary of breath, Drayson wants ‘a healthy and nanotechnology. Foresight in the ‘90s did importing organisational solutions from ongoing situation where scientific insight not identify Lord Drayson’s favourites, the world of profit-driven business. So are translates into profitable business’[1]. stem cells, as ‘hot’, even though they we to expect more of the same? Will new When critics of this approach have were discovered in the ‘60s. Even if initiatives push us further towards the labelled it as flawed, as it reduces the they had, a recent worry is that induced situation in which the hapless ‘Cressida likelihood of unexpected discoveries, he pluripotent stem cells are disturbingly Cormorant’ found herself in last issue’s stated bluntly, ‘I think they’re wrong’. similar to cancer cells – suggesting stem Unbelievable! article? cell therapies are far from imminent [4]. To take an alternative view, some Meanwhile, vast sums have been spent scientists may feel Lord Drayson is Lord Drayson’s perception of British on genome-wide association studies, entitled to think as he pleases, as long as scientific success stories, as reflected in although only a modest proportion of he is prepared to consider that central his reported speeches, certainly focuses risk for common heritable disease is tenet of scientific endeavour, evidence on technological excellence: the World explained by common genetic variants – or rather, lack of it. There is little Wide Web, MRI scanners, satellites, [5]. These examples rather bear out evidence that identifying specific areas to earth observation, space and materials the publicly expressed misgivings of which science funding should be targeted science [1]. Of course, this could reflect scientists (e.g. [6]) as to the advisability increases productivity or innovation. The an agenda of trying to make science of large-scale targeted research. government’s Foresight programme is spending palatable to the wider public, an excellent example of an organisation So, it appears that predicting where in an era of austerity, by focussing on designed to identify such targets. It has money should be best spent is trickier things that are more familiar to people. been going since 1994, which gives us than it seems. One wonders if there will However, these are also the examples a good decade’s worth of outcome, ever be a study to test the view, common he tends to name-check when talking allowing 5 years of leeway to get projects among scientists, that a combination to specifically scientific audiences. off the ground. Foresight’s aim is ‘to of curiosity and ‘chance favouring the Where he speaks of success in the increase UK exploitation of science’ prepared mind’ – serendipity, if you biological sciences, examples have and, according to its web page blurb, to prefer – will do the job just as well. included the recent British contribution ‘identify potential opportunities for the to the pan-European collaboration that Patricia de Winter economy or society from new science witnessed an oesophageal replacement and technologies, and actions to help 1. ‘How can science help build a better using a patient’s own stem cells and realise those opportunities’. It even has future?’ Speech by Lord Drayson at the our capacity for undertaking large scale Cheltenham Science Festival, 3rd June 2009. a ‘horizon scanning centre’ where you clinical trials [2]. He is so captivated can perform a ‘sigma scan’. Before you 2. ‘UK life sciences: ensuring a healthy future’. by trials of stem cell therapies that he Academy of Medical Sciences Forum Annual get too excited, this is just a set of 271 has mentioned them in at least three Lecture delivered by Lord Drayson at the Royal summary papers compiled from more speeches. Again, this may be part of a Society, 3rd March 2009. than 2000 documents, and interviews dual agenda, where it is mainly the wider 3. Life Sciences Blueprint. Satement from the with 300 leading thinkers, that explore public being addressed. A more worrying Office for Life Sciences. July 2009. http://www. ‘potential future issues and trends over interpretation would be that it reflects dius.gov.uk/innovation/business_support/ols the next 50 years which may have an the limit of Drayson’s understanding of 4. Krizhanovsky V & Lowe SW (2009). Nature impact on UK public policy’. We arguably research in the biosciences. 460, 1085–1086. already have a superior version of 5. Frazer KA et al. (2009). Nat Rev Genet 10, There is a saying: ‘He who pays the this – it is called the scientific literature. 241–251. piper calls the tune’. Academic research Incidentally, typing ‘physiology’ into 6. Alberts B (2008). Science 319, 1733.

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The hypothalamic osmolarity, dehydration, stress, blood–brain barrier surrounding the pregnancy, temperature, and PVN is not a barrier per se, rather paraventricular learning and memory. Based on our a filter that allows signalling from discussions it became clear that the blood-borne chemicals and cells. nucleus in health and PVN is a master of ceremonies and From our discussions, it is clear disease orchestrates neuronal, hormonal that these non-conventional lines and autonomic function to maintain of communication affecting PVN A symposium ‘Bristol II’ was held on bodily homeostasis. In addition, neurone excitability (e.g. vascular– Sunday 12th July, 2009 at Baker’s the PVN appears to be a culprit in neuronal; vascular–glia–neuronal) Hall, Brasserie Blanc, The Friary numerous disease states in terms of require further interrogation. Building, Cabot Circus, Bristol, its role in the excessive sympathetic It may also be influenced from organized by David Murphy, Mike nerve activity that is generated in higher brain centres including the Ludwig and Julian Paton. obesity, hypertension, heart failure cerebrum, leaving open the question and diabetes (metabolic syndrome). as to whether it is also a command nucleus regulating the set point of In addition to conventional neuronal numerous bodily functions. synaptic inputs to the PVN, this structure also receives information Based on many papers presented, from forebrain circumventricular it was evident that there is a major organs, via chemical messengers role of the immune system in released from the blood–brain controlling PVN activity. While barrier or resulting from circulating this was described to play a role chemicals or white blood cells that in the homeostatic control of The venue for Bristol II meeting: Baker’s trigger release of mediators from vasopressin release, there was Hall, The Friary Buildings, Cabot Circus, Bristol. In 1227 this was originally either the endothelium and/or glia abundant evidence that cytokines built as a Religious House founded by that encase them. Certainly, under and chemokines affect PVN activity Maurice de Berkeley for the Dominican certain conditions of pathology, under conditions of hyperosmolarity, Order (Black Friars). glia become activated and high levels of angiotensin II, heart communicate with PVN neurones. failure and hypertension. Future There were over 100 attendees It is proposed therefore that the studies clearly need to identify to this highly successful meeting. David Murphy informed us that the venue of the meeting was of great historical importance as it was built originally in the 13th Century as a place of worship for Dominican Friars. After Henry VIII dissolved the monasteries in 1536, Baker’s Hall became a private dwelling. Then, in 1670, it was converted into a Quaker meeting house. It was here that, in 1696, William Penn (founder of Pennsylvania) was wedded at the age of 52 to a 24 year old local lass called Hannah Callowhill. It was also remarked that, coincidentally, one of the organizers (Julian Paton) was wedded in the building in 1996, some 300 years after Penn. So what of the excellent science that was communicated during the day:

It is clear that the paraventricular nucleus (PVN) is a major integrating structure that both receives a plethora of afferent inputs and regulates numerous systems simultaneously. In this symposium, Participants enjoying the sunshine and luncheon interval at Bristol II. Top: Colin we considered the role of the PVN Sumners and Mohan Raizada (both University of Florida) with one of the organisers in the control of food intake, blood (David Murphy, University of Bristol). Below: old friends unite! Scott Young (left; NIH) pressure, blood volume, plasma and Stafford Lightman (University of Bristol).

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alterations in gene expression show which are already moving forward in a high degree of overlap between terms of collaborative experiments, diseases; this requires clarification. laboratory exchange visits, joint Additionally, we need to determine grants and future meetings. how representative the mechanisms are in the PVN to other brain regions The following represents feedback controlling the same function in from speakers and attendees at the health and disease states. This meeting: was clearly out of the scope of the “I’d like to thank you once again for present meeting, designed to focus inviting me to speak at the PVN meeting. Delegates at Bristol II meeting came on PVN specifically, but could form I had a fun and educational time. I’m from far and wide. These three young the basis of a future meeting. sure everyone else did. Everything was physiologists are from Serbia, Germany great.” W. Scott Young (NIH) and Poland. The presentations had a rich the source or sources of these integrative flavour of using multiple “I would like to thank you again for your mediators (adhered white blood techniques and measuring multiple hospitality during the PVN meeting. It cells, endothelium, neurones and/ physiological responses. This was a very nice program and in a nice or glia) as this remains unknown significantly contributed to their location. It was a beautiful day.” Bayram Yilmaz (Turkey) but will be essential knowledge in quality as well as the information guiding potential new therapeutic gleaned. However, despite this, it became evident that to further “I had a great time in Bristol! The interventions. meeting was certainly interesting and our understanding of the PVN in jam-packed.” Jaideep Bains (Calgary) Clearly, with the complexity of integrating physiological outcomes this nucleus in terms of controlling in health and disease, more effort “I would like to thank you for giving me multiple functions, it becomes in the future is needed to combine an opportunity of joining the meeting important that interventions are studies across laboratories with in Bristol. It has been very useful both spatially controlled and cell specific interests; for example, stress scientifically and that’s very kind of specific. Most presentations included response during pregnancy and you also for your hospitality.” Haluk attempts to target different cell alterations in blood pressure control Kelestimur (Turkey) types within the PVN. Magnocellular with an emphasis on pre-eclampsia. “It was a great meeting you organized Also laboratories monitoring food versus parvocellular neurones can in Bristol. Relax full of science and great intake and obesity should join be pinpointed based on their spatial talks and atmosphere. It seems that it is separation within the nucleus but forces with those measuring blood a great place to work your both labs in a note of caution is needed in the pressure and sympathetic activity to Bristol.” William Rostene (Paris) intrinsic inter-cellular signalling look at common PVN mechanisms. that occurs between these cell An emphasis on chronic studies is “I just wanted to let you know that I groups through dendritic release of essential for onward translation into had a great time in Bristol, and I thank vasopressin. Nevertheless, attempts man and the clinical environment. you for giving me the opportunity to are being made to genetically It is hoped that an outcome from participate in the meeting. I think it manipulate vasopressinergic versus the present meeting would be the was a great and successful meeting! I’m oxytocinergic versus glutamatergic initiation of discussions on such looking forward already for the next versus glia cells within the PVN collaborative efforts. one!” Javier Stern (Augusta) as well as interneurones versus “The venue was outstanding and the output neurones such as those The meeting resulted in a number of high-profile collaborations, many of sessions excellent. You really know how with projections to the rostral to put on a great show.” Willis Samson ventrolateral medulla or spinal (St Louis) cord. This is being made possible by the use of transgenesis (germline We would like to thank the following and somatic). This ever increasing for supporting the meeting: sophistication of approach is clearly British Society for working and significant rapid Neuroendocrinology advance in our understanding of the The Physiological Society PVN is being made. The University of Bristol (Faculties of Questions remain as to how unique Medical & Veterinary Sciences and the changes in the PVN are between Some speakers at Bristol II enjoying the Medine & Dentistry) different disease states such as heart symposium dinner. From left to right: Song Yao (University of Bristol), Mike The University of Florida failure, obesity and hypertension. Ludwig (University of Edinburgh), Javier The Wellcome Trust There was some evidence that Stern (Medical College of Georgia) and signalling mechanisms and William Rostene (UPMC, Paris). Julian Paton

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Chorna (Ivan Franko National University Epithelial form, of L’viv, Ukraine). function and A special highlight of the Meeting was environment The Society Dinner held at As You Like It restaurant in Jesmond, Newcastle. Epithelia and Membrane The evening entertainment included Transport Themed Meeting, smooth jazz music from Sarah Morton Newcastle (6–8 September 2009) Peter Agre with local organizer Mike Gray. and Jesse Reed and a fantastic tango On the 6th September 2009 Newcastle performance from Alejandra Heredia University Epithelial Research Group Stewart (University College Dublin, and Mariano Otero, who mesmerised welcomed Members, Affiliates and Republic of Ireland) concluded the day the distinguished audience with a guests of The Physiological Society with the Biller Prize Lecture, which breathtaking show. to the first Epithelia and Membrane focused on the physiological roles of The feedback from the meeting was Transport Themed Meeting. The urea transporters: from bacteria to overwhelmingly positive; networking line-up of invited speakers, without ruminants and man. The third and final and the interaction with young exception leading experts in hot and day of the meeting focused on various scientists was highlighted; however, emerging topics of epithelial research, molecular structures and networks that the quality and the breadth of the promised a broadly focused, exciting allow epithelia to adapt to a changing science were particularly recognised. and vastly informative conference. environment in different organs We would like to thank all who The meeting attracted 152 registered (Jim Anderson, University of North contributed to the success of the participants, the majority from the Carolina, Chapel Hill, USA; Tomas Ganz, Meeting, with special thanks to Sarah UK. However, scientists travelled University of California, Los Angeles, Barnsley and Nick Boross-Toby (The from as far as New Zealand, Australia, USA and Marshall Montrose, University Physiological Society). We gratefully India, Ukraine and Chile to attend the of Cincinnati, USA). Particular emphasis acknowledge the industrial sponsors meeting. The scientific programme was given to the regulation of ion and and The Physiological Society for included 16 invited talks, 25 oral fluid balance in epithelia with keynote financial support. communications and 37 poster presentations from Ole Petersen (University of Liverpool) and Richard presentations. The Themed Meeting At the end of the conference a was organised by Mike Gray and Boucher (University of North Carolina, Chapel Hill, USA). meeting was held to discuss future Andreas Werner of the Institute for Cell Epithelia and Membrane Transport and Molecular Biosciences, Newcastle Days 1 and 2 were concluded with themed events, mainly focussing on University. dedicated poster sessions that the next themed meeting in 2011. The meeting got off to an impressive saw eminent experts, students Symposia were also discussed and start with Sir Nicholas Wright’s and postdocs engaged in scientific although theme members have been (Cancer Research UK, London) insights discussions over a glass of wine or a very successful at securing symposia into intestinal stem cells and their beer. The Physiological Society’s Blue at the main 2010 meeting, it was contribution to tumourigenesis. Riband Poster Competition was won agreed that a strategy is required by Havovi Chichger (University College Further presentations focused on to preserve this strong presence, London) followed by Alice England transdifferentiation (David Tosh, including appointing someone to (University of Sheffield) and Tetyana University of Bath) and epithelial act as an initial point of contact for morphogenesis as well as the cellular coordinating symposia bids and structures involved in these processes disseminating information. Stuart (Diane Barber, University of California, San Francisco, USA; Markus Affolter, Wilson (Dundee) and Doug Bovell University of Basel, Switzerland and (Glasgow) announced that they are John Sayer, Newcastle University). organising an Epithelial Physiology The highlight of the second day was meeting next year in Dundee, on without doubt the talk on aquaporins 2 and 3 September, which would given by Nobel Laureate Peter Agre be open to all Physiological Society (Johns Hopkins Malaria Research Members. It is hoped that this may Institute, Baltimore, USA). The variety become a biannual event. We would of aspects covered in the session was like to thank everyone who stayed impressive: cutting edge molecular on for this meeting and contributed investigations into the cellular to the very positive discussions. physiology of epithelial transporters as well as translational studies were All in all the conference vividly presented (Edith Brot-Laroche, INSERM, demonstrated that epithelial Paris, France; Dianne Ford, Newcastle physiology is alive and kicking, and University; Stefan Broer, Australian hopefully has paved the way for National University, Canberra, Australia many more successful events. and Jashvant Unadkat, University of Washington, Seattle, USA). Gavin Alejandra Heredia and Mariano Otero. Andi Werner and Mike Gray

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Festschrift Edward’s influence on this field. I That evening, a dinner celebration had the pleasure of introducing this was held in the Kingsley Hotel, Cork symposium in honour symposium and could not resist which included speeches honouring reference to a sentence from the Edward Johns. The dinner went of Edward J Johns book Ulysses by the Irish writer James very well and was a social occasion Hormonal, molecular and Joyce, likely to strike a chord with attended by many of Edward’s friends neural control of the kidney renal physiologists ‘Most of all he and colleagues. Of particular note liked grilled mutton kidneys which were Olga Hudlicka, an esteemed gave to his palate a fine tang of faintly colleague from the University scented urine.’ The first speaker was of Birmingham, and Jonathan Jacek Manitius (Medical University Emmerson, Edward’s third PhD of Bydgoszcz, Poland), who gave student to graduate (out of a total of a moving account of Edward’s 30 to date), having a reunion with his supervision of his postgraduate PhD supervisor for the first time in research in renal physiology. This 24 years. Left to right: Jonathan Emmerson, Jacek was followed by a presentation by The first speaker on the second day of Manitius, John Coote, Edward Johns and Michael Snow (University College this symposium was Akio Nakamura Gerard DiBona. Cork, Ireland) on atrial receptors (University School of Medicine, In August 2009, Edward Johns retired and renal function, which sparked Tokyo, Japan), who described the as Head of Department of Physiology, some intense debate about the use of viral vector delivery of -2 University College Cork, Ireland, relative contributions of peripheral β adrenergic receptors for treatment following a highly active, productive and central neural inputs to renal of kidney disease. The final speaker and continuing career in the field of function. Next, Kenju Miki (Nara was Ged Davis (University of Otago, renal physiology. Prior to taking up Women’s University, Japan) gave a New Zealand), on the topic of this position in January 2002, Edward fascinating seminar on the benefits baroreflex control of the kidney in a spent the majority of his academic of immersion in hot springs and the rat model of obesity, a particularly life at the University of Birmingham, physiological effects that this has on pertinent topic given the increasing but also formed strong links with a the vascular and renal systems. John prevalence of this disorder and its worldwide network of collaborators, Coote (University of Birmingham, UK) associated pathologies in the Western trainees and friends during this ended the first session with a talk on world. The meeting was brought to time. Edward’s career has spanned the roles of central and peripheral a close by some video presentations over four decades to date and has peptides determining cardiac–renal by individuals who were unable included major research, academic responses. and scholarly outputs. Furthermore, to attend in person. The highlight aspects of his work have produced of these was a slideshow by Raj direct impacts on the clinical Handa (Indiana University School of management of hypertension in Medicine, USA), which magnificently patients suffering from chronic renal summed up the consensus, glowingly failure. Edward has been a Member positive viewpoint of Edward as both of The Physiological Society since a scientist and a human being. In my 1985 and was elected Convenor of own Southeast London vernacular, the Renal Physiology Special Interest Edward truly is ‘a scholar and a gent’. Group between 1998 and 2000. Left to right: Akio Nakamura, Margaret I would like to take this opportunity He has been a powerful force for Johns, Edward Johns and Gerard DiBona. to thank Patrick Harrison and Gordon collaboration within his field, having Following lunch, Gerard DiBona trained researchers from, and having Reid, who helped organise this (University of Iowa, USA) discussed made sabbatical trips to, numerous event. We are extremely grateful to neural influences on kidney function countries during his career. Edward is Margaret Johns, our co-conspirator in the context of Edward’s life, regarded with the greatest warmth, in this venture, and to all of the including his love of sailing and of esteem and respect by everyone speakers and attendees whose efforts making tea in ‘the correct way’. with whom he has interacted: this and generosity made this such a Ulla Kopp (University of Iowa, was reflected by the atmosphere of wonderful occasion. Finally, we are USA) extended this theme with a a festschrift symposium held at the highly indebted to The Physiological talk on the role of afferent renal Brookfield Health Sciences Complex, Society for generously providing a nerves in renal regulation of sodium University College Cork, on the 17–18 Special Symposium grant, which, in September, in honour of his career. homeostasis. Both Gerard and Ulla combination with funding from The have had long-standing interactions Society for Endocrinology, made this This event included presentations by with Edward at both personal and fantastic event possible. speakers hailing from six different professional levels. Indeed, Gerard nations and four different continents, acted as Edward’s best man at his indicating the global scale of wedding to Margaret. John Mackrill

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Lighthouses and lobsters in Woods Hole When I first saw the call for papers for the Muscle in Health and Diseases meeting organised jointly between the Society of General Physiologists (SGP) and The Physiological Society, I was determined to attend. Organised by David Eisner and H. Lee Sweeney, the meeting offered an impressive list of speakers and a range of research from the basic to more clinical. It also presented the View of the Eel pond at Woods Hole from Swope Centre. opportunity to visit a place I fell in close with a presentation on the brought their sea-legs there was love with over 10 years ago. Thus, at potential therapeutic targets to treat also the walk up to the Nobska the beginning of September I found the myofibril mutations that cause Lighthouse. Later, after recovering myself in Boston wondering if the cardiomyopathy. from the afternoon activities, the trip would live up to expectations. session on disease and repair was Friday began with work on ryanodine started with several presentations Woods Hole is situated in receptor diseases and research that on Duchene muscular dystrophy Massachusetts, Cape Cod and is explores the detailed structure of and was wrapped up with uterine the gateway to Nantucket and the calcium release units. My short smooth muscle activity. There Martha’s Vineyard where some of talk on the regulation of myofibril was still just time to squeeze in America’s rich and famous spend organisation in developing skeletal discussions in the mixer sessions their holidays. The village of Woods muscle was in this session and I was and, if you still had the stamina, at Hole and surrounding area also honoured, if a little intimidated, the Captain Kid pub. contains several research institutes, to find myself sharing a stage with including the Marine Biological very eminent scientists. The calcium The final day of the conference Laboratory (MBL), and has a vibrant started bright and early again with scientific community. The MBL a continuation along the theme has research laboratories on site of disease and repair, this time and offers numerous excellent with a focus on smooth muscle. courses including one on zebrafish There were also presentations on development and genetics, which I the spatial control of pH in heart attended 10 years ago. As anyone function and the development of who has stayed at the MBL will know, cell replacement therapies. Kevin the rooms are minimal and most of Campbell gave the Keynote address your time is spent on science. As on the dystroglycan complex and soon as I had dropped off my bags I the mutations that generate muscle found myself engrossed in the first Lobster supper on the last evening in Swope disease. The meeting wound down evening symposium focused on Dinning Room. with a lobster supper, poster award myosin and molecular motors, which presentations, after-dinner drinks included some eye-catching movies signalling theme continued with and a trip to Captain Kid for those on motor function. True to form a presentation on L-type calcium that didn’t have to get up too early. the morning session, the contractile channels, and the ryanodine The location was as I remembered apparatus, started bright and early receptor coupling and calcium and had a relaxed atmosphere, the at 8.30 am with talks on mechano balance in cardiac fibres. In the sessions were full of interesting sensing and the supermolecule afternoon, despite the weather and science, centred on physiology, and titin, plus electrical and metabolic much debate regarding a possible provided an opportunity for plenty remodelling in cardiac tissue. gale, the scheduled boat trip around of discussion. So back in London and After a break for coffee, to help the harbour did go ahead. Perhaps with time to reflect, I ask myself did combat that early start, the talks fortunately no great whites were the meeting live up to expectations shifted towards disease, starting spotted, as had been reported at and I have to say I ‘would wholly’ with hypertrophic cardiomyopathy the seal colony up the coast, but recommend it to anyone! and then membrane dysfunction we did see some of the beautiful associated with muscular dystrophy. costal scenery that has made this Rachel Ashworth The first full day was brought to a area famous. For those that hadn’t Queen Mary University of London

Physiology News | No. 77 | Winter 2009 | www.physoc.org 7TH JAMES BLACK CONFERENCE PN 9

Translating ‘omics’ who could teach these essential skills This year the 7th James Black would be retiring in the next 5 years Conference, a joint venture by into functional and and there were no replacements! The Physiological Society and the Big Pharma could also see that the British Pharmacological Society, clinical applications UK was going to lose its competitive was held at King’s College London Thelma Lovick enjoyed the edge in research and development, on 1–3 September. It was organised buzz at the 7th James Black and a consensus report: In vivo and led by Mike Collis (our CEO) Conference sciences in the UK: sustaining the who co-ordinates the Integrative supply of skills in the 21st century, Mammalian Biology initiative and In the 1990s, with the molecular published by the Association of the has been closely involved from biology revolution in full swing, British Pharmaceutical Industry and the start. The meeting, Integrative rumblings started about the the Biosciences Federation reached Pharmacology and Physiology – dearth of expertise in the classical similar conclusions (2). It contained translating ‘omics’ into functional techniques that had underpinned a very clear recommendation: and clinical applications, provided research in physiology and more training in in vivo skills at all a showcase for the exciting pharmacology for decades. levels and fast. In 2007 £12million developments that are taking Molecular biology was sexy. It was was made available from a unique place in the field of integrative fast and gave clean answers to consortium of funders: BBSRC, the mammalian biology. Over 3 days, well-defined questions. Genetic BPS, MRC, KTN, HEFCE and SFC and formal presentations were modification was exciting. The a call went out for bids for Capacity delivered mainly by staff members possibilities offered by knockouts, Building Awards in Integrative of the abovementioned Centres, knock-ins and other ‘omics’ wizardry Mammalian Biology which were interspersed with some excellent seemed endless. High throughput designed to rebuild in vivo training short talks by their postgrads and became a buzzword (it still is) and capacity. Four Centres for Integrative postdocs. Topics revolved around classical in vivo physiologists, those Mammalian Biology have now four themes: with blood under their fingernails been established at King’s College (the health and safety police hadn’t London, Imperial College London, Pain, inflammation and injury really got on to this yet) were left and consortia from Manchester standing alongside their slow, and Liverpool Universities and Models of cardiovascular disease – sometimes messy preparations and the Universities of Glasgow and from bench to bedside long experiments, bowed by the Strathclyde. weight of more and more draconian In vivo approaches to studying Home Office regulations. They were metabolism labelled as dinosaurs and we all Models of immuno-inflammation know what happened to them. and infection: clinical predictive But this didn’t happen to physiology. validity Within a few years the new word The speakers highlighted the on the street was ‘translational’. use of new technology for in vivo How were the fabulous advances of research and the integration of molecular biology going to get out molecular technology into the of the PCR machine and into real in vivo approach. There were life? Only with the help of integrative exposées on a wide range of topics physiologists and pharmacologists. including the use of adenoviruses Except that by now they were pretty Mike Collis presents a prize for best to optimise the outcome of vein thin on the ground. It became poster to Craig Robertson (Glasgow). grafting in vivo (Andy Baker), not uncommon to advertise for a how 2-photon microscopy in postdoc to work on an in vivo project vivo can be used to image the and to receive no applications from development of atherosclerotic suitably qualified British candidates. plaques (Pasquale Maffia), the use The Physiological Society and the of luciferases for cell and disease British Pharmacological Society tracking (Nurea Andreu), and decided to survey the in vivo metabolic profiling and inbreeding training opportunities offered in UK to generate models of disease universities and discovered that less (Chris Stevenson). A cautionary tale than 2% of undergraduates studying from Ian Machin (Pfizer) warned physiology or pharmacology about the risk of generating false received any in vivo experience (1). Philip Leadbeater (Imperial College) positive data if behavioural studies But the survey was even more discusses his poster with David Farmer are not adequately blinded and worrying – 25% of the academic staff (Glasgow). Catherine Lawrence (Manchester)

Physiology News | No. 77 | Winter 2009 | www.physoc.org 10 PN JAMES BLACK/JOHN RUSSELL FESTSCHRIFT told us how chronic systemic that is currently being pursued at Festschrift in honour inflammation in obese mice leads institutions throughout the UK. to breakdown of the blood–brain There was also a section on the of John Russell barrier and influences stroke all-important teaching of in vivo outcome. The programme ended sciences in undergraduate courses. with a presentation by Kathryn Chapman (National Centre for the This meeting was extremely Replacement, Refinement, and successful and very well organised. Reduction of Animals in Research), Participants were able to spill out which focussed on the funding from the single lecture theatre into a opportunities for research into the poster viewing area where lunch, tea refinement (good welfare equals and coffee were served and plenty good science) of animal research of time was allowed for going round and the use of the most appropriate the posters and for the essential species (e.g. rodents rather than networking. The meeting was primates for addiction studies). topped off by an excellent dinner at the nearby Waterloo Brasserie, and diners were required only to stagger the 200 metres back to their accommodation, conveniently situated across the road from the conference venue, ready for the next morning’s early start. The mood of the meeting was resolutely upbeat. The Centre for Integrative The overall funding situation may Physiology, University of Edinburgh, still be pretty dire but it is clear that organised a very special event investment in in vivo research in the to honour and celebrate the life Mhairi Macrae (Glasgow, centre) with UK is paying dividends. This is a very and achievements of John Russell Ross Brett and Bob Jones (Strathclyde) encouraging sign. Rather than the (pictured above). The festschrift at the dinner. Photographs by Ivor oft repeated refrain of ‘too little too was held on Wednesday July 1st, Williams. late’, maybe this time it will be ‘just 2009 and almost 100 people enough and just in time’. I do hope gathered at the Hugh Robson Mindful of the needs of the so. Building to hear talks from many of predominantly young audience, John’s friends and colleagues, past an early evening session at the Thelma Lovick and present. end of the first day was devoted References to career development and John started in his career in science funding opportunities for early 1. Leggett M (2005). Teaching of in vivo over 30 years ago, publishing research techniques in UK universities – career scientists. Throughout the wide-ranging and prompt action is needed. more than 150 papers. Over the meeting, more than 70 posters were Physiology News 60, 39-40. years he has held several offices: displayed, reflecting the diverse 2. www.abpi.org.uk/publications/pdfs/invivo_ most notably he was the head range of in vivo research topics brochure.pdf of the former Department of Physiology at the University of Edinburgh and President of the International Neuroendocrine Federation. He is the current Editor-in-chief of the journal Stress. John has been chairman, organiser or co-organiser of many meetings, including the World Congress on Neurohypophysial Hormones and the World Congress on Stress, and he is again active in organising the next ‘Parental Brain’ meeting here in Edinburgh in 2010.

As first or second supervisor he trained over 25 PhD students, and the list of former and present postdoctoral fellows, national

Physiology News | No. 77 | Winter 2009 | www.physoc.org PHYSIOLOGY 2009 – DUBLIN PN 11 and international visitors and Physiology 2009 – collaborators who have worked with John is endless. Dublin I was glad to see that so many of This is the brief report of one local them followed my call to come to organizer of the Main Meeting of The Edinburgh. The program included Society held in Dublin in July. talks from Hiroshi Yamashita, Takashi Higuchi, Mike Kawata, Tatsushi Onaka (Japan), Colin Brown (New Zealand), Richard Ivell, George Fink (Australia), Tony Plant, (USA), Quentin Pittman (Canada), Rainer Landgraf, Inga Neumann (Germany) Gordon Munro (Denmark), and Stafford Lightman, Jonathan Seckl, Colin Ingram, Alison Douglas, Simone Meddle and Paula Musical entertainment after The Brunton (UK). Society’s dinner. Photograph by Tim Ford. This Festschrift was supported by The Physiological Society, There is nothing as powerful as an idea The British Society for whose time has come. The merger of Neuroendocrinology, The sophisticated genetic manipulation and optical signalling should open International Neuroendocrine new areas of exploration. Federation, The Sharpey–Schafer Endowment Fund of the School The dinner was held in The Mansion of Biomedical Sciences of the House which is the residence of the University of Edinburgh and Wiley- It was a particular pleasure to Lord Mayor of Dublin. The Meetings Blackwell, the publishers of the welcome old friends and new guests Secretary, Prem Kumar, reached new Journal of Neuroendocrinology. to the new Medical School on the heights in stand-up comedy and he main campus of University College was followed by a sexy violinist. The fabulous day of interesting talks Dublin. With the passage of time finished with a splendid dinner and some memories are still imprinted an entertaining dinner speech given strongly. Many physiologists were by Gareth Leng. seduced by the new methods of genomic manipulation which are Mike Ludwig becoming more sophisticated PS: If you are wondering, John has than the simple one gene knock not retired yet, he will formally out approach, which resembles a retire from the university at the end simple nineteenth century ablation of next year but we all hope that he experiment. And so this is what I have brought away from Dublin 09: is with us for many years to come. Prem Kumar (left) and Jeremy Ward The Journal of Physiology (right) with Colin Nurse who delivered the Michael deBurgh Daly prize lecture. impact factor rises

The 2008 impact factor for The The organizers of the many symposia Journal of Physiology has been held in Dublin are very pleased with revised upwards from 4.605 to the positive feedback that they 4.649, as a result of a re-count received from their guest speakers of source articles used in the and audience. I wish to express my calculation of the factor. Until sincere thanks to The Physiological another metric is accepted by the John Coote (left) and Andy Ramage in Society team for running the event research community as a good the O’Reilly Hall (which according to so smoothly that I could sit back, indicator of where to publish, the Andy is as pointless as calling a similar forget I was involved at all and just IF will continue to be an important building in the University of Cardiff the enjoy it. element in the journal’s strategic Jones Hall). Photograph by Tim Ford, planning. University of Nottingham. James FX Jones

Physiology News | No. 77 | Winter 2009 | www.physoc.org 12 PN IUPS

IUPS Kyoto 2009 looked familiar and it dawned on me not keen on sushi; however, it is that the Kyoto Protocol on Global hard to avoid eating it in Japan and July 28th–1st August Warming had been signed there. after a few days I was an enthusiastic When Kyoto was confirmed as the Historic surroundings indeed! convert. venue for the 36th IUPS Congress, I wondered why there. I now know The Congress was well organised For me the Congress was a why. and the sessions were all near at memorable one. I left the meeting hand. The science presented was having learnt new things, met I arrived a week ahead of the IUPS excellent and included something for old friends and made new ones, Congress, to attend the International everyone. Many younger scientists got new ideas and formed new Symposium on Exocrine Secretion were given the opportunity to collaborations. (ISES), being held in the University present their work orally, which I felt of the provincial city of Tokushima. added to the many good aspects My abiding memories of Japan are Attending the symposium would of the meeting. There was also an too numerous to mention in full. give me my first ever taste of Japan, excellent array of posters on display However, Kyoto is an interesting in more ways than one. I arrived in each morning and afternoon and place to visit and I found the Osaka and was immediately struck a good number of commercial Japanese people exceptionally polite by how clean and ordered everything companies were represented, which, and friendly and I would recommend was and how little the English considering the economic climate, Japan as a country worth visiting. I language was used. Despite my was no mean feat. would readily go back on holiday to appalling inability to speak Japanese explore it! everybody was extremely courteous Now roll on IUPS 2013 Birmingham. and helpful and I was duly put on the 4.10 pm (and I mean 4.10 pm) Douglas Bovell bus to Tokushima. Communication difficulties certainly created a few amusing situations over the most More on IUPS 2009 basic of things and I became very Set in the beautiful and historical good at ‘Charades’. city of Kyoto, the IUPS Congress Adjusting to the time difference was was a conference brimming with an initial problem, with me waking wonderful science and extraordinary up at all hours of the night; however, culture. The meeting was opened the ISES meeting helped me to get by the newly elected President of my brain into gear and focus on the IUPS, Denis Noble and the opening excellent science that was presented ceremony was attended by His in Tokushima and soon to be at the Imperial Highness, the Crown Prince IUPS Congress. of Japan. The attendance of one of the Imperial family at the meeting A bus took the ISES participants to adds emphasis to how Japan as a Kyoto for IUPS, via numerous stops country values strong scientific to introduce those of us unfamiliar focus. One thing I didn’t know until with Japanese culture to such things the opening speech was that the as traditional dancing, indigo dyeing, Imperial Palace has its own research Japanese puppet theatre and the laboratory which carries out marine famous Naruto whirlpools, which we research. The lab was originally would otherwise not have seen. opened by the grandfather of the Crown Prince. The Congress was in the Kyoto Conference Centre, located in To find a more cultural experience beautiful surroundings. The opening as a backdrop to a conference is ceremony was in the main hall Local youth groups and school hard to imagine than in Kyoto. The and included, as well as the formal students provided lunchtime and city of Kyoto itself is enriched with speeches, examples of traditional evening reception entertainment. 17 World Heritage Sites including Japanese culture. Unfortunately, Clearly – ‘Japan has talent’! The the Kamigamo-jinja Shrine and the no cameras were allowed, for Taiko drummers at the Welcome To-ji Temple. Within the conference, security reasons, as the Japanese Reception were fantastic and had the daily entertainment in the form Crown Prince was attending. audience enthralled. of traditional Japanese dance and Perhaps this was the reason why music entertained everyone. The the registration desk was chaotic The hospitality of the ISES and IUPS traditional lion dance or Shishi-Mai, on that first morning. The main hall hosts was excellent. In the UK, I was performed by local school children

Physiology News | No. 77 | Winter 2009 | www.physoc.org IUPS PN 13

and public outreach. A half-day Cellular & Integrative symposium on Women in Physiology was sponsored by Shiseido Co. Ltd, Neuroscience the Japanese cosmetics company. After a break of 11 years In 2008, Nature reported that the proportion of women in science The Physiological Society is in Japan was just 12.4% and that returning to Cardiff to hold a only 1/87 Japanese universities themed meeting on Cellular was wonderful. The coordination and had a female president (Nature & Integrative Neuroscience, 451, 865). But in Japan, they are precision of the timing to achieve 14–16 December, 2009 the dance inside the costume lion trying to change this with new must take months of practice, not to grants and support networks for mention extreme physical fitness. female scientists. At the symposium experiences of female scientists The array of symposia was amazing. from China, India, Japan, the UK and One interesting symposium I USA were presented and included attended was on the subject of personal accounts, hurdles to brain–machine interfaces as ways overcome and also triumphs. At the to repair connections within the ‘Beyond Gender’ social event after nervous system, chaired by Mitsuo the symposium, Shiseido samples Kawato of ATR Computational were given out to all attendees – it Neuroscience Laboratories, Japan was science slowly approaching Speakers and Tetsuya Yagi of Osaka University, other industries – our version Gary Lewin (Max-Delbrück Center, Japan. This symposium to me of the Oscars afterparty! Not to Berlin, Germany) be too feminine but I am all for reflected how far physiology is Helen Kennedy (University of Bristol, make-up samples at conferences – moving in terms of piecing things UK) back together as described by Birmingham 2013 take note! Professor Noble. Hugh Matthews (University of Fiona Randall Cambridge, UK) Hiroaki Matsunami (Duke University, An introductory Durham, USA) workshop on human Maria Fitzgerald (University College and clinical physiological London, UK) Adam Sillito (University College techniques London, UK) 10–11 December 2009, King’s David McAlpine (University College College London and Imperial London, UK) College London Matteo Carandini (University College Speakers include: London, UK) Steve Harridge (King’s College London, Andrew King (University of Oxford, UK) UK) Irene Tracey (University of Oxford, UK) Techniques in human muscle physiology Edmund Rolls (Oxford Centre for Mike Grocott (University College London, UK) Computational Neuroscience, UK) The human body at high altitude Pieter Roelfsema (Netherlands Institute for Neuroscience, Amsterdam, WgCrdr Nic Green (Royal Air Force) The Netherlands) Acceleration and the body. Physiology of flying fast jets Bridget Lumb (University of Bristol, UK)

Mike Tipton (Portsmouth University, Matt Diamond (SISSA, Trieste, Italy) UK) Top, the Golden Pavilion (Kinkakuji) in Peter Brennan (University of Bristol, The human body in cold water Kyoto, and bottom, reception put on by UK) the Canadian IUPS 2013 bid team. The Kyle Pattinson (University of Oxford, Jens Schouenborg (Lund University, ice sculpture is the CN Tower in Toronto. UK) Sweden) Getting inside the black box, what can we Alongside the science and learn from MRI? Michael Brecht (Bernstein Center for entertainment, there were also Computational Neuroscience, Berlin, Angela Atalla (Imperial College London, Germany) some themed symposia on other UK) aspects of science including equal Integrated physiology in a clinical context: Daniel Wolpert (University of opportunities, ethics of research understanding heart failure Cambridge, UK)

Physiology News | No. 77 | Winter 2009 | www.physoc.org 14 PN A WEEK IN THE LIFE OF...

A week in the life of… a neuroscientist comedian In my experience, if you tell a stranger you’re a neuroscientist, they react with a mixture of surprise, admiration and suspicion. Tell someone you’re a comedian, they respond in the same way but in a more exaggerated manner. Tell someone you’re a neuroscientist comedian, they simply dismiss the ludicrous statement and start discussing the weather

My desire to entertain is something Wednesday: Surgery day. It’s an of a family trait, but my skewed unavoidable aspect of modern world view and overly analytical science that animal experimentation mind has always resulted in me remains necessary, and that a being drawn to science, which is study of the function of specific why I’m completing my PhD in brain regions requires lesioning or Behavioural Neuroscience. Many physical disruption. I’ve had to point comedians started off as scientists out to anti-vivisectionist ‘friends’ (Dara O’Briain, Harry Hill, etc.), but that just because scientists do it, very few have tried to combine it doesn’t mean we enjoy it in any science and comedy, with (as I’ve way. This is true, as performing a discovered) good reason. But I neuroanatomical lesion with any persevere and, slowly, it seems to be degree of accuracy takes several working. It’s impossible to describe hours of concentration at a time. my experiences and career structure If nothing else, it’s boring. This fully in a short article, so here’s a of the NHS: we’d be lost without it, revelation makes me chuckle, but I rundown of a typical week in my life. but that doesn’t mean we don’t hate decide I really shouldn’t mention it it. if I’m ever asked to write a magazine Monday: Monday usually begins article. with checking my experimental That evening I host the regular subjects: weighing, monitoring Student Union comedy night. I No comedy tonight, but I run some health, food levels, etc. My family mention my comparisons between new material past my wife. The look still thinks being a neuroscientist SPSS and the NHS. Unfortunately, she gives me is similar to the one I is a glamorous occupation. If the 30 or so Art and History students give a rat that urinates on my sleeve. this is the case, a morning being in the front don’t know what I’m Thursday: Receive several replies scratched, bitten and defecated on talking about and assume that to job applications for post-PhD by three dozen rats should keep me SPSS is something to do with the positions – all rejections. One grounded. After this, I do more work police. Comparing one government rejection is from a job I never on my next experimental set-up, institution with another really applied for, which does damage the performing cutting-edge research doesn’t have the same impact, but motivation somewhat. After much armed with a large box, some old my wife later points out that the deliberation, I decide to remove Christmas decorations and a packet original joke wasn’t funny either, so the ‘comedian’ section from my of coco-pops. The glamour is almost no real loss there. intoxicating at this point. CV – just doesn’t look right on an academic application. Spend another In the evening, I try out some new 8 hours performing brain lesions. My material at a comedy gig. Backstage careers advisor told me I’d ‘never be I mention that I work with animals a brain surgeon’. She was half right, and another act gets very aggressive I guess. and says, I quote, ‘You’d better not do any of that near me, I’m In the evening, I fill in for a a vegetarian.’ The inanity of this last-minute drop-out at a lovely statement leaves me dumbstruck. gig I know. A French woman in the front row looks confused, so I Tuesday: Have to go over results convert all my jokes to metric and from an earlier experiment, trying she starts laughing. I mention how to find a significant pattern in nonsensical the excuse ‘big bones’ disappointing data. Before starting is for being overweight. A woman my PhD, I had never come across laughs and explains she used to be the statistics package SPSS, and big boned. Reflexively, I ask how I sometimes long for those days long she spent on the International of carefree optimism. For those Space Station, then have to spend unfamiliar with SPSS, it reminds me 5 minutes explaining how prolonged

Physiology News | No. 77 | Winter 2009 | www.physoc.org A WEEK IN THE LIFE OF... /INTERVIEW PN 15 periods of low gravity can lead to Understanding ion channels and their role in bone loss due to calcium depletion. Make a note: it’s important to know brain disorders your audience, and the people of On a recent trip to Seattle Angus Brown took the opportunity Abergavenny aren’t really up to speed on the effects of prolonged to catch up with Professor Bill Catterall, to talk about his microgravity on human skeletal pioneering work in the field of voltage-gated ion channels and structure. to discuss ongoing work in the field of epilepsy

Friday: Today is important – Angus Brown (AB). Where did you it’s my first ever attempt at a carry out your undergraduate and PhD science-themed comedy night. degrees? ‘Humourology’, as I’ve dubbed it (an Bill Catterall (BC). I grew up in off-the-cuff suggestion I don’t like Rhode Island and completed my but which seems to have stuck), is a bachelor studies in Chemistry at night of as many comics as I can find Brown University. From there I went performing material based on and to Johns Hopkins School of Medicine with reference to complex science, in Baltimore where I received a hosted by me. I manage to focus on PhD in physiological chemistry. My my PhD work, but am also illicitly thesis work was on the structure using the photocopier for flyers, and function of F1-ATPase, the which I hope nobody discovers. mitochondrial enzyme that makes ATP, a long way from my current By the time the show starts that AB. Which scientists inspired you in research interests. evening, there are over a hundred your early days? people in attendance. Science AB. You worked with Nobel Prize BC. In my undergraduate and comedy is clearly an untapped niche. laureate Marshall Nirenberg at the graduate training, I read textbooks by The whole thing goes incredibly NIH. What was it like working for a well, particularly my analysis of the Nobel Prize winner that early in your Bernard Katz, on synaptic function, by scientific inaccuracies of classical career? Sol Snyder, on neurotransmitters and jokes. The night wraps up around neurotransmitter receptors, and by 11 pm. After promising to do more BC. Well, all three of my mentors had Pedro Cuatrecasas, who was studying hormone receptors with new chemical Humourology in the near future, I go important influences. Pete Pedersen, biology approaches. I found their work home and pass out, dreaming of the my PhD supervisor at Johns Hopkins, was really crucial in teaching me quite inspiring in turning me toward stardom that is surely to come my about the basics of science – how neurobiology for my postdoctoral way after the success of tonight. to develop a critical hypothesis, to research. Later, the work of Jean-Pierre design an experiment to critically Changeux and Arthur Karlin on acetyl Saturday: Have to go into the lab test a new idea, to design the right choline receptors was very influential to start a testing session. Luckily, control experiments, and to have for me because they were the first spending several hours staring the work ethic of science. Marshall receptor proteins to be characterised at rats in a box undermines my was influential in two equally crucial using biochemical techniques. Since delusions of grandeur. ways. First, he taught me how to I’d been trained in biochemistry, I was identify a big problem to work on. excited about applying those methods Sunday: Same as Saturday, but with He liked to say ‘all science is difficult, to voltage-gated ion channels. I was a later start as I forget my lab access and all experiments are hard to get also influenced greatly by the work card. to work, so make sure you’re working of Hodgkin and Huxley in my choice on something important’. And he of research problem. Understanding So there we have it: a typical week introduced me to neurobiology, how the sodium channel that they in my life. Not a normal sort of which I had not known very much defined functionally could work at the daily existence I admit, but I do about before going to his lab. My molecular level really captured my get a certain satisfaction knowing third mentor was my Departmental interest. I’m probably the only person in Chair at the University of Washington, the country experiencing it and Ed Krebs, who taught me about AB. When did you become aware of academic administration. He used their work? I persevere, as I enjoy combining to say ‘always take administration science and comedy. If anyone does as a hobby’, by which he meant that BC. Not until I was a postdoctoral require my services, in either a he didn’t want administration to fellow, because that’s when I became neuroscientific or comedic capacity, crowd out his research and the other interested in neuroscience and then in please feel free to email me at aspects of his academic life, and I have sodium channels. When you become [email protected] followed his example and tried to interested in sodium channels, you balance teaching, administration and immediately look back to the work Dean Burnett research. of Hodgkin and Huxley that began

Physiology News | No. 77 | Winter 2009 | www.physoc.org 16 PN INTERVIEW the modern era of research on ion AB. You’ve been involved in research in cell culture. Following my move channels. I decided what I wanted to in ion channels since the early to the University of Washington, do when I set up my lab was to apply 1970s. One thing that I think is very I built on those experiments by membrane biochemistry methods to important is that people in your using neurotoxins to identify and voltage-gated ion channels, to which position, who have been intimately purify the sodium channel protein they hadn’t been applied before. involved in the field for several from mammalian brain and later by decades, have a key insight into the using similar approaches to purify AB. Not all of our readers may be development of that field. So from the calcium channel protein. These familiar with all the details of ion the perspective of 30 years could you were exciting experiments for us channels, so could you tell us a little describe where the field was when at the time because they gave us about voltage-gated channels? What you became involved and what have the first glimpses of ion channel was the common ancestor and what been the key advances in the field protein molecules. This advance were the evolutionary forces that over the years? was also important in changing resulted in the appearance of sodium, the focus of the field from studying potassium and calcium channels? BC. I’ll give you my personal ionic currents to characterising the perspective, but I am sure others BC. We’ve learned in recent years molecules that were generating the in the field would have different that sodium and potassium channels ionic currents, and that’s remained a highlights. The first advance are present in bacteria, and that they primary focus of the last 30 years in that I would highlight, which we are important in regulating ion fluxes ion channel research. It’s amazing to contributed to, was discovery of across the cell membrane in response me that there are 143 proteins in the the ion channel protein molecules to the bacterial membrane potential. human genome related to sodium themselves. When I entered the field Calcium channels first appear in and calcium channels and that the in 1972, there was a well-developed eukaryotes, in yeast, and they ion channel protein superfamily is understanding of the ionic currents emerged at the time that calcium- one of the largest families of signal based signalling became important. that generate the action potential, transduction proteins. G protein- Electrical signals by sodium and but there wasn’t any understanding coupled receptors and protein kinases potassium channels control calcium of what ion channel molecules were number in the range of several entry, and calcium in the cytoplasm like. Most people assumed they were hundred, and then ion channels and regulates many different processes. protein molecules, but there was a G proteins number in the range of 140 Even a cell as simple as yeast contains respectable school of thought that to 150 as the next most prominent calmodulin and has many calcium- electrical excitability may be due signalling proteins. So it’s really dependent regulatory processes, so to membrane phospholipids. The a very important and very large I see the development of calcium idea that sodium conductance was family of signalling molecules that signalling as a key step in ion channel mediated by an ion channel with a emerged from experiments aiming evolution. selective pore was first presented to determine what the ion channel clearly in the literature by Bertil protein molecules look like. The next big step in ion channel Hille. He argued that to explain the evolution is in metazoa, the high level of sodium flux compared A second key realisation over the past multicellular organisms. Signal to the apparently small number of 20 years is that ion channels aren’t transduction is more complicated in channel molecules involved in sodium just involved in electrical signalling metazoa in order to control many cells conductance, it was necessary for the in nerve and muscle, but they’re in an organised way, and ion channels permeability pathway to function as involved in virtually every aspect evolved to allow that higher level of a pore rather than as a transporter. of cellular regulation -- in epithelial control. One of the key steps between That turned out to be a very insightful cells, in endocrine cells, even in the single-cell organisms and metazoa proposal, which was confirmed much lymphocytes. In fact, it turns out was the development of action later by single channel recording that potassium channels and calcium potentials driven by sodium channels, and eventually by three-dimensional channels are even crucial in sperm which are used in metazoa to signal structure determination. and eggs. It really is remarkable that, over long distances. A very early from a beginning in highly specialised example is the sodium-dependent When I began to work on sodium excitable tissues, it’s now clear from action potential in the nerve net channels with Marshall Nirenberg, the work of hundreds of scientists that of jellyfish. Finally, in vertebrates the key information that seemed to this signalling system is involved in electrical signalling becomes faster, us to be missing in the ion channel almost every aspect of cell physiology. more precise, more diverse, more field was an understanding of the Of course, that’s why 143 proteins are important, and there are a lot more molecules that form the pores, so needed. ion channels. For example, there are we developed neurotoxins as specific 10 sodium channels and 10 calcium probes of sodium channels and used The third advance that I would channels in mammals compared to them in biochemical experiments. highlight is the realisation that ion one or two sodium channels and We measured neurotoxin binding and channels are involved in a wide range three calcium channels in most of the sodium ion flux in neuroblastoma cell of diseases. None of us would have invertebrates whose genomes I’ve lines that Marshall had developed, predicted in the 1970s and 1980s looked at. which expressed sodium channels that there would be dozens of genetic

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diseases caused by mutations in ion forms, so the intracellular calcium will be the key advances that will channels. Ion channelopathies have signal is also inherently local. The best allow such progress? steadily grown in number, and grown way to have proteins respond to the very much in importance in advancing local change in membrane potential, BC. I agree with Professor Hodgkin how we think about the broader or the local calcium signal, is have that it is frustrating that one can’t do non-genetic forms of these diseases. them bind to the ion channels, and more, but in the years since the 1950s many advances have been made. For example, inherited epilepsy is very we now know of dozens of proteins We have new generations of local rare, but studies of genetically based that are bound for this reason. In anaesthetics, anticonvulsants and the case of sodium channels, there inherited epilepsies have given many antiarrhythmic drugs that are targeted new insights into more widespread are cell adhesion and extracellular at sodium, calcium or potassium forms of this disease. It’s even more matrix molecules like neurofascin and channels. We have the whole true in the heart, where cardiac tenascin and cytoskeleton molecules evolution of calcium channel blockers arrhythmias that are genetically like ankyrin that are important in as drugs that are very important based are quite rare, but they have putting and keeping sodium channels in cardiovascular disorders like given very important insights into in the right place. In addition, arrhythmias, hypertension and angina, the more common types of cardiac there are a whole host of signalling as well as calcium channel blockers arrhythmias that afflict a large molecules – kinases, phosphatases, for control of neuropathic pain. I think number of people. I think this has calmodulin and G proteins -- which all we have the opportunity for even been a very important development in bind to sodium channels and regulate greater progress in this area because understanding complex diseases, and their properties. few of the drugs in the clinic have the ion channelopathies now include taken advantage of the knowledge of endocrine abnormalities, kidney In the case of calcium channels it’s an the 143 different members of the ion misfunction, immunodeficiency and even more well-developed story. Not channel superfamily provided by the several other classes of disease. only are there extracellular matrix and sequencing of the human genome. cytoskeletal proteins, cell adhesion One could make these drugs more AB. It seems to me that the focus molecules, kinases, phosphatases, selective with fewer side effects of ion channel research has moved calmodulin and G proteins, but if we could target individual ion away from purely sequence-based the SNARE proteins and SNARE- channels. That is a major effort in drug studies and is now focussing on binding proteins that are involved in companies now. the relationship between structural exocytosis at nerve terminals and in AB. Could you tell us more about aspects of ion channels and function. secretion in other cell types also bind your work on the Na 1.1 mutant and I’m thinking in particular of your work to calcium channels. An exceptional v its role in human epilepsy? It seems on sodium channels and tenascin, and example of formation of a multi- paradoxical that a loss of function calcium channels and synaptic vesicle protein ion channel signalling complex mutation of sodium channels would components. Is this the case? is provided by a recent proteomic lead to hyperexcitability. analysis of the proteins associated BC. It was a surprise in our earliest with the presynaptic calcium channel BC. You bring up a project that’s biochemical experiments to realise by Bernd Fakler and colleagues. relatively new in our lab and one that the ion channels are multi- Their work showed that more that’s been very rewarding for me and subunit proteins. It didn’t seem than 100 proteins are specifically for my colleagues. As I said before, obvious to us that multiple types of associated with presynaptic calcium one of the major developments in subunits would be needed for proteins channels. Unbelievable! Within our field was the discovery of ion to form a pore. We found in our early those 100 proteins are the many channelopathies beginning in 1990. biochemical experiments that ion calcium channel-associated proteins About 5 years ago, we were struck by channels are formed from two classes that we already knew about, so it a particular ion channelopathy called of subunits -- pore-forming subunits was comforting to know that the severe myoclonic epilepsy of infancy that are related for all members of one-by-one protein approach is (SMEI), which is a very severe form the ion channel superfamily and providing correct answers. I think of paediatric epilepsy that results in auxiliary subunits that differ for the right way to think about ion severe seizures, permanent mental each ion channel type. The auxiliary channels is at the centre of a large retardation and cognitive deficit, and subunits are integral members of ion complex of proteins engaged in a very other serious co-morbid problems channel protein complexes. Moreover, complicated function. for the children who have it. And as there are many more proteins you point out, this was a paradox. It attached, so that ion channels form AB. One thing that sticks in my mind seemed to us that the loss of function signalling complexes containing in reading Hodgkin’s autobiography mutations in sodium channels that many different proteins. I think of is his sense of frustration in that, cause the disease should result the functional consequences of the despite winning the Nobel Prize for in a reduction in brain electrical activity of ion channels as local. When his work on action potentials, he was activity rather than an increase in a single sodium channel opens, the unable to help the legions of people excitability, so we decided to study depolarization that it causes is local. with neurological conditions that this disease by making a mouse When single calcium channels open, contacted him in the hope of a cure genetic model. To our surprise, we a local microdomain of high calcium for their maladies. What do you think found that these mutations cause

Physiology News | No. 77 | Winter 2009 | www.physoc.org 18 PN INTERVIEW a dramatic loss of sodium channel hippocampus, cerebral cortex and transaminase. We’re hoping that function and electrical excitability in various others. drug combinations that aggressively the GABAergic inhibitory neurones enhance GABAergic function will have in the hippocampus without much BC. We think that each of the a positive impact to prevent seizures, effect on the electrical excitability co-morbidities is caused by failure of reduce co-morbidities, and prolong of the excitatory neurones. The firing of a different class of GABAergic life in mice. We’re trying to optimise brain operates on a balance of neurones. In the case of ataxia, these treatments and study their excitatory and inhibitory inputs. we have shown that the cerebellar effects on co-morbidities to see if they When the inhibitory neurones Purkinje neurones, which are crucial also are improved. are prevented from generating for control of movement, have a huge action potentials, and releasing the impairment in their sodium currents AB. I look forward to reading those inhibitory neurotransmitter GABA, the and action potential firing capabilities papers. excitatory neurones have a party and in the mutant mice, so that’s the likely hyperexcitability and epilepsy result. source of ataxia. Of course, GABAergic BC. Well. it’s exciting for us because We’re excited that we’ve been able to neurone functions in the cerebral we haven’t come close to having add some new understanding of the cortex and hippocampus are crucial a direct impact on a disease in our pathophysiology of this devastating for learning and memory, so we think research before. Now we may be able disease. We’re now trying to conduct that the cognitive defect is caused by to do that and resolve a little of the ‘mouse clinical trials’ with different two interacting factors: the failure of frustration that was expressed by Alan drug combinations than those that are GABAergic neurone function, which Hodgkin, which we also feel because used in current therapy of this disease, by itself should be sufficient to cause we have so much new information, realising what its causes are, in order but not yet any really new therapies. to find drug therapies that would be cognitive deficit, as well as cell death more effective in preventing seizures and loss of neurones due to the AB. Recently you were inducted into and the other co-morbidities. seizures that also must contribute to cognitive deficit. We’re actively the Royal Society in the UK. What AB. Is there any significance to the studying that process. does it mean for an American to be fact that as well as epilepsy, the inducted into the hallowed halls of condition affects the cerebellum; AB. So that must be a very difficult Newton, Darwin etc? there is this ataxia associated with clinical problem because you can it which you see in the children, imagine if it were hyperexcitability of BC. Well, it is a great honour to be but which also occurs in the mouse sodium currents – if it was too large inducted into the Royal Society, which model? Does this mean that what it would be fairly easy to knock it holds a very special place in my mind occurs in the mouse exactly mirrors down, but how do you get the sodium for a number of reasons. First, I have the human condition? current to increase, do you try to 100% English ancestry, so it’s very nice increase the open probability? to be recognised in the home country. BC. Well, we feel very fortunate that Second, as we’ve mentioned, the our mouse model mimics the human BC. Well, we think that the problem founders of our field were members disease in all of its parameters. is failure of GABAergic transmission. of the Royal Society – Hodgkin, Children with this disease have Since there isn’t a good way to Huxley, Katz and many others. In several accompanying co-morbidities, upregulate sodium channel activity fact, at the induction ceremony at including ataxia. Another even more in a selective way, we think the right the Royal Society I was honoured to important co-morbidity is cognitive approach is to upregulate GABAergic present my summary of our work at decline, which is dramatic in these transmission, so that the lesser a podium under a picture of Andrew children. They have normal cognitive amount of GABA that is released Huxley, so I could say that our work function and normal developmental has a greater impact. We also think achievement until their seizures derives from the discoveries of this this is a good approach because the exceptional member of the Royal begin about 6 to 9 months of age. GABAergic neurones will try to fire Between year 1 and 2, they typically Society. Finally, there are relatively at the right times in appropriate few foreign members of the Royal reach a plateau in their cognitive physiological or cognitive context, so Society, and it’s a great honour to be and psychomotor development, and enhancement of their activity should included with them. I’m still learning between years 2 and 5 they often be therapeutically useful. We’re decline and lose developmental about the opportunities that foreign trying combinations of drugs that milestones that they have gained membership in the Royal Society increase GABAergic neurotransmission before. Other less devastating presents for advancement of science in multiple ways by enhancing the but scientifically interesting in the UK and around the world. postsynaptic response of GABA co-morbidities include sleep disorder and hypersensitivity to light, and receptors with benzodiazepines, AB. Will we be seeing more of you in amazingly, our mice have every one by enhancing the amount of Britain? of these co-morbidities, so they are neurotransmitter GABA that remains a remarkably good model of the in the synaptic cleft by blocking its BC. Well, it’s a long flight, as you well disease. reuptake into the nerve terminal, and know, but I will try to visit more often, by increasing the amount of GABA as I now have a good B & B in London AB. Obviously multiple areas of the in the nerve terminal by blocking its since members can stay at the Royal brain are being affected – cerebellum, metabolism by the enzyme GABA Society.

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Letter from Japan 3 team atmosphere is great. We are getting ready to head to Chicago for – Embracing a new the annual meeting of the Society for Neuroscience as I write this so culture have been poster making. I miss I am now 8 months into my first the lab at times like this. However, postdoctoral position – where has it is amazing after writing a thesis, the time gone? Life is starting to how short a time a poster seems feel normal here. The experience to take. How your ideas change as of moving to a new country made you progress. I hope one day paper the time go by like a whirlwind. The Me and my fellow classsmates writing will seem quick! I am in the whole thing has been an emotional (Venkatesan Satish from India and Kun Gao from China) trying traditional process of doing that just now. rollercoaster in the least negative summer dress with our Japanese The university encourages way. Being so far away from familiar teacher, Yamauchi-sensei. things means that you do have integration into Japanese culture and moments when you feel the distance here, both pre- and post-Second recently we’ve had the opportunity but then the excitement of constant World War. There used to be castles to take part in local events such challenges of communication and all over the island but sadly most as the Obon and EISA festivals. life in and out of work keep you on were destroyed in the Battle of Both these festivals included lots your toes. Being in a new lab and Okinawa. Some have been restored, of traditional Japanese dance and a new life was so exciting it was at others you can explore the ruins. parades and were amazing to see. actually difficult to focus at times The horrendous stories of what the Even better, I got to try a kimono. and the need to make friends meant Okinawan people endured in the I have now taken the beginners’ I never said no to any invitation to invasion are hard to take when you Japanese class provided by work and socialise. I felt I was totally happy consider the beauty and tranquillity am finding it much more simple to but was worried the bubble would of the island today. The Peace Park get by with the few words I know. burst if I stopped and got lonely – I on the south coast of the island Being able to read a few symbols am sure that is an anxiety most is really breathtaking. Set on the can also be great as some menus in people have when they move to a edge of high cliffs with the sound restaurants don’t have an English new place so far from familiar things. of breaking waves, it is a memorial version here. I am happy to try most I have now lost that feeling and can to all those lost in the battle from things but I don’t want to stretch to relax – I have a good group of friends all over the world and a beautiful the local delicacy of pigs’ ears! and am not scared anymore that it message from the Okinawan people Fiona Randall might go wrong. Now I am settled about the importance of peace. It is and things are calmer I have started hard to believe how few people have Get involved and write an to take up new hobbies. Having had heard of Okinawa. horses all my life I am used to being article for Physiology News constantly occupied when not at Have you done something in work, especially at the weekends. your studies you would like to There is a place to ride here but it is recommend to other young so hot I didn’t fancy it but needed scientists, attended an amazing something to keep me active and training course or got an issue outside. The scuba diving here is you’d like to get off your chest? If you enjoy writing then why not amazing and I have taken my PADI contribute to Physiology News. We course. I tend to dive once or twice have an annual prize of £200 for a week. You see the most amazing the best published article written tropical fish and the coral is so close by an Affiliate or young scientist. you can literally rent a tank and walk An Okinawan butterfly at the Ryukyu If that isn’t enough incentive, in from the shore, or go on a boat to Butterfly Park. contributing to the magazine is a one of the many surrounding islands. great extra on your CV and a nice Things in the lab are really exciting way to tell a broader audience I have just had my mum and friend just now. We have two new postdocs about the things you do. We over to visit which really reaffirmed in the group which adds to the are always looking for people to to me how special a place Okinawa enjoyment of work – more minds, contribute to the Affiliate pages in is. I got to take some time off and more ideas, more brainstorms. the magazine and would love to explore the island more than I have We all work on fairly independent hear from anyone who would like so far. When you are working all projects and are setting up new to get involved. week and the sun is shining at the things so that can be stressful Email us for more information or to weekend it is tempting to lie in it. when it all takes time but the discuss ideas at: There is a vast amount of history discussions are stimulating and the [email protected]

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Excitation-dependent Ca2+ infl ux in vertebrate skeletal muscle is in, again An infl ux of extracellular Ca2+ into skeletal muscle excited by action potentials was originally reported in the 1950s. At least three distinct Ca2+ entry pathways across the transverse tubular system of working skeletal muscle have since been identifi ed. The recently discovered action potential-activated current appears to be the pathway responsible for the excitation-dependent Ca2+ infl ux but its specifi c physiological roles remain speculative Skeletal muscle cells in vertebrates, reduces the Ca2+ infl ux by a small when compared with cardiac muscle amount when the SR Ca2+ is low cells, evolved to be able to deliver (Kurebayashi & Ogawa, 2001). This calcium for the activation of the means that other, more signifi cant contractile apparatus in a faster and Ca2+ infl ux pathway(s) are activated more precise manner, in order to during a depolarization when suit completely different functions the SR Ca2+ is low. In their paper, in the body. In cardiac cells there is Kurebayashi & Ogawa describe a a fundamental need for Ca2+ infl ux store-dependent Ca2+ infl ux into to trigger the cascade of events that skeletal muscle. Using chronic lead to contraction in the process depolarization via ionic substitution known as excitation–contraction From top left of the external bathing solution, coupling (EC coupling; Bers, 2001). clockwise: Bradley they show that most of the Ca2+ in Launikonis, Oliver In contrast, work from Lüttgau’s the SR needs to clear SR in order Friedrich and laboratory in the 1970s showed George Stephenson to induce the store-dependent unequivocally that skeletal muscle current. In non-excitable cells Ca2+ could twitch and develop tetanic the infl ux described by Bianchi & must be lost from the cell to induce 2+ force in the absence of extracellular Shanes (1959; Fig. 1). store-operated Ca entry (SOCE). Ca2+. This represented a major However, in skeletal muscle this is deviation from the physiology of the The L-type Ca2+ channel is activated not likely to occur physiologically. cardiac cell. Nevertheless, Bianchi & during square depolarizing pulses. In skeletal muscle, Ca2+ within SR Shanes showed in 1959 that an infl ux The resulting slow, inward Ca2+ needs only to drop to levels that of Ca2+ into skeletal muscle occurred current is easily detected with cause Ca2+ dissociation from the during excitation by measuring conventional electrophysiological Ca2+-sensing protein, Stim1, located 45Ca2+ entering a muscle after a techniques (Melzer et al. 1995) in the SR membrane (Fig. 1). Ca2+ couple of hours of low-frequency and this is perhaps the reason that released from the SR during muscle stimulation. This observation was this current is so well described, contraction binds to cytoplasmic confi rmed by others over the next at least biophysically. It has been buffering sites, causing transient Ca2+ three to four decades, but a precise assumed that a high frequency of depletion of the SR. Thus, a situation role of this excitation-dependent action potentials in skeletal muscle can occur during periods of intense Ca2+ entry in skeletal muscle cells may be equivalent to chronic was not defi ned by Bianchi & Shanes depolarization, to induce Ca2+ infl ux or the other researchers. Although through the L-type channel. However, no argument can be made for a experimental evidence for this in specifi c requirement of extracellular adult mammalian skeletal muscle Ca2+ to produce force in skeletal is hard to fi nd. Indeed, chronic muscle, if one were to look closely at depolarization and a high frequency some of the force traces presented of action potentials induce very in the work published by Lüttgau & different electrical waveforms across Spiecker (1979), one could notice the t-system, highlighting the need that a smaller initial force level for the current to be examined Figure 1. Ca2+ channels at work in the was achieved at the beginning of a under more physiological conditions. transverse (t) tubules. At least three Ca2+ tetanus in the absence compared to This makes it most unlikely for the channels are known to be active during the presence of extracellular Ca2+. L-type Ca2+ current to be responsible periods of work in skeletal muscle: for the Ca2+ infl ux measured in the L-type Ca2+ channel, store-operated Ca2+ 2+ At least three distinct Ca entry experiments of Bianchi & Shanes. channel and action potential-activated pathways are known across the Ca2+ channel. Note that the peak transverse tubular (t) system Furthermore, a chronic magnitude of the Ca2+ movements across membrane of skeletal muscle fi bres depolarization of muscle in the the t-tubules are tiny compared with the that could be functional during presence of the specifi c L-type peak amplitude of the Ca2+ release fl ux periods of work and responsible for channel blocker nifi depine only of SR.

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receptor before it is first activated by the voltage sensors at the beginning of a tetanus, thus helping the ryanodine receptor to open more fully when it becomes activated. This would also explain the smaller initial force level achieved at the beginning of a tetanus in the absence compared to the presence of extracellular Ca2+ in the experiments of Lüttgau & Spiecker (1979). The APACC will also cause a transient depletion of Ca2+ within the transverse tubules. This depletion may activate extracellular Ca2+ sensors involved in monitoring muscle activity. These and other possibilities remain to be explored. However, it is clear that the excitation-dependent Ca2+ influx in skeletal muscle has returned to the limelight.

Bradley S. Launikonis1, Oliver 2+ Figure 2. Measuring Ca influx across t-tubules. A, a skinned fibre with mag-indo-1 Friedrich1 and D. George trapped in the t-system and bathed in an internal solution with rhod-2 is excited 2 by a single pulse by field stimulation during confocal line scanning. B, confocal line Stephenson scans of cytoplasmic rhod-2 (a) and mag-indo-1 ratio (R) in the t-system (b). Spatially 1 averaged profiles of the fluorescence signals (c) show a net drop in Ca2+-dependent School of Biomedical Sciences, The t-system fluorescence concurrently with the cytoplasmic Ca2+ transient, indicating University of Queensland, Brisbane, 2 that an inward flux of Ca2+ across the t-system must have occurred. Modified from Qld, Australia and Dept of Zoology, Launikonis et al. (2009). La Trobe University, Melbourne, Vic, Australia. muscle work when large amounts t-system is able to repolarise in a of calcium are bound to cytoplasmic suitable cytoplasmic environment References 2+ Ca binding sites causing sufficient and develop action potentials when Bers DM (2001). Excitation-Contraction SR Ca2+ depletion to activate SOCE. stimulated by a field pulse. An action Coupling and Cardiac Contractile Force. 2nd potential-activated Ca2+ current edn, Kluwer Academic Publishers. In skeletal muscle SOCE is activated (APACC) was observed for the first Bianchi CP & Shanes AM (1959). Calcium influx across the t-system (Fig. 1), providing time using this novel approach, in skeletal muscle at rest, during activity, and a proximal source of Ca2+ for the concurrent with the cytoplasmic Ca2+ during potassium contracture. J Gen Physiol 42, 803–815. closely apposed and depleted SR transient (Launikonis et al. 2009). The (Launikonis & Ríos, 2007). Thus, physical properties of this current Kurebayashi N & Ogawa Y (2001). Depletion of Ca2+ in the sarcoplasmic reticulum stimulates extended periods of stimulation can 2+ are consistent with an influx of Ca Ca2+ entry into mouse skeletal muscle fibres. J induce a physiologically important following each action potential Physiol 533, 185–199. 2+ entry of Ca in muscle. However, this at a sustained low frequency of Launikonis BS & Ríos E (2007). Store-operated still does not provide an explanation stimulation or the initial two or three Ca2+ entry during intracellular Ca2+ release in for the results of Bianchi & Shanes action potentials in a train, with a mammalian skeletal muscle. J Physiol 583, (1959). short rest period in between. APACC 81–97. has all the major characteristics of Launikonis BS, Stephenson DG & Friedrich O 2+ 2+ No fast Ca influx activated by 2+ (2009). Rapid Ca flux through the transverse the Ca influx observed by Bianchi & tubular membrane, activated by individual the equivalent of a brief action Shanes (1959) and others, strongly potential has been reported in adult action potentials in mammalian skeletal suggesting that the excitation- muscle. J Physiol 587, 2299–3312. mammalian skeletal muscle using dependent Ca2+ influx occurring http://jp.physoc.org/content/587/10/2299. conventional electrophysiological in the adult skeletal muscle is via long techniques. Recently, a novel APACC. Lüttgau HC & Spiecker W (1979). The effects fluorescence technique has allowed of calcium deprivation upon mechanical and the imaging of Ca2+ transients What then, would be the electrophysiological parameters in skeletal simultaneously within the lumen muscle fibres from the frog. J Physiol 296, physiological role of APACC? 411–429. of the sealed t-system and open Currently, we can only speculate cytoplasmic environment of Melzer W, Herrmann-Frank A & Lüttgau HC on this. The small, action potential- (1995). The role of Ca2+ ions in excitation– 2+ mechanically skinned fibres from rat dependent Ca influx may raise the contraction coupling of skeletal muscle fibres. (Fig 2). In this preparation the sealed [Ca2+] in the vicinity of the ryanodine Biochim Biophys Acta 1241, 59–116.

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Regulation of extracellular pH by purinergic signalling Little is known about extracellular pH regulation, despite its importance for proper organ functioning. We present data supporting a hypothesis that alkaline phosphatase, through pH-dependent ATP hydrolysis, serves as an extracellular pH sensor. Dysregulation of extracellular pH regulation may help explain the tissue dysfunction characteristic of diseases such as cystic fibrosis Enzymes function best in a narrow extracellular ATP increases anion or – pH range. The pH of the intracellular HCO3 secretion through interaction environment is regulated to with P2Y receptors. Indeed, selective within 0.1 pH unit (10–8 M [H+]) by P2Y agonists have been developed to well-described plasma membrane overcome the airway anion secretory acid–base transporters, although impairment characteristic of the the actual intracellular pH sensor is disease cystic fibrosis (CF). not known. While many important enzymes have extracellular catalytic Though intuitively wasteful, cellular sites (ecto-enzymes), less is known regulation by extracellular ATP does about the regulation of extracellular Jonathan Kaunitz and Yasutada Akiba. have the attraction of a signalling molecule present in millimolar pH (pHo) despite its importance for a variety of cellular processes. Of subsurface granules, interaction with concentrations in the cytosol, well-defined purinergic G-protein- numerous sensitive and selective particular interest is pHo regulation in compartments which are thought coupled cell surface receptors or cell-surface receptors, and potent to have pH far from neutrality, ionotropic receptors, and hydrolysis ecto-hydrolases such as alkaline whether acidic in the activated by ecto-hydrolases. Although phosphatase and ecto-nucleotide parietal cell canaliculus or osteoclast purinergic neurotransmission was phosphohydrolase (ENTPDase or lacuna, or alkaline at the proximal initially described in the 1970s, the CD39). Nevertheless, the mechanism duodenal surface, the pancreatic concept that extracellular ATP is an of epithelial non-lytic ATP release duct, salivary gland or the oviduct. important non-neuronal regulatory is not well understood, nor is the molecule is relatively recent function of many other membrane Several ecto-enzymes have (Leipziger, 2003; Burnstock, 2007). proteins and ecto-enzymes that are strongly acidic and alkaline pH Particularly in secretory epithelia, probably involved. optima, such as the acid and alkaline phosphatases. Although these unusual optima were described decades ago, the physiological significance of such unusual conditions has been largely unknown. Nevertheless, the expression patterns of these enzymes provide valuable clues as to their possible function. For example, acid phosphatases are expressed in the aforementioned acid-secreting organs and also on acidic organelles such as lysosomes, whereas alkaline phosphatase is expressed in the alkali-secreting tissues mentioned above. Importantly, both alkaline phosphatase and acid phosphatase hydrolyse purine nucleotides, in Figure 1. Schematic representation of the duodenal ecto-purinergic pHo regulatory addition to the other organic and system. Bulk luminal H+ diffuses to the cell surface, where it increases ATP release inorganic phosphates for which they through a yet uncharacterized non-lytic mechanism. ATP at the cell surface activates 2+ – have hydrolytic activity. membrane P2Y receptors, which in turn raises [Ca ]i, which in turn increases HCO3 – secretion to the cell exterior. HCO3 secretion alkalinizes the cell surface, increasing ATP and other purine nucleotides alkaline phosphatase activity, which hydrolyses ATP, decreasing P2Y activation, and – serve as neurotransmitters as part diminishing HCO3 secretion. The net effect of this feedback loop is to set cell surface of a purinergic signalling system. pH at an alkaline value. ADO has a separate signalling system which includes A2 receptors, adenosine deaminase and nucleoside transporters, which are not shown. Components of the system include Abbreviations: ADO, adenosine; CFTR, cystic fibrosis transmembrane regulator; exocytotic release of ATP from SLC26A, solute cotransporter 26A.

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We have recently published data of alkaline secretion, thus serving the presence of pH-dependent AP supporting a hypothesis wherein as a negative feedback loop. In activity measured in situ. Since AP ecto-phosphohydrolases with this fashion, pHo is regulated by activity had not previously been extreme pH optima serve as pH-sensitive ATP hydrolytic activity measured in intact tissues in living pHo sensors in alkaline or acidic of AP (Fig. 1). To test this hypothesis, animals, we used the fluorogenic compartments. We hypothesized we have studied the rat proximal AP substrate ELF-97 to measure AP that since activation of P2Y receptors duodenum, the dimensions of activity in situ in living rats (Akiba increases alkaline secretion into a which (~5 mm diameter), combined et al. 2007). To vary the pHo, we small compartment, the pH-sensitive with its accessibility, provide a varied perfusate pH or the rate of – hydrolytic activity of alkaline convenient live-animal system. With HCO3 secretion. Perfusion with a pH phosphatase (AP) is dependent on this system we have reported that 2.2 solution, with a > 7 log greater local pH, which in turn is set by the the rat proximal duodenal brush [H+] than the AP pH optimum, rate of alkaline secretion. Thus, for border expresses P2Y1 receptors, AP only decreased AP activity (60% an alkaline compartment, a high rate and ENTPDase, and that exogenous remaining in situ) contrasting with of alkaline secretion increases the ATP augments the rate of epithelial the absent activity predicted at pH – hydrolytic activity of AP, decreasing HCO3 secretion (Akiba et al. 2007; 2.2 when AP activity is measured extracellular ATP concentration Mizumori et al. 2009). One of the in vitro. Augmentation of epithelial ([ATP]o), and decreasing the rate cornerstones of the hypothesis is – HCO3 secretion with an I.V. injection

of PGE2 increased the rate of – HCO3 secretion, presumably due to

elevation of pHo (Fig. 2). The wide availability of potent and selective purinergic agonists and antagonists considerably simplified the biochemical characterization of duodenal ecto-purinergic signalling. Perfusion of the duodenal lumen with an acidic solution, – which increases the rate of HCO3 secretion, releases ATP into the lumen at a concentration ~50-fold higher than during perfusion with a neutral solution (Mizumori et al.

2009). P2Y1 antagonists impair the secretory response to exogenous ATP. Importantly, inhibition of

AP activity augments [ATP]o and – increases the rate of HCO3 secretion, supporting ATP hydrolysis as an important component of the mechanism (Fig. 3). Inhibition of the CF transmembrane regulator (CFTR) interestingly impairs ATP release, suggesting a possible mechanism whereby CFTR dysfunction impairs – HCO3 secretion. Since an alkaline microclimate overlying the duodenal brush border may protect the underlying mucosa from injury due to gastric acid entering the Figure 2. In vivo assay of AP activity in rat duodenum. ELF fluorescence in vivo in the duodenum, we measured injury proximal duodenum was present in the mucus gel layer (A) with little visualization of the epithelial cells with the of the underlying epithelial surface. After mucus removal, ELF fluorescence was seen normally excluded DNA-binding dye on the surface of villi in rat duodenum (B). Internal bar, 100 µm. C, PGE2 I.V. injection increased the catalytic rate of AP compared with saline control, whereas luminal propidium iodide. A P2Y1 antagonist markedly increased cellular damage L-cysteine was inhibitory. D, villous apical surface AP activity was enhanced by PGE2 I.V. and reduced by L-cysteine co-incubation. E, villous apical surface AP activity was during acid perfusion (Mizumori et reduced by luminal acidity (pH 2.2), but 60% activity was still present. AP activity al. 2009), supporting a protective measured while perfusion of the pH 2.2 solution disappeared when the animals were function of the pHo regulatory –1 pre-treated with a selective CFTR inhibitor CFTRinh-172 (CFTRinh, 1 mg kg , I.P.). system.

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The literature abounds with reports of tissues that are likely candidates

for ecto-purinergic pHo regulation due to expression of several of the required components such as surface P2Y receptors and ecto-ATP- hydrolysing enzymes expression combined with the presence of – ecto-nucleotide-provoked HCO3 secretion. Interestingly, many of these tissues also express the CFTR – as part of the HCO3 secretory mechanism and are part of the phenotype of CFTR loss of function (Table 1). Thus, it is possible that similar ecto-purinergic regulatory

systems control pHo in other tissues, where such regulation is important for disparate processes such as sperm capacitation, ciliary beat frequency and bone formation (Kaunitz & Yamaguchi, 2008). We hope that insights derived from further testing of this hypothesis will identify new targets for the treatment of diseases such as CF and other disorders affecting epithelial anion secretion.

Jonathan D Kaunitz1,2,3 and Yasutada Akiba1,2,3

1 – Greater Los Angles Veterans Affairs Figure 3. HCO3 secretion and ATP release in rat duodenum perfused in vivo. A, – 2 HCO3 secretion measured by pH stat. Baseline secretion was enhanced by perfusion Healthcare System, Department of luminal acid, consistent with prior reports. The addition of the AP inhibitor of Medicine, School of Medicine, – L-cysteine further increased HCO3 secretion, whereas the exogenous ATPase University of California Los Angeles, apyrase decreased secretion, consistent with AP-mediated ATP hydrolysis and ATP and 3Brentwood Biomedical – stimulation of HCO3 secretion. B, ATP release, measured by bioluminescence. Research Institute, Los Angeles, CA Luminal acidification increases ATP release, a 50-fold increase. AP inhibition further 90073, USA increases [ATP] o, presumably due to inhibition of hydrolysis of ATP by AP. The ATPase apyrase decreased [ATP]o. References Akiba Y, Mizumori M, Guth PH, Engel E & Table 1. Tissues possibly affected by the ecto-purinergic pHo regulatory system, on Kaunitz JD (2007). Duodenal brush border the basis of expression of key components of the system and secretory responses to intestinal alkaline phosphatase activity affects exogenous ATP. Note that many of these tissues display a phenotype when bearing a bicarbonate secretion in rats. Am J Physiol CFTR loss-of-function mutation. TNAP, tissue non-specific alkaline phosphatase; TrAP, Gastrointest Liver Physiol 293, G1223–G1233. tartrate-resistant acid phosphatase; PLAP, placental alkaline phosphatase. Burnstock G (2007). Physiology and pathophysiology of purinergic Epithelium or HCO - CFTR ATP P2YR CF 3 AP ENTPDase neurotransmission. Physiol Rev 87, 659–797. tissue secretion expression release expression phenotype Kaunitz JD & Yamaguchi DT (2008). TNAP, Airway + + TNAP, PLAP? + + + + TrAP, ecto-purinergic signalling, and bone remodeling. J Cell Biochem 105, 655–662. Bile duct + + TNAP + + + + Leipziger J (2003). Control of epithelial Pancreatic duct + + ? + + + + transport via luminal P2 receptors. Am J Physiol Renal Physiol 284, F419–F432. Epidimydis + + TNAP ? ? + + Mizumori M, Ham M, Guth PH, Engel E, PLAP Oviduct + + ? ? + + Kaunitz JD & Akiba Y (2009). Intestinal alkaline TNAP phosphatase regulates protective surface Duodenum + + IAP + + + ? microclimate pH in rat duodenum. J Physiol 587, 3651–3663. Salivary gland + + TNAP + + + + http://jp.physoc.org/content/587/14/3651. Bone ? + TNAP (TrAP) ? ? + + long

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Fractals in human physiology revisited Although the idea of applying fractals to cardiovascular signals was fi rst suggested over two decades ago, the actual existence of fractal patterns and their relation to the physiology of cardiac control remains largely unexplored. In this article, we provide a brief overview of the theory behind fractals, and discuss implications for application of fractal statistics to physiological patterns

Across a range of scales, from – including moment-to-moment miles to inches, there can appear a changes in the heartbeat. form of self-similarity in structures that is quantifi able by fractal The applicability of fractals to mathematics. It has been suggested cardiovascular signals was fi rst that the natural occurrence of suggested in the late 80s by fractal structures is manifest in Goldberger and colleagues. Since the similarity between the edge then, it has become popular Can Ozan Tan (left) and Andrew Taylor. of a grain of sand and the edge of to assess the fractal nature of beat-to-beat time series of heart a coastline (Mandelbrot, 1982). (perhaps indirect) consequence, the period or arterial pressure. However, Self-similarity is not an uncommon effort to quantify and characterize the idea of a ‘fractal’ time series is form and may have application heart period and arterial pressure abstract; the fractal character of to physiology. For example, variability has been most focused on events that occur at discrete points fractal mathematics have been spectral analysis. However, moving in time is not readily observable. In successfully employed to describe beyond the spectral domain and the branching patterns in the contrast, when Mayer performed into the fractal domain may not be pulmonary vasculature (Lefèvre, his experiments in rabbits almost warranted. Indeed, as Steven Krantz, 1983). However, recent advances in two centuries ago, he observed a in his 1989 critique to Mandelbrot computing power and ready access clearly distinguishable sinusoidal said “the trouble with any subject to sophisticated mathematical pattern in arterial pressure and that relies more on computer output software has allowed broader usage theorized that this pattern relates than on theory is that one has to of fractal statistics to characterize to the physiological control of think of something to say about it.” a range of physiological patterns the cardiovascular system. As a (Krantz, 1989)

What does it mean to be fractal? According to the simplest defi nition, fractal objects are similar at all levels of magnifi cation, displaying an inherent property of self-similarity that is infi nitely complex (see Fig. 1). Therefore, if heart period is fractal, it must fl uctuate with infi nitely long as well as infi nitesimally small periods, each having a similar pattern. However, by defi nition, heart beats are discrete events; as such, the resolution of the structure is limited and can be no smaller than the shortest interval between consecutive beats. In fact, partly because the heart beat is discrete, the complexity of the heart period pattern is diminished with each successive magnifi cation (Fig. 2). Nevertheless, if we assume that heart period does display self-similarity and is infi nitely complex, what would that mean Figure 1. An ‘H-fractal’. Also called ‘Mandelbrot Trees’, H-fractals are among the physiologically? Are fl uctuations simplest objects that are similar at different levels of magnifi cation (property of self- in the heart beat with a period of similarity). 3 s (approximately the length of a

Physiology News | No. 77 | Winter 2009 | www.physoc.org 26 PN FEATURES breath) or 33 years (close to half exponent “should not be considered attractor than like the periodic the human life span) both relevant to be a unique cardiovascular attractor characteristic of truly to cardiac autonomic control? indicator in a separate ‘fractal’ class regular processes” (Goldberger et Certainly not. Spectral analysis of from conventional power-spectral al. 1990), adequate mathematical cardiovascular time series suggests analysis, because it has a clear testing should be employed to that fast fluctuations in heart rate and comprehensible grounding in determine the actual presence of period (around 6 s and faster) are spectral analysis.” Thus, the analysis the pattern. Instead, power-law primarily related to cardiac vagal of patterns in cardiovascular time (1/f) scaling of the power spectral control, whereas slower fluctuations series need not move beyond the density which can be indicative of (around 6–20 s) may reflect both spectral domain into the fractal a self-similar structure is commonly vagal and sympathetic modulation. domain. taken as evidence for fractal (It must be noted, though, that behaviour. However, power-law the use of spectral analysis to The application of fractals to heart scaling and self-similarity are not characterize cardiac autonomic beat time series assumes that sufficient to define truly fractal control is still under debate; Parati these time series can be defined as behaviour (Avnir et al. 1998). (A et al. 2006; Taylor & Studinger, fractal processes and that changes straight Euclidean line is technically 2006.) Therefore, fluctuations in in them reflect changes in cardiac self-similar, but obviously not heart period, induced by autonomic control. This assumption arises fractal.) Indeed, we have recently outflow, appear to have a relatively from anecdotal reports that fractal shown that despite a strong restricted temporal range. So, could behaviour could be inferred based power-law scaling, a majority of the fractal properties of heart period on noisy spectrograms and that heart period time series in healthy still provide unique insight to the cardiac disease produced a less young subjects do not conform to underlying physiology? One answer noisy spectrogram. However, if the the assumed standard fractal model was eloquently provided by Francis ‘trajectory’ of the heart period time and therefore cannot be considered et al. (2002): the fractal scaling series seems “more like a strange fractal processes (Tan et al. 2009). If

Figure 2. Fractal time series (left panel) and actual heart beats (right panel; data from Stein et al. (1999), downloaded from PhysioBank archive) under different levels of magnification (from 500 min to 3 s). Each time series is a magnification of a segment of the plot above (denoted by colour). Fractal time series are generated with the same fractal index as the actual heart beats. In contrast to fractal time series, the complexity of the heart period pattern diminishes with each successive magnification, and almost disappears at time scales (3–30 s) that are most relevant to cardiac autonomic control.

Physiology News | No. 77 | Winter 2009 | www.physoc.org FEATURES PN 27 this is true across the range of unambiguously define the presence Mourot L, Bouhaddi M, Gandelin E, Cappelle S, human health and disease, fractal of a fractal pattern versus simple Nguyen NU, Wolf JP, Rouillon JD, Hughson R & Regnard J (2007). Conditions of autonomic estimates produce completely random noise. reciprocal interplay versus autonomic co- meaningless and irreproducible activation: effects on non-linear heart rate values. More than two decades ago, dynamics. Auton Neurosci 137, 27–36. when it was first proposed that Parati G, Mancia G, Di RM & Castiglioni P Perhaps because of their the heart period is fractal, it was (2006). Point: cardiovascular variability is/ unreliability, fractal estimates suggested that physiology may is not an index of autonomic control of of heart period variability have prove to be a rich source for the circulation. J Appl Physiol 101, 676–678. no identifiable value that could study of fractals as well as other Peng CK, Mietus J, Haussdorf JM, Havlin S, be considered ‘normal’. Fractal types of non-linear dynamics Stanley HE & Goldberger AL (1993). Long- estimates can range from 0, (Goldberger et al. 1990). However, range anticorrelations and non-Gaussian reflecting a so-called fractal Gaussian exploration of fractals should avoid behavior of the heartbeat. Phys Rev Lett 70, 1343–1349. pattern, to 2, reflecting a fractal being self-referential, generating Brownian pattern. These two are “pictures to learn more about the Stein PK, Ehsani AA, Domitrovich PP, Kleiger RE & Rottman JN (1999). Effect of exercise highly distinct; one is stationary pictures” (Krantz, 1989). Although training on heart rate variability in healthy and the other is not. Despite the application of sophisticated analyses older adults. Am Heart J 138, 567–576. obvious discrepancies in finding to cardiovascular data can lead to Struzik ZR, Hayano J, Sakata S, Kwak S & both of these patterns, the recent deeper understanding, it also has the Yamamoto Y (2004). 1/f scaling in heart rate literature reports values as low as potential to cloud our view of the requires antagonistic autonomic control. Phys 0.7 and as high as 1.2 for healthy physiology. Rev E Stat Nonlin Soft Matter Phys 70, 050901. young subjects (Struzik et al. 2004; Tan CO, Cohen MA, Eckberg DL & Taylor 1,2 Mourot et al. 2007). Moreover, very Can Ozan Tan and J Andrew JA (2009). Fractal properties of human large variability can be observed Taylor1,2 heart period variability: physiological and even under the exact same methodological implications. J Physiol 587, 1Department of Physical Medicine 3929–3941. experimental conditions (Tan et al. http://jp.physoc.org/content/587/15/3929. 2009); estimated fractal indices and Rehabilitation, Harvard Medical long School, Boston, MA, USA can range from ~0.5 to ~1.4 for Taylor JA & Studinger P (2006). Counterpoint: healthy individuals during supine 2Cardiovascular Research Laboratory, cardiovascular variability is not an index of rest (Heffernan et al. 2008). To put Spaulding Rehabilitation Hospital, autonomic control of the circulation. J Appl Physiol 101, 678–681. this range in perspective, these are Boston, MA, USA values that have been reported to represent cardiac control in cyclists References Inspire the young during heavy exercise (~0.5; Casties Avnir D, Biham O, Lidar D & Malcai O (1998). scientists of tomorrow et al. 2006) and to reflect the Is the geometry of nature fractal. Science 279, absence of cardiac control in human 39–40. National Science and Engineering heart failure (~1.3; Goldberger et al. Casties JF, Mottet D & Le GD (2006). Non- Week (NSEW) is an exciting 2002). linear analyses of heart rate variability during programme of events hosted by heavy exercise and recovery in cyclists. Int J science enthusiasts across the Lastly, it might be worthwhile Sports Med 27, 780–785. country. In 2010, it will run from 12 to consider the raison d’etre for Francis DP, Willson K, Georgiadou P, Wensel to 21 March. potential fractal behaviour in R, Davies LC, Coats A & Piepoli M (2002). Physiological basis of fractal complexity heart period variability. It has During NSEW, science is high on properties of heart rate variability in man. J the agenda everywhere – making been theorized that the absence Physiol 542, 619–629. of a characteristic time scale (a la it an ideal time to inspire budding Goldberger AL, Amaral LA, Hausdorff JM, physiologists. If you are interested in fractal fluctuations) facilitates the Ivanov PC, Peng CK & Stanley HE (2002). running an event, The Society would functional adaptive capacity of the Fractal dynamics in physiology: alterations be keen to support you through the cardiovascular system by helping to with disease and aging. Proc Natl Acad Sci U S A Outreach grant scheme. prevent ‘excessive mode locking.’ 99, 2466–2472. This would be along the lines of Goldberger AL, Rigney DR & West BJ (1990). Applications for funding should pervasive oscillations present in Chaos and fractals in human physiology. Sci Am 262, 42–49. be designed to encourage some pathological conditions, schoolchildren aged 11–16 to engage such as in heart failure (Peng et al. Heffernan KS, Sosnoff JJ, Fahs CA, Shinsako KK, Jae SY & Fernhall B (2008). Fractal scaling with science, and should be relevant 1993). Improved adaptive capacity properties of heart rate dynamics following to the National Curriculum. via fractal patterns is, in fact, a resistance exercise training. J Appl Physiol 105, plausible theory, and could well 109–113. Your event must have a physiological be true. However, the presence of Krantz SG (1989). Fractal geometry. Math theme and could be related to your random noise (which abounds in Intell 11, 12–16. research or just something fun that biological systems) can serve exactly Lefèvre J (1983). Teleonomical optimization of you think students will enjoy. the same purpose; the contribution a fractal model of the pulmonary arterial bed. For more information on NSEW and of a fractal, scale-independent J Theor Biol 102, 225–248. the Outreach grant scheme, visit the mechanism is not crucial. Therefore, Mandelbrot B (1982). The Fractal Geometry of website: www.physoc.org/education it is incumbent upon the theorizer to Nature. WH Freeman and Co., New York, NY.

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Sheet-like tendons are stiffened by bulging muscles The common shape changes of a contracting muscle can load aponeuroses along multiple axes. The close interaction of these sheet-like tendons with the muscle belly dynamically modulates stiffness and allows aponeuroses to function as variable stiffness springs The forces generated by the contractile muscle’s line of action embedded in machinery of skeletal muscle are an extra-cellular matrix. In fact, the transmitted to the skeleton through same collagen bundle may extend tendons. Most tendons don’t simply from the tendon to the aponeurosis transmit forces but rather behave with no structural separation. These like springs, stretching as muscular shared structural features have been forces are applied and recoiling as used to infer functional similarity forces decline. The significance of between tendons and aponeuroses. Manny Azizi (left) and Thomas Roberts. tendon elasticity is most obvious in It is commonly assumed that the cyclical movements where elastic stiffness of an aponeurosis is the same portion of the muscle belly (Fig. 1). It energy can be stored and recovered as that of the free tendon, though is well accepted that when muscles with tremendous efficiency thereby some recent measurements challenge contract and fibres shorten, the lowering the energetic cost of this assumption (e.g. Magnusson et al. muscle expands in other dimensions movement. An extreme example of 2003). to maintain a constant volume. The this mechanism is the bouncy gaits of image of a flexing bodybuilder is a hopping wallabies, where it has been Although aponeuroses share some familiar reminder that muscles change shown that tendon stretch and recoil structural similarities with free shape when they contract. Given can allow the organism to recycle tendons, they probably undergo a the close association of aponeuroses nearly all of the energy from a previous more complex loading regime. Many with the muscle belly, it is reasonable stride (Biewener & Baudinette, 1995). aponeuroses cover a substantial to predict that shape changes in a This elastic behaviour of tendons contracting muscle may also deform extends well beyond such obviously the aponeurosis along multiple axes. bouncy gaits and also increases the In a recent paper we used high-speed energetic economy of walking and fluoroscopy to characterize running. three-dimensional deformations As a biological spring, the capacity of in aponeuroses during muscle a tendon for storing elastic energy is contraction (Azizi & Roberts, 2009). largely determined by its stiffness. The Our measurements confirmed that mechanical energy stored in tendons aponeuroses are stretched both is a function of the force applied to parallel and perpendicular to a the tendon and length changes the Figure 1. Superficial view of the lower muscle’s line of action during muscle tendon undergoes in response to leg highlighting the Achilles tendon and contraction. This pattern of stretch that load. This relationship simplifies the aponeuroses of the gastrocnemius indicates that the aponeurosis is biomechanical models, where energy muscles. loaded biaxially. storage can be calculated from the modelled muscle force and a tendon’s characteristic stiffness (Zajac, 1989). This approach assumes that a given tendon is governed by a single relationship between force and length that defines a single stiffness. In situ measurements of isolated tendons suggest that this assumption is valid for so-called ‘free’ tendons, such as the Achilles, that span a gap between muscle and bone (Fig. 1).

However, free tendons are not the only elastic structures capable of storing elastic energy. In many muscles the free tendon is continuous with broad sheet-like tendons, or Figure 2. The effect of biaxial loading on stiffness. Inset, a schematic showing the aponeuroses, that function as the deformations that occur in a hypothetical tissue during uniaxial and biaxial loading. attachment and insertion sites for Force–deformation curves for a tissue loaded uniaxially and biaxially. The slopes of muscle fibres (Fig. 1). Both tendons these curves characterize tissue stiffness. The curves highlight the increased force and aponeuroses consist of collagen required to stretch a tissue by a given amount during biaxial loading. Curves are bundles oriented primarily along the modified from Lanir & Fung, 1974.

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To appreciate the functional orthogonal direction, as expected for Variable stiffness in aponeuroses significance of biaxial loading, consider uniaxial loading (Fig. 3). The stiffness may have important implications for a case where the tissue is only loaded measured under these conditions was movement. The use of stiffness values in one direction. When loaded significantly lower than the stiffness based on uniaxial material properties uniaxially any solid material will tend to measured for biaxial loading during may underestimate the elastic energy get thinner in directions perpendicular active force production (Fig. 3). stored in aponeuroses during active to the line of pull; a stretched rubber contractions. Variable stiffness may band displays a characteristic ‘necking’ The effects of biaxial loading may also have implications for motor where it shortens perpendicular to explain previously published results control. If the muscle ‘sees’ a different the direction of loading (Fig. 2). In that were considered difficult spring stiffness under different contrast, under biaxial loading the to reconcile with a model of the conditions, the motor control system tissue is prevented from shortening, aponeurosis as a uniaxially loaded must accommodate this variability. and with enough loading can be spring. Measurements on isolated The degree to which changes in stretched in two dimensions. Biaxial muscles found the stiffness of the aponeurosis stiffness are tuned to the loading requires more force for a given aponeurosis along the muscle’s line mechanical demands of movement stretch (Fig. 2). What this means for of action increases substantially in remain unknown and should provide active as compared with passive force muscle is that the effective stiffness fertile ground for future studies. of the tendon spring is greater in the production (Zuurbier et al. 1994; longitudinal direction than would be Lieber et al. 2000). Such changes in expected for uniaxial loading (Fig. 2). aponeurosis stiffness were difficult Emanuel Azizi and to explain when only deformations Thomas J Roberts We were able to test the idea that along the muscle’s line of action were biaxial loading increases the effective considered. However, when one Brown University, Department of stiffness of aponeurosis by comparing considers the length changes that Ecology and Evolutionary Biology, the aponeurosis stiffness during active occur orthogonal to the muscle’s line Providence, RI, USA and passive force production. When of action, it becomes clear that biaxial the muscle was loaded passively loading provides a likely mechanism for References (by stretching it to long lengths), stiffness modulation in aponeuroses Azizi E & Roberts TJ (2009). Biaxial strain and the aponeurosis shortened in the (Fig. 3). variable stiffness in aponeuroses. J Physiol 587, 4309–4318. http://jp.physoc.org/content/587/17/4309. long Biewener AA & Baudinette RV (1995). In vivo muscle force and elastic energy storage during steady-speed hopping of tammar wallabies (Macropus eugenii). J Exp Biol 198, 1829–1841. Lanir Y & Fung YC (1974). Two-dimensional mechanical properties of rabbit skin. II. Experimental results. J Biomech 7, 171–182. Lieber RL, Leonard ME & Brown-Maupin CG (2000). Effects of muscle contraction on the load-strain properties of frog aponeurosis and tendon. Cells Tissues Organs 166, 48–54. Magnusson SP, Hansen P, Aagaard P, Brond J, Dyhre-Poulsen P, Bojsen-Moller J & Kjaer M (2003). Differential strain patterns of the human gastrocnemius aponeurosis and free tendon, in vivo. Acta Physiol Scand 177, 185–195. Zajac FE (1989). Muscle and tendon: properties, models, scaling, and application to biomechanics and motor control. Crit Rev Biomed Eng 17, 359–411. Zuurbier CJ, Everard AJ, Vanderwees P & Huijing PA (1994). Length-force characteristics of the aponeurosis in the passive and active muscle condition and in the isolated condition. J Biomech 27, 445–453. Figure 3. The behaviour of aponeuroses during passive and active force production. A, a schematic of a muscle showing the deformations that occur in the aponeurosis during passive and active force production (muscle in red, aponeurosis in white). Acknowledgements Length changes along the muscle’s line of action (longitudinal) are indicated by red The authors would like to acknowledge arrows and length changes perpendicular to the muscle’s line of action (transverse) support from the United States National are indicated by yellow arrows. B, data showing that relative length changes Institute of Health grants AR055295 to perpendicular to the line of action (transverse strain) can modulate the stiffness of T.J.R. and AR054246 to E.A., as well as the the aponeurosis along the muscle’s line action (longitudinal stiffness). W.M. Keck Foundation.

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The placebo response: how words and rituals change brain circuitry The study of the placebo response is basically the study of the effects of the psychosocial context and the ritual of the therapeutic act on the patient’s brain. Recent research in Parkinsonian patients indicates that the therapist’s words and rituals may induce molecular and cellular changes in the patient’s brain, thus placing the doctor–patient relationship and psychotherapy into the neurobiological domain The placebo response, or placebo reported motor improvement. effect, is the therapeutic effect that These patients also released larger follows the administration of an amounts of dopamine in the dorsal inert treatment (the placebo), for motor striatum, suggesting a example, a saline solution or a sugar relationship between the amount pill. Neither salt nor sugar will ever of dorsal striatal dopamine release acquire therapeutic properties. What and clinical benefi t. This relationship matters is the psychosocial context was not present in the ventral around the treatment. In fact, a striatum, in which all patients From top left patient who receives a therapy is clockwise: Fabrizio showed increased dopamine deluged with social and sensory Benedetti, Michele release, irrespective of whether stimuli which tell him that a therapy Lanotte and they perceived any improvement. is being performed. This induces Leonardo Lopiano. Compared to the dorsal motor expectations of clinical improvement striatum, the ventral striatum and may affect several systems neurobiological underpinnings of (nucleus accumbens) is involved in and apparatuses, producing a real the placebo response is Parkinson’s motivation and reward anticipation. benefi t. Therefore, the study of the disease, a motor disorder that Accordingly, the investigators placebo response is the study of how is highly responsive to placebo proposed that the dopamine the patient’s brain is affected by the treatments. In 2001, de la Fuente- released in the ventral striatum psychosocial context around the Fernandez et al. (2001) conducted was associated with the patients’ treatment. the fi rst brain imaging study of expectation of improvement in their the placebo effect by means of symptoms, which could in turn be Placebos induce dopamine release positron emission tomography. considered a form of reward. in Parkinsonian patients These researchers assessed the Many medical conditions are release of endogenous dopamine A placebo treatment changes affected by placebo administration. by using raclopride, a radiotracer neuronal activity in the basal Typically, when one administers which binds to dopamine D2 and ganglia a placebo, the patient is given a D3 receptors and competes with In 2004, the fi rst study of the fake treatment along with verbal endogenous dopamine. In this placebo effect at the single-neuron suggestions of benefi t. Overall, study, patients were aware that they level was performed (Benedetti et the whole ritual of therapy would be receiving an injection of al. 2004). Since the subthalamic administration constitutes the either active drug (apomorphine, nucleus plays an essential role in therapeutic act. There is now a dopamine receptor agonist) or basal ganglia functioning and is a compelling experimental evidence placebo, according to classical major target in the surgical therapy that the therapeutic act, together clinical trial methodology. After of Parkinson’s disease, we performed with the doctor’s words and rituals placebo administration, it was found a double-blind study in which the (crucial elements of a placebo that dopamine was released in the activity from single neurons in the procedure), may induce changes striatum, corresponding to a change subthalamic nucleus before and in the patient’s brain, such as the of 200% or more in extracellular release of endogenous opioids and dopamine concentration and after placebo administration was the activation of different brain comparable to the response to recorded to see whether neuronal regions in subjects who are in pain. amphetamine in subjects with an changes were associated to the Likewise, placebos may activate intact dopamine system. The release clinical placebo response. Before different regions in depressed of dopamine in the motor striatum placebo administration, the activity patients, and may also induce the (putamen and dorsal caudate) of neurons was recorded from release of immune mediators and was greater in those patients who one subthalamic nucleus prior to hormones (Benedetti, 2008; Zubieta reported clinical improvement. implantation of the fi rst electrode & Stohler, 2009). and used as a control. After the Although in the studies by de la placebo, which consisted of a One of the most interesting models Fuente-Fernandez et al. (2001) all subcutaneous injection of saline and medical conditions that has patients showed dopamine placebo solution along with the verbal been investigated to understand the responses, only half of the patients suggestion of motor improvement,

Physiology News | No. 77 | Winter 2009 | www.physoc.org FEATURES PN 31

nucleus. In order to rule out the possibility that the difference in fi ring rate between the pre- and post-placebo subthalamic nucleus E

l e was independent of the placebo

c o d e

t r t treatment itself, a no-treatment r

do e c e group (natural history) was studied. l E The patients of this no-treatment + group did not undergo any placebo treatment between the implantation of the fi rst and second electrode. All VA-VLa - these patients showed no signifi cant STN differences between the neuronal + fi ring rates of the two subthalamic SNr nuclei, which indicates that the difference between the fi rst and the second side of implantation in the placebo group was due to the placebo intervention per se.

In a more recent study, these fi ndings were extended from the subthalamic nucleus to other nuclei, thereby characterizing a complex decrease increase neuronal circuit during the placebo pre –post Neuronal firing rate (Hz) Fig. 1 pre response (Benedetti et al. 2009). In those patients who showed a clinical Figure 1. Neuronal changes during a placebo treatment in a Parkinsonian patient. placebo response, there was a Whereas there is a decrease in fi ring rate in the subthalamic nucleus (STN) and decrease in fi ring rate in subthalamic substantia nigra pars reticulata (SNr), an increase occurs in the ventral anterior (VA) nucleus neurons that was associated and anterior ventral lateral (VLa) thalamus. The colour scale indicates the changes in with a decrease in the substantia fi ring rate compared with baseline. The black arrows indicate the excitatory (+) and inhibitory (–) connections between these regions. nigra pars reticulata and an increase in the ventral anterior and anterior neuronal activity was recorded from by means of arm rigidity and ventral lateral thalamus (Fig. 1). By neurons prior to implantation of subjective report of well-being, also contrast, placebo non-responders the second electrode into the other showed a signifi cant decrease of showed either a lack of changes in subthalamic nucleus. Those patients fi ring rate and a shift from bursting this circuit or partial changes in the who showed a straightforward to non-bursting activity compared subthalamic nucleus only. Thus, clinical placebo response, assessed to the pre-placebo subthalamic changes in activity in the whole basal ganglia–thalamic circuit appear to Motor cortex be important in order to observe a clinical placebo improvement. Figure 2. The neuronal circuit that These fi ndings indicate that a is affected by a placebo treatment placebo treatment, which is basically in Parkinson’s disease is shown in Cortex yellow. It is probably only a part of characterized by verbal suggestions Thalamus a more complex circuit, which is of benefi t, can reverse the malfunction of a complex neuronal VA shown in white. The subthalamic nucleus (STN) neurons, which receive circuit, although these placebo- Striatum VLa inputs from the cortex, the striatum, associated neuronal changes are the external globus pallidus (GPe) short-lasting and occur only in some as well as from other regions, send patients but not in others. their output excitatory information GPe STN to different regions, such as the The circuit we have characterized substantia nigra pars reticulata (SNr) (Benedetti et al. 2009) is likely and the internal globus pallidus (GPi). GPi to be a part of a more complex + SNr has an inhibitory connection with + the thalamus, and the thalamus sends circuitry, including the striatum projections to the motor cortex. The and the internal globus pallidus (GPi), that is modifi ed by placebo SNr striatum also sends projections to GPi, which in turn projects to the thalamus, administration (Fig. 2). These and to SNr. placebo-induced changes may have

Physiology News | No. 77 | Winter 2009 | www.physoc.org

Fig. 1 32 PN FEATURES profound implications for both Neuromuscular interaction during human the doctor–patient relationship and psychotherapy. In fact, the walking: how do changes in muscle–tendon psychosocial context and the therapeutic act itself, along with mechanics affect the motor control of verbally induced expectations of walking? clinical benefit, may indeed induce specific changes in the patient’s Prolonged walking can increase the compliance of soleus brain, thus placing the therapist– tendinous tissues, which could ultimately impair the ability to patient communication and recover from a sudden balance disturbance psychotherapy into a therapeutic When humans walk, muscle–tendon context which per se is capable of units in the legs are constantly modifying the patient’s brain. subjected to length changes, which Fabrizio Benedetti1,2, Michele are distributed between the muscle 1 and tendinous tissues within the Lanotte and Leonardo muscle–tendon unit. These length 1 Lopiano changes can affect the activity of 1Department of Neuroscience, afferent receptors located in the University of Turin Medical muscle. One situation where this Neil Cronin. School and 2National Institute of is particularly important is when Neuroscience, Corso Raffaello 30, encountering an unexpected balance Neuromuscular interaction during 10125 Turin, Italy disturbance during walking, such walking: what happens when we walk for a long time? References as a trip or stumble. In order to avoid falling, the central nervous It has previously been shown that Benedetti F (2008). Placebo effects: after a 1 h period of repeated passive understanding the mechanisms in health and system must be able to detect the disease. Oxford University Press. disturbance and initiate a response, stretching of the human ankle Benedetti F, Colloca L, Torre E, Lanotte all in a matter of milliseconds. extensor muscles, the compliance M, Melcarne A, Pesare M, Bergamasco B of the tendinous tissues (outer & Lopiano L (2004). Placebo-responsive Investigating neural and tendon and aponeuroses) increases Parkinson patients show decreased activity mechanical behaviour (Avela et al. 2004). If the same in single neurons of subthalamic nucleus. Nat Neurosci 7, 587–588. simultaneously phenomenon were present during walking, increased tendinous tissue Benedetti F, Lanotte M, Colloca L, A wealth of data have been Ducati A, Zibetti M & Lopiano L (2009). presented investigating sensory compliance could affect the firing Electrophysiological properties of thalamic, feedback in humans during walking, behaviour of sensory receptors subthalamic and nigral neurons during the and this has without question within the muscle–tendon unit, anti-parkinsonian placebo response. J Physiol 587, 3869–3883. improved our understanding of such as the muscle spindles. These http://jp.physoc.org/content/587/15/3869. human motor control. However, receptors are thought to make an long since many of the receptors that important contribution to muscle de la Fuente-Fernandez R, Ruth TJ, Sossi contribute to afferent feedback activation during normal walking, as V, Schulzer M, Calne DB & Stoessl AJ during walking are located in the well as in response to an unexpected (2001). Expectation and dopamine release: balance disturbance (Sinkjaer et mechanism of the placebo effect in muscle and tendinous tissues, it has Parkinson’s disease. Science 293, 1164–1166. become increasingly desirable to al. 2000). Therefore, changes in Zubieta JK & Stohler CS (2009). investigate the behaviour of these tendinous tissue compliance could Neurobiological mechanisms of placebo tissues, and to relate it to sensory affect the motor control of human responses. Ann N Y Acad Sci 1156, 198–210. feedback. One method that has walking. facilitated experiments in this field Swartz Prize is ultrasonography. Although this We recently sought to examine Horace Barlow from the Cambridge method is traditionally associated whether changes in tendinous tissue Physiological Laboratory has recently with fetal scanning, the last two compliance were indeed evident won the Swartz Prize for Theoretical and during human walking in a group Computational Neuroscience. The Prize decades have seen an adaptation to of 11 young, healthy adults (Cronin is awarded annually to: the methodology that has allowed the study of muscle and tendon et al. 2009). Subjects walked on a an individual whose activities over a treadmill for 75 min with a portable period of time have produced a significant length changes during dynamic cumulative contribution to theoretical movements. Although the method robotic actuator attached to the models or computational methods in is naturally limited by the fact that it ankle joint. This device is capable neuroscience, or to: is 2-dimensional, it has nonetheless of eliciting rapid ankle dorsiflexion a person who has made a particularly provided valuable information about perturbations during the stance noteworthy advance over the past several phase of walking (Fig. 1). Full years in theoretical or computational muscle and tendon mechanics neuroscience. during movement. details of the device are presented

Physiology News | No. 77 | Winter 2009 | www.physoc.org FEATURES PN 33

Motor

Bowden wires Velcro TA EMG straps

Carbon fibre SOL EMG shell Position encoders

Heel contact Treadmill

Figure 1. Schematic of the robotic actuator that was used to elicit rapid dorsiflexion perturbations during walking. This device was combined with surface EMG and ultrasonography. A fully instrumented subject is shown in the right panel. elsewhere (Andersen & Sinkjaer, mid and late phases of the 75 min Furthermore, in response to a 2003). By combining this method walking protocol (Pre, Mid and faster perturbation elicited at the with ultrasonography and surface Post, respectively). Between the Pre Post interval, the amplitude of the electromyography (EMG), it was and Post intervals, the amplitude short latency component and the possible to examine changes in both and velocity of fascicle stretch velocity of muscle fascicle stretch muscle fascicle length and muscle both decreased considerably (by both recovered to pre-exercise activation in the soleus muscle 46% and 59%, respectively; mean values (Fig. 2). These findings clearly throughout an exercise protocol. values across all subjects), as did show that when perturbations short and medium latency stretch were elicited at the Post interval, Rapid stretches were imposed reflex amplitudes (by 33 and 25%, the stretch was not transmitted as at the ankle joint at three time respectively) in response to a effectively to the muscle fascicles, intervals representing the early, constant external perturbation. and thus to the muscle spindles.

Pre Mid Post

A 20

10

0 Ankle

angle(deg) 10

B 70 SLR MLR

35 EMG amplitude(V) 0

4.1 C Control Normal stretch 3.8 Fast stretch Fascicle length(cm) 3.5

0 100 200 300 400 500 600 700 0 100 200 300 400 500 600 700 0 100 200 300 400 500 600 700 Time (ms)

Figure 2. Neural and mechanical stretch responses from one representative subject at the Pre, Mid and Post intervals. A, mean ankle trajectory (n = 28); B, SOL EMG activity (n = 28); C, fascicle length (n = 3). Dashed vertical lines represent the onset of the rapid perturbations. The enlarged insets are not shown to scale, but are intended to highlight the individual traces more clearly. SLR and MLR, short and medium latency stretch reflex, respectively.

Physiology News | No. 77 | Winter 2009 | www.physoc.org 34 PN FEATURES

This would explain why short and However, this raises an interesting in the human soleus muscle. J Physiol 587, medium latency stretch reflex series of questions. What happens 4339–4347. http://jp.physoc.org/content/587/17/4339. amplitudes decreased, as they are at in the other muscle–tendon units of long least partly mediated by type Ia and the lower limb? If muscle activation Ishikawa M, Komi PV, Grey MJ, Lepola V & type II afferents, respectively, both decreases in soleus, how does the Bruggemann GP (2005). Muscle-tendon of which originate in the muscle central nervous system compensate interaction and elastic energy usage in spindles. At the Post interval, we in order to maintain the same human walking. J Appl Physiol 99, 603–608. also observed a decrease in fascicle movement pattern? Furthermore, Lichtwark GA & Wilson AM (2008). Optimal length at the point of ground if the amplitude of stretch reflexes muscle fascicle length and tendon stiffness contact and immediately prior to decrease after a sustained period for maximising gastrocnemius efficiency the onset of the perturbation, as during human walking and running. J Theor of walking, and these responses Biol 252, 662–673. well as a smaller fascicle length are important for recovery from change throughout the stance Sinkjaer T, Andersen JB, Ladouceur M, unexpected balance disturbances Christensen LO & Nielsen JB (2000). Major phase. Concurrently, the range of (Sinkjaer et al. 2000), are the role for sensory feedback in soleus EMG joint motion at the ankle during responses to such disturbances activity in the stance phase of walking in man. J Physiol 523, 817–827. walking was unchanged throughout compromised after prolonged the study. Taken together, these walking? As the soleus muscle is findings provided strong evidence just one of the plantarflexors, it is for an increase in the compliance of Brown coats or white? possible that activation of other tendinous tissues after walking in the synergistic muscles increases in In Edinburgh in the late 1940s human soleus muscle–tendon unit. response to decreased soleus students wore white (or, more Interestingly, during normal activation. Indeed, this kind of neural accurately ‘off-white’) lab coats unperturbed walking, a general compensation has been reported for practical classes as did most of decrease in ongoing soleus muscle after higher intensity fatiguing the technicians. Mr Marshall, the activity was observed (‘Control’ exercise (Akima et al. 2002). This histology wizard, chose grey but I traces in Fig. 2). This may be an is a matter of ongoing study in didn’t encounter many brown coats indication that the increased our laboratory, and the results will till I arrived at the (then) Institute tendinous tissue compliance led to help us to understand how the of Animal Physiology at Babraham. a decrease in the ongoing sensory central nervous system adapts to Here they were worn by animal feedback from muscle receptors, time-dependent changes in muscle– house and workshop staff, and which is known to contribute to tendon mechanics. by the indispensable heavy-duty muscle activity during unrestrained handy men – occasionally walking (Sinkjaer et al. 2000). As Neil J. Cronin1,2 termed ‘heavy-handed duty men’ with the responses to perturbations, from their propensity to slosh 1Center for Sensory-Motor this is probably due to the fact that distilled water about the lab while the stretch stimulus reaching the Interaction, Department of Health Science and Technology, Aalborg delivering it in winchesters from muscle fascicles (and receptors) the central still. decreased after the walking protocol. University, Denmark 2 Neuromuscular Research Centre, Babraham’s first Director Ivan de What are the functional Department of Biology of Physical Burgh Daly favoured white coats for implications? Activity, University of Jyväskylä, himself and the rest of the scientific Based on data obtained with Finland staff, despite having worked with ultrasonography, it is known W. M. Bayliss. In his Bayliss–Starling that when a muscle–tendon unit References Memorial Lecture, Daly said that changes length, the actual length Akima H, Foley JM, Prior BM, Dudley GA & Bayliss ‘always wore his brown changes of the muscle and tendon Meyer RA (2002). Vastus lateralis fatigue overall, which had seen better days, components may be uncoupled (e.g. alters recruitment of musculus quadriceps femoris in humans. J Appl Physiol 92, in the laboratory, and as long as I Ishikawa et al. 2005). In this context, 679–684. knew him it did not seem to change. the increase in tendinous tissue Andersen JB & Sinkjaer T (2003). Mobile I imagine therefore that the memo compliance that we have observed ankle and knee perturbator. IEEE Trans to be found in one of his notebooks could enable the muscle fibres to Biomed Eng 50, 1208–1211. which runs “Overalls, 35 inches, price contract relatively slowly (Lichtwark Avela J, Finni T, Liikavainio T, Niemela E & 4s. 3d. [21p] post free” supplied by & Wilson, 2008), whilst the larger Komi PV (2004). Neural and mechanical tendinous tissue stretch during responses of the triceps surae muscle group a firm in Newcastle, was a reminder the stance phase would facilitate after 1 h of repeated fast passive stretches. J in the event of an emergency which Appl Physiol 96, 2325–2332. the storage of elastic energy in never emerged’. Cronin NJ, Ishikawa M, Af Klint R, Komi the tendinous tissues. This could PV, Avela J, Sinkjaer T & Voigt M (2009). I de Burgh Daly (1967) The Bayliss–Starling potentially increase the efficiency of Effects of prolonged walking on neural and Memorial Lecture. J Physiol 191, 1–23. the soleus muscle–tendon unit. mechanical components of stretch responses

Physiology News | No. 77 | Winter 2009 | www.physoc.org TECHNIQUES PN 35

Multiple tests correction, false discovery rate and q value In the second of the microarray data analysis articles of this Techniques series Fumiaki Katagiri (below) from the University of Minnesota, USA, examines the false discovery rate in more detail and reveals why this method is more suitably adapted to multidimensional data, such as that generated by microarrays Major statistical challenges for could measure the expression level analysis of a very large context values from a very large number dependent data set generated by of mice). As shown in Fig. 2, the a highly parallel method, such as a distributions of expression levels in microarray data set, are two-fold: a kidney and liver would be quite well small number of replicates due to separated. We can calculate what the high cost of data generation, and power we would get for this kind of the need for a very large number of truly differentially expressed genes significance tests. The purpose of using 5 replicates and a significance this article is to discuss the latter, the level of 5 x 10-6 according to the problem of multiple testing. Bonferroni correction. The power in this case is 0.006, i.e. if we have 500 What is multiple tests correction? such truly differentially expressed Let’s assume that we measured using a significance level commonly genes among 10 000 genes, then expression level values of 10 000 used when the number of tests is on average we would only identify genes in two tissues, kidney small results in many false positives three genes as being differentially and liver, from each of five when the number of tests is large. expressed. We would miss the vast individual mice (five biological We should use a lower significance majority of them! For most research replicates). We have already level to avoid a high number of false questions, this is not an acceptable applied a transformation, such positives, but how can we determine level of power. So, the Bonferroni correction is too stringent. How can as log2-transformation, to the an appropriate significance level? expression level values to make the Methods to correct the significance we get a good balance between the sample distributions approximately level are called multiple tests numbers of false positives and false normal. We ran a significance corrections (or multiple comparisons negatives? test, such as a t test, for each gene corrections). There are several multiple tests to calculate the P value for the correction methods of the classical hypothesis that the expression levels A classical type of multiple tests type that are more relaxed than the in the two tissues are the same (null correction Bonferroni correction. However, one hypothesis). So, the smaller the P The Bonferroni correction is a common problem associated with value is, the more likely it is that the classical correction method. the classical type of multiple tests gene is differentially expressed. First, According to the Bonferroni correction is that when the number assume that no gene is differentially correction, the significance level of positives is relatively close to the expressed in two tissues, i.e. all the to be used for each of 10 000 tests expected number for false positives, genes are nulls. Figure 1A shows the -6 is 0.05/10 000 = 5 x 10 . Using we cannot estimate how many of the distribution of simulated P values this method, it is very unlikely that positives could be true positives. of the 10 000 genes in a histogram any false positives will be selected with an interval of P = 0.01 each, in the all-null situation in Fig. 1A. False discovery rate (FDR), a new when all the genes are null. Yes, The Bonferroni correction makes type of multiple tests correction it is a uniform distribution – with the probability of selecting one this interval size, each band height or more false positives equal to Due to the issues discussed above, is on average 10 000 x 0.01 = 100 0.05. Unfortunately, a fundamental multiple tests correction of the genes (red line). We will use this principle of statistical analysis is that classical type are not commonly uniform distribution with 100 genes fewer false positives are associated used in analysis of microarray data per interval as the null distribution with more false negatives (type II these days. Instead, false discovery estimate. If we use the significance errors), that is, a higher chance of rate (FDR) has become a standard level (i.e. the threshold P value) missing truly differentially expressed for multiple tests correction in of 0.05 to select positive genes, genes. Let us assume that we had microarray data analysis. The idea approximately 500 genes (left of some genes with a mean expression of FDR put forward by Benjamini the blue line) are selected with the level difference of 2.5 between and Hochberg (Benjamini & null distribution. Since all the genes kidney and liver in mice and that Hochberg, 1995) is that it would are null, these 500 genes are all the expression level in each tissue be convenient to know what per false positives (type I errors). Thus, has a standard deviation of 1 (if we cent of the positives discovered by

Physiology News | No. 77 | Winter 2009 | www.physoc.org 36 PN TECHNIQUES multiple significance tests are false part of Fig. 1B close to P = 0. The narrower interval, we could reduce positives: FDR = (number of false significance level of 0.03, used the significance level further, and positives)/(number of all positives). for arithmetic convenience in this FDR could further decrease. In this Let us see how this works using a example, selects 756 positives in this case, 149 genes are positive at simulated data set. We’ll add truly figure. The yellow part corresponds FDR = 0.05, which corresponds to differentially expressed genes to to the number of true positives a significance level of 0.000732. the all-null situation in Fig. 1A. In (456 genes), and the magenta part Then we get on average 141.5 true Fig. 1B, 500 null genes out of 10 000 corresponds to the number of false positives and 7.5 false positives have been replaced with 500 truly positives (300 genes). Therefore, – what a big difference from the differentially expressed genes with when a significance level of 0.03 is average of 3 true positives and no mean differences of 2.5 and standard used, the FDR = 300/756 = 0.40. false positives by the Bonferroni deviations of 1 in each tissue (genes Now we know that on average 40% correction! with expression level distributions of 756 genes are false positives like the one in Fig. 2). We can see a (note that the number of false In addition, the FDR is more substantial increase in the number positives is an estimate). Similarly, appropriate than the significance of genes with P values close to zero. if we use a significance level of 0.01 level in selecting positive genes by If we use a significance level of 0.03 (green line in Fig. 1C), the number different criteria when we want to (blue line), the yellow part must of true positives is 380, and the compare the positive gene sets. For represent the truly differentially number of false positives is 100, so example, we want to see the overlap expressed genes, i.e. true positives. the FDR = 0.21. You can imagine between a set of genes significantly Figure 1C is a blow-up view of that if our P value histogram had a induced by drug A and a set of genes Number of genes Number of genes

P value P value Number of genes Number of genes

P value P value Figure 1. Simulated P value distributions. A, the P value distribution of 10 000 null genes. The red line shows the estimate of the null distribution, which is a uniform distribution. Five hundred genes are estimated to be false positives at the significance level of 0.05 (blue line). B, 500 randomly selected genes from A are replaced with 500 truly differentially expressed genes whose expression level values are sampled from the distributions shown in Fig. 2. The yellow area represents the estimate of the true positives at a significance level of 0.03 (blue line). C, a blow-up image of B. The yellow and magenta areas represent the estimates of the true and false positives at a significance level of 0.03. D, 3000 randomly selected genes from A are replaced with 3000 truly differentially expressed genes whose expression level values are sampled from the distributions shown in Fig. 2. The estimate of the null distribution should be changed from the uniform distribution shown by the red line to that by the magenta line for a higher power. The null distribution estimates shown by the red and magenta lines correspond to the Benjamini–Hochberg and Storey FDR methods, respectively.

Physiology News | No. 77 | Winter 2009 | www.physoc.org TECHNIQUES PN 37 significantly induced by drug B. If the same significance level is used in selecting these two gene sets, one of them might be almost all false positives. The reliability of the overlap is consistent if both gene sets are selected using the same FDR instead of the same significance Density level. Density

The Storey FDR is useful when many genes are truly differentially expressed The above FDR must be referred to as the Benjamini–Hochberg 0.0 0.1 0.2 0.3 0.4 FDR since a differently defined 2 4 6 8 10 12 Expression level FDR method exists. Let us consider Expression level a situation in which a relatively large number of genes are truly Figure 2. The distributions of expression level values used for the simulations of the differentially expressed. Figure 1D truly differentially expressed genes in Fig. 1. They have normal distributions with a standard deviation of 1, and their mean difference is 2.5. shows a case in which 3000 null genes out of 10 000 were replaced P value while corrections of the old genes selected for FDR = 0.02 are the with 3000 truly differentially type depend only on the number same as the genes with q ≤ 0.02. The expressed genes with expression of tests. It should be emphasized q value can practically (although not level value distributions the same as that both FDR methods assume P exactly) be considered as the FDR- those in Fig. 2. In this case, the red value distributions similar to those corrected P value (or FDR-adjusted P line (100 genes per interval) as an in Fig. 1: higher closer to P = 0 and value). The q value has great utility. estimate of the null gene distribution flattened toward P = 1. In fact, In many cases, the information from appears to be an overestimate. the Storey method uses the flat microarray data is used to select The magenta line (70 genes per part of the P value distribution candidate genes associated with interval) is an appropriate null to estimate the null distribution. a particular biological function, distribution estimate. Thus, the Therefore, it is important to for example, genes involved in the Storey FDR corrects the estimated make sure that your data set has cholesterol metabolism regulation. null distribution of the P values when this kind of P value distribution Candidate genes are then analysed many genes are truly differentially before applying an FDR method. to test for a role in the predicted expressed (Storey & Tibshirani, For example, when an Affymetrix function. Imagine that the 2003). In this way, at the same FDR GeneChip data set is preprocessed throughput of our functional assay is values, the Storey FDR corresponds 20 genes per month, and our project to a higher significance level (P value) by GCRMA (Wu & Irizarry, 2004), period ends in 3 months. We choose than the Benjamini–Hochberg FDR, the P value distribution tends to 60 genes with the smallest q values. hence the Storey FDR has a higher have a substantial peak in the This is no different from choosing power. For example, with the P value middle. This is caused by the genes 60 genes with the smallest P values distribution in Fig. 1D, at FDR = 0.05, whose expression level values are because the conversion of the P 2275 positives are selected by the considered to be mostly noise by the value to the q value does not change Benjamini–Hochberg method at the GCRMA algorithm. Therefore, such the rank of each gene. However, corresponding significance level of genes need to be removed before with the q value, if the gene with 0.0114 (2161 true positives and 114 applying an FDR method. the largest q value among those false positives), and 2568 positives chosen has q = 0.017, we know that are selected by the Storey method at The q value is the FDR-corrected P we expect one false positive among the corresponding significance level value (sort of) the 60 genes. The P value (or the P of 0.0185 (2440 true positives and Storey also proposed the q value, value corrected by a multiple tests 128 false positives). which is defined for each gene as the correction method of the old type) minimum FDR that makes the gene a will not provide such information. The P value distribution for FDR positive (Storey & Tibshirani, 2003). correction For example, a gene with q = 0.02 Local fdr, the ultimate multiple One big difference between FDR is selected as a positive when tests correction? corrections and corrections of the FDR = 0.02 is used, but not when The probability that a gene with old type is that FDR corrections FDR = 0.019 is used. In other words, q = 0.02 is a false positive if it is depend on the distribution of the the FDR is the threshold q value: the selected is higher than 0.02. This is

Physiology News | No. 77 | Winter 2009 | www.physoc.org 38 PN TECHNIQUES because genes with q < 0.02 have which local fdr method is the best References lower probabilities of being false (though see Allison et al. 2006). Allison DB, Cui X, Page GP & Sabripour positives than this gene. Can’t we M (2006). Microarray data analysis: from estimate the probability that a Using FDR methods disarray to consolidation and consensus. particular gene is a false positive If R, a language and an environment Nat Rev Genet 7, 55–65. if the gene is selected? This would for statistical computing Benjamini Y & Hochberg Y (1995). be the ultimate corrected P value (www.r-project.org), is used for Controlling the false discovery rate: for each gene. Such a probability is analysis, the q values based on the a practical and powerful approach called the local fdr or gene-specifi c Benjamini–Hochberg FDR can be to multiple testing. J R Stat Soc B 57, fdr (conventionally lower letters calculated from a set of P values 289–300. are used for the local ‘fdr’). Several using the p.adjust function with an Pounds SB (2006). Estimation and methods have been proposed, option of method=’BH’. The q values control of multiple testing error rates and they are compared in Pounds based on the Storey FDR can be for microarray studies. Brief Bioinform 7, 25–36. (2006). Generally, the better a local calculated using the qvalue function fdr method performs, the more in the qvalue package. Storey JD & Tibshirani R (2003). computationally intensive it is. We Statistical signifi cance for genomewide are not getting into the local fdr Fumiaki Katagiri studies. Proc Natl Acad Sci U S A 100, here. However, it is likely that it will 9440–9445. Department of Plant Biology, become more popular as statisticians Wu Z & Irizarry RA (2004). Preprocessing Microbial and Plant Genomics working on microarray data of oligonucleotide array data. Nat Institute, University of Minnesota, recommend it. Presently, there does Biotechnol 22, 656–658; author reply 1500 Gortner Ave, St Paul, MN, USA 658. not seem to be agreement about

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Physiology News | No. 77 | Winter 2009 | www.physoc.org REPORTS PN 39

The Hodgkin–Huxley– with an experiment of such beautiful Otto Hutter Physiology conceptual simplicity – whatever Katz Prize Lecture may have been the practical Teaching Prize delivered by Eric Kandel diffi culty – that I believe it may be Otto Hutter talks about their regarded as the apogee of Kandelian fi rst meeting reductionism. Having established in tissue culture that a selected synapse between a sensory and a motoneurone may be strengthened for the long-term by repeated pulses of serotonin – in substitution to the activity of a normally facilitatory interneurone – the question arose:

do the structural changes so induced, Photo by Martin Rosenberg. which involve a chain of events leading to gene transcription and Over the past few years, The export of new proteins from the Physiological Society has taken steps nucleus, remain confi ned to that to raise the profi le of physiology Samyuktha Muralidharan Pillai and Eric synapse? To tackle this question teaching. We are now pleased to Kandel. Kandel and his colleagues grew announce the launch of the Otto a single sensory neurone with a Hutter Physiology Teaching Prize, a To hear and meet Eric Kandel I had vehicle for The Society to recognise branched axon that formed synapses fl own to Dublin in vain. So taking the an individual’s contribution to with two motoneurones. On then train from Bournemouth to Waterloo teaching undergraduate physiology. applying pulses of serotonin to and making my way past old one set of synaptic connections, Bloomsbury haunts to the Institute of We are proud that Otto Hutter only that selected set was found to Neurology was my second try. Over has agreed to lend his name to respond with growth of new synaptic the years, from our native Vienna The Society’s new prize. Otto terminals. Subsequent work by onwards, our paths had intersected; begun his career during the war Kandel and his colleagues showed as a scientifi c technician at the and in the mid-60s, when I was on that an activated synapse becomes Wellcome Physiological Research the Editorial Board of The Journal marked for the long-term by local Laboratories, before completing of Physiology, we were in indirect synthesis of self replicating prion-like a BSc and PhD at UCL. As well as contact. But we had never met. proteins, another surprise in a long having a successful research career, I was seated early in the intimate- series of astonishing discoveries. Otto has helped spread physiology sized lecture hall. So I had plenty education to a wider world, both It is not our custom to follow prize internationally and through teaching of time to contemplate the lectures with questions. When a innovation. At Glasgow, he pioneered well-remembered features of lecture is delivered from a prepared perhaps the fi rst, fully integrated Hodgkin, Huxley and Katz projected text this can be a loss: for lecturers electrophysiological lab for junior onto the wide screen. How reveal more of themselves during teaching. He is also a virtuoso of appropriate, I thought, that Eric questioning. This time, however, we small group teaching, famous for Kandel had been invited to give a were soon captivated by Eric Kandel’s throwing the blackboard chalk as lecture founded in honour of these engaging personality. Belying his an inducement to do some of the famed men. For like these great years, Kandel spoke scintillatingly board-work yourself! knights of British physiology, Eric without notes for close on an hour, Nominations for this prize should Kandel has applied the reductionist at the rapid pace of a New Yorker, summarise the nominee’s approach to a fundamental question; with shafts of humour and wit; all and he had learned, from their contribution to teaching in less than the while pacing the fl oor, turning 400 words, and include details of examples –as well as from Stephen to the audience to clarify a point, Kuffl er – that for every biological any supporting teaching materials. and anchored to the speakers desk Self-nominations are welcome. The problem there is an organism in only to press the button calling for which it can be best studied. recipient of the prize will receive the next slide. Altogether, it was an £1000 in prize money (£500 of While I was thus musing, Eric amazing feat by one soon to due which should be used for teaching Kandel had started to introduce the celebrate as octogenarian. Of such resources). audience to the abdominal ganglion virtuous men the psalmist says: Nominations, or any questions of Aplysia, the preparation that had ‘They will still be fruitful in old age, vigorous and fresh they will be.’ regarding this scheme, should be yielded to his quest into the biology sent to [email protected]. It is of memory storage and learning at (Psalm 92). Long may these words yet apply to Eric Kandel. now too late for the 2009 award. The the cellular and molecular level. And winner for this year will be notifi ed by soon afterwards we were presented Otto Hutter the end of the year.

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WHO does not regrouped and decided it would be We were surprised when a statement important to have the support of the was added to the BBC story from the recommend the use of relevant disease programme directors. Society of Homeopaths, saying that Their comments would be respected ‘There is a strong and growing evidence homeopathy for HIV, as expert recommendations and advice base for homeopathy and most notably, malaria, TB, influenza about these diseases. this also includes childhood diarrhoea.’ The studies that the Society presented and infant diarrhoea Together we contacted the Stop TB in favour of homeopathy were flawed In the last edition of Physiology Department, the HIV/AIDS Department, and incomplete. They were all by News (PN76, p. 35) Harriet Teare, a the Global Malaria Programme and the the same author and had not been member of Voice of Young Science Department of Child and Adolescent independently replicated. They also (VoYS), described how homeopaths Health and Development outlining our failed to highlight another study by the are establishing services and clinics concerns. The response was fantastic same author that had a negative result. in Africa and claiming to treat serious with some directors replying instantly. When journalists present an argument diseases such as TB, HIV, malaria, infant Child Health at WHO commented that as having two sides of equal weight diarrhoea and influenza. She explained ‘We have found no evidence to date that when in fact the evidence all falls how, together with their peers in homeopathy would bring any benefit to on one side, it can be confusing and Africa, VoYS had written to the World the treatment of diarrhoea in children’ difficult to make sense of the conflicting Health Organisation (WHO) calling on and the Stop TB department claiming claims. It is not always possible for the body to condemn the promotion their treatment guidelines ‘have no the public to be able to distinguish of homeopathy for treating these five place for homeopathic medicines.’ All the between good and bad science and serious diseases. In August they got a departments responded, stressing the so it is exactly for these reasons that response from the WHO. need for evidence-based conventional scientists need to speak out and treatments. Having these comments respond to misinformation. VoYS is a network made up of over highlights what a serious issue this. 600 early-career researchers, set up However, it required our efforts and More importantly, if no one speaks by Sense About Science to encourage persistence to encourage the right out about these issues, people will researchers to get involved in people in power to speak out. think it is acceptable to promote public debates about science and untested medicines for life-threatening take responsibility for correcting We sent these comments to the disease. The presence of homeopaths scientific misinformation. The use of WHO Director General’s Office who in Africa is undermining people’s homeopathy to treat life-threatening responded, confirming that they ‘clearly faith in conventional health care and diseases really concerned us; lives were express the WHO’s position.’ We then countering the efforts of those who at risk and we had to make a stand sent the comments to every health are trying to deliver the necessary against it. We were disappointed to minister in the world, to highlight help. These countries do not need see that the WHO has no guidelines the problem and give them support homeopathy. They need resources about the dangers of homeopathy to act against these practices in their like a safe water supply, vaccinations, with regard to serious diseases. For countries. It will also help health antibiotics, trained medical staff many people in the world, they are care workers warn of the dangers of and good health education. When the only reliable source of health care homeopathy and strengthen their homeopathy stands in place of these information available and so they have efforts to provide evidence-based vital resources, lives are lost. a responsibility to issue safe guidelines health care. Robert Hagan, a member We have brought this serious issue about disease, based on sound of VoYS said, ‘We need governments evidence. into the public debate and that is a around the world to recognise the great achievement. Even as early-career After the initial publicity of writing to dangers of promoting homeopathy scientists, we can make an impact and the WHO, we were contacted by people for life-threatening illnesses. We hope raise awareness of these issues. You can from all over the world struggling that by raising awareness of the WHO’s get large authorities to speak out; it with these practices and keen to hear position on homeopathy we will be just requires patience and persistence. a response from the WHO. Medics supporting those people who are As Raymond Tallis said, ‘It illustrates working in Africa have explained how taking a stand against these potentially the importance of young scientists, difficult the situation is for them, disastrous practices.’ torchbearers for a better future, taking with local people having little trust a stand and speaking out.’ Our response from the WHO was one of in Western medicine and with many people, including journalists, struggling the top five stories on BBC Online and The more members we have in our to distinguish between real science and this was followed by wide international network the bigger an impact we can suspect practices. coverage in places where we felt make on these projects. If you want to it really mattered including online join the network, or to find out more The WHO is a large bureaucratic news sites in Kenya, Ghana, Brazil, about VoYS, the workshops we hold organisation which can be difficult to India, Argentina and Mexico. Blogs and the publications we’ve produced penetrate and we had to be persistent. and forums were full of comments please visit www.senseaboutscience. We initially contacted the Division and discussions with people from all org or contact Julia at of AIDS, Tuberculosis and Malaria over the world debating whether this [email protected] at the WHO Africa office but were was either a bold step to improve redirected to several offices with no health care or a vicious ‘attack’ on Julia Wilson result. Determined not to give up, we homeopathy. Sense About Science

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Charles Darwin and The veins, and so forth, but certainty such as is required for the progress of any Physiological Society science can be arrived at in the case of physiology only by means of experiments The year 2009 marks the bicentenary of on living animals.” the birth of Charles Darwin (12 February 1809–19 April 1882), as well as the Darwin went on to clarify that he was 150th anniversary of the publication referring to experiments in which of his most celebrated work, On The animals were properly anaesthetised, Origin of Species, which went on sale to and to express his surprise at objections booksellers on 22 November 1859. Given to such procedures: the central position of evolution and Romanes’ work on jellyfish had “It is absolutely unintelligible to me on natural selection in our understanding of a particularly clear evolutionary what ground the objection [to these biology, Darwin has a strong claim to be underpinning, as the analogies of the experiments] is made in this country.” the greatest of all biologists. Both Science jellyfish “muscular bell” with rhythmic and Nature published a range of features muscular systems in higher animals were The physiologists were very appreciative celebrating the anniversary of his birth clear. French explores the influence of of Darwin’s support. The first informal early this year, as did most newspapers. Romanes’ ideas upon the theories of meeting to discuss the founding of The cardiac conduction and rhythmicity then Much or the above will be known to Physiological Society, which took place being developed by WH Gaskell and many, or even all, readers. Some will also at Burdon Sanderson’s London home others. Darwinian influence is clear in the know that Darwin was a friend of the on the 31 March, 1876, was attended opening words of Gaskell’s celebrated founders of The Physiological Society, both by Darwin’s most prominent August 1883 paper, written little more and was elected as one of the first two scientific disciple, Thomas Huxley, and than a year after Darwin’s death: Honorary Members of The Society at also by Darwin’s third son Francis Darwin The Society’s third ever, and first formal “The views held by physiologists upon (1848–1925), then 28 years old. Francis (with a rule book) meeting. But Darwin’s many points connected with the Darwin, who assisted his father in much connections with The Society, and its innervation of the heart have been too of his research and ultimately became early Members, also encompassed many exclusively based upon observations a distinguished botanist and FRS, had detailed scientific exchanges. Following upon a single type of heart, viz. that of been working for his MD thesis in one of his early voyages, Darwin spent most the frog. It is therefore very advisable the London physiological laboratories. of his later career in his home at Down wherever possible to control these The meeting reconvened a few weeks House in Kent, maintaining a voluminous experiments by a corresponding later on 26 April, with Huxley chairing, to scientific correspondence and many elaborate series of observations upon ratify a rule book, including the rule that: scientific collaborations. The Darwin the hearts of a large number of other “Men of distinction in Science who correspondence project [1] tells us: animal types, and in this way to trace the have contributed to the advancement evolution of function in the same way as of Physiology are eligible for election as “Darwin exchanged letters with around the morphologist tracks that of structure.” 2000 individuals over his lifetime...He Honorary Members.” rarely attended meetings of scientific Perhaps Darwin’s greatest gift to The third preliminary meeting, held at societies, typically spent only two weeks physiologists was his unequivocal Romanes’ house, identified those “who a year in London, and only occasionally support for animal experiments as a shall be invited to become Members and received fellow scientists into his home. way of making advances in physiology attend the next meeting of The Society.” And yet he was arguably one of the best and medicine. The founding of The This group included both Thomas Huxley informed scientists of the day...” Physiological Society was a direct and Francis Darwin. The meeting also result of the late Victorian vivisection resolved to elect Charles Darwin as one Darwin’s long-term correspondents controversy, and the 1875 Royal included John Burdon Sanderson, of the first two Honorary Members (the Commission on vivisection. Those other was William Sharpey). Professor of Physiology at UCL and unaware of this history can find a latterly in Oxford, with whom Darwin summary of it on The Physiological Darwin wrote to Romanes on 29 May: “I discussed electrical signals in plants. Society website under “About: History”. was very much gratified by the wholly Michael Foster, the founder of the The Commission’s report became the unexpected honour of being elected Cambridge Physiological Laboratory, basis for the Cruelty to Animals Act of one of the Honorary Members [of The discussed curare with Darwin. A younger 1876, which established the system Society].This mark of sympathy has physiologist who corresponded with and of licences for experiments on living pleased me to a very high degree”. visited Darwin frequently was George animals. Darwin gave evidence in person Romanes (1848–1894), who studied the to the Royal Commission, stating his Darwin remained unswerving in his locomotory system (muscles and their belief in the need for animal work: support for animal experimentation until control) of Medusae (jellyfish). the end of his life. A celebrated letter he “I am fully convinced that physiology can published in The Times in 1881, runs: Darwin’s interactions with Sanderson, progress only by the aid of experiments Romanes, Foster and others amongst on living animals. I cannot think of “I know that physiology cannot the founding Members of The any one step which has been made in possibly progress except by means of Physiological Society, are well described physiology without that aid. No doubt experiments on living animals, and in a fascinating 1970 article by RD many surmises with regard to the I feel the deepest conviction that he French, “Darwin and the physiologists, circulation of the blood could be formed who retards the progress of physiology or the medusa and modern cardiology”. from the position of the valves in the commits a crime against mankind.”

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This letter can be read at the Times online archive [2], along with accompanying material and a commentary by former Physiological Society President and ex-Head of the MRC Colin Blakemore.

Darwin’s death in 1882 was a cause of great sorrow among the scientific men Biosciences community of the day, including at The Physiological unites to launch Society Society. Sharpey–Schafer in his history of The Physiological Society records the of Biology feeling of the Members present at the Mark Downs. The two leading UK biology following meeting: organisations – the Institute of Biology welcoming non-professional as “With respect to [Charles Darwin’s (IoB) and the Biosciences Federation well as professional biologists of all death] the draft of a resolution occurs in (BSF) – have united to form the Society ages and backgrounds. All current the Minute Book, written in pencil and of Biology. members of the IoB and BSF will nearly illegible, which probably expresses automatically be transferred to the an attempt then and there to voice the An Interim Council has been operating feelings of The Society... The draft reads for almost a year to develop the Society and individuals will retain as follows: ‘The effect produced in the structure and objectives of the Society, their postnominals, updated to reflect scientific world by the death of Charles and the Council of the Society of Society of Biology membership. Darwin is so universal and profound that Biology met for the first time on the 7th The interests of members will be any formal motion in reference to it by October. Dame Nancy Rothwell is the represented by two Colleges: the this little Society would appear to be first President, William Marshall, the College of Individual Members and the superfluous, if not impertinent.’” Honorary Treasurer, and David Coates, College of Organisational Members. the Honorary Secretary. Each College will elect a Chair who will The same meeting in 1882 elected serve on the Society’s Council. several new Honorary Members The creation of a single organisation including, perhaps a little symbolically, to represent the biological sciences During the first year, the Society of Thomas Huxley. Huxley and Francis has been fully supported by members Biology will pay particular attention Darwin attended several Society to consulting with its members and Meetings, and physiology in the late of both the IoB and BSF, who voted overwhelmingly in favour of the move partner organisations about their 19th and early 20th century was also expectations for the Society, and will indebted to Darwin’s fifth son Horace at Annual General Meetings held in identify how it can deliver further (1851–1928), founder and long-time early 2009. The Society’s diverse services for members. It will develop director of the Cambridge Scientific membership includes students, Instrument Company. Sharpey–Schafer’s practising scientists and interested regional bases across England, Wales, history makes clear that the approbation non-professionals – as individuals, or Scotland and Northern Ireland and and involvement of men of the standing through learned societies and other seek new partnerships in the UK and of Charles Darwin and of Thomas Huxley organisations. overseas. The Society will further was of the greatest importance to the develop its role as a key advisor to fledgling Society. Commenting on the launch of the government, funders and policy Society, Nancy Rothwell said, ‘It is makers on all relevant activities – a Perhaps an appropriate place to close wonderful that the Society of Biology role previously held by the integrating this brief summary of Darwin’s ties to has been established in the year that organisations. An area of focus will be The Society is an editorial in Science we are celebrating Charles Darwin education at all levels, lifelong learning, earlier this year by past President of the and all that he achieved and changed. continuing professional development Royal Society Robert (Baron) May and The Society will be fully inclusive and and chartered status. Paul Harvey, who drew attention to: aims to engage with all, including the “...Dobzhansky’s memorable injunction most prestigious academics, school Sir Paul Nurse, Nobel laureate and that nothing in biology makes sense except teachers, policy makers, funders and President of the Rockefeller University, in the light of evolution.” the committed (and often expert) said: ‘The establishment of the Society non-professional biologists.’ of Biology is a significant event for This insight can be seen running through UK biosciences. The field of biology papers in The Physiological Society’s The Society’s first Chief Executive, Mark encompasses a wide diversity of journals from the 1870s to the present Downs, has been in post since the 1st disciplines. The creation of a single day. It will doubtless continue to do so November. Dr Downs was previously organisation will enable stronger, more long into the future. the Director of Science and Enterprise effective representation, and will serve at RNID, and has significant experience all with an interest in the future of the French RD (1970). J Hist Biol 3, 253–274. biosciences.’ Gaskell WH (1883). J Physiol 4, 43–230 in science policy in the government, May RM & Harvey PH (2009). Science 323, 687. private and academic sectors. We welcome suggestions for Sharpey-Schafer E (1927). J Physiol 64 (Suppl), 1–76. The Society’s mission is to create a the Society of Biology. For more [1] www.darwinproject.ac.uk/content/ single unified voice for UK Biology information see the website: section/17/112 that will build on and develop the www.societyofbiology.org [2] http://timesonline.typepad.com/ strengths of the IoB and BSF. The aim timesarchive/2009/02/video-ben-macin.html is for the Society to be fully inclusive in Emma Southern

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people really believe this or do they Why I hate epigenetics keep repeating it to get grant money?’ A call to ban the Or is it more sinister? When I was transgenerational methylation young, an ambitious young person in some professions would be advised to and acetylation of DNA ‘Join a Masonic Lodge’. Being a fan of OK, a retrospective change in the conspiracy theories I sometimes wonder environment of my grandfather isn’t if ‘Do you work on epigenetics?’ is not a going to alter some of my unsavoury 21st century equivalent of the statement behavioural traits including my nascent ‘Are you on the square?’. sociopathy and a tendency for alcohol Epigenetics is politically neither fish nor Devious epigenetiscists will squander abuse, but there was a time when I could fowl. How can anybody with classically your grant money. Have you ever plead genetic determinism to avoid defined political sensibilities work on examined the causes of one financial responsibility for my actions and more epigenetics. It’s confusing – it has neither paradox? Why in a period when importantly avoid a vicious beating at a ‘Fascistic’ nor a ‘Marxist’ philosophical British government spending on the hands of a certain Mrs Cormorant. lineage. Take a simple mathematical science climbed to £6.5 billion per By the late 1980’s genetic determinism model of phenotypic development annum, normal respectable scientists was increasingly criticised, the left in in a certain Keith Cormorant based complained that they were starved of particular believed it to be an attempt to on two simple equations. Note to grant money? Where has the extra cash provide a semantic Trojan Horse for the non-mathematicians; X = units of gone? Devious epigenetiscists have introduction of fascist beliefs (if you want genetic determination and Y = units of siphoned off the cash and they will lie to test this idea just mention ‘Genetics environmental determination. and steal to get money to fund their and IQ’ or the book ‘The Bell Curve’ in a habit! Flash new next generation Deep, sociology department, I guarantee you Genetically determined Cormorant Really Deep and Even Deeper Sequencing will be ‘a fascist bastard’). The right did phenotype: X+Y = Cormorant and other bizarre-looking methylation counter with some validity ‘How else do phenotype 1, therefore X = Fascist. detection technologies all cost a fortune. you explain the physical appearance and Some little boxes with a few flashing Environmentally deranged mental state of ***?’ (Insert lights cost over a million quid. That is determined Cormorant the name of your favourite politician expensive enough but no epigenetiscist phenotype: Y+X= Cormorant here). ‘But why can’t life be fairer?’ will ever mention the new building phenotype 2, therefore Y = Marxist. ‘Why can’t society effectively modify you will have to erect to house the 24 a persons phenotype’ suggested the In each equation either X or Y = 0 bioinformaticians that you might need to left who in the 1970’s and 80’s seemed depending on your political and employ to analyse the terabytes of data to be more comfortable with the philosophical world view. It’s simple. generated by analysing the epi-genome intellectual absolutism of environmental But what happens when you examine of just one mouse. determinism to explain both group and epigenetic determination. individual differences. Epigenetics is discriminatory and Epigenetically determined Cormorant causes anxiety to those with unsavoury I never did get what the fuss was about phenotype: X+Y+ parental (epigenetic ancestors. Thanks to the internet I politically speaking. influences+X+Y) + grandparental now realise that I have a number of But eventually every scientist finds (epigenetic influences +X+Y) unsavoury ancestors. They were violent, an individual ‘bête noir’, an individual +zzzzzzzzzzzzzz (sorry I dozed off and alcoholic, born in the workhouse and scientific discipline that they take an fell face down onto the keyboard). some enjoyed extended residences in irrational dislike to. What is this upstart Millbank prison. There is, however, one of a science that needs to be trussed up It’s over complicated and a bit politically thing that fills me with a deep sense and thrown down a well, this insidious ambivalent. Who can you blame when of ancestral shame – my great-great purveyor of methylation and acetylation things go wrong? Contemporary society grandfather was a member of the House to the vulnerable regions of my genome? or your genome – neither has a value of Lords. As a result of this I now realise of 0. Try it, try having a classical nature that my lack of empathy, a tendency to I have a pathological hatred of versus nurture debate with all this consume alcohol, and psychologically epigenetics. politically ambivalent post-modernist, questionable obsessions with conspiracy I have a number of ill-defined transgenerational, methylation rubbish theories and animal cruelty are the result philosophical objections to epigenetics thrown in. of one thing, my unsavoury epigenetic – it muddies the waters, it’s a form of markers. ‘Is it the environment?’, ‘Well not quite!’ transgenerational genomic hijacking and it makes me pay for the sins of ‘What about genetic inheritance’ ‘Well Due to the extreme anxiety caused by my ancestors. Epigenetics is culturally not that either’ epigenetics, I have reluctantly decided revisionist - when I did A level Biology, to conceal the fact that I am, in fact, Lamarck had been consigned to the Epigenetic research is fashionable. genetically related to my own daughter. dustbin of history for 100 years, now he’s Once in a while an attack of collective I lied and explained to her that she back, the demented gloating little troll obsessive compulsive disorder sweeps was adopted – ‘such nice people, your ‘I was right, the environment does mess over a scientific discipline. In my field parents’. I said, ‘lovely ancestors – when with your genome’. every single paper, grant application you choose your ancestors you need to and talk I have been to in the last be a bit cautious and business like, caveat But I do have several specific pathological 5 years keeps repeating the same phrase vendor’ I explained. objections to Lamarck’s gleeful little ‘we believe this to be an epigenetic revenge. effect’. The question I ask is ‘Do these Keith Cormorant

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Musings from the my holiday and my family’s cries of and the long-term strategy is to “Michael, you are not supposed to build on existing success rather than Chief Executive’s desk be working” were worth it after all. to re-invent the wheel. No single area of The Society’s activities is It’s been a busy few months The joint meeting with the BPS seen as having the greatest future since our Main Meeting in July. was also my first experience of priority as they are all important, Looking back at Dublin, I was participating in a podcast. I am and all have the potential to usually the last person to adopt really impressed by the quality of grow, but there is an overall new technology and am perversely the science presented and by the goal developing to increase our proud not to own a ‘pod’. I come number of top-flight international activity in clinical and translational from a generation where you speakers who participated. I think science. One way to encourage listen to music on speakers where that money spent on bringing this development is by increased size really does matter. I tend to the best speakers to our meeting interactions with organisations think that people who walk or is money well spent and that we such as the Academy of Medical cycle around listening to minute should do more of it. It was also Sciences and by encouraging headphones are significantly more good to see a number of Members clinically qualified/aligned scientists likely to be involved in accidents and of the Editorial Boards of both our to join The Society and to put therefore give them a wide berth. journals at the meeting. Their active themselves forward for membership However, I have to report that support and involvement in Society of Council. Another important goal making a podcast was remarkably meetings is always very welcome. is to increase our media presence to painless and I felt quite proud of the The only downside I remember was clearly demonstrate the importance the expense of being in Dublin, result – although I still don’t plan to buy an iPod ! of physiology to the public and to exacerbated by a poor exchange key decision makers in government rate. Paying over £5 for a pint of Continuing on the topic of new and educational establishments. Guinness is hard to swallow (sorry!). technologies and reformed luddites, Consequently we plan to take steps Early September saw the I am also very impressed with the to increase the media coverage joint meeting with the BPS on number of Members who are now The Society gets for papers in its “Integrative Pharmacology and fans of The Society on Facebook. two journals and for all of its other Physiology – translating ‘omics’ into Having avoided social networking activities. functional and clinical applications” sites myself for some years (I only An important organisational held at King’s College London joined Facebook this year to sneak objective that has received (see a report on the meeting on a look at my children’s photos) I significant support in these p. 9). This was the first time I have have to say that The Society page long-term planning discussions organised a meeting from ‘soup is excellent. It looks like a great is to purchase or rent office to nuts’, as the expression goes, way for Members to comment on accommodation in London that can and I found it an exhausting but what The Society is doing and to house all Society staff, combining very satisfying experience. Much make suggestions on what else of the penultimate work on the it could do to support them. We our London and Cambridge meeting had to be done remotely, don’t get enough feedback from offices. Establishing a ‘home’ for as I was away on my summer our Members and I encourage you The Society could have the added holidays during August. The to sign up and use this site to tell us benefits of providing a meeting world-wide availability of electronic what is on your mind. room large enough for Council communications is perhaps a meetings, small scientific meetings Another activity that has been and workshops with additional mixed blessing when one is on occupying me recently has been The holiday, but I was very happy with facilities for Members, such as Society’s long-term business plan hot-desks with computers. Would the result. Over 180 physiologists (see Physiology News 75). Following you like to see The Society housed and pharmacologists attended the discussions at Council, a number in a single building with a range of the meeting and 83 abstracts of proposals for how The Society facilities available for our Members, were presented for poster or oral could develop over the next 5 years and what would these facilities communication. The meeting have been prepared and have now be? The timescale for this move is certainly demonstrated that in been discussed and reviewed with likely to be 3–4 years and we will be vivo physiology and pharmacology Society staff, to get their views and surveying Members’ views on this is alive and well in the UK. The input. standard of the talks presented was in the future. However, your input is high and I was able to use my role as The plan that is developing contains always welcome so please do email ‘holder of the roving microphone’ to a large number of interesting and me about this proposal at any time. sneak in my own questions to nearly novel proposals. The Society is all the speakers. The disruption to already successful and influential Mike Collis

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postdoctoral training in exercise and thermoregulation with Dr Mary Ann Baker at the University of California Riverside. I then moved to of Australia and Professorial Research the Department of Obstetrics and New Editors Fellow at the University of Melbourne. Gynecology, UCLA (1992) and began Nisha Charkoudian He read Physiology and Psychology at my career in fetal physiology. There I the University of Sydney and received developed my interests in cardio-renal his PhD in Physiology at Sydney in development and the development of 1986. Following postdoctoral work in dipsogenesis thirst. I joined Dr Peter Germany, in 1992 he joined Faculty at Nathanielsz at Cornell University in the University of Sydney. He took up his 1996, where the impact of antenatal current appointment in Melbourne in steroid therapy on the developing 2002. cardiovascular system became an additional focus. Today I study the His abiding research interest is signal contribution of maternal nutrition, both The focus of Dr Charkoudian’s research processing in nervous systems, with in excess and insufficiency, on fetal is on sympathetic neural control of the experimental expertise in function brain and cardio-renal development and circulation in humans, as related to and connectivity of afferent visual their contribution to cardiovascular and the regulation of blood pressure and pathways. His research programs have renal disease susceptibility in later life. body temperature in healthy humans addressed how signals from receptors I am currently an Associate Professor as well as in obesity, hypertension and in the eye are fed into separate brain and the Scientific Director of the Center type 2 diabetes. She is interested in pathways which underlie the red–green for Pregnancy and Newborn Research, interactions between humoral control and blue–yellow axes of colour vision. affiliated with the Division of Maternal of blood volume (e.g. angiotensin II) Because defects in colour vision are an Fetal Medicine in the Department of and sympathetic neural control early sign of blinding diseases such as Obstetrics and Gynecology, University of arterial pressure, as evaluated glaucoma, basic experiments such as of Texas Health Science Center at San using direct microneurographic these can improve our understanding of Antonio. I am an author of 80 journal measurements of sympathetic neural visual dysfunction, as well as revealing articles, 120 conference abstracts and 4 activity. Another focus of the laboratory the basis of the colour sensations which book chapters. is the evaluation of mechanisms of so enrich our perception of the world. thermoregulatory control of the skin circulation in type 2 diabetes mellitus. Results of these scientific experiments Harunori Ohmori Ongoing studies include evaluations have been published in over 60 papers of the role of endogenous angiotensin in scientific journals and several in altering sympathetic nerve activity, textbook chapters. More information the roles of systemic inflammation can be found at the National Vision in altering control of sympathetic Research Institute nerve activity and blood pressure, (www.vco.org.au/nvri). and the importance of inter-individual variability in sympathetic neural Mark Nijland and haemodynamic variables in the Professor and a chairman of the control of blood pressure in humans. Department of Physiology and Dr Charkoudian is Associate Professor Neurobiology, Faculty of Medicine, of Physiology in the Department of Kyoto University. Physiology & Biomedical Engineering, Our laboratory activities are focused Mayo Clinic College of Medicine. She on the understanding of mechanisms also has a joint academic appointment of hearing on the basis of synapse and in the Department of Anesthesiology, neuronal activities. Our first work on and her research involves collaborations I was born in Manzini, Swaziland hearing was made on isolated hair cells, with investigators in the Departments and grew up in Swaziland and South focusing on membrane excitability, of Anesthesiology, Neurology and Africa. I am married with two children the mechano-electrical transduction, Medicine (Division of Endocrinology). (son 12, daughter 17). I obtained a and the release of neurotransmitters. BSc in Zoology and Physiology at the Paul R Martin After a series of works on hair cells, University of the Witwatersrand in our interests moved to neural circuits, Johannesburg. I continued at Wits particularly of the auditory system, School of Medicine where I obtained in order to understand how sound a BSc Hons in Animal Physiology and information is processed in the PhD (1988) in Physiology entitled brainstem auditory nuclei; a mechanism ‘The Mechanism and Function of of sound source localization in whole Selective Brain Cooling in sheep (Ovis animals, and the cellular mechanisms aries)’, supervised by Drs Duncan using brainstem slice preparations on and Graham Mitchell. After a brief how the precise coincidence detection Paul Martin is Director of Research at time away from science working in is achieved in auditory nuclei. the National Vision Research Institute the computing industry, I undertook

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From the laboratory, we have a cat and is currently funded by the National at home, which came to our place, Health and Medical Research Council along with other cats, after the big of Australia, the Australian Research earthquake in Kobe 1995; he is now a Council and the Diabetes Australia big cat and alone, but disciplines us in Research Trust. The general aim of the house and urges us to wake up in Dr Watt’s research is to study how the morning and go to bed at night. fats are broken down in muscle, liver My wife and I like bicycling around the and adipose tissue and how these city and enjoy photography, especially processes can be made more efficient. of the cherry blossom in spring and the Italy, teaching medical students and He also studies how defects in fatty coloured leaves in autumn in scenes those on exercise and sports sciences acid metabolism contribute to the with old temples and shrines. courses. He is also Director of the Sport development of insulin resistance. Medicine School at Padova. This research has direct implications Bente Klarlund Pedersen for people with obesity and type 2 Carlo studied medicine at the University diabetes, who store more fat and are of Pavia, graduating in 1972. After a less able to burn fat. Dr Watt’s other few years at the University of Lund in job is listed as a ‘sports tragic’, where Sweden, working in the laboratory of he donates an enormous amount of Professor P Edman, he was appointed time dragging his children to Australian Associate Professor of Physiology back Rules football matches. at Pavia in 1983.

His main physiological interest is the Ulf Ziemann Bente Pedersen is Professor of biophysics and physiology of skeletal Integrative Medicine and a specialist and cardiac muscle, in particular the in infectious diseases and internal relationship between myofibrillar medicine. She is the Director of the proteins, and their isoforms, and Danish National Research Foundation’s contractile performance, and the Centre of Inflammation and Metabolism regulation of myofibrillar protein (CIM): 6 senior researchers, 9 postdocs, expression under certain functional 15 PhD students, a technical staff of 8 conditions. He is funded by European persons and 12 pre-graduate students Union grants, Telethon (an Italian or research assistants. charity supporting research in muscle Current position: Associate Professor pathophysiology) and the Italian Space of Neurology and vice-director of BKP has identified skeletal muscle as Agency (ASI). the Department of Neurology, and an endocrine organ that produces Head of the Motor Cortex Research and releases signal peptides, which Matthew Watt Group, Goethe-University of Frankfurt, are named ‘myokines’. Given that Germany. Special clinical interests: skeletal muscle is the largest organ multiple sclerosis, motoneurone in the human body, the discovery diseases, clinical neurophysiology. of contracting muscle as a cytokine- Special research expertise: Systems producing organ opens up a whole physiology of human motor cortex. new paradigm: Skeletal muscle is an Excitability, connectivity, plasticity and endocrine organ, which, by contraction, learning processes in human motor stimulates the production and release cortex. Pharmacological modulation of of cytokines, which can influence motor cortex excitability and plasticity. metabolism and modify cytokine Matthew Watt completed postdoctoral Methodological expertise: Transcranial production in tissues and organs. work at the University of Guelph and magnetic and electrical stimulation, McMaster University, Canada. His EEG, MEG, MRI, fMRI, diffusion tensor BKP has had many positions of trust. work during this time focussed on imaging, EMG, neuropharmacology. She has served as President for the the factors that break down fat in Prizes: Fellow of the German National International Society of Exercise muscle, particularly during exercise. Academic Foundation, NIH Fellowship and Immunology, President for the Upon returning to Australia, Dr Watt Award for Research Excellence, NIH Danish Society of Infectious Medicine, worked at RMIT University and in the Merit Award, Richard-Jung-Prize 2006 Chairman for the research council Protein Chemistry and Metabolism of the German Society of Clinical at Rigshospitalet, coordinator of the laboratory at St Vincent’s Institute. Neurophysiology and Functional Muscle Research Cluster at the Faculty He worked extensively on identifying Neuroimaging. Editorships: Associate of Health Sciences, University of how defective fatty acid metabolism Editor of Clinical Neurophysiology, Copenhagen and as President for the interacts with inflammatory processes Deputy Editor of Brain Stimulation. National Council for Public Health in and deciphering ways to circumvent Memberships: The Physiological Society, Denmark. these inter-related health issues. Dr Society for Neuroscience, Movement Watt currently heads the Biology of Disorder Society, German Society of Carlo Reggiani Lipid Metabolism group at Monash Clinical Neurophysiology and Functional Carlo Reggiani is Professor of University, Victoria, Australia. He has Neuroimaging, German Society of Physiology at the University of Padova, published 72 papers/review articles Neurology.

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Snakes and ladders Snakey Sue (available for children’s parties). Upon packing up we were As someone who frequently uses the informed that the programme was ‘ping’ of a new email to distract me intended to be the replacement for from paper writing, I saw that I had Tomorrows World, but some highly received one from The Physiological paid media types had decided to Society’s Human Physiology Special update the name to ‘Bang goes the Interest group. Immediately, I Theory’. To our relief the title is opened it, anticipating an interesting misleading in that its premise is not but transient diversion. However, on to disprove conventional scientific this occasion I saw that the beloved thought – a generally healthy beeb (BBC) were on the lookout for attitude, but not when it is me on someone to help with a programme the TV! investigating the autonomic responses one associates with fear. I guess the fact I was referred to as As the paper I was happy to be Dr Dave on camera is symbolic of distracted from was the final draft the ’level’ it is pitched at – horizon (hopefully) of an investigation of the it isn’t. Further filming at the UCL relationship between autonomic by a fellow Physoc Member, James Institute of Cognitive Neuroscience responses, the fear of falling and ‘Jim’ Clark, whose assistance on the was to follow so perhaps the hard locomotor behaviour, I was a little day was absolutely invaluable. Upon science shall come from there. taken aback. our arrival ‘on set’ an extremely Anyway, I’m sure my friends, warm welcome was received, mainly colleagues and family will all find Upon further reading and the due to relief in the fact that we it hilarious. Let’s just see if the realisation that perhaps I should had actually found the place. Then old adage – any publicity is good step up to the plate and offer my following protracted reciprocal publicity – holds true. As for a career assistance I had a fearful experience wonderment of each others’ in the media – let’s just say my agent of my own. After all, I had the equipment and the rather strange (Physoc) is still waiting by the phone, kit (with a little help from my but beautiful grotto (think half cave, so I am sure Lord Winston can sleep friends), the flexitime (the term had half man-made gothic cathedral, not soundly in his bed. Apparently, I ended) and the knowledge (well a large man in red suit and white have a face for radio. hypothetically at least). So after a beard) was complete – scientists and bit of soul searching and discussion crew got to work. The experience was great fun, with colleagues, all of whom said it although scientifically a little would be great for the career and Having overcome light, water, frustrating. As to whether for my real with a little trepidation I offered my power, camera, angry non-informed career it is a snake or a ladder, only ‘services’, although I felt sure that tour guide, presenter and snake time will tell. the beeb would surely choose not to issues, filming began. Now call me use them. naive but I was expecting a filming Dr Dave process where instructions would Dr Dave and the snake story was Strangely, they said ‘thanks very be barked, clapper boards would broadcast on BBC 1 on Monday 24th much’. Following an email exchange, be, well clapped, and we did our August 2009 as part of the Bang goes finally a few sketchy details emerged: science bit in between. In reality the Theory series. they wanted to measure autonomic everything was a little freestyle, with (www.bbc.co.uk/bang) parameters aka the typical flight-or- the distinction between Jim, and the flight responses from a presenter actual director, who disappointingly David Andrew Green getting up close and personal with a came without a cravat or foldable King’s College London snake in a cave – at which point I too chair, becoming increasingly blurred. started to experience significant fear Attempts at scientific rigour and any responses. However, it was too late real explanation took a back seat, Physiology News now to back out. After much to-ing although we did get the job done If you have enjoyed this issue of and fro-ing, the location was set as a and some representative responses Physiology News please don’t throw it cave in Painshill Park, Surrey – they were acquired – an extremely large away. Put it in your coffee room so that were going for the Indiana Jones snake around your neck is quite a others may see it too. snake pit look, ummmm…. potent physiological stimulus! We are always looking for interesting So having checked and then double- I took my turn in front of the camera features, meeting reports, news checked the equipment, bright and – although in a purely non-speaking items and photographs. Contact The early I drove off in the uni van (an role and well away from the beautiful Physiological Society Publications Aussie ute without apparent gear yellow Burmese python called Rah, Office ([email protected]) with box or brakes) to be met on location yes really, provided by the lovely your suggestions.

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XIth Little Brain Big some debates lasting 40–45 min. Society Noticeboard Consequently, the meeting schedule Brain Meeting was designed to cope with this need Scientific Meetings 2009 for flexibility. Furthermore, LBBB For a comprehensive overview visit the presenters are encouraged to discuss website work in progress or research that they wish to develop into independent An introductory workshop on human projects. It is this combination of and clinical physiological techniques debate and of sharing new data that King’s College London and Imperial makes the LBBB an innovative forum College London (10–11 Dec) in which to shape future research View of Kenosha port from the Cellular & Integrative Neuroscience conference hotel. ideas and goals. Themed Meeting This years organisers, David Linden, Cardiff University, UK (14–16 Dec) The city of Kenosha, situated on Simon Gibbons and G. Richard the shores of Lake Michigan, was Locke (Mayo Clinic, USA), did a The Journal of Physiology the setting for the XIth Little Brain tremendous job in managing this Big Brain (LBBB) meeting, held on Symposia 2010 event and ensuring that it adhered to the 24–26th August 2009. This Regulation of neuronal cell volume: the traditions of previous meetings. bi-annual event exists as a forum from activation to inhibition to Simon Brookes (Adelaide, Australia) for early-stage researchers working degeneration and Helen Raybould (UC Davis, USA) in neurogastroenterology to come 26 April, Experimental Biology 2010, moderated the sessions brilliantly, together with their peers and discuss Anaheim, CA, USA allowing all the participants generous their work. Now in its 20th year, time to air their views. Neural processes of orientation and the LBBB is a prestigious meeting navigation and competition for places via Sponsorship for these events is juried applications was fierce. This 2 July at Physiology 2010, Manchester, essential to ensure their survival UK. is no surprise when you consider and this meeting received superb that the alumni of previous LBBBs funding. The Physiological Society For full details of this and other include many of our current senior provided sponsorship directly to Symposia visit http://jp.physoc.org researchers, and from whose labs the meeting and also provided a many of this year’s attendees were generous travel grant for myself. 2010 chosen. In addition, the European Society Metabolism & Endocrinology Themed of Neurogastroenterology and However, the meeting itself was Meeting Motility, the German Society held in a relaxed and convivial Astrazeneca, Macclesfield, UK, 24–26 of Neurogastroenterology and atmosphere, with ample opportunity March Motility and the American for exchanging ideas and germinating Neurogastroenterology and Motility Physiology 2010 – University of collaborative links. Participants were Society, as well as the American Manchester (30 June to 2 July) limited to 38 delegates, ensuring National Institutes of Health were Abstract submission and registration that each person could present their also pivotal in supporting this opens on 1 March 2010 work and receive maximum feedback meeting. The next LBBB is already through protracted post-presentation Cardiac & Respiratory Physiology being planned for Australia in 2011, discussions. The emphasis placed Themed Meeting where the next set of early-stage on these discussions is the hallmark University of Birmingham, 1–3 researchers will have their chance to of the LBBB and differentiates it September benefit from attending this excellent from other scientific meetings. Each event. 15 min presentation is allocated an Non-Society meetings equivalent discussion period, but Christopher Keating Life Science Careers Conference 2009 this was frequently exceeded, with University of Sheffield, UK 25 November, King’s College London

BPS Winter Meeting 2009 Hilton Metropole, Brighton, UK, 15–17 December Joint Annual Meeting of the Scandinavian and German Physiological Societies 27 March to 30 March 2010

Travel Grants Conference delegates. www.physoc.org/grants

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Coming in from the when he had to pull out because as they skiied – these were usually of work commitments, Ben and eaten in the same mouthful though, cold: physiology at the James opened the place on their as the pieces had been warmed up team to general competition and in transit, then fused together in Cheltenham Festival eventually chose Ed Coats, a clinician the freezing temperatures. Despite When TV presenter Ben Fogle and from Bristol, to join the expedition. these high-energy snacks and the Olympic Champion James Cracknell Although lacking the Hollywood hot meal they ate at the end of rowed across the Atlantic in 2005, the credentials, Ed had valuable medical each day, the three-man team lost a pair had little time to prepare for the expertise which ultimately proved total of 7½ stone in weight during physical and mental challenges of the more useful during their month-long the 25 days of the race. This is not race; as a result they had to overcome trek across the snow and ice. surprising when you consider that dehydration, sleep deprivation and a lack of appropriate clothing to complete the journey in just over 49 days. When they decided to team up again to race to the South Pole earlier this year, they had learned the importance of understanding how the body responds to extreme Ben Fogle and James exercise in a hostile environment and Cracknell. Photo by Alexis were determined to prepare as fully Girardet. as possible, with the help of clinicians, survival experts and physiologists. In the run-up to the race itself, Mike Stroud, a clinician with an The two spoke about their physiologists measured an array interest in physiology, calculated that preparations for the Race to the Pole of cardiovascular and respiratory he had used over 11 500 calories and their experiences in Antarctica variables in each of the team on one single day when he trekked at this year’s Cheltenham Science members as they walked on across Antarctica with Ranulph Festival. They were joined at the treadmills in the cold lab or Fiennes in 1991. festival by Dan Martin, an expert submerged themselves in icy The talk was a springboard for a in altitude medicine from UCL, and water; core temperatures were also broad-ranging discussion of ‘extreme the session was chaired by Bristol monitored, as well as peripheral physiology’. The general audience University academic and TV presenter temperatures on vulnerable areas raised interesting questions on the Alice Roberts. The Physiological like the feet and fingers. Ben Fogle difference between frostbite and Society was one of the main sponsors admitted that one of his greatest frostnip, the problems of remaining for the event, which drew a capacity fears during the race had been hydrated when all available water crowd on a cool and rainy Sunday getting frostbite on his nose! The is frozen, and the psychological evening last June. extreme cold in Antarctica was one of the main challenges of the challenges of maintaining motivation Both Ben and James spoke very 495 mile trek. The South Pole is a when even your iPod has given up. informally and openly about their high windswept plateau at an altitude The energetic discussions arising adventures. Their conversation was of ~2900 meters, so the team also from these questions illustrated illustrated one minute with breath- had to cope with the potential effects clearly how an understanding of taking photographs of spectacular of hypoxia and, as the sun never set physiology is integral to the science Antarctic snowscapes and the during the period of the race, the of survival. next with close-up shots of frozen dangers of sunburn and dehydration. Compared to Scott and Amundsen eyelashes or gruesome blisters. Dan Martin spoke of his own almost a century ago, Fogle, Cracknell They described their first exposure experiences on Everest, and explained and Coats had all the benefits of to Antarctic weather conditions the unique challenges of exercising modern science and technology to thousands of miles from the South in such an inhospitable environment. support them in their endeavour. The Pole in a cold chamber in Wiltshire, He also emphasised that the success other five teams also made use of their novice experiences of cross- or failure of an expedition can rest the same scientific and technological country skiing and their training on such basic essentials as a pair of advances though, and in an echo of sessions pulling tyres along the dry socks! The energy demands of that epic race to the South Pole in beach to simulate the weight of the routinely skiing for up to 16 hours of 1911, the British team had to take pulks, or sleds, they would pull across every day was also a challenge. Ben, second place to their Norwegian the snow. They also discussed their James and Ed followed the advice opponents. Science may march on, search for a third team member to of Scandinavian survival experts but sometimes history repeats itself join them in the Race to the Pole. and kept their energy levels up by anyway! Originally, the actor Jonny Lee Miller eating bite-sized chunks of salami, was due to complete the team, but chocolate, cheese and jelly babies Sarah Hall

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Young Physiologists’ Prizes for the oral and poster multiple viewpoints but I found that presentation were kindly sponsored each lecture was slightly too short Symposium, Dublin by The Physiological Society and to go into any real detail. On the Sigma. plus side, it did mean that I could On July 7th 2009, a group of early- go to lectures on subjects I know career scientists from University The winners were: nothing about, yet understand and College Dublin hosted a Young Physiologists’ Symposium (YPS) in Adrianna Teriakidis enjoy them. I attended a lecture the new School of Medicine and University of Edinburgh (oral) on antimatter expecting to be Medical Science. baffled; however, by the end I found Susan Chalmers I was able to pass on information The symposium, entitled University of Strathclyde (oral) to my family about how many ‘Muscle physiology: function and Michael Lawless billion years it would actually dysfunction’, drew delegates from University of Birmingham (poster) take to manufacture sufficient all over the world and provided a anti-hydrogen to make the bomb Eric Lucking good start to Physiology 2009, The in Dan Brown’s Angels and Demons University College Dublin (poster) Society’s Main Meeting. a reality. It was also a great way to Sonia Cadima explore cutting-edge science – I The day started with an opening Smooth Muscle Research Centre, found out that organic solar panels note from Paul McLoughlin, Head Dundalk Institute of Technology are being printed in old colour film of Physiology at UCD, and was (poster) followed by six oral presentations factories, and that a portable roll-up TV screen is being developed to sell on the theme of ‘skeletal muscle I would like to thank all the on the market. in health and disease’. Following a organising committee for their short break, the theme of skeletal hard work and energy. In addition, I was one of several undergraduates muscle continued, mostly focusing thanks to The Physiological Society, who received a bursary to attend on human physiology. The afternoon especially Chrissy for all her help and the Festival, and it was great to have session began with four oral support. We are also very grateful a big group of like-minded people presentations from young, energetic to the judges for taking time out of my own age to hang out with, eat smooth muscle researchers. Each of their busy schedule to help us with dinner with and attend lectures the oral sessions prompted a lot of YPS. Without all of these efforts with. Accommodation was en-suite questions and discussions amongst the Young Physiologist Symposium, and there was a kitchen available if the audience. Dublin 2009, would not have been necessary. Also, internet access was such a great success. The morning and afternoon themes provided in public areas of campus. were neatly divided by lunch and a This event would not have been All in all, the Science Festival was poster session, at which 30 scientists possible without generous support a great experience for finding out presented their work on skeletal and from The Physiological Society and about the cutting edge of other smooth muscle physiology. our commercial sponsors: Sarstead, WPI, Sigma, VWR and Merck. topics and for meeting fellow The day was brought to a conclusion science enthusiasts. by Noel McHale, from the Smooth Karen Griffin Muscle Research Centre, Dundalk Freya Hopper Institute of Technology. Professor McHale’s talk entitled ‘Follow the The British Science Undergraduate Student, University beat’ left the audience inspired. This Festival, Guildford, of Oxford enjoyable presentation was a perfect conclusion to a great day for the September 2009 young physiologists. Undergraduate Prize This year I attended the British The YPS social event was held on the Science Festival with a student for Physiology 2009 same evening, in a stylish restaurant bursary sponsored by The In the previous issue of Physiology in Dublin city centre. Physiological Society. Although News, we included a list of the Festival seemed to be primarily Undergraduate Prize winners. We The standard of presentations, both aimed at younger children, it had so are now pleased to add one other oral and posters, was outstanding. many events that there was always winner to this list: The oral judging panel of: Stuart something interesting going on. Bund, James Jones, Marguerite Clyne Laura Corns from University of and Christine Shortt; and the poster The majority of events were groups Leeds judging panel: Cormac Taylor, John of short 30–45 min lectures with a Baugh and Deirdre Edge, had a tough discussion session afterwards. This Congratulations to Laura. job deciding the winners. had the advantage of presenting

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New Council Members Occasionally being allowed to get my What is your current job(s) title? hands dirty in the lab. Reader in Respiratory Physiology What is the worst thing about your Summarise your career to date current position? Stephen I received my PhD in Physiology from The seemingly endless amount of London University in 1994, and following Bolsover administration and the increasingly a Wellcome Trust Fellowship at the difficult financial climate for higher University of Wisconsin-Madison, USA. I education in general and science in return to the UK in 1997, where I joined particular. Imperial College London to set up the What is the biggest issue facing young Academic Unit of Sleep and Ventilation physiologists today? with my clinical colleagues at the Royal Job security. Obtaining major Brompton Hospital. My research focuses What is your current job(s) title? independent grant income in a fiercely on the interactions between respiratory I am professor of Cell Physiology at competitive arena. control and sleep mechanisms that lead University College London, and Director to breathing-related sleep disorders, Why did you stand for Council? of Studies for the Biomedical Sciences specifically the cardiovascular and Generally, I wanted to make a degrees (Physiology, Pharmacology, cognitive consequences in vulnerable contribution to The Society that has Neuroscience and Biomedical Sciences) populations, such as older people and supported my activity over many years. those with a failing heart. The group is Summarise your career to date Specifically I was nominated to stand for supported by the Wellcome Trust, British I did my undergraduate degree at the post of Treasurer. Cambridge and stayed there to do a PhD Heart Foundation and National Health with Robert Meech. I then went to the Which areas of Council or Society Research Institute. US for a postdoc with Joel Brown firstly activity would you most like to get What is the best thing about your at Stony Brook and then St Louis. I then involved in? current position? returned to England with a lectureship at The role of Treasurer cuts across most The ability to carry out translational UCL and have remained here ever since. areas of Society activity, so there is research, studying physiological I have worked on various aspects of cell scope for wide involvement. One of my mechanisms – then taking our findings biology and neuroscience, concentrating overall goals is to help ensure that we and applying them to clinical practice in on axon outgrowth and calcium imaging. direct as much income as is financially patient populations. prudent towards supporting these Which areas of Council or Society activity activities and The Society’s charitable What is the worst thing about your would you most like to get involved in? objectives. current position? I am most interested in the educational The stress of ‘fitting it all in’. aspects of The Society’s work What is your favourite(s) saying or quotation (and who said it)? What is the biggest issue facing young ‘If politics is the art of the possible, physiologists today? research is surely the art of the soluble. Making the transition from postdoc to Rod Both are immensely practical-minded established lecturer post; there is so affairs.’ Taken from Sir Peter Medawar’s much emphasis on producing results. Dimaline celebrated book of essays ‘The Art Why did you stand for Council? of the Soluble’. More irreverently, I Like many people I have never quite like ‘Nothing shocks me. I’m a forgotten my first Physiological Society scientist.’(Harrison Ford, as Indiana presentation; 7 slides –10 min and Jones). finishing before the red traffic light. The What is the most important thing life What is your current job(s) title? Society has a splendid history that we has taught you? Professor of Physiology. Head of treasure, but we also need to think about Department of Physiology, University of I firmly believe that you have to strike the future. I think The Society has an Liverpool a sensible work–life balance. Science is important part to play in disseminating important, but so are family and friends. our research using new technology. As Summarise your career to date Which other scientist (living or dead) travel becomes more difficult we must BSc Hons and PhD in Physiology at the would you like to have been, and why? also maintain the quality of our national University of Liverpool, specializing in meetings. gastrointestinal physiology. Trained in Not sure that I can specify a single The link between physiological research peptide chemistry at the Center for Ulcer scientist, but for someone working in my and clinical medicine is another Research & Education, Los Angeles with J area, the early 20th century would have feature that I want to bring to the Walsh and J Reeve, 1979–81. Appointed been an exciting time as the work of Council. I will encourage The Society to Lecturer in physiology, University of Bayliss & Starling and others ushered in promote translational research through Liverpool 1979. Visiting Associate the era of modern endocrinology. collaboration with other medical groups. Research Professor at UCLA 1989, Sharing expertise is likely to benefit all. applying molecular biological techniques to physiology, with J Walsh and V Wu. Mary Which areas of Council or Society Current research is focused on molecular Morrell activity would you most like to get regulation of gastrointestinal epithelial involved in? function. I am a member of the Meetings What is the best thing about your Committee, and I think this is important current position? because it is the place where Members Interactions with colleagues, locally, interact, and where new Members nationally and internationally. become engaged with The Society.

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What is your favourite(s) saying or in exercise and the physiology of ultra- Or to use a cricketing tale: quotation (and who said it)? distance running, amongst other things. ‘You’ll bowl a lot worse than that I think my students would say that my In 1979, I transfered to MRC External and take a hatful of wickets, lad’. A favourite saying is: ‘It’s all about the Staff at the University of Nottingham, back-handed compliment I once received data’, or ‘Clean up the kitchen’! as Mervyn’s Research Officer. We from an ex-pro wicket keeper as we My quotation is a poem that was found worked for 7 years in the Department of walked off a cricket field together, him in the purse of a dear friend of mine after Physiology and Pharmacology, studying having kept to me as I exhausted myself, she died of cancer: human muscle function in relation to to no avail, on a very hot day. If you think you are beaten you are ageing, disuse and fatigue. Here I did a I suppose I mean that you have to learn If you think you dare not, you don’t part-time PhD. In 1986 Mervyn took the to accept the lucky breaks and the hard If you’d like to win, but think you can’t foundation Chair in Sport and Exercise knocks and hope that it evens out in the It’s almost certain you won’t Sciences at the University of Birmingham end. Not an easy thing to remember If you think you’ll lose, you’ve lost and I and the group moved there too. In For out of the world we find when ranting about referees comments Success begins with a fellow’s will 1991 I was appointed a Lecturer in the on a grant application which clearly It’s all in the state of mind School of Sport and Exercise Sciences at wasn’t fully read by the referee! If you think you’re outclassed, you are Birmingham, then Senior Lecturer and Which other scientist (living or dead) You’ve got to think high to rise now Reader. I now run a research group would you like to have been, and why? You’ve got to be sure of yourself which works on human cardiovascular I admire all polymaths, such as Erasmus Before you can even win a prize and respiratory control in health and Life’s battles don’t always go Darwin (grandfather of Charles) from disease states. I became a Member of To the stronger or the faster man my adoptive city of Lichfield. He was a But sooner or later the man who wins The Physiological Society in 1991 and am founding member of the Lunar Society Is the one who thinks he can. Anon now an Editor of Experimental Physiology. which met regularly in the Birmingham What is the most important thing life has What is the best thing about your area from 1765 until it closed in 1813, taught you? current position? a few years after Darwin’s death in Education is a passport to freedom Right now the best thing is reading 1802. The name came from their the outstanding contributions that Which other scientist (living or dead) meeting during the full moon, the light have been submitted to Experimental would you like to have been, and why? from which aided their lengthy and Physiology for inclusion in a special Dorothy Hodgkin – she had an amazing one suspects slightly wobbly, journey Winter Olympics edition of the journal life, from the time of the double helix to home, after the sumptuous dinner to be published in early 2010 that Stuart the structure of pencillin, vitamin B12 and fine wines which ended the day’s Egginton and I have put together. and insulin, which she combined with proceedings. Darwin and his fellow her family, travel and politics. What is the worst thing about your ‘lunaticks’ made many important current position? scientific discoveries and had great Attending too many university meetings influence in Britain, yet they seemed to enjoy a work–life balance that is Michael and receiving too many emails which begin ‘with apologies for cross posting’. impossible today. White What is the biggest issue facing young physiologists today? New Affiliate Members Having their work, their worth and so their future employability judged purely on the basis of the £ or $ signs associated with it. Federico Why did you stand for Council? What is your current job(s) title? Formenti It seemed like a good idea at the time! I Reader in Exercise Physiology. have always been proud to be a Member Summarise your career to date of The Society and I want to see it I read Physiology at The University of flourish. I also want to give something Leeds from 1974–77. On reflection, back to a Society which has been good I probably played too much cricket to me. and spent too little time in the library. However, I did gain an interest in exercise Which areas of Council or Society activity Current Job and environmental physiology (I didn’t would you most like to get involved in? Postdoctoral Research Scientist realise until much later that this was I’d better say Society Meetings since that Career sketch not a traditional element of undergrad is the committee that I am on! I obtained a degree in Exercise and physiology courses so I got lucky). After What is your favourite(s) saying or Sport Science in my hometown Verona, graduation I joined the then ~3 million quotation (and who said it)? Italy, before studying towards my PhD unemployed, signed on the dole and ‘We haven’t got the money so we’ve got in human locomotion biomechanics at sponged off my parents in West Cumbria to think!’ (Ernest Rutherford) Manchester Metropolitan University in whilst job hunting. After a 3 month stint the UK. My doctoral research involved ‘If I had all the money I’ve spent on drink, as a fuse grinder in a local factory I got physiological and biomechanical I’d spend it on – drink’ (Sir Henry at an interview for a job that to this day I studies useful to understand the Rawlinson End, Viv (Bonzo Dog Doo-Dah still don’t remember applying for, at the origins and describe the development band) Stanshall’s great comic creation. MRC Environmental Physiology Unit in of cross-country skiing and ice skating London. There I worked with CT Mervyn What is the most important thing life has as means of locomotion. In 2006, I Davies and Martin Thompson (now taught you? joined the Human respiratory and Sydney University) on thermoregulation There are no prizes for hard work! exercise physiology group in Oxford as

Physiology News | No. 77 | Winter 2009 | www.physoc.org NEW AFFILIATE AND STAFF MEMBERS PN 53

a postdoctoral visiting research fellow; Scientist at Syntaxin Ltd. About a over 25 years ago. I have two grown-up here I also started my second (and year or so ago I entered the world of sons, who both live and work in London. last) doctorate. I currently investigate cardiac physiology at the Bristol Heart I studied for a degree in Sociology and the role of a protein called hypoxia Institute, where I am investigating History as a mature student at Anglia inducible factor in the regulation of cardioprotection and ischaemia– Ruskin University. cardiopulmonary physiology and reperfusion injury. I was employed by Cambridge metabolism in humans. Best thing about my current job: University Press for 15 years. Initially Best thing about my current job:? The variety of being involved working in the dictionary department, The fantastic team of my supervisors and simultaneously in both clinical and basic I then cleared permissions to use colleagues, inspiring stimulating ideas. science projects. materials in publications for learners Worst thing? Worst thing: of English as a foreign language. This …it finishes in August 2010. The challenge of juggling both clinical involved requesting permission for The biggest issue facing young and basic science projects. texts as diverse as newspaper articles, instructions to use baby buggies, lyrics physiologists today is: The biggest issue facing young Perhaps carrying on working in a for songs, and menus from fish and chip physiologists today is: shops! research environment, with research jobs Not losing heart and maintaining offered decreasing in number. momentum in their research in the face I’m currently taking two courses in I stood for Council because: of ever-increasing competition. creative writing, so watch out for my best-selling novel! I would like to contribute to the activities I stood for Council because: of The Physiological Society, and to As a ‘newbie’ to physiology research, I represent my peers at the Council want to meet as many people as possible Angela meetings. from The Society and contribute to the Areas of Council/Society activity you activities of The Physiological Society. Breslin hope to get involved in: Areas of Council/Society activity I hope I would like to be involved in the to get involved in: activities related to the Scientific I have taken part in a number of public Meetings. engagement events and schools science Favourite saying/quotation: events which I have enjoyed a lot, so I am ‘Love one another as I have loved you’ keen to get involved in Society activities I am the new Education Administrator (Jesus). in this area. I am also interested in at The Physiological Society. I studied Most important thing life has taught you: science writing, and will be contributing Genetics and Biochemistry at the Speeking-a Engleesh more good than the to Physiology News on a regular basis, and University of Wales, Aberystwyth and other Italians. sitting on the Editorial Board. previously worked as a science teacher If you weren’t you, which other scientist Favourite saying/quotation: at a secondary school. I look forward to would you like to have been and why? Success is the ability to go from one working with everyone at The Society. My supervisor, because he had the good failure to another with no loss of fortune to work with me! (We Italians are enthusiasm. (Winston Churchill) known for our modesty, from our Prime Most important thing life has taught you: Diana Minister down...) Keep smiling and don’t give up – Jones tomorrow is a new day. Sam If you weren’t you, which other scientist Passey would you like to have been and why? Professor Mina Bissell (renowned breast cancer researcher at UC Berkeley, California). Mina is a great character, a great scientist and an inspiration to I am returning to The Society’s women scientists worldwide, showing Publications Office in Cambridge after an that it is possible to overcome almost absence of 7 years. I joined The Society’s staff in 1991 and worked on abstracts Current Job anything to reach your goals, both in and Proceedings of The Physiological Postdoctoral Research Scientist science and in life. Society for 12 years; some Members may Career sketch New staff members remember me as the face of ‘Abstract My research career has been quite Corrections’ at Scientific Meetings (as varied so far. After completing my Diana Greenslade) during the 1990s. Biochemistry undergraduate degree Marie I left The Society in 2002 in order to at the University of Bristol I went on Allan devote more time to bringing up my two to do a PhD where I studied the Rho young children. In recent years I have GTPase family of signalling proteins and been working as a freelance proofreader the actin cytoskeleton in lymphocytes. for a variety of journals. From there I went on to research B cell differentiation at the London School I have now rejoined The Society’s of Hygiene and Tropical Medicine. I Publications Office, and will be working have also worked in industry, both with Emma Ward on Experimental at GlaxoSmithKline for a year during Originally from Suffolk, I moved to Physiology whilst Helen Leedham is on my degree and as a Postdoctoral Cell Cambridge with my husband, Frank, maternity leave.

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Ronald H Cook and television sets. Pye had been set up as a company of instrument 1914–2009 makers by father and son, WT and Ron Cook, who died on 19 July, WG Pye. During the Second World started work in the Cambridge War, they were involved in work Physiological Laboratory in 1948. for the War Department, with Ron His original appointment was as working on proximity fuses and in a Craftsman but he went on to other devices for the RAF. work as Alan Hodgkin’s Instrument Maker then Technical Officer until Ron Cook became Alan Hodgkin’s his retirement in 1987. He was a instrument maker in 1948, continuing very small man but a larger than life to work with very considerable character. This means that he will be distinction until his retirement in in Cambridge. From time to time, I remembered by many physiologists 1987. His immediate role was to would see a diminutive, but highly who spent time in the Physiological build the feedback amplifier used energetic and rather distinguished Laboratory, whether or not working in Plymouth later that year in the figure emerging from the basement in Alan’s lab. In March this year, first voltage clamp experiments on of the Physiological Laboratory. Ron agreed to be included in the squid axon. He went on, of course, I fancied that this might be the Physiological Society’s Oral History to provide the technical support and legendary Lord Adrian, whom I knew Programme so he has left a good the instrument making that formed to have an office down there. Later, record of his many activities. the infrastructure for experimental as Alan Hodgkin’s graduate student, work that laid the foundations of One of his early interests was in I came into contact with Ron on a modern electrophysiology. As well aquaria. This was a lucky coincidence daily basis. He was outstandingly as building countless amplifiers, because he was able immediately supportive to someone just at the with W Nastuk he designed and built to introduce cuttlefish (Sepia) to start of their career and it would be the first microelectrode puller. So Cambridge, where they were used hard to forget – even if I wished to – effective was this puller, compared by Alan Hodgkin and Richard Keynes the kindness and patience shown to with commercial pullers available for the ion flux measurements that someone rather naïve, inexpert and in the early years, that I had one backed up the then new ionic theory uncertain. This was at a time when built to Ron’s design when I moved of the action potential. Vintage cars it was sometimes less fashionable to Leicester. The only obvious were another particular passion. At for chief technicians to be so directly difference from Ron’s construction is the time of his death he had been helpful. in the winding of the solenoid coil – Treasurer of the Veteran Car Club of immaculately neat in his, somewhat Ron was the scion of a family that Great Britain for 41 years so it was less tidy in the Leicester model. So had set up a plastering company in fitting that at his funeral the picture far as I know, the Leicester puller Cambridge. A check of the current on the front of the Service sheet is still in use today. Ron built the company web site (www.georgecook. showed him sitting at the wheel of Perspex model designed and used co.uk) soon dispels the idea that this his 1910 Singer. He was a staunch by Hodgkin and Keynes to mimic was a mundane inheritance, though Churchman with firm views on the their measurements of unidirectional Ron’s father worked instead for the rightness of the King James Bible (and potassium fluxes in squid axon, and University of Cambridge, becoming the wrongness of other versions). this work and the model led directly Assistant Librarian, a position He moved to a neighbouring Church to the concept of an ion channel more elevated than its title might when his own Parish Church stopped as the route for ionic transfer. He suggest. Ron was educated at the using King James. An enthusiastic made the single fibre chamber used Perse School in Cambridge and he gardener, in his last months he was by Hodgkin and Horowicz in their earned considerable pocket money still tending his 1.5 acre plot with only experiments on dissected single during his boyhood, repairing clocks minimal help. He had been a keen muscle fibres; and many more for various shops that advertised cross-country skier, particularly in experimental chambers besides. their (as it turned out lesser) skills Norway, and was a competitive figure He designed and built an ingenious skater. It was a great disappointment in this craft. Rather than completing Faraday cage for Hodgkin’s later to him that the cold spell in February his undergraduate education in experiments on retina, where the this year ended before any skating Cambridge, Ron apprenticed himself experimental manipulations could be championships could be held at to the Electric Master Clock Company, conducted from outside the cage. Earith. He would certainly have whose owner, Hope Jones, soon competed, driving himself there and recognised and used Ron’s talents, His instruments, experimental back. but to an extent that led to Ron chambers and other devices feeling somewhat put upon. So Ron Ann Silver functioned in a state-of-the -art moved to Pye Ltd, a Cambridge way. But there was also a fine, if Peter Stanfield writes: company that was well known in the slightly old fashioned, aesthetic I first noticed Ron Cook when I was UK a generation ago as a maker of in what he did. Instruments were an undergraduate reading physiology radio (perhaps I should write wireless) built in home-made, but beautifully

Physiology News | No. 77 | Winter 2009 | www.physoc.org OBITUARIES PN 55 crafted metal boxes, with front decision to decline a part as an excise diminutive individual who was known panels finished in hammer-tone man in Whisky Galore, offered when as Gunner Sugdon, or Lofty to his enamel and neatly lettered. Having the Hodgkin family were on holiday in friends, and he wore shorts and a pith to make panel-mounting boxes from Barra. helmet. One morning Mr Cook arrived Lektrokit was one of my many later for work dressed in sandals, shorts disappointments in life. Perspex I remember Ron with great and shirt, all beige, and was greeted chambers had the cut edges of the affection, a very widespread feeling with ‘Look out chaps here comes plastic polished so perfectly, that among people who worked in the Gunner Sugdon’. To that comment it was near-impossible to tell which Physiological Laboratory during Ron responded by marching briskly edges had been cut and which were his long service there. Elements down the corridor, arms swinging and part of the surface of the original in his character were quirky and a broad grin on his face. He did like a sheet. unexpected – for example, the joke did Mr Cook. long-time reader of the Morning Ron also designed, set up and for Star, and the man who took pride in many years ran the aquarium in ‘never having called anyone sir in my Jeffrey T Potts the Physiological Laboratory, which life’ belied superficial expectation. 1958–2009 provided access, on condition of their In some ways, he was a little like the (Born 26th December 1958 and died 2nd humane treatment, to Sepia, Carcinus, humane, humorous, ebullient and September 2009) Maia and many other rather exotic genuinely kind character in a Dickens creatures for a place so far from the novel, who intervenes just at the I provide this remembrance of Jeff from the perspective of a mentor and sea. This aquarium also housed frogs, right minute, completely selflessly close friend and with the knowledge used for nerve and muscle research, and with a surprising lack of fuss to that his untimely death from the and terrapins used in work on retina. save the book’s eponymous hero. complications of sarcoma cut short Some of my earliest sightings were of Several scientific careers owe him for the blossoming career of someone him in his green apron – rather larger his generosity, given freely and with destined to be a leader in the field of it seemed than he was – which he wonderfully warm good humour. neurophysiology. wore when on aquarium duty. Jeff was born and raised in New His other great skill, which came from Alan Cattell, Principal Assistant in the Physiological Brunswick, Canada and remained his long-standing repairing of clocks proud of his Canadian roots – even those that others had given Laboratory, Cambridge writes: throughout his life. However, once he up on – was as a great fixer of things. My lasting memory of Mr Cook is had experienced the heat and wide If things didn’t work, the matter was of him striding up and down the open spaces of Texas he longed to put right pretty much immediately. main stairway, two or three steps return there despite his successful This may seem run of the mill, but it at a time, garbed in a green plastic sojourns at the Medical Centers of was far from being so, since you were apron that stretched to the floor. In Johns Hopkins University, Wayne able to take for granted that things one hand would invariably be a pair State University and the University of would work. Oscilloscopes were kept of vernier callipers and in the other Missouri-Columbia. in correct calibration, their amplifiers a piece of equipment or material and time bases working. Manipulators Jeff received his Bachelors of Science that he was working on or with. He did not drift. All this was no mean degree in Physical Education from would rush past saying ‘Morning old feat, as I was to discover later in other the University of New Brunswick in boy’ or calling you Rupert or some places. 1982 and a Masters of Arts degree in other name, but never your own. Exercise Science from Indiana State From time to time, Ron would turn On occasion he would be puffing University in Terre Haute, Indiana. In up to the Laboratory in his veteran on a cigar (which was at that time 1986 he entered the PhD program car. In this he looked a little as though permissible) and he would leave a in the Department of Kinesiology he was auditioning for a main part in trail of smoke as he rushed about at the University of Maryland, but The Wind in the Willows, though his his business. At one period he somewhere along the way felt that enthusiasm was far from ephemeral looked after a number of alligators he wanted more than just an applied that were being used for a research and his competence considerable, as science degree. Why he chose to seek project and unfortunately was badly always. He had perhaps been inspired to join my research program at the bitten by one of them. He was sent to this interest by the film Genevieve, age of 31 and work to obtain a PhD off to Addenbrooke’s Hospital and with the dream of driving Kay Kendall in Biomedical Sciences (Physiology) explained how he got his injury; he has always been a mystery to me, on the London to Brighton run. was surprised when no one would especially when I asked that he obtain Indeed, his car, and he more briefly, believe him. additional courses in the fundamental appeared in the film Those Magnificent sciences before joining me. However, Men in Their Flying Machines, though I In the mid-seventies there was a I could not have been more fortunate have never managed to identify him television programme called ‘It to have him join my group as he soon even after several viewings. But he ain’t half hot Mum’ about an army began to develop his own research almost fulfilled his dream, and indeed concert party based in India and then questions and address them with his he made up for Alan Hodgkin’s earlier Burma. One of the characters was a well-known enthusiasm and insights

Physiology News | No. 77 | Winter 2009 | www.physoc.org 56 PN OBITUARIES into the necessary experiments. physiologist; he had experience of Indeed, he developed a new method of working with both humans (with using our neck pressure/neck suction Peter Raven) and subsequently whole technology to examine the carotid animals in vivo (dog, cat and rat with arterial baroreflex during dynamic Jere Mitchell and Artin Shoukas). exercise from rest to maximal exercise. His particular work was published in What followed from the Southampton the American Journal of Physiology in meeting until his untimely death last 1993–1995. However, his development month was a most enjoyable 11 year of the ‘built curve’ technique of collaboration. We both visited each others laboratories five times each modelling the carotid baroreflex between 1998 and 2007 and spent function has remained a fundamental time together running experiments component of our ability to investigate and then interpreting the data and the arterial baroreflex. After receiving planning subsequent studies for the his PhD degree in 1993 he followed his following day, usually in a bar or pub. interest in developing his background The enjoyment partly came from in computational physiology by joining the science but, importantly, from Artin Shoukas in the Department the extreme fun we had doing the of Biomedical Engineering at Johns work together. Through the work we Hopkins University School of Medicine Jeff on his day of graduation with his mentor Peter Raven. developed a close friendship. On two for a post-doctoral fellowship in occasions Jeff’s visits coincided with Biomedical Engineering. His work Julian Paton writes: me moving house. Such was Jeff’s focused on the role of arterial I first ‘met’ Jeff when with Jere Mitchell generosity he insisted on helping me compliance and venous resistance he wrote a viewpoint article on a both times. This was a remarkable on the carotid baroreflex control of paper we had just published on a gesture of friendship. I could not the circulation and was published in spinal somato-sympathetic generator compete with this but was his best three papers in the American Journal of in The Journal of Physiology (Chizh et al. man at his wedding to Jessica 2 years Physiology. Subsequently, he returned 1998, J Physiol 508, 907–918). Within ago. to Texas and joined Jere H. Mitchell MD their viewpoint article, which was at UT Southwestern Medical Center entitled ‘Synchronization of somato- Jeff was a remarkable athelete who (UTSWMC) in Dallas. Using a more sympathetic outflows during exercise: ran most days for around an hour and reductionist approach, he developed role for a spinal rhythm generator’ (see completed many marathons. This was a new set of skills by which he could Potts & Mitchell, 1998, J Physiol 508, in itself incredible given the serious delve deeper into the mechanistic 646) there was a clear appreciation motor car crash he had many years questions of baroreflex control of for what we had published and how earlier. At that time, doctors were blood pressure and sympathetic it correlated well with work from not sure he would even walk again. activity during exercise pressor reflex their laboratory. These friendly tones Nevertheless, he was impressively activation. It was during this time were soon solidified when, for the fit and whenever I joined him on a (1995–2000) that he published several first time, I met Jeff in person at a run he was kind enough to jog at important papers identifying the Physiological Society meeting in half throttle; he was always such a neurotransmitters within brainstem Southampton in 1998 when he was considerate and thoughtful man. Of medullary centres that are involved in working with Michael Spyer at the course, all this running stimulated a baroreflex and exercise pressor reflex Royal Free Hospital. First impressions favourite pastime of his which was control. Also while in Dallas, he met were a highly charged, serious and drinking good beer with friends and collaborated with Julian Paton, motivated scientist who was full of self and exercising his sense of humour, which allowed him to investigate confidence and on a mission. He knew something we will all miss. these reflexes at a more cellular and what he wanted and he had a very I am delighted that we were successful molecular level. His collaboration with clear and focused agenda. Jeff was an with our latest joint publication Julian was, in my opinion, the one exceptional cardiovascular systems’ together. This was accepted in that in his eyes solidified his place in Circulation Research shortly after his neurophysiological circles and the one death and will be dedicated to his life that confirmed to him that he had as a scientist. achieved a major goal in his life. This collaboration with Julian was ongoing Our thoughts are with his lovely wife, and productive until his death. It is Jessica, their new daughter Nadia, his unfortunate that he could not have parents and his two sisters. Memories a longer time to savour his research of Jeff will of course never die: his success and enjoy his life with his wife, characteristic laugh that boomed Jessica, and newborn daughter, Nadia. across any noisy bar, his inability Jeff enjoying good times in a wine cellar to keep to time with his scientific Peter Raven with Jere with his mentors Jere Mitchell (left), presentations, and his compulsive and Mitchell and Artin Shoukas Peter Raven and Artin Shoukas (right). highly focused attitude to his science.

Physiology News | No. 77 | Winter 2009 | www.physoc.org Themed Meeting of The Physiological Society Metabolism & Endocrinology

Including a focused symposium: Towards an understanding of the enteroendocrine system

Abstract submission and Registration opens 13 January 2010 Abstract submission deadline 10 February 2010 Early Registration & YPBS deadline 24 February 2010 Travel Grant deadline 31 January 2010

AstraZeneca, Macclesfield, UK 24-26 March 2010 www.physoc.org/az2010

10 AZ.indd 1 13/10/2009 14:54:59 Schematic representation of the ecto-purinergic pHo regulatory system (Kaunitz & Akiba, p. 22).

A publication of The Physiological Society www.physoc.org