PHYSIOLOGY NEWS

winter 2008 | number 73

The HoD delusion A Christmas party trick with an intriguing physiology A new organisation for the biosciences Ion channel techniques in Shanghai

PHYSIOLOGY NEWS Editorial 3 Meetings The Society’s dog. ‘Rudolf Vascular and smooth muscle physiology Themed Meeting Magnus gave me to Charles at King’s College London Richard Siow, Margaret Brown 4 Sherrington, who gave me to Latest advances in ion channel techniques Brian Robertson 5 Henry Dale, who gave me to The Make waves for Woods Hole Colin Nichols 20 Physiological Society in October Soapbox 1942’ The HoD delusion 7 Noticeboard 9 Published quarterly by The Physiological Society Features Contributions and queries Motor neuron activation is conditional during muscle fatigue Senior Publications Executive Zachary Riley, Roger Enoka 10 Linda Rimmer Levitating arms: unravelling the mystery Martin McDonagh, The Physiological Society Publications Office Amy Parkinson 12 P O Box 502, Cambridge CB1 0AL, UK A little bit of ammonium may be good for your brain Tel: +44 (0)1223 400180 Païkan Marcaggi, Jonathan Coles 15 Fax: +44 (0)1223 246858 How many sensors in the bladder? Vladimir Zagorodnyuk, Email: [email protected] Ian Gibbins, Marcello Costa, Simon Brookes, Sarah Gregory 18 Website: http://www.physoc.org Does muscle pain increase muscle stiffness? Ingvars Birznieks, Magazine Editorial Board Alexander Burton, Vaughan Macefield 21 Editor Movement automaticity shows less activation, but more Austin Elliott connectivity: a model for brain efficiency Tao Wu, Piu Chan, 23 University of Manchester, Manchester, UK Mark Hallett Members So what does cause the breakpoint of breath-holding? Angus Brown Michael Parkes 25 University of Nottingham, Nottingham, UK Olfactory marker protein: a gift to molecular biologists, an Patricia de Winter enigma to physiologists Johannes Reisert, Frank Margolis 27 University College London, London, UK Animal Research Sarah Hall Openness and animal research: are you doing enough? Cardiff University, Cardiff, UK Corina Hadjiodysseos 30 Munir Hussain AnimalResearch.info 30 University of Bradford, Bradford, UK Unbelievable! Mark Cain 31 John Lee Reports Rotherham General Hospital, Rotherham, UK Hands on science in schools Liz Bell 32 Thelma Lovick Should it be illegal to sell genetic tests except through a University of Birmingham, Birmingham, UK doctor? Liz Bell 32 Fiona Randall Engaging young people with science Liz Bell 33 Newcastle University, Newcastle upon Tyne, UK CMP Making progress training day Fiona Randall 34 Bill Winlow Campaign for Science and Engineering Hilary Leevers 35 Chameleon Communications International, London/ Letters to the Editor 36 University of Liverpool, Liverpool, UK Affiliate News Foreign Correspondents Make the most of opportunities to travel – conference John Hanrahan attendance as a PhD student Fiona Randall 37 McGill University, Montreal, Canada Education John Morley Young Physiologists’ Symposia Chrissy Stokes 38 University of Western Sydney, NSW, Australia Experiment meets theory Lesley Caldwell 38 © 2008 The Physiological Society Undergraduate Prize for Physiology 2008 Irrum Magre 40 ISSN 1476-7996 From the archives Austin Elliott 41 The Physiological Society is registered in England as The Society’s journals a company limited by guarantee: No 323575. Experimental Physiology 42 Registered office: PO Box 11319, London WC1X 8WQ The Journal of Physiology 43 Registered Charity: No 211585. Traces of the past Printed by The Lavenham Press Ltd The history of physiology Dafydd Walters 44 Memorable technicians Ann Silver 44 International News The Society worldwide David Bennett 45 Biosciences Federation Learned societies and publishing Sue Thorn 47 Creation of a new organisation for the biosciences Richard Dyer 47 Obituaries J Murdoch Ritchie Jim Howe, David Colquhoun, Richard Keynes 49 Front cover image by Brian Robertson (from Latest advances in ion channel Book reviews 52 techniques, p. 5) PHYSIOLOGY NEWS

Action points Guidelines for contributors In this issue Grants Welcome to the Winter 2008 These guidelines are intended to For full information on Members ’ Physiology News. assist authors in writing their and Affiliates’ Travel Grants, Non- contributions and to reduce the Society Symposia Grants, As I have written before, the keys to subsequent editing process. The making a magazine worth reading Vacation Studentship Scheme, Editorial Board of Physiology News tries Departmental Seminar Scheme, seem to me to be 'interesting and to ensure that all articles are written relevant', 'variety', and 'good Centres of Excellence, Foreign in a journalistic style so that they will writing'. Looking at the first two, it is Guest Scheme and Junior have an immediate interest value for a to our good fortune that physiology Fellowships visit: wide readership and will be readable is an intrinsically 'broad church' http://www.physoc.org/grants and comprehensible to non-experts. subject, taking in everything from Scientific articles should give a good genomics to behaviour. Just to take Membership applications overview of a field rather than focus three adjacent Science News and Views Applications for Physiological entirely on the authors’ own research. articles from this issue for an Society membership are accepted example, we have a levitating-arm Format of articles party trick that illustrates interesting throughout the year; applications The main message or question posed are reviewed by the Membership principles of human motor feedback should be introduced in the first control (p. 12); ammonium in the bee Committee on a monthly basis paragraph. The background for the retina and its possible relevance to and a decision is normally made topic should then be established, mammalian brain (p. 15); and the within 15 working days of each leading up to the final conclusion. sensing of the fullness of the bladder deadline. For full details please Length of articles (p. 18). I would call that visit: This will be determined by the subject simultaneously relevant and varied. http://www.physoc.org/membership matter and agreed with the Senior Publications Executive. Variety is also why we aim to produce a wide range of feature articles. This Is your membership information Submission of articles time we have a handy guide to how correct? Authors should submit articles as a to be a Head of Department (p. 7), as Please check and update your Word document attached to an email. details at www.physoc.org, under Illustrations should be sent as separate well as features covering meetings, education, news both national and ‘My Physoc Profile’. attachments (see below) and not embedded in the text. international, policy, history and humour. Illustrations and authors’ photographs Physiology News Authors are encouraged to submit Surveys of readers of professional Deadlines diagrams, drawings, photographs or magazines often show that obituaries other artwork with their articles and a are among the most read bits. An Letters and articles and all other photograph of the author(s) should obituary can simply give you details contributions for inclusion in the accompany submissions. Illustrations of a person’s professional history and Spring 2009 issue, No. 74, should and photographs may be colour or black achievements, but better ones give reach the Publications Office and white, prints, transparencies or you that information in the context of ([email protected]) by 23 tiff/jpeg files with a minimum their life and character. The very best January 2009. Short news items resolution of 300 dpi. Electronic obituaries not only do this, but give colour figures should be saved in and letters are encouraged, and CMYK you a real sense of the person. The mode. can usually be included as late wonderful appreciations of J Murdoch copy if space permits. References Ritchie on p . 49–51 fall into this Authors are requested to keep the latter category. Suggestions for articles number of references to a minimum – Suggestions for future articles are preferably no more than two or three. Finally, this issue marks a couple of welcome. Please contact either Please cite all references in the style of anniversaries for me personally. It is the Senior Publications Executive The Journal of Physiology (see Instructions 10 years exactly since I first got or a member of the Editorial to Authors at http://jp.physoc.org). involved with Physiology News, and almost exactly 5 years since I took Board of Physiology News (see The Physiological Society permits the single over as Editor; my first editorial contents page for details). copying of individual articles for private study or research. For permission to copy or meeting 'in the chair' was December reproduce for any other purpose contact 2003. I hope we have kept you [email protected]. informed and entertained this last Physiology News online Opinions expressed in articles and letters decade, and that we can continue to Physiology News online: submitted by, or commissioned from, do so in the future. http://www.physoc.org Members, Affiliates or outside bodies are not necessarily those of The Physiological Austin Elliott Society. Editor EDITORIAL PN 3

It’s not all doom and gloom – the recession and research funding Pessimists will thrive on recent headlines screaming out about the economic downturn; I have heard comments that research funding will be slashed, but how much of this is fact and how much is scare-mongering? Firstly, a definition of ‘recession’ would not go amiss. The standard press definition is at least two quarters of zero or negative growth (gross Figure 1. UK gross domestic product (% growth), quarter on quarter, 1970–2007. domestic product, GDP). Most Dashed line: average GDP since 1955 (source: Office for National Statistics). economists think this definition flawed 1994–95 increase may have been partly BHF is not anticipating a major drop in and prefer to use additional indicators influenced by overheads on research budget next year (personal such as employment figures, real council grants and the post-2005 communication from Jeremy Pearson) incomes and production. GDP increase is likely to have been inflated and recently Harpal Kumar, Chief decreased by 0.5% in the third quarter by full economic costing (Fig.2). The Executive of CR-UK refuted media of 2008, compared with a 0.0% BBSRC was created after the 1990–92 claims that a fall in donations will leave movement the previous quarter*. So, if recession, but the MRC, in existence projects short of funds for up to 5 years, we’re not officially in recession yet, we since 1913, received above-inflation calling such statements ‘incorrect and likely will be by the time this issue goes funding increases during the last grossly misleading’. The key player is to print. recession. The huge increase in total the world’s largest medical charity, the The UK has endured three recessions in SET spending from 2000 came mainly Wellcome Trust. With a well-diversified the past four decades (Fig.1). Not all from increased funding to the Office of investment portfolio and endowment sectors of the economy are negatively Science and Technology and coincides of £15 billion, I suspect it can weather affected to the same extent; some with Lord Sainsbury’s term as Science the current storm. Smaller charities industries are traditionally ‘recession- Minister. may feel the pinch to a greater degree proof’ - for example, education, health but, although this may affect individual This leads us nicely on to funding from and the emergency services. Numbers researchers, it is unlikely to have a charities. There is good news for employed in education, health and major impact on funding as a whole. neuroscientists; in 2005 the public administration remained steady Available evidence thus suggests that aforementioned peer, then 65, during the recession of 1990–91, research funding is reasonably insulated announced his ambition to give away whereas 315 000 jobs were lost in from the vagaries of the economy. So it £1 billion to his trust, the Gatsby distribution, hotels and restaurants, a seems that it’s not all doom and Charitable Foundation, during his recession-sensitive sector*. This is gloom. lifetime. With regard to other comforting for those of us employed to charitable organisations, the CEO of the Patricia de Winter teach but is research recession-proof? One way to answer this question is to examine historical figures and use these to predict what might happen during another recession. UK non-commercial science research is funded mainly by research councils and charities. The income of both might be considered sensitive to economic conditions: simplistically, the Government relies on tax revenue and charities rely on investment income and on corporate and individual donors. Reduced income to these funders might be predicted to impact negatively upon how much they can award to research, but is there any evidence that this occurs? Government spending on science, engineering and technology (SET) has increased since 1986, though the Figure 2. UK Government spending (£ million) on selected biological research councils and the Office of Science & Technology (left axis) and total science budget (right axis) *http://www.statistics.gov.uk (source: Department for Business, Enterprise and Regulatory Reform [BERR]).

Physiology News | No. 73 | Winter 2008| www.physoc.org 4 PN KING’S COLLEGE LONDON MEETING

Vascular and smooth muscle physiology Themed Meeting at King’s College London

consequences within blood vessels which contribute to normal cardiovascular physiology and disease progression.

The Christmas season in central London will provide delegates with an opportunity to sample the festive delights of Borough Market and the South Bank, located in the immediate vicinity of the meeting venue, while transport links, restaurants and accommodation in the local area are excellent.

Abstract submissions for this meeting will be considered on all aspects of vascular and smooth muscle physiology and online registration for the meeting closes King’s College London will host the crosstalk and integration. A number of on Monday 1 December, so there is third Physiological Society Themed world leaders in this field have been still ample time to participate in this Meeting from Monday 15 to invited to speak at the meeting, exciting meeting. We warmly Wednesday 17 December at their including Shu Chien (University of welcome you to attend and look Guy’s Hospital Campus, which is California, USA), Stephanie Lehoux forward to seeing many of you in located close to the River Thames at (McGill University, Canada) and Peter December. For full details go to London Bridge (aerial image above). Davies (University of Pennsylvania, http://www.physoc.org/london2008 USA). The full invited panel of Richard Siow Cardiovascular disease is now speakers is listed on the inside back recognised as a major cause of death cover. This forum truly represents a Maggie Brown and disability in the developed world unique opportunity for the London 2008 Meeting Organisers and arises from the adverse integrated understanding of both Microvascular & Endothelial interaction of disease risk factors, physical forces and their biological Physiology SIG Convenors such as high cholesterol, with the functions of the blood vessel wall, leading to high blood pressure, stroke, angina and heart attacks. Heart disease can often be prevented by lifestyle changes which have a major effect on reducing the risk of developing symptoms. This has resulted in a rise in basic and clinical cardiovascular research over the past two decades as well as public education and interest in this field.

The biophysical interactions between blood flow through arteries and alterations in the function of vascular cells remain a central focus to better understand the mechanisms involved in vascular diseases. This field has recently gained wide interest and this meeting will feature a timely symposium on Vascular responses to mechanical stress: cellular

Physiology News | No. 73 | Winter 2008 | www.physoc.org SHANGHAI INTERNATIONAL WORKSHOP PN 5

Latest advances in ion channel techniques The Society’s International Workshop in Shanghai gave students the opportunity to appreciate state-of-the-art techniques used in a range of cell types

I have seen places that were, no doubt, physiological problems, took place in as busy and as thickly populous as the Shanghai. Our host was Mu-ming Chinese city in Shanghai, but none that Poo, Director of the Shanghai so overwhelmingly impressed me with Institute of Neuroscience (ION), one its business and populousness. In no of the most prestigious neuroscience city, West or East, have I ever had such research institutes in the world. an impression of dense, rank richly Though founded less than a decade clotted life …. it is Life itself (Aldous ago, ION already has 21 separate Huxley's diary, 1926). group leaders and will have 30 laboratories by 2010. Each of these From 12–16 September a labs regularly publishes at the very Physiological Society International highest levels in various disciplines of Workshop, Latest Advances in ion neuroscience. channels techniques applied to The major aim of the workshop was China, with a further three being to provide PhD students (and some Chinese-born investigators in the UK. early postdocs), mainly from the Far Sonja Stoelzle came from Nanion East, with an opportunity to gain an GmbH (Germany) to present on appreciation of state-of-the-art automated patch clamp devices and techniques being employed in the demonstrate their Portapatch study of ion channels in a range of device, which does away with the cell types. Students applied from all need for large and expensive over the globe, and successful conventional electrophysiology rigs. candidates came from as far afield as The speakers work on ion channels in Brazil and Australia, Israel, the a huge variety of tissues, from brain Ukraine and Romania, with some slices to bladder, from sperm to TIRF from the UK and many from China. images of synaptic vesicles in We had 16 speakers, with the neuronal processes, from European contingent originating megachannels derived from isolated from Edinburgh to Belfast to London heart muscle to animals in vivo. The via Cardiff, Manchester and Leeds. variety of lectures revealed to the Maintaining the international flavour, audience just how diverse ion we had five speakers working in channel research can be, and how different tools can be used to ask questions about the physiology or pathophysiology of a particular cell, tissue or organ. Each speaker gave a research talk introducing their particular techniques in the context of their own research problems, be this LTP in brain slices, drug discovery, or how permeation occurs in calcium release channels in the heart. Following each talk there were a couple of small group tutorials, allowing students to come up with their own questions and allowing lecturers to explain technical aspects in more detail.

Aside from all this high-powered and wide-ranging science, there were opportunities for social events, with a welcome banquet and an

Physiology News | No. 73 | Winter 2008| www.physoc.org 6 PN SHANGHAI INTERNATIONAL WORKSHOP absolutely spectacular farewell meal in a new and chic restaurant by the river in Pudong; this was followed by a river cruise, where the full splendour of Shanghai was on display. On the Bund bank, the status architecture of commerce and banking power from the 1930s, but on the ever-changing Pudong side, the breathtaking skyline comprised of some of the confident marvels of 21st century building technology –the movie set of Blade Runner now.

The cuisine in Shanghai is amazing in terms of its quality and variety, and our Chinese hosts made a considerable fuss of us, for which we are extremely grateful. There was only one unfortunate incident, in University, China) won the Wiley- which one of our number decided to Blackwell Prize for Most Innovative sample some authentic street food in Physiology, whilst three others (Shai a crowded road with some major Berlin (Tel-Aviv University, Israel), hospitals and many busy little food Balazs Horvath (University of stalls and booths. It wasn’t clear Debrecen, Hungary) and Bo-Yi Liu whether the food sellers were there (Hebei Medical University, China) to service the large hospitals or vice also received prizes. versa, until a few hours later, when the full and impressive hydraulic Whilst the workshop was a success, power of the human GI tract became there were some lessons to be Iain James (Almac, Belfast) (left), Alan evident, with the poor victim learned that could be used to Williams (Cardiff) and Ian McFadzean assuming a ‘Zen archer’ like total improve future international (King's College) enjoying the river cruise. physical union with the hotel workshops. Some of the students plumbing. felt that more hands on experience attracted to tours than talks. would have been better, though this Overall, however, the overwhelming All of the students presented can be difficult to organise in a impression was of an invaluable excellent posters, which were on faraway location. Is ‘workshop’ the opportunity to explore new avenues display each evening. The speakers right name? One disappointment in physiological research and judged and scored these posters and was the number of students who collaboration, and this is one of the questioned presenters on their work accepted places but couldn’t make aims of The Society. For my own and allied areas. Amazon gift it, and there was no chance to part, I am grateful to everyone who vouchers were awarded for the top replace them at short notice. Sadly, attended, to all the speakers for four posters. Pan-Li Zuo (Peking a few of our attendees were more doing an excellent job, to Mu-ming Poo for allowing us to use his excellent staff, students and facilities, to my co-organisers Ian McFadzean, Weifang Rong and Tian- Le Xu, to David Bennett in The Society’s London office, to Nanion and Wiley-Blackwell for sponsorship, but most of all to Yi-Xi Gu, ION’s, Scientific Exchange Programs Officer who was the not only the most marvellous organiser and fixer, but had a never ending supply of good humour and care. Thank you all. Brian Robertson The Journal of Physiology and Edinburgh College of Art

Physiology News | No. 73 | Winter 2008 | www.physoc.org SOAPBOX PN 7

The HoD delusion A Head of Department writes

It is frequently said, though I forget who started it, that managing academics is like herding cats.

My experience, as both cat owner and Head of Department (HoD), suggests that this is grossly unfair to cats; our feline friends tend not to discuss their destination at length, let alone all the ins and outs of if, why, and how they want to go there; nor do they resist change with nearly as much enthusiasm as academics.

Over several years I have realized that becoming a HoD, rather than cat- herding, is more like becoming a parent – for the following three reasons in particular. First, you take it department that is excellent in being asked of others and with your on in addition to your other jobs; teaching and research. Whatever the other responsibilities. This also has second, nothing really prepares you vision, it is vital that the objective, the advantage of providing a reality for the reality; and third, you and the strategy for achieving it, are check by keeping you in touch with undertake its major responsibilities clear to everybody in the things 'on the ground'. It is also and possible consequences with little department, that they sign up to it, important to lead and manage – if any – appropriate training. I’m and that every decision should help actively to make things happen, and sure there are other reasons too – achieve it. A decision may be large to ensure they are done efficiently, note that I have studiously avoided and far-reaching; small, if no large effectively and fairly, not just shuffle the various possible scatological opportunity presents itself; or no paper. However, this doesn’t mean parenting-HoD analogies that spring decision, which can be valid in some that you have to do everything to mind on bad days. circumstances. All choices made, yourself! There are probably not however, should help achieve the enough hours in the day for the For my own amusement I have objective in an organised and amount of paperwork that your therefore compiled the following 10 transparent manner; opaque institution is capable of throwing at commandments for anyone entering management and crisis management you, which is where the 3rd upon HoD-ship. Although I can’t say are the best possible ways, bar none, commandment comes in: that I have succeeded in obeying all to demoralise a department. of them, they seem important (at 3. Manage your time carefully. When least to me); others might like to 2. Lead from the front. University faced with a new task, you must amuse themselves by compiling their staff are under increasing pressure to decide: Is it urgent? Is it important? own. do all sorts of things: to deliver high (and to whom – as a colleague quality teaching to increasing expressed it, 'a crisis on their side 1. Know your objective(s) and act numbers of fee-paying students, to does not represent an emergency on accordingly. When I was first asked produce high quality research for the mine'). Can it be binned? Can it be to be HoD, I felt the normal mixture RAE, to deal with ever increasing delegated? Delegation is important, of fear, trepidation and received amounts of paperwork to fulfil legal not only for your sanity, but also flattery. Speaking to a friend at a and university obligations, and to because other people have, or can meeting, he told me 'only do it if you undertake many other activities, develop, expertise that means that know what you want to achieve and such as public engagement. As HoD they can do it better than you. This what needs to be done to get there'. you have the (very) dubious pleasure involves them in running the Several years on, this still seems of distributing such responsibilities department as well as developing excellent advice. The role of HoD is fairly. However, if you are asking their responsibilities and hence only worth doing if you can see what more and more of colleagues, it is career progression. The degree of needs doing (and why) to develop only fair that you should also delegation will depend on the the department. The objective may contribute to these activities yourself person, but it does not mean 'do it be the formation of a research – to an extent that is, at the very for me, exactly the way I would do institute, or a streamlined least, commensurate with what is it'. At all costs you must avoid micro-

Physiology News | No. 73 | Winter 2008| www.physoc.org 8 PN SOAPBOX management – if you don’t trust complaint seems unreasonable, try decision, even if you don’t leave somebody to do the job, you and put yourself (metaphorically) in them with a spring in their step. shouldn’t have delegated it to them. the other person’s shoes. Things Next question – if you must do frequently look very different (and 7. Do what you believe to be right something yourself, how perfect more reasonable) when seen from and fair. Take soundings and advice, does it need to be? The more you the other person’s point of view; have discussions, but in the end, take work on something, the less what may appear trivial to you may the decision that you think is right, improvement you achieve per unit not be to them. If more than one rather than being swayed or time, so you need to decide where person is involved, don’t jump to persuaded against your better the cut-off is for each job. Finally, conclusions based on only one side judgement. It’s why you are HoD, keep a diary: put in meetings, of the argument (and don’t respond and you will have to account for the deadlines, times to do things well only to your most vocal colleagues). decision and will be held responsible. before the deadline to allow for Listen to all those involved and draw It is better to be crucified (or praised) slippage, reserve time for research … your own conclusions, after taking for your own decision than to take but you know this already otherwise time to find further information if the rap for something that you you wouldn’t be heading for necessary. didn’t, in your heart of hearts, think HoDship. was right in the first place. 6. Say 'yes' when you can, but learn 4. Be accessible. As HoD it is to say 'no' when necessary. More 8. 'Care but don’t care'. Caring about important to listen to the comments, than 90% of the requests I have all members of the department is complaints, suggestions and received as HoD are entirely central to being HoD: it is your requests of your colleagues if you are reasonable when seen from the point responsibility to look after their well- to have your finger on the pulse of of view of the person making the being and career as well as ensuring the department. There are many request, and the vast majority will that they are treated fairly and have different ways to achieve this, from help the department or individual the opportunity to pursue their regular attendance in the coffee (who will normally know best what personal ambitions (within the room, to walking the corridors, to would be helpful for them) in some constraints of the department’s having an open door policy for all way. Saying yes is, therefore, objectives). However, it is also members of staff. You are working frequently the best response. important that you can switch off, with everybody in your department and don’t take this too much to towards a common goal, which can However (and it is a big however), heart, for two reasons. The first is only be achieved by inclusivity and there may be other factors, or your sanity; the second is so that you good two-way communication. repercussions that the individual is can remain as objective as possible. Personally, though, I have always not aware of, that make it necessary Hence this rather obscure aphorism. found it helpful to listen more than I to turn down a request. If this is the talk – I learn a lot more that way. case, it is important to do so and to 9. Say what you think, especially in explain why – in person if possible, meetings. Meetings are an 5. Don’t judge or act until you have not by e-mail. Most people, if given occupational hazard of academia. heard both sides of the story (if there an explanation, will accept the They flourish in universities, despite is more than one). If a request or necessity and see the reason for your almost universal dislike, and as HoD you will probably find yourself in more than most. They come in a pleasing variety, from the 10 minute one-to-one, to the all day 20 person marathon. One way to amuse yourself during the latter is to calculate the cost of the meeting in time, money (in salaries and overheads), and expertise. You can then mentally ask yourself whether the outcome of the meeting will justify the use of resources, or whether they would be better employed elsewhere. Meetings can be useful for discussion before a decision, although many factors determine their success. These include knowing what the meeting is intended to achieve; ensuring pre- circulated information is relevant and

Physiology News | No. 73 | Winter 2008 | www.physoc.org SOAPBOX / NOTICEBOARD PN 9 concise and not repeated during the phic in the greater scheme of things. Novartis Research Centre, Horsham, UK meeting (academics tend to be good Many people shy away from the role 5–6 February 2009 at assimilating information quickly); of HoD as a thankless, paperwork- Ion channels as therapeutic targets and ensuring that the discussion driven task, somewhere between the www.bps.ac.uk remains focused so that the meeting cleansing of the Augean stables and AstraZeneca, Charnwood, UK is kept as brief as possible. My own extracting gold from base metal, 5–6 March 2009 test of whether a meeting is which takes you away from research. Biochemical basis of respiratory disease worthwhile is whether anything will While this has elements of truth, www.biochemistry.org change for the better as a result. becoming HoD also offers new Justus Liebig University, Giessen, However, while you are in a meeting, perspectives and new challenges Germany say what you really think, rather than (really!), and enables you to try and 22–25 March 2009 what you think will go down well. help your colleagues, your Annual Meeting of the German You are there because your views are department and your science in new Physiological Society relevant, and I have frequently heard ways. After all, academics – at least www.uni-giessen.de/dpg2009 after a meeting 'I’m glad you said those I speak to – know to a man or Lecture Theatre, Hugh Robson that, it’s what I was thinking, but woman how their department or Building, George Square, Edinburgh didn’t like to say so because …'. If faculty really should be run, or at 5–7 April 2009 people agree with you, you have least what is wrong with the way it 7th Junior Academics Meeting 2009. achieved something; if not, at least currently is. Although there will be Molecular mechanisms in exocytosis and you have the satisfaction of knowing evenings when you want to go home endocytosis. Sponsored by The you have done your job. Finally, it is and kick the cat (or at least open a Physiological Society worth bearing in mind the adage bottle of wine and bore your partner www.cip.ed.ac.uk/meetings 'The Romans didn’t build an empire with the woes of the day), being HoD University of Leicester, Leicester, UK by having meetings'. Though it can be a rewarding and frequently 20–21 April 2009 might be wise to ignore the corollary enjoyable job. I can think of no other 3rd Focused Meeting on Cell signalling – 'they did it by killing people who job that can take you from the www.bps.ac.uk disagreed with them' – however soldering iron in the lab, through the Dresden, Germany tempting it might seem at times. pleasures of research and teaching 7–9 May 2009 bright students, to finance, strategy New drugs in cardiovascular research 10. Minimise work that doesn’t and development, all coupled to a www.bps.ac.uk contribute to the primary goals of degree of relative independence and your department. If you have been congenial colleagues. Even on a bad SECC, Glasgow, UK 28 June–1 July 2009 around universities long enough to day, there is no other job I would SEBatGlasgow2009 (SEB Annual Main be HoD you probably know that, if rather do. Meeting 2009) something appears crazy, it probably www.sebiology.org is. You therefore need to judge A (recovering) HoD whether it is worth responding to Matsue, Japan any new memo, diktat or initiative Coming soon: 10 fallacies of academic 23–26 July 2009 management; 10 things you wanted to rd you receive. While it is important to 3 International Symposium on know (or say) about university Physiology and Pharmacology of resist unreasonable or downright administration, 10 ways to wreck a Temperature Regulation crazy requests or suggestions, it is department, 10 unexpected http://www.med.shimane-u.ac.jp equally important to recognise consequences of being HoD, 10 easy University of Edinburgh, UK which battles you have some chance ways to annoy your HoD, the book of 8–10 July 2009 of winning, and are therefore worth HoD lists, and why cats make poor fighting, rather than wasting your BPS Summer Meeting academics ... www.bps.ac.uk time and that of the staff in your department. This commandment Edinburgh, UK therefore has the important sub- NOTICEBOARD 12–15 July 2009 commandment: have a large bin. The Institute of Zoology, Regent's Park, Congress of the European Association for London, UK 'dump, delegate, do' (in that order) Clinical Pharmacology and Therapeutics 4–5 December 2008 principle is important: protect the www.bps.ac.uk Maternal effects; evolution, physiology staff in your department as far as and implications for health and fitness Kyoto, Japan possible from demands that take www.biology.ed.ac.uk/winterasab2008 27 July–1 August 2009 them away from their primary roles IUPS 2009 in research and teaching. Hilton Metropole, Brighton, UK www.iups2009.com BPS Winter Meeting 2008 Manly Pacific Hotel, Manly Beach, And finally – DON’T PANIC. There are 16–18 December 2008 Sydney, Australia bigger problems in the world, it’s BPS Winter Meeting 2009 1–4 September 2009 likely to be soluble, and the outcome 15–17 December 2009 ISAN2009 is extremely unlikely to be catastro- www.bps.ac.uk www.isanweb.org

Physiology News | No. 73 | Winter 2008| www.physoc.org 10 PN FEATURES

Motor neuron activation is conditional during muscle fatigue The timing of the action potentials discharged by a motor neuron when it is recruited during a fatiguing contraction depends on the amount of synaptic input it requires to reach activation threshold. Action potentials are discharged continuously when the force at which the motor unit is activated is close to the target force of the contraction, but the discharge is much less regular when the target force is further below activation threshold of the motor unit

fatiguing contraction involves more due to the continuous synaptic input than a gradual increase in excitation. received by the neuron. The influence of the synaptic input, Discharge variability which comprises both excitation and When a motor neuron is activated by inhibition, on the variation in Zachary Riley (left) and Roger Enoka. the injection of a depolarizing membrane potential is characterized current, the response is dictated by Most fatiguing contractions involve the intrinsic properties of the neuron concurrent changes in the force and the timing of action potentials capacity of the activated muscle elicited by the input is more regular fibres and in the level of activation of than that observed during activity the motor unit pool (Enoka & evoked by synaptic input (Berg et al. Duchateau, 2008). Simplistically, 2007; Matthews, 1996). The one might expect the rate of regularity of the discharge is often increase in motor unit activity to expressed as the normalized match the rate of decrease in force variability (coefficient of variation) of capacity so that the muscle can the duration between consecutive sustain the force required for the action potentials, which are known task. Such a relation is not observed, as interspike intervals. When a series however, because the properties of of brief isometric contractions are the motor neurons and the synaptic performed around the recruitment inputs they receive change during a threshold of a motor unit, the fatiguing contraction. Consequently, interspike intervals vary across the activation of the motor unit pool target forces. In addition to the must accommodate decreases in expected change in mean interspike both the force capacity of the muscle interval with variation in target force, fibres and the output discharged by there is a change in the variability in Figure 1. Representative continuous the motor neurons. the timing of the action potentials. and intermittent discharge patterns exhibited by the same motor unit in The coefficient of variation for biceps brachii. The blue trace indicates When an individual sustains a muscle interspike interval is greatest at a the discharge of the motor unit when contraction at a submaximal target force just above the subject held a constant force that was intensity, motor units that were recruitment threshold of the motor 4.1% below the recruitment threshold activated at the start of the task unit (~30%), and then it decreases to (25.1%) of the motor unit. The motor usually exhibit a decrease in the rate a steady-state value (~10%) with unit was recruited at 72.3 s after the at which they discharge action increases in the target force (Barry et contraction began and initially (see potentials. To maintain the target al. 2007; Matthews, 1996). expanded trace) discharged action force, the nervous system responds potentials at a rate of 13 pulses per second (pps) with a coefficient of to decreases in discharge rate by A motor neuron will discharge an variation for interspike interval (ISI) of increasing the synaptic input to the action potential when its membrane 18.3%. Mean discharge rate for the motor neuron pool. Although the potential is depolarized to a value period shown in the trace was 13.2 pps increase in excitation does not that exceeds the voltage threshold and the coefficient of variation for ISI was prevent the decrease in discharge for the generation of an action 17.5%. The red trace indicates the rate, it does activate previously potential. When a motor neuron is discharge pattern exhibited by the same quiescent motor units provided the activated during a voluntary motor unit when the target force was target force is less than the upper contraction and discharges a series 9.5% below its recruitment threshold. limit of motor unit recruitment of action potentials, the generation The motor unit was recruited at 141.5 s after the start of the contraction with an (Mottram et al. 2005). The discharge of each action potential depends on initial discharge rate of 14.2 pps and a characteristics of the newly recruited the interaction between the recovery coefficient of variation for CV of 32.5%. motor units, however, indicate that of the membrane potential from the Mean discharge rate for the period the synaptic input received by the preceding action potential and the shown in the trace was 12.5 pps and the motor neuron pool during the fluctuations in membrane potential coefficient of variation for ISI was 29.6%.

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Figure 2. Scheme to explain the continuous and intermittent discharge patterns of newly recruited motor units during a fatiguing contraction. At the beginning of the fatiguing contraction (top), synaptic input causes the membrane potential (Vm) of the motor neuron to fluctuate but not to exceed its voltage threshold (Vt). As the contraction progresses, additional synaptic inputs are activated, which is indicated by the dashed lines becoming solid lines, and the membrane potential now reaches threshold and the motor neuron discharges action potentials. The synaptic inputs include both excitation (open symbols) and inhibition (filled symbols). When the target force is closer to the recruitment threshold of the motor unit (–5%), less synaptic input is required to reach threshold. When greater amounts of synaptic input are required (–10%), however, there is an increase in synaptic noise that results in more variable discharge times. as synaptic noise. At low levels of sustained an isometric contraction differences (~10% MVC force) activation, the greater variability in with the elbow flexor muscles at a between the two forces. Mean discharge times is attributed to target force that was less than the discharge rate and the variability of action potentials being generated by recruitment threshold of the motor discharge times differed for the two transient depolarizations of unit. The contraction was sustained patterns and from those recorded membrane potential associated with until the motor unit was recruited during a standardized gradual synaptic noise (Matthews, 1996). and discharged action potentials for increase in muscle force when several minutes. Two discharge recruitment threshold was assessed. Discharge during fatiguing patterns were observed: the newly contractions recruited motor unit discharged Mean discharge rate at recruitment Motor units that are recruited at the action potentials either continuously during the fatiguing contraction was onset of a fatiguing contraction or intermittently (Fig. 1). No motor greater and the coefficient of typically experience a gradual unit exhibited both patterns during variation for interspike interval was decrease in discharge rate that is the same contraction, but individual lower for the continuous pattern attributed to the combined effects of motor units could produce both compared with the intermittent motor neuron adaptation and an patterns in different contractions pattern. Mean discharge rate during increase in inhibitory synaptic input when the target force was varied. the sustained contraction declined (Mottram et al. 2005). Although the during the continuous pattern but progressive increase in net excitation Expression of the two patterns was not the intermittent pattern, and the of the motor neuron pool recruits related to the difference between coefficient of variation remained additional motor units, the discharge the target force and the recruitment greater for the intermittent pattern characteristics suggest a significant threshold of the motor unit. The during the contraction. involvement of synaptic noise in the discharge was continuous when the generation of the action potentials. target force was close to recruitment Because the intermittent discharge Riley et al. (2008) recorded the threshold (~5% of maximal voluntary of action potentials occurred when discharge of single motor units in contraction [MVC] force), whereas it there was a greater difference biceps brachii as participants was intermittent for greater between the target force and

Physiology News | No. 73 | Winter 2008| www.physoc.org 12 PN FEATURES recruitment threshold, the greater Levitating arms: unravelling the mystery variability in discharge during this condition, at least at recruitment A Christmas party trick with an intriguing history and during the fatiguing contraction, physiology might be explained by an augment- ation of synaptic noise (Fig. 2). It’s early evening after a long However, why the discharge Christmas day and the kids are variability remained elevated during fractious. What on earth do you do the intermittent pattern and even next? Time for dad to produce a why the discharge stopped for party trick. How about The several seconds during the sustained mysterious rising arms? Tell your contraction is more difficult to volunteer to stand in a doorway and explain. Presumably, the greater net then, with straight arms, press out as Martin McDonagh and Amy Parkinson. excitation required to reach hard as possible against the door threshold when the target force was frame for a full minute. At the end of Even Harvard professor Alexander further from recruitment threshold the minute the volunteer stops Forbes, a collaborator of Lord Adrian, was accompanied by an increase in pushing and, after a couple of wrote a paper on what he termed inhibitory synaptic input that seconds, the arms rise sideways like 'this rather baffling phenomenon' produced a less regular discharge the wings of a bird in flight (malt- (Forbes et al. 1926). Forbes pattern (Berg et al. 2007). fuelled grandads with dodgy hearts experimentally rebutted the claim should not try this!). Your volunteer made by the Brazilian clinician Jayme Pereira that the aftercontraction Acknowledgements has just experienced the postural took place without ‘action currents’. This work was supported by an award aftercontraction or, more poetically, Forbes noted that the to RME from the National Institute of the Kohnstamm phenomenon (Fig. 1). Neurological Disorders and Stroke in Unravelling the physiology behind electromyograph (EMG) amplitude the USA. this strange phenomenon has did not remain constant once the revealed fresh insights into the arm moved, but grew with the control of movement and posture. movement. However, if the arm was Zachary A Riley blocked in mid movement, the EMG Roger M Enoka The aftercontraction was first levelled off. Forbes took this effect Department of Integrative described by a neurologist, Alberto as evidence of a proprioceptive Physiology, University of Colorado Salmon, at the 1914 meeting of the influence on the motor drive. Boulder, CO, USA Italian Neurological Society in Florence (Salmon, 1914). The Two years earlier, Rupprecht References following year, an ‘internist’ turned Matthaei at the University of Bonn Barry BK, Pascoe MA, Jesunathadas M & Enoka psychiatrist, Oscar Felix Kohnstamm, found that aftercontractions were RM (2007). Rate coding is compressed but demonstrated the same thing at the strong in axial and proximal muscles, variability is unaltered for motor units in a Ärztlichen Verein in Frankfurt such as the deltoid, but weak or hand muscle of old adults. J Neurophysiol 97, absent in the hand and other distal 3206-3218. (Kohnstamm, 1915). Kohnstamm ran a sanatorium in the Taunus Hills Berg RW, Alaburda A & Hounsgaard J (2007). just outside the spa town of Balanced inhibition and excitation drive spike Königstein not far from Frankfurt. activity in spinal half-centers. Science 315, 390-393. The sanatorium became fashionable amongst artists with depression, Enoka RM & Duchateau J (2008). Muscle including the conductor Otto fatigue: what, why and how it influences Klemperer and the expressionist muscle function. J Physiol 586, 11-23. painter Ernst Ludwig Kirchner. Kohnstamm’s 1915 paper drew the Matthews PB (1996). Relationship of firing intervals of human motor units to the attention of several German trajectory of post-spike after- physiologists who began calling the hyperpolarization and synaptic noise. J Physiol aftercontraction the Kohnstamm 492, 597-628. phenomenon. This irritated Salmon Mottram CJ, Jakobi JM, Semmler JG & Enoka who complained bitterly that his RM (2005). Motor-unit activity differs with primacy had been poached load type during a fatiguing contraction. J (scientists don’t change much it Neurophysiol 93, 1381-1392. Figure 1. Neurologist Alberto Salmon seems!). with a patient in 1916. The patient is Riley ZA. Maerz AH, Litzey JC, Enoka RM experiencing an after contraction (2008). Motor unit recruitment in human The Salmon-Kohnstamm following a voluntary abduction of the biceps brachii during sustained voluntary phenomenon attracted much arms against fixed resistance provided by contractions. J Physiol 586, 2183-2193. research interest between the wars. the clinician.

Physiology News | No. 73 | Winter 2008 | www.physoc.org FEATURES PN 13 muscles (Matthaei,1924). I (MM) took Matthaei’s observations as a clue that postural control systems might be involved, including the vestibular apparatus. To investigate a possible vestibular influence on aftercontractions in the deltoid muscle we strapped our subjects on their backs to a rotating board, which could be fixed at any inclination. At each inclination we suspended the subject’s arms from slings. These tricky but enjoyable (at Figure 2. Recording the aftercontraction. The weight of the arm is balanced by a least for the experimenter) counter lever with an adjustable weight. This removes the variation of gravitational experiments revealed a linear load with arm position. A range of experimental loads are added via a pulley wheel so relationship between the body that the loading is constant throughout the movement range. EMG signals are inclination and the amplitude of the recorded from the Deltoid muscle and shoulder rotation angle is recorded by an electrogoniometer. aftercontraction EMG. This clear result was pleasing but not decisive, procedures we used only one arm. increased with muscle shortening as the gravitational load on the arms The gravitational load on the muscle and decreased with muscle also varies with body inclination. increases as the limb moves towards lengthening( Adamson & McDonagh, Could load be a more important the horizontal, so we used a counter 2004) .This is very reminiscent of signal than vestibular input in driving lever to nullify this effect (Fig. 2) Sherrington’s shortening and the phenomenon? We decided to (Parkinson & McDonagh, 2006). In lengthening reactions and also to the go back to where Forbes had left off later experiments we added the release of muscle cramps by and to ask the questions : What is experimental loads via a pulley wheel stretching. Perhaps they share a the proprioceptive influence? How so that muscle loading remained the common mechanism? does it work? And which receptors same at each joint angle. (Parkinson are involved? & McDonagh, unpublished). The Next, we asked: Does joint angle results of these experiments are directly modulate the EMG, or is the In the next experiments we varied illustrated in Fig. 3. We found that source some other factor which is the load on the arm whilst holding the strength of the aftercontraction varying with angle, such as muscle the vestibular signal constant. The depends on both load and joint spindle length? In our more recent subject sat on a chair with the head angle. Earlier experiments revealed experiments we have tried to supported and to simplify the that the size of the response separate these two variables. The subject performs the 60s pre- contraction (see beginning of article) at a variety of joint angles. Activation of gamma, as well as alpha, motorneurones during the 60s precontraction will cause the sensory region of the muscle spindle to be tightened by gamma action. This tightening should result in a similar spindle output at a range of initial joint angles. If the spindle signal modulates the aftercontraction EMG, then the EMG will have a closer relationship to the presumed spindle length than to the absolute joint angle. This is exactly what we found (Fig. 4; McDonagh & Parkinson, unpublished); the tight relationship of emg amplitude to joint angle seen Figure 3. After contraction EMG amplitude through the range of movement at a in Fig. 3 broke down. A future step is range of loadings. Loading are fractions of the total load of a free arm unbalanced by to test the spindle hypothesis by a counter lever. At 0 load the arm is exactly balanced by the counter lever at all direct microelectrode recording angles. EMG amplitude is expressed as a percentage of the EMG during the standard from the spindle afferents in sensory voluntary precontraction. Angle in degrees between arm and trunk. Data from 10 nerves during aftercontractions. subjects.

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as the aftercontraction, it produces more force than needed to maintain arm position against gravity, so the arm moves. Once the arm starts to move the motor drive is increased by two positive proprioceptive influences, muscle shortening and muscle load.

Most of our motor acts are carried out unconsciously. The after- contraction fMRI vividly illustrates that even the most simple of motor acts involves large areas of the cerebral cortex. Furthermore, the proprioceptive mechanisms involved in aftercontractions almost certainly underlie the everyday control of limb orientation in a gravitational field. These positive force feedback, and Figure 4 . Effect of different starting angles on aftercontraction EMG. The isometric negative length feedback, precontraction was performed at 40, 50, 60 and 70 deg and the aftercontraction mechanisms are fruitful areas for ensued. The EMG was then sampled over the angular range. Loading was 0.25 ( see future research in movement legend fig 2) under all conditions. EMGg amplitude is expressed as a percentage of neuroscience. In conclusion, the the EMG during the standard voluntary precontraction. Angle in degrees between aftercontraction is an intriguing arm and trunk. Data from 13 subjects. phenomenon in itself, but its study To summarise so far: the during aftercontractions. We found can also make a valuable aftercontraction is driven by the (Parkinson & McDonagh, contribution to our general nervous system. It is not an intra- unpublished) that the motor cortices understanding of motor control. Not muscular contracture. Loading and are indeed involved in the bad for a party trick. muscle shortening strengthen it and phenomenon, as is the anterior Martin McDonagh forced lengthening weakens it. The cingulate cortex (ACC), an area of proposed sensory receptors are brain which has been implicated in Amy Parkinson Golgi tendon organ load receptors error processing. In voluntary School of Sport and Exercise and muscle spindle length movement, predicted sensory Sciences, University of Birmingham, receptors.However, to fit with the outcome and actual sensory Birmingham, UK data this would require positive force outcome match. In the after- References feedback from the tendon organs contraction movement there is no Adamson G & McDonagh M (2004). Human and negative length feedback from motor command and so no involuntary postural aftercontractions are the spindles, the exact opposite of predicted sensory outcome to match strongly modulated by limb position. Eur J Appl what is produced by the known the actual one. Perhaps the ACC is Physiol 92, 343–351. spinal circuits. This suggests control processing this error signal. Forbes A, Baird PC & Hopkins AM (1926). The from supraspinal centres capable of involuntary contraction following isometric more complex processing. Which It is now clear that the contraction of skeletal muscle in man. Am J areas of the CNS could be generating aftercontraction has both Physiol 78, 81–103. the motor drive? proprioceptive and central Kohnstamm O (1915). Demonstration einer components – so how does the katatoneartigen erscheinung beim gesunden Over the years, the brain stem, basal complete response come about? Our (Katatonuersuch). Neurol Centrbl 34, 290–291. ganglia, cerebellum and motor current hypothesis is as follows. Matthaei R (1924). Nachbewegungen beim cortex have all had their advocates, During the 60s voluntary isometric Menschen (Untersuchungen uber das sog who have based their guesses on pre-contraction, the system Kohnstammsche Phanomen). Pflugers Arch f.d argument and weak circumstantial controlling the arm adapts to a ges Physiol 202, 88–111. evidence. Some have regarded it as a strong opposing force. It changes its Parkinson A & McDonagh M (2006). Evidence purely spinal phenomenon with no stored value of motor drive for this for positive force feedback during involuntary involvement of higher centres. position. Once the pre-contraction aftercontractions. Exp Brain Res 171, 516–523. Recently we took a direct approach ceases, this adaptation is still by taking fMR images of the brain present. When this drive is released, Salmon A (1914). Nuove osservazioni sui movimenti automatici che si compiono dopo gli sorzi muscolari e del loro valore in Visit http://www.metacafe.com/watch/323026/make_your_arms_levitate/ to watch neuropatologia. Atti della Accademia Medico - a video of arm levitation. Fisica Fiorentina, 78–91.

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A little bit of ammonium may be good for your brain Although specific ammonium-transporting proteins are well known in bacteria and plants, only recently has molecular and functional evidence begun to accumulate for ammonium transporters in animals. We describe how an ammonium transporter on the glial cells of bee retina plays an essential role in energy metabolism, and suggest an update of an old idea of a neuron-astrocyte flux of ammonium at synapses in mammalian brain

Ammonium transporters are widespread It is convenient to use the word + 'ammonium' to include NH4 (the Figure 1 (left). Ammonium entry into a 'ammonium' of chemists), NH3 cell. Entry of NH3 produces a large ('ammonia') and the mixture of the alkalinisation. Entry of a similar amount two that spontaneously forms in + of NH4 produces a much smaller water. At physiological pHs the acidification. equilibrium mixture contains about + 98% NH4 and 2% NH3 (see Marcaggi A B

& Coles, 2001). NH3 can diffuse through lipid membranes (although not nearly as well as oxygen does). As shown by measuring intracellular pH, if you add NH4Cl outside a cell,

NH3 entering the cell tends to alkalinize the cytoplasm because D about 98% of the NH3 combines with H+ (Fig. 1). In practice, some C + ammonium goes in as NH4 , not NH3. A small fraction (about 2%) of this + entering NH4 dissociates to form + NH3 and some H ions: the entering + F flux of NH4 would have to be more than about 50 times that of NH3 to produce a net acid shift. In most cells E there is an initial alkalinisation + caused by NH3 entry, then NH4 entry produces a slow secondary acidification, but in some cells there is a primary acid shift, indicating that they take up overwhelmingly the Figure 2. A, A section through a drone retina. Each rosette is composed of six, large, NH + form1. The NH + ion is about 4 4 identical photoreceptors, 450 μm long, which receive light passing through one + the same size as a K ion and the corneal facette. Each rosette is surrounded by about 35 glial cells. There are no blood conservative suggestion was that vessels or chemical synapses (micrograph by PM Orkand). B, Application of + + NH4 was just leaking in via K ammonium (green rectangles) acidifies an isolated bundle of glial cells, and this - + channels or transporters. However, acidification is blocked when the concentration of Cl is reduced. This suggests NH4 - proteins of the Rh family (notorious Cl- cotransport (from Marcaggi et al [1999]. Eur J Neurosci 11, 167–177). C, An for the immune reactions of Rh(-) electron micrograph showing part of two glial cells, packed with glycogen granules, foetuses to the blood of a Rh(+) and part of a photoreceptor containing many mitochondria (from A Perrelet). D, PO in a bee retinal slice measured with an O microelectrode. DAB, present mother) which are expressed not 2 2 throughout this recording, reduces supply of fuel from glial glycogen so consumption only in erythrocytes but also in + of O2 (QO2) falls and PO2 rises. Application of alanine restores consumption. E, [NH4 ] kidney, liver, testes and parts of the + brain, have homology with the Amt in extracellular clefts. In normal Ringer solution, [NH4 ] was hardly detected in the - family of ammonium transporters, dark or during light stimulation of the photoreceptors ("with Cl "). When glial uptake - - + was reduced by removing Cl ("0 Cl ") a much greater [NH4 ] signal was measured. 1 It is easy to get the textbook alkaline F, Scheme of metabolic exchange in drone retina. Methylaminoisobutyrate is thought response: you simply use a damaged cell with to reduce alanine uptake (red dot), and pyruvate bypasses the alanine flux (red an unphysiologically low intracellular pH. arrow). (Figs. D, E, F adapted from Coles et al. 2008) .

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+ - These results suggest a NH4 -Cl cotransporter which may be molecularly related to K+-Cl- cotransporters, but which is different from ammonium transporters of the Amt/Rh superfamily. The bee genome includes three Amt/Rh genes, thus making a minimum possible total of four ammonium transporters in this species.

+ - NH4 -Cl cotransport is central to energy metabolism in bee retina A long series of papers have shown that, in drone retina, glucose is taken up exclusively by the glial cells, where it is converted to pyruvate then alanine. Tsacopoulos et al. (1994) proposed that the alanine is transferred to the photoreceptor neurons where it is deaminated to provide pyruvate for the numerous mitochondria (Fig. 2C), and that ammonium is returned to the glia, to support sustained production of alanine from glucose or glycogen. Two experimental tools not available to the earlier workers have recently been used to test and refine this Figure 3. The glutamate/glutamine shuttle at a vertebrate glutamatergic synapse model (Coles et al. 2008). First, it showing the ammonium flux suggested by Benjamin & Quastel (1975), and the was not known whether these accumulation of ammonium together with glutamate in the synaptic vesicles neurons can actually use alanine as a suggested by Marcaggi (2006). fuel. Normally, in a retinal slice, the huge stocks of glycogen in the glia + - found in apparently all organisms up A NH4 -selective cation-Cl co- provide a supply of fuel to the to and including invertebrates transporter on glial cells of the bee neurons that lasts for many hours. 2 (Huang & Peng, 2005). retina This supply can be reduced by DAB , The drone (male) honeybee has a an inhibitor of glycogen There is general agreement that Amt phosphorylase, as can be seen by a and Rh proteins have an external large eye, which is useful for spotting fall in O2 consumption by the + high-flying queens, and whose retina binding site for NH4 , but lively is composed almost exclusively of mitochondria (present only in the debate about what happens next. photoreceptor neurons and a neurons). It was found that One possibility is that a proton is homogeneous population of glial application of alanine restored O2 stripped off NH + to leave NH which 4 3 cells, arranged with impressive consumption, as predicted (Fig. 2D). passes through a channel, but there regularity (Fig. 2A). When the Second question: do the are also reports of electrogenic intracellular pH of retinal glial cells is photoreceptors release ammonium? + transport, i.e. transport of NH4 or measured with a pH-sensitive Instead of trying to guess + cotransport of NH3 and H (Javelle et fluorescent dye, application of ammonium movements from al. 2008). Surprisingly, although ammonium is found to produce a measurements of pH, the authors Amt/Rh proteins are so widespread, robust intracellular acidification that used a triple-barrelled ammonium- the first ammonium transport is abolished in the absence of Cl- (Fig. sensitive microelectrode to directly + + + measure [NH4 ] in the extracellular selective for NH4 over K to be 2B). This suggests co-transport with demonstrated in an animal cell Cl-. The transporter is selective for clefts. In normal Ringer solution, + + + appears to be by another, NH4 over K (Marcaggi & Coles, extracellular [NH4 ] was below the molecularly different variety of 2000), but it shares with a wide detection limit of these electrodes. + - + ammonium transporter found in the range of K -Cl cotransporters the However, when NH4 uptake by the honeybee retina. presence of inhibitory binding sites glia was blocked by removing Cl- 2 1,4-Dideoxy-1,4-imino-D-arabinitol. for bumetanide and piretanide. from the Ringer solution,

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+ reactant. For example, enzymes of extracellular [NH4 ] was measurable Editor-in-Chief Elect in the dark and shown to increase the glycolytic pathway are The Physiological Society is seeking to during light stimulation (Fig. 2E). stimulated by ammonium and appoint an Editor-in-Chief Elect for its + exogenous ammonium does increase Extracellular [NH4 ] was greatly lactate production in rat brain in vivo prestigious publication The Journal of reduced by methylaminoisobutyrate, Physiology. The Editor-in-Chief Elect (Provent et al. 2007). What would a blocker of amino acid transport, will work alongside the current Editor- really help this field is a good and also by pyruvate, which was in-Chief from mid-2009 and then take membrane permeable ammonium- expected to provide a direct over full editorial control in July 2010 sensitive fluorescent indicator. Please substrate for the mitochondria, when the present Editor-in-Chief, tell your chemist friends. William Large, finishes his term of bypassing alanine (Fig. 2F). Hence, in office. this preparation, we now have very Païkan Marcaggi strong evidence for the neurons Department of Neuroscience, Since 1878 The Journal of Physiology has being fuelled by alanine, with Physiology and Pharmacology, published original research papers in ammonium being returned to the all areas of physiology illustrating new University College London glial cells and taken up by a specific physiological principles or transporter. Jonathan A Coles mechanisms. It also publishes Grenoble Institute of Neuroscience, commissioned reviews and A neuron-astrocyte ammonium- France (present address: Centre for commentaries, and organises sponsored symposia, the proceedings amino acid shuttle in mammalian Biophotonics, University of Strathclyde, UK) of which are published as reports in brain? The Journal. Mammalian astrocytes (at least in + References culture) avidly take up NH4 (see Benjamin A & Quastel J (1975). Metabolism of The Editor-in-Chief works closely with Marcaggi & Coles, 2001). Most of the amino acids and ammonia in rat brain cortex the Managing Editor, Carol Huxley, and glutamate released at glutamatergic slices in vitro: a possible role of ammonia in her staff at The Society’s Publications synapses in the mammalian brain is brain function. J Neurochem 25, 197–206. Office based in Cambridge, UK. The Editor-in-Chief chairs regular meetings taken up into astrocytes by Coles JA, Martiel JL & Laskowska K (2008). A of The Journal’s Executive Committee, glia-neuron alanine/ammonium shuttle is glutamate transporters where, in the comprising Senior Editors and astrocytes, it reacts with ammonium central to energy metabolism in bee retina. J Physiol 586, 2077–2091. representatives of The Society and the to form glutamine. Glutamine, publishers (Wiley-Blackwell). This which does not bind to synaptic Huang CH & Peng J (2005). Evolutionary Committee is responsible for strategic receptors, is transferred back to the conservation and diversification of Rh family planning and operational matters pre-synaptic terminals and genes and proteins. Proc Natl Acad Sci U S A relating to The Journal. Serving under 102, 15512–15517. deaminated to glutamate. By the Senior Editors is an international analogy with bee retina, the shuttle Javelle A, Lupo D, Ripoche P, Fulford T, Merrick Editorial Board of over 50 members, which meets annually. might be completed by transfer of M & Winkler FK (2008). Substrate binding, deprotonation, and selectivity at the ammonium from the neurons to the periplasmic entrance of the Escherichia coli Candidates should submit a CV astrocytes, as originally proposed by ammonia channel AmtB. Proc Natl Acad Sci U S together with a letter of no more than Benjamin & Quastel (1975). Fig. 3, is A 105, 5040–5045. three pages of A4 by 1 December 2008 an update of this proposal which summarising the following: Marcaggi P (2006) An ammonium flux from + shows uptake of NH4 rather than neurons to glial cells. Proc Physiol Soc 3:SA16. • a statement describing the reasons for their interest in the position; NH3, and the co-release of - Marcaggi P & Coles JA (2000). A Cl • an assessment of the current state ammonium with neurotransmitters + + cotransporter selective for NH4 over K in of The Journal; (Marcaggi, 2006). glial cells of bee retina. J Gen Physiol 116, • a vision for the future of The Journal 125–141. and how it could be achieved; Within the astrocyte, ammonium Marcaggi P & Coles JA (2001). Ammonium in • an opinion on the organisation and might act as a signal as well as a nervous tissue: transport across cell composition of the Editorial Board; membranes and fluxes from neurons to glial • any other comments that the cells. Prog Neurobiol 64, 157–183. candidate feels are relevant.

Provent P, Kickler N, Barbier EL, Bergerot A, For full details go to Farion R, Goury S, Marcaggi P, Segebarth C & Coles JA (2007). The ammonium-induced http://www.physoc.org increase in rat brain lactate concentration is rapid and reversible and is compatible with trafficking and signaling roles for ammonium. Going to the US next year? J Cereb Blood Flow Metab 27, 1830–1840. If you are travelling to the USA after 12 January 2009 under the Visa Waiver Tsacopoulos M, Veuthey AL, Saravelos G, Program you will need to apply for Perrottet P & Tsoupras G (1994). Glial cells advance authorization using the online transform glucose to alanine which fuels the process available at Jonathan Coles (left) and Païkan neurons in the honeybee retina. J Neurosci 14, https://esta.cbp.dhs.gov. Marcaggi. 1339–1351.

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How many sensors in the bladder? Sensory neurons projecting from the urinary bladder (bladder afferents) play a key role in neural circuits underlying both urine storage and normal micturition. They are responsible for all sensations from the bladder such as fullness, the urge to micturate, discomfort and pain. Afferents from different regions of the bladder probably have characteristic receptive fields, response properties and conduction velocities. Indeed, recent experiments in vitro have identified several distinct functional classes of bladder afferents. How then can we relate the functions of various types of afferents in normal and pathological states of the urinary bladder?

Based on their conduction velocities, or if chemoreception is mediated by bladder afferents comprise two main polymodal stretch-insensitive groups: faster conducting, thinly mechanoreceptors. Some bladder myelinated Aδ-fibres; slower afferents are excited in vivo only by conducting unmyelinated C-fibres. In distension with isotonic KCl, but not cat bladder, most Aδ-fibres are NaCl, and these afferents have been distension-sensitive, while C fibres considered to be chemoreceptors are not (Janig, 2006). In rats, (Moss et al. 1977). Stretch- however, about 50% of C-fibres insensitive afferents activated by Clockwise from top respond with low threshold to left: Vladimir chemical stimuli (capsaicin, α β bladder distension (Shea et al. 2000). Zagorodnyuk, Ian hypertonic solution, , -methylene Overall, most bladder afferents seem Gibbins, Marcello ATP) in vitro probably correspond to to be polymodal, since they can Costa, Sarah chemoreceptors described in vivo. respond to both mechanical and Gregory and However, the same fibres also chemical stimuli (Daly et al. 2007; Simon Brookes. respond vigorously to gentle Rong et al. 2002; Xu & Gebhart, mucosal stroking (mucosal high- 2008; Zagorodnyuk et al. 2007). responding mechanoreceptors), Nevertheless, there is considerable indicating that they are actually diversity in the range of stimuli that polymodal afferents (Zagorodnyuk activate different classes of bladder et al. 2007). Patients with interstitial afferents. cystitis have enhanced sensitivity to intravesicular instillation of hyper- Mechanoreceptors involved in non-painful sensation tonic KCl solutions, suggesting that Most studies of bladder afferents in from the bladder and contribute to some of their symptoms may be due vivo have identified mechano- reflex regulation of bladder to increased firing of afferents with receptors that fire in proportion to contractility. In contrast, high these properties. intravesical pressure, reflecting the threshold afferents mediate combination of passive distension discomfort and painful sensations Nociceptors and active contraction of the bladder from the bladder (de Groat, 2006; A widely-used classification identifies wall. Thus, they behave as bladder Janig 2006). However, this division two broad categories of small wall tension receptors. Experiments has numerous pitfalls. Firstly, low diameter, slowly-conducting in vitro have revealed three distinct threshold, wide dynamic range nociceptive neurons: classes of stretch-sensitive afferents mechanoreceptors encode a large • those expressing neuropeptides that behave as tension receptors: low range of mechanical stimuli [typically, substance P (SP) and threshold mechanoreceptors in the (distension and contraction) calcitonin gene-related peptide muscle layer; mechanoreceptors at extending into the noxious range. (CGRP)] plus TRPV1 and TrkA the interface between muscle and Secondly, only some high threshold receptors; mucosa (muscle-mucosal mechanoreceptors respond to • those that do not, but which are mechanoreceptors); and high distension (Janig, 2006). To labelled by the isolectin B4 (IB4), threshold mechanoreceptors in the complicate matters further, some and depend on glial-derived muscle layer (Daly et al. 2007; Rong low threshold mechanoreceptors neuronotrophic factor (GDNF) for et al. 2002; Xu & Gebhart, 2008; express capsaicin-sensitive TRPV1 postnatal survival. Zagorodnyuk et al. 2007). There also receptors (Daly et al. 2007) that However, this is almost certainly a may be 'volume' receptors, which normally are associated with misleading simplification. sense bladder distension irrespective functional nociceptors. of pressure (Morrison, 1999). Potentially nociceptive C-fibre Chemoreceptors neurons comprise a functionally It is widely believed that low It is still unclear whether pure diverse array characterised by threshold mechanoreceptors are chemoreceptors exist in the bladder differential expression of various TRP

Physiology News | No. 73 | Winter 2008 | www.physoc.org FEATURES PN 19 and ASIC channels responding to fibres alike, both of which include only 50–60% of spinal sensory temperature and pH, TTX-resistant low and high threshold mechano- neurones projecting to the bladder Na+ channels (Nav1.8 and 1.9) and a receptors. are labelled with neuropeptides such range of K+ channels (Fang et al. as CGRP. So far we do not have a 2006). How these functional 'Silent' afferents reliable neurochemical marker for characterisations correlate with the Up to about 30% of afferent to the visceral afferent endings that do not broad neurochemical categories is bladder apparently do not respond express neuropeptides. Consequent- still largely unresolved. For example, to any level of distension and have ly, nearly half the bladder afferents intravesical instillation of capsaicin, been called 'silent afferents'. never have been specifically which opens TRPV1 channels, However, acute inflammation visualised. Now, however, we can produces burning pain in humans or induces some previously 'silent reveal non-peptide bladder afferents pain-related behaviour in animals. afferents' to become spontaneously by anterogradely labelling However, in guinea pig bladder, active and develop a degree of functionally-characterised fibres with capsaicin activates at least two mechanosensitivity. Thus, they may biotinamide (Fig. 1). Following this different classes of mechanoceptive contribute to nociception from the procedure, several morphological afferents: high threshold stretch- inflamed bladder (Janig, 2006). A types of bladder afferent endings can insensitive mechanoreceptors and subset of them may represent be seen: 'antenna-like endings' in the the mucosal high-responding stretch-insensitive mechano- muscle layers, 'grape-like-endings' in mechanoreceptors which are receptors with endings in the the lamina propria; and free varicose presumably activated in damaged or mucosa (mucosal low responding endings in the lamina propria (Fig. inflamed urothelium (Zagorodnyuk mechanoreceptors). So-called 'cold 1C, D & F). Most probably, 'antenna- et al. 2007). receptors' that express TRPM8 (a TRP like endings' correspond to muscle channel responsible for detecting mechanoreceptors, while 'grape-like As with other nociceptors, both low cold stimuli) probably represent endings' are muscle-mucosal and high threshold another class of 'silent nociceptors' mechanoreceptors. Free nerve mechanoreceptors in the bladder in the bladder, since their density is endings containing CGRP and SP in show sensitisation by inflammatory increased in the suburothelium of the lamina propria (Fig. 1E & F) mediators, such as cytokines, α,β- overactive and painful bladders probably represent capsaicin- methylene ATP or as a result of (Mukerji et al. 2006). sensitive mucosal mechano- cystitis (Rong et al. 2002; Roppolo et receptors, since removal of the al. 2005; Xu & Gebhart, 2008). Thus, Linking structure and function urothelium both abolished their noxious stimuli in the urinary bladder It is commonly believed that all response to light von Frey hair probably are detected by thin visceral afferents have unspecialised stroking (Zagorodnyuk et al. 2007) myelinated Aδ- and unmyelinated C- bare endings (Janig, 2006). In rats, and produced significant damage of

A D

E F B C

Figure 1. Visualising functionally defined bladder afferents. A, Biotinamide-filled nerve trunk including a stretch-sensitive muscle mechanoreceptor. B, probing of receptive field of this afferent with a von Frey hair evoked firing only in a discrete spot (hotspot, marked by carbon particle). C, 'antenna-like ending' associated with the hotspot. D, single biotinamide-filled fiber gave rise to 'grape-like endings' in the lamina propria. E, biotinamide-filled fiber near urothelial cells. F, CGRP-immunoreactive free ending in the lamina propria near the urothelium.

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SP- and CGRP-positive nerve endings Fang X, Djouhri L, McMullan S, Berry C, Make waves for Woods in the lamina propria. Waxman SG, Okuse K & Lawson SN (2006). Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes c-fiber Hole Clearly, there is great complexity in nociceptors with broad action potentials and Start planning for The high Nav1.9 expression. J Neurosci 26, the sensory innervation of the Society’s 2009 joint meeting bladder. There must be around 10 7281–7292. distinct functional classes, each of with the Society of General Janig W (2006). The integrative action of the which has a precise role in signalling autonomic nervous system. Cambridge Physiologists the mechanical and chemical University Press, Cambridge, UK. environment of the bladder. An immediate challenge is to Morrison JF (1999). The activation of bladder wall afferent nerves. Exp Physiol 84, 131–136. characterise each of them fully according to morphological, Moss NG, Harrington WW & Tucker MS (1997). functional, pharmacological and Pressure, volume and chemosensitivity in immunohistochemical criteria. Only afferent innervation of urinary bladder in rats. Am J Physiol 272, R695–R703. then, will we be able to determine which populations of afferents are Mukerji G, Yiangou Y, Corcoran S, Selmer IS, most important clinically, and most Smith GD, Benham CD, Bountra C, Agarwal SK amenable for pharmacological & Anand P (2006). Cool and mentol receptor Have you ever been to Wood’s Hole? manipulation in the treatment of TRPM8 in human urinary bladder disorders and clinical correlations. BMC Urology 6, 6. On the beautiful New England seaside, bladder disorders. doi:10.1186/147I-2490-6-6. this is the setting for the joint Society of General Physiologists and The Acknowledgements Rong W, Spyer KM & Burnstock G (2002). This study was funded by National Heath Physiological Society meeting to be Activation and sensitisation of low and high held from 9–13 September 2009. and Medical Research Council of Australia threshold afferent fibers mediated by P2X grant no. 375123. receptors in the mouse urinary bladder. J Physiol 541, 591–600. The organizers (David Eisner and Lee Vladimir Zagorodnyuk, Ian Sweeney) are putting together a first Roppolo JR, Tai C, Booth AM, Buffington CAT, rate and diverse programme on the Gibbins, Marcello Costa, δ de Groat WC & Birder LA (2005). Bladder A overall theme of Muscle in health and Simon Brookes & Sarah afferent nerve activity in normal cats and cats with feline interstitial cystitis. J Urol 173, disease, running the gamut from Gregory 1011–1015. molecular studies of motor function to Departments of Human Physiology diseases of skeletal, cardiac, and and Anatomy & Histology, Centre for Shea VK, Cai R, Crepps B, Mason JL & Perl ER smooth muscles. (2000). Sensory fibers of the pelvic nerve Neuroscience, Flinders University, innervating the rat's urinary bladder. J Adelaide, Australia Neurophysiol 84,1924–1933. In this meeting, The Physiological Society is an equal participant with the Society of General Physiologists and References Xu L & Gebhart GF (2008). Characterization of so, for the first time ever in North Daly D, Rong W, Chess-Williams R, Chaple C & mouse lumbar splanchnic and pelvic urinary Grundy D (2007). Bladder afferent sensitivity bladder mechanosensory afferents. J America, The Society will have a real in wildtype and TRPV1 knockout mice. J Physiol Neurophysiol 99, 244–253. presence, and the meeting should be 583, 663–674. small enough and friendly enough for Zagorodnyuk VP, Gibbins IL, Costa M, Brookes all. This will be a chance to go to a de Groat WC (2006). Integrative control of the SJH & Gregory SJ (2007). Properties of the beautiful, unspoiled place in America lower urinary tract: preclinical perspective. Br J major classes of mechanoreceptors in the Pharmacol 147, S25–S40. guinea pig bladder. J Physiol 585, 147–163. at the best time of year. In September the temperatures are usually in the 70–80os (22–27oC), and the sea is warm enough to swim in. A ferry boat ride to Martha’s Vineyard or a dedicated whale- watching trip make for a non-standard Society experience and, aside from nightly mixers around the posters, and a traditional New England lobster feast, there are several classic inns, restaurants and bars around Woods Hole and nearby Falmouth. Take a look at the SGP website (http://www.sgpweb.org/), then start making plans to join what promises to be a fantastic meeting. Happy attendees at a Woods Hole meeting; view from the Woods Hole Marine Biological Association (top). Colin Nichols

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Does muscle pain increase muscle stiffness? Animal studies have shown that muscle pain can reflexly excite gamma motor neurones and thus increase muscle spindle stretch sensitivity and discharge rate. According to the popular, but clinically unproven, hypothesis this reflex loop may perpetuate into a sustained 'vicious cycle' - reciprocally aggravating muscle tone and pain. Yet a lack of clear experimental evidence – and recently obtained new data in humans that contradicts this notion – has cast doubt on whether this model can be used to explain physiological mechanisms and translate into the development of treatments

Chronic musculoskeletal pain syndromes (CMPS) are a common group of, usually, activity and work- related myalgias. Unfortunately, the efficiency of treatments available today is very limited, partly because the physiological mechanisms underlying the clinical conditions are not well understood. One of the hypotheses – developed by Peter Sojka and the late Håkan Johansson in Umeå, Sweden – suggests that chronic muscle pain may develop as Alexander Burton (left), Ingvars Birznieks and Vaughan Macefield. a result of a 'vicious cycle' reflex initiated by nociceptive input itself of metabolites (Johansson & Sojka, effects in human subjects by looking (Johansson & Sojka, 1991). This 1991). If the production of at EMG activity, stretch reflexes and hypothesis is based on an elegant set metabolites is reasonably high to proprioceptive function; of experiments in the anaesthetised excite nociceptors, a process nevertheless, they all agree that the animals demonstrating that sustaining a ‘vicious cycle’ might be ‘vicious cycle’ mechanism is very nociceptive afferents excite γ-motor initiated, resulting in a chronic unlikely. neurones and thereby increase muscle pain. stretch sensitivity and discharge rate Due to methodological limitations of the muscle spindles. The resultant In contrast to animal experiments, to the conclusions in regard to excitation of the homonymous α- date clear experimental evidence in modulation of muscle spindle motoneurone pool may lead to humans is lacking. Variable results activity in humans so far have been increased muscle tone, contraction- have been obtained when based on indirect experimental induced ischemia and accumulation attempting to demonstrate these evidence. However, our recent study

Figure 1. Microneurographic recordings from the common peroneal nerve in an awake human subject. Examples of discharge activity of single muscle spindle afferent recorded before and during experimentally-induced muscle pain. This sensory unit was classified as a Ia muscle spindle afferent innervating a peroneus muscle. Despite the strong pain (rated 6 on a 0–10 scale) the instantaneous discharge rate was not affected by nociceptive stimulation. Leg muscles remained relaxed throughout the experiment and there was no surface EMG activity detected. Experimental muscle pain was induced by bolus intramuscular injection of 0.5ml 5% hypertonic saline into tibialis anterior (modified from Birznieks et al. 2008).

Physiology News | No. 73 | Winter 2008| www.physoc.org 22 PN FEATURES has overcome those constraints by An important aspect of human Furthermore, Lund et al. (1991) using microneurography to record experiments is voluntary control, reviewed a wide range of clinical discharge activity of single human which hypothetically might literature and experimental studies muscle spindle afferents during counteract nociceptive activation of and came to the conclusion that experimentally-induced pain in α and γ-motor neurones. Apart from chronic pain tends to inhibit, not muscle and skin (Fig. 1) (Birznieks et the fusimotor system, another less facilitate, voluntary and reflex al. 2008). explored pathway for pain to contractile activity of a painful modulate muscle spindle activity muscle or its agonists. These authors Unitary recordings were made from might be via the sympathetic suggest that those effects are 14 primary and six secondary muscle nervous system. In our paper we beneficial and provide protective spindle afferents, located in the review the studies advocating this adaptation, and are definitely not the ankle or toe extensors or the peronei possibility, but at the same time we cause of pain. muscles, via microelectrodes have to point out contradictory and inserted into the common peroneal inconsistent findings that prevent us In conclusion, due to the controversy nerve. During muscle pain, induced from drawing any definite and conflicting results reported over by intramuscular injection of 0.5 ml conclusions. All previous studies the years, a final chapter on this issue of 5% hypertonic saline, no afferents have been designed to focus on is far from being written yet. increased their discharge activity in either fusimotor or sympathetic response to static stretch, moreover influences on muscle spindles However, now there is new direct the overall net discharge rate separately – a unified model taking experimental evidence indicating decreased during muscle pain by into account of both mechanisms that the key mechanism – on which 6.1%. During skin pain, induced by a would probably provide a better the clinical ‘vicious cycle’ hypothesis subcutaneous injection (0.2 ml), only explanation of experimental results. is based – is missing; in humans small changes in afferent activity activation of muscle nociceptors were observed and the overall net While the major support to the does not cause a reflex increase in discharge rate remained essentially Johansson/Sojka hypothesis has been fusimotor drive. Thus we urge the same. provided by the observation of caution in extending animal data to immediate reflexogenic responses, the clinical setting. To support the ‘vicious cycle ’ which, as we now know, are not hypothesis, nociceptive excitation of present in humans, there is the Ingvars Birznieks1 © fusimotor drive must be substantial. possibility that recruitment of - Alexander R Burton1,2 Experiments on anaesthetised cats, motor neurones might require 1,2 conducted in a comparable plastic changes in nociceptive Vaughan G Macefield experimental setup to our study, circuits that might develop over a 1Prince of Wales Medical Research demonstrated a substantial longer time. However, prolonged Institute, Sydney, Australia reflexogenic increase in mean experimental pain in animals 2School of Medicine, University of discharge rate by ~80% in afferents involving inflammatory agents seem Western Sydney, Sydney, Australia innervating homonymous as well to inhibit γ-motor neurons, thus heteronymous muscles (Thunberg et actually providing an explanation for References al. 2002). This was not the case in the weakness and even the atrophy Birznieks I, Burton AR & Macefield VG (2008). The effects of experimental muscle and skin our human microneurography clinically observed in severe chronic pain on the static stretch sensitivity of human experiments, firmly contradicting cases of muscle damage. muscle spindles in relaxed leg muscles. J animal data and thus questioning Physiol 586, 2713–2723. the clinical relevance of the ‘vicious Finally, what about the clinical Johansson H & Sojka P (1991). cycle’ hypothesis (Birznieks et al. evidence – can any convincing Pathophysiological mechanisms involved in 2008). support for the 'vicious cycle' genesis and spread of muscular tension in occupational muscle pain and in chronic hypothesis be found? While it is musculoskeletal pain syndromes: a An intriguing question to address in common knowledge that hypothesis. Med Hypotheses 35, 196–203. the future is what physiological involuntary muscle contractions are Lund JP, Donga R, Widmer CG & Stohler CS mechanisms are responsible for such seen in patients suffering from pain, (1991). The pain-adaptation model: a discrepancies between species and something other than the muscle discussion of the relationship between chronic experimental approaches reported pain itself might be causing and musculoskeletal pain and motor activity. Can J over the years? In the discussion of maintaining a spasm as, for example, Physiol Pharmacol 69, 683–694. our article (Birznieks et al. 2008) we abdominal rigidity is associated with Simons DG & Mense S (1998). Understanding touch upon several possibilities and peritoneal inflammation. Simons & and measurement of muscle tone as related to clinical muscle pain. Pain 75, 1–17. consider an adaptive peripheral Mense (1998) indicated that usually reflex control of the fusimotor painful muscle shows no EMG Thunberg J, Ljubisavljevic M, Djupsjöbacka M system that reflects a spectrum of & Johansson H (2002). Effects on the activity and, if it is present, it does fusimotor-muscle spindle system induced by function and adaptation depending not correlate with pain either in the intramuscular injections of hypertonic saline. on the context. time or intensity domain. Exp Brain Res 142, 319–326.

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Movement automaticity shows less activation, but more connectivity: a model for brain efficiency Functional MRI (fMRI) was used to investigate interactions in the brain when movements were sufficiently practiced as to become automatic. When a motor task achieved automaticity a group of brain regions became less active, but more strongly connected. Tao Wu and colleagues speculate that this increase in connectivity reflects more efficient brain function when a task is well learned After a great deal of practice people that might be responsible for a can perform some movements behavioural change. In the current automatically. Automaticity implies study, we used functional MRI (fMRI) that movements can be performed and effective connectivity to without attention being clearly investigate the interactions among directed toward the details of the brain regions when movements movement. Previous functional become automatic. neuroimaging studies, including our own, have found that the process of Healthy volunteers were asked to automaticity is accompanied by a Tao Wu (above, left), practice a sequential finger reduction of brain activation in Piu Chan (above) movement, and after extensive several regions, like the cerebellum, and Mark Hallett training they performed the task (left) focus on premotor area (PMA) and dorso- understanding automatically. Automaticity was lateral prefrontal cortex (DLPFC) motor control in evaluated by having subjects (Wu et al. 2004; Poldrack et al. normal and disorder perform a secondary task 2005). However, the physiology of conditions. simultaneously with the sequential automaticity was still far from being movement. No deterioration in understood. A further obvious of the interactions within brain performance indicates that the question that arises from these networks. In recent years, a great behaviour is automatic. fMRI data observations is how people can use effort has been made in exploring analysis was performed with SPM2 less brain resources yet perform inter-regional connectivity in a given software (Wellcome Institute of motor tasks better. We hypothesized task, which is usually characterized in Cognitive Neurology, London, UK). that the acquisition of automaticity terms of functional connectivity or First brain activations during the is not only related to the changes of effective connectivity (Friston et al. novel and the automatic stage were the magnitude of neural activity, but 1993). Effective connectivity implies calculated and compared. fMRI is also associated with a modification an interaction between brain regions results showed that the pattern of brain activity while performing sequential movement was similar at the novel and the automatic stage, but that the bilateral cerebellum, bilateral PMAs, bilateral parietal cortex, left DLPFC, pre- supplementary motor area (pre- SMA), cingulate motor area (CMA), precuneus, and left putamen were less activated as the sequential movement became automatic. Then, automaticity-dependent changes in effective connectivity were assessed using a psychophysiological interaction (PPI) model (Friston et al. 1997). PPI is defined as the change in contribution of one brain area to another due to a change in experimental condition or psychological context, and aims to Figure 1. Results of psychophysiological interaction (PPI) from the cingulate motor explain regionally specific responses area (CMA). Red colour means that these brain regions receive significantly greater in terms of the interaction between influence from the CMA at the automatic stage compared to the novel stage (p < the psychological variable and the 0.05, corrected for multiple comparisons) (from Wu et al. 2008). activity in a specific index area. We

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Table 1. Results show brain areas that commonly receive significantly more a solution to this problem and may influence from five index areas (the cerebellum bilaterally, CMA, pre-SMA, and left be an important generalizable putamen) at the automatic stage compared to the novel stage (conjunction property of brain function. analysis, p < 0.05, corrected). Tao Wu1 Brain area Cluster Coordinates Z-value 1 size x y z Piu Chan L anterior cingulate area 3533 -10 11 34 5.22 Mark Hallett2 L precuneus 435 -16 -46 48 4.92 1Beijing Institute of Geriatrics, L parietal cortex 312 -40 -74 36 4.72 Department of Neurology, Key L cerebellum, posterior lobe 143 -8 -65 -27 3.94 Laboratory on Neurodegenerate R cerebellum, anterior lobe 89 14 -65 -25 3.88 R dorsal premotor area 61 14 -14 60 3.42 Disorder of Ministry of Education, L dorsal premotor area 52 -20 -5 62 3.22 Xuanwu Hospital, Capital Medical University, Beijing, China, and The coordinates are given as stereotaxic coordinates referring to the atlas of Talairach and 2Human Motor Control Section, Tournoux. Cluster size is the number of voxels. All areas were significant at P < 0.05, Medical Neurology Branch, National corrected. The z-value shows statistical difference between the automatic and novel stage. With SPM software, the z-value is determined after transformation of t-values into normal Institute of Neurological Disorders distribution. Abbreviations: L: left; R: right; CMA: cingulate motor area; SMA: supplementary and Stroke, National Institutes of motor area. Health, Bethesda, MD, USA chose the left primary motor cortex motor cortex itself is not a part of References (M1), bilateral dorsal PMA, bilateral the automatic networks, perhaps Friston KJ, Buechel C, Fink GR, Morris J, Rolls E DLPFC, bilateral cerebellum, left indicating that at this stage it is & Dolan RJ (1997). Psychophysiological and putamen, SMA, CMA, and precuneus acting largely in execution mode, modulatory interactions in neuroimaging. as index areas because these regions carrying out the directions sent to it. NeuroImage 6, 218–229. may be involved in the process of The result showing the decreased Friston KJ, Frith CD & Frackowiak RS (1993). automaticity or are important in connectivity of the precuneus can be Time-dependent changes in effective motor learning. We found that the interpreted that the importance of connectivity measured with PET. Hum Brain bilateral cerebellum, CMA, pre-SMA, the cortical attention network Mapp 1, 69–80. and left putamen have stronger decreases when movements become Poldrack RA, Sabb FW, Foerde K, Tom SM, interactions with a number of brain automatic. These findings taken all Asarnow RF, Bookheimer SY & Knowlton BJ regions at the automatic stage together provide evidence for the (2005). The neural correlates of motor skill compared to the novel condition previously poorly supported, but automaticity. J Neurosci 25, 5356–5364. (Fig. 1 and Table 1). In contrast, the widely held, view that the execution Wu T, Chan P & Hallett M (2008). Modification precuneus has decreased effective of automatic movements is shifted of the interactions in the motor network when connectivity at the automatic stage. more subcortically. a movement becomes automatic. J Physiol 586, 4295–4304. These findings suggest that the The brain is constantly learning new Wu T, Kansaku K & Hallett M (2004). How self- process of automaticity is things, but cannot continuously initiated memorized movements become accompanied by a strengthened increase its activity. Increasing the automatic: a fMRI study. J Neurophysiol 91, interaction within much of the functional strength of connections is 1690–1698. central motor networks even though the magnitude of the activation is decreased. With automaticity, brain Paton Prize Bursary regions become less active, but The Paton Prize was established in 1994 by The Society’s History & some of them increase their effective Archives Committee to encourage the study of the major ideas and connectivity. If a movement concepts that have shaped modern physiology. The Prize takes the form of becomes automatic, then learning a bursary to support such studies, with funding of up to £1000 to cover must occur, and thus synaptic travel and incidental expenses. The Committee wishes to promote interest strengths must change. These in the history of physiology among younger Members and Affiliates of The changes appear to allow the brain to Society, as well as established scientists. function more efficiently for the given task, even with a reduced level The bursaries are financed by interest from the Paton Fund, an endowment of activation. The network that does originated by a donation from Sir William Paton, with a matching donation become more connected includes from The Society. the basal ganglia and cerebellum. In contrast, some cortical regions, like For more information on the Paton Prize Bursary, or to suggest a future the DLPFC, PMA, and M1, did not recipient, please contact the Committee Chair, Dafydd Walters show stronger automaticity-related ([email protected]) effective connectivity. The primary

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So what does cause the breakpoint of breath-holding? The precise mechanism causing the breakpoint of breath-holding is unknown, but it is possible that breath-holding eventually stimulates diaphragm chemoreceptors that in turn cause the irresistible urge to breathe

It is not normally possible for relaxing the diaphragm before using humans to breath-hold voluntarily it to attempt to inspire again. until they lose consciousness (Parkes, 2006). This indicates that This in turn suggests that the the voluntary act of breath-holding is ‘holding’ of breath-holding might terminated by some involuntary be achieved by continuously breakpoint mechanism. The nature contracting the diaphragm slightly of this involuntary breakpoint (Parkes, 2006), with the purpose of mechanism might be revealed by the opposing the recoil from the chest. three well known manoeuvres that (It may be easier to oppose this recoil prolong breath-hold duration: by slightly activating a big inspiratory muscle like the • increasing lung inflation; Michael Parkes. diaphragm rather than by intensely • breathing hyperoxic gas mixtures; activating a small group of muscles • lowering arterial PCO2 by chemoreceptors are not obviously such those keeping the glottis previously hyperventilating. involved (although any proposed closed. Substantial diaphragm mechanism must still explain such proprioreception is also unlikely as These three suggest that the prolongations). humans have little conscious breakpoint mechanism might sensation of the diaphragm). involve pulmonary stretch receptors There are three other, and less well and/or the carotid arterial known, manoeuvres that also During breath-holding such an chemoreceptors (not aortic prolong breath-hold duration and unusual, prolonged diaphragm chemoreceptors as these have no that might also reveal the breakpoint contraction may eventually result in effect on breathing in humans). This mechanism. The first appears to be under perfusion of the diaphragm, in turn predicts that humans should voluntarily relaxing the diaphragm at causing a stimulation of diaphragm be able to breath-hold indefinitively the end of the breath-hold. Fowler muscle chemoreceptors that (until consciousness is lost) after (1954, in Parkes, 2006) made one of eventually generates the irresistible pulmonary or carotid chemoreceptor the earliest observations consistent urge to breathe, i.e. the breakpoint denervation. Such denervation with this (subsequently confirmed by of breath-holding. Stopping breath- however has almost no effect on Flume et al. 1994, in Parkes, 2006), holding by relaxing the diaphragm breath-hold duration (see Harty et al. by showing that inhaling an may then allow it to be reperfused, 1996; Flume et al. 1996; Gross et al. asphyxiating gas mixture at ending the stimulation of diaphragm 1976, in Parkes, 2006). So breakpoint enables a second (or even chemoreceptors by metabolites. This pulmonary stretch and carotid third) breath-hold, despite blood gas hypothesis could explain the levels becoming progressively worse. prolongation of breath-hold duration This enabling effect is independent by increased lung inflation, hyperoxia of the number of inhalations of and hypocapnia, with each delaying asphyxiating gas, occurs even with a the onset of such diaphragm single inhalation with no net change chemoreceptor stimulation. Even if in lung volume, or even apparently if diaphragm chemoreceptor stimula- inspiration is only attempted against tion is only perceived vaguely as a closed glottis (Rigg et al. 1974, in discomfort, the ability to tolerate Parkes, 2006). Their one common such discomfort will have a strong feature might be in momentarily subjective component that could also explain the notorious variations Figure 1. Mean ‘breath-hold’ duration in breath-hold duration seen both with 70% oxygen in two subjects pre- between and within subjects (Parkes, (from FRC) and post-curarisation. 2006). Separate symbols indicate each subject. †The anaesthetist terminated the This key role of the diaphragm in the ‘breath-hold’ by restarting the ventilator. Reproduced from Campbell et breakpoint mechanism (Parkes, al.(1966) with permission from the 2006) is supported by the second Lancet (pending) [& see also Campbell et less well known breath-hold al. 1967 & 1969, in Parkes, 2006]. prolonging manoeuvre, paralysis

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(curarisation) of the diaphragm. In 1966–1969 Campbell et al. described two conscious, unanaesthetised subjects whose entire voluntarily (skeletal) musculature was paralysed with curare (except for one arm left intact so that the subject could make hand signals) and who were kept alive by mechanical ventilation. Turning off the ventilator did not induce any intense feeling of suffocation, nor distress, nor any urge to breathe. Fig. 1 shows that the two subjects remained unventilated for as long as the supervising anaesthetist permitted

(about 4 minutes, when arterial PCO2 had reached ~72 mmHg) i.e. ‘breath-hold’ duration was apparently prolonged indefinitely.

Is the mechanism explaining this astonishing observation simply curare preventing the diaphragm Figure 2. Prolongation of breath-hold duration by A, bilateral phrenic block from contracting and hence its blood (reproduced with permission from Noble et al. [1970 & 1971, see Parkes, 2006], the Novartis Foundation, Clinical Science, © the Biochemical Society, the Medical Research flow is never restricted sufficiently to Society and Wiley-Blackwell. B, bilateral vagus and glossopharyngeal nerve block activate diaphragm chemo- (reproduced with permission from Noble et al. [1970], the Novartis Foundation and receptors? Unfortunately, the results Wiley-Blackwell) (and see also Guz et al. 1966; Guz,1966, in Parkes, 2006). Note of this intriguing and alarming breath-holds were at end expiration (FRC). They were from 100% O2 for A (Noble et experiment have not yet been al.1971, in Parkes, 2006) and apparently mostly from 100% O2 for B (Guz et al.1966; confirmed. The one attempt to do so Guz,1966; Noble et al.1970, see Parkes, 2006). Squares & circles indicate individual (Gandevia et al. 1993) was subjects with the mean ±se for each pre and post block condition indicated as unsuccessful, but may be horizontal bars. inconclusive since the three subjects apparently had had enough before to confirm Campbell’s indefinite breath-hold duration under similar their PCO2 levels had even risen ‘breath-hold’ duration is due to hyperoxic conditions (Gross et above normal levels (43 mmHg). incomplete blockade of phrenic al.1976, in Parkes, 2006) and aortic motor efferents and or sensory chemoreceptors have no effect on Most of Campbell’s results are, afferents, or that Campbell’s result is breathing in humans). however, confirmed in a related indeed unconfirmable. experiment. Noble et al.(1970) The breath-hold prolonging effects locally anaesthetised the phrenic The third less well known breath- of diaphragm paralysis, phrenic and nerves bilaterally in three subjects. hold prolonging manoeuvre is the vagus with glossopharyngeal nerve Such anaesthesia blocks the well demonstration (Fig. 2B) by Noble et blockade could be combined in the known motor efferents to the al. (1970) (now also ethically radical suggestion (Parkes, 2006) diaphragm. It also blocks the rarely unrepeatable) that bilateral local that diaphragm afferents might considered but extensive sensory anaesthesia of the vagus and travel partly with or within the vagus afferents in the phrenic nerve that glossopharyngeal nerves prolongs nerves. This idea is not without include those from diaphragm (almost trebles) breath-hold precedent, since the vagus and muscle chemoreceptors (Parkes, duration. The precise afferents phrenic nerves are sometimes in 2006). Blocking either would result involved are unclear, but must close proximity and the phrenic in the loss of afferent activity from involve blockade of non-pulmonary nerve in dogs does contains diaphragm chemoreceptors. Fig. 2A afferents (because pulmonary abdominal and thoracic afferents shows that Noble et al. (1970) denervation itself has no effect on from the heart and vena cava confirmed a prolongation (doubling) breath-hold duration (Flume et al. (Kostreva & Pontus, 1993a; Kostreva of breath-hold duration. 1996; Harty et al. 1996, in Parkes, & Pontus, 1993b). 2006) and blockade of non-carotid Unfortunately these experiments, and non-aortic chemoreceptor Clearly the hypothesis that too, are now ethically unrepeatable. afferents (because carotid diaphragm chemoreceptors play a So it is unclear whether their failure denervation itself has no effect on role on the breakpoint of breath-

Physiology News | No. 73 | Winter 2008 | www.physoc.org FEATURES PN 27 holding is still largely speculative. Olfactory marker protein: a gift to molecular During breath-holding in man we still know almost nothing about biologists, an enigma to physiologists diaphragm activity, nor its perfusion Olfactory marker protein (OMP), a small cytoplasmic protein nor its chemoreceptor activity. almost exclusively expressed in nasal chemosensory cells, has Perhaps the latest developments in imaging will rekindle some interest made major contributions to research progress in olfaction ever in studying the mechanism since its discovery over 35 years ago. However, the function of explaining the breakpoint of breath- OMP and its mechanism of action has remained an enigma. holding in man? Slowly, answers to these questions are beginning to emerge

Michael J Parkes Everyone working in the field of School of Sport & Exercise Sciences, chemosensation knows OMP, but University of Birmingham, UK nobody knows its function. A PubMed search for ‘olfactory marker References protein’ yields around 350 Gandevia SC, Killian KJ, McKenzie DK, publications, but when probing Crawford M, Allen GM, Gorman RB & Hales JP deeper to identify what OMP does (1993). Respiratory sensations, cardiovascular control, kinaesthesia and transcranial physiologically at the cellular or Johannes Reisert (left) and Frank stimulation during paralysis in humans. J molecular level, this number drops to Margolis. Physiol 470, 85-107. single digits. Antibodies to OMP have been used to characterize olfactory utilized, while so little is known Kostreva DR & Pontus SP (1993a). Hepatic vein, hepatic parenchymal, and inferior vena receptor neurons (ORNs) in about its function? caval mechanoreceptors with phrenic numerous species and the OMP gene afferents. Am J Physiol 265, G15-G20. has been used to generate transgenic OMP is a small (~160 amino acids) mice with ORN-specific expression cytoplasmic protein (Margolis, Kostreva DR & Pontus SP (1993b). Pericardial mechanoreceptors with phrenic afferents. Am profiles in hundreds of publications. 1972). Its amino acid sequence is J Physiol 264, H1836-H1846. However, to date only one protein >50 % identical in all vertebrate has been identified that interacts species but has no known sequence Noble MIM, Eisele JH, Trenchard D & Guz A with OMP, and that might provide motifs. OMP is abundantly and (1970). Effect of selective peripheral nerve blocks on respiratory sensations. In Breathing: insight to help elucidate OMP’s virtually exclusively expressed in Hering-Breuer Centenary Symposium, ed. Porter function. So why is OMP so widely mature chemosensory neurons in R, pp 233-247. J & A Churchill (Longmans Group), London.

Parkes MJ (2006). Breath-holding and its breakpoint. Exp Physiol 91, 1-15.

Animals in research: make up your own mind The Physiological Society, in collaboration with GlaxoSmithKline, the Coalition for Medical Progress and the Biomedical Research Education Trust, launched an educational DVD aimed at 14 to 16 year olds, which is now available online. The content, includes a 19 minute film, featuring patients, researchers, doctors and vets, explaining why and how animals are used in medical research. Also Figure 1. Distribution of OMP in coronal sections of the mouse olfactory system included are two supplementary visualized by immunofluorescence staining and confocal laser scanning microscopy at filmed case-study modules on P7. A, Olfactory epithelium: cell bodies of mature ORNs occupy the upper third of the coronary heart disease and malaria, epithelium and are intensely stained, as are their dendrites and dendritic knobs at the plus teachers' resource materials and surface of the epithelium. ORN axon bundles are apparent in the sub-epithelium as sources of further information from all stained circular objects. At this age immature ORNs deeper in the epithelium do not sides of the debate. express OMP. B, Olfactory bulb : The axon bundles project to the olfactory bulb glomeruli seen just below the surface of the bulb where the ORN axons enter. C, To view the DVD online visit Education Vomeronasal organ: sensory neurons in the sensory epithelium of the VNO are seen resources at http://www.physoc.org. to stain for OMP and their stained axons exit superficially, while the non-sensory For copies of the DVD email portion of the VNO is devoid of staining (with the possible exception of one ectopic [email protected]. cell).

Physiology News | No. 73 | Winter 2008| www.physoc.org 28 PN FEATURES the nasal cavity (Fig. 1). As such OMP has been a valued and cleverly Table 1. Indications of biological function of OMP exploited tool to identify and label • OMP induces increased mitotic activity of ORN precursors vomeronasal and ORNs, neurons of • A prolonged developmental delay in ORN axon retraction from bulbar the septal organ and also glomeruli is observed in OMP-/- mice contributed to the recent rediscovery • OMP interacts with Bex 1 and 2 proteins that can bind Ca/CaM of the Grueneberg ganglion, a cluster •OMP-/- ORNs have a reduced ability to extrude Ca2+ from ORN knobs of cells located in the anterior nasal •OMP-/- ORNs have prolonged cAMP kinetics in ORN cilia cavity. Furthermore, the OMP •OMP-/- ORNs exhibit delayed onset and offset of odourant promoter or the OMP locus has been electroolfactrogram responses used extensively to drive expression •OMP-/- ORNs have unaltered axonal conductance velocity of desired genes in chemosensory • Odour detection in OMP-/- mice requires a 50-100x higher concentration neurons. Examples are the markers •OMP-/- mice have altered epithelial odourant response patterns monitored thy1.1, lac-Z or GFP, which have with voltage sensitive dyes. helped to describe fundamental (Relevant references to these reports are found in Reisert et al. 2007) connectivity patterns of olfactory receptor neuron axons to their glomerular targets in the olfactory (instead of a randomly chosen one), Not until the generation of an OMP bulb (e.g. Danciger et al. 1989; or expression of the fluorescent knockout (Buiakova et al. 1996) was Mombaerts et al. 1996), direct exocytosis indicator synaptopHluorin it actually certain that OMP has a role expression of a single identified to image bulbar activity patterns in olfactory transduction (see Table 1 olfactory receptor to every ORN (Bozza et al. 2004). for biological functions of OMP). Immunohistochemical and anatomical analyses of OMP-/- olfactory epithelium revealed no differences in morphology or protein expression, suggesting that OMP may not play a developmental role.

Interestingly, OMP-/- ORN axons are compromised in their ability to properly target the correct glomerulus in the bulb (St John & Key, 2005). In addition, the olfactory bulbs of OMP-/- mice are smaller and display reduced tyrosine hydroxylase activity and CCK content, changes also observed in bulbs of odour- deprived wild-type mice. These observations imply that OMP alters afferent input to the bulb by modulating the activity of ORNs, which is indeed the case. The odour- induced electrolfactogram, a mass epithelial recording, revealed that ORNs which lack OMP have a response, where not a single, but at least three aspects are slowed: response delay, time to peak and the response termination (Buiakova et al. 1996). Single cell recordings confirmed these findings and also Figure 2. Suction pipette recordings from wildtype, A, and OMP-/- , B, olfactory revealed that odour-induced action receptor neurons, which were stimulated with the odorant cineole as indicated by the potential patterns were changed solution monitor above the recordings. Note the compressed time scale in B and the (Fig. 2). Action potentials were severely prolonged termination phase of the response. Such a prolongation was not generated with a 3-fold longer delay observed in OMP-/- ORNs when the phosphodiestease inhibitor IBMX was used to after stimulation onset and firing stimulate (C & D wildtype and OMP-/- ORNs respectively). This stimulation paradigm ‘shortcuts’ early stages in olfactory signal transduction, indicating OMP acts on persisted for longer compared to those early transduction steps. Modified from (Reisert et al. 2007). wild-type recordings (Reisert et al.

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2007), both possibly contributing to vomeronasal neurons also express Buiakova OI, Baker H, Scott JW, Farbman A, the bulbar changes observed in OMP OMP but use an entirely different PLC Kream R, Grillo M, Franzen L, Richman M, Davis LM, Abbondanzo S, Stewart CL & -/- knockouts. OMP ORNs also showed based-transduction pathway. Margolis FL (1996). Olfactory marker protein a severely reduced ability to recover Similarly OMP positive cells of the (OMP) gene deletion causes altered from adaptation due to the 10-fold Grueneberg ganglion express, physiological activity of olfactory sensory slowed termination of the receptor besides odorant receptors, trace neurons. Proc Natl Acad Sci USA 93, 9858–9863. current, an effect which might also amine-associated and vomeronasal contribute to the observed 50-fold receptors. This implies the presence Danciger E, Mettling C, Vidal M, Morris R & reduction in odour sensitivity of of a protein common to all OMP- Margolis F (1989). Olfactory marker protein -/- expressing cells through which OMP gene: its structure and olfactory neuron- OMP mice when tested specific expression in transgenic mice. Proc behaviourally (Youngentob & exerts its function on a range of Natl Acad Sci USA 86, 8565–8569. Margolis, 1999). quite different transduction components. A possible candidate Koo JH, Saraswati M & Margolis FL (2005). might be members of the family of Immunolocalization of Bex protein in the These dramatic and multiple effects mouse brain and olfactory system. J Comp of OMP on the odour response brain expressed X-linked (Bex) genes Neurol 487, 1–14. suggest that it must function at a which have been found to interact regulatory focal point in ciliary with OMP and to be present in ORNs Margolis FL (1972). A brain protein unique to of the main and vomeronasal the olfactory bulb. Proc Natl Acad Sci USA 69, olfactory transduction. In ORNs 1221–1224. activation of an odorant receptor epithelium (Koo et al. 2005). leads, via a G protein, to adenylyl Mombaerts P, Wang F, Dulac C, Chao SK, cyclase activation, increase in ciliary On the other hand, if OMP is truly a Nemes A, Mendelsohn M, Edmondson J & Axel more general modulator of signal R (1996). Visualizing an olfactory sensory cAMP and activation of a Ca2+ transduction cascades, why is its map. Cell 87, 675–686. permeable cyclic nucleotide-gated expression so highly restricted to (CNG) channel, followed by opening Reisert J, Yau KW & Margolis FL (2007). nasal chemosensory neurons, but Olfactory marker protein modulates the cAMP of an excitatory Ca2+-activated Cl- not to other (e.g. chemosensory kinetics of the odour-induced response in cilia channel. Response termination taste or gut) cells? The absence of of mouse olfactory receptor neurons. J Physiol occurs by degradation of cAMP by a 585, 731–740. OMP orthologs in invertebrates CaM-dependent phosphodiesterase suggests that it is not required per se 2+ + 2+ St John JA & Key B (2005). Olfactory marker and removal of Ca by a Na /Ca for chemosensory detection. protein modulates primary olfactory axon exchanger and PMCA activity to Furthermore it can also not be overshooting in the olfactory bulb. J Comp - Neurol 488, 61–69. close the CNG and the Cl channel assumed that OMP only has a role in respectively. On which or on how chemosensory signal transduction, Youngentob SL, Kent PF & Margolis FL (2003). many transduction components since it does not localize exclusively OMP gene deletion results in an alteration in might OMP exert its effect? cAMP to the cilia or vomeronasal microvilli, odorant-induced mucosal activity patterns. J Neurophysiol 13, 13. kinetics have been found to be but is present throughout the entire -/- greatly prolonged in OMP ORNs cell. Youngentob SL & Margolis FL (1999). OMP suggesting that either cAMP gene deletion causes an elevation in production itself is prolonged or Hopefully, in the coming years, OMP behavioral threshold sensitivity. Neuroreport 10, 15–19. degradation slowed. The former is will become less of an enigma and the case, suggesting that the action more of a gift to physiologists too by of OMP in the cilia may be restricted revealing its function and providing to the early stages of signal new insights into signal transduction Icelandic banking crisis: transduction prior to cAMP mechanisms. impact on The Society production: the odorant receptor, G Further to earlier reports on The protein and/or the adenylyl cyclase Johannes Reisert1 Society’s website, I can confirm (Reisert et al. 2007). Hence OMP’s 2 that £523k deposits held with role is to speed up the odorant Frank L Margolis 1 Kaupthing Singer and Friedlander response, which might contribute to Monell Chemical Senses Center, Philadelphia, PA, USA will be guranteed in full by the fast sampling of odour cues and Financial Services Compensation 2 allowing ORNs to re-sensitize Department of Anatomy and Scheme (FSCS). quickly. This is consistent with the Neurobiology, University of alterations in odorant-induced Maryland School of Medicine, The Society has received and -/- mucosal activity patterns in OMP Baltimore MD, USA returned a compensation claim mice (Youngentob et al. 2003). form which will be processed by References the FSCS in due course. Nevertheless, many questions Bozza T, McGann JP, Mombaerts P & remain. Does OMP act directly on the Wachowiak M (2004). In vivo imaging of neuronal activity by targeted expression of a Casey Early previously mentioned transduction genetically encoded probe in the mouse. Finance Manager components? Probably not, since Neuron 42, 9–21.

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Openness and animal animal research' and would much they can take to achieve rather stay 'below the extremists’ transparency and openness without research: are you radar'. But this degree of fear is no provoking those who are sensitive on longer necessary. Recent evidence the issue. doing enough? shows that, thanks to robust police There has been a noticeable shift response and new legislation that If you think that your institution towards more openness on the issue curtails extremist activity, individual should be making considered steps of animal research. In the last few scientists are no longer targeted. towards more openness and would years we have seen more universities like advice and support please post policy statements on their In addition, not all those who oppose contact me ([email protected] websites and an increasing number animal research engage in extremist / 020 7478 4387). of scientists now feel comfortable to activities, in fact the extremists are discuss the animal research aspect of just a minority. Indeed anti- Corina Hadjiodysseos their work more openly. vivisectionist groups use Communications and Public Affairs communications to make their case Manager, RDS This shift did not happen overnight. to the public, not intimidation. Animal rights extremism, the reason AnimalResearch.info most often quoted by those who are Animal research is not a secret to hesitant to being open, is on the those who oppose it. Scientists Scientists and decline. The media have not only publish in peer review journals and researchers are turned against extremists and their present their work at conferences. needed to tactics but are now interested in Those who oppose animal research contribute to a reporting science accurately, know this and regularly search new website on therefore allowing the public to journals for articles. the use of animals understand the scientific process in research better. What’s more, being open about this issue is not about advertising it. It is AnimalResearch.info, a new website In the past 2 years, the Research about communicating the animal about the use of animals in research, Defence Society (RDS) has been research aspect of your research in invites Members of The Physiological spreading the good news and all of your communications Society to share their knowledge and encouraging academic institutions to activities, whether that is with the experience of the research process become more open about animal media, a group of school children, with a wider audience. The website research. members of your local community allows scientists to contribute and politicians. Indeed, the same content directly, putting sound So what do we mean by being open? people that those who oppose information on animal research into Many scientists and administrators animal research are trying to reach. the public domain. If you are across a number of academic interested in making additions to the institutions still remember stories There is a long list of activities site you can register at they have heard about scientists individual scientists and institutions www.AnimalResearch.info. being targeted at their own homes can carry out as part of being open. or being inconvenienced and Our experience in the past 2 years, The site has been developed by RDS, harassed on a daily basis at their however, has shown that in order to in collaboration with like-minded places of work. It comes as no achieve significant change it is organisations worldwide, to provide surprise then that a lot of people important that there is institutional a source of authoritative information have told us that 'they don’t want to commitment on the issue. This is the about the scientific and medical advertise the fact that they do only way to ensure consistency in benefits of animal research. Its wiki- communications which will format allows contributions to be As of December 2008, the Research ultimately work towards gaining made easily by scientists. The articles Defence Society (RDS) will merge with its more public support and creating show how and why particular sister organisation Coalition for Medical better understanding for animal methodologies are used, ultimately Progress (CMP) to create a new research. providing a rationale for your organisation called Understanding research. Animal Research, which will build on the strengths of both. This was the The individual drivers for conclusion of a review by a working institutional commitment may vary Designed with journalists and party of stakeholders in the Summer of from an enthusiastic scientist to an researchers in mind, most of 2008. The work of RDS on openness has equally enthusiastic press officer. AnimalResearch.info’s content is been endorsed by the review committee What’s important is to bring a group presented in a list format, which can and will continue as an integral part of of decision makers together who will be easily searched and sorted. The the activities of Understanding Animal agree on the way forward for the site is written for non-specialists, but Research. institution and identify the steps is referenced and provides links to

Physiology News | No. 73 | Winter 2008 | www.physoc.org ANIMAL RESEARCH / UNBELIEVABLE! PN 31 more technical information and Occasionally, satirists have a different - expert sources. An editorial, review though not altogether pleasant - and validation process ensures that experience, when something they wrote only registered specialists can (Sa)tired as a parody later actually becomes a contribute, keeping the information reality. This happened to one Professor out? of Physiology I know, who penned a on the site clear and credible. The column some years ago in this very slot1 aim is to give scientists a voice and to where he was quite uncomplimentary It is a fair while since I have been here, give non-scientists a better under- about assessing peoples’ research by but current chief satirist Keith standing of scientific research. citation counting and metrics. To Cormorant seems to be on vacation emphasize just how ridiculous it was, he (satirical sabbatical?). Or perhaps he just The content includes summaries of satirically suggested creating an index needed a rest. Anyway, they asked if I called the Centrifugal Factor – a number the animal experiments which led to would return and fill in. Nobel Prize winning discoveries, that quantified an author’s degree of credit for a paper based on his or her details of how particular animal People sometimes ask why I stopped position in the author order. The nearer models are used to study aspects of writing the Unbelievable! column. The to the outer ends of the paper the basic and applied research and main answer is that I ran out of satirical author came – the nearer to either first gas, or more accurately out of subjects general articles or lectures that show or last authorship – the higher the CF, to be satirical about. I sometimes think how animals have contributed to and the more points the author scored. medical knowledge. Contributions each budding satirist only has a certain number of satirical articles, or subjects such as further concise summaries Imagine my friend’s consternation a few of such, in them. Once you have written that show why a particular animal years later when Imperial College was about all of these subjects, you can model is suited to an experiment or reported (notably in these pages by either re-cycle the same themes over 2 area of research are especially and over (a method favoured by many David Colquhoun ) to be using this welcome. national newspaper columnists) or you precise method in computing 'research can simply admit that you have 'dried' output metrics' for their staff. Those who work with animals often and that it is time to quit the stage. As they say: you couldn’t make it up. find it difficult to speak about their research beyond scientific circles. A different reason sometimes given by satirists for retiring is that reality itself So, after all that gloom, is satire dead? The new website now gives scientists Well, despite the above gloom, an opportunity to be more open has gone beyond satire. As I write this, one of the two US political parties has hopefully not – at least as long as there about their work, sharing the nominated a candidate for the Vice are satirists, or subject matter. And both rationale for their research with a Presidency, Sarah Palin, who believes in of these do seem to renew themselves, wider audience. With your support, intelligent design rather than evolution by despite the problems of parodic reality we hope that AnimalResearch.info natural selection. She has also been and personal satirical atrophy. Individual will become the ultimate source of reported to believe in witches, that satirists come and go, but satire seems expertise in this area. dinosaurs and people co-existed not that to keep going. long ago, and perhaps that the earth is However, if there is one thing all satirists To view the current content, register only 6000 years old. This in the 21st are agreed on, it is that is that we never century. as a contributor, or make have enough ideas. suggestions for improvements, visit And by the time you read this, she may www.AnimalResearch.info. For Which is where you come in. further information please contact even be Vice President. I do struggle to see how satire can compete with that. [email protected]. The inspiration-starved satirists here at Physiology News are keen to hear your This view is not original to me, of course. ideas for subjects for satirical columns. The great American musical satirist Tom So all ideas, please, or accounts of things Physiology News Lehrer made the same point back in the that have happened to you that are mid 70s, after the Nobel Committee If you have enjoyed this issue of crying out to be parodied, to the awarded the 1973 Peace Prize to Henry Physiology News please don’t Executive Editor3. throw it away. Put it in your coffee Kissinger and Le Duc Tho, two noted room so that others may see it too. exponents of war and Realpolitik. Since Dr Kissinger had been heavily involved in We promise only to steal the good ones. one the 20th century’s greatest bombing We are always looking for campaigns – the 'carpet-bombing' of Mark Cain interesting features, meeting Cambodia, a country the US was not Notes reports, news items and even at war with at the time – the 1973 1 Anon (2005). Unbelievable! Physiology News photographs. Contact Linda Peace Prize award was – how shall I put 58, 50. Rimmer in The Physiological this? – imaginative in concept. As Lehrer 2 Colquhoun D (2007). How to get good Society Publications Office said, it was hard to know where you science? Physiology News 69, 12–14. ([email protected]) with your could go with satire when real life events 3 Email ([email protected]) under a suggestions. exceeded, in parodic power, anything pseudonym if you prefer – I recommend an one could dream up as a mere parody. anonymous Gmail account – will be fine.

Physiology News | No. 73 | Winter 2008| www.physoc.org 32 PN REPORTS

Hands on science in done within a school environment, such as looking at materials under schools very high resolution, access to telescopes and monitoring remote Chrissy Stokes and I went along to environments such as Mount Everest, this Parliamentary and Scientific and getting around various Health Committee seminar on 22 April, and Safety issues. It is hoped that chaired by Douglas Naysmith MP. such initiatives will also foster The future of physiology to some interest in collaborative, and extent depends on children being international research, and enhance enthused by science in school, and science provision at poorly funded getting a good grounding in institutions. There are important practical science skills. Our Society implementation issues, such as has become very concerned in the schools needing good IT knowledge last few years about how this may be and equipment to access such becoming neglected in schools, so programmes, and the available we were keen to hear what they had commercial software often has many to say. The seminar was addressed by shortcomings. The subsequent Tina Overton (Higher Education Various initiatives now exist to try to debate showed people’s concerns Academy/Department of Chemistry, promote practical science teaching. that resource problems in schools University of Hull), Karen Bultitude These include an EU funded scheme, might lead to teachers favouring (Science Communications Unit, Hands on science, various Higher remote resources over the more University of the West of England) Education Funding Council projects ‘ hands on’ stuff, but it was generally and Hugh Cartwright (Department (e.g. Chemistry: the next generation). agreed that all sorts of resources and of Chemistry, University of Oxford). Often these initiatives are mainly opportunities should be made about curriculum enrichment, but available wherever possible, as our The main points that struck us from they are becoming increasingly over-riding concern is to get kids to the discussion were as follows. ‘ whizz bang’, hands on, and trying study science. to attract potential students to local A HEFCE report in 2005 resulted in universities. Important aims are I had the opportunity in the debate the Secretary of State identifying enhancement and enrichment, such to flag the existence of our Bristol STEM disciplines as being vulnerable, initiatives need to enhance what colleagues’ Lab on a lorry, which in particular the high profile closure teachers are already doing. Projects takes physiology experiments of some university departments. include Robocop junior, Awesome around schools and other venues. Even the biosciences are vulnerable if athletics and Meet the gene machine This was felt by participants to be an you exclude currently popular (which uses drama to stimulate excellent initiative, and I suggested subjects such as sports sciences. The debate). There was a strong that Government should fund the situation is stark when you consider consensus that the best way for creation of lorries to support that the higher education sector has children to learn is through doing teaching in other STEM disciplines. quadrupled in the last few years, so experiments. Practical science our STEM ‘market share’ has initiatives need to enthuse by taking Liz Bell plummeted. Recruitment of science a cross-curricular approach whilst students has not been helped by a being closely linked to curriculum crisis in science teaching in schools, requirements, to be interactive and Should it be illegal to sell with the core science subjects participatory, build on existing genetic tests except increasingly not being taught by networks, acknowledge that their subject area specialists. Good teaching time is precious, be realistic through a doctor? science role models in schools are about equipment needs and This energetic and topical Wellcome essential, reinforced by good careers availability, and be good at reaching Debate on 10 July with the general advice. Some efforts are being made disadvantaged kids. public included presentations from to tackle this, including giving Christine Patch (Consultant Genetic ‘golden hellos’ to science graduates This support for all things to do with Counsellor, Guy’s/St Thomas’s to enter the teaching profession. Hands on science, led to a very lively Hospital), Kari Stefansson (Managing Science Learning Centres are there to debate at the seminar, when Hugh Director, deCODE Genetics), Alison try to give support to teachers, but discussed the potential contribution Stewart (Principal Associate, Public an issue is that they have to charge of Hands off science to the issue, by Health and Genomics Fdn) and Mark for courses, and need teachers to be providing remote access to Henderson (Science Editor, The released from their duties, making experiments in schools. This has the Times). It was facilitated/refereed by participation a difficult issue for advantage of giving children access Toby Murcott (science writer/ under-resourced schools. to experiments that could not be broadcaster).

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The session started with Henderson to be clear. Companies should be Osborne (Professor of Science sharing his experiences of buying an allowed to market their products Education, King’s College London). off-the-shelf genetic profile of direct to the consumer but be held His research interests include how to himself. It gave him a lot of useful to high technical and other develop students’ understanding of statistical information, but held no standards. Thus an outright ban is the nature of science, exploring what great surprises from what he was not the right way to go, but there is a scientists and science educators expecting from his own knowledge policy and regulatory gap, and the should be taught about the nature of of his family history. An issue was healthcare professions need to be science and a major ESRC funded how much use this additional more closely involved as gatekeepers project exploring Science careers and statistical information would be in and intermediaries. This needs to be aspirations: age 10–14. I found his the average 10 minute consultation addressed to prevent possible talk very thought provoking. with a family GP. scandals leading to public loss of confidence and the inhibition of Some of the key points I took home The other presenters then shared future developments. More could included the mixed messages we are strikingly similar perspectives on the probably be done using existing getting on whether the state of issue. There was a general feeling consumer protection legislation. A school science education in the UK is that independent genetic testing public funded healthcare system is a problem. Governments around the should not be illegal, but should be vital to prevent financial incentives world are very worried about this better controlled. Real harm can leading to misuse of results. More issue, with various pessimistic result when such activities are driven public funding for tests should also reports about the future supply of into the illegal sphere as patients will be considered to prevent potential scientists. However, the situation always be tempted to access such 'ghettoisation' of the poor in terms may not be as bad as people fear. tests, if need be via the internet from of access. The number of A Level students countries that do not have strict taking chemistry and biology will hit controls. Benefit or harm depends It was also felt that genetic tests current Government targets, very much on the context in which it were part and parcel of a new although physics is a problem. In the is used, and can include false re- relationship between patients and USA, the supply of biomedical PhDs assurance, causing anxiety (including the healthcare professions. Patients aged 35 or younger has increased by to other family members who have now actively seek information on 50%, but the number of tenured not taken the test) and inappropriate their conditions, and expect to be positions available remains flat and and expensive healthcare follow up. directly involved in the processes of the unemployment statistics indicate Genetic tests can be particularly diagnosis and treatment. There is that there is no real shortage of useful in identifying health issues not also a bigger emphasis on people in general. Some specific obvious from an individual’s family preventative health management areas, such as maths and history. Results need interpretation with people expecting to manage pharmacology, may have problems. for the patients, as well as basic actively their own health. Tests are Science is now a global endeavour, analysis, and people facing risk of enabling a more pro-active approach with people routinely being recruited serious disease need specific to managing potential illnesses, are to fill positions from other countries, counselling. People often find it already saving lives and can be so the future of science is not just difficult to understand the difference expected to dramatically alter our dependent on engaging the interest between relative risk and an existing, largely reactive, healthcare of local school children. individual’s personal absolute risk of system. Policy makers will need to suffering from any disease. From an pay particular attention to the Various surveys have noted that in ethical standpoint, there is a general impact on the insurance industry, developed countries, students seem view in Europe that children should and consider how far tests for generally less interested in studying not be tested for adult diseases, but specific issues should be allowed to science than in the developing world, sometimes this is essential where undermine the long established particularly the girls. So how do we some diseases need to be diagnosed insurance principle of spreading risks engage them? Girls seem to prefer early for effective treatment. by distributing them across the subjects showing the social population. relevance of science, for example To ensure good standards we need cancer, boys preferring more gung- to know that reputable labs are Liz Bell ho subjects such as atom bombs, conducting the tests, that the and traditional approaches to efficacy of tests is based on good Engaging young teaching solid blocks of physics, peer reviewed evidence, that people chemistry and biology only seem skilled in interpreting the results are people with science to work for a minority of 14–16 involved, that we control who has year olds. Evidence shows that if access to the results, and that there How, why and when? you are going to interest young is proper follow up. Ways of getting The Science Council guest lecture people, you need to grab their redress if things go wrong also need was given on 13 June by Jonathan attention before age 14, after that

Physiology News | No. 73 | Winter 2008| www.physoc.org 34 PN REPORTS they have already started shutting support, science teachers, or none of training day began with a speech their mental doors on potential the above will happen. from John Meredith (CMP) about the careers. Success in maths at schools aims of the course and an ice- also strongly influences people’s Liz Bell breaker. It was amazing to meet so interest in taking up areas such as many volunteers from diverse physics, but does not correlate so scientific areas and countries and to strongly in decisions to study life CMP Making progress hear about each research area. What sciences. training day really struck me was that each person has such great passion and A new initiative has been developed There may also be issues with enthusiasm for what they do. Rob by Coalition for Medical Progress current teaching approaches, with Kitson and Caroline Cutler (EdComs) (CMP) to train scientists to go into too much emphasis on the recall of talked about engaging a young schools and talk to young people facts rather than facilitating audience, drawing from their own about the uses of animals in medical understanding, an over-reliance on experiences in the classroom as research. The hope is that this 'transmission' making it seem teachers. Ian Garrod (Pfizer), who initiative will have massive positive authoritative and boring, too much has years of school speaking impact on the debate about ethical copying and repetition, and lack of experience, gave a lot of brilliant animal research by increasing public space for genuine discussion. advice about the issues and difficult understanding and, consequentially Attracting and engaging are more questions from young people. He the support of this. CMP aims to important than force-feeding facts. showed the presentation he gives to make a national, coordinated There may be a particular problem in schools, which gave great ideas for network of school speakers, and primary schools where there is too things to include when preparing aims to be able to provide a much focus on testing kids. The talks. The real highlights of the day volunteer to every school that danger here is that the brightest kids were the talks by the volunteers. requests a speaker within 2 years. will not see science as an intellectual Before attending the day we were Some pharmaceutical companies, in challenge. Additional problems asked to prepare a 5 minute talk on particular Pfizer, have well include lack of adequate careers an animal research-related topic. All established school speaker advice, problems in recruiting the talks were unique and it was programmes but these do not cover enough science teachers to fill really good to get feedback from the entire country which is what vacancies, and making sure that the experienced teachers and schools CMP aims to do. Although there has science teachers we do have are well speakers about the good and bad been increasing public support of informed. bits. animal research in recent years, CMP feels the battle is not yet won He concluded by painting a vision of Training days will be occurring across because there is still a lack of real what science education should look the country in the coming year. CMP understanding of science. This like in the future. To engage more would like to encourage volunteers initiative will aim to reinforce the children’s interest, we need to from all scientific areas who want to public ‘acceptance’ of science and address the needs of the non- share their knowledge with young educate them about it. The initiative scientist, and promote a broader people. Contact John Meredith has come at a great time as the new vision of why science matters, e.g. in ([email protected]) for science curriculum for schools has an feeding the world, controlling more details and to register for emphasis on research ethics and this diseases, water supply, energy volunteer updates. provides a niche into which school production, climate change, etc. to speakers can fit. generate a vision of pursuing a Fiona Randall greater good for humanity. Careers I attended the first Making progress advice should emphasise not just training day on 5 August at the Get involved – write an potential jobs in science, but the Wellcome Centre in London. other career paths that open up article for Physiology News Personally, I wanted to increase my when people study science, talking Have you done something you’d confidence about speaking to school about 'careers from science' as much like to recommend to other young children about animal research. I as 'careers in science'. Science should scientists, attended an amazing have no problems talking to adults be seen as a vital part of a broad training course or got an issue about it but wanted to hear more education, with an emphasis on how you’d like to get off your chest? If from experienced speakers about the it works, not just factual recall. It you enjoy writing then why not common problems that occur when needs to address the interests of girls contribute to Physiology News. We talking to a younger audience. I was and other marginalised groups, and have an annual prize of £200 for mid-thesis writing at the time and make stronger links outside the the best published article written wondering how much I would learn classroom to demonstrate its on- by an Affiliate Member or an from the course, but I was totally going relevance. Finally, we really author within 2 years of obtaining stupid to be apprehensive. The need to invest adequately in, and a PhD.

Physiology News | No. 73 | Winter 2008 | www.physoc.org CaSE PN 35

Campaign for Science Universities will be the sector most affected by the points based visa and Engineering system which is currently being CaSE has been looking at ways to rolled out. There is much to be address the skills shortage evident in welcomed in the new system: the most areas of science, technology, ability of highly-skilled workers to be engineering and mathematics granted a visa to seek work, the (STEM). There are three main strands flexibility of the system to respond to to this work: improving education, labour shortages and the granting of facilitating diversity and ensuring the recent graduates with an UK is attractive and welcoming to opportunity to stay in the UK to seek international students and workers. work. However, the confusion and haste with which the new system is Our first report in this area, being introduced is raising some published last June, developed from anxiety, as is the unresolved question a CaSE meeting at the House of Lords about the status of academic on Secondary science education, visitors. identified as the critical period for Hilary Leevers. boosting numbers of science The UK must also be prepared for graduates. Our second report, own education system can produce changes in the relative attractiveness Delivering diversity: making science the graduates we need. However, of different destinations for STEM and engineering accessible for all, retaining STEM workers here from students and workers. So many followed on from an Opinion Forum developing countries could result in factors in the international world meeting on Under-represented groups 'intellectual asset stripping'. may affect immigration flow and, in science and engineering. Enhancing indeed, emigration. Some of these the diversity of STEM students and International students now play a are self-imposed, for example workers will not only increase the vital role in keeping course numbers changes in the visa system. Some of size of the workforce, but also its up in many of our universities, as do these are external; for instance innovative potential, aside from its the international academics teaching moves by home nations to merit on equality grounds. Finally, those courses. Furthermore, the fees encourage their emigrants back. And we are preparing to launch a report of international students make an some of these factors are global and based on our Opinion Forum important contribution to hard to predict let alone plan for, the meeting on International scientists universities and their living expenses, most shocking instance of which is and engineers held this July, which to the wider economy. On the other the current financial crisis. It is hard you will get a taste of here. hand, there are concerns that high to know how this will eventually levels of international students may affect different countries as a The Government has the ambition of impact upon how some courses are destination of choice for work or making the UK a world leader in perceived or taught. study, but we can be sure that it will. science and innovation. For this to happen, we need the best and Looking at the university subject CaSE reports are sent to politicians brightest scientists and engineers grouping of anatomy, physiology and policy makers as well as our from the UK and around the world to and pathology, international members, and lay the basis of our study and work here. As well as students make up a modest 10% of responses to relevant consultations helping us address skills shortages, students (undergraduate and and continuing campaign work. international scientists and engineers graduate combined). However, the benefit the UK in many ways, such as number of overseas students is Although we have not yet launched increasing diversity and therefore growing 10 times faster than UK the international report, we have innovation and in facilitating students, rising 21% from 1380 in already brought our concerns to the international collaborations. 2005 to 1670 in 2007, as compared attention of ministers and responded with a 2% rise in UK students from to a consultation on the new visa It is important to be aware of various 14945 to 15260. It is essential that system. We urge the Government to tensions around international rising student numbers are properly ensure that it has a wide-ranging and students and workers. For instance, attributed so that we can understand coherent vision for STEM skills in the international workers may ease our their implications and not interpret UK, incorporating the role of skills shortages; this takes the them as indicating that schooling international workers and students. pressure off making sure that our problems have been dealt with. Hilary Leevers All of CaSE’s reports are available at www.sciencecampaign.org.uk/documents/index.htm Campaign for Science and The Physiological Society is a member of CaSE and we appreciate its support and active involvement. To learn more about our work, please visit www.sciencecampaign.org.uk Engineering, London, UK

Physiology News | No. 73 | Winter 2008| www.physoc.org 36 PN LETTERS TO THE EDITOR

A maverick view of the first sentence gives views, held an outlet, and internet-based presumably by all 10 investigators, communication of scientific ideas Physiology News that are totally at variance with the and data offers more ways for Authors of articles in Physiology News modern Joule / Helmholtz views of theories to find their audience. are encouraged to open up new the First Law of Thermodynamics. Our science News and Views articles fields of study and to question The sentence reads: 'Motility is one are mainly ‘sourced’ by asking whether it is possible to improve the of the characteristic features of many authors of recent papers that caught peer review of the science or non- living organisms and involves the our eye in the peer-review science content of some articles. transduction of chemical into mechanical energy' (my under- physiology journals if they would like What does one do if each and all lining). to write a short perspective on their relevant editorial boards for the last paper, and its scientific context, for a 100 years have been actively Physical chemists will note that this slightly more general audience. supporting peer reviews of a false false deduction is not put as a Given this, these articles in Physiology scientific concept and so clothing the working hypothesis but as a definite News necessarily reflect the kind of muscle literature with the erroneous statement. The wrong views are science published by peer-review opinions that they have become the widespread in the muscle literature physiology journals. One could establishment views of editorial and include support by the editorial certainly call that ‘mainstream’, but boards – all without any explicit boards that own the largest impact to me this is a long way from the dissent by Physiology News. factors. Your Editorial Board is no conscious policy of suppression of exception, but all peer reviewers and the scientifically unorthodox that Thus, the view that muscle protein editorial board members clearly Wilfred Widdas seems to be was able to convert the chemical need to give reconsideration to this implying. energy of adenosine triphosphate field of muscle science. Mechanical into the mechanical work of work can produce heat energy, but Hairs’ apparent shortening has been held for a not the reverse. century, although based on an experimentally unsupported Wilfred Faraday Widdas* assumption and quite at variance University of London, UK with the Joule / Helmholtz concept of the First Law of Thermodynamics. Editor’s note: This view of the First Law of the Professor Widdas' ideas about 1840s has been accepted and the SI muscle and energy are for others unit of molecular energy is now the than me to debate. I am, though, a Joule. bit puzzled by his remarks about Physiology News. The American physiologist Wallace O Fenn published the right ideas in Although Physiology News has an I can shed some light on the 1923–24, but his work has been Editorial Board, this does not operate photograph in your last issue largely neglected by peer reviewers in the way that learned journal (Physiology News, , 48). and editorial boards. However, after editorial boards do, since Physiology 72 being denied printing space by the News is a magazine and not a The woman on the left in the front editorial boards of five reputable scientific journal. Submissions to row is Pat Barford. She graduated journals I have been able to publish Physiology News are not peer- with a PhD in biochemistry from an article on the unorthodox views reviewed in the traditional journal Cardiff University and moved to of Joule’s and Fenn’s work in the sense, either by external experts or Leicester with her husband, Derek, open access journal Int J Mol Sci by the Editorial Board. They are read who was a lecturer at what was then (2008, 9, 1730–1752) … and this is by the Editorial Board, and Leeds Poly. She worked on the now available to anyone interested. sometimes edited for clarity, but biochemical side of Reg Chapman’s that is all. work then, but shortly after that The unsupported view widely held by Derek moved to the medical school muscle scientists is well illustrated in It is hardly a secret that maverick in Birmingham and Pat left Leicester a multi-author paper on x-ray views have a harder time getting into University and took up a post at analysis in Science (Rayment I et al print in scientific journals than Aston University, I think. The woman [1993] 261, 50–58 ). The analysis of ‘ mainstream’ views, and are on the right is Josie, who was Reg x-ray structures is very important but subjected to tougher scrutiny. Chapman’s technician. The photo is However, this is one of the prices for probably from 1971. * We are saddened to report that having peer review. There are now so Wilfred Widdas died peacefully in his many scientific journals that a sleep on 29 October. An appreciation will David Cotterrell follow in a future issue. determined author will always find University of Chester, UK

Physiology News | No. 73 | Winter 2008 | www.physoc.org AFFILIATE NEWS PN 37

Make the most of opportunities to travel – Federation of European Physiological Societies (FEPS), International Brain conference attendance as a PhD student Research Organisation (IBRO), Guarantors of the Brain and the Attending conferences is part of the Graduate School at Newcastle job when you are a scientist and, in University. I have presented posters my opinion, one of the best bits and and talks at a large number of great fun. Doing a PhD or even a conferences ranging from Harrogate post-doc in the lab can be isolating, to Australia. I have been able to working alone on a focused project. meet top researchers in my field, Attending a conference, if you make people from other areas of research the most of it, can be invigorating and other young scientists. It is great and gives you the chance to see what to mix with other young scientists other people do, how they do it and exchange ideas and discuss differently or even how you do it Fiona Randall presents a poster at the experiences. Talking about work in better! Every aspect of a conference FENS meeting in Geneva (above); Social this setting can help you to think is a learning experience that allows activity staff pictured with Naturally 7, about where you want to go in the who played at the opening night of the you to think about your science, future, and there are worldwide FENS meeting (below). Daniel Haggerty, think about other peoples’ science opportunities. There is always a and think about your own future in Newcastle PhD student, takes time out from the IBRO conference in Australia large programme of symposia where science. As scientists at the very (bottom). you can hear the lead scientists in early stages of our career, conference your specialist area speak and also attendance is the gateway to our opportunities that attending learn about the great array of work futures, the chance to meet face to conferences provides for young that goes on outside your field. This face with other scientists, see how scientists. Conferences provide the is a great place to put names to faces they work and whether we’d like to chance to present your work to a - those big names on the papers you work with them or in their area. new audience, and discuss ideas and read have a face you can remember - network, and see the world. You just this is especially good if they come to What I am really trying to do in this need to convince your supervisors to chat to you at your poster! article is make you aware of the let you out of the lab! Submitting your first abstract to brilliant funding opportunities for present at a conference is so exciting. travel available to PhD students and During my PhD I have kindly received It reminds you that your work is young post-docs. There are more funding to present my work from important and you can be proud to travel awards available at this stage, The Physiological Society, British show it off to the scientific and this reflects the invaluable Neuroscience Association (BNA), community. Poster presentations provide a perfect opportunity to practice talking about your work to a new audience in a fairly informal manner, where you can chat, exchange ideas, brainstorm. Giving talks can be daunting but really rewarding at the end when the audience give feedback and ideas.

Conferences occur all the time, all over the world. It is definitely worth finding out the best conferences in your field. Choose the ones with good science AND a good location. Attend the conference social programme - they always provide a more informal environment for networking!

The Physiological Society provides travel awards up to £400 for Affiliate Members to attend conferences up . See www.physoc.org for details. Fiona Randall

Physiology News | No. 73 | Winter 2008| www.physoc.org 38 PN EDUCATION

Young Physiologists’ Symposia Young Physiologists’ Symposia – 2009 Each year, The Physiological Society provides support for small groups of Sheffield University scientists at the early stages of their 6–7 April research careers to set up and run a Physiological signalling: from scientific meeting. genes to function The symposium will provide an Organising a scientific meeting is opportunity to showcase research complex and requires the on physiological signalling, with a development of management skills – focus on multidisciplinary with regards to people, time and approaches, such as microscopy and genetics. Sessions will include: budget – all of which are useful in cardiovascular physiology, metabolism and endocrinology, neuronal and the pursuit of careers in and outside sensory physiology and non-excitable cell signalling. of the lab. Registration is now open. All abstracts will be accepted for poster In 2008, The Society supported two presentation. For more information please visit Young Physiologists’ Symposia (YPS) www.bms.dept.shef.ac.uk/yps or contact [email protected]. – one in Manchester earlier in the year, and the second, reported here, which ran as a satellite to Physiology University College Dublin 2008. The feedback from organisers 7 July and delegates, as always, was Muscle: function and dysfunction positive: organisers value the The symposium will include sessions on skeletal muscle plasticity in health opportunity to develop skills outside and disease and the role of smooth muscle. of research, and delegates appreciate the opportunity to present their University of Leicester work amongst their peers. 23 – 24 September In 2009, we will be supporting four Ion channels and receptors in events as outlined in this section. We cell physiology hope this increased support will This symposium will focus on how enable a greater number of early- ion channels and receptors regulate stage scientists to benefit from the physiological processes in cardiac, opportunities YPS offers. neural and vascular tissues as well as in apoptosis. The presence of leading researchers in the four featured areas More information regarding this will provide the young investigators attending the meeting with an scheme can be found on our website unprecedented opportunity to hear cutting edge research in their selected at www.physoc.org/education. areas. Additionally, the breadth of research areas being covered across the sessions provides exposure to a broad range of cell physiology techniques. Chrissy Stokes For more information please visit www.le.ac.uk/CPP/events/events.html or Experiment meets contact [email protected]. theory Young Life Scientists’ Symposium 2009 (YLS2009) Lesley Caldwell reports on the The Physiological Society will also be supporting YLS2009, which will be Young Physiologists’ Symposium hosted at Bristol University in Spring 2009. The title of the symposium is Neurological disorders: from molecules to medicine and will include sessions at the University of Cambridge on degenerative disease, mental health and regenerative medicine. The 2008 Young Physiologists’ Symposium, Experiment meets theory: This event has been co-sponsored by the Biochemical Society, the Genetics integrated approaches to neuroscience, Society, the British Pharmacological Society and Promega, who will be was hosted by the Department of supporting The Promega UK Young Life Scientist Competition. Physiology, Development and Neuroscience (PDN), at the If you would like more information on YLS2009, please email University of Cambridge, UK on July [email protected]. 12 and 13, preceding The Physiological Society's Meeting, Physiology 2008.

Physiology News | No. 73 | Winter 2008 | www.physoc.org EDUCATION PN 39

The symposium was organised for young scientists by young scientists (neuroscience PhD students and post-docs from the University of Cambridge), providing an excellent opportunity for presenting cutting edge experimental and theoretical neuroscience among peers.

The symposium attracted over 100 delegates from 16 countries, and featured 24 oral presentations and 47 posters organised into three sessions: Intracellular signalling in health and disease; Information processing in neurons and neuronal networks; and Neural control of homeostasis and behaviour.

The standard of presentations was very impressive, creating an incredibly difficult task for our judges (academic volunteers from PDN). We Young Physiologists’ Symposium 2008 awarded prizes for the best oral organising committee (above): back row presentation (Talitha Kerrigan, from left: Amanda Sferruzzi-Perri, Xavier Alzheimer’s disease: a result of the d’Anglemont de Tassigny, Arne + Nagengast; centre row: Yevheniia deterioration in K channel Mikheenko; front row: Joyce Lam, Olga homeostasis?) and for the three best Larina, Lesley Caldwell (Absent: Rebecca posters (First prize: Tomás Ryan, Rancourt and Kojiro Yano). Delegate NMDA receptor molecular evolution). packs (right) each included a cuddly A prize was also awarded for the neuron toy. Peterhouse college reception students’ favourite presentation and dinner (bottom). (Alexander Arenz, Synaptic representation of whole-body motion Research, the Company of Biologists in cerebellar granule cells). and the Journal of Experimental Biology. In addition, the International To enhance the, already exciting, Brain Research Organisation (IBRO) programme, Michael Shadlen provided £4500 for travel grants, (Professor of Physiology and which enabled students as far afield Biophysics, Howard Hughes Medical as the Ukraine and India to attend Institute, USA) gave a well received the meeting. and inspiring key note lecture, A neural mechanism for decision I would like to express my gratitude making, or how I learned to stop to the hard working committee and worrying and love the bound. to The Physiological Society for their funding, support and advice, Following the first day of talks, the especially Nick Boross-Toby and organising committee hosted a Christabel Stokes. I would also like to symposium dinner and wine acknowledge the invaluable help of reception in the beautiful dining hall our judges and other members of at Peterhouse College, the oldest the Department, namely Alan Cattell college at the University of and Aileen Briggs. Cambridge. This provided an excellent opportunity for the Lesley Caldwell delegates to mingle in more informal PhD Student, Schwiening Lab, surroundings. Department of Physiology, Development and Neuroscience, To support the event, additional University of Cambridge, on behalf funding was raised from the MRC, of the Young Physiologists’ Chroma Technology Corp. USA, Cairn Symposium Organising Committee.

Physiology News | No. 73 | Winter 2008| www.physoc.org 40 PN EDUCATION

Undergraduate Prize Undergraduate Prize winners 2008 for Physiology 2008 Ruth Mears Cardiff University Each year, The Society offers Ales Towers universities throughout the UK and (prize shared with Sarah Towner) Keele University Ireland the opportunity to nominate Sarah Towner a student to receive an (prize shared with Alex Towers) Keele University Undergraduate Prize for Physiology. Umair Shafique King’s College London Nominations, made by The Society Laura Staniland Manchester Metropolitan University Representative, can be for an Orla McDonnell Queen’s University Belfast outstanding student who has Luke Mappley Royal Holloway, University of London performed consistently well throughout their degree, or for a Benjamin William Sansom St George's, University of London student who has completed the best Ciara Lee University College Dublin BSc Honours physiology research Farhabanu Manga University College London project. Luisa Mowat University of Aberdeen Simon Anderson University of Birmingham This year, nominated students were Daniel Towie University of Bristol awarded a prize of £100, free Society Arjun Chandna University of Cambridge membership for 1 year and a certificate of achievement. We are Laura Brown University of Dundee pleased to announce here the 2008 Jennifer Bush University of Edinburgh awardees. David Paton University of Glasgow Tavga Muhammed University of Huddersfield Many additional students were also Sarah Bailey University of Leeds awarded ‘runner-up prizes’of a Yusuf Bhagatte University of Leicester year’s free Society membership. Rebecca Morse University of Liverpool Congratulations to all students on Hayley Dingsdale University of Manchester their achievements! Nichola Jane Conlon University of Newcastle upon Tyne Louise Gates University of Nottingham Society Representatives will be Alice K England University of Sheffield notified by email once the nomination process begins for 2009. Jacqueline King University of Southampton Enquiries relating to the prize should Katy Elizabeth Robinson University of St Andrews be directed to Irrum Magre Shona Cowper University of Strathclyde ([email protected] / 0207 269 Lisa Kennedy University of Sunderland 5726). Claire H McTaggart University of Warwick Helen Webb University of Wolverhampton Irrum Magre Hayley Tyrer University of York Life Science Careers Physiological Society, the Biochemical Society, the Society for Endocrinology Conference 2008 and the Society for Experimental Wednesday 26 November 2008 Biology), will feature talks from bioscientists who are working in (13:00–18:00) different careers ranging from research New Hunt’s House, King's College to science communication. London, Guy’s Campus The Biosciences Federation is holding a In addition, there is a lengthy session custom-made careers conference on presenting yourself in a CV (with designed by scientists for scientists. specific examples of bioscience CVs), The conference will highlight some of as well as the opportunity to visit the the opportunities available to life exhibition, which includes employers science graduates, specifically and not-for-profit organisations. targeting students who are looking for ideas and contacts related to careers in Full programme and online registration the biosciences. (£10, including refreshments) at www.physoc.org/lscc2008. The conference, sponsored by Astra Zeneca (with additional support from Registration on the day if space the Biosciences Federation, The permits.

Physiology News | No. 73 | Winter 2008 | www.physoc.org FROM THE ARCHIVES PN 41

100 years ago the key respiratory controller until pO2 variations as are obtained by artificially falls below about 60 mm Hg, at which altering the barometric pressure ...' The effects of low atmospheric point what we would now call 'hypoxic Ward’s paper is a curious mix of pressures on respiration. AE Boycott & drive' (a direct stimulatory effect of the travelogue and experimental account, JS Haldane (1908). J Physiol 37, 355–377. reduced pO on breathing) becomes 2 reminiscent of a personal journal and Alveolar air on monte rosa. R Ogier apparent. They also note: 'When the Ward (1908). J Physiol 37, 378–389. conjuring up an era of intrepid travellers. alveolar [pO2] falls to about 30 mm [Hg], The effects of want of oxygen on At points I was reminded of Eric Newby’s urgent symptoms (marked cyanosis and famous A Short Walk in the Hindu Kush respiration. JS Haldane & EP Poulton tendency to fainting) are produced.' (1908). J Physiol 37, 390–407. nearly half a century later. Ward writes: 'On August 3rd, the day of arrival, [I] This time I want to draw attention to In the third paper Haldane and Poulton validate and extend the conclusions of the experienced in a slight degree symptoms, three papers that appear together in the such as shortness of breath, headache, December 1908 issue of The Journal of Boycott and Haldane paper using different gas mixtures at normal atmospheric chilliness, which may be attributed to the Physiology. The key linking figure in these effect of altitude; these however passed papers, and a co-author of two of them, is pressures. This paper employs a re- breathing set-up (illustrated in their Fig. off, but were succeeded on the following James Scott Haldane CH FRS day by a severe bilious attack which came (1860–1936). Haldane was the leading 1) that will look familiar to anyone who has ever been involved in undergraduate on during the night and lasted twenty- respiratory physiologist of his day, though four hours.' outside physiology he is probably less physiology classroom respiration famous than both of his children. These experiments with Douglas bags or drum Although Ward, like Haldane back in were John Burdon Sanderson ('JBS') spirometers. Haldane and Poulton Oxford, was suffering for science, one of Haldane (1892–1964), the mathematician actually mention classes, in another his traveling and experimental turned evolutionary biologist and writer, excerpt that will ring bells with some companions, ‘WDH’, had far worse and the novelist and poet Naomi readers: 'Complete loss of consciousness mountain sickness, despite being Mitchison (1897–1999). without any noticeable signs of preceding ’ undoubtedly the better physically hyperpnoea has also been observed by trained.' Manfully, they completed their JS Haldane first seems to have become one of us in a student of physiology who readings despite the discomforting interested in respiratory physiology via his was performing the class experiment of symptoms. work on mine safety and the role of gases. re-breathing the air of a bag through As was typical of the day, self- soda-lime, so as to demonstrate the Part of WDH’s misfortune, it appears, was experimentation was the norm for effects of gradually increasing want of to have a lower 'normal' alveolar pO2 than Haldane’s work. In a famous study a few oxygen apart from those of a Ward. Indeed, one of the interesting years earlier (Haldane & Priestley, 1905), simultaneous increase in the [%] CO2. He things that emerges from these Haldane and John Priestley (1880–1941) showed the usual marked cyanosis, but experiments on a few select subjects is had established that blood CO2 levels did not even notice any discomfort or the pronounced variability between were the key regulator of ventilation. To show any signs of hyperpnoea.' individuals of parameters like the alveolar do this they collected samples of their CO2 'set-point' for respiration. own alveolar air for the measurement of This demonstration of hypoxia remains a common practical class experiment, O2 and CO2 – used as a surrogate for Among the authors, Arthur E Boycott measuring blood gas levels – under though usually without inducing the (1877–1938) was one of the founders of different atmospheric pressure experimental subject to lose experimental pathology in the UK, later conditions, or more specifically: consciousness – at least in the modern becoming Professor of Pathology at 'at the bottom of Dolcoath Mine in era. The experimenters of 1908 were University College London, and elected Cornwall (2240 feet below sea-level); at made of stern stuff, though, even the then FRS in 1914. 48 year old Haldane. At the end of one the top of Ben Nevis (4406 feet above sea- Haldane published many papers with experiment (reaching an alveolar pO2 of level); and in the chamber for treating students or other junior members of the patients with compressed air at the around 25 mm Hg) he is recorded as: 'At end very blue and confused. Great Oxford Physiology Department. Poulton Brompton Hospital, London (at an excess and Ogier Ward are listed on the 1908 of pressure of about two-thirds of an hyperpnoea and distress, much twitching.' papers as 'B.A.' and thus seem likely to atmosphere).' have been clinical medical students who The three 1908 papers share the habit of The middle paper of the three, by R Ogier had earlier completed physiology the authors being simultaneously the Ward, takes a quite different form. Ward intercalating degrees. Both subsequently experimental subjects. The experiments in was also an experimental subject in the went on to distinguished medical careers, the first paper were carried out: experiments in the Boycott and Haldane Poulton as a consultant physician at Guy’s '… in the large steel [pressure] chamber paper. We learn in his own paper that he Hospital, and Ogier Ward as a leading recently presented to the Lister Institute was 'nominated by the Royal Society to urological surgeon. A nice account of by Dr Ludwig Mond. This chamber… is the International Laboratory on Monte Haldane’s science, including his famous sufficiently roomy to enable three persons Rosa.' This laboratory (still in operation) work on decompression sickness and its to work comfortably … Any desired was a mountain hut dedicated by Queen avoidance in divers, can be found in West negative pressure can easily be obtained.' Margherita of Italy in 1893 as an altitude (2008). science research station. It stood at In this paper, Boycott and Haldane extend 15 000 ft near the peak of Monte Rosa, Austin Elliott the earlier analysis of Haldane and the second highest in the Alps. Ward Haldane JS, Priestley JG (1905). J Physiol 32, Priestley to lower pressures, and hence states: 'The object of these experiments 225–266. lower levels of ambient and alveolar O2 was to compare the effects upon the West JB (2008). In Poulin MJ & Wilson RJA than had previously been possible. Their composition of alveolar air, produced by (eds) Integration in Respiratory Control. main conclusion is that CO2 levels remain living at great altitudes, with such Springer.

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Historical Perspectives The final Historical Perspective article has now been published. The full series is available online as an Article Collection or ‘Virtual Issue’ (http://ep.physoc.org [Article / Subject Collections]).

Editor-in-Chief David Paterson hosted the Experimental Physiology Editorial Board Meeting and a splendid Centenary Dinner at Merton College Oxford (above) on 12 September. Editors attending the meeting (below) included (from the left): Denis Noble, Peying Fong, Nick Simmons, Mike Shattock, Mike Hogan, John Coote, Mike White, Jim Deuchars, Stuart Egginton, David Paterson, Nic Smith, Kenneth Baldwin, Clive Coen, Margaret Brown, Paul McLoughlin, Peter Raven and Steve Harridge.

The size of the journal will be increased from 1000 to 1200 pages in 2009. Submissions have continued to increase since publication of the journal moved to Wiley-Blackwell in 2004 with an allocation of 1000 pages and, despite reducing the acceptance rate, there are more acceptable papers than pages available for publication.

The 12 monthly online issues of 2008 have contained an interesting mix of articles with more invited articles than usual to reflect the centenary year (see pi chart, right) .

Physiology News | No. 73 | Winter 2008 | www.physoc.org THE SOCIETY’S JOURNALS PN 43

support for the policy and a jump from 19% compliance during the period of voluntary submission Symposia a significant event in the history of (2005–7) to 56% compliance open access publishing …, as a following the introduction of the Friday 20 March 2009 leading commercial publisher has new policy mandating submission. Altered placental functions as a cause of The report states that the policy ‘is altered fetal growth now expressed confidence in a business model once deemed, at designed to preserve the critical role At Society for Gynaecological of journals and publishers in peer Investigation, Glasgow, UK. best, experimental, and often called untenable. ’ In the same month the review, editing and scientific quality Monday 20 April 2009 Open Access Scholarly Publishers' control processes’. NIH will continue The world within – impact of the intestinal Association (http://www.oaspa.org/ ) to consult with community to microbiota on whole body physiology and was launched by 10 founding implement the policy in ‘the most pathophysiology member organisations involved in efficient and effective manner At Experimental Biology 2009, New open access publishing, to support possible’. Orleans, LA, USA. and represents the interests of open Carol Huxley Wednesday 8 July 2009 access publishers. Novel insights into oestrogen actions References At The Physiological Society Annual Open access and citations. The LJ Academic Newswire Oct 7, 2008 Meeting, Dublin, Republic of Ireland. first randomised trial shows no (http://www.libraryjournal.com) effect Davis P. M. et al. (2008). Open access Friday 31 July 2009 (10:00–12:30) publishing, article downloads and Dynamic aspects of functioning membrane Another thread in the open access movement relates access to articles citations: randomised controlled trial. proteins BMJ 337, a568. and with usefulness – are open access Friday 31 July 2009 (10:00–16:30) articles cited more? If access to http://publicaccess.nih.gov Physiological regulation linked with relevant articles is a problem for physical activity and health scientists, they should be. A number The disinherited hyphen At IUPS, Kyoto, Japan. of studies have been published, with Experimental Physiology, like The Journal conflicting results, but in July the of Physiology, has a well-deserved For full details of these, and other British Medical Journal published the Symposia as they are approved, visit reputation for its consistent style. The http://jp.physoc.org/misc/sympspecial.shtml first truly randomised controlled trial consistency owes much to the Black of open access. The study by a group Book, the style guide compiled in The from Cornell University used articles Society’s Publications Office over the Developments in open from the American Physiological years and updated as conventions access publishing Society journals, making random change. Biochemical nomenclature has articles open access and then normally accorded with that in the Springer buys BioMed Central. measuring citations after a year. No Biochemical Journal. Is open access publishing effect of open access was found, becoming mainstream? suggesting that while patient groups In 1992 PC Pook et al. submitted a may be troubled by lack of Rapid Communication to Experimental Early in October, BioMed Central Physiology. It was quickly accepted (77, immediate access to the latest (BMC), the first free-to-read journals 529–532) and the copy-edited proof research, researchers are not. It has publishing company, was sold to the sent to Jeff Watkins, the corresponding been pointed out that a year is very large commercial publisher, Springer. author. Jeff asked why 2 mM Mg2+ had early in the life of a physiological BMC was set up in 2000 as statement been changed to 2 mM-Mg2+. On being research article to be measuring its of faith by proponents in open access told that the Biochemical Journal used a publishing, with authors and usefulness and lead author Phil Davis hyphen, he again said ‘Why?’ When sponsors paying the costs of has indicated that the study will questioned, the longest-serving publication. To date BMC has relied continue. member of the Biochem J editorial staff heavily on sponsorship to cover said ‘Because that’s how it always has costs, and the inequities of author- NIH consultation. No change been.’ Although The Physiological pays publishing – only the well- in policy Society likes to maintain its own funded can pay – are still being The NIH has completed a traditions, it had no compunction debated. It remains to be seen consultation with publishers, patient about casting off those of the whether current full open access to advocates, scientists and university biochemists. The hyphen was ejected all articles in BMC journals continues, administrators on its policy requiring from both our journals as rapidly as their Press deadlines allowed. but the acquisition is a sign that the funded investigators to submit their Interestingly, it disappeared from the open access publishing model is final accepted manuscript to PubMed Biochemical Journal in January 1993. coming of age. According to the US Central within 12 months of Library Journal, this development ‘is publication. They report broad Ann Silver

Physiology News | No. 73 | Winter 2008| www.physoc.org 44 PN TRACES OF THE PAST

The history of Physiology Department in the 1950s stick in my mind: Pat Smith and physiology George Renwick. As a student, I had The Society’s History & Archives little contact with the Head Committee actively promotes Technician Tom May. interest in the history of physiology. We aim to preserve the experiences, Pat worked in Surgeons Hall (the skills, ingenuity, anecdotes and home of the Royal College of artefacts of physiology. The Surgeons of Edinburgh) as well as in Committee is seeking help from the Department of Physiology. As Society Members in two of its befitted an Irishman, he was keen on activities – preserving physiological the horses and ever ready to place equipment and recording oral bets for any one who asked. His histories. stories from his early years in the department were usually gruesome. Physiological equipment Edinburgh at that time had a The Committee would very much considerable population of meths like institutions and departments to drinkers (methylated spirits identify and maintain any historically produces prolonged drunkenness important physiological equipment. Historically important physiological associated with optic neuritis and In particular we look out for unique equipment on display at The Society’s blindness). These unfortunates used pieces of equipment, usually hand- Cambridge meeting – Richard Adrian’s to congregate under the back made or modified in departmental ‘ muscle bicycle’(above) and the Keith windows of the department from workshops, which have contributed Lucas spring pendulum, 1908 (below). which the lab boys would drop to the advancement of the subject. If meths-soaked cotton wool pledgets. you or your colleagues (including people who have been involved in They also dropped penny coins – but older technicians) are aware of any physiology. The individuals include here’s the rub – the horrid boys first such equipment please do let us technicians, research assistants as made these red hot in a Bunsen know. We cannot promise to take well as physiologists. Indeed the burner. them off your hands – a lot depends former often give more insights into on size – but we can either ask the what really happened than the latter! George was much younger than Pat Science Museum to store particularly The histories are recorded – a lab boy rather than a technician. important articles or suggest discussions which are transcribed He was always cheerful despite museums local to you who are often and stored in The Society’s archives. marked kyphosis (TB was then rife in delighted to exhibit them. What interests us, and we hope Scotland with all students having a future historians of science, is how compulsory annual chest X-ray). Oral histories things happened; what the When one of Mary Pickford’s visiting The Committee oversees a growing circumstances were which lead to a colleagues told George that Mary collection of oral histories from particular piece of work or discovery; wanted some of his blood he, ever what the cultural context of the time willing, gave it unquestioningly was. If you can suggest anyone though, when asked, he did say that whose experiences you think are he’d never given any before. Luckily, worth recording, we would be Mary discovered the confusion of delighted to hear from you. George, the boy, with George, one of her experimental dogs, before her If you are able to help in either experiment was wrecked. activity, please do get in touch with me ([email protected]) A little bit of freelance photography one lunch time got George into hot Dafydd Walters or, rather, cold water. He had left his Chair, History & Archives Committee prints to rinse under a running tap. When the plughole blocked, the water that flowed down the stairs Memorable bore with it the identity of the technicians perpetrator in the form of several Physiology News 67 (p. 47) contained self-portraits. a memoir of Jock Austin that I wrote with Iain Donaldson. Two other Ann Silver technicians in the Edinburgh University of Cambridge, UK

Physiology News | No. 73 | Winter 2008 | www.physoc.org INTERNATIONAL NEWS PN 45

The Society worldwide In 2007, David Eisner finished his term as International Secretary. David’s tenure was hugely successful, and a great deal of work had been done to advance physiology as a discipline – and to advance The Physiological Society’s reputation – worldwide.

However, many of the schemes we had in place were devised a number of years ago, and in response to the collapse of the Soviet Union. Therefore, this was judged a good time to review The Society’s international activities. Stepping back and looking at why a society such as ours needs an international policy reveals two overarching principles:

International relations Maintaining established relation- Fireside singalong at the 2006 Kiev • maintaining established relation- International Workshop (above); ships with outside groups and ships with outside groups and societies participants at the 2006 Venezuela societies; International Workshop (below). • setting up links with groups or The Society is an integral member of societies with whom we have both the Federation of European good way of maintaining more formerly had little contact. Physiological Societies (FEPS) and regular contact than the 4 year IUPS the International Union of cycle and sporadic FEPS meetings. Development Physiological Sciences (IUPS). Key to • helping to develop resources and the success of both these Furthermore, once we have good practice in areas where international bodies is the established relationships with groups physiology teaching and/or maintenance of good links between or societies with whom we have research suffer from lack of their largest members. Closer ties formerly had little contact (e.g. resources. with other large physiological recently the Brazilian and Chinese societies (e.g. American, societies) we need to make sure An international strategy based on Scandinavian, and German societies) these links are preserved for longer these principles would enhance The would allow better coordination of than the initial meeting. Again Society’s profile and reputation, and strategy within both FEPS and IUPS. smaller activities, run in partnership support physiology internationally – with these societies, would be a way which is part of our charitable Small activities, run in partnership of maintaining these links. objectives. with these societies, would be a Setting up links with groups or societies with whom we have formerly had little contact The establishment of relationships may overlap somewhat with the developmental aspects of our activities. The aim should be that The Society has contacts with those involved in physiology everywhere in the world. As mentioned above, newly established relationships need to be followed up and maintained.

Spreading resources and good practice The development aspects of The Society’s international policy are

Physiology News | No. 73 | Winter 2008| www.physoc.org 46 PN INTERNATIONAL NEWS well established. There are two ways whereby we sponsor symposia at a large society such as ours can offer each other’s Main Meetings. This help to those whose physiology is activity – the Joint International less developed: Exchange Symposia scheme – is to be formalised and extended to • by providing financial support; include the German and • by exporting the knowledge and Scandinavian physiological societies. experience of our Members. Indeed the former has kindly submitted a proposal for Physiology We are lucky in this country in 2009, which has been accepted having physiologists of the highest alongside one from the APS. The standard – in both teaching and Scandinavian society has agreed to research - who have access to the submit a proposal for 2010 in very best equipment. Utilising this Manchester. huge resource would not only do more for the advancement of Participants at the 2006 Joint As ever, The Society will work very physiology worldwide, it would save International Meeting in Brazil (above); hard in a developmental capacity, The Society money, and get more of entertainment at the 2006 Kiev spreading resources and good the membership engaged in Society International Workshop (below). practice to groups or societies where activities. schemes – and draw up some new physiology needs support. The ones – in order to refresh our International Senior and Junior If we agree that utilising the international strategy. Research Grants will support knowledge and experience of our physiological research overseas, Members is the best way to help As before, International Workshops through financial support and physiology internationally, then and Joint International Meetings interaction with a sponsoring there are two ways of doing this: (such as next year’s meeting with Member of The Society. Alongside • we support our Members going the Society of General Physiologists this, the David Jordan International abroad to the places they are in Woods Hole, USA) can be used to Teaching Fellowship will give needed; establish and maintain relationships. teachers/learning support staff • we support overseas The same is true of the International based within UK and RoI, or overseas, physiologists visiting the UK. Guests (previously Foreign Guests) an opportunity to visit an institution scheme, which will see leading of their choice in order to develop or Both can be of use, however a skew physiologists from the international acquire teaching methods of benefit towards the latter seems the more scientific community attend to the teaching of physiology in their sensible, as we have state-of-the-art Physiology – our Main Meeting – home institution. equipment and institutions in the UK which in 2009 will take place in from which foreign visitors would Dublin. The details for all these schemes are benefit hugely. still being finalised, with a view to Maintenance of relationships is an accepting applications from next With these guiding principles in extremely important element of this year. mind, I have been working with the new strategy, in the past we have Executive, Meetings, and Education had an informal agreement with the As international strategy touches on Committees to review our current American Physiological Society (APS) all the activities which The Society undertakes, Mike Spyer as Deputy President of The Society will be responsible for overseeing the strategy and its implementation.

We are always grateful to hear from Members of The Society who have contacts overseas. At the moment, we are particularly looking to expand our contacts in India and south Asia. I would very much like to hear from anyone who has knowledge of, or contacts in, either of these areas.

David G Bennett International Activities Coordinator [email protected]

Physiology News | No. 73 | Winter 2008 | www.physoc.org BIOSCIENCES FEDERATION PN 47

that will benefit UK biosciences and provide value to the membership. A prospectus for the NO has been Learned societies and of the publishers would carry out the prepared by Richard Dyer for the BSF deposit for the author, especially outlining the background to the publishing where a fee is paid. discussions between the BSF and IoB, a reduced version of which follows. The Biosciences Federation (BSF) Do you really know what open The full version, which contains more published a report in July with the access is? information on the finance, results of several questionnaires it The survey of researchers, which had structures and immediate goals of had conducted earlier this year. 1349 usable responses, showed the NO, is available from the BSF Thanks to all those who took part. substantial confusion about what website (http://www.bsf.ac.uk), The survey and report were carried open Access (OA) means. Many out by the BSF Journals Committee, respondents seemed unable to tell chaired by Sue Thorn of the Society The opportunity the difference between online The excitement of modern biology is for Endocrinology*. Some key details journals that are free at the point of palpable to all on a daily basis. are included below as a taster. use (because the library has paid a Uniquely important issues are You get more out of your society subscription fee) and Open Access frequently discussed by the media financially than you put in ones, where all the material is free. and the public. How many in this You probably knew that already, but Almost half the OA journals country are not aware of the debates we can now show that the UK respondents said they read, and a about stem cells, loss of species university system as a whole gets third of those they published in, through global warming and modern more money from bioscience were not OA journals at all. agriculture, the teaching of biology societies than it spends with those in schools or what our diet is doing Only around 15% of the respondents societies in journal subscriptions. The to our bodies? But how do the had tried to access OA publication survey showed that, for the 23 biologists join these debates about funds from their institutions or societies who responded, they put biology? If they do at all, it is research funders to pay for author- 2.16 times as much money into the through a myriad of possible routes side charges. Of these 53% had found UK university system by way of and representing too many it very difficult or fairly difficult. Sue grants, meeting support and other organisations. The need for a unified Thorn and Steve Byford are taking educational services than they take voice for all the biosciences has never part in a Universities UK working out by way of journal subscription been greater. Our vision is to provide group to try to resolve this issue. and licence fees. The societies that unified voice in debates about analysed contributed almost £4M of Interestingly, as regards self-archived the development of policy and best such support in the last year. You material (usually an earlier version, practice in education, career might want to make sure your Vice- such as the author’s submitted development, legislation and the Chancellor is aware of that in the manuscript), only 3.5% of funding of research. In undertaking light of some of the more radical respondents said they access this these roles, strong outreach to all Open Access people who want only a version if they have access to the the regions of the UK will provide free repository system which would final published version, and 67% strong local foci of relevant interest probably cause the collapse of most rarely or never access the self- for all the membership including journals and of the support that their archived version even if they don’t teachers, research scientists and owner societies provide. have access to the published version. regional organisations. In addition, the report shows that all Background the societies provide free access to Creation of a new The exciting diversity of the much of their journal material, biosciences has led to the formation usually after 12 months, although organisation for the of very many special interest groups many also make selected material biosciences where scientists and others with available earlier than that, eg review shared interests and mission The Councils of the Biosciences articles. productively work together. There Federation (BSF) and Institute of are, for example, scores of learned Most of the societies allow Biology (IoB) have proposed that a societies and medical research researchers to self-archive free in an new organisation for the biosciences charities, as well as many individuals institutional or other repository (e.g. (NO) should be created. This with a passion for biology, whether it PubMed Central) after a delay. Most organisation will embrace the is on a professional or personal basis. of them would allow immediate self- activities and strengths of both the Although it is difficult to be precise archiving on payment of a fee. Many BSF and IoB, and add new activities about figures, these organisations *The full report can be seen at alone probably comprise more than http://www.bsf.ac.uk/journals/BSF_survey_report_July_2008_FINAL.pdf. 200 separate and independent

Physiology News | No. 73 | Winter 2008| www.physoc.org 48 PN BIOSCIENCES FEDERATION

organisations, while there may be Key implementation issues tens of thousands more individuals, • Membership of NO will be open to both individuals and organisations from any some with no affiliation. This land- sector of the biological sciences; scape is unique for the biosciences: • The Council of the NO shall comprise a Chair and 12 members – four elected by physics, chemistry, mathematics and the individual membership, four from the institutional membership and four engineering are represented by very nominated by Council to ensure that there is a good balance of representation few organisations, which are wealthy and that the Council is fit for the purposes expected of a charity in the 21st and influential. century; • The NO shall have a Royal Charter and continue to offer chartered status and Whilst special interest groups fellowship to individual members. undoubtedly bring advantages of focus to research or fundraising, the Finance and structures public more generally will be built fragmentation of the biosciences The NO can be launched successfully through the regional groups that already leads to huge disadvantage in other with the present combined incomes exist in the IoB. There is considerable scope for exciting new ventures. areas – for example, in outreach to of the BSF and IoB. In 2007 the corporate subscription income for schools or in representing biology to The NO will also focus on increasing Governments and funders. In order BSF was £235k and the membership outreach to the membership as a whole to ameliorate this problem various income for IoB was £860k. For 2009 through regional scientific meetings and groupings have come together under the total subscription income for the high quality lectures and debates. The an umbrella organisation where two organisations will be circa leadership, both executive and non- matters of common interest can be £1200k. In addition, the IoB raises executive, will ensure that the activities dealt with more effectively than by a about £200k from other sources and of NO are not solely based in London or multiplicity of individual actions. the BSF about £100k per annum SE England. from member organisations for But in the biosciences this increased Finally there is the prospect of identified projects. This à la carte effectiveness is diluted because there substantially increasing the effectiveness are several umbrella organisations funding is an important element for of outreach through the media – both (e.g. the Institute of Biology and future development. directly and by partnering with the Biosciences Federation) and some Science Media Centre. of the problems associated with A full business plan for NO will be fragmentation remain. produced by mid November 2008. Policy work Both BSF and IoB have been largely Recently the councils of the IoB and The IG is not focused on the detail of reactive to policy initiatives coming from BSF proposed that a new organisa- the structures that may be set up governments and funders. Although tion should be created that will within NO: that will be a these responses are important it is embrace the activities and strengths responsibility of the first Council and equally important to be proactive in order to set the national agenda. In this of both BSF and IoB, and add new new Chief Executive. However, the context national means UK as a whole activities that will benefit UK IG is determined to suggest some and the four countries of the union. biosciences and provide greater overarching principles for the value to the membership. This organisation of NO and in particular Why now? proposal was unanimously endorsed that it is a flat structure with the Both IoB and BSF could do many of by a joint meeting of the IoB and BSF ability to make rapid decisions. the activities that are proposed for at the Royal Society in May 2008. NO. But in undertaking these Immediate goals for NO activities IoB and BSF would not Implementation group Membership In order to move this ambitious plan engage all the heartlands of the There will be an immediate drive to biosciences. To meet the challenges forward, the BSF and IoB have increase the number of individual and of today, biology needs a single established a joint Implementation institutional members. Currently some Group (IG) chaired by Sir Brian Heap. large areas of the biosciences are poorly voice. Our subject needs an Other members of the IG are Bridget represented in both the BSF and IoB. organisation like the Royal Society of Ogilvie, Nancy Rothwell, Malcolm Chemistry or the Institute of Physics Press, Keith Gull, David Coates, The NO will retain a Royal Charter and which has the respect of the Alan Johnston, Alan Malcolm and offer chartered status to its individual community as a whole and where members. An immediate goal will be to Richard Dyer. Members of the IG are individuals are proud to be members strengthen the standing of this unanimously agreed on the key because of the standards maintained qualification by introducing a structured and the quality of project delivery. issues highlighted in the box. “Career and Professional Development” With your support NO can achieve programme. The aim will be to increase Currently the IG is preparing the the esteem of all qualifications, including this status rapidly: this is urgently papers that will need to be put to the Fellowship. needed and the current opportunity memberships of BSF and IoB for the must be embraced. approvals necessary for these Outreach proposals to be implemented. Structured outreach to schools and the Richard Dyer

Physiology News | No. 73 | Winter 2008 | www.physoc.org OBITUARIES PN 49

J Murdoch Ritchie 1925–2008 J Murdoch Ritchie, Higgins Professor Emeritus of Pharmacology at Yale University School of Medicine, died peacefully on 9 July 2008 in Hamden, Connecticut, after a long battle with Alzheimer’s disease. Murdoch made several major contributions to our understanding of the conduction of impulses in peripheral nerve, and Murdoch Ritchie (centre) with Larry Cohen (left) and Richard Keynes (photo by Roger was a major figure in the burgeoning Thomas). field of neuropharmacology in the second half of the twentieth century. Murdoch and Brenda take a also quantified the unequal sabbatical leave and accompany him, distribution of sodium and Born in Aberdeen, Scotland on 10 which they did. After returning to potassium channels in myelinated June 1925, he obtained a BSc in England for a year, Murdoch nerve that underlies normal saltatory mathematics & physics from accepted an Associate Professorship conduction. Together with Peter Aberdeen University in 1944. He in Gilman’s department in 1958. At Gray, Stuart Bevan, Peter Shrager then took a position as a research Einstein, Murdoch and Douglas and Bill Chiu he was the first to show physicist at the Telecommunications continued their work on nerve, work that satellite cells in both the Research Establishment at Malvern in that resulted in a series of classic peripheral and central nervous the south of England, where he was papers in the late 1950s. Greengard system (Schwann cells and part of A V Hill’s team that was also joined the department at astrocytes) expressed voltage-gated instrumental in the development of Einstein, and the three papers on ion channels. radar. In 1946 Murdoch followed Hill local anaesthetics that he and to University College London (UCL), Murdoch co-authored in the early Murdoch was elected a Fellow of the where Hill formed the world’s first 1960s remain relevant today. In 1968 Royal Society in 1976 and a Fellow of Department of Biophysics. Working Murdoch was recruited to Yale as the Institute of Physics (London) in with Hill as a research student on the Chair of Pharmacology, bringing with 1997. Though he had a keen, dynamics of skeletal muscle him both Douglas and Greengard. quantitative intellect and was contraction, Murdoch received a BSc comfortable with complicated in physiology in 1949. After a 2 year Initially with Richard Keynes, and theory, his scientific approach was stint as a junior lecturer at UCL, in later with Humphrey Rang, David strongly grounded in experimen- 1951 Murdoch moved to the Colquhoun and Gary Strichartz, tation. One morning when I worked National Institute for Medical Murdoch was among the first to with him he suggested an Research at Mill Hill. The same year apply radioligand binding to studies experiment and I started going on he married Brenda Bigland, herself a of the nervous system, using about possible outcomes. Murdoch rising young physiologist. Murdoch radiolabelled tetrodotoxin and soon began to alternately tap both received a PhD in biophysics in 1952 saxitoxin to count sodium channels feet, a clear sign that his patience (for work on the production of initial in peripheral nerve. He also worked was wearing thin. He let me go on a heat in muscle fibres) and was (with Vic Howarth and Keynes) for couple more minutes and then broke awarded a DSc in biophysics in 1960, several years on the production of in with 'Look, we can sit here and talk both from UCL. heat in nerve and was proud to say about it all morning or we can go and that he closed this field, ultimately do it'. I have retold this story At Mill Hill, Murdoch became close showing that it had little to do with countless times over the years to my friends with his fellow Scot, Bill the mechanistic basis of conduction. own students and post-docs when Douglas, and in 1955 they began In addition, Murdoch made they started indulging in virtual work on the control of blood important contributions to our science. Murdoch simply loved the pressure by unmyelinated nerves. understanding of metabolic changes hands-on aspects of experiments, That same year, a young American during nerve activity and the role of and for that reason he rarely worked postdoc named Paul Greengard the Na/K-ATPase in maintaining with more than two people at a came to Mill Hill to work and the transmembrane ion gradients. In the given time. Murdoch was in his 60s three became friends. The following 1970s and 1980s, Murdoch turned to when I was in the lab, but it was still year Douglas accepted a position in models of demyelinating disease to a continual challenge to match his Al Gilman’s new Department of characterize the changes in ion energy. He was an early riser, and Pharmacology at Albert Einstein channel density and conduction that most days when I arrived Murdoch College of Medicine in the Bronx. accompany demyelination in would be racing around finishing an Douglas casually suggested that diseases like multiple sclerosis. He experiment he had begun that

Physiology News | No. 73 | Winter 2008| www.physoc.org 50 PN OBITUARIES morning. He would then pitch in and help me. No aspect of an experiment was too tedious or trivial for Murdoch, and while I pulled patch pipettes he would scurry around making solutions or whatever else needed doing. Despite his other responsibilities, he almost never missed the patch-clamp recording in the afternoon, which typically began with him announcing 'time to get down to the verbs'. I don’t usually like someone watching over my shoulder, but I looked forward to Ritchie’s lab, circa 1971. these afternoons, since he would pepper his scientific comments with throughout and attending most of in his dealings with others ribald innuendos involving actresses those given by others. His legendary characterized the man, and we will and bishops and humorous lecture on alcohol began with him miss him.' I think everyone who knew anecdotes about the giants of breaking a raw egg into a glass of Murdoch would second this neurophysiology and neuropharma- single malt whisky, which he then set portrayal. Murdoch’s positions on cology. There was never a dull day aside. At the end of the lecture, issues were always guided by what when Murdoch was around. One of Murdoch would raise the glass, point he thought was right, not necessarily the stories I like best about Murdoch out that the whiskey had denatured by what was right for him. He truly is from the time he worked on the the protein in the egg white, and was the best kind of man – a man of garfish olfactory nerve. When the then quickly down the contents in a principle. live garfish arrived from Florida, single gulp, all to the great Murdoch would prepare for the amusement of the students. He J Murdoch Ritchie is survived by his messy dissection not by donning a served on many university wife Brenda, son Alasdair, and lab coat, but by stripping to the committees and was Director of the daughter Joceyln. waist. Murdoch continued to Division of Biological Sciences at Yale conduct his own experiments until from 1975–1978. In the late 1970s, Jim Howe he closed his laboratory in 2000 at he championed the establishment of Professor of Pharmacology, Yale the age of 75. the first core facility at Yale to University provide technical support for scientific and biomedical computing. Murdoch’s obvious zest for life was David Colquhoun adds: He was also co-Director of the equally evident in his personal In 1970, Heinz Schild allowed me Interdepartmental Neuroscience demeanor. A charismatic figure, his sabbatical leave and, on the advice of bearing and lively personality Program at Yale from 1993–1999. Humphrey Rang, I went to work with naturally commanded attention. He This was a critical period for the INP, Murdoch Ritchie during the time when was an avid skier, and he religiously a time when its inter-departmental he was chairman of the Department of attended Winter Brain Conferences nature was being questioned and Pharmacology at Yale. It turned out to and vacationed with his family in his before the program had an be the best thing I could have done. His beloved Zermatt for decades. In the independent training grant. Haig enthusiasm for doing experiments was legendary. This was not a lonely job in a summer, he could often be found at Keshishian (Professor of Biology and currently INP co-Director) corner of the lab of some distant great his home in central Vermont, much man. Despite his being chairman at the volunteered the following thoughts of which he built with his own hands. time, we were doing experiments when he learned of Murdoch’s together every day. He’d occasionally Murdoch viewed sharing knowledge death: 'Murdoch's abiding approach to disappear for a few hours for a meeting, as an important part of scientific life. education was to place the interests of but then he’d be back at the rig. Not The five editions of Goodman & his students first. In practice this is only was he there doing the experiments Gilman spanning 1965–1985 contain much easier to say than to do. Running with me, but the experiments were fun. chapters carrying his name on the a very unusual graduate program that There was a constant stream of jokes between the serious stuff. At the time I pharmacology of local anesthetics, cut across departmental boundaries certainly appealed to Murdoch. I was single, and it was pretty obvious that aliphatic alcohols, and caffeine. He it was not entirely coincidence that every sensed a certain rebellious glee in his enjoyed writing, and he authored rotation student in the lab was female. and edited over 70 reviews, chapters, Scottish accent when he found a way Murdoch seemed to get a lot of fun from books, and monographs. Murdoch to straighten out a student's problems speculating about my progress with directed the pharmacology course in a fair way, perhaps at the expense of them (and I had a lot of fun letting him for second year medical students at a department's traditions or interests. speculate). He and Brenda Ritchie (née Yale for 30 years, lecturing himself Fairness, common sense, and decency Bigland) could not have been better

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hosts. I spent a lot of time at their lovely experimenter I have ever met, and his house in Deepwood Drive, and the only influence on my attitude to science was price that was exacted was to help with huge. There could never have been any the mammoth leaf-sweeping job in the fraud in Murdoch’s lab. He was there, Fall. His competitive streak was also very doing things with his own hands. much in evidence when playing Scrabble in his Vermont log cabin (actually rather For many years after my time in Yale, I large and luxurious). Luckily, he was very used in lectures the trick mentioned in good at Scrabble. Jim Howe’s obituary, to demonstrate the denaturing effect of alcohol on proteins. The first thing I had to do when I arrived In fact I embroidered it a bit by hiding was to buy a car, and I found a under the bench a cocktail shaker demonstration Mustang Convertible at a containing ice and lemon juice: at the good price. This sparked Murdoch’s end of the lecture the products of the considerable competitive streak, and demonstration were poured into the very soon he had gone out to buy the shaker and converted to a whiskey sour. new model, on the grounds that nobody It was the most (possibly the only) Murdoch Ritchie in Northern Italy could have a newer model than the popular lecture I gave, and that is yet (1989), after a meeting on peripheral chairman. I tried to keep a straight face another reason to be grateful for nerve. Murdoch’s influence. when, a bit later, he left the brake off and saturated the Institute’s taste for them. his new model rolled into a lake. On one We got together at intervals to work on Murdoch revelled in the many good unforgettable occasion Murdoch drove permeability problems several times things of the American way of life, I don’t me into the lab, in the middle of winter, after that, but our most memorable recall him ever showing any inclination to with the top down, his large scarf research project was to measure the return to his roots. The only thing that blowing in the wind. We took an indirect temperature changes in the olfactory made him seem uncomfortable was route so he could demonstrate skidding nerves of pike during nervous activity, politics. If the talk got too political, he’d on the icy road. An article about him these fishes having exceptionally small shift uneasily from foot to foot and the appeared in a Yale magazine with the nerve fibres with a favourable surface to subject was soon changed. Perhaps that title 'the Flying Scotsman'. The title volume ratio for such measurements. For was influenced a bit by the fact that only could not have been more appropriate. this purpose we went to Switzerland, the year before at Yale he had been at where a good supply of living pike was the heart of the great student revolts of We were trying to measure the density available in the lakes on the estates of the late 1960s. He seemed at his of sodium channels by measuring the wealthy gentry in the country, and happiest in the lab or at a barbecue binding of tritiated tetrodotoxin and our very good friend and colleague Alex party. His enthusiasm was infectious, as saxitoxin, quite a novel method at the von Muralt was an eminent physiologist was his generosity. At the end of my stay time (use of radiolabelled molecules for at the University of Berne, who knew at Yale, the first pocket calculator binding measurements had been everyone ready to supply us with a pike. appeared that would do logs and introduced only 5 years earlier, by Paton This led, in 1975, to the publication of a exponentials, the Hewlett Packard HP45. & Rang, 1965). Later it turned out that paper by Howarth, Keynes, Ritchie and On my last trip into the lab I found a note our values were not very accurate von Muralt on the heat production on my desk. It said: 'the HP45 is in the because of poor radiochemical purity of associated with the passage of a single drawer. If it is not there tomorrow, it the ligands, but it was a start on a impulse in a pike nerve, which was won’t be missed'. I still have it. I shall problem that Ritchie and others later possibly the last work to be done on this miss him. brought to perfection. particular problem, as described in a review by Keynes and Ritchie in Quarterly The project raised some interesting Richard D Keynes adds: Reviews of Biology in 1985. My only regret theoretical problems too. The rate at I collaborated with Murdoch Ritchie for a was that I happened to be away on the which binding approached equilibrium good many years, and he was my great day when my colleagues reported was, we suspected, not limited by the favourite colleague because he was that the unfortunate pike had been rate of binding to receptors, but by always able to make me feel so cheerful delivered at the university with all the diffusion, slowed by concurrent binding, about life! impressive pomp usually restricted to the in the desheathed rabbit vagus nerves arrival of royalty! that we used for most experiments. I first met him when he was still working Numerical solution of the non-linear in London at University College, and he I last worked with Murdoch Ritchie 10 partial differential equations for diffusion came to help me at Babraham on the years later on the binding of labelled with binding was done on the Yale permeability of desheathed rabbit vagus saxitoxin to a squid axon, for he was said mainframe IBM. A comma missing in the nerves to radioactive potassium ions in, I to be famous in the USA for having program meant bringing back your think, 1963, as a visiting Fellow of persuaded their Central Intelligence corrected box of punched cards and Churchill College. I knew that he was Agency to allow him in 1975 to use this handing it in to the computer operators familiar with such nerves, and hoped that very poisonous neurotoxin for labelling so you could collect the results next day. my boss at the ARC would regard rabbits sodium channels in physiological Despite his mathematical background, as authentically agricultural, unlike the experiments instead of destroying it as this aspect seemed to interest Murdoch squid on which I was always more likely dangerous, as had been suggested by less than dissecting the nerves and to experiment. The handsome white President Nixon. It did indeed become a getting experimental measurements. He rabbits that we used were also very good very useful agent for use by neuro- was certainly the most enthusiastic to eat, though I am afraid that we soon physiologists.

Physiology News | No. 73 | Winter 2008| www.physoc.org 52 PN BOOK REVIEWS

The cult of statistical 13–16), foisted the p < 0.05 upon an experimenters alike. The great pity I unsuspecting public, and used his found in this book is that the significance influence (and enormous intellect) to message, which is blindingly obvious How the standard error costs us quash any dissent. to those who have considered the use jobs, justice and lives of statistics applied to experimental In essence what Fisher did was to By Stephen T Ziliak & Deirdre data, is blurred by the obtuse text. create a statistical black box into The authors’ website tells us a N McCloskey which experimenters would input The University of Michigan Press. forthcoming study of Gosset is in the their data and the results would come pipeline, which should be of more 352 pp, £18.50 out the other end with no thought interest to readers of this publication. ISBN 0472050079 required by the experimenter. Data The tenet of this book, zealously either were or were not significant Angus Brown delivered by the authors, is to forego and that was that. How different this statistical significance in favour of is from Gosset’s view where careful Oxford handbook of substantive significance. Rather than experimental design and good transcranial stimulation seeking the statistical Rubicon of considered judgement were of prime p < 0.05, instead use quantitative importance. Edited by Eric M Wassermann, judgement to draw your conclusions Charles Epstein, Ulf Ziemann, from experimental results. This focus It is unlikely a life scientist would seek Vincent Walsh, Tomas Paus and on the quantitative dimension (or out this book in preference to a Sarah Lisanby. Oxford University oomph as named by the authors) is standard statistical textbook. The Press, 748 pp, £59.95 reiterated throughout the book, with main obstacle the book presents is ISBN 978-0-19-856892-6 not based on statistics, but rather the numerous examples to illustrate the This book is a well organized collection style of writing, which is full of point. Although the authors are of chapters by experts in the field of dreadful puns, a staccato delivery that economists and a large proportion of transcranial magnetic stimulation is infuriating and the occasional haiku the book is devoted to this field, the (TMS). It is divided into six sections, thrown in for light relief. What the strategy they advocate is universal the first of which gives excellent detail book is crying out for is a chapter in and equally applicable to the life on the physics and biophysics of TMS. sciences. which the equations related to all the The next four sections deal with: TMS calculations/tests described in the measures of cortical and corticospinal The first two chapters are heavy going text are illustrated and appropriate excitability; motor-evoked potentials indeed, and the middle section only example data used to demonstrate in health and disease; TMS in eases up slightly in highlighting the key points. Without this the relevance perception and cognition; TMS and statistical crimes committed in the of the standard error of the title may brain mapping. fields of economics and psychology, not be immediately apparent. As such but the last 50 pages or so are the this book can never hope to appeal to The final section of the book discusses most interesting to the casual reader, the casual reader. The changes in the therapeutic applications of TMS relating the contributions of Gosset statistical reporting demanded by the including its use in depressive and and Fisher to statistical testing. This is authors would require a monumental anxiety disorders, schizophrenia, in fact the main point of the book – shift in the editorial policy of journals, bipolar disorders and movement how Fisher manipulated Gosset’s t and the authors direct their pleas to disorders. It is here that the true distribution (Physiology News 71, journal editors and individual potential of the technique becomes fully apparent, particularly as a recent phase III clinical trial (O’Reardon et al, 2007) has shown TMS to be effective in treating major depression with minimal side effects, thus offering clinicians a possible alternative to medication in the long term.

The book is well written and edited and should become a standard reference work for those interested in TMS and its uses. Bill Winlow Reference O’Reardon JP et al (2007). Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry 62, 1208-1216.

Physiology News | No. 73 | Winter 2008 | www.physoc.org King’s College London Vascular and smooth muscle physiology Themed Meeting 15–17 December 2008

The international panel of speakers includes

Stephanie Lehoux (McGill Division of Experimental Medicine, Quebec, Canada) Dynamics of shear stress-induced remodelling Qingbo Xu (James Black Centre, London, UK) Stem cell differentiation into vascular cells induced by mechanical stress Per Hellstrand (Lund University, Sweden) Stretch-dependent growth and differentiation in vascular smooth muscle Paul Cahill (Dublin City University, RoI) Bio-mechanical activation and notch signalling – how vascular cells respond to stress! John Tarbell (The City College of The City University of New York, USA) Mechanotransduction and the glycocalyx Gerard Nash (University of Birmingham, UK) Modulation of inflammatory responses of endothelial cells by changes in local shear stress Cormac Taylor (University College Dublin, RoI) Regulation of gene expression by hypoxia Axel Pries (Charité-Berlin, Germany) Intergration of haemodynamics and molecular factors in vascular adaptation Akos Koller (Semmelweis University, Hungary) Mechanotransduction of shear stress and regulation of microvascular resistance Stuart Egginton (University of Birmingham, UK) Haemodynamic forces as in vivo angiogenic stimuli Robert Reneman (Maastricht University, Netherlands) To download the provisional Wall shear stress distribution in the arterial system. programme and for further Reconsiderations based upon in vivo measurements information please visit Peter F Davies (University of Pennsylvania USA) http://www.physoc.org Endothelial phenotype plasticity in unstable flow regions of the cardiovascular system: Differential microRNA expression Shu Chien (University of California, USA) Effects of shear flow on selectin expression in endothelial cells co-cultured with smooth muscle cells Robert Krams (Imperial College London, UK) Shear stress, inflammation and atherosclerosis Ann Canfield (University of Manchester, UK) Engineering vascular grafts Gary McVeigh (Queen’s University Belfast, UK) Waveform analysis and microcirculatory function Vascular and smooth muscle physiology Themed Meeting at King’s College London, 15–17 December (p. 4)

A publication of The Physiological Society http://www.physoc.org