PHYSIOLOGY

anniversary NEWS th issue 25 spring 2008 | number 70

25 years in physiology Adventures in neurobiology Sir Andrew Huxley at 90

The Nike-Adidas CO2 footprint Spring books special International Symposium in honour of Sir Andrew Huxley on the occasion of his 90th birthday 14 November 2007 University College London

See also Gerald Elliott’s report on the symposium and more images on p. 37 (photos by Martin Rosenberg and Roger Thomas).

Sir Andrew Huxley (front, centre) also celebrated his 90th birthday at a Society dinner with Prem Kumar (back, left), Colin Blakemore, Mike Collis, Graham McGeown, Dafydd Walters and Ian McGrath (front, left) and Denis Noble. PHYSIOLOGY NEWS Editorial 3 Twenty five years in physiology Physiology then (1983) and now (2008) Ole Petersen 4 The Society’s dog. ‘Rudolf Magnus gave me to Charles Meetings Sherrington, who gave me to Determining control of the cardiovascular system in health Henry Dale, who gave me to The and disease: from brain to blood vessel Susan & Jim Deuchars 8 Physiological Society in October Physiology 2008 Bill Harris 9 1942’ IUPS 2013 David Eisner 22 Living History Published quarterly by The Physiological Society Adventures in neurobiology David Wallis 10 Contributions and queries Five years in the life of ... Senior Publications Executive ... a web site Liam McKay 12 Linda Rimmer Features The Physiological Society Publications Office Cold facts about AMPK in fat Kurt Saupe, Jacob Mulligan 14 P O Box 502, Cambridge CB1 0AL, UK Insight into how the human retina obtains its need of Tel: +44 (0)1223 400180 vitamin B1 Hamid Said 16 Fax: +44 (0)1223 246858 Selectivity: a stick affair? Antonio Peres 18 Email: [email protected] Breaking the barrier; the role of actin filaments in somato/ Web site: http://www.physoc.org dendritic peptide release Mike Ludwig, Vicky Tobin 21 Magazine Editorial Board Coupling or not coupling of mitochondria to Ca2+ sources in Editor neurones. Soma and neurites differ Lucía Núñez, Carlos Austin Elliott Villalobos, Javier Garcia-Sancho 23 University of Manchester, Manchester, UK Exercise-induced adaptations in tendon tissue Katja Heinemeier, Jens Olesen 25 Members Angus Brown Modifying the excitability of motor cortex with direct current University of Nottingham, Nottingham, UK stimulation Jonathan Norton, Hollie Power, K Ming Chan 28 A starring role for astrocytes Guido Mannaioni, Hongjie Yuan, Patricia de Winter Justin Lee, Stephen Traynelis 31 University College London, London, UK Lack of a role for arterial chemoreceptors in the breakpoint Sarah Hall of breath-holding Michael Parkes 34 Cardiff University, Cardiff, UK Reports Munir Hussain Marine Biological Association David Ogden 30 University of Liverpooll, Liverpool, UK Sydney Ringer’s life and work commemorated at Lastingham John Lee David Miller 36 Rotherham General Hospital, Rotherham, UK Sir Andrew Huxley at 90 Gerald Elliott 37 Thelma Lovick Pre-emeritus symposium for Richard Olver Anil Mehta 39 University of Birmingham, Birmingham, UK Your skills, our future 40 Fiona Randall Programming of the neuroendocrine and immune stress Newcastle University, Newcastle upon Tyne, UK responses in early life and their role in health and disease Bill Winlow David Phillips, Dirk Hellhammer 41 Chameleon Communications International, London/ First year bioscience laboratory classes – score gamma? University of Liverpool, Liverpool, UK Mike Collis, Alan Gibson, Ian Hughes, Gill Sayers, Martin Todd 42 Cystic fibrosis Liz Bell 43 Foreign Correspondents Systems biology and medicine: from reactive to predictive John Hanrahan McGill University, Montreal, Canada personalised, preventative and participatory medicine Liz Bell 45 Science and education Liz Bell 45 John Morley Education University of Western Sydney, NSW, Australia The role of the laboratory practical in undergraduate © 2008 The Physiological Society teaching Maxine Lintern 46 ISSN 1476-7996 Affiliate News The Physiological Society is registered in England as A career scientist ... to be or what (else) to be? Fiona Randall 48 a company limited by guarantee: No 323575. Who are the true custodians of public opinions in science? 48 Registered office: PO Box 11319, London WC1X 8WQ Rehana Jawadwala Registered Charity: No 211585. The Society’s journals Printed by The Lavenham Press Ltd Experimental Physiology 50 In search of ‘quality ’ Carol Huxley 50 The Journal of Physiology Symposia 51 Society News 51 Biosciences Federation 52 Unbelievable! 53 Obituaries John Richard Pappenheimer Rosamond Zimmermann, Charles Michel 54 John Ramsey Bronk George Kellett 55

Front cover image from Norton et al. Book reviews 56 (p. 28). Graphics by Jan Kowalczewski. From the archives 60 PHYSIOLOGY NEWS

Action points Guidelines for contributors In this issue Grants These guidelines are intended to assist This issue of Physiology News For full information on Members ’ authors in writing their contributions celebrates several anniversaries, and Affiliates’ Travel Grants, and to reduce the subsequent editing and also welcomes some new Network Interaction Grants, Non- process. The Editorial Board of faces. Society Symposia Grants, Physiology News tries to ensure that all Vacation Studentship Scheme, articles are written in a journalistic style The first ever Physiological Society so that they will have an immediate magazine (then the Newsletter) Departmental Seminar Scheme, interest value for a wide readership and Centres of Excellence and Junior appeared in 1983, which makes will be readable and comprehensible to th Fellowships visit: non-experts. In particular, scientific this our 25 anniversary issue. http://www.physoc.org/grants articles should give a good overview of a Since we published a historical field rather than focus entirely on the retrospective on our 20th Membership applications authors’ own research. anniversary (see PN 54, 30–32), for Applications for Physiological our quarter century we have Format of articles Society membership are accepted decided to look at how physiology The main message or question posed should itself has changed in the interim. throughout the year; applications be introduced in the first paragraph. The are reviewed by the Membership background for the topic should then be Physiological Society President Ole Committee on a monthly basis established, leading up to the final Petersen gives a personal view on and a decision is normally made conclusion. pages 4–7. within 15 working days of each Length of articles Yet another anniversary is that of deadline. For full details please This will be determined by the subject matter Experimental Physiology, which is visit: and agreed with the Senior Publications celebrating its centenary – you can Executive. http://www.physoc.org/membership read a little about its first ever Submission of articles paper on p. 60, while for more on Change of address Authors should submit articles as a Word Its history Society Members can go Members should inform the document attached to an email. Illustrations to the January issue at Administration Office of any should be sent as separate attachments (see http://ep.physoc.org/content/ changes of address, telephone, below) and not embedded in the text. vol93/issue1. fax or email address. Changes can Illustrations and authors’ photographs We also welcome some new faces be emailed to: [email protected] Authors are encouraged to submit diagrams, drawings, photographs or other artwork with to Physiology News. Since the rest their articles or to suggest appropriate of the editorial team are, to put it Physiology News illustrations. A photograph of the author(s) politely, a fair way the wrong side should also accompany submissions, if of 30, younger faces were needed, Deadlines possible. Illustrations and photographs may be colour or black and white, prints, and we are delighted to welcome Letters and articles and all other transparencies or tif/jpeg files with a two of them – Fiona Randall and contributions for inclusion in the minimum resolution of 300 dpi. Electronic Rehana Jawadwala, who between Summer 2008 issue, No. 71, colour figures should be saved in CMYK them will be covering Affiliate mode. should reach the Publications issues (and other things) and Office ([email protected]) by References hopefully giving us a bit of a fresh 30 April 2008. Short news items Authors are requested to keep the number of perspective (p. 48). are encouraged, and can usually references to a minimum – preferably no be included as late copy if space more than two or three. Please cite all Finally, I have left the most permits. references in the style of The Journal of memorable anniversary until the Physiology (see Instructions to Authors at last. In November 2007, Professor http://www.physoc.org). Suggestions for articles Sir Andrew Huxley FRS, Nobel Suggestions for future articles are Laureate, celebrated his 90th welcome. Please contact either birthday with a symposium in his the Senior Publications Executive The Society permits the single copying of individual articles for private study or honour at UCL. We are delighted to or a member of the Editorial research. For copying or reproduction for any wish him a slightly belated happy Board of Physiology News (see other purpose, written permission must be birthday, and to salute his contents page for details). sought from The Physiological Society ([email protected]). magnificent scientific achievements (see p 37–38 and Physiology News Online Opinions expressed in articles and letters the inside front cover). Physiology News is now available submitted by, or commissioned from, Members, Affiliates or outside bodies are not on The Society’s web site: necessarily those of The Physiological Austin Elliott http://www.physoc.org. Society. Editor EDITORIAL PN 3

Why fight for the inclusion of more basic A short-sighted decision Physiology in medical science in the curriculum for some teaching professional degree, if the degree is A few weeks before this issue went to owned by another departent which press, Nature reported (17 Jan) that the Basic science knowledge among, and seems disinclined to listen? Novartis Foundation (formerly the CIBA teaching to, UK medical students – and Foundation), located in London’s Portland students on other "biomedical" However, my firm view is that this is too Place, was to close its doors1. This will vocational degrees – is back in the news. easy a way out. And we have been here have saddened many scientists, including before, in some cases, back when the physiologists, who have benefited from Undergraduate medical training in the changes to medical degrees were first the Foundation’s activities. The UK underwent a major shake-up in the proposed more than a decade ago. There Foundation was established as a scientific mid 1990s, with a major theme being to was a definite strand of opinion within meeting house in 1949. Since then it has decrease the amount of 'detail' in physiology departments then to the run more than 400 symposia, typically medical curricula. In the years since, a effect that, if medicine wanted to teach small-scale 3-day events with 30 or so number of established medical schools students by PBL, and to decide what participants modelled on 'mini-Gordon have shifted to more integrated or (most basic science – if any – was in and how Conferences', but followed by open radically) to problem-based learning they wanted it taught, then we scientists meetings to allow a wider audience to (PBL) teaching systems, while the new would tell them they were welcome to it hear the speakers. medical schools established since 2000 – provided they did it all themselves and have also mostly adopted these less left us out of it. Physiologists would Novartis has now decided to pull the plug. traditional methods. Other universities simply get on with research, and with Nature quotes a Novartis spokesman as have retained the traditional '2 years training BSc and PhD students. stating that the meetings 'did not allow basic science, 3 years clinical' model. [Novartis] to maximize our impact'. This was perhaps a natural reaction to Although the Academy of Medical Since the mid 1990s there have been the high-handedness that many Sciences seems likely to take over the ongoing rumblings about 'loss of core physiologists tell me they detected, and building in Portland Place, without a knowledge'. PBL takes most of the public sometimes still detect, in medical significant sponsor the symposia seem set flak, with the caricature being of tutorials curriculum groups. But it was a to disappear. with tutors who are forbidden to speak, dangerous road to go down. If there are 2 and students acquiring 'communication now medical degrees which don’t In an accompanying editorial , Nature skills' but bypassing basic grounding in contain enough physiology – and there is characterizes Novartis’ decision as anatomy, physiology and pharmacology. more hot air than evidence on this point 'blinkered', while making the point that The rumbling has got a bit louder – then I would expect to find them in the Foundation could perhaps have done recently, largely as a side-effect of the precisely the universities where more, both to modernize in recent years unease over the disastrous attempt at disengagement of basic scientists from and to campaign publically to try and change Novartis’ mind. In an age beset reform of postgraduate medical training. medical teaching is most marked. In (cursed?) by seemingly endless which case, the fault does not necessarily reorganisations, few scientists would It is not my purpose here to debate lie entirely on one side. medical teaching methods, although, for probably argue with Nature’scomment the record, I am an organiser of part of a The key to having basic sciences properly that 'It is easier to destroy an organization PBL medical course and the caricature I incorporated in a medical degree course with a strong reputation and institutional have just outlined is a long way from the is surely to have basic scientists as a core knowledge than to build one up from reality as I experience it. I would, though, part of the group of people designing, scratch.' like to comment on some of the broader running, and delivering the course. If we Many Physiological Society Members will issues of university physiology groupings surrender these responsibilities wholly to have participated in one or other of the – I hesitate to say 'departments' any medical education specialists and Foundation’s activities, or even just more – and medical student teaching. clinicians, then we cannot complain stayed in the rooms at Portland Place, about the results. Where physiologists teach both students which have always been available, between conferences, as a (somewhat doing BSc degrees – including physiology In other words, engagement means idiosyncratic) place for scientists to stay in – and students from professional degrees influence. Most basic scientists think – London. In addition, the Foundation’s 'owned' by other departments, there is and I include myself here – that basic bursary scheme has allowed selected obvious potential for this to default to scientists know a lot more about young scientists to attend the 'closed' being seen as teaching 'our' and 'their' teaching underlying physiological symposia and then work for a period in students. And as modern curricula for concepts to medical students than the laboratory of one of the symposium degrees like medicine have diverged medical doctors do. And most would participants. from the standard 'yr 1 lecture course in worry about curricula where students basic physiology' model, the divide has rarely see a basic scientist outlining and It is sad to contemplate the end of these widened. Under these circum-stances, explaining those concepts, whether that activities, and of a UK-based tradition of the potential for staff in basic science is as a lecturer or as a tutor. But this is the international scientific meetings, and one departments to lose a sense of kind of point that needs making, would therefore hope that a new sponsor ownership of the 'service' teaching – forcefully – and even if those there don’t for the Foundation’s activities can be including medical teaching – is obvious. seem to want to hear it – from within found. Perhaps if any Physiological Society And with this loss of ownership comes an curriculum committees. Not just from a Member has contacts among the super- inevitable inclination to disengagement. lab a safe distance away. rich they might like to have a quiet word?

1 Nature 451, 233 (2008). http://www.nature.com/news/2008/080116/full/451233a.html 2 Nature 451, 224 (2008). http://www.nature.com/nature/journal/v451/n7176/full/451224a.html Austin Elliott

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Physiology then (1983) and now (2008) Ole Petersen looks at the changes in physiology during a quarter of a century of The Society’s magazine, and has confidence that the future is in excellent hands

In 1983, when The Physiological Society started publishing its magazine, most medical schools in the UK had a physiology department, there was no national Research Assessment Exercise (RAE), no journal publishing short (trends-like) physiological review articles and most neurophysiologists regarded themselves as physiologists rather than neurobiologists. The first RAE was conducted in 1986 and in that same year NIPS (News in Physiological Sciences now Physiology) was launched by the American Physiological Society (APS) and the International Union of Physiological Sciences (IUPS). The neuroscientists Figure 1. Symposium celebrating Rod Gregory’s 70th birthday during a meeting of gradually became more inclined to The Physiological Society at Liverpool University in 1984. From left to right, front row: separate themselves from the Viktor Mutt, Roger Guillemin, Rod Gregory, Charles Code; back row: John Walsh, Irene physiological community, Schulz, Ole Petersen, Ken Agarwal, Andrew Soll, Graham Dockray. increasingly holding their own meetings and establishing their own Gregory FRS as George Holt Graham and me. One visible early journals (Neuron was established in Professor of Physiology in 1981. sign of this was the successful 1988). On the other hand, two of the However, it could easily have become meeting of The Physiological Society techniques that have dominated an even longer period, since my in Liverpool in 1984, at which major parts of physiological research contract – in line with the general Graham and I organized a these past 25 years were invented trend at the time of my appointment symposium celebrating Rod and already yielding important – specified that my chair was linked Gregory’s 70th birthday (Fig. 1). information before 1983, namely the to the headship of the Department patch clamp technique (Hamill et al. and the expectation was that I, like 1983 was a good year for my own 1981; Verkhratsky et al. 2006) and my predecessor, would remain in research. Yoshio Maruyama was my the recording of Ca2+ signals with charge of the Department until my closest collaborator in the laboratory fluorescent probes (Tsien et al .1982; retirement. If I had not succeeded in at that time, having arrived from Petersen et al. 2005). obtaining an MRC Professorship in Sendai (where he is now Professor of 1998, this would probably have been Physiology) while I was still in In this short article it is, of course, my fate! Dundee. As described in the written impossible to do justice to the version of the first John Young general theme concerning how the In 1981, when I had moved from the Memorial Lecture which I delivered field of physiology has changed over University of Dundee – where I had at the Gordon Conference on Salivary the past 25 years. I can only do so been Head of the Physiology glands and exocrine secretion in from the rather narrow perspective Department for 6 years – to California in 2005 (Petersen, 2005), of my own experience and work. I Liverpool, I was the only professor in Yoshio (Fig. 2) built our first patch nevertheless believe that some the Department. One of my first clamp amplifier and recorded the points will emerge from even such a actions in Liverpool had been to first single channel currents from limited exercise that may illustrate make sure that Graham Dockray was epithelial cells (Maruyama & Petersen some of the general trends for the promoted to a chair, and this 1982). Soon thereafter we found, to subject. happened in 1982. The whole our great surprise, that the salivary development of physiology in gland acinar cells, which do not 1983 Liverpool, which led to the conduct action potentials, In 1983 I was only a couple of years Department becoming recognized in nevertheless possess voltage-gated + 2+ into what would turn out to be a every single national RAE as the K channels, namely Ca -activated + long period (17 years) as Head of the leading research department in the maxi-K channels (Fig. 2). In the Physiology Department at Liverpool UK, was forged in a close and Nature paper describing these results University, having succeeded Rod interactive collaboration between (Maruyama et al. 1983), we

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undoubtedly my period as Foreign Secretary of The Physiological Society (1992–1998). At the 1997 IUPS Congress in St Petersburg, I attended my first IUPS General Assembly as representative of the UK and my assistant, Nina Burdakova, organized and manned The Physiological Society stand at the Congress (Fig. 3). It is never possible to sum up briefly the multitude of events at an international congress. Every individual attending, depending on his or her research interests, will inevitably have a different experience. It is neverthe- less clear, when inspecting the 1983 Figure 2. The first demonstration of voltage-activated ion channels in a transporting IUPS programme, that the then epithelium. Patch clamp single channel current recording from inside-out membrane relatively new patch clamp technique patch excised from baso-lateral surface of a mouse submandibular acinar cell (reproduced from Maruyama et al 1983). The membrane potentials at which the was much in evidence at the current traces were obtained are given (in mV) to the left. The left column of current congress. Erwin Neher gave one of traces were recorded with [Ca2+] = 10-8 M in the solution in contact with the inner the invited main lectures and in the membrane surface, whereas the traces shown in the right column were obtained many different symposia there were from the same patch after [Ca2+] had been elevated to 10-7 M. The picture shows a substantial number of lectures on Yoshio Maruyama together with Ole Petersen at a meeting in Okazaki, Japan in 1993. single channel current recordings from nerve, muscle and gland cells. suggested that this first direct IUPS Congress took place in Sydney demonstration of a voltage- and and I, and very many other UK Calcium signalling, on the other Ca2+-activated K+ channel in a physiologists, made our way to hand, did not feature much at the transporting epithelium was of major Australia. This was many years before 1983 Sydney Congress. To be sure functional significance, since Ca2+- I became involved in running IUPS. there were several talks on voltage- 2+ activation of the channel would At that time Schmidt Nielsen from gated Ca channels, but at this point enhance the opportunity for the US was President and Scherrer in time there were still not many 2+ recirculation of K+ taken up by the from France Secretary General of reports on intracellular Ca measurements and imaging of the Na+, K+, Cl- co-transporter and the IUPS. Otto Hutter was the UK representative on the IUPS Council. intracellular [Ca2+] distribution was Na+,K+ pump, whereas the voltage- At that time I had, of course, no idea not technically possible. sensitivity would provide a negative that I would eventually become very Nevertheless, 1983 became the feed-back loop. Together this would closely involved in the IUPS effective starting point for the field allow very fine and acute regulation organization. The start of this was that we now call Ca2+ signalling. This of transport thereby, for example, explaining the control of fluid secretion from exocrine glands. This theme was dealt with in much more detail in our subsequent review article for Nature (Petersen & Maruyama 1984), which became our most cited paper (ISI Citation Classic 1993), but this topic received its perhaps most definitive treatment in the annual review article I wrote for The Journal of Physiology (Petersen, 1992).

Looking back at my diary for 1983, I am amazed at the large number of invitations to deliver lectures in the US and throughout Europe that Figure 3. The Physiological Society’s stand at the IUPS Congress in St Petersburg in followed so quickly after the 1997. Sitting: Joan Abbott (left) and Nina Burdakova. Standing: Ole Petersen (middle) publication of the April 1983 Nature with two Bulgarian scientists supported at that time by The Physiological Society’s paper. In the summer of 1983, the Centre of Excellence Scheme.

Physiology News | No. 70 | Spring 2008| www.physoc.org 6 PN TWENTY FIVE YEARS IN PHYSIOLOGY development came late in the year with the publication of a paper in Nature jointly from the groups of Irene Schulz at the Max Planck Institute for Biophysics in Frankfurt and Michael Berridge and Robin Irvine at Cambridge University (Streb et al .1983). The paper showed that the small water soluble molecule inositol 1,4,5- 2+ trisphosphate (IP3), can release Ca from a non-mitochondrial store in permeabilized pancreatic acinar cells. The general significance of this Figure 4. The last night of the 2003 Gordon Research Conference on Ca2+ signaling in observation was very quickly South Hadley, Massachusetts. From left to right: Katsuhiko Mikoshiba, Michael confirmed in many cell types by Berridge, Irene Schulz and Ole Petersen. many different groups and led to a 2+ other research fields. However, these dramatic increase in the interest in first Gordon Conference on Ca signalling was held in New developments should not necessarily Ca2+ signalling, which in subsequent Hampshire and 10 years later, on the be taken as an indication that years became, and still continues to final night of the 2003 Ca2+ signalling physiology as a discipline is not be, a large and immensely Gordon Conference in doing well. As the President of IUPS productive research field. An Massachusetts, we celebrated the and I have pointed out in a recent important vehicle for publishing Ca2+ 20th anniversary of the discovery of editorial for the journal Physiology signalling work had in fact been 2+ (Kaneko & Petersen, 2007), the created a couple of years earlier by the Ca releasing action of IP3 (Fig. 4). physiological journals are actually Maynard Case. The journal Cell doing extremely well. As European Calcium was established already in 2008 Executive Editor of Physiological 1980 and it is a major credit to Now, 25 years after the start of The Reviews (Physiol Rev) I am certainly Maynard that he already at that time Physiological Society’s magazine, pleased that Physiol Rev is in the top so clearly saw the potential for such a the ‘physiological world’ looks in 10 of ALL scientific journals with journal, which later benefited many ways very different from 1983. regard to Impact Factor (IF), ahead of enormously from the discovery of In the UK there are few free-standing – for example – all Nature review 2+ the Ca -releasing IP3 effect as well as physiology departments and in the journals, except Nature Reviews the invention of a new generation of 2008 RAE there is no specific Cancer. As described in the recent fluorescent Ca2+ sensors that finally physiology unit of assessment, but Physiology editorial, many other allowed high resolution Ca2+ imaging physiology is assessed by a ‘Pre- physiological journals have also seen experiments to be conducted clinical and Human Biological healthy rises, some very substantial, (Petersen et al. 2005). In 1993 the Sciences Panel’ together with many in their IFs in recent years. Because physiology is THE integrative science and we have entered a period where the techniques exist for evaluating even very sophisticated integrative actions, for example in the brain of awake behaving animals (Ferezou et al. 2007), there is not the slightest doubt that the future of physiological research is very bright.

2008 is not an international physiological congress year, but the preparations for the forthcoming 2009 IUPS Congress in Kyoto are almost finished (Fig. 5). One of the more imaginative symposia scheduled for the 2009 Congress Figure 5. The IUPS Council at the Kyoto International Conference Center in December 2007, inspecting the venue for the 2009 IUPS Congress. From left to right, front row: which, I believe, contains many of Marjan Rupnik, Cecilia Hidalgo, Irene Schulz, Ole Petersen, Malcolm Gordon and Tai the most crucial future elements of Yao; 2nd row: Aki Kaneko, Quentin Pittman, Sue Orsoni, Ann Sefton, Tony Macknight, physiology, is entitled Mapping of Daniel Riquier and Antonio Campos de Carvalho. signalling networks and is chaired by

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Arthur Konnerth from Munich’s grateful to the American and the IUPS editorial IV. Physiology 22, 354. Technical University and Hideo Scandinavian Physiological Societies Maruyama Y, Gallacher DV & Petersen OH (1983). Voltage and Ca2+-activated K+ channel Mogami from Hamamatsu University for kindly sponsoring this in baso-lateral acinar cell membranes of th in Japan. This symposium deals with symposium to celebrate my 65 mammalian salivary glands. Nature 302, 827- the dynamic mapping of both large birthday. The symposium will range 829. scale networks in the visual and widely, reflecting my interests, barrel cortex (Ferezou et al. 2007) of starting with molecular and cellular Maruyama Y & Petersen OH (1982). Cholecystokinin activation of single-channel the brain in awake behaving animals, physiology, moving on to currents is mediated by internal messenger in as well as intracellular dynamic neurobiology, then on to cellular pancreatic acinar cells. Nature 300, 61-63. signalling networks (for example endocrinology and ending up with Ca2+ movements through various epithelial function. I am very happy Park MK, Choi YM, Kang YK & Petersen OH intracellular organelles (Park et al . (2008) The endoplasmic reticulum as an that such an important figure as integrator of multiple dendritic events. 2008), protein kinase C and Bernd Nilius, who is leading the Neuroscientist 14, 68-77. calmodulin translocation and increasingly exciting TRP channel substrate phosphorylation). Alexei field, has agreed to give the Opening Petersen CCH (2007). The functional Tepikin from Liverpool University, Lecture and that many other world organization of the barrel cortex. Neuron 56, 339-355. who has recently devised a clever leaders have accepted the invitation fluorescent technique for monitoring to speak. It will be a privilege to be Petersen OH (1992). Stimulus-secretion dynamic Ca2+ concentration changes together with an outstanding group coupling: cytoplasmic calcium signals and the in single endocytic vacuoles in intact of colleagues and friends from whom control of ion channels in exocrine acinar cells. J Physiol. 448, 1-51. living cells (Sherwood et al. 2007) is one can learn so much and the work one of the invited speakers in this being done, particularly by some of Petersen OH (2005). Ca2+ signalling and Ca2+- symposium. the younger invited speakers activated ion channels in exocrine acinar cells. (Burdakov et al. 2006; CCH Petersen, Cell Calcium 38, 171-200. In 2008, we still have a Physiology 2007), gives me confidence that the Department in Liverpool, now future of physiology is in excellent Petersen OH & Maruyama Y (1984). Calcium- headed by Susan Wray, but whereas activated potassium channels and their role in hands. there were only two professors in the secretion. Nature 307, 693-696. Department in 1983 there are now Ole H Petersen Petersen OH, Michalak M & Verkhratsky A nine professors! Personally, I am in Department of Physiology, School of (2005). Calcium signalling: Past, present and the lucky situation of continuing to Biomedical Sciences, University of future. Cell Calcium 38, 161-169. benefit from the MRC Professorship, Liverpool, UK and President, The which has freed me from all Physiological Society Sherwood M, Prior IA, Voronina SG, Barrow university administration and SL, Woodsmith JD, Gerasimenko OV, Petersen OH & Tepikin AV (2007). Activation of undergraduate teaching. This does References trypsinogen in large endocytic vacuoles of not mean that 2008 will necessarily Burdakov D, Jensen LT, Alexopoulos H, pancreatic acinar cells. Proc. Natl. Acad. Sci. be an easier year than 1983, since Williams RH, Fearon IM, O’Kelly I, USA 104, 5674-5679. Gerasimenko O, Fugger L & Verkhratsky A work on the pre-clinical RAE panel, as + (2006). Tandem-pore K channels mediate Streb H, Irvine RF, Berridge MJ & Schulz I well as several Royal Society inhibition of orexin neurons by glucose. (1983). Release of Ca2+ from a non- committees and many other society Neuron 50, 711-722. mitochondrial intracellular store in pancreatic involvements will take up a lot of acinar cells by inositol-1,4,5-trisphosphate. Ferezou I, Haiss F, Gentet LJ, Aronoff R, Weber Nature 306, 67-69. time. Nevertheless, in 2008 – like in B & Petersen CCH (2007). Spatiotemporal 1983 – I shall be speaking at a dynamics of cortical sensorimotor integration in behaving mice. Neuron 56, 907-923. Tsien RY, Pozzan T & Rink TJ (1982). Calcium number of international symposia homeostasis in intact lymphocytes – and congresses throughout the Hamill OP, Marty A, Neher E, Sakmann B, cytoplasmic calcium monitored with a new, world. In addition to the Sigworth FJ (1981). Improved patch clamp intracellularly trapped fluorescent indicator. J considerable excitement of hearing techniques for high-resolution current Cell Biol 94, 325-334. about new scientific discoveries and recording from cells and cell-free membrane patches. Pflügers Arch 391, 85-100. Verkhratsky A, Krishtal OA & Petersen OH integrating them into the (2006). From Galvani to patch clamp: the physiological world picture, there Kaneko A & Petersen OH (2007). The development of electrophysiology. Pflügers will also be great pleasure in meeting International Union of Physiological Sciences Arch 453, 233-248. up with many old and new friends from all over the world. One meeting The Physiological Society International Workshop I am particularly looking forward to Latest advances in ion channel techniques applied to physiological problems this year is the symposium on Shanghai, China, 12–16 September 2008 Frontiers in physiology to be held at A workshop for young physiologists. aimed at providing a unique the Royal Danish Academy of opportunity to gain an appreciation of state-of-the-art techniques being Sciences and Letters in Copenhagen, used to study ion channels in a range of cell types. the first academy that elected me as a member, 20 years ago. I am Full details from http://www.physoc.org/international/Shanghai2008

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Determining control of the cardiovascular system in health and disease: from brain to blood vessel Physiological Society Themed Meeting at the University of Invited speakers Mike Andresen Leeds (17–19 March 2008) Tom Cunnane Susan Deuchars will also be a lecture given by Andy Sheila Gardiner Ramage in memory of David Jordan, Michael Gilbey John Greenwood an eminent and well respected Roger Hainsworth Society Member who sadly passed Ida Llewellyn-Smith away last year. Janice Marshall Chris Matthias Elspeth McLachlan There will, of course, be plenty of Shaun Morrison Local hosts Susan and Jim Deuchars. opportunity to meet with colleagues Donal O'Leary We extend a warm invitation to what informally. Leeds is not short of bars David Paterson (from traditional Yorkshire to trendy Julian Paton we believe will be an exciting Tony Pickering inaugural Physiological Society modern) and restaurants to cater for Andy Ramage Themed Meeting here at the almost any taste in food. Frederic Roche University of Leeds. We have lived Larry Schramm Kevin Shoemaker and worked in Leeds for nearly 10 To further tempt you, the Sunday years now – we have loved every preceding the meeting (16 March) Symposia minute of it and hope that some of will see a Festschrift for Michael Supraspinal control of autonomic outflow the great atmosphere in both Spyer sponsored by The Society’s Role of exercise in controlling autonomic University and city infuse the journal, Experimental Physiology. For function in health and disease full information see p. 50. Spinal circuitry controlling sympathetic meeting. nervous activity Effects of spinal cord injury on autonomic The meeting The Institute of Membrane and function This is the first of the new style Systems Biology (IMSB) Autonomic function in the periphery Physiological Society Themed The meeting will be hosted by Sue Meetings which enables us to invite and Jim Deuchars from the IMSB. an internationally renowned cast to The Institute is one of three research speak over a science-filled 2.5 day institutes in the Faculty of Biological schedule. The meeting will take the Sciences at Leeds. It contains 46 form of five mini-symposia academic staff (including addressing the main theme, each independent research fellows) within lasting half a day. An important two Research Groups – Integrative aspect is that each session has free Membrane Biology and communications drawn from Cardiovascular and Sports Sciences. submitted abstracts associated with Interests are broad-ranging, from it. These are traditional Physiological fundamental studies on the The Garstand Building (above) and Ilkley Society style talks lasting 10 structures and functions of Moor (below). minutes. membrane proteins, to physiological questions in the mammalian There are also poster sessions on cardiovascular and nervous systems each day. These communications are – all the way to studies of health, not necessarily restricted to the exercise and disease in humans. To themes of the symposia and we will facilitate these studies there are also be happy to accept abstracts on any close links with physiologists aspect of the cardiovascular, throughout the University, located in respiratory and autonomic control the Faculty of Medicine and Health theme. During this meeting there and elsewhere.

Further information Society Meeting web site http://www.physoc.org/meetings/leeds2008 IMSB http://www.fbs.leeds.ac.uk/institutes/imsb About Leeds http://www.leeds.gov.uk/About_Leeds.aspx Brass band event http://www.leedsconcertseason.com Leeds rugby http://www.leedsrugby.com

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The city The Physiological Leeds is often referred to as the fastest growing city in the UK and Society Annual currently has a population of 750000 within the city boundaries. It has Meeting 2008 certainly changed in our time here It is winter in Cambridge now, but and such change appears to be the meeting organisers of The continuing apace. There is apparent Physiological Society have been hard commercial prosperity in areas of at work so that the main 2008 finance, business and media. This is meeting here will be a splendid one all complemented by a vibrant mix of for you! culture, commerce and style, making Besides the exceptional Plenary talks, Leeds the primary social hub of the Prize Lectures and the Young North. Leeds has just been voted as Physiologists’ Syposium, there will one of the top three places to shop in be many interesting and exciting the UK by numerous independent Symposia to attend, including: surveys, and offers a huge range of shops and stores to suit all tastes. • New insights into nociceptors The Lonely Planet guide recently • NMDA receptors: building function called it the Knightsbridge of the from structure North. • pH dynamics in the central nervous system – a matter of life or death? If you are more inspired by country- • Regulation of placental function side than shops, museums, clubs and and pregnancy outcome pubs then not far away are the • Cardiac cell effects of exercise impressive Yorkshire Dales with awe- training inspiring scenery and the huge • The neural basis of reward and selection of outdoor activities and economic decision-making • Fuel for thought: current pursuits. • Teaching Workshop – Systems controversies in brain glucose physiology teaching and learning sensing Yorkshire is also home to the ancient st in the 21 century • Mouse models for human epithelial city of York (about a 30 minute train • On the perceptions of action and disease: novel insights and new ride away), with historical attractions of affective touch, and their horizons such as the Viking and Roman contribution to the somatic self heritage, the Minster, Shambles and • Physical inactivity: a biological basis for • Novel concepts in potassium metabolic disease. a selection of Museums. channel transport, targeting and recycling More information about the Yorkshire is famous for its brass • Endothelial aging: molecular meeting, the extensive social bands and there is, in fact, a brass mechanisms and functional programme of extracurricular band performing in town during the significance activities, and the host department meeting if you wish to sample it. • Parental genetic influences on will be published in the next offspring growth, metabolism and Physiology News (PN 71). As with most British cities, sport is energy homeostasis also a major pastime. The world • Role of the t-tubules in subcellular But before then, don’t forget the famous Headingley stadium houses a modulation of cardiac excitation- important dates given below. contraction coupling premiership rugby union team See you in Cambridge this summer! (Leeds Carnegie), a premiership • Recent advances in taste rugby league side (Leeds Rhinos) and processing and recognition Bill Harris top class cricket (Yorkshire Cricket • Co-transmission in the autonomic Department of Physiology, Club). There is also a football team, nervous sytem Development and Neuroscience, Leeds United, at Elland Road. In fact, • Information processing in the Cambridge University, UK near the time of the meeting (14 and cerebellar cortical ‘neuronal 20 March) there are two Leeds machine’ Full information on Physiology 2008 is Rhinos matches – this could be a rare • Hypothalamic regulation of available at: chance to take in some rugby league. mammalian fertility http://www.physiology2008.org

Jim Deuchars Abstract submission opens 1 March 2008 Abstract submission closes 31 March 2008 Susan Deuchars Travel Grants deadline 31 May 2008 University of Leeds, UK Early registration closes 6 June 2008

Physiology News | No. 70 | Spring 2008| www.physoc.org 10 PN LIVING HISTORY

Adventures in neurobiology with David Wallis

David Wallis (right) retired from the writing experience, although it made established Chair in Physiology at me realise that if I was going to write Cardiff University in 2000 where, for any sort of scientific autobiography I 33 years, his research was focused on needed to do it now, while there was neural signalling in mammals. His still an opportunity to talk to the time at Cardiff saw the now-familiar characters involved. Also, the whole evolution of an independent process of conceiving, researching Department of Physiology into a and writing the book has kept me – I facet of a larger School of would like to think – mentally alert Biosciences. Although these changes and on the lookout for developments could provide rich material for the in the subject areas covered by the subject of a book, David has spent book. the last couple of years writing about and integration of scraps of the early part of his career as a PhD SH Could you describe your book? knowledge into a growing whole. student studying animal behaviour DW It recounts my early career and subsequent post-doctoral work during some crucial years in SH Has it been fun to revisit your on the electrophysiology of neurobiology. The book follows my early years in science? olfaction. Now that the manuscript career trail as it progressed from DW Oh, yes! It has been a great is finished, he is embarking on the studies of ant behaviour to opportunity for reminiscing. Some next step of finding a publisher for electrophysiological investigation of of the early technologies had the book, which has the arresting smell and taste in the blowfly. I hope aesthetic pleasures that have been title In pursuit of the blood-red I have provided an insight into the lost in the digital era. I remember slavemaker – adventures in kinds of investigations that underlie the thrill of achieving a perfect neurobiology. After first learning that the advance of science and a glimpse smoked drum record or capturing an the blood-red slavemaker is a species of the kinds of recording devices that oscilloscope trace on camera and of ant, Sarah Hall talked to David were used at the time. It’s really a developing the film successfully in about his early research, pre-digital collection of personal stories and the dark room. On the other hand, I technology and the process of anecdotes which illustrate the also remember the trials associated writing a scientific autobiography. process of scientific research or, if with ageing the radio valves for the you like, a history of science relating cathode followers in our recording SH (Sarah Hall) What made you to a particular time and one person’s apparatus, in order to minimise the decide to spend your retirement experience. noise interference. writing your memoirs of your life in science? SH Do you think it was a particularly My journey across the Atlantic on the DW (David Wallis) Good question! exciting time? SS Bremen to my post-doc position in When I first retired, I wrote a local DW It was – and that’s part of the Philadelphia was also unforgettable. history of my home town of reason I tried to write the book. In The Bremen docked in New York and Stevenage and really enjoyed the the late 1950s there was a unique discharged her passengers into long focusing together of psychologists, queues at Customs and Immigration. zoologists, neuroanatomists and, of Having eventually reached the front course, physiologists, to try to of the queue, I had my papers understand neural processing. scrutinised and stamped, then I was Ethologists in Cambridge, where I allowed to continue on. As I left, I was studying, were excitedly was mortified to realise that I was debating new approaches and recent short of one stamp, so I went back to discoveries. From this foundation, I the queue I had just left and, have retained a fascination with the thinking surely I don’t have to line mysteries of the nervous system up again, I went to the front of the throughout my career. I hope the line to find the same official I had just book gives the reader an idea of seen. Uproar! Horror! Undesirable Figure 1. A threat gesture – mandibles what it is like to be part of a alien at large! Police shouted and held wide open – shown by the ant on community of scientists engaged in converged on me waving their the left to an alien fusca from another an exploding area of knowledge. I Tommy guns. A brief vision I had of colony. David Wallis faced threatening hope it also illustrates how science gestures from US Customs and being pumped full of lead was Immigration officials when he arrived in proceeds not so much by amazing mercifully curtailed by the official New York to start his post-doctoral breakthroughs and flashes of recognising me … welcome to the career. inspiration, as through accumulation Land of the Free!

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In those early years I met and learned from so many of the founding fathers in the fields of ethology and insect physiology, but at one time I also shared an office with a male bullfinch - it was being raised in the absence of birdsong as part of a study of song learning by my colleagues in the lab next door, so it grew up listening to me instead!

SH The book covers your early career and your post-doc activities in the USA, but your later career in physiology is not included. Is that the subject of the next book? Figure 2. Amazon ants (Polyergus rufescens, light colour) raiding a colony of Formica DW Maybe! That was a point in my fusca (dark colour), whose nest is in dry soil under a stone. David Wallis’s career in career where there was a distinct end science began by studying such ant behaviour. to a chapter. The considerations of my young family and the expiry of DW Yes, I have always enjoyed reader, and to explain any vital my visitor’s visa in America meant painting and drawing, and creating technical terms. The intention is to that I returned to the UK, to work in effective illustrations for the book provide a personal approach that Aberdeen with Hans Kosterliz, who has been part of the challenge of the brings some of the innovators in was subsequently to lead his group whole project. neurobiology to life. towards the discovery of enkephalins. I was using my SH Who do you think will read this SH Has your experience of writing electrophysiological expertise, but book? and publishing research articles now I was working in mammalian DW The target audience is quite helped? systems for the first time. This job hard to define, and this is certainly DW Yes, but the publication side is also brought me into a physiology something that potential publishers very different. I have been advised to department for the first time, and I are struggling with. I suppose it’s a use an agent to submit the have remained a physiologist ever popular science book for the manuscript, rather than sending it since. educated reader, but it is off to the publishers myself. So far, I nevertheless a scholarly text aiming haven’t been able to find an agent SH The book is illustrated with some to contribute to the history of the and have decided that it’s not a exquisite pen and ink drawings. Are subject. I’ve tried to write in a style promising avenue. I’m hoping to you the artist? that is accessible to the general have a publisher soon, though. Any helpful advice would be welcome, as would any agent.

SH What next? DW Well, I think there’s a fascinating story to be told about the biology of serotonin, its discovery, its roles in the body and the evolutionary history of its receptors. I have mentioned the prospect of the ‘5-HT story’ to a number of publishers but have yet to catch a fish with this particular worm. You never know, though … watch this space!

David can be contacted at [email protected] Figure 3. Sonograms of chaffinch songs showing learnt elaboration superimposed on the basic innate pattern. A, B, Normal full songs from wild caught birds. C, Song- Reference pattern of bird hand-reared in visual and aural isolation from other birds (from Thorpe WE (1956). Learning and instinct in Thorpe, 1956). David Wallis shared his office with a songbird. animals. Metheum, London.

Physiology News | No. 70 | Spring 2008| www.physoc.org 12 PN FIVE YEARS IN THE LIFE OF ...

Five years in the life of a web site IT Manager Liam McKay (right) looks back at the development of The Society’s new site on the eve of its launch 2004 an ever growing list of new features My first week at The Physiological and functionality, such as secure Society was an interesting one. online ordering, integration with Having had a couple of days working back office systems and the delivery in the Cambridge and London of a variety of multimedia content. A offices, I was invited to meet the web site developed in the mid 90s then Chairman, Giovanni Mann. was crying out for development by Newly in post himself, I sat in his the mid 2000s! • To offer our Members a community office and the agenda was set with environment in which to communicate four words: new web site please. 2005–2006 and share information. Having spent my first year Internal aims Our existing web site, created in the familiarising myself with the IT • To fully integrate our back office mid 90s, had served its purpose for a systems and needs of The Society, I felt confident to embark upon databases with our front end web site; number of years. The platform and • To allow non technical staff to input redeveloping our web site. It soon programming on which the site their own content; resided gave The Society a means to became apparent that the sky was • To develop a variety of online features present static textual information. the limit in terms of the number of that allow us to directly communicate Later came some dynamic content, features a new web site could have Society business with our Members such as the publication of our within a reasonable budget. We and site visitors. abstracts and the online version of needed to focus on the aims of our Armed with these aims, I set to work the magazine you are now reading, site redevelopment. After meeting obtaining proposals from a number which all proved popular. with staff and Executive Committee and Council members, we came up of third party developers, most of our aims. whom I had encountered on visits to However, as the years passed by, new IT seminar and exhibitions. I also felt web technologies meant new External aims it important to forge relationships expectations of web sites. Web site • To give our web site a professional with fellow societies – what systems, users were slowly becoming and user friendly design and navigation features and providers were working accustomed to more professionally structure; well for them, and what were not. designed sites with improved • To offer web site visitors secure online navigation and accessibility. payment, membership subscription Some of the proposals were and renewal, and events booking; Organisations were keener to utilise expensive, some fell short, some were overly ambitious. One of the proposals came from our existing database supplier, Fisher Technology. By retaining our existing database and supplier relationship, both of which we were happy with, and utilising the web development services Fisher offered, their proposal won on both the functionality they could offer and the overall and ongoing costs of project.

2006–2007 The following year began with the development of a project plan. We initially had to indentify which features our site could benefit from. Fisher had a raft of choice: from forums to photo libraries, from bulletins board to news boards, from blogs to wiggets – they could even provide bliggets (yes, you’ve Figure 1. Something old: the existing Society web site. guessed it – a bligett is a widget with

Physiology News | No. 70 | Spring 2008 | www.physoc.org FIVE YEARS IN THE LIFE OF ... PN 13

with 35 Communications, the agency involved in our recent rebranding, we were able to create the new look for our site. Features were slowly added to a test site, then tested, fine tuned, retested, fine tuned again, and retested. Nothing could be signed off until it was unbreakable!

Of course, with a project of this size, problems were encountered. Some elements of the site, in particular, online membership application took much longer to get right than anticipated. However, slowly, but surely, we made careful progress.

2008 and beyond 2008 was the year light could be seen at the end of the tunnel. Many Figure 2. Something new: the redeveloped Society web site. elements of the site had been completed, and final testing of our a blog). A lot of choice, a lot of time, increase the accuracy of the membership application and events avenues to pursue. information we hold, whilst giving registration processes were our Members a speedy, secure and underway. Based upon our web statistics we efficient online experience. knew which areas of our current site We have recently moved to an online got regularly high usage. Areas such We were also keen to give our staff system for tracking progress on the as the news and jobs listings, the the ability to create and edit online final elements of the site that need online magazine, our meetings content without the need for correcting – a thankfully short list. programme and international programming or design skills. Staff The site has really taken the shape of section all prove popular. were emailing me copy or creating what we originally envisaged, and content in applications such as something very different from its We also wanted to develop an online Microsoft Word, only for me to current incarnation! community feel for our Members. duplicate this online. By allowing Features such as forums, blogs, staff to input content directly into We are now looking forward to a bulletin boards, profile pages, and a templates using a simple online launch. We decided, through searchable Member directory would content management application, experience, not to promote a ‘go give Members a portal through duplication of work is removed. live’date until now. I am pleased to which to communicate and share announce the last week of March information. After many review meetings with 2008 as our new site launch. We will Fisher and staff, a detailed picture of be contacting all our Members with Another key aim was integrating our all our procedures was created. information on the array of features office procedures and Member From our initial aims, a final proposal nearer this date. database into our new web site. was created and fine-tuned. Each Many of our current processes, such element of the site was included into We have already been thinking about as membership and grants a project plan with associated costs, future developments to the site: applications, events registration, and time and people resources required. online movie streaming, podcasts, membership renewals, involve a lot an educational resource portal, of office administration. By The next stop was to deliver the integrated wikis and facebook – the transferring these manual proposal to our Executive list grows. However, for the time procedures to an automated system, Committee and then to Council. The being, I am confident our new web Members would be able to input plan was positively received. A need site will give our Members the online their information directly online, had clearly been identified and final experience they can expect from a which in turn would activate a approval to proceed with the project modern society site. completely online review process was given. Now the real work began! ending in direct input into our Liam McKay database. Such technology would Over the next 18 months, elements IT Manager, The Physiological dramatically reduce administrative of the site were developed. Working Society

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Cold facts about AMPK in fat

Adenosine monophosphate is based on reports that AMPK activated protein kinase (AMPK) has activates PGC-1α, a transcription been called the ‘metabolic master factor central to mitochondrial switch’, and ‘cellular fuel gauge’ biogenesis (Jager et al. 2007). because of its ability to sense intracellular energetic stress in the AMPK activity in brown adipose form of a decreased ATP/AMP ratio tissue during acute and chronic and respond by increasing ATP cold exposure synthesis and decreasing ATP A main function of brown adipose consumption (Hardie & Carling, tissue is generation of heat via non- 1997). Here recent findings that Kurt Saupe (far right) with his lab group. shivering thermogenesis during AMPK is highly abundant in brown times of environmental cold adipose tissue and regulated in novel acetyl-coA carboxylase (ACC), the exposure. During acute cold ways in both brown and white rate-limiting step in fatty acid exposure this response includes a adipose tissue are discussed. These synthesis (ACC1) and inhibition of large increase in oxidation of free findings suggest possible novel roles fatty acid oxidation (ACC2). Both fatty acids. Given the established for AMPK in regulation of body ACC isoforms are heavily role of AMPK in regulating free fatty weight, body temperature, and phosphorylated (inhibited) in brown acid oxidation in tissues such as liver pathogenesis during hyper- adipose tissue, presumably by AMPK. and muscle, one might anticipate adrenergic states. Such a massive pool of ACC would be that activation of AMPK would be ideal for the simultaneous needed to allow the increase in free AMPK activity in brown adipose lipogenesis and β-oxidation that fatty acid oxidation during the first tissue takes place on a large-scale during hours of cold exposure. Instead, During the last 15 years, studies non-shivering thermogenesis. Upon during the first 1–24 hours of conducted largely in liver and muscle induction of non-shivering exposure to 4° C, AMPK activity does have shown that activation of AMPK thermogenesis, selective not increase, suggesting that further stimulates ATP producing reactions dephosphorylation of ACC1 by an activation of AMPK above the high such as free fatty acid oxidation, unknown effector might rapidly basal level is not necessary for the while inhibiting ATP consuming release the inhibition of fatty acid initial induction of non-shivering processes. This has led to the synthesis, while ACC2 remains thermogenesis. It should be noted perspective that high AMPK activity inhibited by AMPK, allowing β- that in cultured brown adipocytes is associated with a state of cellular oxidation. It is also tempting to adrenergic stimulation increases the energy conservation. Brown adipose speculate that a high AMPK activity amount of phosphorylated AMPK tissue is in some ways the antithesis is necessary to maintain the high within minutes (Hutchinson et al. of an energy conserving tissue since mitochondrial density present in 2005). However, the meaning of this its uncoupled metabolism converts brown adipocytes. This speculation intriguing finding is unclear since in reducing equivalents into heat instead of useful chemical energy (ATP), in a process termed non- shivering thermogenesis. Thus it was surprising to find that α1 AMPK expression and activity in BAT is the highest yet for any reported tissue, being 3-fold higher than in liver (Mulligan et al. 2007). This AMPK activity is entirely attributable to the α1 isoform, occurs in multiple species (Fig. 1) and appears to be secondary to high levels of expression of the protein.

While currently we can only speculate as to the physiological role Figure 1. Comparable levels of AMPK activity in brown adipose tissue across this high level of AMPK activity plays mammalian species. Enzymatic activity of the two isoforms of AMPK measured in in brown adipose tissue, it is brown adipose tissue of four species of mammals (n=5-8). In all four species, the α1 accompanied by extremely high isoform had a very high level of activity in absolute terms, and when compared to the levels of its downstream target, activity of the α2 isoform.

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vivo no increase in AMPK activity Cold Norepinephrine CL 316,243 occurs during the first hours of cold Liver No exposure. Brown adipose tissue Yes No Chronic cold exposure causes brown White adipose tissue Yes Yes Yes adipose tissue to remodel in a way Figure 2. Mechanisms upregulating tissue AMPK activity are highly tissue specific. that increases its heat generating Environmental cold exposure (14 days at 4oC) significantly increases α1 AMPK activity capacity including tissue in both white and brown adipose tissue but not liver. This upregulation can be hypertrophy, mitochondrial mimicked pharmacologically in white adipose tissue (epididymal fat pad) by chronic biogenesis and upregulation of UCP1 administration of either norepinephrine, or the β3-adrenergic specific agonist CL and other enzymes important for 316,243. non-shivering thermogenesis. We found that the expression and sympathomimetic drugs caused the containing β3-adrenergic receptors activity of AMPK increases expected upregulation of UCP1 (white and brown adipocytes). significantly in brown adipose tissue levels. This indicates that However, it seems unlikely that the in response to chronic (7–14 day) upregulation of AMPK does not go brown adipocytes located within cold exposure. Critical insight into hand-in-hand with upregulation of white fat increase AMPK in response the physiological role of AMPK in UCP1 and other enzymes linked to to β3 adrenergic stimulation since brown adipose tissue will likely come non-shivering thermogenesis, and β3-adrenergic stimulation does not from determining which of the many suggests the existence of an upregulate AMPK in brown adipose cell types within brown adipose alternative non-sympathetic tissue. tissue contain high levels of AMPK mediated pathway for cold-induced activity that are further upregulated gene regulation in brown adipose Significance for human in response to chronic cold exposure. tissue. pathophysiology While one might assume that it is AMPK is now recognized to play a the brown adipocytes, this has not Link between sympathetic nervous key role in regulating aspects of yet been established. system and AMPK in WAT whole body energy balance such as While white adipose tissue was once appetite (Minokoshi et al. 2004). A Chronic cold-induced upregulation regarded largely as an inert storage role for AMPK in regulating caloric of AMPK also raises the questions of depot for excess energy, it is now expenditure by brown adipose tissue whether the high AMPK activity recognized as an organ central to the may be a second way in which AMPK observed in brown adipose tissue at etiology of diseases such as type 2 contributes to the regulation of body 'baseline' is in part a response to the diabetes mellitus. A major part of weight. Given the central role of relative cool temperature at which this new understanding comes from AMPK in regulating cellular experimental mice are usually the recognition that white adipose metabolism, its high activity in housed (approximately 5° C below tissue is an endocrine organ that brown adipose tissue suggests the their thermoneutral temperature), depending upon its state of 'health', intriguing possibility that by and whether chronic environmental produces variable amounts of the manipulating AMPK activity one heat exposure might cause down- adipokines that regulate factors such could regulate the number of regulation of AMPK in brown adipose as appetite and insulin sensitivity. calories dissipated as heat. 'Firing up' tissue. We found that in white adipose brown adipose tissue to treating tissue AMPK activity was robustly obesity in humans has gained What is the mechanism by which upregulated by chronic cold support from a recent report chronic cold exposure increases exposure, as it was in brown adipose identifying small, distinct regions of AMPK activity in brown adipose tissue (Fig. 2). However, in contrast brown adipose tissue in humans – tissue? Since most, if not all, cold- to brown adipose tissue, primarily in the area of the collar induced changes in brown adipose administration of norepinephrine for bone and along the spine tissue biology are mediated by a 14 days in vivo significantly increased (Nedergaard et al. 2007). Future cold-induced increase in sympathetic white adipose tissue AMPK activity. studies will be required to determine nerve activity, we tested whether the To our knowledge, this is the first what role AMPK in brown adipose effects of cold on AMPK activity demonstration of an in vivo link tissue plays in regulating body could be reproduced by between these two important stress weight and body temperature. sympathomimetics. However, response systems. To identify the neither chronic norepinephrine nor adrenergic receptor subtype Congestive heart failure, metabolic the β3-adrenergic agonist CL responsible for this effect, the β3- syndrome and obesity are often 316,243 administered to mice for 14 specific agonist CL 316,243 was hyperadrenergic states that cause days using implanted micro-osmotic administered. It too was sufficient to desensitization of adrenergic pumps caused an upregulation of increase AMPK activity in white signaling in peripheral tissues. Our brown adipose tissue AMPK activity. adipose tissue, narrowing the search data raise the intriguing possibility This despite the fact that these for the relevant cell type to those that desensitization of adrenergic

Physiology News | No. 70 | Spring 2008 | www.physoc.org 16 PN FEATURES signaling might lead to a loss of Insight into how the human retina obtains its AMPK activity in the white adipose tissue of these patients. The idea that need of vitamin B1 loss of AMPK activity can be central The retina has a substantial need for a variety of nutrients, to pathology is supported by the including vitamin B1. This vitamin is involved in a variety of successful clinical use of the AMPK activators metformin and metabolic reactions and, thus, is essential for normal functions thiazolidinediones to treat type 2 and well-being of the retina. Hamid Said (below) and colleagues diabetes (Musi & Goodyear, 2006). examined how human retinal epithelial cells transport the Currently, we are at the very early vitamin, how the transport process is regulated, and what stage in understanding how AMPK happens when clinical mutations in a thiamin transporter (that activity is regulated in adipose tissues, and the (patho)physiological occur in the genetic disorder thiamine-responsive megaloblastic meanings of this regulation. As anemia) affect the ability of this membrane protein to function during the last decade, our as a transporter of the vitamin perspective on AMPK continues to expand, with a new focus on its The human retina is a highly multiple roles in whole body energy differentiated (specialized) tissue balance. whose cells are considered to be among the most metabolically active Kurt W Saupe in the human body. Due to the Jacob D Mulligan central role it plays in vision, the Departments of Medicine and retina is protected from the Physiology, University of Wisconsin, fluctuations in the surrounding Madison, WI, USA environment by what is called the blood-retina barrier (BRB). This limited supply of appropriate human References barrier also controls access of nutrients, growth factors and RPE cells, their limited survival in Hardie DG & Carling D (1997). The AMP- activated protein kinase--fuel gauge of the hormones to the different cells of the culture, the low homogeneity of the mammalian cell? Eur J Biochem 246, 259– retina. Retinal pigment epithelia primary preparations of these cells, 273. (RPE) represent an important part of and the tendency of such primary the BRB and separate the outer cells to lose their epithelial Hutchinson DS, Chernogubova E, Dallner OS, Cannon B & Bengtsson T (2005). Beta- retina from its choroidal blood phenotype with time in culture. adrenoceptors, but not alpha-adrenoceptors, circulation. This single layer of stimulate AMP-activated protein kinase in epithelial cells plays many Our recent study examined the brown adipocytes independently of physiological functions that include mechanism by which vitamin B1 uncoupling protein-1. Diabetologia 48, 2386–2395. transport of nutrient/substrates into (thiamine) is taken up by cells of the and from the retina. In order to human RPE, determined the Jager S, Handschin C, St-Pierre J & Spiegelman perform such an important function, molecular identity of the membrane BM (2007). AMP-activated protein kinase cells of the RPE have developed a transport systems involved in the (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad host of specialized systems for process, and identified intracellular Sci U S A 104, 12017–12022. transporting nutrients/ ions/ and extracellular factors that affect substrates across their plasma (regulate) the vitamin uptake Minokoshi Y, Alquier T, Furukawa N, Kim YB, membranes. A defect in the ability process (Subramanian et al. 2007). Lee A, Xue B, Mu J, Foufelle F, Ferre P, Thiamin is an important Birnbaum MJ, Stuck BJ & Kahn BB (2004). AMP- of these systems will have negative kinase regulates food intake by responding to consequences on the well-being of micronutrient for the well-being and hormonal and nutrient signals in the the retinal tissue (Meire et al. 2000; health of the retina. As with all other hypothalamus. Nature 428, 569–574. Scharfe et al. 2000). Thus studies cells of the human body, retinal cells cannot synthesize thiamin and thus Mulligan JD, Gonzalez AA, Stewart AM, Carey into how these systems function, HV & Saupe KW (2007). Upregulation of AMPK how they are regulated and what must obtain the vitamin from the during cold exposure occurs via distinct intracellular and extracellular factors surrounding environment. The mechanisms in brown and white adipose that affect/regulate their function vitamin plays an important role as a tissue of the mouse. J Physiol 580, 677–684. are of significant importance. cofactor in a variety of intracellular Musi N & Goodyear LJ (2006). Insulin Knowledge in these areas has been metabolic reactions including those resistance and improvements in signal forthcoming in recent years, involved in energy metabolism. The transduction. Endocrine 29, 73–80. especially following the vitamin also has the ability to reduce establishment of appropriate cell cellular oxidative stress and to Nedergaard J, Bengtsson T & Cannon B (2007). Unexpected evidence for active brown lines for use in in vitro investigations. prevent apoptosis (programmed cell adipose tissue in adult humans. Am J Physiol Such preparations have eliminated death). Thus, reduction in the level Endocrinol Metab 293, E444–452. the problems associated with the of thiamin in retina cells leads to

Physiology News | No. 70 | Spring 2008 | www.physoc.org FEATURES PN 17 disturbance in cellular metabolism. A Such a reduction in intracellular thiamin level occurs in the genetic disorder of thiamine-responsive megaloblastic anemia (TRMA; also known as Roger’s Syndrome), and leads to retinal abnormalities and visual disturbances in the affected subjects. The cause of TRMA is due to mutations in the human thiamin transporter-1 (hTHTR-1) (Diaz et al. 1999; Fleming et al. 1999; Labay et al. 1999), a major player in moving thiamin into a variety of cell types. B Results of the Subramanian et al studies showed for the first time the existence of an efficient and specific transport process for the internalization of thiamin into cultured human-derived retinal pigment epithelial cells (hRPE). This process was found to be mediated via the function of the two transport systems, the hTHTR-1 and the human thiamin transporter- 2 (hTHTR- 2). These studies also showed that the thiamin uptake by the hRPE cells is adaptively up regulated (turned on) when the cells are maintained in conditions of low Figure 1. Distribution of individual clinically relevant hTHTR-1-GFP mutants (fused to thiamin availability via a mechanism the green fluorescent protein, GFP) in the human retinal pigment epithelial ARPE-19 3 that involves activation of genes of cells. A, uptake of H-thiamine in control ARPE-19 cells and those transiently both the hTHTR- 1 and hTHTR- 2 expressing vector (GFP), native hTHTR-1 (hTHTR-1-GFP), mutant 1 (hTHTR-1[D93H]- GFP), mutant 2 (hTHTR-1[S143F]-GFP), mutant 3 (hTHTR-1[G172D]-GFP). (i.e., the SLC19A2 and SLC19A3 B, representative confocal lateral (xy) images showing localization of individual genes, respectively). To understand mutant constructs in ARPE-19 cells, 24-48hrs after transient transfection. how clinical mutations in the hTHTR- 1 that are found in TRMA affect the foundation for further investigations Labay V, Raz T, Baron D, Mandel H, Williams H, function of this thiamin transporter into ways to improve the delivery of Barrett T, Szargel R, McDonald L, Shalata A, Nosaka K, Gregory S & Cohen N (1999). and how the cells process the the vitamin to cells of the human Mutations in SLC19A2 cause thiamine- mutant proteins, these investigators retina, especially in disease responsive megaloblastic anaemia associated generated these mutants conditions associated with low with diabetes mellitus and deafness. Nat Genet experimentally (by means of site- cellular thiamin homeostasis. 22, 300–304. directed mutagenesis) then Meire FM, Van Genderen MM, Lemmens K & introduced (transfected) them into Hamid M Said Ens-Dokkum MH (2000). Thiamine-responsive cultured hRPE cells. They then Departments of Medicine and megaloblastic anemia syndrome (TRMA) with followed the movement of the Physiology, University of California cone-rod dystrophy. Ophthalmic Genet 21, 243–250. fluorescently labeled proteins inside School of Medicine, Irvine, CA, USA the living cells by mean of imaging Scharfe C, Hauschild M, Klopstock T, Janssen using confocal microscopy. The References AJM, Heidemann PH, Meitinger T & Jaksch M results showed that these mutations Diaz GA, Banikazemi M, Oishi K, Desnick RJ & (2000). A noval mutation in the thiamine lead to malfunctioning of the hTHTR- Gelb BD (1999). Mutations in a new gene responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of 1 (Fig. 1A). This was found to be due encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia respiratory chain complex I. J Med Genet 37, to either the inability of the cells to syndrome. Nat Genet 22, 309–312. 669–673. move the mutated proteins to the cell membrane or that the cells do Fleming JC, Tartaglini E, Steinkamp M, Subramanian VS, Mohammed ZM, Molina A, move the mutated proteins to the Schorderit DF, Cohen N & Neufeld EJ (1999). Marchant JS, Vaziri Nosratola D & Said Hamid The gene mutated in thiamine responsive M (2007). Vitamin B1 (thiamine) uptake by cell membrane, but that the proteins anaemia with diabetes and deafness (TRMA) human retinal pigment epithelial (ARPE-19) not functional (Fig.1B). Collectively, encodes a functional thiamine transporter. Nat cells: mechanism and regulation. J Physiol results of these studies lay the Genet 22, 305–308. 582, 73–85.

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Selectivity: a sticky affair? In analogy to some ionic channels, substrate selectivity in ion-coupled cotransporters appears to imply a low flux rate. However, in the presence of potassium the hornworm KAAT1 transporter reconciles selectivity and high transport rates, writes Antonio Peres (below)

The problem of coupling high choose Ca2+ over Na+, an ion with selectivity with high flux rate in ionic similar dimensions but much more channels has been clarified by concentrated in the extracellular Roderick MacKinnon, who received medium? The observation that when the Nobel prize in 2003 for his Ca2+ was absent Na+ ions were able to studies on the potassium channel generate a much larger current KcsA (MacKinnon, 2003). Fig. 1A through the same channels led to illustrates the structure of the the notion of a 'sticky' channel, i.e. selectivity filter of KcsA, formed by to the idea that the pore contained a the ‘potassium signature’ residues high-affinity binding site for Ca2+. TTVGYG. Each of the four subunits that constitute the oligomeric This was later identified in a ring of assembly contributes four main- place to the next due to charge four glutamates (the EEEE motif), chain carbonyl atoms that surrogate repulsion. each located in the same relative + the interactions between K ions and position of the P-loops of the four water in the bulk solution. The This elegant demonstration confirms homologous domains of the protein. resulting organisation of the K+ an explanation proposed many years Structural modelling of this region binding sites in the pore, in addition before, on the basis of purely (Lipkind & Fozzard, 2001) showed to providing selectivity by way of its functional observations: that of that a Ca2+ ion is strongly bound by intrinsic electrostatic properties, also selectivity by affinity (Hess & Tsien, the carboxyl oxygens of the allows high throughput, because the 1984). This idea developed from glutamates (Fig. 1B). At physiological 2+ proximity of the potassium sites results on Ca -selective channels: Ca2+ concentrations, however, this causes the ions to hop from one how was it possible for a channel to electrostatic trap is weakened by the simultaneous presence of two other A B Ca2+ ions bound to two flanking low- affinity sites, allowing a significant flux to occur.

Figure 1. A, atomic structure of the selectivity filter of the KcsA channel; the four blue meshes show the allowed position of dehydrated potassium ions (only two positions are normally occupied) (reprinted from Mackinnon, 2003. Copyright 2003, with permission from Elsevier). B, homology modelling in the L-type calcium channel suggests that C the Ca2+ ion bound to the EEEE motif (central violet ball surrounded by eight red balls representing the carboxyl oxygens) is flanked by two other Ca2+ ions bound to lower affinity sites (upper and lower violet balls). In this arrangement the electrostatic trap formed by the oxygens is weakened and ion flux may occur (reprinted, with permission, from Lipkind & Fozzard, 2001. Copyright 2005 American Chemical Society). C, structure of the

binding site of the LeuTAa transporter showing the participation of a sodium ion (Na1) in the interaction with leucine (reprinted by permission from Macmillan Publishers Ltd: Nature [Yamashita et al. 2005], copyright 2005).

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A B

Figure 2. Recordings of inward transport currents elicited by leucine, alone or in combination with threonine or proline, in an oocyte expressing KAAT1, when the driver ion is Na+ (A) or K+ (B). In Na+ solution the presence of leucine together with proline or threonine reduces the current amplitude approximately to the level of leucine alone, while in K+ solution, leucine causes currents that approach the higher leucine-alone level. All substrate concentrations are saturating. (Adapted from Miszner et al. 2007).

Thus, K+ channels and Ca2+ channels Indeed, the competition respect to the paradigm relating appear to teach us that efficient experiments reported by Miszner et high selectivity and low flux rate, and discrimination among similar ion al. strongly recall the Ca2+ block of will require better knowledge of the species requires a toll in terms of a the current carried by other ion substrate-transporter interactions significant reduction in conductivity, species in the Ca2+ channel (Hess & and of the conformational changes and that further structural Tsien, 1984). The neutral amino acid involved in the substrate specialisations are needed to transporter KAAT1, cloned from the translocation. increase flux rate. midgut of the larva of the KAAT1 belongs to the SLC6A family invertebrate Manduca sexta, has a of transporters, a bacterial member Selectivity in transporters rather wide spectrum of transport- of which, LeuT , has been recently The application of electro- able substrates and, in addition, is Aa crystallized and its atomic structure physiological and biophysical able to exploit either the Na+ or the resolved (Yamashita et al. 2005). On approaches to the study of K+ electrochemical gradients as the basis of the leucine binding site electrogenic cotransporters is a energy sources for active transport. of LeuT , and examining the relatively young area of research, In this transporter leucine acts as a Aa differences in sequence between that has become possible following dominant substrate: although in KAAT1 and CAATCH1 (a very similar the cloning of the proteins of interest presence of Na+ threonine and transporter in which leucine act as a and their overexpression in proline may be transported at higher blocker), we have identified serine heterologous systems. This delayed rates, the concomitant presence of 308 in KAAT1 (S256 in LeuT and start has offered in return the leucine, even at a lower Aa advantage of finding ready-to-use concentration, reduces the T308 in CAATCH1) as a critical ideas and rationales that had been amplitude of the transport- residue for leucine transport. previously developed in the field of associated current to the level Replacing S308 in KAAT1 with the ionic channels. Many analogies produced by leucine alone (Fig. 2A). threonine present in CAATCH1 between channels and transporters converts leucine from a transported have been found, such as channel- substrate to a blocker. Indeed in a like behaviour of transporters, This electrophysiological observation transport system whose selectivity is transient currents reminiscent of the is confirmed by radioactive uptake based on high-affinity binding sites, gating currents of voltage- experiments, that show that in the difference between a permeating dependent channels, and properties presence of both leucine and species and a blocker may be rather threonine, or leucine and proline, compatible with single-file subtle, as shown by Ca2+ ions in Ca2+ only leucine is actually translocated. permeation mechanisms. channels (Hess & Tsien, 1984). The Quite interestingly, the negative + S308T mutation in KAAT1 may The observations described in our dominance seen in presence of Na , simply increase the strength of + recent paper (Miszner et al. 2007) is reversed in presence of K : in this leucine binding to such an extent point to a further possible analogy condition the leucine-associated that translocation or dissociation between transporters and channels, current is higher, and addition of very rarely occur, thereby blocking namely that selectivity by affinity leucine increases the amplitude of the transporter. may constitute a useful idea also in the currents elicited by threonine or understanding the functioning of proline alone (Fig. 2B). This last The amino acid corresponding to transporters. finding represents a variant with KAAT1 S308 has been found to play

Physiology News | No. 70 | Spring 2008 | www.physoc.org 20 PN FEATURES an important role in substrate pore walls of the channel, the small Dodd JR & Christie DL (2007). Selective amino selectivity in other transporters of organic molecules that are acids substitutions convert the creatine transporter to a g-aminobutyric acid the family as well. The two glycine translocated by cotransporters are transporter. J.Biol.Chem. 282, 15528–15533. transporters GlyT1b and GlyT2a may generally highly asymmetric and be distinguished by their differential would consequently require an Forrest LR, Tavoulari S, Zhang Y-W, Rudnick G ability, shown by the former but not asymmetrical binding site. It is not a & Honig B (2007). Identification of a chloride ion binding site in Na+/Cl--dependent by the latter, to transport also surprise then that while the pore of transporters. Proc.Natl.Acad.Sci.USA 104, + 2+ sarcosine. Replacing serine 481 of the K and Ca channels is at the 12761–12766. GlyT2a (corresponding to S308 of centre of a tetrameric assembly, each KAAT1) with the glycine present in subunit of the oligomeric Hess P & Tsien RW (1984). Mechanism of ion permeation through calcium channels. Nature GlyT1b makes GlyT2a capable of transporters appears to function 309, 453–456. sarcosine transport, while the independently (Yamashita et al. reverse mutation G305S in GlyT1b 2005; Boudker et al. 2007). The lack Kilic F & Rudnick G (2000). Oligomerization of suppresses sarcosine transport of symmetry in transporters implies serotonin transporter and its functional consequences. Proc.Natl.Acad.Sci.USA 97, (Vandenberg et al. 2007). greater complexities in the number 3106–3111. Furthermore, the creatine and types of interactions among the transporter CRT may be induced to distinct molecular entities involved. Lipkind GM & Fozzard HA (2001). Modeling of transport GABA by a number of the outer vestibule and selectivity filter of the The recent definition of the atomic 2+ selected amino acid substitutions, L-type Ca channel. Biochemistry 40, structure of LeuTAa has offered the 6786–6794. among which the replacement of tools for the study of these glycine 318 (corresponding to S308 interactions, and the challenge is MacKinnon R (2003). Potassium channels. of KAAT1) with the alanine present in now to understand their dynamics FEBS Lett. 555, 62–65. the same position in the GABA during the transport cycle. Miszner A, Peres A, Castagna M, Betté S, transporter GAT1 (Dodd & Christie, Giovannardi S, Cherubino F & Bossi E (2007). 2007). Acknowledgement Structural and functional basis of amino acid Many thanks are due to Dino Fesce, specificity in the invertebrate cotransporter KAAT1. J.Physiol. 581, 899–913. It appears, therefore, that position Elena Bossi and Stefano Giovannardi 256 of LeuTAa, located in the for critical reading of the manuscript. Vandenberg RJ, Shaddick K & Ju P (2007). unwound region of the sixth Molecular basis for substrate discrimination by transmembrane segment, plays a glycine transporters. J.Biol.Chem. 282, Antonio Peres 14447–14453. fundamental – though not exclusive Department of Biotechnology and – role in determining substrate Molecular Sciences, University of Yamashita A, Singh SK, Kawate T & Gouaux E specificity in a number of SLC6A Insubria, Varese, Italy (2005). Crystal structure of a bacterial transporters. homologue of Na+/Cl- -dependent neurotransmitter transporters. Nature 437, References 215–223. In ionic channels selectivity and Boudker O, Ryan RM, Yernool D, Shimamoto K permeation involve only two & Gouaux E (2007). Coupling substrate and Zomot E, Bendahan A, Quick M, Zhao Y, chemical species, the ion and the ion binding to extracellular gate of a sodium- Javitch JA, & Kanner BI (2007). Mechanism of protein. Conversely, in dependent aspartate transporter. Nature 445, chloride interaction with neurotransmitter: 387–393. sodium symporters. Nature 449, 726–730. cotransporters at least three actors are involved: the protein, the ion(s) and the organic substrate. This is Managing without 'water receptors' very clearly demonstrated in the At an unrecorded meeting in the late 1940s or early 1950s Yngve snapshot of the structure of LeuTAa Zotterman reported the discovery of water receptors in the tongue of the + (Fig. 1C), in which a Na ion is shown frog. to participate in shaping the leucine binding pocket. Furthermore, the Jack Eccles in the audience commented that, as someone from a very controversial role of Cl- ions in this thirsty country, he was very pleased to hear about these receptors. family of transporters is beginning to 'Panzee' Wright, later Professor of Physiology at Melbourne University be elucidated as an optional fourth (who was ever a generous and convivial host) immediately objected that component, in those transporters of he had never heard of an Australian drinking water. this family that lack an acidic residue in the position corresponding to In later years Zotterman discovered that, although these water receptors E290 of LeuTAa (Forrest et al. 2007; were present in several species, they were absent in humans and rats. No Zomot et al. 2007). doubt Jack and Panzee nevertheless continued to enjoy slaking their thirst, each in his own way. Indeed, as already noted (Kilic & Rudnick, 2000), whereas ions Liam Burke present a symmetrical surface to the Sydney, Australia

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Breaking the barrier; the role of actin filaments in somato/dendritic peptide release In many cells actin filaments are organised in a dense web beneath the plasma membrane and can be transiently depolymerised in response to stimulation, suggesting that actin filaments provide a barrier for vesicles to access sites of release

The magnocellular neurons of the release appears to be enhanced if membrane, they noted that hypothalamic supraoptic and calcium has been released from regulation of exocytosis may rely on paraventricular nuclei secrete the intracellular calcium stores, controlling the access of the vesicles neuropeptides vasopressin and suggesting that the release to the plasma membrane. This led to oxytocin from the posterior pituitary mechanism can be 'primed'. Priming the suggestion that this control may gland into the general circulation. causes vesicle movement into pools be exerted by cytoskeletal elements, The pioneering work of David Pow from where they can be released as in classical endocrine cells. In and John Morris (1989) indicated more readily by subsequent stimuli addition to a network throughout that these peptides are also released for a prolonged period in large the cytoplasm, the cell bodies of directly into the hypothalamus, and quantities (Ludwig & Leng, 2006). magnocellular neurons possess a the major source of this central network of filamentous or F-actin release are the dendrites of When Pow and Morris showed that beneath the plasma membrane. In magnocellular neurons. Over the last peptide release from magnocellular endocrine cells, this cortical F-actin decade, studies have amplified the neurons was not restricted to any engulfs secretory vesicles, data on dendritic peptide release and particular part of the plasma segregating them from the plasma revealed many aspects of its control and function. It appears that part of the function of dendritically-released neuropeptides is to autoregulate the electrical activity of the cells of origin, as both neuropeptides act directly on their respective neurons via specific receptors and modify their excitability. In addition, neuropeptides persist in the brain extracellular fluid for relatively long periods and are able to diffuse considerable distances. In a hormone-like fashion the peptides may act on more distant brain regions concerned with behaviours that are known to be influenced by oxytocin and vasopressin. Most often these regions richly express peptide receptors, but they are innervated by few, if any, oxytocin or vasopressin containing projections. Although it has been known for more than 20 years that there is local release of vasopressin and oxytocin Figure 1. Immunohistochemical detection of vasopressin and F-actin (visualised by within the hypothalamus, it is only in fluorescently tagged phalloidin) in an isolated magnocellular vasopressin cells. To recent years that the molecular and investigate a role of F-actin depolymerisation in regulating evoked (high potassium) cellular mechanisms that mediate peptide release from magnocellular neurons in vitro, we used latrunculin B, a toxin dendritic release have begun to be from marine sponges that sequesters actin monomers. To determine the effect of F- actin polymerisation, jasplakinolide, a membrane permeable cyclic peptide that understood. While electrical activity promotes the formation and/or stabilisation of F-actin filaments, was used. F-actin in the cell bodies is generally depolymerisation significantly enhanced high K+-induced somato/dendritic accompanied by release from axon vasopressin and oxytocin release (data for oxytocin are not shown) within the terminals, release from dendrites is supraoptic nucleus (SON), whereas F-actin polymerisation inhibited peptide release. generally not. Dendrites appear to Vasopressin and oxytocin secretion from axon terminals of the neural lobe (NL) was have release properties different not altered by any of the treatments, suggesting that high-K+ evoked release in the from those of axon terminals, and SON, but not the NL, requires opening of the F-actin barrier.

Physiology News | No. 70 | Spring 2008 | www.physoc.org 22 PN FEATURES membrane. As F-actin undergoes release of vesicles from both the IUPS 2013 fast, transient and reversible somata/dendrites and axon Readers may remember that, at the depolymerisation during hormone terminals in magnocellular neurons IUPS San Diego meeting in 2005, we secretion, and areas of exocytosis does not appear to occur at successfully bid to host the 2013 IUPS have been found to be lacking F- morphologically distinct active zones meeting. Since then we have been actin, cortical F-actin has long been (as described for neuronal synapses), negotiating with conference sites and proposed to act as a barrier, actin filaments could provide I am pleased to announce that the restricting movement of secretory transport, tethering, barriers and meeting will be held from 21–26 July vesicles to their release sites at the support structures at different times at the International Convention Centre plasma membrane (Aunis & Bader, and locations. (ICC) in Birmingham (pictured below). 1988; Vitale et al. 1995). Not only is the ICC an excellent conference centre, but it is in the Once again the magnocellular recently refurbished Birmingham City In magnocellular neurons, the neurons of the supraoptic nucleus Centre, surrounded by restaurants and cortical F-actin of the have proved to be a tractable pleasant canal side walks. somata/dendrites is rapidly and preparation for revealing important reversibly depolymerised by factors aspects of neuronal function. These known to stimulate secretion (e.g. were among the first cells to provide depolarisation by high potassium). evidence that endocrine cells Moreover, depolymerisation of F- containing peptides could also act as actin with latrunculin stimulated neurons. Their terminals in the oxytocin and vasopressin secretion posterior pituitary provided a readily from both the axon terminal and accessible preparation for pioneering dendritic compartment. Acute studies on stimulus-secretion treatments with jasplakinolide coupling. inhibited stimulated dendritic We want the 2013 meeting to be a peptide release; however, there was Now, studies indicate that these cells no effect on release from axon celebration of physiology. Our are again leading the way in original bid had the (only slightly terminals. Thus the evoked release revealing that dendrites can take from somata/dendrites requires tongue in cheek) subtitle of Back to the their place as full players in both the future . The development of powerful depolymerisation of F-actin (Tobin & transmitting and receiving stages of modern techniques in genetics, Ludwig, 2007). Our data are cellular communication. imaging, etc. allows us to address the consistent with other preparations, questions that have interested such as insulin secretion from β-cell Mike Ludwig physiologists for 150 years and IUPS lines and isolated rat islets. 2013 will highlight this. Vicky Tobin However, there is evidence that the Centre for Integrative Physiology, There is much to do. So far, planning F-actin cortex, classically viewed as a University of Edinburgh, Edinburgh, has been in the hands of the IUPS barrier that hinders the movements UK 2013 Steering Committee consisting of granules to the plasma of David Eisner (Chair), Graham membrane, might also play a McGeown, Ian McGrath, Prem Kumar, References Bridget Lumb, Clive Orchard and Ole positive role by providing either Petersen, with day- to-day 'tracks’ permitting docking at Aunis D & Bader MF (1988). The cytoskeleton as a barrier to exocytosis in secretory cells. J organization by The Society’s Events appropriate sites, or by spatially Exp Biol 139, 253–266. Team – Nick Boross-Toby (Manager), constraining components of the David Bennett and Heidi Adnum. In exocytotic machinery. This suggests Ludwig M & Leng G (2006). Dendritic peptide the next year or so we will set up the that activation of secretion does not release and peptide-dependent behaviours. various organizing committees, simply trigger the disassembly of the Nat Rev Neurosci 7, 126–136. including a Programme Committee. barrier, but rather a reorganisation of At this time we would be grateful for Pow DV & Morris JF (1989). Dendrites of F-actin which allows the granules input from readers. Are there things hypothalamic magnocellular neurons release that you particularly like and/or hate access to the exocytotic sites and neurohypophysial peptides by exocytosis. about IUPS and other large meetings? provides the structural support Neuroscience 32, 435–439. Do you have suggestions for what we necessary for exocytosis. In the should do? Above all please take every magnocellular system, it appears Tobin VA & Ludwig M (2007). The role of the available opportunity to let your actin cytoskeleton in oxytocin and vasopressin that F-actin remodelling plays a part release from rat supraoptic nucleus neurons. J colleagues know about the meeting. in regulating the availability of Physiol 582, 1337–1348. Please feel free to submit comments functionally mature and readily- by email to [email protected]. releasable vesicles in different parts Vitale ML, Seward EP & Trifaro JM (1995). of the cell and thus is involved in the Chromaffin cell cortical actin network See you in 2013! dynamics control the size of the release-ready differential control of secretion from vesicle pool and the initial rate of exocytosis. David Eisner different parts of the cell. Given that Neuron 14, 353–363.

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Coupling or not coupling of mitochondria to Ca2+ sources in neurones. Soma and neurites differ Bioluminescence imaging of aequorin targeted to mitochondria shows that these organelles are closely coupled to the endoplasmic reticulum in the soma but not in the neurites of sympathetic neurones. This functional organization could contribute to generate spatial differences in neuronal Ca2+ signals

Ca2+ signals play a pivotal role in mitochondrial pool may reach as neuronal functions including much as 10-3 M, a value 100 fold excitability, secretion, learning and larger than previous estimates. In memory. They are triggered by the fact, a quantitative estimation of the opening of plasma membrane, Ca2+ redistribution after stimulation voltage-operated Ca2+ channels of chromaffin cells suggested that (VOCCs) and amplified by Ca2+- most of the Ca2+ entering cells induced Ca2+ release (CICR) from the through VOCCs is actually cleared endoplasmic reticulum (ER). It is from the cytosol by the surrounding becoming evident that, in addition mitochondria rather than by other to their role as cell powerhouses and extrusion systems (Villalobos et al. central players in the intrinsic 2002). In chromaffin cells, the same pathway for apoptosis, mitochondria Lucía Núñez (above mitochondrial pool is functionally are essential for modulation of Ca2+ left) Carlos coupled to VOCCs and ER. This signals. However, research on Villalobos (above) organization may help to avoid and Javier García- 2+ mitochondrial Ca2+ homeostasis has spreading of entering Ca towards Sancho. been hampered by technical the cell core and to tune up local ATP constraints and the difficulty for generated near mitochondria close synthesis to power exocytosis. accurate monitoring of enough to the mouth of the Ca2+ Ca2+ signalling in neurones can be mitochondrial Ca2+, particularly in channels at sites of Ca2+ entry or even more complex. It has been single neurons. The introduction of 2+ release. The Ca concentration at proposed that distinct intracellular protein Ca2+ probes targeted to these hot spots would be high Ca2+ transients in neurites and mitochondria has paved the way for 2+ enough to activate rapid Ca uptake somata may integrate neuronal better understanding of through the uniporter in 2+ signals (Johenning et al. 2002). The mitochondrial Ca signalling surrounding mitochondria. For mechanisms underlying the (Rizzuto et al. 1998). example, mitochondria in close generation of spatially specific Ca2+ 2+ contact with ER take up Ca from signals is not well understood. 2+ 2+ Mitochondria can take up Ca high Ca microdomains in the Mitochondria modulate cytosolic 2+ 2+ through the mitochondrial Ca mouth of the Ca release channels Ca2+ signalling in neurons by uniporter, a low-affinity, high opened by IP3 (Rizzuto et al. 1998). buffering the Ca2+ rises evoked by capacity system that permits Ca2+ Ca2+ entry or Ca2+ release. This was uptake towards the huge Aequorins with low affinity for Ca2+ indirectly suggested by the increase electrochemical gradient built at the were initially developed for 2+ inner mitochondrial membrane by 2+ in the cytosolic Ca responses after monitoring high Ca levels inside 2+ the respiratory chain. As Ca2+ uptake the ER, but their targeting to preventing mitochondrial Ca by mitochondria requires relatively mitochondria revealed two uptake with protonophores in sensory neurons (Shishkin et al. high cytosolic Ca2+, it was believed important new concepts in 2002). The low level of for a long time that mitochondria did mitochondrial Ca2+ homeostasis bioluminescent light emission by 2+ (Montero et al. 2000). First, that only not play a role in Ca signalling aequorin has hampered imaging of under physiological conditions, a pool of mitochondria, the one close mitochondrial Ca2+ in individual being only able to buffer large, enough to sites of Ca2+ entry and neurons for a long time. However, pathological Ca2+ overloads. release, is able to 'sense' the high 2+ combining the use of ultra-sensitive However, recent evidence has shown Ca microdomains. This photon counting cameras with high- 2+ 2+ that mitochondrial Ca influx follows mitochondrial pool takes up Ca efficient protein expression systems almost always normal, avidly, whereas the remaining has enabled recently imaging of 2+ 2+ 'physiological', cytosolic Ca mitochondria do not see the Ca hot individual neurons expressing increases. To explain these findings it spots and take up much less Ca2+. targeted aequorin (Núñez et al. has been proposed that high Ca2+ Second, that the increase in 2007). Fig. 1 shows the photonic microdomains are transiently mitochondrial Ca2+ in the sensitive emissions imaged from sympathetic

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Ca2+ signal, the increase in mitochondrial Ca2+ promotes local ATP synthesis that may be required for exocytosis. In addition, Ca2+ taken up by mitochondria is released later back to the cytosol. This delayed enhancement of cytosolic Ca2+ has Figure 1. Imaging of photonic emissions reflecting mitochondrial Ca2+ increases in been suggested to be involved in the soma and neurites of sympathetic neurons expressing mitochondria-targeted post-tetanic potentiation. Thus, aequorin. Neurons from adult mouse superior cervical ganglion expressing aequorin coupling or not coupling of + + targeted to mitochondria were stimulated with high K solution or caffeine. High K mitochondria to the different Ca2+ 2+ induced mitochondrial Ca increases in the soma and the neurites whereas caffeine sources may lead to region-specific 2+ promoted mitochondrial Ca increase on in the soma. The bright field image is modifications of Ca2+ signals that shown at left (see Nuñez et al. 2007 for details). may underlie important neuronal functions.

Lucía Núñez Carlos Villalobos Javier García-Sancho Instituto de Biología y Genética Molecular, University of Valladolid and Spanish Research Council, A B Valladolid, Spain. Figure 2. Coupling of mitochondria to ER and plasma membrane in the soma and in the neurites. In the soma, a pool of mitochondria is located close to the sites of 2+ 2+ References Ca entry and release. The other pool is distant and hardly senses the high Ca Johenning FW, Zochowski M, Conway SJ, domains. In neurites mitochondria are functionally coupled to plasma membrane Holmes AB, Koulen P & Ehrlich BE (2002). Ca2+ channels but not to sites of Ca2+ release. Thus, Ca2+ release is buffered by Distinct intracellular calcium transients in mitochondria in the soma but not in neurites, leading to region-specific cytosolic Ca2+ neurites and somata integrate neuronal increases. The colour intensity is meant to be proportional to Ca2+ concentration. signals. J Neurosci 22, 5344–5353. Calcium filled organelles are the coloured ones. A, calcium entry through calcium Montero M, Alonso MT, Carnicero E, Cuchillo- channels; B, calcium release from intracellular stores. Ibañez I, Albillos A, García AG, García-Sancho J & Alvarez J (2000). Chromaffin-cell stimulation neurons expressing aequorin with high K+ (Fig. 1). As a triggers fast millimolar mitochondrial Ca2+ targeted to mitochondria. The consequence of the lack of transients that modulate secretion. Nat Cell Biol 2, 57–61. neurons were stimulated with either mitochondrial buffering, the + high-K solution, which depolarises cytosolic Ca2+ rise induced by Núñez L, Senovilla L, Sanz-Blasco S, Chamero the plasma membrane and triggers caffeine was larger in the neurites P, Alonso MT, Villalobos C & García-Sancho J Ca2+ entry trough VOCCs, or with than in the soma (Núñez et al. 2007). (2007). Bioluminescence imaging of mitochondrial Ca2+ dynamics in soma and 2+ caffeine, which stimulates Ca These results agree with previous neurites of individual adult mouse release from the ER. Both stimuli reports where mitochondria seemed sympathetic neurons. J Physiol 580, 385–395. triggered photonic emissions, which to buffer Ca2+ entry but not Ca2+ 2+ Rizzuto R, Pinton P, Carrington W, Fay FS, reflects the mitochondrial Ca release in dorsal root ganglion Fogarty KE, Lifshitz LM, Tuft RA & Pozzan T uptake induced by Ca2+ entry or Ca2+ neurons (Svichar et al. 1997). In (1998). Close contacts with the endoplasmic release. Only a subpopulation summary, these results suggest that reticulum as determinants of mitochondrial Ca2+ responses. Science 280, 1763–1766. (30–40%) of mitochondria 'sensed' strategic location of mitochondria in different regions of the neuron may these stimuli, suggesting the Shishkin V, Potapenko E, Kostyuk E, Girnyk O, contribute to the generation of existence of two different pools of Voitenko N & Kostyuk P (2002). Role of 2+ mitochondria in intracellular calcium mitochondria, one functionally spatially specific Ca signals (Fig. 2). For example, direct measurements in signalling in primary and secondary sensory coupled and the other not coupled neurones of rats. Cell Calcium 32, 121–130. cell bodies and in the proximal and to the different Ca2+ sources. distal dendrites of cerebellar Purkinje Svichar N, Kostyuk P & Verkhratsky A (1997). Interestingly, mitochondria at soma neurons showed that amplification Mitochondria buffer Ca2+ entry but not 2+ and neurites behaved differently. due to CICR is more efficient as the intracellular Ca release in mouse DRG neurons. Neuroreport 8, 3929–3932. Whereas mitochondria in the soma dendritic branches become thinner. were stimulated by caffeine, Whether local mitochondria take up Villalobos C, Núñez L, Montero M, García AG, Ca2+ or not may have important Alonso MT, Chamero P, Alvarez J & García- mitochondria at neurites were not. Sancho J (2002). Redistributión of Ca2+ among These differences were not seen physiological consequences. Apart cytosol and organella during stimulation of when the neurons were stimulated from the buffering of the cytosolic bovine chromaffin cells. FASEB J 16, 343–353.

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Exercise-induced adaptations in tendon tissue Training induces changes in the mechanical and biochemical characteristics of tendon tissue. What mechanisms are involved and are these changes in proportion to skeletal muscle hypertrophy? It is well known that regular exercise response in muscle tissue relates Katja Heinemeier (left) and Jens Olesen can lead to hypertrophy of skeletal closely to the loading stimulus, the muscle, and there is a relatively good tendon’s response appears far less in the tendon tissue ‘quality’. In line understanding of the mechanisms sensitive. with this, training-induced tendon involved in this adaptive process. But hypertrophy has been shown in what happens with the tissues that Long-term training does seem to animals, and in humans the cross support the skeletal muscle when induce changes in both the sectional area of Achilles tendons in strength is increased as a result of mechanical and biochemical individuals who regularly perform training? Tendons, which connect characteristics of tendon tissue. weight-bearing exercise is larger muscle to bone, are essential for Several studies indicate that the than in sedentary individuals transmission of force and storage of tendon becomes stiffer (so that it (Magnusson et al. 2007). The elastic energy during muscle elongates less at a certain amount of loading-induced hypertrophy of the contraction, and it seems logical that applied force) (Magnusson et al. tendon tissue is presumably based they should adapt along with the 2007), and in animals a greater on an increase in the local synthesis muscle tissue, to keep the muscle- maximal load can be sustained by of type I collagen – the main tendon unit functioning. the tendons (Wang, 2006). Changes ‘ building-block’ of tendon tissue – in the mechanical tendon properties as both acute exercise and long-term It is clear that tendon tissue responds can be related both to an increase in training appear to induce the to loading, but while the adaptive cross sectional area and to changes production of this protein (Langberg A et al. 1999; Langberg et al. 2001). Possible role of collagen inducing growth factors One of many unanswered questions is how exercise/training can lead to increased production of collagen in the loaded tendon tissue.

B In vitro studies indicate that certain collagen-inducing growth factors, including transforming growth factor-β-1 (TGF-β-1), connective tissue growth factor (CTGF), and insulin like growth factor-I (IGF-I), are candidates to act as mediators of mechanically induced collagen synthesis in connective tissue (Chiquet et al. 2003). These growth factors are produced by fibroblasts in C vitro in response to mechanical stimuli, and they can subsequently induce the expression of collagen in the mechanically stimulated cells (by autocrine stimulation) (Fig. 1). This mediator role is especially well documented for TGF-β-1, and a recent study shows that Figure1. Possible mechanism for loading induced collagen synthesis in tendon tissue. Based on the knowledge from in vitro studies, it is hypothesized that tendon mechanically induced collagen cells embedded in the tendon extra cellular matrix, A, will be stretched during muscle synthesis in cultured patella tendon contractions and respond to this stimulus by altered intracellular signalling, fibroblasts is directly dependent on represented by black arrows, ultimately leading to increased expression of collagen- TGF-β-1 function (Yang et al. 2004). inducing growth factors (e.g. TGF-b-1), B. This will lead to stimulation of collagen production by the autocrine action of the newly synthesized collagen inducing In a recent study we aimed to growth factors , C. investigate whether TGF-β-1, CTGF

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A B are still debated, it is likely that repeated loading can lead to changes in the properties of the tendon tissue matrix. In line with this, it has been suggested that an increase in the number of cross-links between collagen molecules could be part of the tendon response to mechanical loading. This would lead to stabilization and strengthening of the fibrillar collagen structures and thus to increased stiffness of the tendon matrix.

Lysyl oxidase is essential for the Figure 2. Expression of type I collagen and TGF-b-1 in rat Achilles tendon after formation of cross-links between strength training. newly formed collagen molecules, COL1A1 mRNA (A) and TGF-b-1 mRNA (B) normalised to tissue weight in rat Achilles and we have found that the tendons after a 4-day unilateral plantar-flexion resistance training program of either expression of this enzyme is induced shortening, lengthening or static contractions (grey bars) vs. contra lateral controls more than 35 fold in rat Achilles (white bars). Values are geometric means ± SE, and data are presented as fold tendons in response to 4 days of changes relative to the mean of all control values (*p<0.05, **p<0.01, ***p<0.001). resistance training (Heinemeier et al. A B 2007a). This finding definitely supports that an increase in cross- link formation could be an important part of the adaptive process in loaded tendons. In fact, it may be speculated that collagen turnover is increased in response to loading (Langberg et al. 2001) to give the opportunity to assemble new collagen fibres with a higher content of cross-links. Such a response could explain a training-induced increase in stiffness without changes in cross Figure 3. Expression of mechano growth factor (MGF) in rat Achilles tendon and sectional area. gastrocnemius muscle after strength training MGF mRNA normalised to tissue weight in rat Achilles tendon (A) and gastrocnemius Can tendons keep up with muscle? muscle (B) after a 4-day unilateral plantar-flexion resistance training program of There is no doubt that tendons either shortening, lengthening or static contractions (grey bars) vs. contra lateral respond to repeated loading. But controls (white bars). Values are geometric means ± SE, and data are presented as how well does the tendon response fold changes relative to the mean of all control values (*p<0.05, ##p<0.01, correspond with the response of the ***p<0.001). skeletal muscle tissue? and the IGF-I isoforms – IGF-IEa and induce the expression of collagen In the rat training study discussed mechano growth factor (MGF) – and suggest a potential role for TGF- above, three different types of could be involved in the loading- β-1 and the IGF-I isoforms in muscle contractions – shortening, induced changes in collagen mediating this effect (Heinemeier et lengthening and static contractions production in tendon tissue in vivo. al. 2007a; Heinemeier et al. 2007b). – were applied. With this setup the We found that the level of mRNA for lengthening contractions led to a type I collagen was substantially Tendon ‘quality’ and collagen substantially greater force increased in rat Achilles tendons cross-linking production than the shortening after a 4-day plantar-flexor strength Changes in tendon mechanical contractions, while the static loading training programme (Fig. 2). At the properties do not necessarily depend led to an intermediate force same time the expression of TGF-β-1 on changes in tendon size. Several production. We found that the and IGF-I isoforms (IGF-IEa and MGF) studies have shown a markedly expression of growth regulatory were increased, while no change was increased tendon stiffness without factors, IGF-IEa, MGF and myostatin, found in the level of CTGF mRNA any increase in tendon cross in the trained muscle tissue was (Fig. 2 & 3). These results underline sectional area (e.g. Reeves et al. highly reflective of the force that loading of tendon structures can 2003), and although these results production (Fig. 3). Surprisingly

Physiology News | No. 70 | Spring 2008 | www.physoc.org FEATURES PN 27 however, in tendon the expression of levels of cross-linking between expression of myostatin and IGF-I isoforms in both collagen, growth factors, and collagen molecules. Importantly, the rat muscle and tendon: differential effects of specific contraction types. J Appl Physiol 102, lysyl oxidase was equally induced tendon tissue seems less sensitive 573–581. with all training types and thus than skeletal muscle to changes in unrelated to force production (Figs. mechanical stimulus. Langberg H, Rosendal L, & Kjaer M (2001). 2 & 3) (Heinemeier et al. Training-induced changes in peritendinous 1 type I collagen turnover determined by 2007a;Heinemeier et al. 2007b). In Katja M Heinemeier microdialysis in humans. J Physiol 534, other words it appears that tendons, Jens L Olesen2 297–302. compared to muscles, are relatively 1Institute of Sports Medicine, insensitive to the degree of Langberg H, Skovgaard D, Petersen LJ, Bulow J, Bispebjerg Hospital, Copenhagen, mechanical stimulus, and it could be & Kjaer M (1999). Type I collagen synthesis Denmark and 2Department of and degradation in peritendinous tissue after speculated that the tendon Rheumatology, Aalborg Hospital, exercise determined by microdialysis in adaptation will not 'keep up' with humans. J Physiol 521, 299–306. Aalborg, Denmark the muscle adaptation if muscle contractions with high loads are Magnusson SP, Narici MV, Maganaris CN & References Kjaer M . Human tendon behaviour and performed repeatedly. This may help Chiquet M, Renedo AS, Huber F & Fluck M adaptation, in vivo. explain the high incidence of tendon (2003). How do fibroblasts translate 10.1113/jphysiol.2007.139105. overload injuries in sports. mechanical signals into changes in extracellular matrix production? Matrix Biol Reeves N, Maganaris CN & Narici MV (2003). 22, 73–80. Effect of strength training on human patella In summary, repeated loading tendon mechanical properties of older appears to change the mechanical Heinemeier KM, Olesen JL, Haddad F, individuals. J Physiol 548, 971–981. characteristics of tendons. These Langberg H, Kjaer M, Baldwin KM & Schjerling P (2007a). Expression of collagen and related Wang JH (2006). Mechanobiology of tendon. J changes could be explained by an growth factors in rat tendon and skeletal Biomech 39, 1563–1582. increased tendon cross sectional area muscle in response to specific contraction – possibly relating to a growth types. J Physiol 582, 1303–1316. Yang G, Crawford RC & Wang JH (2004). factor-induced collagen production – Proliferation and collagen production of Heinemeier KM, Olesen JL, Schjerling P, human patellar tendon fibroblasts in response but also by changes in the tendon Haddad F, Langberg H, Baldwin KM, & Kjaer M to cyclic uniaxial stretching in serum-free tissue matrix, such as increased (2007b). Short-term strength training and the conditions. J Biomech 37, 1543–1550.

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Modifying the excitability of motor cortex with direct current stimulation

In recent years there has been an require the application of any large increase in interest in techniques magnetic fields, it can be applied to a that can modify the excitability of wider population, including those the motor cortex. It is widely who have had neurosurgical believed, with some experimental aneurysm clipping (i.e. in some evidence, that if the excitability of stroke and traumatic brain injured the cortex can be increased then patients). rehabilitation strategies after neurological insults may be more We have recently shown that DC Jonathan Norton (left), Ming Chan and efficacious. Three techniques have stimulation affects the cortical Hollie Power. emerged, or re-emerged, that offer control of a movement, as assessed the potential to modify the placed on the scalp. The time course by intermuscular coherence (Power excitability of the cortex: repetitive of the intervention and the effects et al. 2006). Typically the currents transcranial magnetic stimulation are similar across all three protocols, applied at the scalp are of the order (rTMS), paired associative with each intervention lasting about of 1mA. The two electrodes are stimulation (PAS) and direct current 10 minutes and its effects lasting for positioned over motor cortex, stimulation (tDCS). While the first around an hour. Clinically tDCS contralateral to the muscle/limb of two of these approaches may act shows considerable promise since interest and over the opposite through spike-timing dependent the effects appear comparable to forehead (i.e. ipsilateral to the plasticity (at least for PAS), the third other cortical excitability modifying muscle/limb of interest). In Fig. 1 we approach is different in nature. In this protocols but the equipment is illustrate a tDCS experimental set- strategy, a comparatively low level substantially cheaper than that up, and typical results from an constant DC field is applied across required for either PAS or rTMS. experiment in which cathodal the motor cortex through electrodes Since the intervention does not stimulation was applied. Briefly, there is a decrease in the amplitude A B of the MEPs, area of β-band coherence and region of activation of the cortex assessed using fMRI. In this review, we will examine some of the recent evidence regarding the possible cellular mechanisms of action of tDCS (Fig. 2).

It appears that the response to tDCS is not just at the level of the pyrimdal C D tract neuron (PTN) itself but rather primarily at the level of the interneurons projecting onto the PTNs, since tDCS does not alter the amplitude of TES-evoked MEPs. NMDA-glutamate receptors are known to be important for the induction of cortical neuroplasticity in long-term potentiation and depression. Strikingly, administration of the NMDA receptor-antagonist dextrometh- orphane completely eliminated both Figure 1. Experimental setup of tDCS and typical results from cathodal the short- and long-lasting after- stimulation. A, depicts the setup for tDCS stimulation on the scalp and recording effects of tDCS, independent of electrodes in the contralateral arm. B, shows the results of fMRI (Baudewig et al. stimulation polarity (Liebetanz et al. 2001). During a figure tapping task following cathodal stimulation, the area of 2002; Nitsche et al. 2003). In activation in the motor cortex became substantially suppressed (blue pixels) addition, GABAergic mechanisms are compared to baseline (yellow pixels). Correspondingly, the size of the motor evoked also likely involved in the after- potential (MEP) from transcranial magnetic stimulation in panel C (subject at rest) and β-band intermuscular coherence obtained during weak static contraction of the effects of tDCS as Nitsche et al. EDC and FDI muscles shown in panel D were reduced following cathodal tDCS (red (2004) showed that administration dotted line) compared to baseline (black solid line). of lorazepam, a GABAA receptor

Physiology News | No. 70 | Spring 2008 | www.physoc.org FEATURES PN 29 agonist, resulted in late enhance- ment of excitability following anodal tDCS. The reasons for the delay are not clear, even though remote mechanisms such as connections with cortico-thalamic and nigrostriatal neurons could be at play because they primarily use GABA as their inhibitory neurotransmitter. In contrast, cathodal tDCS after-effects were not affected by lorazepam. Since benzodiazepines do not directly activate GABA receptors themselves, but rather facilitate the transmission of already active receptors, this finding cannot exclude inhibition of the GABAergic system in the cathodal after-effects.

Several animal studies have demonstrated the importance of dopaminergic mechanisms in NMDA receptor-mediated neuroplasticity. Figure 2. Mechanisms of tDCS. Locations of the relevant receptors and ion channels Similarly, studies examining various on the pyramidal tract neuron (PTN) are shown in the top right drawing. While the types of learning have shown that NMDA, GABAA and dopamine 2 receptors, sodium and calcium channels all play a role dopaminergic systems are important in response to anodal stimulation, only NMDA and dopamine 2 receptors have been in human neuroplasticity. Nitsche et shown to have an effect on cathodal stimulation. al. (2006) found that by administering a D2-receptor antagonist, sulpiride, the after- administration of carbamazepine, a mechanistic insights may also allow + effects of tDCS were completely Na channel blocker, selectively tDCS to be used as a diagnostic tool. abolished. However, co- eliminated the short-lasting after- effects of anodal tDCS. This result is Acknowledgements administration of pergolide, a Work in the authors’ laboratories is D2/D1-receptor agonist with in accordance with early animal studies demonstrating that anodal supported by the Alberta Heritage sulpiride, could not re-establish the Foundation for Medical Research, the excitability changes induced by tDCS involves depolarization of the neuronal membrane. A similar result Canadian Institutes of Health tDCS, indicating that D1 receptor Research, the National Institutes of was obtained for the Ca2+ channel activation alone is not capable of Health and the Canadian Foundation blocker flunarizine (Nitsche et al. restoring tDCS after-effects. In for Innovation. The authors are 2003). The fact that these voltage- contrast, when pergolide was grateful to their colleagues in the dependent drugs had no effect on administered alone without Centre for Neuroscience, especially cathodal stimulation is perhaps not sulpiride, it caused the tDCS- MA Gorassini, KE Jones and RB Stein surprising since the generated excitability changes to last for many helpful discussions hyperpolarization that occurs with for up to 24 hours after stimulation, concerning cortical excitability and cathodal tDCS already results in suggesting that activation of D2- rehabilitation. receptors has a consolidation- inactivation of the Na+ and Ca2+ enhancing effect on the excitability channels. Jonathan A Norton1,2 changes induced by tDCS. These 1 findings are potentially interesting Taking the studies demonstrating Hollie A Power 1,3 because the administration of D2 changes in TMS, but not TES evoked K Ming Chan agonists may allow use of tDCS as a MEPs, the functional imaging studies 1Centre for Neuroscience, therapeutic tool to produce and the new data on intermuscular 2Department of Surgery and sustained changes in motor cortical coherence it is becoming 3Division of Physical Medicine and excitability. increasingly evident that the intra- Rehabilitation, University of Alberta, cortical networks are predominantly Edmonton, Alberta, Canada Additionally, non-synaptic affected by the actions of tDCS. In mechanisms are likely also involved addition to establishing the basis of References in the after effects of tDCS. Liebetanz tDCS as a potentially useful Baudewig J, Nitsche MA, Paulus W & Frahm, J. et al. (2002) showed that therapeutic method, these (2001). Regional modulation of BOLD MRI

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responses to human sensorimotor activation by transcranial direct current stimulation. Systems neuroscience Magn Reson Med 45, 196-201. Microelectrode workshop at the techniques Liebetanz D, Nitsche MA, Tergau F & Paulus W for cell physiology (2002). Pharmacological approach to the Marine Biological mechanisms of transcranial DC-stimulation- th induced after-effects of human motor cortex Association 25 Plymouth Workshop excitability. Brain 125, 2238-2247. In September 2007 a practical 10– 24 September 2008 workshop, Systems Neuroscience, was Nitsche MA, Fricke K, Henschke U, Schlitterlau run during the Plymouth The Marine Biological A, Liebetanz D, Lang N, Henning S, Tergau F & Paulus W. (2003). Pharmacological Microelectrode Techniques Association of the UK modulation of cortical excitability shifts Workshop at the Marine Biological Citadel Hill, Plymouth, PL1 2PB induced by transcranial direct current Association. stimulation in humans. J Physiol 533, 293-301. Microelectrode recording and The workshop taught in vivo injection, voltage clamp, patch Nitsche MA, Lampe C, Antal A, Liebetanz D, whole–cell recordings from neurons clamp single channel and whole cell, Lang N, Tergau F & Paulus W (2006). slice recording, ion selective Dopaminergic modulation of long-lasting in different modalities. It took place electrodes, fluorescent indicators, direct current-induced cortical excitability during the second week of the capacitance, amperometry, changes in the human motor cortex. Eur J traditional 2 week workshop on Neurosci 23, 1651-1657. electronics, microscopy electrophysiological techniques, Nitsche MA, Liebetanz D, Schlitterlau A, with a separate experimental and Application details and poster at Henschke U, Fricke K, Frommann K, Lang N, lecture programme open to www.mba.ac.uk/courses Henning S, Paulus W & Tergau F (2004). students attending both workshops. GABAergic modulation of DC stimulation- email: induced motor cortex excitability shifts in The students were post-doctoral humans. Eur J Neurosci 19, 2720-2726. researchers and lab heads from [email protected] laboratories that are using or Power HA, Norton JA, Porter CL, Doyle Z, Hui I planning to use these methods. Fee £1200 & Chan KM (2006). Transcranial direct current including accommodation stimulation of the primary motor cortex (bursaries available) affects cortical drive to human musculature as The workshop was coordinated by Troy Margrie and colleagues Ede assessed by intermuscular coherence. J Physiol Applications by 30 April 2008 577, 795-803. Rancz and Alex Arenz from University College London. Supported by The Physiological Society, Toothbrush not terminology MRC, BBSRC, EPSRC and the Company As mentioned in Physiology News 66, The first lecture entitled The barrel of Biologists 25, The Society Minutes for the 1954 cortex was given by Bert Sakmann Meeting at Mill Hill noted that in a from MPI Heidelberg and the discussion of terminology for the additional neuroscience lectures by Tom Mrsic-Flogel, Damian Hayden- autonomic nervous system, Bernard Systems neuroscience Katz had proposed ‘sympathetic ’ Wallace, Jim Donnett, Kate Jeffrey, and ‘unsympathetic’ as alternatives Ole Paulsen, Tim Bliss, Albert Lee and workshop David McAlpine. The Microelectrode to the terms ‘orthosympathetic ’ 10–17 September 2008 and ‘parasympathetic’ suggested by Techniques Workshop is supported RC Garry and JS Gilespie. by the Physiological Society. The Marine Biological Association of the UK David Ogden Katz took up the question of Citadel Hill, Plymouth, PL1 2PB nomenclature again in his Whole cell recording, experimental Sherrington Lectures in which he design and data analysis in vivo. said: (Coordinator Troy Margrie, UCL)

‘ Controversies about words, like Application details and poster at arguments about priority, are www.mba.ac.uk/courses dominated by emotion, and I well remember W Feldberg’s dictum, email: namely that there is a type of [email protected] scientist who, if given the choice, would rather use his colleague’s Fee £600 toothbrush than his terminology.’ Bert Sakmann lecturing on The barrel including accommodation cortex in the Common Room of the MBA, Plymouth during the Systems Applications by 30 April 2008 Ann Silver Neuroscience and Microelectrode Cambridge, UK Techniques Workshops.

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A starring role for astrocytes Recent evidence continues to re-cast the role of astrocytes in brain function. Astrocytes now appear to express a rich repertoire of signalling mechanisms, can respond to neuronal signals and rapidly signal back to neurons. The recent work of Stephen Traynelis and his colleagues has further emphasized the ability of astrocytic receptors to control excitatory synaptic transmission. Thus these cells have emerged as active participants in brain function

As recently as two decades ago, the back to neurones (Parpura et al. primary function of astrocytes was 1994). Indeed, when single still sometimes mistakenly described astrocytes were directly stimulated as only a supportive matrix for the to increase internal calcium and Guido Mannaioni (top, left), Hongjie brain's neurones. Although the word release glutamate, calcium levels of Yuan (top, right), Justin Lee (above, left) astrocyte means ‘star’ shaped cell, adjacent neurones were increased. and Stephen Traynelis. astrocytes were certainly not Since this discovery, multiple lines of thought to play a starring role in experimentation have defined vesicles that undergo exocytosis central nervous system function at numerous examples of neurone- following an increase in intracellular that time. Rather, they were astrocyte and astrocyte-neurone Ca2+. Channel-mediated glutamate typically assigned a number of communication. However, the release is thought to involve supportive and nutritive roles. Over molecular mechanisms by which glutamate permeation through the years, this perception has neurone-astrocyte communication channels that open in response to gradually shifted. Today (more in line takes place as well as its specific role various stimuli. with their name), astrocytes appear in physiology and/or pathology to take part as primary actors in the remain an active topic of A number of studies have suggested regulation of synaptic transmission, investigation. One particularly that glutamate released from a process known to be crucial to the interesting set of results suggest that astrocytes is capable of activating biological computations that G-protein-coupled receptors on the ionotropic or metabotropic underlie thought and perception. cell surface of astrocytes can glutamate receptors on neurones. Astrocytes can respond to stimulate release of Ca2+ from Furthermore, in a recent report, neurotransmitters used in synaptic intracellular storage sites. Several activation of neuronal G-protein transmission, clear lines of evidence suggest that the coupled metabotropic glutamate neurotransmitters from the subsequent elevation of intracellular receptors by astrocytic glutamate extracellular space to terminate Ca2+ levels can trigger release of the release has been proposed to synaptic signaling, and fine-tune the neurotransmitter glutamate from potentiate NMDA receptor function strength of connections through a astrocytes by a number of different (Wirkner et al. 2007). This is variety of different mechanisms. processes (e.g. Parpura et al. 1994; supported by recent findings from Thus, there is now clear appreciation Bezzi et al. 1998; Araque et al. 2000). our lab (Lee et al. 2007). Further- of the more active and important Glutamate released in this manner is more, the low level activation of roles being considered for estimated to reach concentrations NMDA receptors that we report astrocytes. between 1-6 micromolar, enough to appears to potentiate synaptic 2+ activate neuronal glutamate NMDA receptor function by a Mg - The first clue about the receptors and influence neuronal dependent mechanism rather than communication between astrocytes function (Lee et al. 2007). intra-neuronal post-translational and neurones was noted in the modification. By using a sensitive 1980s when it was found that Even though the Ca2+-dependent bio-detector of glutamate release, astrocytes could respond to the release of glutamate from astrocytes we demonstrate that activation of chemical signals sent by neurones. is now a well-documented P2Y purinergic receptors, bradykinin Astrocytes express on their cell phenomenon, both the mechanism receptors, and protease activated membrane a large number of and physiological roles are still receptors (PARs) all stimulate neurotransmitter receptors, and debated. Two classes of mechanisms glutamate release from cultured or these can be activated by that have been proposed for acutely dissociated astrocytes (Fig. neurotramsitters released from astrocytic glutamate release include 1A, B). We chose protease activated neurones. A major step forward regulated vesicle exocytosis and receptor PAR1 as a model system to occurred in 1994 when Parpura and channel-mediated glutamate release. study in depth because of favorable co-workers showed for the first time In the first mechanism, glutamate is pharmacological and molecular that astrocytes were able to signal hypothesized to be packaged into tools, its prominent expression in

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astrocytes, and its high relevance to neuropathological processes. Astrocytic PAR1-mediated glutamate release in vitro is Ca2+- dependent and activates NMDA receptors on adjacent neurones in astrocyte- neurone co-cultures. Activation of astrocytic PAR1 in hippocampal slices evokes an APV-sensitive inward current and causes APV- sensitive neuronal depolarization in CA1 neurones. PAR1 activation enhances the NMDA receptor-mediated component of synaptic miniature EPSCs recorded under voltage clamp, evoked EPSCs under voltage clamp, and evoked EPSPs under current clamp. Magnesium is a divalent ion that is capable of blocking neuronal NMDA receptors at resting membrane potential, and all forms of potentiation are Mg2+-dependent. The data described in this paper suggest that any potential neuronal depolarization mediated by dendritic NMDA receptors in response to astrocytic glutamate release, regardless of the mechanism of release, may be capable of reducing Mg2+-dependent block and potentiating the NMDA receptor component of EPSPs. A large number of G-protein-coupled receptors are coupled to release of intracellular Ca2+ from internal stores through the Gαq/11 signalling Figure 1. Use of GluR1(L497Y) transfected HEK cells as biosensors for astrocytic glutamate release. pathway. These receptors are expressed by mammalian astrocytes, A, A schematic illustrating experimental setup is shown together with GFP and these results suggest that many fluorescent image of astrocyte – GluR1(L497Y)/GFP transfected HEK cell co-culture of these additional receptors might (left two panels). The right two panels show the ratio image (510 nm emission; 340 be able to engage the proposed nm/380 nm excitation) of Fura2-AM loaded co-cultures before and after brief (<1 sec) mechanisms. However, a recent pressure-application of the PAR1-selective agonist peptide TFLLR (500 µM in pipette; study showed transgenic astrocyte- µ µ EC50 10 M). Calibration bar is 20 m. targeted expression of a peripheral B, Quantification of the fluorescence increase in response to brief (<1 sec) pressure G-protein-coupled receptor that µ µ µ application of 500 M TFLLR, 300 M ATP, and 180 M bradykinin from a pipette in a mediates Ca2+ signaling did not wild type astrocyte (upper traces) recorded together with the inward current induced detectably alter neuronal function. in an adjacent GluR1(L497Y)-transfected HEK cell (lower traces). These data suggest that Ca2+ C, The current response to pressure application of TFLLR was converted to concentration using the dose response relationship and maximal current response of signalling in astrocytes might not be the GluR1 (L497Y) transfected HEK cell determined at the end of the experiment. involved in synaptic modulation, and EC50 value for glutamate activation of GluR1 (L497Y) in transfected HEK cells was 6.1 also raise a caveat regarding the µM (Hill slope 1.3). transfer of conclusions reached from D, Concentration responses from 7 cells are shown superimposed (upper panel) and experiments involving activation of below as an average (lower panel). one astrocytic G-protein coupled E, A summary is shown for peak glutamate concentration responses determined from receptor to other G-protein coupled HEK cells expressing the non-desensitizing glutamate receptor GluR1 (L497Y) to brief receptors (Fiacco et al. 2007). application of the PAR1-selective agonist TFLLR onto cultured astrocytes from wild type mice (WT; 1.1 ± 0.24 µM) and mice lacking PAR1 (PAR1-/-: 0.23 ± 0.13 µM, * p < One important implication of our 0.05, unpaired t-test). Modified from Lee et al. 2007. recent experiments (Lee et al. 2007)

Physiology News | No. 70 | Spring 2008 | www.physoc.org FEATURES PN 33 is that the level of glutamate estimated to be released from astrocytes (~1-6 µM; Fig. 1C, D, E) following activation of G-protein- coupled protease activated receptors is much lower than that in conventional neuronal synapses. Intra-cleft glutamate has been estimated to reach 1 mM during vesicular release (Clements et al. 1992), nearly a thousand times higher than the levels we estimate for astrocytic glutamate release. Even if our estimation of glutamate release was off by several fold, the Figure 2. Mechanisms for potentiation of synaptic NMDA receptor function by astrocytic PAR1 activation. The diagram illustrates how PAR1 activation in astrocytes extracellular concentration still could subsequently lead to potentiation of synaptic NMDA receptor responses would be sufficient to activate NMDA secondary to glutamate-mediated spine head depolarization (green) and reduction in receptors, but insufficient to activate Mg2+ block of synaptic NMDA receptors. Modified from Lee et al. 2007. AMPA receptors. Another feature of our results is that we find different G- release glutamate in a Ca2+- References protein coupled receptors with dependent fashion to shape the Araque A, Li N, Doyle RT & Haydon PG (2000). similar whole cell Ca2+ signalling (Fig synaptic NMDA responses at nearby SNARE protein-dependent glutamate release from astrocytes. J Neurosci 15, 666–673. 2) mediate different levels of synapses. Furthermore, the glutamate release. For example, mechanisms described here are most Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi activation of P2Y G-protein-coupled likely to be shared by a wide range of D, Rizzini BL, Pozzan T & Volterra A (1998). receptors release enough glutamate astrocytic receptors that can elevate Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, µ 2+ (estimated peak of 6 M) to cause intracellular Ca . Perhaps most 281–285. significant activation of group I importantly, mechanisms within metabotropic glutamate receptors astrocytes could be potential targets Clements JD, Lester RA, Tong G, Jahr CE & (EC 10 µM), which can potentiate Westbrook GL (1992). The time course of 50 for new therapies to alleviate glutamate in the synaptic cleft. Science 258, NMDA receptor responses (Wirkner cognitive and muscle-control deficits 1498–1501. et al. 2007). By contrast, the release for people with brain or spinal cord of 1 µM glutamate by protease- damage. Thus, true to its form, a Fiacco TA, Agulhon C, Taves SR, Petravicz J, activated receptor-1 is predicted to Casper KB, Dong X, Chen J & McCarthy KD star-shaped brain cell may finally be (2007). Selective stimulation of astrocyte cause little mGluR1 activation, even ready to play a starring role in calcium in situ does not affect neuronal though this level can trigger modulation of synaptic transmission. excitatory synaptic activity. Neuron 54, localized postsynaptic 611–626. depolarizations. Thus, there may be 1 Guido Mannaioni Lee CJ, Mannaioni G, Yuan H, Woo DH, mechanisms that render compart- Hongjie Yuan2 Gingrich MB & Traynelis SF (2007). Astrocytic mentalization and specificity for 3 control of synaptic NMDA receptors. J Physiol astrocytic G-protein coupled C Justin Lee 581,1057–1081. receptor signalling to neurones. 2 Stephen F Traynelis Parpura V, Basarsky TA, Liu F, Jeftinija K, 1Department of Pharmacology, Jeftinija S & Haydon PG (1994). Glutamate- In the last decade a watershed event University of Florence, Florence, Italy mediated astrocyte-neuron signalling. Nature has been the acceptance that 2 369, 744–747. astrocyte-neuronal communication Department of Pharmacology, can take place by many mechanisms, Emory University School of Medicine, Wirkner K, Gunther A, Weber M, Guzman SJ, 3 including glutamate release from Atlanta, GA, USA and Center for Krause T, Fuchs J, Koles L, Norenberg W & Illes Neural Science, Division of Life P (2007). Modulation of NMDA receptor astrocytes. Our data suggest that current in layer V pyramidal neurons of the rat this can provide a unique mechanism Sciences, Korea Institute of Science prefrontal cortex by P2Y receptor activation. of NMDA receptor potentiation via and Technology, Seoul Korea. Cereb Cortex 17, 621–631. relief of Mg2+ block. This mechanism may reflect spine head depolarization and consequent Physiology of an athlete reduction of NMDA receptor Mg2+ An open day for local schools and the general public at the University of Essex, block during subsequent synaptic Colchester on Friday 4 April, aims to educate, promote and excite families currents (Fig. 2). Our study provides about physical activity and the effect it has on the body and enhance learning compelling evidence that astrocytes for A-level and GCSE in science and physical education. Sponsored by The not only remove synaptically Physiological Society. More information from [email protected] released glutamate, but also actively

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Lack of a role for arterial chemoreceptors in the breakpoint of breath-holding Oxygen levels in the blood influence breath-hold duration, yet the peripheral chemoreceptors that detect arterial hypoxia appear to have little or no role in determining the breakpoint of breath-holding. Debate about this paradox may have eclipsed another important feature of the breakpoint mechanism

It is a truism that the longer you hold to expect the PaO2 at breakpoint to your breath, the lower the partial be constant, i.e. a PaO threshold 2 Michael Parkes. pressure of oxygen in arterial blood should exist beyond which breath- (PaO ) falls and the higher that of 2 holding is impossible. PaO2 is not constant either (Parkes, 2006). carbon dioxide (PaCO2) rises. It is also normally around 100 mmHg in A breakpoint still occurs even if well established that breath-hold eupnea. The mean PaO2 at humans breath-hold from low PaCO2 duration can be almost doubled by breakpoint is typically 62 ±4 mmHg levels (following hyperventilation preoxygenation and almost halved for breath-holds from maximal lung and in a high oxygen mixture with by previously breathing hypoxic gas inflation with air (Lin et al. 1974). maximum inflation) and blood gas mixtures (Parkes, 2006). Since This low PaO2 at breakpoint, levels at such breakpoints can be aortic arterial chemoreceptors make however, is not constant. A remarkably benign (Cooper et al. no demonstrable contribution to breakpoint still occurs for breath- 2003; Parkes, 2006). breathing in humans (Guz et al. holds from maximal inflation with 1966a; Lugliani et al. 1971), the 100% O , even though the PaO at Thirdly, if the carotid chemo- carotid chemoreceptors are the only 2 2 breakpoint (Lin et al. 1974) is receptors were crucial in controlling known means of detecting Pa0 that 2 remarkably higher (553 ±16 mmHg). the breakpoint, indefinite breath- might influence respiratory control. Conversely, following maximal holding (until unconsciousness) For this reason there has always been inflation with hypoxic gas mixtures, should be possible following bilateral a determination to implicate carotid the PaO at breakpoint is much carotid body resection. Such bilateral arterial chemoreceptors in the 2 lower (24-33 mmHg) than usually destruction of the carotid mechanism explaining the break- seen at breakpoint (Ferris et al. chemoreceptor afferents was point of breath-holding. This is 1946). originally performed to attempt to despite the following evidence that treat asthma and results in failure to they have little or no role! Secondly, it cannot even be the case increase breathing in 12% hypoxia that under some of these conditions and to respond to hypercapnia via First, if the carotid chemoreceptors there is a reinforcing stimulus to peripheral chemoreceptors and Pa02 were crucial in controlling carotid chemoreceptors from the (Davidson et al. 1974; Gross et al. the breakpoint, it would be simplest PaCO2. The PaCO2 at breakpoint is 1976). Yet such indefinite breath- holding is not seen. Fig. 1 shows that their breakpoints persist. There is no difference in mean breath-hold duration vs. intact controls following

maximal inflation with 100% O2. Fig.1 nevertheless does show that mean breath-hold duration is 54–65% longer in denervated patients following maximal inflation with either air or hypoxic gas mixtures. This prolongation has never been explained. One interpretation is that it merely represents a difference between the Figure 1. Effects of bilateral carotid body denervation on mean breath-hold duration. healthy controls and these severe asthmatics, since breath-hold Seven intact subjects breath-holding at inspiratory capacity from 100%, 21% & 12% O2 (joined by lines) vs. five denervated subjects [from Gross et al. (1976); Parkes (2006), duration was not measured before with permission from the American Physiological Society and Experimental operation. (Prolonged breath-hold Physiology]. Note denervated subjects still have a breakpoint. Although their mean duration was not seen, however, in breath-hold duration with 100% O2 is not prolonged, their mean durations with 21 or other asthmatics). Thus carotid

12% O2 are 54-65% longer [see also Davidson et al. (1974)]. chemo-receptors may have no role in

Physiology News | No. 70 | Spring 2008 | www.physoc.org FEATURES PN 35 the breakpoint. Another explanation inflation, deflation or irritation. But is that the absence of chemoreceptor this cannot be the explanation either, afferents contributes to a lessening because breath-hold duration is no of the sensation of discomfort that different in patients with pulmonary accompanies breath-holding in air vagus denervation (i.e. with lung and hypoxia. Thus carotid chemo- transplantation) vs. either intact receptors may make some little controls (Harty et al. 1996) or contribution to the duration and patients with heart transplantation hence to the breakpoint. These (Flume et al. 1996). So apparently differences have never been resolved there remains another unidentified and the experiments may not be afferent in the vagus (or repeatable with modern ethical glossopharyngeal) nerves that makes concerns. an important contribution to the Figure 2. Prolongation of breath-hold breakpoint. Of course Noble et al. The reason for publicising this duration by bilateral vagus and glosso- (1970) only describe three subjects. pharyngeal nerve block. Three normal debate about carotid No-one has ever confirmed their subjects breath-holding from the end of chemoreceptors is that it may have results (certainly with modern a normal deflation (at FRC) and eclipsed one further, even older ethical concerns they never will!). apparently from 100% O2 (Guz, 1966; experiment that may be important Moreover, even this unidentified Guz et al. 1966b; Noble et al. 1970). for our understanding of the afferent does not provide a complete Circles joined by lines indicate individual breakpoint mechanism. explanation, because breath-hold subjects with the mean ±se for each pre In 1966–1970 Noble et al. (1970) duration was only prolonged. and post block condition indicated as infiltrated local anaesthetic into Subjects still could not breath-hold horizontal bars [from Noble et al. (1970); Parkes (2006) with permission from the regions around the glossopharyngeal to unconsciousness. (IX) and vagus (X) nerves bilaterally Novartis Foundation and Experimental in three normal, conscious subjects. Physiology ] (see also Guz, 1966; Guz et So how can it be that breath-hold al. 1966b). Adequate cranial nerve blockade was duration is so affected by oxygen established by inability to swallow (X levels, yet the only chemoreceptors & IX), almost complete absence of JBM & Campbell EJM. pp. 65–71. Wiley- known to detect arterial hypoxia Blackwell, Oxford. phonation (X), development of a have little or no role in the bovine cough (X), absence of cough breakpoint mechanism? Guz A, Noble MIM, Widdicombe JG, Trenchard to ammonia (X) but no paralysis of D & Mushin WW (1966a). Peripheral the tongue (XII). Breath-holds were chemoreceptor block in man. Resp Physiol 1, from the end of a normal lung Michael J Parkes 38–40. School of Sport & Exercise Sciences, deflation and apparently from 100% Guz A, Noble MIM, Widdicombe JG, Trenchard University of Birmingham, O2. Fig. 2 shows that mean breath- D, Mushin WW & Makey AR (1966b). The role hold duration was almost trebled. Birmingham, UK of vagal and glossopharyngeal afferent nerves in respiratory sensation, control of breathing The absolute durations are also and arterial pressure regulation in conscious remarkable because breath-holds References man. Clin Sci 30, 161–170. were only from end lung deflation Cooper HE, Parkes MJ & Clutton-Brock TH (whereas those in Fig. 1 were from (2003). CO2-dependent components of sinus Harty HR, Mummery CJ Adams L, Banzett RB, Wright IG, Banner NR, Yacoub MH & Guz A maximum lung inflation). It is also arrhythmia from the start of breath-holding in Man. Am J Physiol 285, H841–H848. (1996). Ventilatory relief of the sensation of remarkable that breath-holding even the urge to breathe in humans: are pulmonary receptors important? J Physiol 490, 805–815. remains possible without motor Davidson JT, Whipp BJ, Wasserman K, Koyal SN control of the glottis. & Lugliani R (1974). Role of carotid bodies in Lin YC, Lally DA, Moore TA & Hong SK (1974). breath holding. N Engl J Med 290, 819–822. Physiological and conventional breath-hold These experiments have been break points. J Applied Physiol 37, 291–296. eclipsed because of the possibility Ferris EB, Engel GL, Stevens CD & Webb A that the prolongation was explained (1946). Voluntary breath-holding III. J Clin Lugliani R, Whipp BJ, Seard C & Wasserman K Invest 25, 734–780. by blockade of carotid (1971). Effect of bilateral carotid body resection on ventilatory control at rest and chemoreceptor afferents. But we Flume PA, Eldridge FL, Edwards LF & Mattison during exercise in Man. N Engl J Med 285, now know from Fig. 1 that carotid LE (1996). Relief of the 'air hunger' of 1105–1112. nerve resection has no effect on breathholding. A role for pulmonary stretch breath-hold duration from maximal receptors. Resp Physiol 103, 221–232. Noble MIM, Eisele JH, Trenchard D & Guz A (1970). Effect of selective peripheral nerve inflation with 100% O2. So the Gross PM, Whipp BJ, Davidson JT, Koyal SN & blocks on respiratory sensations. In Breathing: prolongation must be explained by Wasserman K (1976). Role of the carotid Hering-Breuer Centenary Symposium, ed. Porter something else. One possibility is bodies in the heart rate response to breath R. pp. 233–247. J & A Churchill (Longmans holding in man. J Applied Physiol 41, 336–340. that it was due to blockade of the Group), London. pulmonary afferents in the vagus Guz A (1966). Effects of blocking the vagus Parkes MJ (2006). Breath-holding and its nerve that detect pulmonary nerves in Man. In Breathlessness, eds. Howell breakpoint. Exp Physiol 91, 1–15.

Physiology News | No. 70 | Spring 2008| www.physoc.org 36 PN SYDNEY RINGER

Sydney Ringer’s life and work commemorated at Lastingham

At last, Sydney Ringer is properly commemorated at St Mary’s Church, Lastingham, North Yorkshire, where he was buried nearly 100 years ago. Ringer was not recorded in much detail Sydney Ringer (above), with the Italian stained glass which he commissioned visible in the village, despite having funded in the windows behind the altar; Alastair Ferguson, David Miller, David Eisner and Neil the major restoration of the ancient Davidson (below, top); Dafydd Walters unveiled a plaque and toasted Ringer’s church in 1879. Furthermore, with his memory (below, bottom). family, he had contributed significantly to public life in the area where they physiologists, filled St Mary’s. My that Ringer was born in 1836 – rather had a holiday home for 40 years. On 27 lecture emphasised Ringer’s life and than 1835 as his gravestone and other October, at the invitation of the times, especially those in Lastingham, sources have it – was made after the Friends of Lastingham, I gave the 4th but also illustrated the reasons for his plaque had been engraved.) annual Lastingham Lecture, with David being celebrated in physiology, Eisner as the supporting act. We spoke pharmacology and medicine. David The evening continued in the Village from the aisle, next to St Mary’s pulpit, Eisner gave a splendid insight into how Hall, built to be the School House in if not actually in it; a first for us both. Ringer’s foundation of the 'calcium’ memory of Ringer’s mother-in-law Dafydd Walters unveiled a plaque and story underpins modern and, again, largely at his own expense. the recently published booklet on understanding of the life of our body The splendid Yorkshire ‘otpot supper Ringer’s life* was launched. We were cells ‘from conception to death’. was a sell-out event, greatly enjoyed by supported by the presence of Clive and Whether the lay public felt encouraged about 60 diners; the Blacksmith’s Margaret Orchard, Sue Wray, Matthew to take calcium pills, or the opposite, Arms pub kindly sent over jugs of beer Lancaster, Sandra Jones and Linda was a discussion point later. Dafydd as lubricant. Remembering a great Rimmer as well as Dafydd’s wife and Walters proposed a toast to Ringer’s scientist and physician can have mine, as we sought to show memory as he unveiled a plaque near unexpected bonuses. The phalanx of Lastingham’s villagers why The Society the South Porch. The new brass physiologists toasted their generous has a serious regard for their old plaque, sponsored by The Society, hosts who were led by Neil Davidson, parishioner and benefactor. twins one that names Ringer’s Chairman of the Friends of daughter, Annie, whose tragically early Lastingham, and the Rev Dr Alastair A large, paying audience of local death had prompted the 1879 Ferguson, the vicar. people, plus the delegation of restoration. (Regrettably, my discovery Visitors to Lastingham, a tourist gem of the North Yorks Moors, can now *A solution for the heart can be downloaded at www.physoc.org/downloadfiles/RingerBooklet.pdf read a little about Ringer for Paper copies (£1 each) can be obtained from The Society's Publications Office ([email protected]) themselves and, we hope, learn and will be available at Society meetings. Donations made at St Mary’s church for the booklet will help to defray printing costs. David Miller has been awarded the Paton Prize by The Society’s History and something of the contributions to Archives Committee for this work (see also p. 51). science and medicine that have kept his name alive, at least amongst physiologists. We can hope that one of the great, early experimentalists in our subject will steadily gain the wider audience that his pioneering discoveries on calcium, physiological saline and the heart really do deserve.

If you have favourite ‘fathers’ or ‘mothers’ of physiology, I encourage you to look into their lives and times too. Research and teaching is done by real people; knowing more about the context of their work extends our understanding of what was done and, perhaps, the more elusive ‘why’.

David Miller Glasgow

Physiology News | No. 70 | Spring 2008 | www.physoc.org SIR ANDREW HUXLEY PN 37

Sir Andrew Huxley at 90 Marine Biological Laboratory, showed for the first time the positive overshoot of the action potential (Fig. 1) and was a masterpiece of technique and observation. Any scientist at the peak of their career would justly be proud of such an achievement, let alone a 22 year old medical student. The work was then interrupted by the outbreak of WW2, and the full description of the pre- War Plymouth experiments, with Sir Andrew Huxley (above); symposium detailed methodology, had to wait organisers David Trentham (left) and until the October 1945 J Physiol: 'the Jonathan Ashmore (below) (photos by experiments … were made in 1939 Martin Rosenberg). and the bulk of the paper was written in 1940' (Hodgkin & Huxley, Figure 1. (from Hodgkin & Huxley, 1945). 1939).

The definitive quantitative analysis of After lunch the meeting nerve conduction followed some concentrated on muscle contraction, years later in 1952 in the classic which Huxley turned to in 1952, series of Hodgkin-Huxley papers partly because he started to give the On 14 November 2007 there was a published in J Physiol (116.4 and Cambridge lectures on the subject very well-attended meeting in the AV 117.4). This tour de force led when his friend David Hill (DK Hill, Hill Lecture Theatre at University eventually to the award of the Nobel son of AV) left for London. Sir College London, organised by Prize for 1963 (with Hodgkin and Andrew is now the unchallenged Jonathan Ashmore, David Trentham coupled with John Eccles’ work on doyen of muscle physiologists. With and Roger Woledge to celebrate the nerve synapses). Rolf Niedergerke he developed 90th birthday of Professor Sir Andrew interference-microscope techniques Huxley, OM FRS and Nobel Laureate The morning ended with an to examine the behaviour of striated in Physiology and Medicine. interesting and illuminating muscle A- and I- bands during overview of the physiology of contraction, and this was the basis of The talks illustrated the wide- hearing given by Robert Fettiplace, another classic paper in Nature ranging interests of Sir Andrew’s shortly to take over as Professor of (Huxley & Niedergerke, 1954), one of scientific career, starting with nerve Physiology at Cambridge University. the pair of papers that established conduction. His initial short Nature Sir Andrew made a theoretical the sliding-filament model. [The paper with Alan Hodgkin in the contribution to that field that has other paper of the pair, published summer of 1939 (Hodgkin & Huxley, proved important in subsequent back to back, was by Hugh Huxley 1939), published from the Plymouth years (Huxley, 1969). and Jean Hanson using phase- Participants at the international symposium honouring Sir Andrew Huxley OM, FRS, Nobel Laureate, on the occasion of his 90th birthday (photo by Neal Cramphorn)

Physiology News | No. 70 | Spring 2008| www.physoc.org 38 PN SIR ANDREW HUXLEY

Gerald Elliott (left) and Richard Tregear catch up; symposium participants (right) (photos by Neal Cramphorn). More images on the inside front cover.

Tripos at Cambridge he had read physics, chemistry and maths, intending to become an engineer. However, needing a fourth subject he had picked on physiology and quickly become fascinated. He then began a clinical degree, which at the time was the gateway to professional contrast microscopy on single physiology, but at the outset of the contraction I often recall a metaphor muscle myofibrils (Huxley & Hanson, Blitz he had gone into operational from a hymn that I used to sing at 1954)]. research in gunnery. In parenthesis, school assembly 60 years ago: ‘each he worked in the Admiralty in a sees one colour of the rainbow light; The afternoon programme began section headed by the physicist we are not perfect till we find the with a movie made by Andrew Patrick Blackett, later Nobel Laureate seven ’. (Poignantly, George Huxley in 1965, Muscular contraction in Physics and Lord Blackett of Matheson, who wrote those words, under the microscope. This was Sir Chelsea. It has been said, though I became blind in adulthood). Andrew in his prime and his presence forget by whom, that the young Personally I retain doubts that the and distinction were commanding. Andrew looked very dashing in his total spectrum of how muscles Some years before this he published naval officer’s uniform! Blackett was produce tension has yet been his seminal review article on the later President of the Royal Society illuminated. However, there can be cross-bridge mechanism in muscle (1965-1970), succeeded by Alan absolutely no doubt that the superb contraction (Huxley, 1957), setting Hodgkin (1970-1975) and later by experimental work and the great out a mathematical model that has Andrew Huxley (1980-1985). mechanical insight of Sir Andrew has been hugely influential, and indeed contributed more to the vision as we Back in Cambridge after the war dominant, in the field to this day. now have it than any other living Andrew Huxley was a Fellow of scientist has done. Trinity, teaching and carrying on his After the movie Malcolm Irving, research. In 1960 he was offered and Anne Houdusse and Justin Molloy The day closed with a dinner for Sir accepted the Chair of Physiology at described current experimental work Andrew, the speakers and other University College London. He had, that has illuminated understanding friends. he said, consulted someone of the workings of the muscle cross- important (AV Hill, as I remember it) Gerald Elliott bridges. There were also some and had been told ‘You should start interesting personal accounts by Nuffield Laboratory of in Cambridge and perhaps finish Vincenzo Lombardi, Yale Goldman Ophthalmology, University of Oxford there, but mid career you should and Bob Simmons of what it was like work in another environment’. Sir to work closely with ‘Prof’. Bob References Andrew did end up in Cambridge; Simmons suggested that if there Hodgkin AL & Huxley AF (1939). Action after his distinguished period as potentials recorded from inside a nerve fibre. were to be an SI unit for excellence in President of the Royal Society he was Nature 144, 710-711. scientific research it should be called Master of Trinity, and is now Senior an ‘Andrew Huxley’. Hodgkin AL & Huxley AF (1945). Resting and Fellow of the College. He is also a action potentials in single nerve fibres. J member of the Order of Merit and Physiol 104,176-195. For me, the true highlight of the was recently pictured in the meeting came at the closing newspapers with the Queen and the Huxley AF (1957). Muscle structure and reception in the Jeremy Bentham theories of contraction. Prog Biophys Biophys limited membership of that Chem 7, 255-318. Room when wine was served and Sir outstanding Order, chosen Andrew gave his own personal personally by the Sovereign. Huxley AF (1969). Is resonance possible in the account of his scientific life. This was cochlea after all? Nature 221, 935-940. truly the stuff of scientific history The study of muscle exemplifies and we hear such accounts too Huxley AF & Niedergerke R (1954). Structural beautifully the different approaches changes in muscle during contraction: rarely. He told us how, as a boy at that can be used to search for interference microscopy of living muscle school, he had been mechanically information about molecular fibres. Nature 173, 971-973. minded, interested in how things mechanism; physiological, worked and in mechanisms in Huxley HE & Hanson J (1954). Changes in the biochemical, biophysical and most cross striations of muscle during contraction general, and had been inspired by his recently 'molecular structural'. and stretch and their structural interpretation. physics teacher. Starting the Science When I think about muscle Nature 173, 973-976.

Physiology News | No. 70 | Spring 2008 | www.physoc.org PULMONARY ION TRANSPORT PN 39

Pre-emeritus symposium for Richard Olver

The Physiological Society generously Although sodium and chloride supported a pre-emeritus always remained centre stage, a symposium for Richard Olver in related theme played an important Dundee in September to celebrate role, namely signalling pathways his many contributions to the affecting lung development with understanding of ion transport in the many discussions on topics as developing lung. Rather than diverse as stem cells, lineage branch Richard Olver makes his virtuoso speech, focusing on his many achievements, points, tracheal versus alveolar combining his roles as a scientist and Richard, with characteristic modesty, morphogenesis and of course, ion clinician (above); symposium delegates wanted the symposium to reflect on channel regulation itself. (below). 40 years of research into pulmonary Contributions were received on such To enliven post-prandial proceedings ion transport [he later explained that topics from the USA, Switzerland and in the afternoon, Ray Frizzell (USA) it was only 33 years since he and EU. See the full list of topics at returned to the ENaC topic to review Leonard Strang first reported active www.dundee.ac.uk/mchs/ndpk . the regulation of that channel with ion transport in the mammalian lung the remit to stir the ingredients for in The Journal of Physiology (Olver & The aim of the first morning was to the pro-con debate. This debate was Strang, 1974) but 40 years since the update the delegates on new ideas in designed to test the hypothesis that initial groundwork had been laid at the control of epithelial sodium and drug-based inhibition of the UCL]. My own task was to ensure chloride transport by a pleotropic recognised excess sodium channel that the delegate list and speakers protein kinase, CK2 (formerly casein activity found in cystic fibrosis were reflective of his wish and in the kinase 2). Karl Kunzelmann airway epithelia would lead to event, around 50 scientists (Germany) focused on the role of therapeutic benefit. It was contributed to this meeting. The CK2 in the expression and function immediately clear that Jeff Whitsett feedback from the delegates was of the epithelial sodium channel and Ray Frizzell, who chaired the overwhelmingly positive. (ENaC) and Lorenzo Pinna (Italy) debate, would have their work cut provided new data on the complex out in controlling the protagonists Prem Kumar started proceedings interaction between CK2 and the (Marcus Mall (Germany) versus Steve with an overview of the role of The nucleotide binding domain 1 in Ballard (USA) and Fred Becq (France) Society in fostering such events and CFTR. This was followed with an versus Bob Scholte (Netherlands)). then proceeded to briefly examine overview from Robert Clarke (UK) on Rapidly, opinion became as polarised the Olver & Strang paper, epithelial stem cell lineages together as the epithelium in question with commenting that the with a functional review by Jeff apical and basolateral camps forming understatement of its important Whitsett (USA) of the processes segregated views of remarkable conclusions was very different to controlling lung development. Jeff intransigence. Bob Scholte was in his current practice. The symposium had given a talk on the previous day element and vigorously opposed the then proceeded with a lively where he drew on parallels between motion. Ballard harnessed his atmosphere of debate, sometimes developmental pathways and their considerable native southern US with great controversy when reactivation during oncogenesis in charm but was more circumspect in treatment approaches to the adult life and in his second talk his glandular view of CF disordered sodium transport in provided new insight into disorders pathogenesis whilst trying to see the cystic fibrosis were discussed (but of lung development using mouse other point of view. Mall outlined more of that later). models. broad strategies from his animal

Physiology News | No. 70 | Spring 2008| www.physoc.org 40 PN PULMONARY ION TRANSPORT / YOUR SKILLS, OUR FUTURE model data but the house felt that in speeches to complement Richard’s the University of Dundee for their the absence of a true CF animal earlier virtuoso speech that had logistic support. We also thank the model, the interpretation of the combined his roles as a scientist and EU Framework 6 (EuroCareCF, protective effect against lung a clinician with a hitherto hidden www.eurocarecf.eu) and David damage of sodium channel inhibition talent for comedy. Delegates retired Sheppard in particular as the remained unproven. GB Shaw once to the bar after dinner, but were coordinator for supporting the pro- said that progress is only made by ready bright and early the following con debate and are grateful to the CF those who disagree but, despite the morning for the second feast of Foundation of the USA for their great man’s views, no clear science. This began in exemplary generous contribution to this event. consensus emerged from the debate fashion when Markus Affolter other than the feeling that such (Switzerland) gave a masterful Anil Mehta pharmaco-therapy, whether directed overview of how to make a trachea University of Dundee, Dundee, UK against proteases targeting the from scratch (and a few genes) channel or against the channel pore albeit, at this stage of Reference Olver RE & Strang LB (1974). Ion fluxes across was well worth pursuing even understanding, focusing on fly the pulmonary epithelium and the secretion though the exact end points to tracheal morphology. This was of lung liquid in the foetal lamb. J Physiol 241, gauge success remained unclear. followed by further analysis of mucus 327–357. and fluid secretion in gland function Delegates were now ready for an in large airways from Steve Ballard. hour of reminiscences, both The picture was completed by Mike Your skills, our future humorous and serious, covering Gray (UK) who agreed to move away Richard Olver’s career. The early from his beloved pancreatic duct to Olver years in Londinium were show us how the airway was really a covered by Dafydd Walters and pancreas in disguise because of the Robert Boyd (UK), who focused on vital role it plays in bicarbonate his days at University College. As secretion. with many things in science, the discovery that adrenaline could The symposium was naturally stimulate lung liquid absorption rounded off by a return to the came about by accident when a sodium theme. The final talks beta-adrenoceptor agonist was focused on ENaC and its potential Students undertaking comple- administered for a completely role in airway diseases and it seemed mentary medicine and adult nursing different reason by Dafydd. But, as fitting for this section to focus on the degrees, along with practitioners they say, chance favours the latest developments in thinking and educators from within the prepared mind and the rest is about the roles of cell energy, industry, attended the Your skills, our history. The middle Olver years were intracellular kinase mediated future conference organised by the covered by a double act that would pathways and a look into the future. London and Counties Society of have had Laurel and Hardy laughing A sterling job was done by Debbie Physiologists and the University of in their seats when Debbie Baines Baines, Marcus Mall, Stuart Wilson Central Lancashire (UCLan) at and Harry McArdle (UK) took stage. and David Sheppard (UK) to set up Herons’ Reach Hotel in Blackpool. They described the embryogenesis the close, with a look to the future in Kay Byatt (Leader, Complementary of the Department of Child Health a combined presentation from Ray Medicine Division at UCLan) gave the with caricatures of such luminaries as Frizzell and Margarida Amaral key note lecture on the state of play Paul Kemp (in absentio, sadly) and (Portugal). All in all much fun was regarding education, research and the supportive roles played by other had. Richard, now emeritus and development of complementary members of the University. Finally, shorn of managerial responsibilities, medicine in the UK. Peter Stuart Wilson described the has been spotted in the laboratory Mackereth (Clinical Leader, Christies conjoinment of Child Health in its much more frequently. So watch this Hospital) and Miguel Diego initial configuration as the Tayside space for more discoveries from the (Researcher, Touch Institute, Miami Institute of Child Health (TICH) to its City of Discovery. Florida) also gave presentations. fusion to create a combined Obstetric and Paediatric research In summary, we celebrated 40 years Concurrent sessions allowed entity, Maternal and Child Health of ion transport research but only delegates to participate in clinical Sciences. concluded that it may take another workshops relating to massage, 40 of the best science to make touch and other body work By this stage of the evening, inroads into disease pathogenesis. therapies. Delegates came from a delegates had earned their supper, diverse range of backgrounds, with during which Sir Robert Boyd and the We thank The Physiological Society varying degrees of clinical capability. Principal of the University of Dundee, for their support without which this Some were therapists with years of Sir Alan Langlands, made impromptu would not have been possible, and clinical experience, whilst others

Physiology News | No. 70 | Spring 2008 | www.physoc.org YOUR SKILLS, OUR FUTURE / STRESS WORKSHOP PN 41 were students with no clinical skill in stress response, there is also a massage. significant genetic basis. There is a large body of research indicating The diverse groups made the that single nucleotide practical workshops interesting and polymorphisms (SNPs) impact on the nothing could be taken for granted HPA and autonomic function. about people’s knowledge base. However, each SNP only accounts for Massage treatments were performed a small amount of the variance. More by students from the Northern recent work has shown that there is Institute of Massage and were very epigenetic modification of many well received by delegates. components of the system. Epigenetic variation is known to Student nurses attending the unique mix of disciplines including interact with both genetic variation conference (some of whom are neuroscientists, psychobiologists, and with the environment pictured on p. 40) thoroughly epidemiologists and clinicians. experienced during development in enjoyed the opportunity to find out determining the eventual more about complementary The major themes were stress as an phenotype. Finally, studies of the medicine and commented that the exposure, stress as a mediator, and phenomenon are further event would help with their studies. stress as an outcome which complicated by the data that gender Students studying complementary recognises the way in which and age of the offspring appear to medicine, and especially massage as maternal stressors affect have additional modifying effects on a therapy, were able to learn about neuroendocrine development of the the magnitude and nature of the the evidence base for massage and fetus which in turn leads to long- HPA and autonomic response. were impressed with the quality of term changes in the set-point of evidence available regarding the adrenocortical (HPA), autonomic and The evidence that these systems are measured benefits of massage. immune function. In adult life these important in determining changes may increase the susceptibility to adult disease Pauline Stuttard (Senior Lecturer, susceptibility to a variety of adult depends largely on cross-sectional, UCLan) hoped that a similar conditions which not only include association studies showing, for conference would take place next cardiovascular and metabolic disease example, that measures of vascular year and would be open to UCLan but also susceptibility to mental function, or glucose homeostasis are students studying in the Nursing illness. related to prevailing glucocorticoid Department and Complementary levels or autonomic activity. There Medicine Unit. Discussion centred on the major are fewer prospective studies but research problems in this area and where these have been carried out, applying what has been learnt from the results have been encouraging. Programming of the animal studies to understand human There is, however, a need for neuroendocrine and fetal programming. This is difficult experimental studies and trial because of substantial species evidence, which will be greatly immune stress differences in the way these systems helped by the development of responses in early life work. The assessment of maternal pharmacological strategies to stress has proved to be problematic. modify the stress response. and their role in health Much depends on a woman’s recall. and disease However, measures of perceived The heterogeneity of stress stress are poorly associated with responses in different individuals A workshop was held at Rottnest peripheral physiological measures. described above represents a Island, Perth, Western Australia on To complicate things further, there is considerable difficulty. One possible 11 and 12 November to discuss very substantial intra-individual way of getting round this problem is current advances in our variation in the way different to define categories of physical and understanding of the way that mothers respond to different psychological symptomatology as alterations in stress responses might stressors. How maternal stress recognisable and distinct be one of the key processes linking affects the developing phenotypes. These have been early adverse environmental neuroendocrine systems in the fetus termed neuropatterns. Preliminary exposures and poor somatic growth is also a challenging problem to data suggest that three common with health and disease in adult life. assess in viviparous animals because neuropatterns are associated with The workshop was sponsored by The the signals from mother to fetus are early adversity: Physiological Society and Johnson & imperfectly understood and hard to Johnson, with over 40 people measure. Although the fetal and • Locus coeruleus hyperactivity, attending. They were from 13 infant environments have important characterised by evidence of different countries and represented a modifying effects on the offspring anxiety, autonomic activation and

Physiology News | No. 70 | Spring 2008| www.physoc.org 42 PN STRESS WORKSHOP / PRACTICAL SURVEY

related conditions including PTSD, resulted in a halving of the rate of experienced at school to those they hypertension and irritable bowel offending in their 15 year old were experiencing at university syndrome; offspring. (‘ very good explanations and • CRF/PVN hyperactivity with demonstrations given; much more help hypercortisolism, depression and Fetal neuroendocrine programming given; a lot more teaching around the the metabolic syndrome; is becoming an important area of subject before the practical and told science in which both basic science exactly what to do and why ’). • Adrenal hypoactivity, and systems physiology is going to characterised by symptoms of play an important role and that Although student views were varied, burnout, fatigue and fibromyalgia. progress will depend on there was clear identification of the collaborations between scientists best features of university laboratory This workshop underlined that much from different disciplines. An classes as: of the fundamental biology is not important positive outcome of the understood. A further key question is • learning new skills and using new workshop was the recognition that whether we will ever be able to equipment; the group needs to develop an intervene usefully. There are, • the opportunity for social identity and meet regularly in the however, a number of primary interaction with students and future. intervention studies underway. Most teachers; of these are nutrition trials and •the function of practicals to include for example, pregnancy David Phillips illustrate material given in lectures; supplementation with vitamins B12, University of Southampton, UK • the acquisition of new knowledge folic acid and vitamin D, use of an Dirk Hellhammer through practical classes; omega 3 rich diet and nutritional University of Trier, Germany • high interest value of practicals. supplementation of teenagers of low socio-economic status. There are Students identified the worst also trials to prevent gestational First year bioscience features of university laboratory diabetes by limiting weight gain in laboratory classes – classes as: pregnancy or encouraging physical • the length of practicals (‘too activity. The proposed outcomes of score gamma? long’); these trials are improvements in It is recognised there is a shortage of • the poor organisation (‘always growth or physiological parameters bioscience graduates with laboratory waiting about for stuff’); related to cardiovascular risk and skills and aptitudes. It was therefore • the associated write-up (‘too time - few, if any, are evaluating the effect thought worthwhile to discover consuming, too long'); on neuroendocrine stress responses. students’ views on the laboratory • the tedious/boring/repetitive However, these additional measures work they undertook in year 1 of nature of practicals; could easily be incorporated in small bioscience courses so that changes • the variable contribution of staff subsets undergoing the trial. could be made which might improve (‘ staff were rude if you didn’t the students’ view of laboratory understand something ’). Interventions to reduce psychosocial work and feed through to later years stress during pregnancy represent a student body more interested and Discussion another possibility but are more involved in laboratory work. In Overall the data raises concerns that difficult to carry out. However, many conjunction with AstraZeneca and for many students the experience of governments are currently the British Pharmacological Society, laboratory work in the first year Is introducing measures to improve the Centre for Bioscience has not good and there are some themes conditions for pregnant women, for therefore surveyed 1st year which suggest ways forward. example by allowing more generous bioscience students about their maternity leave and increasing the views on laboratory classes they The effectiveness and consistency of availability of financial help during were undertaking. Returns from 695 staff at all levels teaching the pregnancy. Again it would be of students (70%) in nine UK practicals. It is appropriate to ensure great interest if the effect of these universities were obtained between staff are competent and able to interventions on neuroendocrine February and April 2007. While this TEACH (as opposed to just run the function could be evaluated. In the was a good response rate, it must be practical). The importance students longer term, however, it is likely that borne in mind that an opinion place on knowing people in their a multifactorial approach may offer expressed by say 40 students class and their teachers and forming the best intervention. An example of represents less than 5% of the friendship networks should be this has been pioneered by David returns. recognised and enabled. Olds showing that targeting poor health behaviours (including diet, Results Students find 1st year practicals long, smoking and social support) in Most students preferred the boring and tedious. While women of poor economic status laboratory classes they had appreciating that teaching skills are

Physiology News | No. 70 | Spring 2008 | www.physoc.org TODD SURVEY / CYSTIC FIBROSIS SEMINAR PN 43 important (and valued by students) ‘ students should be able to do a lab there should be an additional explicit again until they are satisfied with objective for 1st year practicals – it’and ‘it would be useful to have a enthusing and interesting the take away example of a perfect students in laboratory work by experiment for revision purposes’. ensuring they experience the excitement of discovery. Finally, reporting some very positive comments made: The issue of organisation in ‘ on the whole I love them and find practicals. The students’ emphasis them really useful and always fun to on ‘waiting around’ for one thing or do’and ‘brilliant lab classes with another. In part this may be an issue helpful tutors and great instructions. of equipment shared between too I ’ ve learned a lot and enjoyed so much. many students. Thanks.’ Vicky Cowell and David Sheppard (above) and Mike Gray (below). We need to address the heavy Conclusions emphasis students place on While most students in the equipment (complicated, advanced, November was EuroCareCF, Co- biosciences progress to careers not Ordination Action for Research in better) and get across that involving practical work, some will equipment is not an end in itself. Cystic Fibrosis, a forum funded by become involved in practical studies th Repeatedly, students emphasised the European Commission’s 6 in education, research and industry. Framework Programme for all their interest in equipment, never The early experience in university is what it enabled them to do. individuals working to defeat the likely to have profound effects on disease. Our speakers were Vicky whether some students see practical Cowell (the mother of Laura, a cystic The issue of students enjoying science as an attractive and exciting practicals at school because they felt fibrosis (CF) patient in her early 20s), career choice. The survey results Mike Gray (Newcastle University and more relaxed may come from the st suggest ways in which 1 year Deputy Chairman of the Research greater familiarity they have with the bioscience practical classes could be school environment. At the first Advisory Committee of the Cystic more engaging and stimulating and Fibrosis Trust), Alastair Innes practical, everything and everybody is moving from gamma to beta or even new to students at university. (Consultant Physician and Director of alpha.* the Scottish Adult Cystic Fibrosis Service, Western General Hospital, The magnitude of the transition Mike Collis which students are undergoing from Edinburgh), The Society’s President, school to university needs to be Alan Gibson Ole Petersen (Liverpool University), recognised. As one student said ‘it King’s College, London and David Sheppard (Bristol felt like I’d been thrown in at the deep Ian Hughes, Gill Sayers University, Co-Ordinator of end and without a float’. We should Centre for Bioscience, University of EuroCareCF). The event aimed to consider starting in a very supported Leeds explore some of the basic science environment and allow students to Martin Todd underlying CF, recent research developments, their likely impact on make the necessary transitions over AstraZeneca a set of laboratory classes during clinical applications, and the semester 1. perspective from the point of view of Cystic fibrosis CF patients and their families. We must recognise that 50% of Latest advances in medical students taking biosciences courses The seminar therefore covered a research and implications for great deal of ground. Points made may take employment outside patients and their families bioscience, let alone involving that particularly struck me on the day included the history that the laboratory work, and courses at This was the first in a new series of disease has been known for a very university need to provide a good Physiological Society external long time, with old European folklore and appropriate experience for ALL relations events, aiming to discuss referring to 'the child that tastes students. the relevance of physiological research to audiences who might not Two interesting suggestions normally attend our meetings. The emerged which might be areas for Society’s partner for the event at development: The Royal Society In London on 19

* Full results of the survey are available at: ftp://www.bioscience.heacademy.ac.uk/reports/1styearlabs.pdf).

Physiology News | No. 70 | Spring 2008| www.physoc.org 44 PN CYSTIC FIBROSIS SEMINAR salty will die', a practical reference to Vicky gave an eye-opening and often CF patients having a high hilarious account of life as a CF mum. concentration of salt in their sweat. Her daughter Laura was born with We now know from Nobel Prize the condition in 1985, with winning research that defective physicians failing to spot the chloride channels in the epithelium problem for some time. Explanations are to blame, with the responsible for Laura’s constant crying and gene (CFTR) having been identified, failure to put on weight included causing havoc in many key tissues of possible allergy to dairy products. the body, from the lining of the lungs She was lucky that her GP had stayed to pancreatic cells. The clinical with a family in Australia with CF, and symptoms of failure of these core spotted that Laura was the salty baby systems are life threatening, the one of folklore. Vicky said that another killing most CF patients being the good symptom to look for in a CF inability of the lungs to clear baby is truly appalling nappies, themselves of secretions and apparently nothing stinks like it! bacterial infection. Clinical practice Eventually the hospitals started to has made radical advances in get their act together, and Vicky and managing the symptoms over the Laura got stuck into the treatments last few decades, greatly extending that have kept Laura alive. The good CF patients’ lives, with many of news is that the condition is now those who would otherwise have more widely known in the medical died in infancy living for decades into profession, and babies are routinely adulthood (median survival now 36 screened so that treatments can and rising). Tried and tested life start early. Vicky worked hard to saving treatments include learn the nursing skills necessary to physiotherapy to help clear patients’ support her daughter, including lungs, antibiotics to treat lung and giving injections, and she and Laura other infections and, in extreme have also worked hard to live life to cases, organ transplantation. But this the full, fitting CF into their lives, not places a heavy burden on patients vice versa. and their families, requiring many hours of effort each day to manage Question time with David Sheppard The event went down very well with the various symptoms. (top); Alastair Innes (centre); Laura the participants, many of whom Cowell, born with cystic fibrosis (above). were medical professionals and Radical advances in research mean students who were not Members of that we can now start to move from detect it, and therefore needs The Society, and would not normally managing the symptoms to modification before use. Manu- come to one of our events. A addressing the underlying condition, facture of the gene of the right contingent of undergraduate for example targeting the action of quality has now been achieved, with physiotherapy students were the mutated relevant gene with the next UK clinical trial in 2009. particularly impressed with the novel drugs for ion channel therapy. Potential gene therapies pose relevance of physiological research A long term cure may eventually be particular ethical questions. to their future professional lives, and effected by manufacturing the Regulatory authorities will not wondered if we might run more healthy version of the gene and permit gene therapies that might be events on other health related topics. transporting it into affected inheritable; treatment of somatic This has got us thinking of possibly patients’ tissues. The vector can cells is much more acceptable. When staging events within medical and pose some challenges, various to treat patients also raises ethical other health profession schools, viruses that infect our respiratory dilemmas. Older patients have something that would tally well with systems could help, but can be already suffered significant damage, the objectives of our Working Group blocked by the body’s immune have less to lose, and can give on Medical Training with the British response. Non-viral liposome vectors informed consent; whereas babies Pharmacological Society. The success may be less immuno-genic, but have still have good lungs, with the of the event means that we are no particular affinity with epithelial advantage that successful gene planning to run it again in the near surfaces. Manufacture of the gene to therapy can protect their lungs future at a venue likely to reach be transposed can also raise before damage occurs. But they schools, media and the general immuno-genic issues. A gene cannot give consent. public, at the BA Science Festival in manufactured by bacteria can be September 2008. different enough from mammalian After the science and clinical DNA for the immune system to applications had been discussed, Liz Bell

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Systems biology and which modifies it. It is possible to look at our physiology as molecular medicine: from machines executing individual functions, connected by biological reactive to predictive, networks that capture and transmit personalised, information. Disease arises from perturbations in these networks, preventative and eventually we should be able to participatory medicine design drugs to specifically re- engineer these. As our Society has a strong interest in systems biology, I went along to So how could this change the world Leroy Hood, President and co-founder of hear what Leroy Hood (President and from the patient’s and clinician’s the Institute for Systems Biology, Seattle. co-founder, Institute for Systems points of view? The hunt is on to find Willetts praised science as being a Biology, Seattle, Washington), one of relevant diagnostic markers for central part of our culture, a the entrepreneurs driving this, had various health and disease states in fundamental value. In his view, to say when he gave the UK Focus for the blood. The aim is then to be able schools had a natural dual role in Biomedical Engineering Annual to do routine in vitro screening for training future scientists and in Lecture on 13 November . Hood is a patients using micro- training others to appreciate science, very interesting character, his efforts fluidics/nanotechnologies, tying this and that our aim should be to make in the area going back to his early into knowledge of a patient’s all children familiar with the scientific work developing automated DNA personal genome, to generate cast of mind. Maths teaching should sequencers and other probabilistic health histories. Clinical be particularly supported in school, instrumentation which enabled attention will shift towards a more as this not only unlocks all the genomics to take off. He founded preventative approach, focusing on scientific disciplines but is also many new biotechnology companies promoting wellness rather than just fundamental to understanding the on the back of these technologies, treating disease. It is hoped that economy. Scientific qualifications and realised in the 1980s that early, effective treatments and should be widely valued outside systems biology was going to be the prevention will reverse the current academia; people with science way forward. He is convinced that a escalating costs of medicine and degrees who are not doing science revolution is coming in medicine, make medical technologies more jobs should not be regarded as with a move away from current accessible to the developing world. failures as they are applying scientific reactive practices to a more The technologies involved will be modes of thinking to other essential personalised, predictive, patient 'disruptive'. IT, etc. will become problems. However, Willetts was centred medicine. This is only essential in the training of physicians. concerned that science is in retreat in becoming possible from the How will medical schools adapt to schools with many science and development of a cross-disciplinary this and the other changes that will maths teachers not having biology, where chemists, computing be required? Hood’s plans for the appropriate qualifications, and only scientists, engineers, future include looking for a medical 58% of science specialist schools mathematicians and others are school willing to risk re-engineering being able to offer separate biology, integral to the work. This was the itself to take these issues on board, physics and chemistry courses. He ethos behind his setting up the and approaching Bill Gates to help thought that those teachers that are Institute for Systems Biology in set up a new Institute of Systems in place need the support of Washington. Engineers and rd Biology to develop 3 World continuing professional development biologists are both interested in capacity. He will be someone to in science throughout their careers. doing parts assessments to analyse watch with interest! School children need to understand basic functions, and then to try to that science degrees can have a life understand how the assemblage Liz Bell time premium of earnings of 40% works when it is all connected up. st above arts based subjects. The Complexity is the challenge for 21 Science and education decline of practical science teaching century biology, the one gene/one was a particular loss, children need Always interested in what possible protein approach is limited. We are to experience the world in 3D, the future Ministers think about things now seeing a grand convergence of 2D world of an increasingly screen of concern to us, I went along to hear genomics with modern computing based childhood does not develop David Willetts, MP (Shadow making it possible to take a systems this. I was left feeling rather unclear Secretary of State for Innovation, approach to the analysis of disease. about what any future Government Universities and Skills) give the Biology is an informational science he might be a part of intended to do Campaign for Science and with two basic types of information: about any of this. We shall see! the ‘digital’ core of the genome and Engineering Annual Lecture on 17 the environmental information October. Somewhat predictably, Liz Bell

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The role of the laboratory practical in undergraduate teaching Maxine Lintern, right, questions the purpose of the extensive practical classes for physiology/science/medical undergraduates

This is a serious question as we can experiments always work, and that no longer take it for granted as an you can get through them by 1630; automatic part of the curriculum. not, I suspect, the intended take Should practicals: home message! • demonstrate underlying principles/ concepts; How can we get practicals to teach This leads to the question: what do • re-enforce theoretical teaching students what we want them to our students think practicals are for, received in lectures; learn? Perhaps we need to use a and is it the same as you? • build teamwork/communication and range of practicals to focus on cooperative working skills; different things. For instance, if Expectations • teach students how to generate useful teaching how to measure and data and develop their ability to Do students learn from practicals interpret an electrocardiogram, interpret and understand it in light of a (and other learning situations) what particular hypothesis; medical students need to learn this they think they should learn or what • develop their understanding of as a concept within a clinical we tell them they should learn? It research methods or ‘how we do framework for diagnosis and as a skill seems that students who expect to research’; they will have to perfect to use on encounter concept/skill X in a • be fun… real patients. Science students, on practical will report that they have Is it advisable, or even possible, to the other hand, need to understand learned X, even if X is not actually achieve these aims all of the time? ECG within a scientific framework, to part of the intended outcomes. Probably not. We have distinct help them explore and question the Similarly, if they did not expect to groups of students working at latest research in cardiac function. learn Y, Y is not learned even if the different levels with different needs, Maybe it would help to separate out lecturer thought it was an explicit not to mention variations in learning the ‘skills learning’ from the outcome (Kirscher et al. 1993). styles and approaches. We also have ‘ concepts learning’. This may help Going back to our ‘cookboooking’ to consider the practicalities of lab students to better understand what analogy this means that students teaching. It can be expensive, time it is a practical session is trying to who only see the practical as being consuming and hard work, especially teach them. As students move to A+B = C, will never consider the with increased student numbers. research labs for final year projects, possibility, desirable or not, of However, we must still ensure there ‘skills’ learning may need an getting D, E or F! Similarly, if they is a return on our ‘investment’ in additional boost. This can be done expect the practical (computer terms of good learning for our successfully as additional ‘lab skills based, paper or wet) to be students. How can we do this? training’ (Lintern, 2007), but could boring/pointless/not real learning/ this skill acquisition be more explicit just a game – it may well fulfil their The first step may be to take a long in all of the practical experiences? expectations. hard look at our current provision and acknowledge that many Research skills such as enquiry, This behaviour is often influenced by practicals may end up as innovation and the ability to previous experiences. When ‘ cookbooking’ exercises. This is interpret are transferable attributes considering computer based learning when students add A to B and, due imperative for the employment (CBL), the conceptual gains made by to your well written lab script and destination of any science graduate. students often depend on previous the technical expertise of your staff, Are these then more important to experiences with the www or other they more often than not get the most of our students than the computer aided learning. intended C. They don’t know (or underlying science principles? Before Inexperience may encourage even care) why they wanted C, or you throw your hands up in horror, I students to work through the have anything more than a am not suggesting we take out the package too quickly, see it as superficial idea of how they got it. If science, just that we may need to peripheral rather than central to the asked ‘why did you add A to B?’ they communicate more clearly the dual learning, and dismiss the concepts will answer something like, ‘because role of the practical class to our covered as trivial by association is says so here in the script’. students. Otherwise there is a (Watson, 2001). Does this then Effectively they are going through danger that they just become mean that a student who has had a the motions without engaging with another part of the module ‘bad’ experience now cannot learn anything. What are they actually landscape, and their impact as a from CBL, and does this extend to learning here? Possibly that unique learning opportunity is lost. wet practicals too? There is some

Physiology News | No. 70 | Spring 2008 | www.physoc.org EDUCATION PN 47 evidence that students are often not This could involve separating out the current practices in light of some of sure what learning is supposed to various skills or ‘jobs’ that scientific these issues and concerns we may be look like. Phrases such as, research requires. For example, able to develop this exciting and ‘independent learning’ are mis- many practical classes are assessed fundamental teaching method to interpreted as ‘left to get on with it’. by the lab report. Report writing is a achieve all that we need it to, for the Differences between school and HE skill in its own right which can be benefit of our students’ learning learning styles may mean that taught and assessed independently experiences. Use the summary students have not been prepared for of experimental results generated in questions below as a tool to reflect this kind of learning (Cooke & class. Another way of assessing on your lab classes and who knows Hockings, 2007). Is this an even ‘results’ may be via a ‘journal of where the answers may take you: greater problem for lab based understanding’ written by the • what is the primary outcome of your learning? If so, we may need a students on what they think they practical class – skill, concept or both? greater focus on support so that our have learned. This can be a better • how well does the practical integrate students don’t only go through the indicator of a student’s progress, with the rest of the module? motions in our lab classes. which cannot be ‘cookbooked’ and • what are the student expectations/ is hard to plagiarise. Similarly, if we assumptions about the outcomes of Perhaps we should be using new want to explore how well a student the practical? technologies even more to take can handle data, plot and interpret • how are you managing/developing advantage of the 24/7 anytime- graphs, would a dry practical with these expectations to match your own? anywhere approach to learning given data do just as well as a • what is the best delivery method for students now expect. The flexibility learning tool? There is a danger that the learning outcomes; wet, dry, of virtual learning environments this approach will be perceived as virtual etc. in light of the student (VLEs) such as WebCT and ‘pretend’, but surely it is no more numbers, staff and resources? Blackboard, and ‘re-usable learning pretend than the completely • what is the students’ experience of objects’ (RLOs) could give us a structured lab class. By separating working with this method? completely new way of teaching lab out the skills and concepts in this • do the students need help in learning skills and concepts (not to mention way we can ensure understanding to learn in this way? more educational acronyms). Most and competence before putting • are students leaving the practical class understanding what it is they should importantly, they may give us the them back together for more have learned? opportunity to encourage students complex research projects. This kind • is your practical class ‘fit for purpose’ to create their own learning of approach is not new and you and delivering the outcomes intended? experiences (James & Graham, 2007) probably use it in some areas, but which could engage students on a the question is – do your students Maxine Lintern more personal level and consign know and understand what you are Academic Practice and ‘ cookbooking’ to the past. These doing? Organisational Development, ideas are a long away from the ‘lab University of Birmingham, UK class every Tuesday 1400–1700’! We can take this further by actively and explicitly developing the References Change of focus students’ ability to reflect on their Cooke S & Hockings C (2007). What students tell us about teaching and learning. HEA Annual How can we use the questions raised own practice/learning styles/ Conference Presented Paper D1, Harrogate. here to generate a way forward? progress; possibly using their Perhaps we need to primarily focus reflections for assessment (Nicol et James AM & Graham N (2007). Engaging the on what we want the lab class to al. 1994). This type of approach is iPod generation. HEA Annual Conference Presented Paper L13, Harrogate. achieve, i.e. the learning outcomes much closer to the type of skills we or objectives; and only then decide need to see in our graduate research Kirschner P et al (1993). Agreement between on how to achieve it. We then need students. Put simply, the goal is to student expectations, experiences and actual to look very hard at the students’ change the questions asked by objectives in the natural sciences at the Open University of The Netherlands. International expectations for the practical and students in laboratory classes from Journal of Science Education 15, 2. consider how we can develop these ‘ when will we finish?’ to ‘can I take into what we want them to another reading because I’m Lintern MC (2007). Developing laboratory skills ready for embarking on a research project or encounter and experience. In other beginning to see a pattern …’ Research isn’t a series of lab practicals! words we need to interrogate the ftp://www.bioscience.heacademy.ac.uk/casestudies ability of the chosen method to Interrogating your practice deliver the learning outcomes from This exploration of the role of the Nicol DJ, Kane KA & Wainwright CL (1994). Case study: Improving laboratory learning the student point of view. We may practical class in physiology teaching through group working and structured then need to train students to learn has posed many questions and not reflection and discussion. Innovations in in this way. Effectively we must provided many answers. Only you Education and Teaching International 31, 4. invest time in teaching students how can come up with these: for your Watson B (2001). Kay factors affecting to learn in practical classes, wet or students, in your practicals, in your conceptual gains from CAL materials. British dry. environment. By interrogating our Journal of Educational Technology 32, 5.

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A career scientist … to be or what (else) to be? excitement when a good result comes out of a long day’s experiment. There are job opportunities all over the world, I find myself in a position common conferences to attend worldwide, among early career scientists. As I lots of intelligent and interesting approach the end of my PhD I am people to meet and collaborate with facing the ‘dilemma’ about what to and there are always more questions do next. Is an academic role for me? to answer. I can no longer imagine a Or am I more suited to industry? Am future without these exciting I suited to being a scientist at all? challenges and I’m sure a lot of you Perhaps the big question is whether feel the same. this really is a ‘dilemma’, or simply the most exciting opportunity a Now I had better update my CV and young scientist can ever have? This start writing my thesis! article aims to highlight some of the opportunities and choices available to young scientists as we aim to take Fiona Randall our careers forward, and also to PhD Student in Neuroscience, emphasise the excitement that can Fiona Randall, our new Affiliate Newcastle University, Newcastle go with a career in research. representative. upon Tyne, UK In science, there are the long hours One major plus point of a scientific in the laboratory and the constant Who are the true career is that science happens all pressures to get quality results and custodians of public over the world. Universities and publications. The salaries can also industry have worldwide seem disappointing when compared opinions in science? employment opportunities. Having to careers in, for example, the chance to spend time living and investment banking or finance. A working in another country whilst graduate in those industries can actively pursuing a career is very often earn a similar or better salary attractive. Another plus is that the to a post-doc in science. laboratory and analytical skills acquired during your PhD can be At the International Brain Research transferred from one area of research Organisation conference in to another quite easily so if you get Melbourne, Australia (July 2007) I tired of your specific area of work attended a symposium on epilepsy. there are sure to be opportunities to At this symposium as well as leading change to a new field using similar scientists working in the field, they skills and expertise. had invited patients with epilepsy to talk about their experiences with the I have been lucky enough to spend disease. After a very emotional talk time in both industry (as an by a 20 year old girl who had been Rehana Jawadwala, our new special undergraduate industrial placement cured of very severe epilepsy by a correspondent. student) and academia ( as a temporal lobe resection, a PhD technician and then a PhD student) student in the audience stood up. When we think about the role and and have my own opinions on the He thanked the girl for her talk and responsibilities of a scientist, we best bits of both. It is a personal said that, nearing the end of his PhD, think of rigorous research, answering choice and one doesn’t beat the he had started to become questions about the natural world other – it depends on what you enjoy disillusioned about what to do next. and investigating things that are as and where you like to apply your She had reminded him of why he was yet unknown. It is this inquisitiveness skills. In industry, exploratory doing research as scientific research that is common to all those research tends to be focused on does make a difference to people’s researchers who toil away in the dark specific diseases and involves lives. I felt inspired, as he had. hours. But how much thought do we working as part of a multidisciplinary give to our responsibilities to team. Academic research can be In my opinion the good points of society? One such responsibility is much broader and often individual. what we do outweigh the bad; the communicating what we do. How Both can be rewarding and exciting constant learning and developing, often do we actually take pleasure in but it is important to identify an area the constant questions and ‘dumbing down’ our complicated of work you are passionate about. challenges, the intellectual worlds? How often do we consider Obviously, not everything is perfect. engagement and even the sharing our ‘eureka’ moments with

Physiology News | No. 70 | Spring 2008 | www.physoc.org AFFILIATE NEWS PN 49 the public, the people who really And, to serve that sceptic in me So – I have now resolved that, if I matter, and (often) who ultimately right, I was placed with the Daily can’t write up my own work in a pay our wages? Mirror! I found myself going to press simple jargon-free 200 words, I will conferences given by scientific not go into the coffee room and talk Scientists have a certain culture of experts, explaining their studies in about The Sun or the Guardian being incomprehensible but, in my 20 min blocks. How could I, a getting a story skewed. And I will not opinion, this elitist attitude will scientist, not comprehend what they complain about the general public eventually slow us down. were saying? After all, I do very being complacent or ignorant when similar statistics and apply similar they voice their opinions on public I recently participated in the BA’s methods in my work. Slowly, as days health, scientific research methods Media Fellowship Scheme where, for went by, I realised where the glass and trends and education policies. As a few weeks, I wore the hat of a wall lay. From where I sat this time scientists, who tend to feel we ‘own’ science journalist. Yes, one of those around it was the scientists who this debate, we do not do our bit to very journalists we love to call found it difficult to make things educate them and keep them names, those sly people who simple and talk about their work as if informed. And then, when the lobby sensationalise science and who make it were an engaging story, leaving groups get to them quicker, we only all scientists look like mad boffins or the poor journalists very little to hold pucker up our noses in disgust. meddlers with nature. I was as on to. But when I sit at my desk in sceptical as they come; I had read the lab, with my molecules dancing So it is high time we all looked up stories about how the discovery of about in perfect harmony, from our spectrophotometers – or one gene was a panacea for curing performing a ballet, I see the lot – PCR machines or patch-clamp rigs – disease, and headlines that claimed a the story, the melody and the dance. and participated whole- heartedly in ‘super’ pill that would cure cancers, And that is what the man on the getting our Society talking about obesity and everything in between. I street, the tax payer, wants to see as science the way it should be talked often used to wonder how easy it well. Surely we shouldn’t deprive about. In a nutshell – ‘put up or shut was for journalists to pick up a them of this performance – up’. Or, best of all, speak up. complex scientific paper, interpret especially as it is ultimately their years of hard work, collaborations money we are all looking to tap into Rehana Jawadwala and theories and distil it into a 200 in our next funding bid. Further- Demonstrator/Researcher in Sports word piece; but I had no idea what more, how can we ignore the same Science, Faculty of Science and was really involved until I actually people who will benefit from the Technology, University of Central had to do it myself. cures we search for? Lancashire, Preston, UK

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Festschrift for K Michael Spyer As part of Its Centenary celebrations Experimental Physiology is sponsoring a Festschrift in honour of K Michael Spyer, Professor of Physiology at University College, London, UK.

Friends and former colleagues including Jim Deuchars, Susan Deuchars, Brunello Ghelarducci, Michael Spyer in 1986 (left) and in 2007 Michael Gilbey, Alexander Gourine, (above) (photos by Martin Rosenberg). Robin McAllen, David Paterson, Julian Paton and Luis Silva-Carvalho will speak about their work with him.

The Festschrift will take place on Sunday 16 March from 1430 in the Centenary Gallery, Parkinson Building (right), University of Leeds, Those coming to Leeds for The Society's Themed Meeting Determining Control of the cardiovascular system in health and disease: from brain to blood vessel (17–19 March) are warmly invited to attend. In search of ‘quality’ journal staff to relieve them of the highest quality for the least cost. unnecessary admin. tasks, and, at the The impact factor of a journal, the Quality is a word much bandied around strategic editorial board level, sound recommendations of their institution’s in discussion about journals publishing, advice on how they can contribute to academic staff (who are also readers, but what does it mean to those that the development of a journal. authors, reviewers and editors), speed produce and use a journal? An editorial of publication, good ‘findability’ and in the latest issue of Learned Publishing, Reviewers see quality in terms of the usage of the content, and the cost the journal of the Association of support system provided: a simple determine the journals that make it Learned and Professional Society system for submitting reports and onto their lists. Publishers, usefully dissects the concept screening submissions to ensure their into the aspects of the process that time is not wasted on inappropriate All these metrics of quality need careful really matter to those involved. papers. management by editorial boards, journal staff and publisher partners. For authors, a high-quality service Readers need to have confidence that Economies of scale and automation can means a fast but fair review, a simple- a journal will publish articles that reduce costs without compromising to-use submission system, helpful describe current high-quality research. quality, but people, those most journal staff, accuracy in copy editing They want to be directed to the content expensive of commodities, are an and typesetting, clear information of most interest to them and therefore essential part of the process. As Sally about what is required of them during appreciate filtering systems, both Morris says in her editorial: ‘how well the publication process and how they within a journal and on its publisher’s the links in the chain all communicate may use the publisher-enhanced web site, that allow them to focus with each other are, in the end, a version of their paper, and efficient and quickly on relevant material. They want matter for the people who do them. All wide dissemination of their work the articles they read to be concisely this costs time and money, but we through publisher marketing and and clearly written and presented; like economize on quality at our peril’. electronic means (linking and search authors, they appreciate, often without engine indexing). recognising it, the services of expert Carol Huxley copy-editors and typesetters. Managing Editor, The Physiological Editors look for quality in the support Society Journals they receive for their unpaid services to Librarians bring financial considerations a journal: an easy-to-use manuscript to the question of quality in publishing. Morris S (2008). What is quality in journals tracking system, the assistance of They look primarily for value for money; publishing? Learned Publishing 21, 4-6.

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Wednesday 9 April (0800–1000) The role of GABA and glutamate on In brief ... Symposia adult neurogenesis. At EB 2008, Congratulations to Society San Diego Convention Center, San President Ole Petersen who was Diego, CA, USA. awarded a CBE for services to Saturday 26 April (1230–1635) science in the New Year Honours Symposia List. The role of GABA and glutamate on adult neurogenesis Retinal ganglion cells in model

Wednesday 9 April 2008 from 0800 to 1000 at Experimental Biology 2008, San Diego Convention Center, San Diego, CA, USA organisms: development, function Society Member Ismaeel M Bin- Chairman and Organising Editor and disease. An educational course Stefano Vicini (Georgetown University, DC, USA) Jaliah was elected Secretary Speakers 0800 Angelique Bordey co-sponsored by ARVO and The (Yale University, CT, USA) GABA and glutamate signalling provides homeostasis in General of the Saudi Society for the neurogenic forebrain Physiological Society at Broward 0820 Linda Overstreet Wadiche Medical Educationin November (University of Alabama, AL, USA) GABAergic signalling to adult generated neurons County Convention Center, Fort 0840 Hanna Monyer 2007. Ismaeel is Assistant (University of Heidelberg, Germany) Lauderdale, FL, USA. Postnatal neurogenesis of distinct GABAergic interneurones Professor of Neurophysiology and 0900 Alejandro F Schinder (Instituto Leloir, Buenos Aires, Argentina) Neurogenesis in the adult hippocampus: rewiring the Thursday 10 to Saturday 12 July Director of the Medical Education brain 0920 Hongjun Song Synaptic basis of disease. At FENS Centre at King Khalid University in (Johns Hopkins University, MD, USA) Activity-dependent regulation of adult hippocampal neurogenesis Forum of European Neuroscience, Abha, Aseer, Saudi Arabia. Centre Medical Universitaire, Call for related papers Symposium proceedings will be published in a special issue of The Journal of Physiology. Geneva, Switzerland. The Paton Prize was established in To submit a related manuscript for inclusion in the issue, please visit www.jphysiol.org 1994 by The Society’s History and The Journal of Physiology Symposia Full details and programmes at: Archives Committee to encourage programme for 2008 will include: http://jp.physoc.org the study of the major ideas and concepts that have shaped modern physiology. The Prize takes the The Physiological Society EGM form of a bursary to support such 17 March 2008 studies, with funding of up to £1000 to cover travel and The Council of Trustees has resolved specifically within the Executive incidental expenses. The that an Extraordinary General Committee, and clarify the system Committee wishes to promote Meeting be held on Monday 17 for the annual election of Council interest in the history of March in the Medical Lecture Members. physiology among younger Theatre, Worsley Building (pictured Affiliates and Members of The below) at the University of Leeds at Normally such resolutions would be Society, as well as established 1245. proposed at the AGM. However, with scientists. The bursaries are both the current President (Ole financed by the interest from the Petersen) and Chair of the Executive Paton Fund, an endowment Committee (Ian McGrath) ending originated by a donation from their terms of office in July 2008, the Professor Sir William Paton, with a Council would like to implement the matching donation from The changes in time for the forthcoming Society. The first Paton Prize was elections for Council members and awarded in 2007 to David Miller for the Executive Committee. his research into the life and work of Sydney Ringer (see p. 36). For If you will not be attending the EGM, more information on the Paton the Council urges you to use your Prize, or to suggest a future proxy vote to instruct the Chair of recipient, please contact the The EGM takes place during The the EGM how you wish your vote to Committee chairman, Dafydd Society’s Cardiac & Respiratory be cast. Proxy voting is online only, Walters ([email protected]). Themed Meeting. Each Ordinary and with a deadline of 14 March 2008. Honorary Member (including those The Editorial Board of Experimental registered as Retired) has the right For full information about the Physiology is pleased to welcome to attend and vote at the EGM. meeting and resolutions, and details five new Editors – Kenneth Baldwin of how to register a proxy vote see (California, USA), Peying Fong The business of the meeting will be http://www.physoc.org/egm. (Kansas State, USA), Wayne Giles to consider and, if thought fit, to (Calgary, Canada), Stephen pass two resolutions to amend the For further information, please Harridge (London, UK) and David Articles of Association and Domestic contact Simon Kellas, Company Murphy (Bristol, UK). Rules. These changes address the Secretary, [email protected] or 020 lines of authority within The Society, 7269 5725. More details in the next issue.

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recommendations is that a small minority skills) as a profession. number of Masters programmes However, the country needs these st Science skills in the 21 could be introduced to help alleviate skills. a shortage that is already with us and century is having important effects in the Clearly the skills landscape is complex There are frequent reports and pharma-ceutical sector. We propose and varied. The question to face is comments about the shortage of 36 dedicated studentships for this whether or not the delivery of highly skills in the biosciences: shortages programme for each of the next specialised skills can continue to be that are important and potentially 3 years. This is an important area and left to the vagaries of the market damaging to the prosperity of our yet the solution involves really small place. This essay is not leading to a country. However 'skills' do not exist numbers: in vivo skills are definitely conclusion that, for example, all in some semi-independent context. It not required in all life science universities with a life science degree is always necessary to define what the graduates. Of course, practical skills have Masters programmes for in vivo 'skills' are needed for, and this can are very definitely required because skills, or that all plant science produce conflicts for those most science and most biology are departments have top level responsible for the delivery of our intensely practical subjects. taxonomic skills. That would be bioscience skill base. absurd! But the question to answer is There are many other areas of the how we produce those experts that The first skill that we all need is the biosciences where skills are being lost the country requires – and in skill to be a good and productive and yet the solution needs relatively sufficient numbers. citizen. In a knowledge-driven small numbers of practitioners. Take economy, scientific skills should be for example the field of systematics Not everyone will like the last part of the skills portfolio of as many and taxonomy. There is no doubt sentence! Some will have a wider citizens as possible, even though they that we are losing the capacity to view, especially in the context of their do not themselves pursue a career in identify precisely some of our native own expertise! But that can be left to science. For me, it is highly desirable species – for example lichens. Yet we the market place. What we need is that we have more citizens who need really expert individuals in this confidence that the UK will have the understand the scientific method, area, today perhaps even more than full portfolio of bioscience skills that who appreciate the difference in the past: we cannot monitor the will be essential if we are to maintain between probabilities and absolutes effects of climate change on our flora our strong global position in this area. and who make decisions on the basis and fauna unless we can identify These are skills that would be difficult of evidence and not Luddite species correctly! Perhaps we will end to 'buy in' if our own skill base was prejudice. With this training, public up relying on the 'gifted amateurs' lost. discussion about climate change, who already contribute much in this biodiversity or disease will be better area – but in this case the academic What is needed is top down informed and there will be greater subject will be lost. management, coupled with understanding of the contribution inducements, in order to build a few that practicing scientists are making The production of modest numbers excellent teams in minority subjects to the debate. In time, the public of high level experts in many areas of that are nonetheless essential. Let trust in scientists, which is already the biosciences is predominantly the funding be ring-fenced and quite good, might improve further. responsibility of our universities and, universities/institutes compete for The knowledge driven economy to a lesser extent, the Research the money to provide leadership in demands a scientifically literate Councils. I write 'lesser extent' these areas. This is not a new idea: it population. Delivery of this because some disciplines – for happens often. For example, if you essential skill is an important example taxonomy – can be want capital equipment for structural responsibility of our schools and internationally excellent without biology from the BBSRC you have to universities. relying on large grants. And this apply from one of about 10 leads to a second problem. Much universities. What is new is the However, more usually a skills biology today is rightly 'big science' – argument that this should be done to shortage is used to describe a more big grants and big teams. The sustain skills – and there is the key specific problem than the generic business of running a university word. Any initiative must be need to have science as part of our means that these big science teams sustainable in the long term. These everyday cultural base. The are financially more attractive than are not arguments for 5 years and Biosciences Federation (BSF), those individuals virtually grant-free. then the money can be recycled into together with the Association of the some other project. These are British Pharmaceutical Industry Furthermore, individuals without arguments for a generation – and, (ABPI), has just published a report grants are likely to find it difficult to sadly, as a consequence they will not entitled In vivo sciences in the UK: meet the charges that open access seem very dynamic where it matters! sustaining the supply of skills in the 21st brings. The result, of course, is that century (the report is available at there is real pressure on systematics Richard Dyer www.bsf.ac.uk). One of our and taxonomy (and many other Chief Executive Officer

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idlers would lay down fat, not starch. Adipose tissue is surely an excellent way of sequestering carbon. The metabolic rate of adipose tissue, Jogging and global once built, is pretty close to zero. warming, or the And when they do eventually come to burn it off, either in exercise or, I Nike-Adidas CO2 suppose, eventually in a footprint crematorium, remember that the RQ for fat is only 0.7. Less CO2 production in the end too! Have you ever wondered how much generate some (150 x 100)/1000 =

CO2 all those frantic joggers add to 15kg of CO2. If those same four More cynically still, has Gaia perhaps the global warming problem? And passengers were to run the 100 km found the right strategy to save the how does it compare with travel by instead of riding, they would planet by changing the shape and the vilified car? Given the result of generate about (4 x 21 x 100)/1000 = reducing the life expectancy of the some simple physiological 8.4kg between them, a little over average American (because they calculations, I suspect some will be half as much as taking the car. But can’t be persuaded out of their surprised. we have overlooked something. SUVs)? This is not for the squeamish After about an hour, when the car – achieving ideal carbon A car running at about 40 mpg and arrives and stops, it ceases to sequestering requires an early death

100 km per hour – very achievable produce any more CO2. However, our for our tubbies, ideally from an for modern vehicles – will generate passengers will still be respiring at abrupt cause since wasting diseases about 150g CO2 per km (according their resting rate as will our runners rather defeat the objective (I said this to published data that you can check too (once they have stopped puffing was cynical). Obesity-driven CVS in any recent car advert). For an after their 100 km ‘jog’). Thus, they problems fit the remit. And finally, exercising, efficient human we can carry on producing at least 30g of disposal of the body demands an assume a near-maximum, steady- CO2 per hour, day and night. Indeed hermetically-sealed mode of burial state, oxygen consumption of about they were still producing that much, to avoid carbon recycling. 50ml O2 per kg body weight per even when being driven in the car. In minute. Let’s take the conventional 24 hours, after just one 100km trip, The arithmetic implies we should eat ‘ textbook’ 70kg man; that equates our four car travellers will generate more and exercise less to help save with 3.5 litres of O2 consumed per 2.9kg themselves and their car 15kg; the planet. I rather suspect a better minute. Assume, at this stage, that a total of just under 18kg for the day. answer lies elsewhere! he’s running his metabolism on The runners, who spent 5 hours David Miller carbohydrate; the respiratory running and 19 at rest, will produce quotient (RQ) for this substrate is (8.4 + (4 x 19 x 0.03)) = 10.7kg for Glasgow, UK about 1.0. This means his oxygen the day. So, the car journey only consumption will result in about 3.5 produced an ‘extra’ CO2 output litres of CO2 breathed out per comparable with four or five people Tissue engineering minute. The density of CO2 is nearly sitting around doing nothing for a An NC3Rs/BBSRC free 1 day multi- 2g per litre (under standard few days. If the journey were shorter, disciplinary meeting on 30 April on Engineering tissue alternatives to conditions) which means a CO2 the CO2 ‘ gap’ would obviously be production of 7g per minute. He will less remarkable too. And animals, to highlight the potential also be running at close to his furthermore, unlike the car, in order of tissue engineering as a means of maximum, sustainable, aerobic to run at this speed, our joggers providing scientifically robust speed. If our runner is pretty fit ( … would have to be jogging almost alternatives to animal models. very fit!), he might be running at 5 daily to keep fit between trips too; Information and registration minutes per mile rate, or ‘training’ generates still more CO2 . approximately 3 minutes per (deadline 4 March) at: kilometre. Thus, to run a kilometre, What’s the alternative? If our http://www.nc3rs.org.uk he will generate (3 x 7) = 21g of CO2. travellers continued sitting around Watch out for more exciting Of course, if he was less fit or doing nothing, thereby becoming initiatives to come from the efficient, he’d be producing more couch potatoes, they would not NC3Rs, now that Ian Pearson, CO2 to cover each kilometre, and also travel or run as far, but they would reduce their global CO ‘ footprint ’ Minister of State for Science and taking longer over it. 2 Innovation has announced that by 75% for the day. But there is a their funding is set to double over So, if our car was carrying four further bonus. The term ‘couch the next 3 years. people, over a 100 km trip it would potato’ is misleading because our

Physiology News | No. 70 | Spring 2008 | www.physoc.org 54 PN OBITUARIES

John Richard He collaborated with colleagues from two visiting post-doctoral fellows around the world, including Frank (Soto-Rivera and Borrero) and a Pappenheimer Winton, Glen Millikan, Bjorn Folkow, research student (EM Renkin) when Manfred Karnofsky, JM Krueger, J John Pappenheimer was in his mid 1915–2007 Madara and Charles Michel. 30s. By the time he was 40, his other investigations had had a major An avid mountain climber, skier, impact on studies of muscle blood gardener, tennis player, woodsman, flow, haemodynamics, on and `cellist, John Pappenheimer measurements of respiratory dead embodied the Renaissance man. In space and on the autoregulation of 1949 he married the violinist Helena F renal blood flow. In addition, he had Palmer, with whom he shared a published papers with Winton on the passion for quartets. Together they effects of diuretics in the isolated raised four children, three golden perfused kidney and spent the retrievers and numerous goats. He period 1940–1945 monitoring leaves behind his wife of 58 years, Helena Palmer, Cambridge MA, three hypoxia in USAF pilots and children (Will Pappenheimer, developing onboard oxygen NYC/Tyringham MA, Rosamond generators for aircrew. In the second Zimmermann, Lexington MA and Rick half of his life he would go on to Plant, Melbourne, Australia), five make the first quantitative grand children (Leo and Martha measurements of CSF secretion and Zimmermann, Rudy Ott, Ramsay and drainage in conscious animals, make Freya Plant). major contributions to the central John Richard Pappenheimer, George chemical control of breathing, Higginson Professor of Physiology, Rosamond Zimmermann pioneer the investigation of the Emeritus, at Harvard Medical School neurochemical basis of sleep and died on 9 December at the age of 92. Charles Michel writes: then – after retiring when he was John Pappenheimer was unique well into his 70s – publish three John Pappenheimer’s work in among 20th century physiologists in sequential papers In the Journal of capillary permeability and molecular the wide range of topics that he Membrane Biology on intestinal sieving are classics in physiological absorption. In all these investigations literature. He contributed valuable influenced, attacking different he carried out experiments himself research to a wide range of disciplines questions with imaginatively within physiology: capillary designed experiments and bold and sometimes with a research permeability, respiratory physiology, reasoning. During his period as a student or a post-doctoral fellow. He blood-brain CSF transport, the research student of Frank Winton in continued to work on intestinal neurochemical aspects of sleep, and 1930s’ Cambridge he learnt the absorption seeing his last full paper most recently to the understanding of methods of classical mammalian published in The Journal of Physiology the absorption of sugars and amino physiology and he went on to when he was 88. acids in the intestine. combine these skills with a rigorous quantitative approach and Some of his conclusions led to controversy and his theory for the Born in NYC, Pappenheimer attended remarkable grasp of physical the Lincoln and Loomis schools. He principles. These qualities are most autoregulation of renal blood flow received a BS from Harvard College conspicuous in his two classic papers was shown to be incorrect. He had and a PhD from Clare College, on capillary permeability in 1948 and no regrets about this, pointing out Cambridge, England. In 1953 he was 1951. The first reveals a close that at the time he put forward his awarded the lifetime Career attention to experimental detail and 'plasma skimming' theory, it was Investigator position from the describes highly reproducible results clearer than any other idea of American Heart Association for his leading to clear conclusions. The autoregulation, and that it had work on capillary permeability and in much longer 1951 paper uses the provoked others to carry out respiratory physiology. He was same experimental methods in an experiments to disprove it. appointed the George Higginson imaginative experimental design to Professor at Harvard Medical School make the first estimates of This attitude is stated at the end of in 1969. He was a member of the microvascular permeability and then his Bayliss-Starling lecture (on sleep) American Physiological Society develops a new theory of restricted at UCL in 1982, when he quoted (President 1964-1965), the Academy diffusion through membrane pores Bayliss '... it is better to hold to a of Arts and Sciences, the National to interpret the data. The latter is well-understood and intelligent Academy of Sciences and Honorary itself a tour de force. opinion even when it is wrong, than Member of The Physiological Society. to be content with a (muddle- He published numerous articles of This work on microvascular headed) mixture of conflicting views original work over a span of 70 years. permeability was carried out with ...’

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From his experiences as a research John Ramsey Bronk and career development long before the student, John Pappenheimer more formal systems of today. He also retained a deep affection for this 1929–2007 played a key role in setting up cancer country and particularly for research in the Biology Department with laboratories funded by Yorkshire Cancer Cambridge and for The Physiological Research. Society. He greatly valued his Honorary membership of The Ramsey had a deep understanding of Society and took a continuing metabolism, which formed a large part interest in The Society’s of his teaching. He wrote two major development. Apart from numerous successful textbooks; one, Chemical brief visits and the occasional holiday biology, which reflected the nature of the in the UK he spent the academic year York degree course, and the other, 1971/72 as a visiting fellow at Human metabolism, which I subsequently used as a textbook for the course we had Churchill College Cambridge and taught in together. His tutorials, in 1975/76 as George Eastmann particular, were very much appreciated Visiting Professor at Oxford. An by the students. In research, Ramsey was internationalist, he was critical of the one of the first to appreciate the inward looking attitudes of some of importance of mitochondria and he his American colleagues and devoted produced ground-breaking papers on the much time to the IUPS, serving for 9 regulation of oxidative phosphorylation years on its Council. Ramsey Bronk, first Professor of by thyroid hormones. Subsequently he Biochemistry at the University of York, worked extensively on metabolic aspects of chemotherapeutic drug delivery by I first met him nearly 40 years ago died at the age of 78 in Oxford. peptide transport across the small and, while initially being in awe of his Ramsey grew up in Pennsylvania and was intestine. His long-standing collaboration legendary reputation, was delighted exposed to the company of scientists at with Richard Boyd (Oxford) and Pat by his friendliness and an early age. His father, Detlev Bronk, Bailey (Keele) contributed strong encouragement, particularly as I was President of the then Rockefeller evidence for the now accepted view that soon saw how devastatingly critical Institute (now Rockefeller University) and peptide transport is proton-dependent, he could be in discussions at later of the US National Academy of as opposed to the sodium-dependent scientific meetings. As I came to Sciences. After graduation from transport of many other nutrients. Their know him informally, casual Princeton University, Ramsey came as a work also contributed much to the structural understanding of the delivery conversations revealed his Rhodes Scholar to Oxford in 1952. There he studied for his doctoral degree in the of peptide-linked drugs. Always happy to astonishing breadth of knowledge of laboratory of the great intestinal suggest new ideas, Ramsey transformed English and American literature, of physiologists Fisher and Parsons, where me in mid-career from a structural world history and current affairs, he met his wife Sylvia. They returned to biologist to an intestinal physiologist quite apart from music, which was Washington in 1956, where they both simply by asking me, in the course of one probably equal to science in his worked in the National Institutes of of our many chats, if I would supervise a priorities. It was immensely Health. Two years later, Ramsey was final year undergraduate project on stimulating to talk to him and even appointed as Associate Professor of intestine. when he was in his late 80s he was Zoology at Columbia University, where Brought up in America, but a lover of all full of challenging questions and he became full Professor shortly before coming to York. Ramsey was appointed things English, Ramsey became gentle humour. It was a great as Professor of Biochemistry by York’s essentially a mid-Atlantic figure and was privilege to have known him and first Vice-Chancellor, Lord James, to the also a strong supporter of European worked with him for undoubtedly he Department of Biology headed by Mark Science. He was a founding member of, was one of the greatest physiologists Williamson; Ramsey arrived in October and regular contributor to, the European of the 20th century and a very 1966 and remained until his retirement Intestinal Transport Group and Chairman remarkable and delightful person. in 1997. of the European Editorial Committee of Physiological Reviews, as well as a Ramsey was instrumental in setting up Distributing Editor for The Journal of The Society also notes with regret and developing the very successful Physiology. the deaths of Margaret Stanier and biochemistry degree course run jointly Peter Lewis. by the Departments of Biology and Ramsey was an expert yachtsman, an Chemistry. He oversaw the provision of accomplished carpenter and an able Margaret became a Society Member equipment needs essential to the cook. A great family man, he leaves in 1964. Based at Babraham, she successful launch of biochemistry behind his wife of 52 years, Sylvia, their was a Fellow of Newnham College, teaching and research at the University. sons, Richard and Christopher, who are Cambridge where she was well Many staff had cause to be grateful to both in academic life, and four known to many medical students. Ramsey for he was very supportive of grandchildren, Justin, Philip, Edmund and staff at all levels. In particular, Ramsey Eleanor. Peter, a pioneer in the cholinesterase took a special interest in the technical field, became a Member in 1954. staff and matters affecting their welfare George Kellett

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Regulatory was a Foreign Member of the Royal that Ebashi and he had hoped that Society and in 1979 gave a the book would ‘become a milestone mechanisms of memorable Croonian Lecture on The for future developments in the study of regulation of muscle contraction the regulation of muscle contraction striated muscle (Ebashi, 1979). That lecture lucidly and related biomedical sciences'. I contraction reviewed the history of the hope they are successful in that Volume 592, Advances in recognition of the calcium ion as the objective, as the book deserves it. sole regulatory factor of muscle Unfortunately, though, the price will experimental medicine and contraction at the molecular level be prohibitive for any young research biology. Edited by S Ebashi & I and the role of the troponin- worker. Can scientific publishers do Ohtsuki. Springer,Tokyo, tropomyosin system in responding nothing to deal with this problem? I Berlin, Heidelberg and New to changes in the calcium levels. It see that when I purchased the York. 407 pp, UK price £96.00 bears mentioning that this story was proceedings of the 1962 Dedham initially controversial. Annemarie conference it cost me US $18.00, ISBN 10-4-431-38451-0 Weber in her letter in the Volume about £60 in today’s money. The reminds us that, at the Dedham difference between £60 and £96 may A Festschrift for a great scientist muscle conference in 1962, she and seem little enough, but junior tends either to be largely historical or Ebashi were in a distinct minority researcher’s or lecturer’s salaries are to be a state of the art survey of the who then accepted the role of the not now what they were then, and field that the master initiated. It is calcium ion as a messenger. It was surely desk-top publishing should rare that it manages to be both. the persistence and the careful have slashed production costs in the Volume 592 of Advances in experiments of that minority that intervening 45 years? experimental medicine and biology is finally gave the scientific community the proceedings of a meeting held at the picture that now graces all the Setsuro Ebashi himself was already Okazaki, Japan in 2005 to text books. The history of this work, disabled from the residual effects of commemorate the 40th anniversary set out in several papers in the first a stroke in 2000 when the Festschrift of the discovery of the filament- part of this book, deserves a very meeting took place; he attended based troponin-tropomyosin careful read and holds lessons for us some sessions in a wheel-chair, regulatory system by Setsuro Ebashi all. Sam Perry’s letter emphasised loyally and lovingly supported by (Ebashi, 1963; Ebashi et al. 1964; that some details of the picture are Fumiko Ebashi, his wife and long- Ebashi et al. 1969). still controversial, perhaps the mark term scientific collaborator. A video of an active scientific field. record was made for him to follow at This volume does indeed address his leisure. Very sadly he died in July both aspects of the Festschrift and 2006 before the final publication of does so remarkably well. The list of The other major part of this book is this volume (Editor-in-Chief, 2007). attendees was outstanding and made up of many useful accounts of The Japanese meeting and this book studded with luminaries; Ebashi the current state of research by the can stand, though, as a fitting tribute himself, both Andrew and Hugh protagonists of today. Any selection to a humane man and a very great Huxley, John Gergely, Andrew Szent- is bound to be a personal matter – scientist. Györgyi and Makato Endo (most of I was particularly interested in Mike them in their ninth decade). The Geeves’ chapter, which sets out younger cohort featured Mike clearly the difference between the Gerald Elliott 2+ Geeves, Yuchiro Maeda, Rick Moss Ca - dependent behaviour of the and John Solaro, among many extracted proteins and that of the References others. Warm messages were muscle myofibril in situ. Yuchiro Ebashi S (1963). Third component received from Sam Perry and Maeda’s papers on the participating in the super precipitation of ‘natural actomyosin’. Nature 200, 1010. Annemarie Weber, who were both crystallography of the troponin too infirm to travel so far. Only Jean complex were also impressive. Ebashi S, Ebashi F & Maruyama K (1964). A Hanson, who died tragically early in Finally, as the husband of someone new protein factor promoting contraction of 1973, was absent from the roll-call. working in a Department of actomyosin. Nature 203, 645–646. Cardiovascular Medicine I will find Like the D-day veterans reviewed by Ebashi S, Endo M & Otsuki I (1969). Control of Queen Elizabeth on the beaches at Section III (Regulation in cardiac muscle contraction. Quart Rev Biophys 2, Arromanches in 2004, we shall muscle and disorders) of great value. 351–384. probably not see such a parade Ebashi S (1979). The Croonian Lecture, 1979; again. This book should certainly be on the Regulation of muscle contraction. Proc Roy Soc shelves of all research workers and B 207, 259–286. Ebashi was among the most research groups in the field, as a important post-WWII Japanese source of both inspiration and Editor-in-Chief (2007). Obituary: Professor Setsuro Ebashi 1922-2006 – the discovery of muscle scientists and was very well reference. Iwao Ohtsuki, the co- troponin and forty years of its impact. J Musc known outside his native land. He editor, remarks in the introduction Research Cell Motil 28, 1–10.

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Neurobiology of Various model systems are then but easy to read, thanks to the discussed as is the role of anti- efforts of Caroline Richmond, a Alzheimer’s disease inflammatory drugs to delay onset medical journalist who has Molecular and cellular and slow disease progression. The collaborated on the project. cellular targets of amyloid β peptide rd neurobiology, 3 Edition are considered and two later In reality there are two stories here. Edited by David Dawbarn & chapters consider amyloid-based The first is the14 cases themselves, which raise some interesting issues Shelley J Allen. 2007, Oxford therapies for diagnosis, prevention or treatment of AD. Intervening regarding the actions of insulin University Press, Oxford. chapters deal with neuro- which are not well known to either 468 pp, £49.95 transmitters, nerve growth factors, clinicians or scientists. For example, ISBN 0-19-856661-1 clinical assessment of AD, molecular there are several cases in which and biological markers and current substantial significance is placed on It is estimated that 18–24 million pharmacological approaches to the observation that vomiting is very people suffer from Alzheimer’s treatment – the ordering of the rare in severe hypoglycaemia disease (AD) worldwide. AD is chapters could have been better. induced by insulin, though it does marked by dementia. At autopsy, occur in hypoglycaemia due to other extracellular amyloid plaques, causes, such as sepsis. The β All things considered, if you want to containing amyloid A , and know more of what is going on in explanation offered is that insulin- intracellular neurofibrillary tangles terms of understanding and treating induced hypoglycaemia speeds the containing the tau protein, which Alzheimer’s disease, then this book transit of food from the stomach to normally stabilises microtubules, are is for you, but remember that what the small intestine, and that this is an found in the neocortex and you are seeing is a snapshot of what adaptive mechanism to expedite the hippocampus, which become was happening up to 2006. I look passage of glucose back into the progressively atrophied. Early forward to future editions to see bloodstream. Interesting idea, but it diagnosis is important and it is what further advances have been may be that there's more work to be imperative that new biochemical achieved in our understanding of this done here. Since sepsis-induced markers and imaging techniques deeply distressing, progressive hypoglycaemia does cause vomiting should be found to aid diagnosis, illness. (and presumably also responsive with a hope that future research will hypoinsulinaemia), this seems to lead to therapies that slow or halt Bill Winlow imply that there are more wrinkles to the progress of AD. the story of glucose, insulin and gastic emptying than are This book sets out to give ‘an immediately apparent. Is it the accessible overview of the major Insulin murders: true interplay of these factors that areas of knowledge and controversy ’ life cases inhibits vomiting in insulin overdose, in research on AD. Within the By Vincent Marks & Caroline or is it a specific effect of very high or confines of a multi-author volume, it very low insulin levels, or something does it very well in a fast moving area Richmond else entirely? in which the editors claim that nearly RSM Press, 2007. 190 pp, half of the papers have been £12.95 The book's other story (though one published since 2000. The chapters ISBN 978-1-85315-760-8 that is told indirectly and would have are well chosen and well written by benfited from a chapter of its own) is an international team of Like any strong medicine, insulin can that of the methods used to measure contributors, with good use of be used for good or ill. The miracle insulin. In the past these have been headings to guide readers through drug which transformed the outlook fraught with unreliability and caveats the text. Each chapter has a for the previously rapidly fatal of the sort that courts neither substantial bibliography. My major disease of diabetes was first recorded understand, nor seem to take much criticism is that the volume would in a case of attempted suicide as interest in, preferring to hope that an have been better divided into early as 1927. But the first case of expert witness will clear it all up for sections, and that the chapter murder proved to have been caused them. The thing that will probably sequence could have been improved. by insulin was not until 1957, in surprise and alarm you, is that England. Since then, Vincent Marks, although the tests have improved, it The book starts with a review of 100 a clinical biochemist with a special remains true to this day that the years of investigation into AD and is interest in hypoglycaemia, has results of forensic biochemistry are followed by chapters on collected about 50 other instances. not at all straightforward to neuropathology, genetics, molecular Reports of 14 well documented interpret, even for something as biology and biochemistry, including cases, often involving Marks in the apparently clearcut as insulin. Expert a chapter on protein misfolding, expert witness stand, make up this witnesses often disagree on the aggregation and fibril formation. book. The style is somewhat quirky, meaning of forensic results, and the

Physiology News | No. 70 | Spring 2008| www.physoc.org 58 PN BOOK REVIEWS courts often fail to follow the going on anyway? It's a tribute to the Essays in biochemistry arguments and try to latch on to "the perseverance of physiologists that truth" of scientific certainty, when the answers now amount to some – oxygen sensing and they should instead be trying to pretty meaty tomes. understand forensic results in their hypoxia-induced correct statistical and case-based Out of this work have emerged many responses context as one piece of evidence general principles, such as 'All Edited by Chris Peers. Portland among many. There is at least one extraocular motorneurones are case in the book which seems a clear involved in all eye movements and Press, Colchester, 2007. miscarriage of justice, with an innervate basically functionally 184 pp, £21.95 individual serving a long prison similar muscles.' Well that's what I ISBN 1-85578-160-3 sentence for a crime that almost thought too. But it is the purpose of certainly never existed. Worryingly, this slim but excellent update Oxygen is essential for most forms of the appeal court seemed no clearer volume, an emanation almost life. Though hypoxia does not in its understanding of the scientific entirely from German departments normally occur under physiological evidence than the original judge had led by Munich, to refine our ideas on conditions, there are a number of been. Here too there are many issues this and many other matters. In fact, pathological states where it does. which need more work both at the it turns out that distinct twitch and This publication is an overview of bench and in the courts. non-twitch motor fibres are present current research on oxygen sensing, within the eye muscles and are responses instigated by hypoxia and I recommend Insulin Murders as an differentially distributed, that they pathological states linked with interesting general read, but also as are innervated by distinct hypoxia. Each chapter is well laid out food for thought for those with a populations of neurones with their with an abstract, introduction, scientific interest in insulin and own positions in the oculomotor conclusion and summary; the cited hypoglycaemia, since it seems to me nuclei, and that these neurones references are an invaluable source that the book raises more questions receive different inputs from of further reading. than it answers. premotor locations in the brainstem. Excellent, more complications. But John A Lee Coleman and Ratcliffe introduce HIF very interesting too. In addition to a (Hypoxia Inducible Factor) and its chapter detailing these new modification, Bell and Chandel anatomical niceties, there are highlight the role of mitochondrial Neuro-ophthalmology: contributions on methods of reactive oxygen species in its neuronal control of eye recording eye movements, the activation by hypoxia, providing a mechanics of the orbit and good introduction to HIF. Galkin, movements contributions of the eyelid, saccadic, Higgs and Moncada examine the smooth pursuit and disconjugate eye Edited by A Straube & multiple roles of nitric oxide in movements, optokinetic nystagmus, response to hypoxia. U Büttner. 2007, Karger. 198 and the vestibulo-ocular reflex. In pp, €141.50 addition, there is a modelling Kumar and Evans discuss oxygen chapter, and one considering the ISBN 978-3-8055-8251-3 sensing in specialised tissues in therapuetic considerations for eye chapters on the carotid body and If the eyes are the windows on the movement disorders emerging from pulmonary vasculature respectively. soul, then the small group of new findings. I first became Kemp and Peers focus on ion oculomotor neurones are what interested in the oculomotor system channels that respond to hypoxia; ensures that they are deployed to as a student when I read the chapter these three chapters also discuss maximum effect. But any idea that on it in my copy of the 14th (and chemotransduction mechanisms in analysis of the co-operative sadly the last) edition of hypoxia sensing. Hue and Rider movements of the six pairs of eye Mountcastle's superb physiology review AMP-activated protein kinase, muscles involved might be relatively text, and it continues to amaze me an enzyme cited in earlier chapters as simple was quickly dispelled a long how much new and insightful and a putative hypoxia sensor. time ago. As befits such important fascinating and relevant work is still portals, there's a lot more to it than being done on this rather small up and down, left and right. Hardly (though admittedly very important) Nanduri and Prabhakar discuss the any of the muscles insert into a group of nerves and muscles. This clinical significance of intermittent straightforward position on the really very good and highly hypoxia, while Paffett and Walker globe of the eye with respect to its recommended update volume shows follow on by outlining the vascular axis, there's torsion to consider that the march of new ideas in this adaptations resulting from chronic (torsion?), and, given how sensitive field shows no sign of abating. hypoxia. LaManna takes a look at the eyes are and how quickly they flit how the brain to adapts in chronic about, how do you measure what's John A Lee hypoxia.

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The last two sections deal with Meetings (http://www.physoc.org/meetings) hypoxia and pathological conditions - Peers, Pearson and Boyles linking 2008 hypoxia to Alzheimer’s disease, Leeds, UK (17–19 March) Brahimi-Horn and Pouyssegur Cardiac & Respiratory Physiology Themed Meeting with a Focused looking at hypoxia and HIF in tumour Symposium on Determining control of the cardiovascular system in health and development. disease: from brain to blood vessel. Cambridge, UK (14–16 July) There is overlap between some of Main Annual Meeting. the chapters, inevitable when Oxford, UK (9–11 September) sections are written by different Metabolism & Endocrinology Themed Meeting with a Focused Symposium on authors. The text forms a good Orchestration of metabolism in health and disease. introduction to those at degree level Shanghai, China (12–16 September) and those new to hypoxia, though it International Workshop on Latest advances in ion channel techniques applied to is also a good resource for those physiological problems. more familiar with the field. Beijing, China (20–22 October) Selina Pearson Joint International Meeting of The Physiological Society with the Chinese Association for Physiological Sciences and the Canadian, Australian and American Physiological Societies. Other books recently received King’s College London, UK (15–17 December) Observed brain dynamics by Partha Vascular & Smooth Muscle Physiology Themed Meeting with a Focused Symposium Mitra and Hemant Bokil. on Vascular responses to mechanical stress: cellular cross-talk and integration. 2009 Sex differences in the brain: from genes University College Dublin, Republic of Ireland (6–10 July) to behavior. Edited by Jill B Becker, Main Annual Meeting. Karen J Berkley, Nori Geary, Elizabeth Woods Hole, MA, USA (September) Hampson, James P Herman and Joint International Meeting of The Physiological Society with the Society of General Elizabeth Young. Physiologists on Basic biology and disease of muscle.

Beijing Joint Conference of Physiological Sciences 2008 Physiology in medicine: bridging bench and bedside October 19–22 2008

Jointly supported by the Chinese Association for Physiological Sciences, The Physiological Society and the American, Australian and Canadian Physiological Societies

Abstract submission opens 15 April 2008 Abstract submission closes 31 May 2008

Full details at http://www.beijingphys2008.org

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A collection of firsts the late 1880s, where she was taught the interest he has taken in the work'. and influenced by the eminent (and Coincidentally, the second paper in this On the time taken in transmission socially progressive) comparative first volume of Q J Exp Physiol is by of reflex impulses in the spinal cord anatomist E Ray Lankester. Her first Sherrington. of the frog published papers, on invertebrate Florence Buchanan (1908). Q J Exp anatomy, appear between 1889 and Buchanan’s earlier J Physiol papers of Physiol 1, 1–66. 1893 in the Quarterly Journal of 1899 and 1901– the latter a Microscopical Science, forerunner of the monumental 77 pages – are 'from the In January 1908, the Quarterly Journal of present-day Journal of Cell Science. Physiological Laboratory', but later in her Experimental Physiology (now simply time at Oxford she held a post in the Experimental Physiology) published its Precisely when Buchanan began University Museum – where first ever issue. The first paper in this working with Burdon-Sanderson in institutional hostility to women was less historic first volume is also a first in Oxford is unknown, although it seems than in the Colleges – and this is the another way, since its single author is likely to have been the mid 1890s. In affiliation listed on the 1908 paper. Florence Buchanan, one of the first June 1896 in Oxford Buchanan achieved Buchanan was clearly a figure of some group of five women elected to The another landmark as the first woman to note in early 20th century physiology, Physiological Society in 1915. Florence be present – as a guest – at a Society receiving grant support from the Royal Buchanan worked for many years in meeting. In her first paper from Oxford, Society – acknowledged in the paper – Oxford, first with John Burdon- published in 1899 in The Journal of and presenting work to them. She had Sanderson, though she published her Physiology, she states that the experi- earlier gained a DSc from the University papers independently (they do appear ments 'were begun in October 1896'. of London in 1902. Her last paper on together as authors on several spinal reflexes appeared in 1912, also in communications to The Society). After Oxford at the end of the 19th century Q J Exp Physiol, but even before this she Burdon-Sanderson’s death Buchanan was rather unwelcoming to women, had started to work on investigating continued working alone. who were not considered suitable or cardiac electrical events via ECG probably even eligible for College recordings. She later published several The paper, at a heroic 66 pages, Fellowships. In addition, the Oxford of papers on heart rate in different animals concerns the speed of spinal cord the 1880s and 90s was dominated by and birds. In September 1913 Buchanan neurone excitation of skeletal muscle the attitudes of the Anglican Church, th reflexes. The preparation is not very is listed as a speaker at the 9 and notably less receptive to science in different from the classic frog sciatic International Congress of Physiological general than either Cambridge or UCL. nerve-gastrocnemius muscle, with Sciences (now IUPS) in Groningen on After Burdon-Sanderson arrived to nerve stimulation and EMG recording Cardiac events observed with the ECG. occupy the new Waynflete Chair in from the muscle surface. The figures Physiology in 1882 he had to battle Shortly after this Buchanan finally look a little unfamiliar to a modern eye, anti-vivisectionists within the University achieved membership of The since they show tracings recorded with to get a lab built at all, though he won Physiological Society, nearly 20 years a capillary electrometer which have to through, overseeing the opening of the after she had first attended a Society be read 'backwards', from right to left. Physiological Laboratory and becoming scientific meeting, and more than 15 Despite her undoubted status as a Regius Professor of Medicine in 1895. years after her first J Physiol paper. Had pioneering British woman physiologist, Burdon-Sanderson retired in 1904 and she been a man, it seems inconceivable relatively little is known about Florence died in November 1905, just over 2 Buchanan would not have been elected Buchanan, as Tilli Tansey has previously years before the publication of a Member in the 1890s. However, commented (Tansey, 1993). Buchanan Buchanan’s Q J Exp Physiol paper. The women were not then eligible and she was born in Marylebone in London in paper contains the following extended had to wait until her middle age. The 1868, the daughter of the physician, acknowledgement to him: story of the debate over admitting epidemiologist and civil servant George women to The Society is entertainingly 'All the experiments described … were made recounted by Tansey (1993). Buchanan (1831–1895), later Sir with apparatus which belonged to Sir John George Buchanan FRS and a long-time Burdon-Sanderson, and on which he had Buchanan’s career is harder to trace friend of Burdon-Sanderson. Buchanan spent a great deal of labour, time, and money after her last publication in Q J Exp was a pioneer of public health medicine … I had already been using it in its different Physiol in 1912 and the Groningen in Victorian Britain, ultimately stages for some years, and any work that has Conference the following year, though yet been done or will be done with it may in a becoming Chief Medical Officer, and a she is later mentioned as 'retiring from medical contemporary of Burdon sense be regarded as a continuation of his work. That this should be continued, and that [a job as] a part time lecturer' at Royal Sanderson’s in the latter’s pre- Holloway College in 1921. It seems physiology career as a physician. Both what was already done in his lifetime should be made use of to the fullest extent possible likely that she died in the mid 1930s, men served as 'Medical Officers of for suggesting new lines of research and for since a bequest to the Marine Biological Health' – public health doctors – for the acquirement of new knowledge, is, I feel Association (MBA) in her name is listed inner London districts in the 1850s and sure, the tribute to his memory which he in the MBA records for 1936–8. 60s, Buchanan for St Giles and Burdon- himself would most desire'. Sanderson for Paddington. It thus Austin Elliott seems highly likely that Burdon- Buchanan also thanks Professor Reference Sanderson knew Florence Buchanan (Charles) Sherrington, then in Liverpool Tansey T (1993). In Women Physiologists, from the time she was born. Buchanan but later to occupy the Waynflete Chair Chapter 1, ed Bindman L, Brading A & Tansey attended University College London in in Oxford 'for valuable criticism and for T. Portland Press, London & Chapel Hill.

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Amazon ants (Polyergus rufescens, light colour) raiding a colony of Formica fusca (dark colour), whose nest is in dry soil under a stone (Living History, p. 10)

A publication of The Physiological Society www.physoc.org